Neoplasms (Benign, malignant, precancerous)

Question 1

Neoplasms of blood vessels

Answer 1

Tumors of blood vessels vary in their behavior and aggressiveness, and may be:
- Endothelial derived – e.g., hemanigioma, lymphangioma, angiosarcoma) – can be detected by stains for CD31 or CD34 which are present only on endothelial cells. Or can:
- Arise from cells that support the blood vessels – e.g., glomus tumor, hemangiopericytoma.
These are divided into 3 categories:

Benign tumors and tumor-like conditions:
These are farther subdivided into 5 subcategories:
1. Hemangiomas – common benign tumors characterized by - increased number of vessels (capillaries or larger channels) filled with blood, arise from the endothelial cells. 3 types:
 Capillary hemangiomas– mash of capillaries – appears on the skin, mucous membranes, and lips. Can be:
• Strawberry hemangiomas – benign capillary hemangioma of infancy -in the first few weeks of life (1/200 births), grows rapidly and regress spontaneously at 5-8 years old. Can also occur in the liver, spleen and kidneys.
• Cherry hemangiomas – benign capillary hemangioma of elderly. Doesn’t regress, frequency increases with age.
 Cavernous hemangiomas – larger, dilated interconnecting blood filled spaces, appear in deep structures, may be locally destructive, don’t regress spontaneously. Generally not dangerous, but they are dangerous when appear in the brain – produce pressure or bleeding.
• Von Hippel-Lindau disease – hereditary. the patient develops multiple cavernous hemangiomas, especially in the retina and CNS (cerebellum and brain stem) – hemangioblastomas.
 Pyogenic granulomas (Lobular capillary hemangiomas) – polypoid hemangioma showing capillary loops within edema fluid, associated with trauma or pregnancy (granuloma gravidarum - less frequent), that ulcerate and bleed easily. May spontaneously regress or require surgical excision.
2. Lymphangiomas – benign lymphatic counterpart המקביל of hemangioma – increased number of lymphatic vessels filled with lymphatic fluid, arise from the endothelial cells. 2 types:
 Capillary lymphangiomas – small 1-2 cm, look like fluid-filled blisters, occur on head and neck, distinguished from capillary hemangiomas by the absence of RBCs.
 Cavernous lymphangiomas (cystic hygromas) – larger lesions, appear on the neck and associated with turner synrome.
3. Glomus tumor (glomangiomas) – benign extremely painful tumors arising from smooth muscle cells of the glomus bodies – arteriovenous structures involved in thermoregulation. Typically found on the fingertips under the fingernails. [A glomus body (or glomus apparatus) is a component of the dermis layer of the skin, involved in body temperature regulation. The glomus body consists of an arteriovenous shunt surrounded by a capsule of connective tissue. Glomus bodies are most numerous in the fingers and toes.]
Vascular ectasias – tumor-like abnormal localized dilation of preexisting vessels (telangiectasia – local dilation of microcirculation – capillaries, arterioles, and venules). Few types:
 Nevus flammeus (“birthmark”) – most common ectasia, flat lesions made of abnormally dilated vessels in the dermis. The blood reflects to the skin → appears as a birth mark. Regress.
• Port wine stain – nevus flammeus that grows with the baby and doesn’t regress. In encephalotrigeminal angiomatosis (Sturge-Weber syndrome), these occur where the trigeminal nerve is found, and it’s associated with CNS congenital abnormalities.
 Spider telangiectasias – dilated arteriole reaches the skin and gives spider appearance – blood flows from its center to the periphery – blench with pressure. Classically seen in pregnant women. Associated with hyperestrogenic state (pregnancy and liver cirrhosis).
 Hereditary hemorrhagic telangiectasia – AD disease causing dilated capillaries and veins that are present at birth, widely distributed on the skin and mucous membranes. These masses easily bleed, thus producing → epistaxis, hemoptysis, and hematemesis (GIT bleeding → vomit blood).
5. Bacillary angiomatosis – vascular proliferation in immunocompromised patients (AIDS), creating capillary skin papules. Caused by the Bartonella gram (-) bacilli family:
 Bartonella henselae – found in cats, in immunocompetent causes cat-scratch disease.
 Bartonella Quintana – cause of “trench fever” in World war I.
Frequently mistaken for Kaposi sarcoma.

Intermediate-grade (Borderline) tumors:
1. Kaposi sarcoma – derives from endothelium, caused by human herpesvirus 8 (HHV) = Kaposi sarcoma herpes virus, associated with AIDS. Produce multiple red-purple patches most commonly on the skin, but also in the mouth, GIT, and respiratory tract. Frequently mistaken for bacillary angiomatosis.
 Pathogenesis – the virus enters the endothelial cells and produces:
• Cyclin D-like protein – which drives proliferation by stimulating the cell cycle.
• Protein that impairs p53 – preventing repair of mutated DNA.
In immunocompetent people, such transformation results in cell death by immune mechanisms.
 Morphology – the cutaneous lesions progress through 3 stages:
• Patches – red-purple macules typically confined to the lower extremities.
• Raised plaques – dermal accumulations of dilated vascular channels, spread proximally.
• Nodules – more distinctly neoplastic.
Higher stages means more advanced stage of the disease.
Microscopically – cells are spindle shaped.
 Types:
• Classic KS – European or Mediterranean origin, red-purple skin plaques on the lower extremities.
• Endemic African KS (lymphadenopathic) – in African children and young adults, associated with generalized lymphadenopathy.
• Transplant-associated KS – occurs in patients on immunosuppression for organ transplants, involves skin and viscera, and may regress with reduction of immunosuppression.
• AIDS-associated KP – most common HIV-related malignancy. Most common in homosexual male AIDS patients. Aggressive form with widespread visceral dissemination.
 Common sites – skin, GIT, lymph nodes, and lungs.
 Responses to AIDS drugs, chemotherapy, and interferon-alpha – reduced dramatically the incidence of Kaposi sarcoma in these patients.
2. Hemangioendotheliomas – spectrum of vascular neoplasms originating from epithelial cells. One type is epithelioid hemangioendothelioma occurring around medium and large-sized vessels.
Malignant tumors:
1. Angiosarcoma – rare highly malignant and aggressive tumors derived from the endothelial cells, with high mortality. Commonly occur in the – skin, breast, soft tissues, and liver:
 Skin – usually in elderly, on sun-exposed areas.
 Hepatic angiosarcoma – are associated with carcinogenic exposure to arsenic, chloride, and thorotrast (radioactive contrast agent formerly used in radiologic imaging). Associated also with radiation therapy.
 Lymphangiosarcome – arising from lymphatic vessels, classically present as lymphedema of ipsilateral upper extremity several years after mastectomy due to breast cancer.
Microscopically – all features of malignant cells are seen – all degrees of differentiation…
2. Hemangiopericytoma – arise from pericytes – myofibroblast cells associated with capillaries and venules. Very rare.

Question 2

Neoplasms of the heart

Answer 2

Cardiac tumors can be divided into:

• Primary – rare, neoplasms originating in the heart. May be benign & malignant.
• Secondary – most, metastatic tumors to the heart. Found in 5% of all patients dying of malignancies.

Primary:
The 5 common primary tumors, all benign, in descending order are:
1. Atrial myxoma – most common in adults - benign tumor arising within the left atrium near fossa ovalis. They arise from multipotential mesenchymal cells found in the connective tissue of the septum (not from cardiomyocytes).
Carney’s syndrome – cases in which myxomas appear in familial patterns – AD, appear in the heart and in extracardiac sites (for example in the skin).
 Pathology:
• Macroscopy – mesenchymal proliferation with gelatinous appearance. Mucopolusacharides. Sessile/pedunculated .
• Microscopy – abundant ground substance, contain multinucleate satellite-shaped myxoma cells.
 Complications:
• “Ball valve” obstruction – as they tend to extend and disturb the mitral valve function (and maybe also other valves). Thus, it’s associated with multiple syncopal episodes. This obstruction is position-dependent, meaning, with change in position the tumor can obstruct or relieve the valve.
• Tumor emboli.
 Diagnosis:
• Diastolic “tumor plop” sound on auscultation.
• Transesophageal echocardiography – best way to examine the left atrium.
• Constitutional symptoms – neoplastic cells release IL-6 – low grade fever, malaise…
2. Fibromas. – C.T benign tumor derived from fibroblasts. In all ages and both sexes. Usually found on the ventricular septum or ventricles. Firm, white-greyish with central calcification, very large, Uncapsulated.
3. Lipomas – composed of mature fat cells, can occur in the subendocardium, subepicardium, or myocardium.
 Location – lipomas are most often located in the:
• Right atrium.
• Left ventricle.
• Atrial septum – may occur as nonneoplastic depositions of fat called “lipomatous hypertrophy” – include white and brown adipose tissues.
 Complications – can be asymptomatic or produce ball-valve obstruction or arrhythmias.
4. Papillary fibroelastoma – unusual benign neoplasms, occurring on valves:
 Macroscopy - Hair-like projections – resemble the trivial Lambl excrescences – small filiform thrombi on the aortic valves of older individuals.
 Microscopy – covered by endothelium, surrounding a core of myxoid connective tissue.
5. Rhabdomyoma – most common tumor in children – tumors arising within the myocardium preferentially in the ventricles. They are associates with tuberous sclerosis (a rare genetic disease that causes benign tumors in multiple organs principally the brain). They derive from abnormal apoptosis during cardiac development.
 Often regress spontaneously – thus may be considered as hamartomas rather than true neoplasms.
 Pathology:
• Macroscopically – gray-white myocardial masses, usually multiple.
• Microscopically – bizarre markedly enlarged myocytes. Routine histological processing often reduces their cytoplasm, causing them to look like “spider cells”.
**Malignant primary tumors – rhabdomyosarcoma, angiosarcoma [see Dana’s Q.!]

Secondary:
Occur due to metastatic spread, or due to direct extension from adjacent structures. Especially from breast and lung carcinomas, melanoma, and lymphoma – these cancers love to go to the heart. Usually cause:
 Pericarditis - Neoplastic cells mainly infiltrate the pericardium – this results in pericarditis and especially – Hemorrhagic pericarditis.
 Pericardial effusions.

Question 3

Thymus neoplasms

Answer 3

Histology:
- Derived from 3rd + 4th pharyngeal pouches – at birth it weighs 10-35 gm → grows until puberty, achieves maximus of 20-50 gm → undergoes involution to 5-15 gm.
- Structure – consists of 2 lobes:
 Inside – stroma – reticular epithelium (TECs – Thymic epithelial cells).
 C.T capsule – extends septa that divides the parenchyma into non-true lobules – cortex (basophilic) is lobulated but medulla (lighter stained) is continues.
• Hassall corpuscles – aggregation of degrading TECs, which become keratinized, and create bodies interspersed in the thymus.

Diseases of thymus:
1. Developmental disorders:
- DiGeorge syndrome (Thymic hypoplasia) – T-cell deficiency due to failure of development of the 3rd and 4th pharyngeal pouches – responsible for thymus development.
 22q11 deletion.
 Presentations – lack of structures derived from the 3rd and 4th puches:
*T-cell deficiency – lack of thymus , *Hypoclcemia – lack of thyroids,
*Heart, face, and vessels abnormalities.
- Isolated thymic cysts – uncommon lesions that are usually discovered postmortem – spherical, lined by columnar or stratified epithelium, containing serous or mucinous fluid. Not clinically significant – but if they become symptomatic, it should provoke a search for a neoplasm.
2. Thymic follicular hyperplasia – enlargement of the thymus or failure to involute due to appearance of B-cell germinal centers within the thymus.
- Frequently in myasthenia gravis – most common. But also in – Graves disease, SLE, scleroderma, and other autoimmune disorders.
- May be mistaked radiologically for a thymoma.
3. Thymoma – primary tumor of the thymus arise from TECs (and not from its lymphocytes).
- Epidemiology – adults > 40 years old, rare in chidren.
- Macroscopy – lobulated, firm, grey-white masses of 15-20 cm.
- Microscopy – classifies thymomas into 3 types:
 Benign (noninvasive) thymoma- composed of medullary TECs – elongated cells arranged in swirling pattern. Only a few lymphoid cells are interspersed.
 Malignant thymoma – By definition – invasive thymomas penetrate through the capsule into surrounding structures.
• Type I – Benign invasive - composed of cortical TECs – abundant cytoplasm, aggressive and likely to metastasize.
• Type II – Thymic carcinoma – most are either:
 Squamous cell carcinoma – mostly.
 Lymphoepithelial carcinoma.
Thymomas are known for their association with paraneoplastic syndromes:
- Myasthenia gravis – most common.
- Hypoagammaglobulinemia.
- Erythroid hypoplasia – pure red cell aplasia.
And others.

Question 4

Tumors of nose, paranasal sinuses and nasopharynx

Answer 4

37. Tumors of nose, paranasal sinuses and nasopharynx:
    Generally speaking- most head and neck are squamous cell carcinomas.
    **field cancerization- carcinogen damage to a wide mucosal area leading to multiple tumors developing independently following the exposure.
    Nose and sinuses:
    Benign tumors;
38. Capillary hemangioma: commonly seen on the nasal septum. Can resemble inflammatory granulation tissue. [hemangioma = benign tumor of blood vessel. mesenchymal]
39. Sinonasal papilloma: benign tumor of the respiratory mucosa of nose or sinuses.
    • Also, called Schneiderian papilloma (schneiderian mucosa lining the nose).
    • The growth of the tumor can be exophytic (outwards), endophytic (inwards), or cylindrical (around blood vessels).
    • The endophytic type is especially aggressive –can complicate and invade the orbit or cranial vault. And can undergo malignant transformation in 10% of cases.
    • Associated with HPV virus, usually types 6 and 11.
    Malignant tumors:
40. Olfactory neuroblastoma: tumor of the neuroectodermal olfactory cells in the nasal mucosa- superiorly located at the nasal cavity.
    • Commonly seen at 15 and 50 years of age.
    • Patients complain about nasal obstruction and epistaxis.
    • Highly malignant small cell tumor of neural cell crest origin cells- making it sometimes indistinguishable from other small cell tumors- lymphoma, small cell carcinoma, Ewing sarcoma, rhabdomyosarcoma or undifferentiated carcinoma.
    • Treatment includes surgery, radiation and chemotherapy→ 40%-90% survival rates in 5 years
41. Carcinomas: usually squamous cell carcinomas are the nasal cavity and sinuses, called also sinonasal carcinomas.
    • Seen in elderly people with heavy smoking history, or wood workers.
    • Tumors extends both locally- to bone and soft tissue, and metastasize widely.
    Nasopharynx:
    Benign:
    Nasopharyngeal angiofibroma: benign tumor of nasal mucosa composed of blood vessels and fibrous tissue.
    • Classically seen in adolescence males- even more commonly in fair skin red-headed.
    • Present with profuse epistaxis.
    • Surgical removal is the treatment of choice, but the tumor has 20% recurrence rates.
    • Histologically-the tumor is composed of endothelium and myofibroblasts.
    Malignant:
42. Nasopharyngeal carcinoma: malignant tumor of nasopharyngeal epithelium.
    • Associated with EBV- has a distinguished geographical distribution: Africa (in children) and china (in adults).
    • The cells composing the tumor can be of 3 types- keratinized squamous cells, non-keratinized squamous cells and undifferentiated (transitional) basaloid cell.
    • Usually associated with enlarged lymph nodes- metastases to them in 70% of cases.
    • Histologically- pleomorphic epithelial cells with lymphocytes at their background. The epithelial cells are checked for keratin positivity to distinguish them from other types of cancer.
    Embryonal rhabdomyosarcoma: malignant tumor of striated muscle.
    • Seen mainly in children under 12 years.
    • The tumor appears as a gelatinous mass in the deep subcutaneous tissue or between muscles- generally with no direct relationship to the skeletal muscle itself.
    • Microscopically- the tumor cells resemble the embryonal stage of development of muscle fibers.
43. Malignant lymphoma: tumor of the lymphoid tissue of nasopharynx and tonsils.
    Diffuse b cell, marginal
44. NUT midline carcinoma: a very aggressive tumor of the squamous epithelial cells.
    • Can occur in the nasopharynx, salivary glands or other midline structures of the thorax and abdomen
    • Morphologically- it is almost indistinguishable from squamous cell carcinoma but has special genetic features.
    • A chromosomal translocation forming a chimeric protein is seen in this tumor made of NUT (a chromatin regulator) and a portion of BRD4 (a chromatin reader) (15,19) translocation. This mechanism is usually seen in acute leukemia but rarely in epithelial cancers- making it extremely aggressive.
    • Usually survival of up to 1 year following the diagnosis

Question 5

Tumors of larynx and trachea

Answer 5

Tumors:
Benign tumors:
1. Vocal cord nodules: reactive nodules located on the vocal cords Most often seen in singers or heavy smokers (singer’s nodules)
• Formed due to excessive use and therefore are usually bilateral.
• Composed of loose myxoid connective tissue (degenerated) covered by epithelium.
• Macroscopically- small, less than 1 cm, round and smooth on the true vocal cords.
• Characteristically change the person voice- cause hoarseness
• Resolves with rest of the patient.
• Pseudotumor=an enlargement that resembles a tumor; it may result from inflammation, accumulation of fluid, or other causes, and may or may not regress spontaneously.
2. Laryngeal papilloma:
• Benign papillary tumor of the vocal cord.
• Macroscopically- appears as warty growth on the true vocal cords, epiglottis and sometimes trachea and bronchi
• Associated with HPV types 6 and 11 (low risk to develop to carcinoma)
• Usually single lesion in adults and can be multiple in children.
• Microscopically- finger like papillae containing a fibrovascular core covered by stratified squamous epithelium.
• Presents with hoarseness.
• Morpho: rusberry

Malignant tumors:
Laryngeal carcinoma: squamous cell carcinoma (95% of cases) originating from the lining of the vocal cords.
• If not squamous cells- adenocarcinoma or sarcoma.
• Risk factors are tobacco and alcohol abuse, in males over 40.
• Can be classified according to origin-
 Extrinsic- arise or extends outside of the larynx
 Intrinsic- arise and confined to the larynx.
• Can be classified according to location:
 Glottic- most common, on true vocal cords
 Supraglottic- involves ventricles and arytenoids
 Subglottic- in the walls of subglottic.
 Marginal zone- between epiglottis tip and aryepiglottic folds.
 Laryngo-hypo-pharynx- in the pyriform fossa, and posterior pharyngeal wall.
• The epithelial changes usually include- hyperplasia, atypical hyperplasia, dysplasia and invasive carcinoma. Usually, the changes become gradually worse with years of heavy smoking. And the changes can gradually regress after smoking stops.
• Macroscopically- glottis type is usually seen, appears as a small, pearl white plaque like thickening that may or may not be ulcerated.
• Microscopically- can be keratinizing or non-keratinizing squamous cell carcinoma or it can be one of 2 special types- verrucous carcinoma- a variant of well differentiated squamous carcinoma, and spindle cell carcinoma- elongated tumor cells(pseudosarcoma)
• Presents with hoarseness, dysphagia and dysphonia.
• Prognosis highly depends on clinical staging.
• Treatment can involve laser or micro-surgery, chemotherapy and radiation.

Question 6

Lung tumors

Answer 6

When dealing with masses we can divide them into 3 types:
1. Pseudotumors- a non-neoplastic pathological lesion mimicking a neoplasm.
2. Benign neoplasms
3. Malignant neoplasms
Pseudotumors of the lung:
 Granulomas- see question 50
 Pulmonary Abscesses- a local supurative process that produce a necrosis to the lung tissue. Associated with many bacteria, especially staph. Aureus. They vary in diameter, and can appear at any part of the lung. The cardinal sign of all abscesses is suppurative destruction of the lung parenchyma within a central area of cavitation.
 Mycetoma

• Chondrohamartoma: pseudotumor!
  Chondrohamartoma:
• Definition- Disorganized proliferation of epithelial and mesenchymal tissue- meaning lung tissue and cartilage. When present in the lung it is called bronchial hamartoma.
• Pathogenesis:
  Microscopically- epithelial clefts, cartilage, adipocytes and fibrous tissue.
  Macroscopically- usually small (>2cm), firm and sometimes calcified.
• Progression- completely benign, no progression to malignancies.

Benign neoplasms of the lung:
1. Bronchial adenoma
2. Bronchial papilloma
Malignant neoplasms of the lung- lung cancer:
Lung carcinoma:
There are many possible tumurs that can arise in the lungs, but in 95% it will be carcinoma.
Incidence- the 2nd most common cancer and the first cancer cause of death. Occurs mainly between 40-70 years, and rarely before 40 (2% of cases). Risk factors include:
1. Smoking- 80% of lung cancer occurs in active smokers. Cigarette smoke contains many carcinogenic factors including arsenic and polycyclic aromatic hydrocarbons. We can count amount of cigarettes in pack years. Also passive smoking increases the risk X2
2. Radon- a nobel gas, involved in the decay of uranium that induces lung cancer. Uranium miners are also in increased risk. Radon and uranium can be discharged from the ground as a colorless odorless gas, especially associated with people staying in basements for long periods of time.
3. Asbestos- with a latent period of up to 30 years from exposure to cancer appearance, people who were exposed are in much greater risk, especially if associated with smoking.
Clinical manifestation:
• Non-specific symptoms- cough, weight loss, post-obstructive pneumonia, hemoptysis, chest pain and more nonspecific symptoms in an adult smoking patient aware our attention.
• In X-ray- coin lesions- solitary nodules will appear. At this point we should compare the x-ray to an older one and to see if it was present before and if so did it change its diameter.
• Biopsy- will confirm the diagnosis.
Symptoms due to Complications: lung carcinoma is associated with many complication effecting the clinical signs: (SPHERE of complications)
• Superior vena cava syndrome- its obstruction, causes distended head and neck veins, edema, and cyanosis of the face and arms.
• Pancoast tumor- located at the apex of the lung and compresses sympathetic chains- leads to ptosis, pin-point pupils and anhidrosis- no sweating mainly in forehead.
• Horner syndrome
• Endocrine (paraneoplastic syndrome)
• Recurrent laryngeal nerve or phrenic nerve compression- hoarseness and diaphragmatic paralysis.
• Effusions- pleural or pericardial.
• Pleural involvement- mainly adenocarcinoma-peripheral tumor.
Pathogenesis:
We can classify the carcinoma according to its location and according to its cell origin:
• Classification according to location- usually devided to central and peripheral but a second option is: (see picture)
• Classification according to cell type:
1. Small cell carcinoma- surgery is not possible 15% of cases
2. Non-small cell carcinoma- surgical approach is possible. 85% of cases
 Adenocarcinoma -40%
 Squamous cell carcinoma- 30%
 Large cell carcinoma 10%
 Other

Small cell carcinoma:
• Histology- poorly differentiated small cells originating from neuroendocrine tissue- small dark-blue cells, positive to chromogranin A and enolase.
• Incidence- more common in males, highly associated with smokers.
• Location- central
• Molecular changes- amplification of myc oncogenes and P53 loss of function.
• Treatment- chemotherapy, with/without radiation
• Others- rapid growth and early metastasis- very aggressive! Associated with paraneoplastic syndrome- endocrine associated syndromes including ACTH (Cushing), SIADH, or Lambert-Eaton myasthenic syndrome- production of antibodies against presynaptic Ca+2 channels leading to muscle weakness.
Squamous cell carcinoma:
• Histology- keratin pearls and intercellular bridges (desmosomal connections between the squamous cells). Many times it originates from squamous metaplasia or dysplasia in the bronchial epithelium that transforms to a carcinoma in situ.
• Incidence- most common tumor in smoker males
• Location- central- hilar masses
• Molecular changes- P53 mutation.
• Others- CCC- can form Cavitation, Cigarette associated and hyperCalcemia- due to parathyroid hormone related protein synthesis that increases levels of calcium.
Adenocarcinoma:
• Histology- invasive malignant epithelial tumor, glandular pattern of cells, often stains positive for mucin
• Incidence-most common tumor in non-smoker patients and females.
• Location- peripheral
• Molecular changes- active mutations in KRAS, EGFR, and ALK genes.
• Others- has an important subtypes:
• Adenocarcinoma in situ= bronchioloalveolar carcinoma- lesion >3cm, composed of dysplastic columnar cells containing mucus – originating from Clara cells. Cells grow along the alveolar septa and causes “thickening” of the alveolar wall. On CXR, hazy infiltrates are seen, similar to pneumonia. It has better prognosis.
Large cell carcinoma:
• Histology- undifferentiated, pleomorphic giant cells that lacks the cytologic features of the other tumors – no keratin pearls, intercellular bridges, glandular appearance or mucin.
• Incidence- associated with smokers
• Location- peripheral
• Treatment- less responsive to chemotherapy- surgically removed
• Others- has a very poor prognosis.
Macroscopic appearance-
Beside for the location (central or peripheral) most carcinoma look the same-tissue is gray-white and firm, with focal areas of hemorrhage or necrosis that can bee seen. The necrotic foci sometimes cavitate (squamous cell).

TNM Staging:
Lung cancer is usually staged according to this method:
T- Size and local extension of the tumor
N- Spread to regional lymph nodes (mainly hilar and mediastinal)
M- metastasis- unique and important site of spread is the supra-renal glands.

Carcinoid:
• Definition- small hyperplastic nets of neuroendocrine cells, seen in areas of scarring or chronic inflammation. Low grade malignancy!!!
• Incidence- most patients are under 40, equal incidence in both sexes.
• Pathogenesis:
• Macroscopically- polypoid intra-bronchial mass, projecting into the lumen, and covered by intact mucosa.
• Microscopically- small, round, uniform cells growing in nets, chromogranin A positive
• Electron microscope- Tumor cells contain argyrophilic neurosecretory granules such as serotonin, ACTH and bombesin
• Progression- the carcinoids can be sub-classified to
• Typical- small amount of mitotic division, and no necrosis, regular uniform cells with round nuclei
• Atypical- greater amount of mitotic divisions and a foci of necrosis, as well as increased pleomorphism in their shapes, prominent nucleoli and more likely to grow in a disorganized way and invade lymphatics→ making the potentially malignant.
• Clinical manifestations- highly depends on their intrabronchial growth and secretion of vasoactive amines. Cough, hemoptysis, infections due to impaired drainage, emphysema and even atelectasis can occur. Carcinoid syndrome- seen in 10% of bronchial carcinoids, intermittent attacks of diarrhea, flushing and cyanosis.
• Healing and prognosis- 95% survival in 5 years for typical, and 70% for atypical.

▪ Prognosis:
The prognosis with lung cancer is dismal: The 5-year survival rate for all stages of lung cancer combined is about 16%.
Overall, NSCLCs carry a better prognosis than SCLCs.
When NSCLCs (squamous cell carcinomas or adenocarcinomas) are detected before metastasis or local spread, cure is possible by lobectomy or pneumonectomy.
* The first lymph node involvement is usually the hillar and mediastinal lymph nodes.

Question 7

Tumors of the pleural cavity

Answer 7

55. Tumors of the pleural cavity:
    The pleural cavity can contain tumors as:
    • Primary tumors- the ones originating from the pleura itself
    • Secondary tumors- metastatic involvement, more common, especially from lungs and breast and the colon].
    Primary pleural tumors- mesothelioma:
    Definition- an uncommon tumor of the mesothelial lining of the serous cavities. Most commonly it appears at the pleural cavity, rarely it can occur in the peritoneal cavity and the pericardial sac.
    *Mesothelium = the epithelium that lines the pleurae, peritoneum, and pericardium.
    Classification- 2 types:
56. Benign mesothelioma- solitary fibrous tumor.
57. Malignant mesothelioma- diffused.
    They can be distinguished by their gross appearance- solitary discrete masses are usually benign, whereas diffusely growing masses are usually malignant.

Benign solitary mesothelioma:
Also called pleural fibroma or solitary fibrous tumor
Pathogenesis:
Macroscopy- a solitary בודד lesion, well circumscribed, firm mass, usually small in size, 3>cm, but rarely can reach sizes of more than 10 cm. it is made of dense fibrous connective tissue.
Microscopy- collagen fibers whorls, with interspersed fibroblast.
Markers- the cells are CD34 positive and keratin negative.
Clinical manifestation- usually no symptoms unless the size is dramatically big,

Malignant mesothelioma:
A rare, highly malignant tumor with high mortality rates.
Etiology-
• Highly associated with asbestos exposure-90% of cases are related to it- with a long latent period from exposure to tumor growth- up to 45 years
• SV40 virus- simian vacuolating virus was also found to have a relation to mesothelioma development.
Pathogenesis:
Macroscopy- diffused lesion, forming a thick, gelatinous, and gray- pink, fleshy coating over the parietal and visceral surface.
Microscopy- malignant mesotheliomal cells can have one of three patterns:
1. Epithelial pattern- 60% of tumors, the cells are cuboidal, columnar or flat, well differentiated, arranged as in a tubular and tobulo-pappilary formation. Resembles an adenocarcinoma.
2. Sarcomatoid pattern- 20% of tumors, loosely-arranged whorls of elongated, spindled fibroblast-like cells with abundant collagen in-between them, resemble fibrosarcoma.
3. Mixed pattern- mixed epithelial and sarcomatoid patterns.
Asbestos bodies can be seen in all 3 types of cellular arrangements.
Markers- the cells are CD34 negative and keratin positive.
Clinical manifestations- chest pain, dyspnea, pleural effusion and infections.
Complications- the tumor spreads rapidly by direct invasion to the lung and indirectly to the hilar lymph nodes and the pericardium via the lymph. Distance metastasis to the lymph can also occur.
Healing and prognosis- poor prognosis, 50% of patients die within 1 year following the diagnosis.

Secondary pleural tumors:
Metastatic malignancies in the pleura are much more common.
Originating from- can originate from any body location, but most commonly from:
• Lung and breast- through the lymphatics
• Ovarian cancer- via haematogenous rout.
Appear as small nodules scattered over the lung surface with varying microscopical types.

Question 8

Tumors and pseudotumors of the oral soft tissues, orofacial epithelial neoplasms

Answer 8

Precancerous lesions:
1. Leukoplakia and Erythroplakia –
- Definitions:
 Leukoplakia - “white patch” that can’t be scrapped off and can’t be diagnosed as another disease (no apearant reason – thus white patches from infection (candidiasis) or lichen planus are not leukoplakias).
 We always look on it as precancerous leison. 30% progress to oral cancer.
 Erythroplakia – “red patch” with markedly atypical mucosa. Higher risk for malignant tranformation than leukoplakia. 60% progress to oral cancer.
 Leukoerythroplakia – combined leukoplakia and erythroplakia.
- Epidemiology – adult, male>female (2:1). Causes:
 Tobacco use – of all forms.
 Alcohol abuse.
 HPV.
- Pathology –
 Macroscopy – solitary of multiple patches usually appear on the vermilion border of lower lip (most common site), buccal mucosa, floor of the mouth , palate, and gingiva.
 Microscopy - initially show squamos hyperplasia (acanthosis) with hyperkeratosis (as long as the epithelium below is normal it’s still benign) → progress to squamos dysplasia (different severity – grade 1-3, which is precancerous situation for → squamos cell carcinoma.
- Biopsy must be performed – high risk for progression.
2. Actinic keratosis – precancerous patch, usually of the skin but can occur also on the lips → may lead to squamos cell carcinoma. Usually in people exposed to the sun. show atypical keratinocytes, with epidrmal thickening extending to the basal layer of the epidermis.
Pseudotumors:
1. Fibrous proliferative lesions (Epulis) – fibrous masses that grow typically on the gingiva, as a reactive process All are importnt differential diagnostics from malignancies. Common are:
- Irritation fibroma (fibrous epulis) – submucosal nodular mass of fibrous connective tissue occur primarly on the gingiva or buccal mucosa. Reactive proliferation due to chronic irritation of the mucosa. Treated with complete surgical excision.
- Pyogenic granuloma – inflammatory lesion on the gingiva, typically in chilren, young adults, and pregnant women (pregnancy tumor). also related with mucosal irritation.
• Macroscopically – red-purple, often ulcerated, alarmingly rapid growth – raising the fear for malignancy (it resembles hemangioma).
• Microscopically - highly vascular proliferation of organizing granulation tissue.
• Fate – can regress and form dense fibrous masses, or progress into a peripheral ossifying fibroma. Treated with surgical excision.
- Peripheral ossifying fibroma – red, ulcerated nodules on the gingiva, with ossification of connective tissue. Typically between the frontal teeth.
- Peripheral giant cell granuloma – reactive mass on the gingiva, usually not ulcerated that appear due to irritation. Histologically giant cells are found. Should be distinguished from central giant cell granuloma – which occurs in the maxilla, and from “brown tumors” seen in hyperparathyroidism.
3. Condylomata accuminatum (ventral wart) – caused by HPV types 6, 11, and 16 – connective tissue papillae covered by epithelium. Appear on the genital region and in the oral mucosa.
4. Mucocele – (question 66) – A.K.A mucus cysts – cystic dilation of mucous glands (salivary) of the oral mucosa (lined by true epithelium). The cyst often ruptres and incites inflammation.
5. Ranula – large mucocele, located on the floor of the mouth.
6. Dermoid cyst – due to developmental malformation found in the floor of the mouth.
7. Torus palatinus and torus mandibularis – benign bony outgrowth from the palate (more common) or mandible (respectively). It’s very common and not cancerous.
Tumors:
Benign:
1. Squamous papillomas – most common - exophytic finger-like projections with fibrovascular connective tissue core covered by squamous epithelium. Can be found anywhere in the mouth.
2. Granular cell tumor – (granular cell myoblastoma) – it is neuroectodermal!!!!
Not mesenchymal tumor composed of large polyhedral cells, with granular acidophilic cytoplasm. Most common on the tongue. Occurs exclusively in females. Similar lesion appears in infants is called congenital epulis.
3. Haemangioma – benign vascular tumor derived from endothelial cells, most commonly of capillary type. When it occurs on the tongue it may cause macroglossia.
4. Lymphangioma – , no RBC, large lymphatic spaces lined by endothelium containing lymph - may develop on the tongue producing macroglossia, or on the lips producing macrocheilia.
5. Fibroma – collagenous connective tissue covered by stratified squamous epithelium creating - fibrous superficial pedunculated mass, probably due to physical trauma.
6. Fibromatosis ginginae – fibrous overgrowth of the entire gingiva, unknown etiology. Fibrous tissue may cover the teeth.
7. Tumors of minor salivary glands – such as pleomorphic adenoma.

Malignant:
1. Squamous cell carcinoma (SCC) – malignant neoplasm of squamous cells lining the oral mucosa. Most commonly in the floor of the mouth.
- Epidemiology - Most common – 95% of cancers of head and neck.
 Man > women.
 Risk factors:
• Tobacco + alcohol – individually, and when together have synergetic effect.
• HPV – particularly HPV 16.
• Lichen planus.
- Pathogenesis – accumulation of mutations, frequently involve p53, and in case of HPV-associated – inactivtion of p53 and RB patheays by E6 and E7 proteins.
- Pathology – most common locations are – floor of the mouth > lower lip > tongue lateral border.
 Macroscopy:
• Early SCC – firm plaques, patches, mistaked with leukoplakia or erythroplakia.
• Late SCC - patches enlarge with time create endophytic (ulcerating) and exophytic (protruding) masses with irregular borders – create different types:
• Types – SCC of the oral cavity may have the following types:
 Ulcerative – most frequent – indurated ulcers with firm elevated edges.
 Verrucous (papillary) – Verrucous carcinoma – finger-like projections.
 Nodular – firm, slow growing submucosal nodules.
 Scirrhous – infiltrate into deeper stractures.
 Microscopy:
• Progression with time – as described for leukoplakia – hyperplasia+keratosis → mild dysplasia → severe dysplasia (carcinoma in situ) → invasive SCC.
• SCC – invasion of malignant keratinocytes + nets of keratinization. Neoplastic cells range from well-differentiated to anaplastic.
- Metastasis – to cervical and mediatinal lymph nodes. Prognosis depends on staging.
- Prognosis –
- Nearly all patients with lip cancer survive five years. By contrast, of those with carcinoma of the floor of the mouth, only about one third survive.
Basal cell carcinoma – most common cancer of upper lip. Associated with exposure to UV light.
3. Oral malignant melanoma – more aggressive and worse prognosis than in the skin, showing irregular masses with irregular pigmentation. Can be of two types:
- Superficially spreading melanoma.
- Nodular melanoma.
Verrucous carcinoma –
Is an uncommon low-grade variant of squamous cell carcinoma that is associated with HPV infection (may be subtypes 16 or 18, but types 6 and 11 have also been reported).

Clinically, it presents as an exophytic white mass with a verrucous or pebbly surface. The size varies from1 cm in the early stages to very extensive lesions. The buccal mucosa, palate, and alveolar mucosa are the most common sites of involvement.

It can invade underlying tissue but almost never metastasizes.
It has a good prognosis compared to typical oral squamous cell carcinoma.

Question 9

Odontogenic tumors

Answer 9

Odontogenic tumors are a group of uncommon lesions of the jaw derived from the odontogenic epithelium, ectomesenchyme (oral cavity mesenchyme derived from neural crest cells), or both. Most are benign.

Benign:
1. Ameloblastoma – most common - benign, slow-growing, locally invasive tumors, arising from the odontogenic epithelium especially from the enamel organ (rests of malassez) or the rests of the dental lamina- serres. May become malignant – malignant ameloblastima or ameloblastic carcinoma (2 different things).
- Forms – 3 common variants are discussed, divided into 2 groups based on location, morphology, and prognosis:
 Central - Intraosseous – within the alveolar bone, usually aggressive, consist of the following:
• Common/solid/polycystic ameloblastoma – most common – slow growth, locally invasive, and high rate of recurrence after treatment. Seen in patients 30-40 years old.
 Mostly in the mandible – especially near the ramus of mandible, molars.
 “Soap-bubble” appearance – results from bone destruction.
 Macroscopy – asymptomatic in early stages, later gradually increases in size causing facial asymmetry, loosing of teeth, and pain.
 Microscopy – multiple islands of tumor cells, which may undergo cystic degeneration and form multiple microcysts.
 Treatment – resection.
• Unicystic ameloblastoma – this is a cystic tumor, meaning it has the components of a cyst but behaves like a tumor. It has one large cyst with a central cavity, epithelial lining of ameloblasts, and a connective tissue capsule. It’s formed an unerupted 3rd molar. Seen in younger patients – around their 20s. They are less aggressive with lower recurrence rate than the common type.
 Mostly in the mandible.
 May arise from a dentigerous cyst – as the lining epithelium undergoes neoplastic transformation.
 Macroscopy – as in polycystic ameloblastoma.
 Microscopy – show 3 distinct types:
a. Luminal – the cystic epithelium has basal columnar cells, upon which lie stellate reticular cells.
b. Intraluminal – nodule of epithelium projects into the lumen, showing a plexiform pattern of ameloblastic epithelium.
c. Mural – follicular islands of ameloblastic epithelium (similar to common type) in the cystic wall.
 Peripheral – extraosseous ameloblastoma – arise from odontogenic epithelial remnants within the gingiva. It’s very rare, seen
as a nodule in the gingiva. Good prognosis.
- Histology – different patterns as explained above:
 Follicular – most common – the tumor consists of follicles of variable size separated from each other by fibrous tissue.
 Plexiform – 2nd common – form network of strands.
 Acanthomatous – squamous metaplasia within the islands of tumor cells.
 Basal cell pattern – similar to basal cell carcinoma of the skin.
 Granular cell pattern – characterized by appearance of acidophilic granular tumor cells.
Odontomas – these are hamartomas rather than true neoplasms (so it’s actually a normal dental tissue that has grown in an irregular way), contain both epithelial and ectomesenchyme components. There are 2 subtypes:
- Complex odontoma – consist of enamel, dentin, and cementum which are not differentiated, so that the structure of actual tooth is not identifiable.
 Usually in posterior part of the mandible.
- Compound odontoma – comprised of differentiated dental tissue elements forming a number of denticles (small teeth) in fibrous tissue.
 Frequent in anterior part of the mouth.
3. Adenomatoid odontogenic tumor (AOT) – commonly associated with an unerupted anterior tooth and thus closely resembles dentigerous cyst radiologically. More frequent in young females (20s). Not invasive and doesn’t recur after enucleation.
- Macroscopy – swelling over unerupted tooth.
- Microscopy – extensive cyst formation of tubule-like structure, hence the name ‘adenomatoid’ (gland-like).
4. Keratocystic odontogenic tumor (=keratogenic odontocyst) - proliferation of epithelium that arises from the dental lamina (rests of Serres), creates a cyst lines by keratinized stratified squamous epithelium. Has to be distinguished from other cysts due to being locally aggressive. Can arise anywhere in the jaw, most commonly in the angle of mandible, with spread.
Treatment requires complete removal, due to being locally aggressive and with high recurrence.
5. Calcifying epithelial odontogenic tumor (CEOT) – locally invasive, slow growth, characterized by the presence of amyloid material that may become calcified.
- Forms:
 Central – intraosseous.
 Peripheral – extraosseous.
- Microscopy – closely packed epithelial cells with cytological atypia, in a homogenous and hyalinized stroma in which small calcified deposits are seen as a striking feature.
6. Ameloblastic fibroma – consist of epithelial and connective tissue derived from the odontogenic apparatus. It resembles ameloblastoma but can be distinguished from it because it occurs in a younger age group (below 20), and its clinical behavior is always benign
- Microscopy – consists of epithelial follicles similar to those of ameloblastoma, set in a very cellular connective tissue stroma. This appears with no dental hard tissue.
If it does appear with a dental hard tissue, it can be of 2 types:
 Ameloblastic fibrodentinoma – hard tissue derives from dentin.
 Ameloblastic fibro-odontoma – hard tissue derives from dentin and enamel.

Malignant:
Can be either:
Odontogenic carcinomas:
In general – rare, aggressive, metastasis is possible, high recurrence rate.
1. Ameloblastic carcinoma – rare - ameloblastic tumor having cytologic features of malignancy in the primary ameloblastoma. Aggressive with possible metastasis. 2 types:
- Primary – arises de novo.
- Secondary – arises from benign ameloblastoma.
2. Malignant ameloblastoma – term used for the uncommon metastasizing ameloblastoma.
3. Primary intraosseous carcinoma – primary squamous cell carcinoma of the jaw leading to bone destruction and metastasis. In many cases derived from preexisting odontogenic cyst.
Odontogenic sarcoma:
One rare example – ameloblastic fibrosarcoma. It resembles ameloblastic fibroma but the mesodermal component in it is malignant whereas the ameloblastic epithelium remains benign.

Question 10

Neoplasms of salivary glands

Answer 10

More than 30 tumors have been identified, but small number represent 90% of the neoplasms.
- Epidemiology – most commonly occur in the parotid gland, and most are benign. In general:
 Major salivary glands tumors – are more likely to be benign.
 Minor salivary glands tumors – are more likely to be malignant.
Mostly in adults.
- Clinically – typically present as painless mass/swelling. Facial pain or paralysis suggests malignant involvement of cranial nerve VII.

Benign tumors:
1. Pleomorphic adenoma (mixed tumor) – benign tumor composed of a mixture of epithelial tissue (e.g., glands), myxoid, and cartilage (sometimes). It has been thought that the tumor arise from all these tissues, but immunohistochemistry has proved that the neoplastic cells are epithelial only, and due to being saliva-producing cells, it gives this mixture of substances appearance (=pleomorphic).
 Epidemiology – most common salivary gland tumor.
•
Projections
Females > males.
• Usually in the parotid.
 Pathology:
• Macroscopy – painless, moveable, circumscribed mass at the angle of the jaw.
 Cut – shows grey-white areas of myxoid, and blue-translucent areas of cartilage.
• Microscopy – epithelial cells (resembling ducts) intermix with myxomatous and cartilogenous stroma surrounded by a capsule. Tumor projections through the capsule increase the risk for recurrence – as many times when the surgeons cut the tumor, these projections remain, and begin a new one.
Different amount of components – if it has more myxoid tissue, it’s more jelly like.
 Complications:
• Rarely transforms into carcinoma – called carcinoma ex pleomorphic adenoma, presents with signs of facial nerve damage. Very aggressive. So if a patient had the painless swelling for many years, and suddenly he has facial pain, it suggests the transformation to carcinoma.
• Compression of facial nerve.
2. Warthin tumor (=adenolymphoma, Papillary cystadenoma lymphomatosum) – benign cystic tumor, with abundant lymphocytes and germinal centers. Even though there are many lymphocytes – it’s not a lymphoma. These are just lymphocytes reacting to this neoplasia (thus the name adenolymphoma is misleading – historical name Warthin named it when he discovered it).
 Epidemiology - 2nd most common.
• Males > females – 50-70 years old.
• Increased risk for smokers – 8 times more than non-smokers.
 Pathology – arises almost exclusively in the parotid gland.
• Macroscopy – pale-grey, with cysts filled with mucous or serous. Generally rigid, but if the number of cysts is high, it’s softer.
• Microscopy – encapsulated mass of cysts coveres by a double layer of eosinophilic neoplastic epithelial cells, resting on a dense lymphoid stroma, sometimes with germinal centers.
Upper layer – columnar epithelium which is granular (due to many mitochondria – featured known as “oncocytic”). These are the secretory cells, responsible for secreting mucous / serous into the cyst.

Lymphocytes stroma with germinal centers.
Mucous / serous
Lower layer: cuboidal epithelium
3. Morphomorphic adenomas – in contrast to pleomorphic adenoma, these are composed of single cell types. These are rare, and include:
 Oncocytoma – composed of oncocytes (granular, eosinophilic cells – due to high level of mitochondria). Were discovered first in the thyroid gland.
 Basal cell adenoma.
 Canalicular adenoma.
 Ductal papillomas.
These are all solid in consistency.

Malignant tumors:
Generally are low-grade carcinomas, with low metastatic potential (but still can be also intermediate or high grade).
1. Mucoepidermoid carcinoma – malignant tumor composed of 2 types of epithelial cells – mixture of squamous cells and mucous secreting cells. It has 2 varietns, one has a low-grade malignancy, while the pther has high-grade malignancy.
 Epidemiology – most common malignant salivary gland tumor.
 Pathology – usually arises in the parotid, commonly involves the facial nerve.
• Macroscopy – white-grey in cross-section.
• Microscopy – lack capsule, mixture of squamous and mucous-secreting cells, contain mucous-filled cysts.
2. Adenoid cystic carcinoma (cylindroma) – malignant tumor of epithelial cells of ducts and myoepithelial cells.
 Pathology – 50%-50% in minor glands and major glands.
• Microscopically – ductal epithlial cells and myoepithelium are arranged in duct-like structures, creating cribriform appearance - cylindromas (but be careful, there is also cylindroma of sweat glands, which is totally different – benign tumor of sweat glands), these have typical cyst-like spaces, containing PAS-positive basopihilic material.
The spaces between the tumor cells are filled with hyaline material, represent excess basement membrane.
3. Acinic cell carcinoma – uncommon - composed of cells resembling the normal serous acinr cells of salivary glands. Mostly in the parotid.

Question 11

Tumors of the oesophagus

Answer 11

Most common tumors are cancers, either adenocarcinoma or squamous cell carcinoma. Benign tumors are uncommon.
Benign:
Mesenchymal:
1. Leiomyoma – most common benign tumor of the esophagus.
2. Lipomas, fibromas, neurofibroma, rhabdomyoma, hemangioma, and lymphangioma.
Epithelial:
Project as intraluminal masses:
1. Squamous cell papilloma – arising from squamous epithelium.
2. Adenoma – arising from columnar epithelium of glands.

Malignant:
Esophageal carcinoma: - most important.
These in general have low metastatic potential, but are considered very aggressive due to local invasion into the mediastinum which is almost incurable. Most people don’t survive for a long time.
Pateints present with – progressive dysphagia – starts as dysphagia for solids and progresses to dysphagia for both solids and liquids, weight loss, pain, and hematenesis.
1. Adenocarcinoma – most common in western countries, mostly arise from Barret’s esophagus – as the metaplastic intestinal epithelium is considered as a gland → thus it occurs in the lower 1/3 of the esophagus.
- Epidemiology – risk factors – smoking and obesity. Conversly, risk is reduced by diet eich in fresh fruits and vegtables, and by some serotypes of H. pylori infections, due to causing gastric atrophy → which in turn lead to reduced acid secretion and reflux.
- Pathology:
 Macroscopy:
• Early – flat or raised patches of neoplastic masses.
• Later – may ulcerate and invade deeply.
 Microscopy:
• Barret esophagus – seen adjusent to the tumor.
• Tumor form glands – which produce mucus.
- Less than 25% if metastasis and 80% if non invasive.
2. Squamous cell carcinoma – most common esophageal cancer in developing countries/worldwide – malignant proliferation of squamous cells, usually arises in the upper and middle third of the esophagus.
- Epidemiology – men > women.
 Risk factors – basicaly, any irritation of the esophageal mucosa:
• Smoking – most common cause.
• Alcohol.
• Hot drinks.
• Achalasia – when the esophagus is full of food it irritates the mucosa.
• Esophageal web + Plummer Vinson syndrome – blocks food → pile up → irritation.
• Esophageal injury.
Pathology:
 Macroscopy – 3 types of patterns:
• Polypoid fungating – most common, flower-like friable mass protruding into the lumen.
• Ulcerating - 2nd common, looks like necrotic ulcer with everted edges.
• Diffuse infiltrating type – annular stenosing narrowing of the lumen.
 Microscopy:
• Start as carcinoma in situ – intraepithelial neoplasia.
• Moderately to well differentiated cells.
 Metastasis – tumors in upper third – metastasize to cervical lymph nodes, tumors in middle third – to mediastinal or tracheobronchial lymph nodes, lower – to celiac or gastric nodes.
- Clinically – in additional to the wrriten above, these also have hoarse voice – due to invasion of the tumor to the recurrent laryngeal nerve, and cough – du to invasion to the trachea.
- This is critical, because 5-year survival rates are 75% in individuals with superficial esophageal squamous cell carcinoma but much lower in patients with more advanced tumors.

Question 12

Neoplasms of the stomach

Answer 12

Pseudotumors:
1. Hyperplastic polyps – most common – associated with chronic gastritis, which initiates the injury that leads to reactive hyperplasia and polyp growth. Incidence increases with H. pylori infections, and its eradication results in polyp regression. Mostly benign, cut risk of dysplasia correlates with size – polyps larger than 1.5 cm should be resected.
- Macroscopy – mostly larger than 1 cm, frequently multiple, ovoid with smooth surface/erosion.
- Microscopy – dilated hyperplastic glands, edematous lamina propria, ± surface ulceration.
2. Fundic gland polyps – occur either sporadically or in individuals with familial adenomatous polyposis. Their prevalence has increased due to usage of proton pump inhibitors → which lead to gastrin secretion → and thus gland growth. Potential dysplasia and transformation to cancer may occur in FAP-associated polyps.
- Macroscopy – in body or fundus, well circumscribed, with smooth surface, single / multiple.
- Microscopy – cystically dilated irregular glands lined by flattened parietal and chief cells.
Epithelial neoplasms:
Benign: - These are rare compared to carcinomas.
1. Adenomas (Adenomatous polyp) – true benign neoplasms, almost always occur on a background of chronic gastritis with atrophy and intestinal metaplasia. Increased risk in individuals with FAP, men > women. Risk for adenocarcinoma is increased in lesions > 2 cm. Precancerous, with higher risk for malignancy than in intestinal adenomas.
- Macroscopy – solitary, usually less than 2 cm, mostly in antrum.
- Microscopy – intestinal-type columnar epithelium, varying degrees of dysplasia (low-high grade).
Malignant:
1. Gastric adenocarcinoma – most common, 90% - malignant proliferation of surface epithelial cells. often (90%) asymptomatic, or have early symptoms resemble to chronic gastritis and PUD, including – weight loss and anorexia, epigastric abdominal pain mimicking peptic ulcer, occult bleeding and iron deficiency anemia, early satiety – thus they are often discovered in advanced stages.
- Epidemiology:
 Incidence – decreased in the USA, increased in Japan (related to smoked food).
- Pathology – we can divide gastric carcinoma into 2 types:
 Intestinal type – most common, primarily in the antrum.
• Risk factors:
 Intestinal metaplasia – associated with H. pylori.
 Nitrosamines in smoked food – carcinogens found in smoked food. Mainly in Japan.
 Smoking.
 Blood group type A.
 Achlorhydria.
 Chronic gastritis.
• Pathogenesis – mostly loss-of-function mutation of APC and gain-of-function mutation of β-catenin.
• Macroscopy – gastric tumors with intestinal morphology, composed of glandular structures:
Early carcinoma:
 Polypoid – forming exophytic mass, which depending on its invasion can be:
o Intramucosal – good prognosis.
o Submucosal – worse prognosis.
 Ulcerated - Large, irregular ulcer with heaped-up margins, most commonly in the lesser curvature of the antrum.
o Worse prognosis.
Advanced carcinoma – invasion reaches the muscularis externa → necrosis → perforation → peritonitis.
• Microscopy – intestinal gland-forming cells invade through the stroma.
 Diffuse type – much less common, all the stomach is involved.
• Risk factors – not associated with H. pylori, intestinal metaplasia, nor nitrosamines.
• Pathogenesis – loss-of-function mutation in CDH1 gene coding for E-cadherin.
of diffuse gastric cancer.
• Macroscopy – composed of signet-cells that diffusely infiltrate the gastric wall (not glands).
 Linitis plastica – thickening of the stomach wall due to desmoplasia – reactive response of the wall stroma, fibrous tissue and blood vessels that result in wall thickening. When there are large areas of infiltration, diffuse rugal flatterning + thickened wall impart a leather bottle appearance – linitis plastica.
 Loss of peristalsis.
• Microscopy – diffuse infiltration of signet-cells – don’t form glands, but instead have large mucus vacuoles that expand the cytoplasm and push the nucleus to the periphery. Loss of E-cadherin is a key step in development These cells spread diffusely probably due to the loss of E-cadherin.
- Clinically – presents late – initially (90%) asymptomatic, or have early symptoms resemble to chronic gastritis and PUD → thus they are often discovered in advanced stage.
 Weight loss and anorexia.
 Epigastric abdominal pain – mimicking peptic ulcer.
 Anemia – iron deficiency anemia and occult bleeding.
 Early satiety – classic in the diffuse type - due to the thickening of the wall, the stomach can’t expand and the patient feels full.
- Complications – metastasis – sites most commonly involved are:
 Virchow node – left supraclavicular node.
 Sister Mary Joseph nodule – metastasis to periumbilical region, causing subcutaneous nodule. Seen with the intestinal type.
 Krukenberg tumor – bilateral metastasis to the ovaries, infiltration of signet cells – seen with the diffuse type.
 Liver – most commonly involved site.
 Peritoneum, bones, lungs.
- Diagnosis – metastasis are often detected at time of diagnosis.
 Paraneoplastic skin lesions:
• Acanthosis nigricans – thickening and darkening of the skin mainly in the axillary region. Rare.
• Leser Trelat sign – multiple seborrheic keratosis over their skin.
Biopsy – depth of invasion.
- Treatment – chemotherapy, radiation, surgery if possible in early stages.
- Prognosis – the depth of invasion and the extent of nodal and distant metastases are the most powerful prognostic indicators.
 5 year survival rate – less than 30%. If surgical resection is possible, it jumps to 90%.
2. Gelatinous carcinoma – rare, has macroscopic appearance of gelatin due to mucous production.

Lymphomas:
Extranodal lymphomas:
1. MALTomas – Marginal zone B-cell lymphomas. Most common. These usually arise at sites of chronic inflammation, thus in the stomach they usually result from chronic gastritis. H. pylori infection is the most common nducer, while its eradication results in remission.
 Microscopy – diagnostic lymphoepithelial lesions – neoplastic lymphocytes infiltrate gastric glands.
2. Diffuse large B-cell lymphomas. – progression from MALTomas.

Neuroendocrine neoplasms:
1. Carcinoid tumor – well-differentiated neuroendocrine tumors, mostly found in the small intestine (respiratory system is next in frequency). Quite rare in the stomach, and associated with other conditions – endocrine cell hyperplasia, MEN-I, and Zollinger-Ellison syndrome. Symptoms depend on the hormone they produce – tumors that produce gastrin may cause Zollinger-Ellison syndrome, while ileal tumors may cause carcinoid syndrome. However they have a very low-grade malignancy (almost benign).
- Carcinoid syndrome – vasoactive substances (e.g., serotonin) are secreted by the tumor to the circulation. If the tumor is confined to the intestine, and released to the portal system – the vasoactive substances are inactivated by the liver. However, if the tumor metastasize to the liver, it can release the substances directly to the systemic circulation → may go to the heart → cause carcinoid heart disease – fibrosis of the right-heart valves, manifested by tricuspid regurgitation and pulmonary valve stenosis. If it didn’t metastasize and the serotonin just got to the liver, the only thing we will see is increase in 5-HIAA in urine → the breakdown metabolite of serotonin (by MAO enyme). Carcinoid syndrome is classically present at: bronchospasm, diarrhea, and flushing of the skin. These symptoms are triggered by drinking alcohol and by emotional stress.
- Macroscopy – polypoid lesions – intramural or submucosal masses that create polypoid lesions, yellow or ten in color, very firm (due to intense desmoplastic reaction) → may case obstruction.
- Microscopy –
 Nodule – composed of tumor cells embedded in dense fibrous tissue.
 Islands or strands of neoplastic cells.
 Cells – eosinophilic granular cytoplasm, with round nucleus and points of chromatin, described as “salt and pepper”.
- Prognosis – depends on location:
 Foregut tumors – esophagus, stomach, and duodenum – rarely metastsize and generally cured with resection. If it’s associated with atrophic gastritis it’s less aggressive, if it’s not – more aggressive.
 Midgut tumors –jejunum and ileum – aggressive – greater invasion, larger.
 Hindgut tumors – appendix and colon. Uncommon to metastasize.
2. Neuroendocrine carcinomas.
3. Small cell carcinoma.
Mesenchymal tumors:
1. Gastrointestinal stromal tumor (GIST) – most common, more than half in the stomach – arise from the interstitial cells of Cajal – pacemaker cells of the gastrointestinal myenteric system. Can be benign, border-line or malignant.
- Epidemiology – average – 60 years old.
- Pathogenesis – gain-of-function mutation in receptor tyrosine kinase KIT.
- Pathology:
 Macroscopy – very large (up to 30 cm), solitary, well circumscribed fleshy mass – covered by intact epithelium or ulcerated. Metastasis (in tumors larger than 10 cm) can be multiple serosal nodules throughout the peritoneum or liver.
 Microscopy – can be of 2 types depending on type of cells:
• Spindle cell type – elongated cells.
• Epithelioid type – epithelial appearing cells.
Can also be mixed.
- Complications:
 Blood loss + anemia – in case the mass is ulcerated.
 Obstruction.
- Diagnosis – immunohistochemistry detecting KIT.
- Treatment – complete resection.
2. Leiomyomas / leiosarcomas.
3. Lipomas.

Question 13

Neoplasms of the intestines

Answer 13

Polyps:
Polyp – any growth or mass arising from the mucosal epithelium (some may also arise from submucosal or mural mass) and protruding into the lumen. Polyps are most common in the colo-rectal region but may occur anywhere in the GIT. Macroscopically, polyps can be:
- Stalked (pedunculated) – having protruding stalk (fibrous connective tissue with vessels) ending with a pedunculated head.
- Sessile – without a stalk, head grows directly on the surface. May become stalked.
Intestinal polyps are classified into 3 major groups:
1. Non-neoplastic.
2. Neoplastic.
3. Polypoid deep-seated neoplasms.
Non-neoplastic:
Most common, and farther sub-classified into:
1. Hyperplastic polyp – most common among all polyps – arise due to epithelial hyperplasia at the base of the crypts (hyperplasia of glands, where stem cell are), resulting from decreased epithelial turnover and delayed shedding of the surface epithelium → leading to “piling up” of enterocytes and goblet cells.
Benign with no malignant potential.
 Location – usually arise in the left colon – rectosigmoid portion.
 Macroscopy – sessile or stalked, smooth, typically less than 5 mm.
 Microscopy – Serrated appearance – “tooth-like” – thus, must be distinguished from sessile serrated adenomas that are histologically similar but have malignant potential.
2. Hamartomatous polyps – growth of normal colonic tissue with disordered architecture. In general, are solitary nodules without a significant risk or transformation, but it’s possible. 2 important:
 Juvenile polyps – most common in children < 5 – focal malformation of the epithelium and lamina propria, due to mucosal hyperplasia.
• Location – rectum – typically present with rectal bleeding.
• Pathology – 2 possible forms:
 Sporadic juvenile polyposis – solitary polyps, with very rare chance for dysplasia.
 Juvenile polyposis syndrome – AD, multiple polyps, may require colectomy to limit the chronic bleeding associated with their ulcerations. Associated with dysplsia → 30%-50% of patients develop colonic adenocarcinoma by the age of 45.
 Macroscopy – typically pedunculated, smooth, reddish, with cystic spaces on cut-section.
 Microscopy – these cysts are dilated glands filled with mucin and inflammatory debris.
 Peutz-Jeghers syndrome – rare AD, around 10-15 years of age, presents with multiple hamartomatous polyps in the small bowel (less common in stomach and colon), and mucosal hyperpigmentation of the buccal mucosa and lips. Increased risk (>50%) for malignancies - colorectal, breast, and gynecologic cancers.
• Pathology:
 Macroscopy – multiple, large, pedunculated with lobulated contour polyps.
 Microscopy – network of connective tissue, glands, and smooth muscle – that is in a tree like branching originating from the muscularis mucosa → this help to distinguish it from juvenile polyps. All this is lines by normal-appearing intestinal epithelium

3. Inflammatory polyps (pseudopolyps) – polyps forming from chronic cycles of injury and healing, such as seen in ulcerative colitis (healing of the ulcers). Classically seen in solitary rectal ulcer syndrome – due to impaired relaxation of the anorectal sphincter, here is reccurent abberations and ulcerations of the underlying mucosa → polypos are formed due to the healing process.
    Microscopy – include inflammatory infiltrates, epithelial hyperplasia, and superficial erosions – typical or inflammatory polyps.
   Neoplastic:
   The most common neoplastic polyps are adenomas, 2nd most common type of colonic polyp (rectum, sigmoid, rare in small intestine) - neoplastic proliferation of glands, benign, but premalignant → may progress to adenocarcinoma via the adenoma-carcinoma sequence (see later). Colorectal adenomas are characterized by the presence of epithelial dysplasia.
   Adenomas have 3 main varieties based on histology:
4. Tubular adenoma (adenomatous polyp) – most common – mostly in the sigmoid colon. May be asymptomatic or have rectal bleeding. Best prognosis.
    Macroscopy – usually small (<1cm), pedunculated polyps, look like a mushroom.
    Microscopy – adenomatous polyp is composed of:
   • Neoplastic epithlieum – surface epithelium – seen much darker than the normal glands (loose ability to produce mucus).
   • Tubular glands - in the lamina propria.
   • Dysplasia – glands are lined by dysplastic epithelium (nuclear pleomorphism, enlarged with bizzare shape, changed plasma:nucleus ratio, pseudostratification of surface epithelium.
   • Core of submucosa.
5. Villous adenoma – less common – in rectosigmoid, always symptomatic – rectal bleeding and diarrhea. Worst prognosis (higher chance for transformation).
    Macroscopy – sessile.
    Microscopy:
   • Papillae – finger-like projections, each with a fibrovascular stromal core.
   • Dysplasia – as described above. varied from benign to anaplastic cells.
6. Tubulovillous adenoma – intermediate between tubular and villous:
    Macroscopy – sessile or stalked.
    Microscopy – mixed pattern of villi, having tubular glands in the deeper parts.
   Risk factors for malignancy transformation:
   - Adenoma > 2cm – 40% risk of malignancy.
   - Multiple polyps.
   - Sessile polyps.
   - Polyps with increased villous component – 40% risk of malignancy.
   Transformation to adenocarcinoma – adenoma → dysplasia → carcinoma in situ → intramucosal carcinoma → submucosal invasion by carcinoma → carcinoma with deep invasions.
   If the neoplastic cells destroy the muscularis mucosa then it’s carcinoma!!!If not, it’s still adenoma – if we succeed to remove it completely before it reaches blood vessels – we cure the patient.
7. Sessile serrated adenomas – different type, overlap histologically with hyperplastic polyps, but are more commonly found in the right colon. Have malignant potential even though they lack dysplasia that is present in other adenomas. Histologically they have serrated architecture (“saw-tooth”) throughout the all length of the glands including the crypts. Arise due to CpG hypermetylation of MSI pathway (see later) and mutation in BRAF.
   Screening for polyps:
   Adenomas occur mostly after the age of 60 – thus it’s recommended that all adults after 50 will undergo surveillance (especially if there is family history).
   - Colonoscopy – go in and look for the polyps → all polyps are removed and examined microscopically.
   - Test fecal occult blood – because sometimes the polyps bleed (mostly asymptomatic).
   The goal is to remove all these polyps before it progresses to carcinoma.

Familial Adenomatous Polyposis (FAP):
AD disorder characterized by 100s-1000s of adenomatous (tubular) colonic polyps, due to inherited mutation of APC (tumor-suppressing gene
Epidemiology – polyps develop between 10-20 years of age, malignant transformation to colorectal carcinoma develops in 100% of untreated patients between 30-50 years of age.
- Diagnosis – recognition of at least 100 polyps.
- Treatment – prophylactic colectomy – colon and rectum are removed.
- Associations – FAP together with some specific associations create new dosorders:
 Gardner syndrome – FAP with fibromatosis (non-neoplastic proliferation of fibroblasts, usually arises in the retroperitoneum and is locally destructive) and osteomas (benign tumors of bones usually arises in the skull).
 Turcot syndrome – FAP with CNS tumors, especially medulloblastomas and glial tumors (astrocytomas).

Colorectal Adenocarcinoma:
Adenocarcinoma arises from the colonic or rectal mucosa.
- Epidemiology – 3rd most common cancer, and 3rd most common cancer related to death.
 Age – 60-70 years old. Decreasing in incidence due to screening. 25% with family history.
 Risk factors:
• Diet - Low-fiber diet + diet low in fruits and vegetables + high meat consumption.
• Smoking.
• Adenomatous polyposis coli.
• Hereditary nonpolyposis colon cacer (Lynch syndrome, see later).
• Ulcerative colitis – in general IBD, but UC > CD.
NSAIDS (especially aspirin) – have protective effect – due to inhibition of COX-2, see later.
- Pathogenesis – 2 important molecular mechanisms contribute to adenocarcinoma developmet:
 Adenoma-carcinoma sequence – APC/β-catenin pathway – 80% of sporadic colon cancers – APC is a negative regulator of β-catenin. Both copies of APC must be inactivated:
1) APC mutation – causes risk (no morphological changes yet) for development of a polyp. By the Knudson hypothesis, the 2 copies must be inactivated (“first and second hit”), thus:
 Somatic mutation (acquired) – requires inactivation of the 2 copies during life.
 Germline mutation (inherited) – inherit one mutated copy → higher risk, need to acquire only 1 mutation of the only normal copy they have.
With loss of APC, β-catenin translocates to the nucleus where it activates transcription of genes (MYC, cycline D1) that promote proliferation.
2) KRAS mutation – promote development of the polyp – promote growth and prevents apoptosis.
3) TP53 mutation + ↑COX expression – promote development of carcinoma. Because ↑COX is important, aspirin is protective against this sequence. COX-2 is necessary for production of PGE2, which promotes epithelial proliferation, particularly after injury.
 Microsatellite instability (MSI) pathway - occurs in patients with mismatch repair defect, resulting in accumulation of mutations in microsatellites repeats, condition known as MSI. Mutations of microsatellites found promotor regions of specific genes cause troubles:
• Promotor of TGF-β receptor - result in its inability to response to TGF-β signal, which is supposed to inhibit epithelial proliferation.
• Promotor of the proapoptotic BAX – loss of BAX enhance the survival of neoplastic cells.
Germline mutation of mismatch repair cause Hereditary Non-Polyposis Colorectal Cancer (HNPCC) – see later.

• Pathology – cancer can arise anywhere along the entire length of the colon, mostly rectosigmoid > ascending > descending:
   Right sided carcinomas – proximal colon (cecum + ascending colon) - grow as polypoid exophytic masses, they tend to bleed (seen in stool, and involved with iron deficiency anemia). The right side is wider than the left side, thus it’s not obstructed easily, and thus it tends to bleed.
  Usually associated with the MSI pathway.
   Left sided carcinomas – distal colon – rectum and sigmoid – form circumferential, annular lesions around the caliber of the lumen that produce “napkin-ring” constrictions (“napkin-ring” lesions – seen as ween a napkin is put in a ring) → causing luminal narrowing and thus tend to obstruct. An important sign is decreased stool caliber (as the stool pass through the constriction, its diameter becomes thinner).
  Usually associated with the adenoma-carcinoma sequence.
   Microscopy – right and left-sided are similar histologically:
  • Dysplastic epithelium – of tall columnar cells resemble this of adenomas → on the surface still adenomas can be seen.
  • Invasion beyond the muscularis mucosa – show glands deeper in the wall and, elicit a strong stromal desmoplastic response, which is responsible for their firm consistency, and tend to constrict the left side.
• Complications:
   Increased risk for Streptococcus bovis endocarditis – so if we see that a patient has endocarditis, and S. bovis in the blood, we have to think about colorectal carcinoma.
   Mucinous carcinoma – rare – the tumor cells produce abundant mucin (opposite than the normal that lack the ability to produce mucin) that accumulates within the intestinal wall giving it a shiny appearance. These are associated with poor prognosis.
   Obstruction – intestinal stenosis.
   Bleeding – leading to iron deficiency anemia.
   Necrosis – leading to perforation → and stercoral peritonitis.
   Metastasis – liver (most common), lymph nodes, peritoneum, lungs, bones, and brain.
• Diagnosis – screening >50, or >40 if 1st degree relative had polyps/cancer.
   Colonoscopy – together with biopsy.
   Feccal occult blood.
   Fecal immunechemical test – uses antibodies to detect globin.
   Fecal DNA test – human DNA is extracted in stool, DNA alterations are tested.
   CEA serum marker – useful for assessing treatment response and detecting recurrence, but not for screening.
   “Apple core” – seen on barium enema x-ray or left-sided carcinoma.
• Prognosis – done by all means, (typing, grading) but staging is most important:
   T – depth of invasion , N – spread to regional lymph nodes, M – metastasis – in case of metastasis, prognosis is poor.
  Hereditary Non-Polyposis Colorectal Cancer (HNPCC) = Lynch Syndrome:
• Hereditary - occurs due to a mutation in the DNA mismatch repair enzymes. Occurs at younger ages.
• ## Non-polyposis – means that the carcinoma arises de novo, without a previous development of carcinoma.Explain carcinoid syndrome, from question 73
  Colorectal cancer – emphasizes the increased risk for colorectal carcinoma, but also to ovarian and endometrial carcinomas.
  Proximal colon is always involved.
  Neuroendocrine neoplasms: - can be described depending on their grade:
  1. Well-differentiated neuroendocrine tumor (NET G1) – Carcinoid tumor – malignant proliferation of neuroendocrine cells with low-grade malignancy. Positive for chromogranin. Small bowel is the most common site (but can occur in all the GIT and lungs), grows as submucosal polyp-like nodules.
  2. Well differentiated neuroendocrine carcinoma (NET G2) – Malignant carcinoid.
  3. Poorly differentiated neuroendocrine carcinoma (NEC) – large cell, and small cell carcinoma – occurs mostly in the lungs, the worst form of these neuroendocrine neoplasms.
  Tumors of the appendix:
  Most common tumor of the appendix is carcinoid tumor.

Question 14

Neoplasms and pseudotumors of the liver and intrahepatic biliary tree

Answer 14

Pseudotumors:
1. Nodular hyperplasias – nodular masses of hepatocytes of unknown causes, probably due to alterations in hepatic blood supply (congenital or acquired) – obliteration of small branches of portal vein, with compensation of arterial blood supply. Usually incidental finding. 2 such conditions are:
- Focal nodular hyperplasia (FNH):
 Epidemiology – mostly in young women.
 Pathology – appears in a normal liver.
• Macroscopy – usually solitary.
 Well-demarcated but poorly encapsulated mass - of a few centimeters.
 Central depressed stellate scar – from which fibrous septa radiate to the periphery, and contain blood vessels (arteries).
• Microscopy – broad scar with arteries separating regenerating nodules – however – this is not cirrhosis because it’s focal! (While cirrhosis is always diffuse).
- Nodular regenerative hyperplasia – liver transformed entirely into nodules, macroscopically look like micronodular cirrhosis – but without fibrosis. It occurs in association with conditions that affect the hepatic blood supply, particularly in renal transplantation. Can lead to portal hypertension.
2. Hepatic cysts – mainly of 3 types:
- Congenital cysts – uncommon, usually small (<1cm) and lined by biliary epithelium. May be single or occur as polycystic liver disease (associated with polycystic kidney).
- Simple (Non-parasitic) cysts – occur in women, solitary, large (up to 20 cm) cyst under the (Glisson’s capsule – C.T capsule of the liver) lined by biliary-type epithelium (⁓cuboidal). It produces a palpable mass.
- Hydatid cysts (Echinococcosis)– parasitic cyst as a result of infection by the tapeworm Echinococcos granulosus transmitted to humans feco-orally from dogs. It reaches the liver (which is the first filter for them) and develop there (or if continues, stops in the lungs and develop there). The cyst has 3 layers:
 Pericyst – outer host inflammatory reaction.
 Ectocyst – intermediate layer of hyaline material.

Biopsy is contraindicated due to risk of hemorrhage.
Endocyst – inner layer lined by epithelial-like cells containing daughter-cysts.


Biopsy is contraindicated due to risk of hemorrhage.
Endocyst – inner layer lined by epithelial-like cells containing daughter-cysts.
Benign tumors:
1. Cavernous hemangiomas – most common – mash of cavernous spaces, generally asymptomatic but rarely rupture and bleed into the peritoneal cavity.
- Macroscopy – red-purple-blue soft nodules < 2 cm, with a spongy appearance (due to caverna), usually directly beneath the capsule.
- Microscopy – cavernous blood-filled spaces lined by a single layer of endothelium and separated by fibrous connective tissue.
2. Hepatocellular adenoma – benign neoplasms developing from hepatocytes.
- Epidemiology – women > men. Caused by:
 Oral contraceptives (estrogen)– 30-40 fold higher risk. It regresses upon cessation. But actually there are 3 types of them, and only some are associated. However, we didn’t know them before the use of oral contraceptives.
 Anabolic steroids.
 Von Girke glycogenosis – glycogen storage disease. Unknown why it’s associated.
- Pathogenesis – 3 subtypes based on mutations, with different malignancy potential. See later.
- Pathology – never in cirrhosis – thus if there is cirrhosis it’s a suspicion for carcinoma.
 Macroscopy – usually solitary, up to 30 cm, encapsulated, well defined.
 Microscopy – resemble normal liver but lack portal tracts. Based on different mutations:
• HNF1-α – associated with steatosis and accumulation of glycogen – no metastatic potential.
• β-Catenin – have high degree of hepatocytes dysplasia → risk for malignancy.
• Inflammatory – some fibrosis + telangiectatic vessels, associated with NAFLD. No malign.
- Complications – tendency to rupture in pregnancy → intraperitoneal hemorrhage.
3. Bile duct adenoma (cholangioma) – rare intrahepatic or extrahepatic bile duct benign tumor.
Malignant tumors:
Malignant tumors of the liver can be primary or metastatic.
1. Hepatocellular carcinoma (Hepatoma) – malignant tumor of hepatocytes.
- Epidemiology – most common primary liver cancer in adults.
 Risk factors:
• Chronic hepatitis – particularly HBV and HCV infections.
• Cirrhosis – thus any disease leading to cirrhosis – alcoholic and NALD, Wilson disease, hemochromatosis, α1-antitrypsin deficiency…
• Aflatoxins derived from aspergillus – aspergillus molds grow on certain food (greins, vegetables) as they start to decay, and produce aflatoxins on it. When this is eaten and metabolized in the liver, it binds DNA and induces p53 mutation.
In general – HCV > alcoholic cirrhosis > HBV.
 Precursor lesions – lesion found in chronic liver diseases show cellular dysplasias and have high chance for transformation:
 Large cell change – larger than normal hepatocytes but with normal cytoplasm:nucleus ratio.
 Small cell change – hepatocytes have high nuclear:cytoplasm ratio.
 Low grade dysplastic nodules.
 High grade dysplastic nodules.
Pathogenesis – mostly caused by conditions in which the liver is in continues cycle of damage and repair → raising the chance for development of mutations (thus any disease leading to cirrhosis). Common mutations are activation of β-Catenin and inactivation of p53.
- Pathology:
 Macroscopy – HCC has 3 types of growth, in decreasing order of frequency:
1) Unifocal large mass – single yellow-brown mass with central necrosis/hemorrhage/bile.
2) Multifocal masses – multiple masses scattered throughout the liver.
3) Diffuse infiltrating – diffusely spread throughout the liver.
Pale compared to surrounding liver, with irregular borders.
 Microscopy – different histologic patterns (decreasing order):
1) Trabecular (sinusoidal) – trabeculae of neoplastic cells (groups) separated by vacular spaces (sinusoids) which are endothelial-lined (looks like they got farther from sinusoids).
2) Compact – neoplastic cells form large masses without inconspicuous sinusoids.
3) Scirrhous (fibrolamellar carcinoma) – characterized by more abundant fibrous stroma.
 Cytologic features – cells resemble hepatocytes characterized by neoplastic features (pleomorphism, large nuclei…) and also:
• Eosinophilic cytoplasm – becomes basophilic with increasing malignancy.
• Bile, fat.
- Clinically – very non-specific and symptoms of cirrhosis often mask to progression of carcinoma → thus HCC has poor prognosis.
 Over 1/3 are asymptomatic.
 Abdominal pain – common initial presentation.
 Rapid enlargment of the liver
 Cirrhosis symptoms – with increased ascites and blood in the fluid.
- Complications:
 ↑ Risk for Budd-Chiari symdrome – HCC tends to invade the hepatic veins and block them. This may lead to liver infarction and present with painful hepatomegaly and ascites.
 Metastasis – hematogenous spread - most common to the lungs.
- Diagnosis:
 ↑ α-fetoprotein (AFP) – produced by the tumor cells
 ↑ ALT and GGT – sudden increase in these enzymes is a characteristic finding in HCC.
 ↑ Ectopic hormones – produced by tumor cells – EPO, PTH, and insulin-like hormone.
 CT, US, MRI and angiography – shows tumor vascularity.
- Treatment:
 Surgery removable – in ⁓ 20% of cases – even then 5 years survival of 30-50%.
 Liver transplantation.
 Radiation and chemotherapy are usually not helpful.
2. Cholangiocarcinoma (CCA) – adenocarcinoma - malignant tumor arising from intra- or extrahepatic bile ducts.
 Intrahepatic – only 10% of cholangiocarcinomas.
 Extrahepatic – 90% - include 2 forms:
• Perihilar – Klarskin tumors – located at the junction of the right and left hepatic ducts.
• Common bile duct tumors.
- Epidemiology – 2nd most common primary tumors of the liver.
 Risk factors – all related to chronic inflammation and cholestasis.
• Primary sclerosing cholangitis – most common cause in the USA.
• Clonorchis sinensis (liver fluke).
• Thorotrast – thorium dioxide.
• Cysts of the biliary tree – choledochal cysts or Caroli disease.
- Pathogenesis – inflammation and cholestasis promote somatic mutations in cholangiocytes.
- Pathology:
Macroscopy - tumor is firm and whitish-greyish.
 Microscopy – adenocarcinoma - invasive malignant glands in stoma with desmoplastic reaction.
- Clinically – poor prognosis – ⁓ 6 months from diagnosis to death because usually detected late.
 Obstructive jaundice.
 Hepatomegaly.
- Diagnosis – US, ERCP.
- Treatment – surgery – but even then has poor prognosis.
3. Hepatoblastoma (embryoma) – rare, but most common liver tumor of early childhood (< 3). The tumor grows rapidly and causes death by hemorrhage, hepatic failure, or metastasis.
- Pathology:
 Macroscopy – circumscribed lobulated mass of 5-25 cm in diameter.
 Microscopy – hepatoblastoma consists of 2 components in varying proportions:
• Epithelial component – contain 2 types of cell “embryonal hepatocytes” which are smaller and darker stained, and “fetal hepatocytes” which are larger and lighter stained.
• Mesenchymal component – includes fibrous connective tissue, cartilage, and osteoid.
Frequently associated with Familial adenomatous polyposis due to relation to the APC gene.
4. Angiosarcoma – malignant tumor of endothelial origin, associated with exposure to arsenic and vinyl chloride. Aggressive with poor prognosis.
5. Metastasis to the liver – (secondary hepatic tumors) - much more common than primary tumors of the liver.
- Most common arise from – GIT, lungs, and breast.
- Pathology:
 Macroscopy – multiple nodular masses → cause hepatomegaly and a very heavy liver. On physical examination it’s possible to feel the nodules on the free edges of the liver.
 Microscopy – neoplastic cells resemble those of the primary tumor.

Question 15

Neoplasms of gall bladder and extrahepatic biliary tree

Answer 15

Benign tumors – are very rare and can be – papilloma, adenoma, fibroma, lipoma, myxoma, and hemangioma.

Malignant:
1. Gallbladder carcinoma – most common – arising from gallbladder epithelium that lines the gallbladder wall.
- Epidemiology:
 Elderly women – classically with cholecystitis.
 Risk factors:
• Cholelithiasis + cholecystitis – 95% of cases. However, only 1% of patient with gallstones develop it.
• Porcelain gallbladder – especially high risk – gallbladder with dystrophic calcification ⁓ 50% risk for progression to cancer, thus requires immediate surgical removal of the GB.
• Chemical carcinogens – nitrosamines and pesticides.
• Genetic factors – higher incidence in certain populations.
- Pathology – commonest sites are – fundus > then neck of gallbladder.
 Macroscopy – 2 types:
• Infiltrating – irregular area of diffuse thickening and induration of the bladder wall. May have deep ulcerations that can invade the wall and the liver.
• Exophytic – “fungating” – irregular growth into the lumen and at the same time invades the wall.
 Microscopy – can be of the following patterns:
• Adenocarcinomas – most (90%) – papillary or infiltrative, well or poorly-differentiated.
• Squamous cell carcinomas – 5% - arising from squamous metaplastic epithelium.
• Adenosquamous – combination.
• Others – carcinoid, or combined carcinomas with sarcomas (carcinosarcomas).
- Clinically – poor prognosis – majority have already locally invaded the liver and metastasize when discovered. If symptomatic, it’s the same symptoms associated with cholelithiasis – abdominal pain, jaundice, anorexia, nausea, vomiting.
 Metastasis – high potential - lymph nodes, peritoneum.
 5 year survival rate < 2%.
- Treatment – surgery – when possible.
2. Carcinoma of Extrahepatic bile ducts and Ampulla of Vater –
- Epidemiology - rare (but still more common than the benign ones).
 Males > females – which is different than other disease of the biliary passages.
 Risk factors:
• No association with gallstones.
• Ulcerative colitis, sclerosing cholangitis, parasitic infections.
- Pathology – extrahepatic bile duct carcinoma may arise anywhere in the biliary tree but the most frequent sites are: ampulla of Vater > distal common bile duct > hepatic ducts.
 Macroscopy – small, 1-2 cm, thickening of the affected duct.
 Microscopy – usually well-differentiated adenocarcinoma, with frequent perineural invasion. (also occur in prostate)
- Clinically – obstructive jaundice + pruritus. Metastasis to regional lymph nodes.
3. Cholangiocarcinoma (CCA) – adenocarcinoma - malignant tumor arising from intra- or extrahepatic bile ducts.
 Intrahepatic – only 10% of cholangiocarcinomas.
 Extrahepatic – 90% - include 2 forms:
• Perihilar – Klarskin tumors – located at the junction of the right and left hepatic ducts.
• Common bile duct tumors.
Epidemiology – 2nd most common primary tumors of the liver.
 Risk factors – all related to chronic inflammation and cholestasis.
• Primary sclerosing cholangitis – most common cause in the USA.
• Clonorchis sinensis (liver fluke).
• Thorotrast – thorium dioxide.
• Cysts of the biliary tree – choledochal cysts or Caroli disease.
- Pathogenesis – inflammation and cholestasis promote somatic mutations in cholangiocytes.
- Pathology:
 Macroscopy - tumor is firm and whitish-greyish.
 Microscopy – adenocarcinoma - invasive malignant glands in stoma with desmoplastic reaction.
- Clinically – poor prognosis – ⁓ 6 months from diagnosis to death because usually detected late.
 Obstructive jaundice.
 Hepatomegaly.
- Diagnosis – US, ERCP.
- Treatment – surgery – but even then has poor prognosis.

Question 16

Neoplasms of the pancreas

Answer 16

Malignant:
1. Pancreatic carcinoma – mostly adenocarcinoma arising from the pancreatic duct (see later in pathology).
- Epidemiology – mostly seen in elderly (60-80). 4th leading cause of cancer death in the USA.
 Risk factors:
• Smoking – most common.
• Chronic pancreatitis.
• Obesity, diet high in red meat
• Diabetes and cirrhosis.
• Inheritance – germline mutation of BRCA2 has high risk.
- Pathogenesis – a sequence of events (as in colorectal cancer) occurs – starting from non-invasive precursor lesion in the ducts – pancreatic intraepithelial neoplasia (PanIN) → accumulate mutations, and progress → to carcinoma. Both oncogene and tumor suppressor genes are inactivated:
 KRAS – oncogene - leading to development of PanIN of early stages.
 CDKN2A – tumor suppressor coding for p16 - lead to farther progression of the PanIN (not invasive) – grade 1 to 3.

Normal duct
TP53 – tumor suppressor – cause progression to invasive carcinoma.
- Pathology – most occur in the head (60%) > diffuse all over > body > tail.
 Macroscopy – poorly-defined, hard, grey-white masses with loss of the normal lobular structure of the pancreas.
 Microscopy:
•
Desmoplastic reaction

Forms a mass
Adenocarcinoma – ductal epithelium - most common – can be mucinous and non-mucin secreting types, and has 2 important characteristic features:
 Highly invasive – even in early stages extensively invade pancreatic tissues. Can invade adjacent organs – spleen, adrenals, colon…
 Elicit strong desmoplastic response – fibrosis.
These are moderate to poorly-differentiated.
•
Invasive Abnormal glands
Acinar cell carcinoma – rare – produces pattern of normal acini, have zymogen granules and produce exocrine enzymes. Commonly develop metastatic fat necrosis – release of lipase into the circulation causes fat necrosis in distant fat sites in the body.
- Clinically – most are widely disseminated when discovered.
 Epigastic abdominal pain + weight loss – in 90% of cases.
 Obstructive jaundice + pale stool + palpabale gall bladder – in tumors of the head of pancreas → blocks the common bile duct, CB leaks to the blood, backpressure to gallbladder makes it palpable (Courvoisier sign).
 Secondry diabetes mellitus – in tumors of body or tail, where most islets are found. This is an important differential, because if we get a thin elderly with diabetes, which is abnormal for this age to be thin with diabetes but more common to be obese with DM-II, we should think about pancreatic carcinoma.
 Pancreatitis – if the tumor blocks the ducts → decreases floe of pancreatic enzyme → activation.
 Superficial migratory thrombophlebitis – Trousseau sign – due to release of procoagulants from the neoplastic cells or its necrotic products. Seen in 10% of patients.
 Metastasis to – principally to liver and lungs. Virchow node (supraclavicular) and Sister Mary Joseph sign (periumbilical) as seen in stomach cancer, can also be seen here.
- Diagnosis:
 CA19-9 serum marker – gold standard tumor marker.
 CEA – carcinoembryonic antigen.
 ↑ Serum amylase and lipase.
All these are not specific.
 Helical CT – shows “C” sign – tumor indents the duodenum, loos like “C”.
 Biopsy – CT guided.
Treatment:
 Whipple procedure – resection of the head and neck of pancreas, proximal duodenum, and gallbladder.
 Radiation, chemotherapy.
- Prognosis – very poor – 5-year survival rate < 5%, 1 year < 10%.
2. Pancreatoblastoma – rare neoplasms in children, distinct appearance microscopically – squamous islands mixed with acinar cells. Better survival than ductal adenocarcinoma.
Benign:
1. Cystic neoplasms (serous cystadenomas) – range from harmless benign to precancerous cysts. These represent only 5%-15%, as most are actually pseudocyst.
- Serous cystic neoplasm – multicystic neoplasms occurring in the tail of pancreas. Small cysts, lined by glycogen-rich cuboidal cells and contain serous fluid (straw-colored). Always benign. More in females.
- Mucinous cystic neoplasms – arise in tail, larger cysts, mucin-filled cavities lined by columnar mucin-producing epithelium. Had dense “ovarian” stroma. Precancerous to invasive carcinoma. 95% occur in females.
- Intraductal papillary mucinous neoplasms – mucin-producing neoplasms involving the larger ducts of the pancreas. Usually in the head of pancreas, and more common in men. Precancerous.
- Solid pseudopapillary neoplasms – large, well-circumscribed, that have solid and cystic components filled with hemorrhagic debris, grow with pseudopapillary progections. Malignant but locally aggressive.
2. Others - fibroma, lipoma.

Pancreatic neuroendocrine tumors: – question 170:

1. Insulinoma.
2. Gastrinomas – Zollinger-Ellison.
3. Others.

Question 17

Kidney neoplasms

Answer 17

Epidemiology:
 2% of the total amount of human cancer- its incidence is rising.
 twice as common in men
 Risk factors include smoking, obesity and cadmium exposure, as well as genetic predisposition.
 The highest incidence in the world according WHO is in the Czech Republic!
Symptoms:
 Silent for a long time- due to the kidney’s high reserve capacity, and because of its retroperitoneal location that allows its unlimited growth. Therefore it is usually discovered by chance.
 Hematuria- only when the tumor reaches the urinary tract passages.
 Dull flank pain
 Abdominal mass- only when it is in advanced, very large stage
 Metastasis- sometimes are the first to be discovered. Early hematogenic spread is often seen.
Classifications:
1. According to histological groups: WHO divides the kidney tumors into approx. 10 different groups according to their histogenic character.
2. According to its malignancy- benign or malignant
3. According to age association- childhood or adult.
Benign tumors of the kidney:
Renal adenoma:
Definition- a kidney neoplasm with tubulopapillay architecture, with diameter less than 15mm, without clear cell components and without atypia (cellular abnormality) or mitosis.
Incidence- commonly found in autopsies.
There are 3 types of adenomas in the kidney:
1. Tubulopapillary adenoma
Macroscopy:
 usually located within the cortex
 Small encapsulated nodules with yellow-gray color.
Microscopy:
 Cuboidal cells organized in a cysto-papillary structure
2. Metanephric adenoma:
Microscopy:
 Small dark cells
 Acinar and glomeruloid structure
3. Oncocytoma:
Benign epithelial cell tumor arising from collecting ducts.
Macroscopy:
 Located on kidney cortex
 Tan or even brown color- different than most neoplasms that are white-grey.
 Can reach large size- up to 12 cm, but it’s still benign.
Microscopy:
 Eosinophilic granular cells with bizarre nuclei
 Many mitochondria are filling the cytoplasm
Treatment includes surgical removal of the tumor to exclude malignancy, while sparing the healthy portion of the kidney.
Angiomyolipoma:
Definition- a mixed mesenchymal tumor of the kidney, composed of vessels, smooth muscle cells and fat.
Associated with tuberous sclerosis
This is a benign tumor, but in rare cases can be also malignant
Macroscopy:
 Located at the kidney cortex
 Yellow appearance due to fat tissue
 Can be large, multiple or bulging.
Microscopy: An admixture of fat, muscle and vascular structures.
Malignant tumors of the kidney:
Renal cell carcinoma- adenocarcinoma of the kidney:
Definition- malignant tumor of the kidney, originating from the epithelium of the kidney.
Incidence- commonly seen in adults, around 60-70 years, twice as common in men than in women (2:1).
Etiology- the tumor can be sporadic or hereditary:
• Sporadic- most cases, risk factors include:
 Tobacco- cigarette, pipe or cigars, all are in risk for the disease.
 Obesity
 Patients with chronic renal failure
• Hereditary- account for 5% of cases:
 Von-Hippel-Lindau (VHL) syndrome- VHL gene is a tumor-suppressor gene. The syndrome is associated with its loss, leading to:
 Increased IGF-1 synthesis- increasing the tumor growth.
 HIF (hypoxia inducible factor) transcription factor- increasing both VEGF and PDGF →angiogenesis and tumor growth.
 These patients are also in increased risk for hemangioblastoma of the cerebellum.
 Hereditary familial clear cell carcinoma
 Hereditary papillary carcinoma- mutation in MET proto-oncogene, AD transmission.
There are 3 types of renal adenocarcinoma:
1. Clear cell renal cell carcinoma- CCRCC- Grawitz tumor
• The commonest type- accounts for 75% of kidney carcinomas.
• Arising from proximal tubule epithelium
• Cytogenetics- in all forms (hereditary or sporadic) there is a loss of function mutation of VHL gene on short arm of chromosome 3. Can be as a result of deletion or translocation.
• Macroscopy:
 Yellow mass, encapsulated, solid or cystic
 Cut surface is not homogenous- due to scaring and hemorrhage
• Microscopy:
 Water clear cytoplasm- full of fat and glycogen
 The cells are round or polygonal shape
• Staging and grading of the tumor-
 Grading- based on the shape and size of the nuclei and nucleoli
 Staging- based on 3 main factors denoted as letters:
 T- primary tumor: its size, and expansion into inferior vena cava
 M-regional lymph nodes metastasis- present or absent
 N- Distal metastasis- present or absent.

2. papillary carcinoma:
   • Accounts for about 10% of cases
   • Arising from distal tubule epithelium
   • Appear hypo-vascularized in X-ray
   • Cytogenesis:
    trisomy or tetrasomy of chromosomes 16 and 17 –sporadic form
    in males- missing Y chromosome- sporadic form
    mutation of C-met oncogene and trisomy of chromosome 7- hereditary form
   • Macroscopy: can be multifocal and bilateral, usually hemorrhagic and cystic.
   • Microscopy: 2 types can be distinguished-
    Type I- cuboidal cells
    Type II- cylindrical cells. Have worse prognosis.
    Both can have stromal macrophages that resemble clear cells- not to be confused!
3. Chromophobe renal carcinoma:
   • Accounts for about 5% of cases
   • Arise from the intercalated cells of the collecting ducts.
   • Better prognosis compared with the other carcinomas
   • Cytogenetics- multiple chromosomal losses- 1,2,6,10,13,17,21
   • Macroscopy- brown color
   • Microscopy:
    Eosinophilic or clear cytoplasm
    Raisin shaped nuclei with a perinuclear halo
    Positive in iron staining (Hale’s colloidal Fe staining)
    Really similar to oncocytoma
4. Collecting duct carcinoma:
   • Accounts for about 1% of kidney carcinomas
   • Arise from collecting duct cells in the medulla
   • Prognosis is not good.
   • Microscopy:
    Adenocarcinoma stroma with urothelial like cells
    Hobnail cells- small nail with a large head
    Mucin production
   Clinical manifestations of all kidney carcinomas include:
    Hematuria
    Flank pain
    Palpable mass
    Fever and weight loss
   Complications:
5. Metastatic spread: the metastasis occure before symptoms, therefore in 25% of cases- they are present at the time of presentation.
   Most common places for metastasis include: (in order of their frequency):
    Lungs- more than 50%
    Bones
    Regional lymph nodes
    Liver
    Adrenal gland
    Brain.
6. Hematuria→ anemia
7. Paraneoplastic syndrome: increased hormone production:
    Erythropoietin→ reactive polycythemia
    Renin→ hypertension
    Parathyroid hormone releasing peptide→ hypercalcemia
    ACTH→ Cushing syndrome
8. Left sided varicocele- appears in 5% of patients, due to tumor penetration to the left renal vein, and the occlusion of the testicular vein as a result.
   Healing and prognosis- 5 years survival rates is about 50%, and in the absence of metastasis even 70%.
   Wilms tumor- nephroblastoma:
   Also known as embryonal adenosarcoma, the most common childhood tumor of the kidneys.
   Incidence- appear usually at age 2-5, both males and females with same incidence.
   Etiology: the tumor can be both sporadic and hereditary.
   Cytogenetics- Wilms tumor is associated with mutation it WT1 gene on chromosome 11, special syndromic cases are associated. This gene is critical for normal renal and gonadal development
    WAGR syndrome: WT1 “first hit” loss of function mutation is hereditary.
    Wilms tumor
    Aniridia
    Genital anomalies
    Mental Retardation
    Beckwith-Weidemann syndrome: characterized by organomegaly- tongue, kidney, liver, hemihypertrophy. WT2 gene, also located on chromosome 11, is usually expressed only from paternal allele. When the mutation occurs in this gene- silencing of the maternal allele is lost, resulting in over-expression of IGF2 from the mother.
    Denys-Drash syndrome: characterized by gonadal dysgenesis and renal abnormalities. In this syndrome there is a mutation causing the silencing of WT1 gene
   Morphology:
   • Macroscopy:
    Grey-white large retroperitoneal mass
    Palpable through the abdominal wall
    Soft and homogenous
    Can be unilateral or bilateral (more common in girls)
   • Microscopy:
    Undifferentiated renal blastemal (mesonephric mesoderm)- primitive tissue from which the kidney is formed.
    Tubular and glomeruloid formations may be present.
    Anaplasia- cells with large hyperchromatic, pleomorphic nuclei with abnormal mitoses. Correlates with mutation in P53. Seen in 5% of cases. When present –bad prognosis!
   Clinical presentation:
    Unilateral palpable mass in a child with hypertension
    Lung are the most common site for metastasis
    Hematuria (sometimes following minimal trauma)
   Healing and prognosis: more than 90% survival rates after 5 years with combined treatment (resection and chemotherapy. Cases with anaplasia have bad prognosis.
   Follow up for these patients is important- looking for nephrogenic rests-residual nest of nephrogenic blastemal found in the kidneys, can predispose for recurrence of the disease.

Question 18

Neoplasms of the urinary tract

Answer 18

The majority of lower urinary tract tumors are epithelial tumors. Fluin movement

Most of the malignant tumors (90%) occur in the bladder.
Tumors of lower urinary tract:
Various lesions and neoplasms can be found in the urinary bladder (mainly) and also in the urethra. 90%of these lesions are of urothelial (transitional) origin.
Urothelial cancer:
Urothelium- the special transitional epithelium covering the urinary passages and bladder.
Normal structure:
 Multilayer- up to 6 layers with different cell types:
• Basal stem cells
• Neuroendocrine cells
• Superficial: umbrella cells
 Tight junctions- holding the cells together, inhibiting fluid penetration
 Protein plaque coating- assisting in the isolation as well.
 The bladder mucosa changes according to its filling- wrinkled with rugae when empty, and unfolded when full.
 The changes of urethelium varies from slight reactive lesions to actual carcinoma.
Reactive lesions of urothelium:
1. Metaplasia: as a result of urothelium proliferation→ harmless.
 Mucinous metaplasia- urothelial cells migrate to lamina propria and form mucin filled cysts lined with cuboidal cells→ called Von Brunn’s nests.
 Squamous metaplasia- as a reasponse to injury or irritation, the urothelium is replaced with squamous cells, The squamous cells are nonkeratinized, similar to vaginal type epithelium.
2. Hyperplasia: regular increase in number of urothelial layers >7, with slight increase in nuclei size and preserved architecture. Frequently occurs as a result of inflammation.
This cells can develop to precancerosis to papillary neoplasms.
3. Dysplasia: disturbances of normal urothelium architecture and cytology- leading directly to neoplasms. 2 types of neoplasms can develop as a result of dysplasia: (the grading is according to level of dysplasia)
 LG IUN- low grade intraurothelial neoplasia.
 HG IUN/CIS- high grade intraurothelial neoplasia/ carcinoma in situ.
Urothelial cell carcinoma:
Incidence- about 3% of total human cancer with increasing incidence
Risk factors:
 Age- mostly occur in older patients 50-80 years old.
 Sex- males are 3 times more effected
 Carcinogens:
 Phenacetin- analgesic drug, banned from usage today.
 Smoking
 Analine- organic compound used in rubber and dyes
 Cyclophosphamide- medication used in chemotherapy and autoimmune diseases
 Alcohol abuse
 Schistosoma hematobium- infection usually seen in men from Middle East.
 Extended dwell time (urine stays long in bladder)
Clinical manifestation:
 Hematuria- first to be mentioned!
 Obstruction- leading to hydronephrosis
 Metastasis
Urothelial cell carcinoma:
Incidence- about 3% of total human cancer with increasing incidence
Risk factors:
 Age- mostly occur in older patients 50-80 years old.
 Sex- males are 3 times more effected
 Carcinogens:
 Phenacetin- analgesic drug, banned from usage today.
 Smoking
 Analine- organic compound used in rubber and dyes
 Cyclophosphamide- medication used in chemotherapy and autoimmune diseases
 Alcohol abuse
 Schistosoma hematobium- infection usually seen in men from Middle East.
 Extended dwell time (urine stays long in bladder)
Clinical manifestation:
 Hematuria- first to be mentioned!
 Obstruction- leading to hydronephrosis
 Metastasis
Urothelial carcinoma:
There are 2 main pathways of urothelial carcinoma development
1. Papilloma: circumscribed solitary papillary finger like lesion, covered with normal epithelium (cytologicaly and architecturaly). Usually small- up to 5cm, attached to the mucosa by a stalk, its core made of loose CT.
2.
2
Papillary Urothelial Neoplasm of Low Malignancy Potential (PUNLMP): same appearance as papilloma, but larger, and with slight dysplasia and increased number of urothelial layers.
3. Low-grade papillary carcinoma: architecturally and cytologicaly ordered appearance, with small nuclear atypia and mild variation of size. Usually noninvasive (10%)! can recur.
4. High-grade papillary carcinoma: marked cytologic atypia, messy architecture, some cells are poorly differentiated, high mitotic activity. High incidence of invasion (80%)!
5. Carcinoma in situ- flat urothelial carcinoma, cytologicaly malignant cells within a flat urothelium. Can spread through the whole surface of the bladder or as scattered malignant tumors. High incidence of invasion to muscle layer (70%)!
Invasive neoplasms: the level of invasion represents the staging of the cancer and effect prognosis
 Lamina propria invasion
 Detrusor muscles invasion
 Perivesical tissue
 Surrounding organs
Other epithelial tumors:
Also arise from urothelium, but the cells are differentiated into cells other than urothelium.
Squamous cell carcinoma:
• Incidence- 5% of bladder cancers, more common in endemic areas of Schistosoma hematobium.
• Can develop from squamous cell metaplasia
• Lesions usually appear in multiple locations and the epithelial cells are keratinized
• Causes are all related to chronic irritation:
 Reccurent infections
 Kidney stones
 Schistosoma hematobium- flat worm that lay its eggs in the bladder mucosa- causing chronic infection and irritation.

Adenocarcinoma:
• Least common
• Histologically identical to GIT adenocarcinomas
• Can produce mucus- causing mucinuria
• Frequently metastasize
• The most common tumor in people with bladder extrophy.
• Adenocarcinoma can also originate from the urachus.
Mesenchymal bladder tumors:
• Very rare
• Include:
 Leiomyoma
 Vascular- hemangiomas and hemangiosarcomas
 Malignant lymphomas
Neuroectodermal bladder tumors:
 Melanoma
 Neurofibromas in Recklinghausen’s disease.
Complications of urinary trackt cancer:
 Local recurrence- regular follow-up is necessary including cytology examination
 Progression
 Metastasis- mainly to the local lymph nodes

Question 19

Neoplasms of the penis and scrotum

Answer 19

112. Neoplasms of the Penis and Scrotum: Big Robbins – 970, Kaplan – 227, Goljan - 533 12/4/2017
     Penis:
     Benign:
113. Condyloma accuminatum – benign warty growth on the genital skin, due to HPV 6 or 11 infection.
     Macroscopy – cauliflower-like appearance.
     Microscopy – villous-papillary connective tissue stroma with:
     Koilocytosis – structural changes of the cells due to HPV infection – the virus infects the nucleus which becomes abnormal, and the cells with very clear cytoplasm are seen in the epidermis of the lesion.
     Acanthosis – hyperkeratosis and thickening of the epidermis.
114. Peyronie disease – penile fibromatosis resulting in lateral curvature of the penis, due to chronic inflammation of the tunica albuginea involving fibrous plaques and scarring of the tunica albuginea. The cause is unknown, thought to be cause by injury to the penis during sexual intercourse.
     Pre-malignant:
115. Carcinoma in citu – cytological changes of malignancy confined to epithelial layers only without evidence of invasion beyond the basal lamina. All have strong association with HPV infection (most commonly type 16). 3 condition have been described:
     Bowen disease – involves the skin of the shaft of penis and scrotum, in men > 35 years old.
     Macroscopy – solitary thick grey-white plaques (⁓leukoplakia).
     Microscopy – acanthosis and parakeratosis (keratinization with retention of the nuclei in the stratum corneum).
     10% risk for transformation to SCC of penis.
     Erythroplasia of Queyrat - involves the mucosal surface of the glans and prepuce.
     Macroscopy – shiny red-velvet and soft lesions (⁓ erythroplakia).
     Microscopy – same as Bowen disease, with variable degree of dysplasia.
     Risk for transformation to SCC – sometimes considered as a subtype of Bowen disease.
     Bowenoid papulosis – same as Bowen disease but in younger sexually active adults.
     Macroscopy – multiple reddish-brown papules.
     Microscopy – indistinguishable from Bowen disease.
     No malignancy potential – never develops into invasive carcinoma. Regresses spontaneously.

Malignant:
1. Squamous cell carcinoma of the penis – malignant proliferation of the squamous cells of the penile skin.
Epidemiology – usually affects males 40-70 years old.
Risk factors:
High-risk HPV 16 and 18 – 2/3 of cases. Synergic effect with tobacco smoking.
Lack of circumcision – circumcision reduces exposure to carcinogens that concentrate in the smegma and decrease likelihood for infection by HPV. Thus, extremely rare in Jews and Muslims.
Bowen disease + erythroplasia of Queyrat.
More common in Asia, Africa, and South America – uncommon in the USA.
Pathology – slowly growing, locally invasive:
Macroscopy – usually begins on the glans and prepuce. Has 2 major macroscopic patterns:
Papillary – simulate condylomata acuminate with cauliflower fungating mass.
Flat – appear as areas of epithelial thickening with greying and fissuring of the surface.
Microscopy – 3 patterns with varuent degrees of differentiation:
Papillary.
Flat.
Verrucous carcinoma – exophytic well-differentiated variant of SCC, locally invasive but its invasion is small and very limited, thus rarely metastasize.
Other less common patterns – basaloid, warty.
Complications – metastases to inguinal and iliac lymph nodes, but widespread dissemination is extremely uncommon, until the lesion is far advanced.
Clinically –
Slowly growing – thus takes a year or more until brought to medical attention.
Painless lesions – until ulcerations and infections occur.
Prognosis – without spread to lymph nodes 5-year survival rate – 66%, while 30% if metastasis occurs.
Treatment – partial amputation of the penis.

Scrotum:
1. SCC:
Epidemiology – most common type of primary scrotal cancer. Over 60 years old.
Risk factors:
Occupational exposure – chimney sweeps, tar workers, truck drivers.
Poor hygiene.
HPV infection.
Pathology:
Macroscopy – red plaque or white-grey granular lesions.
Microscopy – well-moderately differentiated SCC of the usual type in most cases. Papillary, verrucous, wary types also exist.
Treatment – local excision with bilateral lymphadenectomy.
Prognosis – done by Lowe’s staging:
A1 – localized to the scrotum.
A2 – involve adjacent structures – e.g., spermatic cord, penis, testis.
B – metastasis to inguinal lymph nodes.
C – metastasis to pelvic lymph nodes.
D – metastases to distant organs.
2. Primary extra-mammary Paget – adenocarcinoma in situ (non-invasive) of the scrotal skin.
Epidemiology – males > 70 years old.
Pathology:
Macroscopy – erythematous plaque or raised lesions.
Microscopy:
Intraepidermal clusters of large vaculated cells with pale granular cytoplasm.
Hyperkeratosis and parakeratosis – may be present.
Treatment – wide surgical excision.

Question 20

Neoplasms of the testis

Answer 20

114. Neoplasms of the Testis: Big Robbins – 975, Kaplan – 228, Goljan – 536, F.A - 618 12/4/2017
     We have 3 major groups of testicular neoplasms:
115. Intratubular germ cell neoplasias (ITGCN) – precursor intratubular in situ lesions.
116. Germ cell tumors – generally malignant – 95% of all testicular tumors.
117. Sex cord-stromal tumors – generally benign.
     Others of less importance:
118. Gonadoblastoma - Tumors of both germ-cell and sex cord-tromal tumors.
119. Hematopoietic tumors - testicular lymphoma.
120. Tumors of collecting ducts and rete testis.
121. Tumors of paratesticular structures – benign / malignant mesotheliomas of tunica vaginalis.
     Intratubular germ cell neoplasias (ITGCN):
     Preneoplastic lesions of the testes confined to the tubules, with 50% chance of developing germ cell tumors in the next 5 years (but not to spermatocytic seminoma, yolk sac tumors, and teratomas).
     Pathogenesis – ITGCN are believed to arise in utero and stay dormant until puberty, after which it may progress to germ cell tumors. They share genetic alterations with germ cell tumors, one particularly important is reduplication of the short arm of chromosome 12 in the form of an isochromosome – alteration that invariably found in invasive germ cell tumors.
     Pathology:
     Microscopy – replacement of the normal germ cells with large neoplastic cells with clear cytoplasm.
     Diagnosis:
     Immunohistochemistry – placental alkaline phosphatase (PLAP) antibodies, highlights ITHCN cell membranes in 95% of cases.
     Germ cell tumors:
     Epidemiology – most common type of testicular tumors.
     Most common tumors of men between 15-35 years old – whites > blacks.
     Risk factors:
     Cryptorchidism.
     Klinefelter syndrome – (XXY).
     Germ cell tumors arise from germ cells of any stage, but because these cells are totipotent (= are aimed to form a whole organism, give rise to pluripotent and multipotent cells) they can give rise to other structures  and therefore also other types of tumors. Based on this, germ cell tumors are classified into:
     Seminomas – composed of cells that resemble early germ cells. Subclassified into:
     Classic seminoma – most common germ cell tumors (50%)
     Spermatocytic seminoma.
     Non-seminomas – composed of undifferentiated cells that resemble embryonic tissues, creating:
     Embryonal carcinoma.
     Yolk sac tumor. Most common in children!
     Choriocarcinomas – tumor of placental tissue.
     Teratomas.
     Mixed tumors – combinations of seminomas and non-seminomas or types within the groups.
     Extragonadal germ cell tumors – tumors arise outside the scrotum.
     Seminomas:
122. Classic seminoma – most common, parallel to dysgerminomas of the ovary.
     Epidemiology – young men around 30s. No in infancy.
     Pathogenesis – contain isochromosome 12p.
     Pathology:
     Macroscopy:
     Large Homogenous mass with no necrosis or hemorrhage –very important.
     Greyish-pinkish – up to 10 times the testes normal size.
     Well defined – in contrast to most malignant tumors (another well-defined to remember is renal cell carcinoma) – with lobulated appearance on cut surface.
     Local spread limited by tunica albuginea – which is usually not penetrated. If invaded it shows that the tumor is in a high stage.
     Microscopy:
     Lobules of neoplastic cells divided by fibrous septa – with lymphocytes infiltration within the septa.
     Large cells with clear cytoplasm – full with glycogen that stain positive with PAS reaction. The cells also produce placental alkaline phosphatase which can be detected. Low mitotic activity.
     Varients – a few important varients are:
     Anaplastic seminoma – high mitotic activity and aggressive behavior.
     Syncytiotrophoblastic seminoma – characterized by large multinucleated giant cells and produce hCG – thus serum hCG are elevated.
     Complications – metastasis – to lumber – para-aortic lymph nodes (not to inguinal!!). Mainly metastasize via lymphatics, less via blood.
     Diagnosis:
     Painless, firm non-translucent testicular mass.
     Ultrasound.
     Positive PLAP.
     No biopsy – all testicular tumors are not biopsied – due to risk of seeding the scrotum. It’s removed by radial orchiectomy.
     Treatment – excellent response to radiotherapy and chemotherapy.
     Prognosis – excellent – 95% curable.
123. Spermatocytic seminoma:
     Epidemiology – rare – occur in older adults (> 55 years old).
     Pathogenesis – different from classic seminoma clinically, histologically and even genetically. It’s a low-grade malignant tumor (almost benign), slow growing, with very low metastatic potential.
     Pathology:
     Macroscopy – soft, pale-grey cut surface, gelatinous, sometimes with mucoid cysts.
     Microscopy – contain 3 cell populations, all intermixed:
     Small-size cells – resemble lymphocytes or secondary spermatocytes.
     Medium-size cells – most numerous, round nucleus and eosinophilic cytoplasm.
     Giant cells – mono- or multinucleated.
     The stroma has no lobules separated by fibrous septa with lymphocytes as in classic type.
     Prognosis – excellent.
     Non-seminomas: - in general, more aggressive than seminomas.
124. Embryonal carcinoma – very aggressive, rapidly-growing malignant tumor of immature, primitive cells that may form glands, and in contrast to seminoma characterized by necrosis and hemorrhage.
     Epidemiology – 20-30 years old.
     Pathology:
     Macroscopy:
     Bulky mass with hemorrhage and necrosis – usually don’t replace the all testis.
     Poorly-defined.
     Microscopy:
     Cells grow in variety of patterns – tubular, papillary, glandular, or solid.
     Highly anaplastic tumor cells – large, indistinct border.
     Complications:
     Metastasis – hematogenous before lymphatic.
     Chemotherapy may cause differentiation – because it’s such a primitive cell, upon therapy it can become a more mature cell  resulting in its differentiation into teratoma, yolk-sac tumors or choriocarcinoma.
     Diagnosis – the tumor secrete both AFP (typical for Yolk sac tumor) and hCG (typical for choriocarcinoma). Cytokeratine immunohistochemistry positive.
     Prognosis – intermediate – less sensitive to radiotherapy than seminomas.
125. Yolk sac tumor (=endodermal sinus tumor) – malignant tumor that resembles yolk-sac elements.
     Epidemiology – most common testicular tumor in children < 3 years old. In adults frequently occur in combination with embryonal carcinoma.
     Pathology:
     Macroscopy – soft, homogenous, yellow-white, mucinous appearance (possibly with areas of necrosis and hemorrhage).
     Microscopy:
     Variety of patterns – papillary, tubular, reticular network, or solid.
     Schiller-Duval bodies – consist of a core of central capillaries and a visceral and parietal layers of cells, resembling and primitive glomeruli (glomeruloid structure).
     Eosinophilic granules – containing α-fetoprotein (AFP).
     Diagnosis:
     ↑ Serum AFP.
     Immunohistochemistry for AFP.
     Prognosis – good in children.
126. Choriocarcinoma – highly malignant tumor of placental-like tissue containing syncytiotrophoblasts and cytotrophoblasts. Pure form is rare, commonly occur in combination with other germ cell tumors.
     Epidemiology – 20-30 years old. Rare (1% of all germ cell tumors).
     Pathology:
     Macroscopy – small palpable nodule that often doesn’t cause testicular enlargment, commonly with necrosis and hemorrhage.
     Microscopy – the tumor contains 2 cell types (without placental villous formation):
     Syncytiotrophoblasts – giant multinucleated cells with eosinophilic vacuoles containing hCG.
     Cytotrophoblasts – polygonal cells with clear cytoplasm.
     Complcations –
     Hematogenous metastasis – as these are placental-like cells which tend to seek blood. This creates a characteristic of this tumor that it tends to have a small primary tumor in the testes, and large secondary metastatic tumors throughout the body (which is opposite than most other tumors). Commonly spread to the lungs.
     Hyperthyroidism – hCG has a similar α-subunit as the hormones FSH, LH, and TSH – therefore patients can present with hyperthyroidism because the hCG can activate the TSH receptors.ot:
     Gynecomastia – because hCG activates FSH and LF receptors.
     Diagnosis:
     ↑hCG – in 100% of cases.
     Immunohistochemistry against hCG.
     Prognosis – poor – most aggressive testicular tumor.
127. Teratoma – tumors from totipotent cells differentiating into derivatives of all 3 germ layers – ectoderm, mesoderm, and endoderm – thus it’s possible to find all types of tissues occurring in the body. Can be Malignant in males (as opposed to females which is usually benign).
     Epidemiology – all ages, but:
     Children – have more frequently pure form.
     Adults – have most frequently mixed form with other tumors.
     Usually benign in children and malignant in adults.
     Pathology:
     Macroscopy – solid or cystic, grossly depends on components (e.g.,cartilaginous):
     Cystic – usually benign.
     Solid – risk for malignancy.

Microscopy – collection of many types of tissue – neural, muscle, cartilage, thyroid, brain, teeth, etc… all embedded in fibrous or myxoid stroma.
These can appear in different forms, based on which we classify teratomas:
Mature teratomas – fully differentiated elements.
Immature teratomas – poorly differentiated resembling fetal and embryonic tissues. We are not able to recognize the structures.
Teratomas with malignant transformation – can give rise to either carcinoma or sarcoma. It’s important to recognize these are these are chemoresistant – thus, the only hope for cure resides in the resectability of the tumor.
Diagnosis:
↑ AFP and/or hCG.
Prognosis – good.
Mixed tumors:
The vast majority of germ cell tumors are mixed.
Common combinations are:
Seminoma + embryonal carcinoma.
Teratoma + embryonal carcinoma + yolk sac tumor.
Embryonal carcinoma + teratoma = teratocarcinoma.
Prognosis is based on the presence of types with worse prognosis.
Extragonadal germ cell tumors:
Usually arise in midline locations.
In adults – most commonly in the retroperitoneum, mediastinum.
Children – sacrococcygeal teratomas are most common.

Staging of germ cell tumors:

1. Stage 1 – tumors confined to the testes.
2. Stage 2 – metastases confined to the retroperitoneum below the diaphragm.
3. Stage 3 – metastases outside the retroperitoneum and above the diaphragm.

Sex cord-stromal tumors:
Tumors that resemble the normal sex cord tissue (the cords formed during gonads developments) and are usually benign. These are generally rare – only 5% of cases. The most important members are:
1. Leydig cell tumor – characteristically these cells produce androgens, sometimes estrogens, and rarely corticosteroids. Causes precocious puberty in boys and gynecomastia in men.
Epidemiology – any age, most commonly 20-60 years old.
Pathology:
Macroscopy – circumscribed small nodules (< 5 cm), golden-brown in cut section.
Microscopy:
Cells resemble normal Leydig cells.
Reinke crystals – rod-shaped inclusions of unknown function.
2. Sertoli cell tumors – produce structures resembling seminiferous tubules, usually hormonally and clinically silent. Mostly benign, but 10% pursue a malignant course.
Pathology:
Macroscopy – small nodules with homogenous grey-white cut surface.
Microscopy – look like seminiferous tubules with neoplastic sertoli cells.
Many times these 2 types combine.
3. Granulosa cell tumors – very rare – contain structures identical with ovarian tumors.

Gonadoblastoma – rare, combination of germ cell tumors + sex cord-stromal tumors.

Testicular lymphoma – aggressive non-Hodgkin lymphomas are the most common neoplasms in men over 60 years old. Usually bilateral, diffuse large B-cell lymphoma.

Question 21

Neoplasms of the prostate and seminal vesicles

Answer 21

116. Neoplasms of the Prostate and Seminal Vesicles: Big Robbins – 983, Goljan – 541, F.A – 619 14/4/2017
     Prostate:
     Prostatic intraepithelial neoplasia (PIN):
     PINs are precursor lesions to prostatic carcinoma which are mostly found before cancer arises. PINs are characterized by multiple foci of cytologically atypical cells overlying diminished number of basal cells in the glands.
     Can be:
     Low grade PIN.
     High grade PIN – corresponds to carcinoma in situ (although it’s usually not proper to use this term in PIN).
     Epithelium is very high and basophilic – projecting into the lumen.

Prostate adenocarcinoma:
Malignant proliferation of the prostatic glands.
Epidemiology:
Most common cancer in adult males – 2nd most common cause of cancer death.
Males > 50 years old - 70% incidence in men > 70.
Risk factors:
Advancing age – most important risk factor.
Race - Afro-Americans > Caucasians – rare in Asians.
First-degree relatives – tend to develop the disease in earlier age.
Diet high in saturated fats + cigarettes smoking.
Pathogenesis – very unclear, but the growth is androgens-dependent (DHT) – this is proven by treatment, as after castration or antiandrogens treatment, regression of the disease is observed (unfortunately most tumors become resistant to androgen blockade).
AR gene polymorphisms – this gene has CAG (codes for glutamine) repeats. The shorter the repeats, the higher the risk for developing cancer. African-Americans have the shortest repeats.
Men with BRCA2 germline mutation – have 20-fold increased risk for prostate cancer.
Many other mutations – of TP53, MYC and others.
In most cases PIN lesions form before.
Pathology – mostly arise in the peripheral zone of the prostate, classically in a posterior location where it may be palpable on rectal examination. Thus, it usually doesn’t produce urinary symptoms until very late stages.
Macroscopy:
Firm-gritty yellow appearance – on cut-section it may be difficult to see it, thus it’s better felt on palpation (it gets solid appearance in contrast to the normal spongy appearance).
Invasion of the prostatic capsule.
Microscopy – 4 histologic types are described;
Adenocarcinoma – 95% of cases. Most important and the one generally referred as carcinoma of the prostate. Characterized by:
Loss of basal cell layer – thus they are cytokeratin antibodies negative. Important marker.
Well differentiated glands – look well-defined, however they usually lack the typical infoldings and convoluted appearance of glands, they are smaller, and the cells have nuclei with prominent nucleoli. Lined by a single-layer (no basal cells).
However can range between well to poorly differentiated. Can be basophilic cytoplasm (as in the picture), but can also be eosinophilic.
Cribriform pattern – is also possible.
Diffuse infiltrating pattern – is also possible – small groups of neoplastic cells.
Transitional cell carcinoma.
Squamous cell carcinoma.
Undifferentiated carcinoma.
4 hallmarks of malignancy – invasion:
Invasion of the capsule around the prostate.
Blood vessels/lymphatic invasion.
Perineural invasion.
Extension into the seminal vesicles or base of the bladder.
Grading – done using the Gleason system – describes 5 grades based only on architecture (not on nuclear atypia), which correlate with the degree of aggressiveness of the disease:
Grade 1 – most well-differentiated tumors with well-defined glands.
In this stage it’s still difficult to recognize the cancer, thus antibodies against basal cells are used.
Grade 5 – show no glandular appearance, with tumor cells infiltrating the stroma in the form of cords, sheets, and nests.
Most tumors contain more than one pattern, thus a Glison score is made by adding grades to each other (for example grade 2 + grade 5 = 7). Always combining 2, thus if more than 2 are present, we take only the 2 predominant ones (lowest score – 1+1=2, highest 5+5=10). Prognosis is better for the lower scores, and worst for the higher.
Staging – is also done – T1-T2 confined to the prostate, T3-T4 – spread.
Complications:
Metastasis:
Lymphatic spread – to para-aortic nodes.
Hematogenous spread – chiefly to bones, especieal of the axial skeleton (lumbar spin), typically osteoplastic (a feature that in men points strongly to prostatic origin). Spread occurs also to viscera but not in a massive way (lungs and liver). The spread occurs via the Batson venous plexus.
Clinically – clinically silent until advanced stages.
When symptomatic:
Obstructive uropathy – implies extension into the bladder base.
Low back/pelvic pain – due to metastases to the axial skeleton.
Compression of the spinal cord – due to metastasis.
Diagnosis:
Screening – due to its asymptomatic course screening begins in the age of 50, and include digital rectal exam and PSA.
PSA > 10 ng/mL – highly predictive of cancer (normal 0-4, with age 4-10, but never >10).
Decreased free serum PSA – measurement of free vs. bound PSA is important – in benign hyperplasia the free PSA increases, while in cancer the bound PSA increases (thus we measure decreased amount of free PSA).
PSA doubling time – the time that the amount of PSA is doubled, reflecting the time it takes for the number of tumor cells to double. Shorter doubling time  aggressive tumor.
** PSA normal function – proteolytic enzyme that cleaves and liquefy the seminal coagulum formed after ejaculation.
Biopsy - required to confirm the presence of carcinoma – done by transrectal needle biopsy, must be performed before the prostate is removed. Diagnosis of the biopsy is challenging, thus 12 samples are taken. Done when digital rectal exam + PSA values are indicative.
↑ alkaline phosphatase – due to the osteoblastic metastasis.
US (transrectal), CT, MRI, Radionucleotide bone scan – evaluate the extent of the disease.
Treatment:
Early local disease – prostatectomy.
Advanced disease:
GnRH analogs (leuprolide) – when continuesly given, they shut down the hypothalamus, which then reduces LH and FSH release  decreasing the ability of the cancer to thrive because it’s androgen dependent.
Androgen receptor inhibitors (flutamide).
Prognosis – 5 years survival rate for all stages – 99%, 10 year – 90%, 15 years – 75%.
Miscellaneous tumors and tumor like conditions:
1. Ductal adenocarcinomas – arise from prostatic ducts. Poor prognosis.
2. Colloid carcinoma of the prostate – prostate cancers that reveal abundant mucinous secretions.
3. Small cell carcinoma=neuroendocrine carcinoma – the most aggressive variant of prostate cancer. Rapidly fatal.
4. Urothelial cancer – the most common cancer to secondarily involve the prostate. 2 patterns:
Invasive urothelial cancers – can directly invade from the bladder into the prostate.
Carcinoma in situ of the bladder – can extend down into the prostatic ducts and acini.
5. Mesenchymal tumors.
6. Lymphomas.

Seminal vesicles:
1. Seminal vesicles adenocarcinoma – very rare, must rule out invasion from the prostate.
Usually a papillary adenocarcinoma resembling architecture of normal seminal vesicle.
Usually unresectable and patients die within 2 years.
2. Seminal vesicles neoplasms due to spread from other locations – from:
Prostatic adenocarcinoma.
Bladder urothelial carcinoma.

Question 22

Neoplasms of the vulva

Answer 22

118. Neoplasms of vulva:
     HPV infections:
     The commonest STD- found in almost 90% of adult population.
     When discussing neoplasms of the lower female genitalia that includes cervix, vulva and vaginal canal- we must refer to human papilloma virus.
     Depending on the strain of HPV infection, different lesions can occur- see picture.
     Majority of infections are transient- cleared or become latent after 1-2 years
     High risk HPV strains tend to clear more slowly- posing a greater risk for malignancy development (usually after 10 years)
     All HPV viruses have a common histological feature- koilocytic atypia
     Benign vulvar lesions:
     Condiloma acuminatum:
     Verrucous, wart-like lesions
     Located on the vulva, perineum, vagina or cervix
     Etiology- most commonly due to HPV types 6,11
     Microscopically:
     koilocytic changes- raison like nuclei of cells,
     acanthosis (diffused epidermal hyperplasia:
     Hyperkeratosis and parakeratosis (retention of nuclei in the stratum corneum).
     Macroscopically- usually numerous, watery lesions.
     Rarely progresses to carcinoma.
     Papillary hidradenoma:
     Benign tumor of the apocrine sweat glands
     Occurs along the milk line
     Macroscopically- painful reddish lesions on labia majora, tendency to ulcerate.
     Microscopically- similar to intraductal papilloma of the breast:
     Papillary progections with 2 layers of cells
     First layer- columnar secretory cells
     Second layer- myoepithelial cells.

Malignant vulvar tumors:
Vulvar carcinoma:
Incidence- 3% of all female genital cancers, usually in women over 60.
Squamous cell carcinoma- the most common type seen
Etiology- the vulvar carcinoma is classified according to its etiology into 2 types:
HPV related: basaloid and warty carcinomas
Incidence- accounts for 30% of vulvar carcinomas, women around 45 (10 years after infection)
Etiology- associated with infection with high risk HPV- mainly 16
Arises from Vulvar Intraepithelial Neoplasm (VIN) - a dysplasia induced by the virus, similar process occurs in cervix. Cells are poorly differentiated
Macroscopy- leukoplakia is seen
Microscopy- nests and cords of small squamous immature cells (similar to the basal cells). Koilocytic changes of nuclei.

Non-HPV related: keratinizing squamous cell carcinomas
Incidence- 70% of vulvar carcinoma, seen mainly in elderly women- >70 years.
Etiology- arises from long standing Lichen sclerosis- that causes chronic inflammation and irritation, eventually leading to carcinoma.
Arises from differentiated VIN- similar appearance to VIN, but the epithelial cells are differentiated
Macroscopy- leukoplakia
Microscopy- nests of malignant squamous epithelium with prominent central keratin pearls.
Extra-mammary Paget disease:
Malignancy epithelial cells in the epidermis of vulva
Develops from the apocrine glands, can appear in the nipples (Paget’s disease) and vulva (Extramammary Paget’s disease).
Morphology:
Macroscopy- erythematosus, pruritic ulcerated skin, usually labia majora
Microscopy- intraepithelial proliferation of malignant cells- large cells with a halo separating them from the environment.
Differential diagnostics melanoma
Pegets disease- PAS+, keratin+, and S100—
Melanoma- PAS-, keratin-, and S100+
No underlying cancer- the malignant cells are confined to the epidermis.
Malignant melanoma:
Incidence- very rare, seen in women at 60-70 years.
Same characteristics as melanomas in other body parts.
5 years survival is 30% mainly due to late detection of the lesion.

Question 23

Neoplasms of the vagina

Answer 23

120. Neoplasms of vagina:
     Vaginal carcinoma:
     Primary vaginal carcinoma— uncommon finding.
     Can be detected by a Pap smear
     Invasive vaginal carcinoma occurs as 2 types:
121. Squamous cell carcinoma:
     Carcinoma arising from squamous epithelium lining the vagina
     Less than 2% of all gynecologic malignancies
     Usually associated with high risk HPV.
     The precursor lesion is vaginal intraepithelial neoplasm (VAIN)
     The regional lymph node spread of this tumor depends on location within the vagina:
     Cancer from lower 2/3 of vagina- spreads to inguinal lymph nodes
     Cancer from upper 1/3 of vagina- regional iliac node
     That is due to the different embryonic origins.
122. Vaginal adenocarcinoma:
     Malignant proliferation of glands with clear cytoplasm
     Originates from vaginal adenosis- as a complication of DES usage of the mother during pregnancy with a female embryo.
     Due to these findings- DES is banned from using now a days.
     Embryonal rhabdomyosarcoma: (sarcoma botryoides)
     Malignant mesenchymal proliferation of immature skeletal muscle
     A rare condition, seen in children under 4 years old.
     Macroscopically- grape like mass, rounded and bulky, protruding out of the vagina
     Microscopically-
     Rhabdomyoblasts- small cells, spindle shaped and cross striations
     Cambium layer- groups of tumor cells lying under vaginal epithelium
     Central core of the mass- loose, myxoid stroma with many inflammatory cells.
     The tumor invades locally and can cause death by penetration to peritoneal cavity or obstruction of urinary tract.

Question 24

Cervical precanceroses

Answer 24

122. Cervical precanceroses:
     Cervical carcinoma goes through progressing levels of dysplasia and carcinoma in situ before its final state. This makes it possible to recognize the forming dysplastic changes by Pap screen:
     Early diagnosis
     Better prognosis and treatment methods.
     Premalignant lesions:
     Cervical intraepithelial neoplasia (CIN):
     Definition- dysplastic changes (an abnormal appearance of the cell—a precancerous lesion) visible on the cervical epithelium and further classified according to its spread:
     CIN-I: mild dysplasia, up to 1/3 of epithelial wall thickness is involved. 33% to reverse.
     CIN-II: moderate dysplasia, up to 2/3 of epithelial wall thickness is involved. 66% to reverse.
     CIN-III: almost full thickness involvement of epithelial wall, very unlikely to reverse.
     Carcinoma in situ (CIS) - full thickness involvement, irreversible.
     ** Very difficult to actually distinguish CIN-III from CIS, therefore often considered together.
     Squamous intraepithelial lesions (SIL):
     A second classification of the dysplastic changes according to the treatment approach
     The decision regarding treatment of patient is:
123. Ordered observation
124. Surgical treatment
     So the 3 CIN classes are further divided to:
     Low-Grade SIL- corresponds to CIN-I
     High-Grade SIL- correspond to CIN-II and CIN-III and CIS. 30-50% of untreated lesions progress to invasive cancer over a 30-year follow-up period
     Etiology and Pathogenesis:
     All These lesions are associated with:
125. HPV infections:
     The commonest STD- found in almost 90% of adult population.
     Highly associated with neoplasms of the lower female genitalia -cervix, vulva and vaginal canal
     Depending on the strain of HPV infection, different lesions can occur- see picture.
     HPV strains:
     High risk strains- 16,18,31,33
     Produce E6 (P53 inactivation) and E7 (RB inactivation)
     Tend to persist- integrate into the DNA
     Low risk strains- 6,11
     Usually found in condilomata acuminata
     Cause transient infection- clears after 1-2 years.
     Majority of infections are transient- cleared or become latent after 1-2 years
     High risk HPV strains tend to clear more slowly- posing a greater risk for malignancy development (usually after 10 years)
     common histological feature- All HPV viruses show koilocytic atypia
126. Risk factors for cervical dysplasia includes:
     multiple sexual partners
     young age of first intercourse
     high risk male sexual partner- with previous multiple sexual partners
     immunodeficiency- (cervical carcinoma is AIDS associated illness)
     smoking
     Oral contraceptives.
     Morphological findings:
     Macroscopy:
     Most commonly located at the transitional zone and the squamocolumnar junction
     Microscopy:
     abnormal cellular proliferation
     abnormal maturation
     cytologic atypia:
     nuclear pleomorphism
     increased N/C ratio
     hyperchromatic nuclei
     koilocytes- pathognomonic for HPV!
     increased mitotic activity
     Clinical finding:
     usually asymptomatic
     may present abnormal vaginal bleeding, mainly postcoital (following intercourse)
     Cervical cancer prevention:
     Primary prevention:
     include attempts to reduce the risk for infection with high risk HPV
     done by:
     vaccination- quadrivalent vaccine against 6,11,16,18, good for 5 years
     prevention of contact with HPV- education to safe sex
     Secondary prevention:
     based on early detection and treatment
     done by population screening methods like:
     Pap smear
     colposcopy
     HPV test
     Pap smear findings:
     All women above the age of 21 are recommended to have Pap screens annually.
     Technique- using a small brush, cells are collected from the cervix- from the transformation zone and around external os.
     Evaluation of the smear:
127. First we evaluate the adequacy of the specimen:
     Satisfactory for evaluation
     Satisfactory but limited
     Unsatisfactory for evaluation
128. Than we give general diagnosis- normal or abnormal smear
129. Descriptive diagnosis:
     Benign cellular changes
     Reactive cellular changes
     Abnormalities of epithelial cells
130. Cellular abnormalities are further divided to:
     ASCUS- atypical squamous cells of undetermined significance
     L-SIL
     H-SIL
     Limitations of the Pap smear:
     Inadequate sampling of the transformation zone results in false-positive results
     Limited detection ability of adenocarcinoma
     Diagnosis- actual diagnosis following Pap smear is done by colposcopy and biopsy.

Question 25

Neoplasms of uterine cervix

Answer 25

123. Neoplasms of uterine cervix:
     Cervical cancer is usually of carcinoma type
     Pseudotumors:
     Endocervical polyp
     Benign tumors:
     Squamous cell papilloma
     Condyloma accuminatum
     Leiomyoma
     Malignant tumors:
     Epithelial tumors:
     Definition- Invasive carcinoma that arise from the cervix epithelium.
     Incidence- most commonly seen in women >40- the precancerous lesions take time to progress to actual carcinoma.
     Epidemiology:
     Decrease in frequency in developed countries- due to early detection of CIN in Pap screen
     Higher incidence in developing countries- 3rd leading cause of cancer mortality
     Risk factors: same as for precancerous lesions
     multiple sexual partners
     young age of first intercourse
     high risk male sexual partner- with previous multiple sexual partners
     immunodeficiency- (cervical carcinoma is AIDS associated illness)
     smoking
     Oral contraceptives.
     Chlamydia trachomatis infection
     Morphology:
     Macroscopy:
     Invasive cervical carcinoma can appear in 3 forms:
     Fungating- most common, appears as cauliflower-like growth, infiltrating the adjacent vaginal wall.
     Ulcerating-
     Infiltrating
     Usually located at the transitional zone or at the squamocolumnar junction
     Characterized by infiltration and destruction of its environment- bladder, rectum, lymph-nodes and vagina.
     Metastasis can be found in: lungs, liver, bone marrow and kidney
     Microscopy: there are 3 possible patterns:
     Epidermoid (squamous cell) carcinoma:
     The most common invasive cervical carcinoma (75%)
     The cells may be of different patterns:
     Moderately differentiated non-keratinizing large cells- 70%, better prognosis
     Well-differentiated keratinized- 25%
     Small cell undifferentiated (neuroendocrine)- 5%, poor prognosis
     Adenocarcinoma:
     Responsible for 20% of invasive call carcinoma
     Glandular architecture of cells
     May produce mucus (depends on histotype of the cells:
     Cells can be:
     Mucinous
     Endometrioid
     Clear cell
     Serous
     Others: the remaining 5% are a variety of other cancers such as adenosquamous carcinoma, verrucous carcinoma, and undifferentiated carcinoma.
     Clinical staging:
     Because of its tendency to locally spread- we can stage it according to the local spread
     Stage 0- carcinoma in situ
     Stage 1- carcinoma confined to the cervix
     Stage 2- extending beyond the cervix, but not to pelvic wall and not to lower 1/3 of vagina
     Stage 3- extending to pelvic wall, lower 1/3 of vagina, but not the rectum
     Stage 4- Extends beyond true pelvic, involving mucosa of bladder or rectum, or have metastatic disseminations.
     Clinical manifestation:
     Bleeding- mainly after intercourse
     Hydronephrosis and kidney failure- due to invasion of tumor into the bladder, obstructing the ureter

Question 26

Neoplastic diseases of endometrium

Answer 26

125. Neoplasms of uterine body:
     Pseudotumors:
     Endometrial polyp:
     Definition- exophytic proliferation on the tissue surface
     Incidence- common, seen in up to 25% of endometrial biopsy done due to abnormal uterine bleeding.
     Cause- believed to be related to hyperestrogenism
     Risk- patients taking tamoxifen (drug treating breast cancer) it has a pro-estrogenic effect on the endometrium.
     Important- polyp is not a diagnosis, it is just a macroscopic description. The origin of the polyp can be tumor origin, hyperplasia, or many other origins, therefore it must always be histologically examined to determined its origin

Malignant tumors:
Endometrial tumors:
Endothelial Tumors of the female genitalia are miliary tumors- several types of carcinomas originating always from the same cell type but can occur in all different parts of the system (cervix, uterus, fallopian tubes, or ovaries) in different frequencies. That is due to the ability of the coelomic epithelium to differentiate into multiple type of cells, forming different types of carcinomas
The different types of carcinomas include:
Mucinous carcinoma- originating from mucinous cells in the cervix
Endometrioid carcinoma- originating from endometrial tissue
Serous carcinoma- arises from the secretory cells in the fallopian tubes
Clear cell carcinoma- un-known origin of cells.
The origin of the different carcinomas is highly important- each of them has a different treatment method and different prognosis.
The carcinomas are classified into 2 types according to their pathogenesis:
Type I carcinomas:
Low grade carcinomas- moderate differentiation and superficial invasion
Histologic subtypes:
Low grade Endometrioid
mucinous
Precursor lesion- endometrial atypical hyperplasia
Highly associated with PTEN- tumorsuppressor gene loss of function mutation.
Incidence- the most common type, occurs mainly around 60 years, and rarely before 40.
Etiology- the risk factors include:
Unopposed estrogen excess
Obesity
Diabetes
Hypertension
Nulliparous state- women who never gave birth.
Good prognosis- they cause abnormal heavy bleedingearly diagnosisgood prognosis
Type II carcinomas:
High grade carcinoma with aggressive behavior- poor differentiation and greater invasiveness
Incidence- usually women over 70
Histologic subtype:
High grade Endometrioid
Serous
Clear cell
Not related to estrogenic stimulation
Precursor lesion- endometrial intraepithelial carcinoma (cells look like serous carcinoma but with no invasion)
Associated with P53 mutation
Morphology:
Macroscopy-
2 possible structures:
Polypoid tumor
Diffused tumor
The tumor is exophytic
Fragile irregular gray-tan mass
Involves also the cervix in 20% of cases.
Metastasis to surrounding lymphatics and to distant sites like lungs liver and bones
Prognosis- depends on the histological type, grading and staging:
Grading: depends on the amount of glands and solid mass ratio
G1- well differentiated cells, <5% solid masses
G2- moderately differentiated cells, 6-50% solid masses
G3- poorly differentiated cells, >50% solid masses.
Staging- depends on invasion and metastasis:
Stage I- confined to corpus uteri
Stage II- involves also the cervix
Stage III- extends out of uterus but limited to true pelvic
Stage IV- extends out of the true pelvic, or involve wall of bladder or rectum.
Mesenchymal tumors:
Leiomyoma:
Definition- benign proliferation of smooth muscle arising from the myometrium
Incidence- common, found in 20% of women above 30, before menopause
Etiology- associated with estrogen exposure- increase during pregnancy and shrink during menopause.  RHYTHMIC TUMOR [?]
Morphology:
Location- can appear in different layers of myometrium:
Intramural- within the myometrium, most common
Subserosal- within the serosa
Submucosal- beneath the endometrium
Macroscopy:
spherical, firm, multiple tumors
gray-white color, Pale
sharply demarcated
microscopically:
composed of smooth muscle cells and connective tissue
Clinical manifestation- usually asymptomatic. Can present with uterine bleeding, pelvic pain and infertility.
Complications- can evolve to malignancy in 0.5 of cases

Leiomyosarcoma:
Definition- malignant proliferation of smooth muscle arising from myometrium
Incidence- uncommon tumor, seen in postmenopausal women
Etiology- arises de-novo,
Morphology:
Macroscopy:
Single lesion
Soft and fleshy mass, poorly demarcated
Usually located intramural
averages 6-9 cm in diameter
cut surface: gray-yellow or pink, often with areas of necrosis and hemorrhage
microscopically:
high mitotic activity- more than 10 mitosis per HPF
cellular atypia is usually seen
The more mitosis- worse prognosis.
Prognosis- poor prognosis: 5 year survival rate 15-25%
Mixed epithelial and mesenchymal tumor:
Carcinosarcoma:
Definition- a malignant mixed mullerian tumor, Composed of malignant epithel + mesenchymal cells.
Frequently have a polypoid appearance
Has poor prognosis.

Question 27

Epithelial ovarian neoplasms

Answer 27

128. Epithelial ovarian neoplasms:
     The ovary is the 3rd most common site of primary malignancy in female genitalia.
     Its etiology is not as clear as the one of cervical or endometrial tumors, but 3 risk factors are common for all:
129. Nulliparity- higher incidence of ovarian cancer in women with little or no children.
130. Heredity- 10% of ovarian cancers are of genetic association- mainly BRKA 1 and 2
131. Complex genetic syndromes- several syndromes are associated with ovarian cancer:
     Lynch syndrome
     Peutz-Jeghers syndrome1- associated with sex-cord stromal tumors
     Gonadal dysgenesis- gonadoblastoma.
     Classification of ovarian tumors:
132. Tumors of surface epithelium- the most common type
133. Tumors of germ cells- similar tumors are seen in the male testicles
134. Sex-cords stromal tumors- heterogeneous and relatively rare
135. Metastatic tumors- secondary tumors
     Tumors of surface epithelium:
     Tumors originating from the coelomic epithelium lining the surface of ovaries.
     Classifications:
     classified according to appearance:
136. Gross appearance- a less important classification in clinical aspect:
     Cystadenoma
     Cystadenofibroma
     Adenofibroma
     Surface papilloma
137. Microscopic appearance- the important classification regarding treatment and prognosis:
     Serous tumors:
     Low grade
     High grade
     Endometrioid
     Mucinous
     Clear cell
     According to their behavior:
     All tumors are further divided into 3 types:
     Benign- single layer of well differentiated columnar cells, if papillary- the projections are covered by same epithelium, no invasion to stroma. Form cystadenomas
     Malignant- poorly differentiated epithelial cells, multilayered, stromal invasion, with very poor prognosis.
     Borderline- tumors with low malignancy potential, they have some morphological malignant features such as multiple layers, nuclear abnormalities, or increased mitotic activity, but they are non-invading. Much better prognosis than malignant tumors.
     Benign tumors- cystadenoma
     Morphology:
     Composed of a single cyst, usually unilateral
     Single layer of cell lining the cyst
     Incidence- Most commonly seen in premenopausal women around 30-40 years.
     Clinical manifestation-nonspecific symptoms:
     Pelvic pain and discomfort
     Asymptomatic pelvic mass
     Ascites- due to irritation the tumor causes in the peritoneal cavity leading to hypersecretion of fluid and ascites.

Serous:
Incidence- the commonest type of ovarian tumors
Histogenesis-cells resemble secretory cells in the fallopian tubes
Serous cystadenoma:
A single cyst with a single flat lining- covered by serous cells, filled with serous secretion.
Seen in women in premenopausal age (30-40)
Microscopic papillae can appear
Mucinous:
Incidence- less common than serous ones.
Histogenesis- cells resembles the mucinous cells in the cervix
Mucinous cystadenoma:
Large than serous tumors (the largest tumor in the world was 136 kg!)
The cyst is multilocular- divided by thin septa full of thick gelatinous fluid
The cells have basal nuclei and apical mucinous vacuoles.
Usually no papilla are seen on the surface.
Endometrioid:
Called endometrioma
Chocolate cyst
Brenner tumors:
Incidence- uncommon, 2% of all ovarian tumors
Histogenesis- transitional epithelium (urothelium)
Morphology:
Macroscopy: solid, pale-yellow-tan, appears encapsulated
Microscopy- nests, and columns of urothelium, scattered in fibrous stroma. coffee bean nuclei on H&E staining
Cystadenofibroma:
Histogenesis- bundles of spindle shaped fibroblasts (proliferation of the fibrous stroma underlying the lining epithelium).
Microscopy- the epithelial lining can be mucinous, serous, Endometrioid or transitional

Borderline tumors
Morphology:
Increased epithelial proliferation- multiple layers of cells
Non-invasive
Has a metastatic potential, but very low.
Clinical manifestation- similar to those of benign tumors.
Complications of borderline tumors:
Develop to carcinoma
Local complications due to spread of the tumor to the abdominal cavity- causing local changes.
Complications due to therapy- surgical or chemotherapy
Borderline serous lesions- micropapillary carcinoma:
Increased number of papillary projections, often bilateral
Stratification of the epithel with some nuclear atypia but no invasion.
Precursor lesion to low grade serous carcinoma.
Borderline mucinous tumor- atypical proliferation:
Stratification of lining epithel- 2-3 layers of cells.
No stromal invasion

Malignant epithelial tumors (cystadenocarcinoma) - ovarian cancer:
Incidence- ovarian cancer represents 30% of cancers of female genitalia, 90% of them are epithelial tumors.
Risk factors:
age- increased incidence in postmenopausal women
reproductive factors:
early menarche
late menopause
high socioeconomic status- due to less pregnancies at older age
BRCA1 and 2
Protective factors:
Increased parity
Oral contraceptive use- for more than 5 years of use, a beneficial side effect
Surgically induces hysterectomy, salpingo-oophorectomy- in patients with genetic predisposition.
Pathogenesis- it was previously believed that all of these tumors arise from the surface epithel of the ovary. These days, researches showed that most of these tumors arise from other primary tumor locations (such as fallopian tubes) that developed as inclusions, or arise as metastatic secondary tumors.
Clinical manifestation- generally appear at late stages of the disease:
Nonspecific Abdominal symptoms- pain and fullness
Signs of compression within the pelvic- increased urination frequency
Ascites- due to metastasis to peritoneum (omental caking in greater omentum- thickening of it).
Prognosis- depends on histogenesis, grading and staging (TNM)
CA 125 tumor marker- elevated in ovarian cancer, used to monitor treatment and screen for recurrence.
Serous carcinoma:
Can be high or low grade- depending on atypia of cells and rate of progression.
Both are cystic- cystadenocarcinoma composed of complex cysts with thick shaggy lining
High grade serous carcinoma:
Incidence- 70% of epithelial carcinomas
Pathogenesis- the tumor can originate from:
Intraepithelial carcinoma in the tubal fimbriae- spread and cause secondary tumor in the ovary
Endosalpingiosis- presence of fallopian tube epithelium out of the fallopian tube. Inclusion of the fallopian tube epithelium into the ovary can lead to carcinoma.
Surface epithelium of the ovary that invades the ovary.
Morphology-
Frequently bilateral
Marked nuclear atypia
Psamoma bodies- concentric calcifications
Large amounts of solid or papillary tumor mass.
Complications- local spread, mainly to peritoneum.
Prognosis- bad due to late diagnosis of the disease.
Low grade serous carcinoma:
Incidence- accounts for <5% of epithelial tumors
Precursor lesion- serous borderline tumor
Morphology- destructive infiltrative growth, but progresses slowly and therefore years of survival with this tumor are greater than the high grade type.
Endometrioid tumors:
Incidence- accounts for 10% of epithelial ovarian cancers, in 15-30% of cases endometrial adenocarcinoma is also found.
Precursor lesion- endometriosis
Morphology:
Macroscopy: tumors are partly solid and partly cystic
Microscopically: Glandular pattern- resembles the one of Endometrioid adenocarcinoma
Prognosis- 5 years survival rate- 75%

Clear cell tumors:
Incidence- accounts for 10% of ovarian epithel cancers.
Precursor lesion- endometriosis
Morphology:
Macroscopy- cystic or solid tumors- cyst is lined by clear cells, and solid tumors- cells are in sheets.
Microscopically- large clear cells with abundant glycogen in their cytoplasm
Complications- tends to be aggressive and spread beyond the ovary.
Prognosis:
If no metastasis- 65% survival over 5 years
If already spread- 5% survival over 5 years.
Mucinous tumors:
Incidence- accounts for 3% of malignant epithelial tumors
Precursor lesions- believed to be:
Endometriosis
Walthard nests- Mucinous metaplastic cells clustered together in the connective tissue of fallopian tube
Germ cell origin

Question 28

Germinal tumors of ovary

Answer 28

129. Germinal tumors of ovary:
     Different tumor types, derived from the primitive germ cells.
     Incidence:
     2nd most common ovarian tumors (30% of cases)
     Seen mainly in women of reproductive age- 15-30 years.
     Classifications- the tumors have different subtypes, representing the different tissues that are normally produced by germ cells:
     Embryonal tissue- teratoma (cystic teratoma)
     Yalk sack tissue- yolk sack tumor
     Chorion and placenta- Choriocarcinoma
     Germ cells themselves- dysgerminoma
     Teratoma:
     Definition- a cystic tumor composed of fetal tissue, derived from the 3 embryonic layers (endoderm, mesoderm, ectoderm). Within the tumor hair, bone, teeth, skin and more structures can be found
     Incidence- the most common germ cell tumor in females, bilateral in 10% of cases.
     Pathogenesis- it is believed that this tumor arises from a single ovum after its first meiotic division.
     Classification- teratoma are classified into 3 subtypes according to the character of the cells within it
     Mature teratoma- benign:
     The most common form of the lesion
     Mature differentiated tissue elements
     Usually cystic with Rokitansky’s protuberance- solid protrusion due to hard tissues in the cyst.
     The thin wall of the cyst is lined by wrinkled epithelium and hair shafts protruding it.
     Many types of tissues- skin and its adnexa, cartilage, bone, and also neuronal tissue.
     1% of tumors can go through malignant transformation of its mature structures (somatic teratoma).
     Immature teratoma- malignant:
     The components of the lesion include immature embryonal structures
     Rare- 0.2% of all ovarian cancers
     More common in pre-pubertal women (under 20 years)
     Macroscopy:
     Solid tumor
     Areas of necrosis and hemorrhage
     Admixture of tissue elements- hair, bone, cartilage or others can be present.
     Microscopy:
     Immature cells of many tissue types
     The most common type- immature neuro-ectodermal tissue.
     The grading of the tumor and its tendency to metastasize depends on the amount of neuro-ectodermal tissue within it.
     somatic teratoma:
     When the fetal tissue cells composing the tissue acquire a somatic mutation.
     Occurs in 1% of benign teratomas
     Most commonly of the squamous skin cells squamous cell carcinoma.
     Specialized teratoma:
     Teratomas composed of a single tissue type
     2 important forms are mentioned:
     Struma ovarii- teratoma composed only of thyroid tissue, can lead to hyperthyroidism
     Carcinoid tumor- arising from enteroendocrine cells of intestinal epithelium. Can lead to carcinoid syndrome if producing 5-HT (serotonin receptor)

Dysgerminoma:
Definition- malignant tumor of large cells with clear cytoplasm and large nuclei originating from germ cells. Represents the ovarian parallel of testicular seminoma.
Incidence- the most common malignant germ cell tumor, occurring in childhood or ages 10-30.
Morphology:
Macroscopy:
Solid mass
In cut section: gray-white, lobulated and soft
Foci of hemorrhage and necrosis
Microscopy:
Cells are arranged in islands, separated by a thin fibrous stroma
Cells are large with clear cytoplasm- full of glycogen (“fried egg” cells)
Lymphocytic infiltrate can be seen
Tumor markers- hCG and LDH
Treatment and prognosis- the tumor is highly reactive to radiotherapy, giving it a good prognosis.
Yolk sac tumor (endodermal sinus tumor)
Definition- malignant tumor that mimics the yolk sac
Incidence- the most common germ cell tumor in children
Morphology:
Macroscopy: solid tumor, yellow, and friable (with hemorrhages).
Microscopy:
Schiller-Duval body: glomeruloid structure- central blood vessel, enveloped by germ cells, within a space lined by germ cells (Represents a papillary projection with a central blood vessel within it).
PAS positive hyaline globules- composed of alpha-fetoprotein (AFP).
Tumor markers- alpha-fetoprotein and alpha 1 antitrypsin
Prognosis and treatment- a highly aggressive tumor
Choriocarcinoma:
Definition- a malignant proliferation of placental-like tissue. Composed of trophoblasts (syncytiotrophoblasts and cytotrophoblasts) without villi. Extra-embryonic malignant differentiation.
Classification- Choriocarcinoma can be related to gestation or non-gestational originating in the ovary. We now discus only the non-gestational germ cell composed, originating tumor.
Incidence- seen in girls under 20 years.
Morphology:
Macroscopy: hemorrhagic, soft and fleshy mass.
Microscopy:
Usually appears in combination with other germ cell tumors
No villi are present- only trophoblasts
Tumor markers- high levels of HCG
Treatment and prognosis:
Very aggressive- disseminates by blood (highly survive in blood stream!) stream to lung, liver, bone, brane and kidney
Non-responding to chemotherapy and commonly fatal.
Embryonal carcinoma:
Definition- malignant tumor composed of large primitive embryonal cells.
Histologically similar t tumors arising in testes
Very aggressive with early metastasis.

Question 29

Gonadostromal and mixed tumors of ovary

Answer 29

130. Gonadostromal and mixed tumors of ovary:
     Gonadostromal tumors:
     Definition- tumors originating from specialized ovarian stromal cells of the developing gonads- the sex cords. Including:
     Granulosa cells granulosa cell tumor
     Theca cells thecoma
     Sertoli and leydig cells leydig and sertoli cells tumors
     Fibroblasts of stromal origin fibroma or fibrosarcoma
     Incidence- comprise 8% of all ovarian cancers.
     These cells normally secrete sex hormones- therefore has either a feminizing or masculinizing effect.
     Granulosa-theca cell tumors:
     A group of tumors that includes:
     Pure granulosa cell tumors
     Pure thecomas
     Combination of granulosa-theca cell tumors
     Fibromas and fibrothecomas
     Granulosa cell tumor:
     Definition- A malignant tumor of granulosa cells
     Incidence- may occur in all ages, each will show different symptoms.
     The tumor often secrete estrogen- causing clinical manifestations of the patient:
     In pre-pubertal young girls- premature puberty appears
     In middle age women- heavy menstrual bleeding
     In post-menopausal women- endometrial hyperplasia and post-menopausal bleeding.
     Morphology:
     Macroscopy- small, solid, usually unilateral tumor.
     Microscopically- Call-Exner bodies: nests of granuloma cells trying to form primitive follicles.
     Prognosis- 10- years survival rate is 85%
     Complications- due to estrogen secretion- endometrial carcinoma, cystic disease of the breast
     Tumor marker- inhibin will be elevated in serum

Thecoma:
Definition- neoplasm of the theca cells, when pure (only Thecoma) it’s almost always benign.
Incidence- mainly seen in postmenopausal women
Morphology:
Macroscopy- firm mass, up to 10 cm, yellow cut-section.
Microscopy- spindle shaped theca cells- cytoplasm full of lipid vacuoles positive lipid staining.
Clinical manifestation- tumor secretes estrogen causing endometrial hyperplasia and bleeding
Complications- because of estrogen secretion endometrial carcinoma, cystic disease of the breast
Granulosa-theca cell tumors:
Combined tumors
Fibromas and fibrothecomas:
Definition- benign tumor of the ovarian stromal fibroblasts, occasionally mixed with theca cells (these are called fibrothecoma).
Incidence- relatively common- 4% of ovarian cancer.
Morphology:
Macroscopy- unilateral (in over 90% of cases), firm, large and fibrous.
Microscopy- spindle shaped fibroblasts and collagen. Theca cells in fibrothecoma.
Clinical manifestation-
Meig’s syndrome: ovarian tumor, ascites and pleural effusion.
Pooling sensation in the groin

Sertoli-Leydig cell tumors:
Definition- a tumor that mimics the sex cords stromal cells of the testicles.
Incidence- can occur in all ages, peak incidence around 30 years.
Morphology:
Macroscopy- resemble granulosa-theca cell tumors
Microscopy- mimic the organization of testes, classified according to:
Well differentiated- cells forming well defined tumors
Intermediate differentiation- immature tubules
Poorly differentiated- spindle cells resembling sarcoma with interspersed leydig cells.
Reinkes crystals- cytoplasmic inclusions found in the leydig cells
Clinical manifestation- masculinization of the patient due to production of androgens by the tumor- causing breast atrophy, amenorrhea, sterility and more.
Mixed tumors of ovary:
Gonadoblastoma:
Definition- complex neoplasm composed of a mixture of gonadal elements- such as large primordial germ cells, immature Sertoli cells or granulosa cells of the sex cord, and gonadal stromal cells. Usually benign
Incidence- very rare, associated with dysgenetic gonads, mainly in females. Typically seen under 30 years.
Morphology: a mixture of germ cells and sex cords components.
Clinical manifestation- this tumor I highly associated with chromosomal abnormalities such as:
Androgen insensitivity syndrome
Turner syndrome
So it manifests as women with amenorrhea, palpable abdominal mass or virilizing features.
Metastasis to the ovary:
10% of ovarian cancers are secondary carcinomas.
The metastasis can be from:
Tumor of mullarian origin- such as uterus, fallopian tubes, or contralateral ovary.
Hematogenous spread- of tumors from far organs such as stomach.
Two types are especially mentioned:
Krukenberg tumor:
Definition- bilateral mucinous carcinoma of ovaries, originating most commonly from primary diffused gastric carcinoma that metastasized to ovaries.
Morphology:
Macroscopy- bilateral firm large masses, white on cross section with areal of necrosis and hemorrhage.
Microscopically- signet ring cells- giant cells full of mucus with peripheral nucleus.
Pseudomyxoma peritoneii:
Definition- clinical condition describing abundant amount of mucin present in the peritoneum, usually originating from mucinous carcinoma of the appendix. The carcinoma tends to also metastasize to the ovaries.

Question 30

Neoplasms of breast

Answer 30

134. Neoplasms of breast:
     According to the breast normal histology- we can classify the neoplasms into
135. Epithelial tumors- arising mainly at the TDLU
136. Stromal tumors- further divided to:
     Intralobular stroma
     Interlobular stroma
     Epithelial tumors of the breast:
     Benign epithelial lesions:
     2 types of benign epithelial tumors- papilloma and adenoma:
     Papilloma:
     Definition- a benign fibrovascular finger like projection covered by both epithelial cells and myoepithelial cells.
     Incidence- mainly seen in premenopausal women
     Morphology:
     Macroscopy:
     Intraductal- within the large ducts, mainly in the lactiferous sinus, one big papilloma.
     Intracystic- within the small ducts, multiple smaller papillomas.
     Clinical manifestation- bloody nipple discharge due to damage to the papilloma.
     Adenoma:
     Definition- a benign, pure epithelial neoplasm of the breast.
     Incidence- seen during reproductive age
     Classification- can be tubular, lactating (more common) or apocrine (uncommon).
     Tubular adenoma-
     Macroscopy- solitary, well-circumscribed, firm mass.
     Microscopy- tightly packed tubular or acinar structures that are very regular in size and shape are seen with little amount of cellular stroma.
     Lactating adenoma-
     The most prevalent breast mass during pregnancy and puerperium.
     Macroscopy- small (<3cm), well circumscribed and lobulated tumor
     Microscopy- hyperplastic lobules with acini proliferation lined by actively secreting cuboidal cells.

Breast cancer- breast carcinoma:
Epidemiology:
Breast cancer is the commonest cancer in adult women (excluding skin cancer) (1:8)- more than 95% of breast cancers are adenocarcinomas:
2nd most common cause of women mortality (1st is lung cancer)
Average age is 64 years, increased risk with age
A slight decrease in incidence is seen due to early detection and screening
Second most common cancer producing death in adults.
Risk factors:
Female gender
Age
Prolonged estrogen stimulation:
Due to early menarche or late menopause
Due to Nulliparity and not breastfeeding
Obesity- aromatization of androstenedione to estrogen
Hormone replacement therapy in postmenopausal women
Family history and genetics:
First degree relative with the disease- (sister mother or daughter).
BRKA1 and 2- autosomal dominant inheritance
Li-Fraumeni syndrome- inactivation of P53 gene.
Atypical hyperplasia
Diet- high caloric diet, rich in animal fat and proteins
Lack of physical exercise

Signs and symptoms:
Clinical manifestations:
Palpable mass in the breast- usually at the upper outer quarter is the commonest sign.
Axillary lymphadenopathy (rarely)
Skin or nipple retraction
Nipple inversion
Nipple discharge
Changes in the shape or size of the breast
Hepatomegaly and one pain- if metastasis has occurred
Mamography- a screening test to detect un-palpable breast masses, doesn’t distinguish benign from malignant tumors:
Reduces death from breast cancer by about 1/3
Microcalcifications are detectable
In case of 5 or more clustered Microcalcifications- punctate (with tiny holes) or branching, suspected for breast cancer.
Prevention of breast cancer:
Primary prevention- reduce the risk of its development:
Healthy diet- low on fat, with weight control
Bilateral mastectomy- in patients with genetic predisposition after 40 years of age
Limit lifetime estrogen exposure- manage hormonal therapy
Secondary- early detection and cure:
Breast self examination- the most important prevention method
Mammography- annual testing above 40 years of age
Annual physical examination by a physician.

Classifications of breast carcinoma:
Breast carcinoma is classified according to:
1. location:
Within the TDLU- the carcinoma can be
Ductal
Lobular
2. Invasiveness:
Carcinoma in situ- up to basement membrane
Invasive carcinoma- penetrates the basement membrane.

Invasive carcinomas:
Invasive ductal carcinoma:
Also called non-special type (NST) invasive carcinoma.
Commonest group of invasive breast cancer- represents up to 80% of breast cancers
Morphology:
Macroscopy- irregular structure (stellate infiltration), grey-white on cut section, 1-5cm in diameter.
Microscopy- the general structure seen is duct like structures in a desmoplastic stroma. But the organization of the structure is very heterogeneous:
Architecture- solid, glandular, trabecular…
Tumor cells- varies from normal cells to highly atypical.
Tubular carcinoma- tumor is organized in tubules surrounded by a desmoplastic stroma. Highly resemble normal breast tissue- but the tubular cells have only one cell type- distinguishing them from the normal tubules. Very good prognosis!
Mucinous carcinoma- cuboidal tumor cells are seen floating in lakes of mucin, the tumor is softer than usually. Excellent prognosis, occurs especially in elderly women.
Medullary carcinoma- large tumor cells with syncytial arrangement and stroma infiltrated by multiple lymphocytes. The tumor has “brain like” texture, better prognosis. Associated with BRKA1 mutation
clinical manifestations- rock hard mass with sharp margins and skin dimpling
Invasive lobular carcinoma:
Definition- tumor of the lobular epithelium that grows into the connective tissue of the breast
Less common- responsible for 5% of breast cancer cases
Morphology:
Macroscopy- diffused growth pattern- poorly circumscribed with irregular growth.
Microscopy:
small cells with infrequent mitosis
noncohesive cells- individually dispersed or arranged in a single file linear pattern- lack E-cadherin

Inflammatory breast cancer:
Definition- a clinical pathological entity showing distinct clinical and pathological features:
Clinical features:
Rapid breast enlargement with skin changes- redness, edema and Peau d’orange skin.
Diffused firmness of the breast- usually without a palpable mass
Pathological features:
Dermal lymphatic invasion by the tumor cells- blocking lymphatic drainage
The underlying invasive carcinoma is usually of ductal type.
Important to think of in differential diagnosis when treating acute mastitis and Paget disease.
Prognosis is bad- the tumor has already invaded the lymph.

Non-invasive carcinomas:
Ductal carcinoma in situ (DCIS):
Definition- malignant proliferation of cells in the ducts, without invasion.
microscopically the tumor is classified into 4 subtypes that can appear in different combinations:
Solid pattern- tumor cells fill and plug the ductal lumen
Comedo pattern- necrotic cells in the center of the lumen surrounded by neoplastic cells in the duct
Papillary pattern- intraductal papillary projections, lacking a fibrovascular stalk (difference from intraductal papilloma)
Cribriform pattern- fenestrations in the intraductal tumor
Clinical manifestations:
Usually manifests without clinical symptoms- 80% of cases are detected by calcification in mammography.
Can produce a palpable mass and nipple discharge
Paget disease of the nipple- malignant glandular cells extend within the ductal system, via the lactiferous sinuses nipple skin epithelial layer- without crossing the basement membrane.
Paget disease is therefore usually associated with underlying ductal carcinoma. (Can also be seen in invasive ductal carcinoma).
Tumor cells manage to infiltrate to the epidermis, and extracellular fluid reaches the nipple surface- producing a crust on the nipple.
Macroscopically- the nipple is crusted, fissured, erythematoused with fluid discharge from the lesions.
Microscopically- Paget cells in the epidermis- large, spherical, hyperchromatic nucleus with a halo around.

Lobular carcinoma in situ:
Definition- malignant proliferation of cells in more than 50% of the acini of the lobules.
No clinical manifestations- no calcifications or mass, therefore it is recognized incidentally during breast biopsy taken from a different reason.
Morphology:
Macroscopy: no visible tumor is identified
Microscopy- acini are full of dyscohesive cells lacking E-cadherin
The lesions are commonly multifocal and bilateral
Treatment- LCIS is considered as a risk factor for developing invasive carcinoma in the future, so the approach is to conserve it in its current state and prevent its progression. That is done by:
Tamoxifen- anti-estrogen agent
Close follow up

Grading, staging and prognosis:
Histological grading and clinical staging together determines the clinical course and prognosis of the patient.
Histological grading- (determined according to the following parameters):
Histological type of tumor- all tumors are further classified to:
Non-metastasizing- DCIS and LCIS
Less commonly metastasizing- medullary, mucinous, papillary, tubular…
Commonly metastasizing- invasive ductal and lobular cacinomas and inflammatory carcinoma
Microscopic grading- according to 3 features:
Tubule formation
Nuclear pleomorphism
Mitotic count
Tumor size- the greater the tumor, the worse the prognosis
Axillary lymph node metastasis- number of involved node and their proximity to the tumor.
Estrogen and progesterone receptors- positivity for receptor is of better respond to therapy
Her2- human epidermal growth factor receptor 2:
A proto-oncogene encoded by the ERBB2 gene
This gene is over expressed in 20-30% of breast cancers
Associated with worse prognosis and increased disease recurrence
Responsive to Herceptin (trastuzumab) treatment
DNA content- aneuploidic tumors have worse prognosis
Clinical staging- by the American Joint Committee of cancer (AJCC) (modified TNM method)
The cancer is staged from 0-4 according to the histological grading and spread of the tumor:
Prognosis:
Overall, generally speaking the 10 years survival rates are 35-55%

Stromal breast tumors:
There are 2 types of stroma in the breast, each giving rise to different tumors:
Intralobular tissue- fibroadenoma and phyllodes tumors
Interlobular tissue- lipoma, sarcoma, fat necrosis
Fibroadenoma:
Definition- benign tumor of fibrous tissue and epithelial glands
Incidence- the commonest benign tumor of female breast, usually seen in women <30 years.
Hormonal sensitive- the tumor epithel is estrogen sensitive and increases in size during lactation and pregnancy.
Morphology:
Macroscopy:
Marble-like, movable, well circumscribed, usually up to 3cm in diameter.
May be multiple
Grey-white in cut surface.
After menopause- becomes dense and hyalinized
Microscopy:
Admixture of stromal and epithelial proliferation
Complications- no increased risk for carcinoma.

Phyllodes tumor:
Definition- Fibroadenoma-like tumor with overgrowth of the fibrous components. Usually benign.
Incidence- uncommon tumor, usually seen in women around 50-60 years
Morphology:
Macroscopy-
4-5 cm, but can reach 10<
Well circumscribed
Grey-white on cut surface with areas of hemorrhage and necrosis
Whorled pattern- resembling leaf buds
Microscopy- stromal hypercellularity, can be classified to benign, malignant or borderline according to:
Mitotic activity
Cytologic atypia
Nature of tumor borders

Question 31

Neoplasms of the brain and meninges

Answer 31

146. Neoplasms of the Brain and Meninges: Robbins – 1306, Goljan – 720, Harsh – 886, F.A – 496, Kp -288 22/4/2017
     Epidemiology: - CNS tumors can be:
147. Primary – 50% - to more. Very important – malignant tumors rarely metastasize.
     Adults – mostly arise above the tentorium.
     Frequency – glioblastoma multiforme (GBM) > meningioma.
     Children – 2nd most common cancer in children (after hematopoietic). Mostly below tentorium.
     Frequency – medulloblastoma > Pilocytic astrocytoma > brain stem glioma.
148. Metastatic – up to 50% - most commonly from the lungs, breast, and kidney. Compared to primary tumors they are – multiple, well circumscribed, located at the junction between the white and grey matter (all opposite than primary).
     Clinically:
     Headache + vomiting – worse at night, person wakes up.
     Seizures – especially when involving the cerebral cortex.
     Symptoms of ↑ICP – peritumoral edema, blockage of CSF flow.
     Focal neurological symptoms – depends on the area of the brain involved.
     Mental changes – e.g., deficits in memory, concentration…
     Grading – WHO grading of CNS tumors – Grades I to IV, as - Grade I – well circumscribed, slowly progressive, cured by resection  Grade IV – highly malignant, rapidly fatal.
     Classification – WHO (classification) – histologic classification based on cell type:
149. Neuroepithelial tissue – neuronal tissue – divided into:
     Gliomas – most common 1o tumors - astrocytomas, Oligodendrogliomas, and ependymomas.
     Neuronal tumors – far less common – gangliogliomas, central neurocytoma, and dysembryoplastic neuroepithelial tumor.
     Choroid plexus tumors – choroid plexus papilloma  choroid plexus carcinomas.
     Pinealoma
150. Embryonal tumors / poorly differentiated – medulloblastoma, and atypical teratoid/rhabdoid tumor.
151. Meningeal tumors – meningioma.
152. Germ cell tumors – germinoma, embryonal carcinoma, yolk sac tumor, and teratoma.
153. Peripheral nerves tumors – Schawannoma, neurofibroma, malignant peripheral nerve sheath tumor.
154. Primary CNS lymphomas.
155. Tumors of the sellar (sella turcica) region – craniopharyngioma.
156. Mesenchymal – hemangioblastoma, sarcoma.
157. Metastatic tumors.
     Neuroepithelial tissue tumors:
     Gliomas:
     It’s no longer thought that these tumors derive from the mature cell type, but probably arise from a progenitor cell that [referentially differentiates to one of the glial cells;
158. Astrocytoma – most common gliomas – 70% of all neuroglial tumors. Pathological classification used to be based on 3 histologic grades: fibrillary, protoplasmic (based on type of astrocytes) and gemistocytic (neoplastic astrocyte with eosinophilic cytoplasm). Today, it’s done by the WHO:
     WHO classification divides the astrocytomas based of grading. Low grade astrocytomas are more frequent in children and young patients and high grade astrocytomas in adults. These are divided into 2 categories:
     Diffusely infiltrating astrocytomas – Grades II – IV - include:
     Grade II – diffuse astrocytoma – arise everywhere, but most commonly in the frontal lobes. Can be fibrillary or protoplasmic. Survive > 5 years.
     Macroscopy – poorly defined, grey-white, infiltrative mass that distorts the invaded brain. Range from a few cm  expand to a size that replaces an entire hemisphere. May appear demarcated, but spreads below.
     Microscopy – well-differentiated astrocytes (transition between neoplastic to normal tissue is indistinct), with cellular density greater than the white matter, no atypia or mitoses.
     Grade III – anaplastic astrocytoma – intermediate between II and IV:
     Macroscopy – like diffuse astrocytoma.
     Microscopy – more densely cellular, more atypia and mitotis, gemistocytic astricytome.
     Grade IV – glioblastoma multiforme (GBM) – malignant, high-grade, most aggressive astrocytic tumor. Most common malignant CNS tumor in adults. Very poor prognosis – 15 months survival.
     Macroscopy – necrotic, hemorrhagic, infiltrating mass – with some areas of yellow necrosis, and others of hemorrhage and cysts. Characteristically crosses the corpus callosum, thus also termed “butterfly glioma”.
     Microscopy:
     Pseudo-palisading nexrosis – areas of necrosis in a serpentine manner, surrounded by rows of neoplastic cells (palisading = to line up).
     Vascular/endothelial cell proliferation – vessels with at least double-layer of endothelium. Due to VEGF.
     Gliomatosis cerebri – a diffuse glioma with extensive infiltration of multiple regions in the brain, even the entire brain. Grade III-IV.
     Localized astrocytomas – Grade I:
     Pilocytic astrocytoma – benign tumor of astrocytes, most common CNS tumor in children, usually arises in the cerebellum.
     Macroscopy – cystic lesion with a mural nodule (nodule of the tumor next to the cyst).
     Microscopy:
     Spindle-shaped fibrillary neoplastic astrocytes – long bipolar processes.
     Rosenthal fibers – thick eosinophilic structures derive from
     hypertrophic processes of astrocytes.
     Pleomorphic xanthoastrocytoma – looks pleomorphic and alarming, but has favorable prognosis.
     Diagnosis – besides the usuall imaging (MRI, CT, PET):
     GRAP positive – glial fibrillary acidic proteic – the intermediate filaments in all glial cells. Immunohistochemistry with antibodies against them.
159. Oligodendroglioma – infiltrating malignant tumors of oligodendrocytes (grade II-III), occurring in adults (40s-50s). average survival – 5-10 years.
     Pathology – usually involving the frontal lobe, especially in the white matter.
     Macroscopy – well-circumscribed, grey-white, gelatinous masses with cysts – which tend to calcify – seen on imaging.
     Microscopy:
     Fried-egg cells – cells look like eggs – nucleus is the center, with a very pale cytoplasm.
     “Chicken-wire” capillary pattern –network of anastomosing capillaries.
     Clinically – presenting with seizures.
     ** Oligoastrocytomas – mixed oligodendroglioma with neoplastic astrocytes (astrocytoma).
160. Ependymoma – malignant tumor of the ependymal cells lining the ventricles and central canal of the spinal cord. Poor prognosis, tend to recur after surgery. Frequently associated with neurofibromatosis type 2.
     Epidemiology – more common in children, but can also occur in adults:
     Children – arise in the 4th ventricle.
     Adults – arise in the spinal cord, usually in the cauda equina.
     Pathology:
     Macroscopy – well circumscribed papillary exophytic mass, projecting into the lumen.
     Microscopy – neoplastic cells resemble ependymal cells and form:
     Ependymal rosettes – cells create a lumen and organize around it (like around a canal).
     Perivascular pseudorosettes – cells arranged around vessels with their ependymal processes directed toward the vessel.
     Blepharoplasts – basal body of the cilia is seen near the nucleus.
     Clinically – may present with hydrocephalus.
     Neuronal tumors:
     Since neurons are non-dividing cells, their tumors are much less common than glial tumors. In general, these tumors are seen in younger adults and present with seizures. The main neuronal tumors are:
161. Gangliogliomas – most common - mixed tumors of mature neuronal and glial cells. Mostly in the temporal lobe, cystic, and slow growing unless the glial component becomes anaplastic.
162. Dysembryoplastic neuroepithelial tumor – grade I, mostly in the temporal lobe, multiple nodelus of small cells arranged in columns in a myxoid background. Good prognosis.
163. Central neurocytoma – low-grade (II), found within the ventricles.
     Choroid plexus tumors:
164. Choroid plexus papillomas – mostly in children in the lateral ventricles (if in adults – in the 4th ventricle). The neoplasm forms a papillary structure looking exactly like the choroid plexus. Usually present with hydrocephalus due to obstruction of the ventricular system. May progress to:
165. Choroid plexus carcinoma – very rare, resemble adenocarcinoma. Mostly in children. In adults, they must be differentiated from metastatic carcinoma, which is much more common.
     Pinealomas:
     Tumors of the pineal gland, arising from pineocytes, which have features of neurons.
166. Pineocytomas – well-differentiated, with no evidence of mitoses and necrosis. Affect adults.
167. Pineoblastomas – high-grade, anaplastic, with mitoses and necrosis, commonly spread through the CSF. Affect children.
     Histologically they resemble germ cell tumors – e.g., seminoma.
     Complications:
     Parinaud syndrome – compression of the tectum  vertical gaze palsy.
     Obstructive hydrocephalus – compression of the cerebral aqueduct.
     Precocious puberty in males – produces hCG.
     .
     Embryonal tumors / poorly differentiated neoplasms:
     These tumors have no markers of mature neural cells, poorly differentiated, and retain cellular features of primitive, undifferentiated cells. A.K.A PNET – primitive neuroectodermal tumors.
168. Medulloblastoma – most common brain tumor in children – malignant tumor (grade IV) of children derived from the granular cells of the cerebellum, thus they occur exclusively in the cerebellum. Poor prognosis.
     Pathology – usually located in the midline of the cerebellum.
     Macroscopy – soft grey-white mass, commonly compresses the 4th ventricle  leading to hydrocephalus.
     Microscopy:
     Small, round, blue cells – form densely sheets.
     Homer-Wright rossets – neoplastic cells wrap around small areas of neuritic processes.
     Clinically – poor prognosis – complications can be:
     “Drop metastases” - the tumor grows rapidly and spread to the CSF via the 4th ventricle  and goes down to the spinal cord.
     Hydrocephalus – when it compresses the 4th ventricle.
169. Atypical teratoid/Rhabdoid tumor – highly malignant (grade IV) tumor of young children arising in the posterior fossa. Characterized by tumor which differentiates to epithelial, mesenchymal, neuronal, and glial components.

Meningeal tumors:
1. Meningioma – benign tumor of arachnoid cells (meningothelial cells – line the dura but not adherent to it), occurring in adults.
Epidemiology – most common benign tumor in adults. Risk factors include:
Females > males – neoplastic cells have estrogen and progesterone receptors.
Radiation therapy – of head and neck.
Neurofibromatosis type 2.

Pathology – extra-axial (outside the brain parenchyma) - mostly arise in a parasagittal location, commonly in the olfactory groove.
Macroscopy – round encapsulated masses that compress (not invade) the underlying brain. Grow en plaque – spread in a sheet-like fashion along the dura (“tail”).
Microscopy – different types of meningiomas, with no prognostic significance:
Syncytial – whorled clusters of cells without apparent membranes, that when calcify form psamomma bodies.
Fibrinous – with elongated cells and collagen deposition.
Transitional (mixed) – syncytial + fibrous.
Secretory – with PAS-positive droplets.
Microcytic – with spongy appearance.
Clinically – often asymptomatic, may present with seizures (compression of underlying brain).
Diagnosis – imaging – reveal round masses attached to the dura.
Treatment – resection.
2. Atypical meningiomas – intermediate between benign and malignant (G-II) - grow more rapidly and are more prone to recurr after surgical resection. Show cellular atypias, and different patterns (clear cell and choroid).
3. Anaplastic meningiomas – malignant – rare, highly aggressive (G-III), anaplastic, which may invade the underlying brain or spinal cord. Can be:
Papillary – with pleomorphic cells arranged around fibrovascular cores.
Rhabdoid – sheets of tumor cells with hyaline eosinophilc cytoplasm (intermediate filaments).

Germ cell tumors:
Germinoma (same as seminoma, but in the CNS), embryonal carcinoma, choriocarcinoma, yolk sac tumors and teratomas. It’s unclear how they arrive to the CNS, may be remnants of development. Should be distinguished from metastasis from gonadal germ-cell tumors.

Tumors of cranial and peripheral nerves:
All are peripheral nerve sheath tumors, mostly arise from Schwann cells. Most are benign, commonly associated with familial tumor syndromes – NF1, NF2, and Schannomatosis.
1. Schwannomas (neurilemmomas) – benign tumor of Schwann cells.
Pathogenesis – associated with NF2 (even when sporadic involve this gene, when in NF2 - bilateral), and can arise either in the cranial (mostly involve CN VIII and V), spinal nerves, or along peripheral nerves, producing:
Acoustic schannoma – schanomma of CN VIII located in the cerebellopontine angle – manifested by tinnitus (ringing in the ears) and sensorineural deafness.
Intraspinal schwannoma – arise in the transition from oligodendroglial myelination  to Schwann cells myelination  thus tend to occur within the dura, usually in the thoracic region.
Peripheral nerves schwannoma – occur as solitary nodules, possibly on any sheathed nerve.
Pathology:
Macroscopy – well-circumscribed, encapsulated masses on the nerve.
Microscopy – mixture of hypercellular dark areas with hypocellular myxoid areas, termed:
Antony A – dense, hypercellular areas with palisading cells (lined-up). With Verocay bodies – the areas within the lines of cells.
Antony B – loose, hypocellular myxoid area.
Schwann cells are spindle-shaped.
Diagnosis – immunohistochemistry S-100 positive.
Treatment – surgical resection – good prognosis.

2. Neurofibromas – benign tumors composed of a mixture of Schwann cells and fibroblasts (and others – such as mast cells, and CD34+ spindle cells).
   Epidemiology – may be sporadic or associated with NF1.
   Pathogenesis – loss of NF1 gene  loss of neurofibromin which is an inhibitor of RAS.
   Pathology – different types of neurofibromas based on their growth pattern:
   Localized cutaneous neurofibromas – seen isolated if sporadic, or multiple if in NF1.
   Macroscopy – small nodular lesions in the dermis and subcutaneous tissue.
   Microscopy – hypocellular stroma with mixture of the tumor cells.
   Diffuse neurofibroma – NF1-associated.
   Macroscopy - present as plaque-like elevations of the skin – similar nodules as in the localized type, but the growth is different – the tumor diffusely infiltrates the dermis abd subcutaneous wissue, entrapping fat and produce plaque-like elevated nodules.
   Microscopy – Pseudo-Meissner corpuscles – focal collection of cells mimicking the appearance of Meissner corpuscles.
   Plexiform neurofibroma – the rumor grows within and expand nerves fascicles, under the perineurium which remains preserved, creating nodules encapsulated by the perineurium.
   Macroscopy – abnormally enlarged nerve, with “bag of worms” appearance due to thickening of multiple nerve fascicles.
   Microscopy – same as other neurofibromas.
3. Malignant peripheral nerve sheath tumors (MPNST) – high-grade tumors, may arise either de novo or from a pre-existing plexiform neurofibroma. 50% associated with NF1.
   Macroscopy – poorly-defined mass along the nerve, invading adjacent soft tissues.
   Microscopy – general appearance resemble a fibrosarcoma. Receives the name Triton tumor when has areas of rhabdomyosarcoma, cartilage, and bone.

Primary CNS lymphomas lymphomas:
Most common CNS neoplasms in immunosuppressed patients. These are multifocal in the brain parenchyma (while metastatic lymphomas rarely involve the parenchyma, and seen in the CSF). These are aggressive, with the worst outcomes compared to other lymphomas. B-cell origin. Commonly involve Epstein bar infeciotn. Mostly diffuse large B cell lymphoma, but also plasmocytoma.

Tumors of the Sellar region:
1. Craniopharyngoma – benign children tumors arising from epithelial remanants of the Rathke’s pauch (as the piruitary gland is formed from the brain [cranio] + pharynx [pharyngoma] – so remanents may stay close to the gland or on the sella torcica, but the tumor is not from the gland).
Macroscopy - presenting as a supratentorial mass in children, which may compress the optic chiasm and produce bitemporal hemianopia, thus it may be confused with pituitary adenoma. But if we have bitemporal hemianopia in a child we must think of craniopharyngioma. Calcification is common and seen in imaging.
Microscopy – cholesterol crystals with tumor cells, looks like fluid within the tumor.
2. Pituitary adenoma – question 160.

Mesenchymal tumors:
1. Hemangioblastoma – vascular tumors of the CNS. Occur either sporadic or part of von Hippel-Lindau syndrome. Characterized by a cystic mass containing hemorrhagic fluid, microscopically seen large number of thin-walled vessels.

Metastatic tumors:
Mostly from – lungs, breast, skin (melanoma), kidney, and GIT. Prostatic adenocarcinoma almost never metastasize to the brain. Form sharply demarcated masses at the junction of the grey and white matter.

Question 32

Tumors and tumor like lesionsof bones

Answer 32

154. Tumor and tumor like lesions of bone:
     Primary bone tumors are classified by the WHO according to both histogenesis and histologic criteria:
     Bone forming tumors.
     Cartilage forming tumors.
     Hematopoietic tumors.
     Fibrogenic tumors.
     Unknown origin.
     Notochondral tumors.
     Neuroectodermal tumors.
     Bone forming tumors: All of these tumors have tumor cells that produce bone.
     Benign bone forming tumors:
     Osteoma: benign tumor of bone.
     Epidemiology:
     Males>females
     Can appear at any age.
     Primary location is on the surface of facial bones.
     Rare tumor
     Slow growing, low clinical significance.
     Pathology- well differentiated mature lamellar trabecules, separated by fibrovascular stroma.
     Clinical manifestation- usually asymptomatic, may show symptoms if they compress surrounding organs:
     Obstruction of a sinus cavity
     Compression of brain or eye.
     Incomfort in the oral cavity.
     Association- Gardner syndrome- associated with multiple osteomas- familial adenomatous polyposis, fibromatosis in retroperitoneum and osteomas of the facial bone.
     Osteoid osteoma: benign tumor of osteoblast producing osteoid, surrounded by a rim of reactive bone (osteoma)
     Epidemiology:
     Young adults- <25 years
     Males>females.
     Arise in the cortex of long bones- 50% of cases in the femor or tibia
     Usually located at the diaphysis.
     Pathology:
     Trabecules of osteoid, surrounded by osteoblasts, separated by C.T stroma.
     Hemorrhagic, tan appearance, Smaller than 2cm.
     Clinical manifestation- bone pain, nocturnal, that resolves with aspirin. (Pain is due to PGE2 produced by proliferating osteoblasts).
     Diagnosis- imagine shows a bony mass with a radiolucent (osteoid) core.
     Osteoblastoma- same as osteoid osteoma with 3 key differences:
     Larger- greater of 2 cm.
     Arises at the medulla of the vertebra.
     Presents with bone pain that is irresponsive to aspirin.
     Malignant bone forming tumors:
     Osteosarcoma: malignant tumor of osteoblasts (mesenchymal origin), producing bone matrix.
     Epidemiology: Commonest primary malignant tumor of bone.
     Males>females
     2 peaks- most cases are at Ages 10-25 years, or less commonly in elderly people.
     Risk factors:
     In young age- familial retinoblastoma.
     In elderly- Paget’s disease of bones, irradiation exposure and fibrous dysplasia.
     The tumor is usually located at the metaphysis of long bone- usually tibia or femur.
     Types of osteosarcoma:
     Can be classified according to its location:
     Medullary osteosarcoma: the commonest type of osteosarcoma.
     Further divided according to its pathogenesis:
     Primary osteosarcoma– more common, unknown etiology but highly associate with mutations in:
     RB gene
     P53
     Secondary osteosarcoma- develops over an underlying disease, more aggressive:
     Paget disease
     Fibrous dysplasia
     Chronic osteomyelitis
     Bone infarct.
     Pathology:
     Macroscopy- gray-white bulky mass at the metaphyseal end of long bones. Areas of hemorrhage and necrosis can be seen as well.
     Microscopy:
     Sarcoma cells- large, undifferentiated, pleomorphic mesenchymal cells.
     Osteoid production- by the tumor cells, forming an eosinophilic osteoid surrounding the cells.
     Clinical manifestation- pathologic fractures, bone pain with swelling.
     Diagnosis- imaging method shows:
     Sunburst appearance- (sun rye extending from the mass) due to osteogenesis in the tumor.
     Codmans triangle- angle between the elevated periosteum and the cortex surface.
     Complications- hematogenous metastasis occurs in up to 20%, most commonly to the lungs.
     Surface osteosarcoma: much less common and less important. Better prognosis, occurs in elderly.
     Cartilage forming tumors:
     2 main features:
     Arise from the medulla
     Location:
     Benign tumors- occur in small bones of hands and feet
     Malignant tumors- occurs centrally, in pelvic or central skeleton.
     Benign tumors:
     Osteochondroma (exostosis): benign tumor of exophytic bony stalk with an overlaying cartilage cap.
     Epidemiology: the commonest benign bone tumor.
     Males>females
     Seen in 10-30 years old.
     Etiology:
     Sporadic- 85% of cases, solitary lesion.
     Hereditary- multiple hereditary exostosis syndrome- EXT1 and 2 genes germline mutation causing defective endochondral ossification.
     Occurs in the metaphysis of bones of endochondral ossification- lateral projection of the growth plate, mainly around the knee.
     Pathology:
     Macroscopy-1-20cm mushroom shaped bony protrusion. Covered in cartilage cap, full of marrow (continuous with the long bone it originates from).
     Microscopy- mature lamellar bone and medullary marrow, covered with mature cartilage cap.
     Clinical manifestations- usually they are incidentally detected- asymptomatic, can compress a nerve and cause pain.
     Complications- the cartilage can transform to chondrosarcoma. More common in hereditary form.
     Chondroma: benign tumor of hyaline cartilage.
     Chondromas can be:
     Enchondroma- located centrally within the medulla of affected bone. Most common.
     Subperiosteal Chondroma- on the surface of bone.
     We now refer to the common type- enchondroma.
     Epidemiology:
     Males=females.
     Seen at 20-40 years.
     Located in small tubular bones- mainly in hands and feet.
     Commonest benign cartilaginous tumor.
     Associations:
     Ollier disease- syndrome of multiple enchondromas.
     Maffucci’s syndrome- multiple enchondromas with soft tissues hemangiomas.
     Pathology:
     Macroscopy- <3cm, cartilaginous mass, bluish- grayish appearance in the medullary space.
     Microscopy- nodular appearance of mature hyaline cartilage tissue, the periphery can be calcified.
     Clinical manifestation- asymptomatic, detected by incidence.
     Diagnosis- X-ray shows radiolucent well circumscribed structure, s surrounded by a rim of dens bone.
     Complications- multiple enchondromas can develop to chondrosarcoma.
     Chondroblastoma: rare (less than 1%) benign tumor of cartilage, located in the epiphysis of long bones.
     Epidemiology- males>females, seen in patients under 20 years.
     Pathology- <5cm, soft chondroid tissue with hemorrhagic and necrotic foci, surrounded by thin bony capsule.
     Clinically- usually painful, can cause restriction of joint movements (because of its close distance to it).
     Malignant cartilage tumors:
     Chondrosarcoma: a group of malignant cartilage forming tumors.
     Can be classified according to:
     Location of origin:
     Central chondrosarcoma- medullary cavity.
     Peripheral chondrosarcoma- cortex.
     Histologically:
     Conventional- hyaline
     Clear cell
     Mesenchymal
     90% of chondrosarcomas are of central conventional type. We now refer to this subtype only.
     Epidemiology- second most common malignant bone tumor after osteosarcoma.
     Males>females
     Patients are usually over 40
     15% arises from pre-existing enchondroma or Osteochondroma.
     Commonly located at the pelvic bones or at the proximal femur.
     Pathology:
     Macroscopy- large, lobulated and firm mass, bluish-white gelatinous appearance with foci of calcifications.
     Microscopy- 2 halmarks:
     Invasive character
     Lobules of anaplastic chondrocytes- pleomorphic, giant cells and hypercellularity.
     Clinical manifestation: pain in bones.
     Grading- the grading describes the biological behavior of the tumor:
     Grade I- reactive thickening of the cortex, no metastasis
     Grade 2- can destroy the cortex and form a soft-tissue mass
     Grade 3- penetrates cortex and metastasize mainly to lungs and other bones.
     Complications- lung metastasis.
     Treatment- surgical excision.
     Neuroectodermal tumors:
     Ewing sarcoma- malignant tumor of poorly differentiated cells derived from neuroectoderm.
     Epidemiology:
     Males>females
     Patients are 10-15 years old.
     Caucasians > black population.
     Main locations are pelvic girdle, femur or ribs.
     Pathogenesis- Associated with chromosomal translocation of 11; 22 forming a chimeric transcription factor leading to abnormal proliferation and survival.
     Pathology:
     Macroscopy:
     Tumor originated in the medullary cavity of diaphysis of long bones spreads to the cortex, periosteum and soft tissues surrounding it.
     Gray-white and soft
     Microscopy:
     Sheets of Small round cells. (Resembles lymphocytes- can be mixed with lymphoma and osteomyelitis).
     Homer-Wright rosettes- cells arranged in circle around a central fibrilar space (indicates about neuronal differentiation).
     Clinical manifestation- painful enlargement of bone, with local signs of inflammation. Systemic symptoms- fever, anemia and leukocytosis are sometimes seen as well (DD with osteomyelitis).
     Diagnosis- onion skin appearance in X-ray- due to reactive bone deposition in periosteum.
     Complication- metastasis.
     Treatment- chymotherapy.
     Tumors of unknown origin:
     Giant cell tumor: benign (mostly), rare tumor, comprised from multinucleated giant cells and stromal cells.
     Epidemiology:
     Patients usually 20-40 years.
     Males=females.
     Tumor arises in the epiphysis of long bones (femur and tibia).
     Giant cells express RANKL- effecting the RANKL/RANK signaling pathway.
     Locally aggressive tumor- local damage but low chance for metastasis.
     Pathology:
     Macroscopy: large, red-brown tumors, can have cysts. Epiphysis location.
     Microscopy- multinucleated giant cells with mononuclear stromal cells at the background.
     Clinical manifestations- pain, swelling and pathological fractures.
     Diagnosis- “soap bubbles” appearance on X-ray.
     Treatment- surgery.

Tumor like lesions of bone:
Fibrous dysplasia: benign tumor like lesion of mesenchymal cells that failed to completely develop fibrous CT replacement of bone.
Epidemiology:
Males=females
Patients usually between 10-30 years
Can effect:
A single bone- monostotic (80% of cases).
Multiple bones- polystotic
Albright syndrome- polystotic form of disease with café-au lait and precocious sexual development.
Most common locations:
1. Ribs
2. Femur
3. Tibia or craniofacial bones
Pathogenesis: defect in osteoblast maturation replacement of medullary bone with fibrous tissue.
Pathology:
Macroscopy:
2-5 cm diameter, sharply demarcated, located within the cancellous bone.
The lesion is tan-white and sand like. Cysts may develop.
Microscopy- trabecules of woven bone with no osteoblasts surrounding them, fibrous tissue in the background.
Clinical manifestation- pain and swelling around the bone.
Complications:
Pathologic fractures.
Malignancy- in less than 1%, to osteosarcoma or fibrosarcoma.
Diagnosis- imagine techniques shows ground glass appearance with well-defined margins.
Treatment- surgery.
Non-neoplastic conditions mimicking tumors in their appearance (Pseudotumors).
Aneurismal bone cyst: benign bone tumor of multiloculated blood filled cystic spaces.

Question 33

Pseudotumors and tumors of joints

Answer 33

156. Pseudotumors and tumors of joints:
     Pseudotumors:
     Ganglion cyst (synovial cyst):
     A small round subcutaneous cyst swelling, located proximally to joints.
     Causes:
     Herniation of synovuium
     Postrheumatic degeneration of connective tissue
     Morphology:
     Macroscopy- most common location is dorsum of the wrist, may or may not communicate with the joint cavity, full of clear fluid resembling synovium.
     Microscopically- the cyst wall is composed of dense connective tissue lined by either synovial cells or other undetermined cells.
     Clinically- usually painless, unless it compresses a nerve.
     Benign tumors:
     Tenosynovial Giant cell tumors: a group of benign neoplasms, made of proliferated synoviocytes with deposition of iron, giant cells and xanthoma cells. Located at the synovial lining of joints, tendon sheets and bursae.
     Epidemiology- males=females, patients are 20-40
     Morphology- there are 2 distinct forms according to their spread:
     Localized type (nodular tenosynovitis):
     Macroscopy- intraarticular nodules, usually at tendon sheaths of fingers, yellowish-brown cut.
     Diffused type (pigmented villonodular synovitis):
     Macroscopically- villous projections and solid tumors within the synovium, have red- tan color. Usually appears at the knee (80%).
     Microscopically both are composed of many cell types:
     Xanthoma cells- full of cholesterol.
     Multinucleated giant cells.
     Laden macrophages.
     Inflammatory cells.
     Clinical manifestation- pain. Swelling and movement limitation.
     Treatment- excision.
     Synovial chondromatosis: metaplastic cartilaginous nodules surrounded by hyperplastic synovial villi.
     Epidemiology:
     Primary- with no other joint disease.
     Secondary- to other join pathologies like osteoarthritis, rheumatoid arthritis etc.
     Males>females.
     Pathogenesis- proliferation of the synovium to villi due to unknown reason, and differentiation of these proliferation to cartilage in their center.
     Pathology:
     Macroscopy- whitish- translucent cartilaginous bodies of variable sizes (few mm- few cm), either embedded within villi of freely floating. Located within large joints- usually shoulder, knee or hip.
     Microscopically- clusters of chondrocytes, in nodular appearance.
     Clinical manifestation- pain and movement limitations. Can also be asymptomatic.

Malignant tumors:
1. Synovial sarcoma: mesenchymal malignant tumor arising from synovial tissue. It is located close to the joint but almost never located within its cavity. Slow growing, aggressive tumors.
Epidemiology: Young adults- 20-40 years.
Histogenesis- mesenchymal cells that differentiated along different cell lines.
Pathogenesis- associated with a specific translocation of chromosomes 18 and X.
Pathology:
Macroscopy:
Most commonly located at the lower extremities- around the knee or thigh.
Encapsulated, with Gray-white color in cut section.
Calcifications are commonly seen- can be recognized in radiography.
Microscopy- 2 types of cells are associated with the tumor- epithelial cells and spindle fibroblasts. They can be distributed according to different patterns:
Biphasic type- both types of cells are recognized. Gland like structures of epithel surrounded by spindle cells.
Monophasic fibrous type.
Monophasic epithelial type.
Positive for keratin- differentiation from sarcoma together with the translocation.
Clinical manifestation- slow growing painful mass.
Treatment- surgery and chemotherapy.
2. Fibrosarcoma: a malignant tumor of fibrous connective tissue. Previously, many tumors were considered to be fibrosarcoma but today these tumors are differentiated using immunohistochemistry methods.
Pathology:
Macroscopy:
Can be found in any location in the body- most common at the deep soft tissues of the extremities.
Unencapsulated, infiltrative with areas of hemorrhage and necrosis.
Microscopy:
Variable degree of differentiated fibrocytes.
Herring-bone pattern- in well differentiated tumors.
Clinical- aggressive tumors, 50% recurrence, 25% metastasis.

Question 34

Neoplasms of the pituitary gland

Answer 34

160. Neoplasms of the Pituitary Gland: Robbins – 1074, Kaplan – 100, Harsh – 792, F.A - 335 27/4/2017
     The Pituitary gland has an average weight of ⁓ 500-600 mg, slightly heavier in females.
     It’s divided into:
     Adenohypophysis – anterior pituitary, which is farther subdivided into:
     Pars distalis – 80% of the gland – different cells:
     Basophils:
     Thyrotrophs – TSH.
     Gonadotrophs – FSH + LH.
     Corticotrophs – ACTH.
     Acidophils:
     Somatotrophs – somatotropin (growth hormone).
     Lactotrophs – prolactin.
     Chromophobes.
     Pars tuberalis.
     Pars intermedia – follicles (remnants of Retcke’s pouch).
     Neurohypophysis –
     Pars nervosa – axons with Herring bodies (storage), pituicytes, and capillaries.
     ADH – produced by the supraoptic nuclei in the hypothalamus.
     Oxytocin – produced by the paraventricular nulcei in the hypothalamus.
     Median eminent.
     Disorders can be divided into – hypofunction, hypopituitarism and hyperfunction, hyperpituitarism:
     Hyperpituitarism is mostly caused by an adenoma in the anterior lobe, or carcinoma (less common) - Characterized by secretion of one (monohormonal) or more (combined) of the pituitary hormones.

Adenomas:
These are benign tumors of the anterior pituitary, typically found in adults. These can be:
Functional – tumors that produce an excessive hormone. The tumors are classified based on the hormones they produce.
Clinically - shows symptoms of excessive hormone secretion and possibly of mass effect.
Nonfunctional – tumors that don’t produce an excess hormone. No clinical symptoms are seen.
Clinically – depending on its size, the tumor will produce only symptoms of mass effect:
Bitemporal hemianopsia – loss of lateral vision in both eyes due to compression of the optic chiasm by the tumor.
Hypopituitarism – due to compression and destruction of the parenchyma.
Headaches.
Pathogenesis – pituitary adenomas are most frequently associated with mutations of:
G-protein mutation – lead to G-protein hyperactivity, and most of the hypothalamic hormones which stimulate the pituitary bong G-protein coupled receptors on the pituitary cells.
MEN I and others – mutations of these are associated with familial pituitary adenomas.
TP53 mutations – associated with aggressive behavior.
Pathology:
Based on size, piruitary adenomas are designated:
Microadenomas – when < 1 cm.
Macroadenomas – when > 1cm.
Based on behavior and pathological features, pituitary adenomas are divided into:
Typical adenomas:
Macroscopy – soft, well circumscribed, that if large protrude from the sella turcica where it compresses the optic chiasem. These protruding adenomas are termed invasive adenomas.
Microscopy:
Monomorphism of cells – uniform polygonal cells in sheets or cords, all look the same (of the same type)  contrast it from normal parenchyma where different types of cells are mixed.
Absence of reticulin – these cells rest almost on no reticulin fibers, compared to the normal parenchyma where reticulin serves as a resting network of the cells.
Low mototic activity.
Based on the appearance of the cytoplasm affected by the amount of RER, adenomas can be:
Sparsely granulated – all are chrophobe cell adenomas (see later). Chromophobe cells can produce all types of hormones, thus can contribute to any of the adenomas.
Densely granulated – which are monomorphic, of the specific hormone-producing cell.
Atypical adenomas – more aggressive, shows high mitotic activity. Correlates with TP53 mutation.
Pituitary carcinoma.

Specific adenomas:
The most current classification describes the adenomas based on the cells that overproliferate  and thus based on the hormone that is over secreted. Therefore these adenomas can be:
Acidophilic adenomas.
Basophilic adenomas.
Chromophobe adenomas.
Mixed.
Acidophilic adenomas:
1. Lactotroph ademomas = prolactinoma – the most common pituitary adenoma.
Pathology:
Macroscopy – microadenomas in females, macroadenomas in males.
Microscopy - sparsely or densely granulated adenomas.
Dystrophic calcification – prolactinomas tend to undergo dystrophic calcification, ranging from psammoma bodies  to calcification of the all tumor – “pituitary stone”.
Clinically:
Females – usually have microadenomas:
Amenorrhea – loss of menses, because prolactin inhibits GnRH  resulting in ↓FSH/LH.
Galactorrhea – spontaneous flow of milk from the breast without childbirth.
Males – usually have macroadnomas:
Decrease libido – loss of sexual desire, again - prolactin inhibits GnRH  ↓FSH/LH.
Headaches – due to mass effect, as tumors tend to be larger in males.
Diagnosis – prolactin secretion exhibit diurnal rhythm – highest in the morning. Therefore, it’s important not to collect the blood in the morning (frequent mistake of measurement), blood must be collected later than 10 am.
Serum prolactin > 200 ng/mL – however high levels of prolactin doesn’t necessarily mean prolactinoma. Differential diagnosis can be of Pseudoprolactinoma can be:
Hypothyroidism – TRH stimulates prolactin secretion from the pituitary (in addition to TSH), while dopamine inhibits prolactin secretion. Thus in case of hypothyroidism, there is no negative feedback  ↑TRH secretion  ↑prolactin.
Antidopaminergic drugs.
↓ Serum FSH and LH – leading also to decreased levels of estrogen and progesterone.
Treatment – dopamine agonists and surgery – this is the only adenoma that responses to pharmacological treatment  tumor shrinks in up to 50% of cases and gonadal function is restored.
2. Acromegaly / gigantism – growth hormone overproduction in adults / children (respectively).
Pathogenesis – due to somatotroph adenomas  GH does its normal function, stimulating release of IGF-1 (insulin-like growth factor 1) from the liver  IGF-1 stimulates osteoblasts in bones  resulting in bone growth. In addition:
GH stimulates gluconeogenesis.
Feedback relationship with glucose – hyperglycemia inhibits GH.
Pathology:
Macroscopy – macroadenoma – very large > 10 mm.
Microscopy - sparsely or densely granulated subtypes.
Clinically – these adenomas are large (>10 mm)  thus they produce local effects due to increased size of the gland, as well as systemic effects due to GH production. All the changes are irreversible (compared to Cushing sy.).
Headache and visual fields defects – due to compression by the tumor.
Gigantism in children – due to increased linear growth of bones, as their epiphyseal growth plate is not fused yet.
Acromegaly in adults:
Increased lateral growth – of the hands, feet, and jaw (with space between teeth) – no linear growth occur because the epiphyseal growth plate is fused.
Enlarged visceral organs – dilated cardiomyopathy – results in heart failure, which is the most common cause of death in those patients, and macroglossia, kidneys, thyroid.
HTN – GH is related to Na+ retention, and due to cardiomegaly.
Hyperglycemia – GH increases gluconeogenesis and glycogenolysis  leading to secondary diabetes (very important).
Higher risk for cancer – as GH stimulates growth.
Diagnosis:
↑GH, ↑IGF-1 – also have diurnal rhythm, but opposite than cortisol – highest at night. GH is too large to pass in the urine, thus repeated serum measurements are needed, but IGF-1 is stable, thus one measurement is enough.
↑ALP - alkaline phosphatase is increased in active acromegaly.
Suppression tests – oral glucose – normally glucose suppresses GH, however if there is GH adenoma, it can’t suppress it and GH levels will remain elevated.
CT and MRI.
Treatment:
Octreotide – somatostatin analogue, suppressing the release of GnRH from the hypothalamus.
GH receptor antagonists.
Surgery – to remove the tumor.
In combined adenomas, the most common to be secreted together are growth hormone + prolactin  somatolactotrophs.
Basophilic adenomas:
1. Corticotroph adenomas  Cushing syndrome (/ disease, hypercortisolism) – disorder characterized by hyperproduction of cortisol from the adrenal cortex.
It’s important to distinguish between Cushing syndrome – which is a more general term meaning overproduction of cortisol – but this can be central (pituitary) or peripheral (adrenal glands). In contrast, Cushing disease is a subtype of Cushing syndrome, referring specifically to central (pituitary) Cushing syndrome.
Clinically, the symptoms are the same – but the level of ACTH differs (see later).
Pathogenesis – Cushing syndrome can be broadly divided into:
Exogenous – most common – “iatrogenic”, administration of exogenous glucocorticoids. Reversible if treatment is ceased.
Endogenous – farther subdivided based on dependence on ACTH:
ACTH-dependent – can be due to:
Pituitary adenoma/carcinoma – most common (70%) of cases – Cushing disease  resulting in hyper-stimulation and hyperplasia of the adrenal glands. Characterized by increased ACTH and cortisol.
Paraneoplastic – due to ectopic production of ACTH or CRH from tumors outside the pituitary – commonly by small cell carcinoma of the lungs. Markedly increased ACTH and cortisol.
Carcinoid tumor – able to produce many hormones, which one of them is ACTH.

ACTH-independent – peripheral Cushing syndrome  adrenal origin:
Adrenal adenoma/carcinoma – characterize by elevated serum levels of cortisol with low/normal levels of ACTH. Apparently cortisol production is regulated by other hormones (such as ADH and LH), as their receptors are overexpressed on the adrenocortical cells for an unknown reason.
Pathology:
Macroscopy:
Pituitary – usually will show enlargement due to adenoma.
Adrenal glands – depending on the reason:
Bilateral adrenal cortex (zona fasiculata) atrophy – seen in case of exogenous glucocorticoids use – due to lack of ACTH stimulation to the cortex (exogenous cortisol suppresses the adrenal cortex). In contrast, in ACTH-dependent it can be:
Diffuse hyperplasia – found in individuals with ACTH-dependent Cushing syndrome – bilateral yellowish (due to lipids) enlarged glands.
Macronodular hyperplasia – adrenals have prominent nodules up to 3 cm.
Micronodular hyperplasia – adrenals have smaller (1-3 mm) nodules. In both cases, the nodules are pigmented – probably due to lipofuscin.
Adenomas – yellow capsulated tumors up to 30 gm.
Carcinomas – much larger, unencapsulated masses reaching 200-300 gm.
In case of ACTH-independent Cushing syndrome, one adrenal will be enlarged (the one with the tumor) and the other will be atrophic (due to high release of cortisol by the tumor, ACTH is not produced  the other adrenal becomes atrophic).
Microscopy:
Pituitary – show Crook hyaline change – the normal granular basophilic cytoplasm of corticotrophs become homogenous paler, due to accumulation of intermediate keratin filaments in the cytoplasm. Mostly densely granulated.
Lipid-poor cells in the zona fasiculata – as normally, not during stressful situations these cells are supposed to be full with lipids (due to producing steroid hormones).
Well differentiated or anaplastic cells – in adenoma or carcinoma respectively.
Clinically – if from pituitary adenomas, usually local changes due to pituitary growth are not seen, because corticotroph ademonas are usually microadenomas (see next question). Thus the symptoms seen are mainly systemic signs and symptoms due to cortisol:
Muscle weakness with thin extremities – as cortisol is responsible for increasing the glycemia by gluconeogenesis  breaking down proteins in muscles ( which go to the liver).
Weight gain – fat deposition in different places produces typical – “moon facies” (fat deposition in the face), “buffalo hump” (in upper back), and truncal obesity (trunk). This is because hyperglycemia  results in hyperinsulinemia, and insulin increases storage of fat in adipose tissues. Farther complication – DM type II (30% of patients).
Abdominal purple striae – cortisol weakens impairs synthesis of collagen, so when there is not eough collagen in blood vessels, they can rupture easily  resulting in the striae.
HTN – cortisol upregulates α1 receptors on arterioles  increasing the effect of norepinephrine (cortisol is necessary for life for stress and because it helps to maintain vascular tone).
Osteoporosis – cortisol inhibits Ca2+ absorption in the gut.
Immunosuppression – 3 main mechanisms by which cortisol results in immunosuppression:
Inhibits phospholipase A2 – thus it’s impossible to produce arachidonic acid metabolites.
Inhibits IL2 – which is an important T cell growth factor.
Inhibits release of histamine from mast cells – essential for inflammation.
Peptic ulcers – similar to stress ulcers. Cortisol stimulates gastric acid production.
** Nelson syndrome – enlargement of preexisting adenoma after bilateral adrenalectomy (sudden drop in cortisol causes an increase in synthesis of ACTH).
Diagnosis:
24 hours urine cortisol test – first choose - since cortisol shows diurnal rhythm – serum levels change during the day, as they are the highest in the morning and lowest at night, it’s better to measure cortisol in the urine, which is related to serum cortisol and gives some average of plasma cortisol. It’s also possible to measure in plasma a few times a day in hospitalization. In Cushing syndrome, there will be no diurenal decrease.
↑↓ ACTH – depending on the type of Cushing syndrome. In high levels of ACTH, it also stimulates aldosterone secretion  thus we also have ↑aldosterone  leading to ↑Na+ amd ↓K+  hypokalemic metabolic alkalosis.
Hyperglycemia – cortisol enhances gluconeogenesis  DM.
Suppression tests – important to know is – dexamethasone test – dexamethasone is a cortisol analogue, thus normally after administration ACTH is supposed to decrease. Thus in case of pituitary origin, even after administration the levels of ACTH remain elevated. This can help us distinguish pituitary adenoma origin from ectopic origin – because high dose can suppress the pituitary but not an ectopic tumor (e.g., small cell carcinoma of the lungs).
Other less common adenomas are:
2. Gonadotroph adenomas – producing FSH and LH.
3. Thyrotroph adenomas – produce TSH. Rare cause of hyperthyroidism.

Other tumors related to the pituitary:
1. Craniopharyngoma – benign children tumors arising from epithelial remanants of the Rathke’s pauch (as the piruitary gland is formed from the brain [cranio] + pharynx [pharyngoma] – so remanents may stay close to the gland or on the sella torcica, but the tumor is not from the gland).
Macroscopy - presenting as a supratentorial mass in children, which may compress the optic chiasm and produce bitemporal hemianopia, thus it may be confused with pituitary adenoma. But if we have bitemporal hemianopia in a child we must think of craniopharyngioma. Calcification is common and seen in imaging.
Microscopy – cholesterol crystals with tumor cells, looks like fluid within the tumor.
2. Metastasis – from the lungs.

Question 35

Neoplasms of the thyroid gland

Answer 35

163. Neoplasms of the Thyroid Gland: Robbins – 1093, Kaplan – 237, Harsh – 810, F.A - 330 27/4/2017
     Thyroid = ⁓ 15-20 gm (reaches even 60 gm in goiter), right + left lobes connected by isthmus. Produces T3 (triiodothyronine) and T4 (thyroxine) – but mainly thyroxine, which is a “precursor” for the more potent T3 conversion in the periphery (mainly kidneys and liver).

Thyroid neoplasms are present as a distinct solitary nodule (more likely to be neoplasms than multiple nodules), and are mostly benign (10:1).
Epidemiology – the following clinical criteria provide clues about the nature of a solitary nodule:
Females > males – x4. However, nodules in males are more likely to be neoplastic than those in women.
All ages – including children and young adults – in whom nodules are more likely to be neoplastic.
Only 1% are malignant.
A history of head and neck radiation.
Radioactive iodine uptake studies – decreased uptake of 131I is seen in adenoma or carcinoma compared to Graves disease or nodular goiter where uptake is increased.
If uptake is decreased, fine needle biopsy (FNA) must be taken – only by FNA! Otherwise, severe bleeding may occur as it’s a very bloody organ.
Primary (adenomas, carcinomas) or secondary (metastatic).

Benign:
Benign tumors of the thyroid gland are adenomas, derived from the follicular cells, thus known as follicular adenomas:
1. Follicular adenoma – benign proliferation of follicles surrounded by a fibrous capsule. Most are nonfunctional (“cold noules”), but rarely may be functional and secret thyroid hormones (“hot nodules”, “toxic nodules”)  producing hyperthyroidism.
Pathogenesis – in toxic adenomas - mutation of TSH signaling pathway.
Pathology:
Macroscopy – a few features distinguish follicular adenoma from multinodular goiter:
Solitary nodule – average 3 cm, but can reach more than 10 cm.
Complete intact capsule – sharply demarcated from the surrounding parenchyma.
Compression of adjacent parenchyma – resulting in pressure atrophy.
Color on cut-section – ranges from gray-white to red-brown depending on colloid level.
Microscopy:
Complete capsule – crucial to distinguish it from follicular carcinoma.
Follicles with colloid – formed by the neoplastic cells. Can be micro-, normo-, or macrofollicular depending on their size. Occasionally the cells become:
Hurthle cells (oxyphil) – as they acquire eosinophilic granular cytoplasm.
Clinically – mostly unilateral painless mass.
Diagnosis:
“Cold nodule” – mostly, on radionucleotide scanning.
FNA.
Histologic examination after resection – is crucial to evaluate the capsule integrity.

Carcinomas:
Account for about 1% of the cancers, usually involve a gain-of-function mutation in the RAS pathway.
There are 4 major types of thyroid carcinomas, 3 arise from the follicular cells (the exception is medullary).
1. Papillary carcinoma – most common (80%), slow-growing, arising from the follicular epithelium.
Epidemiology – females>males, 20-50 years old, but can occur in all ages.
Risk factor – ionizing radiation of head and neck – classic example is a child who was radiated for severe acne  increasing the risk for papillary carcinoma later in life.
Pathogenesis – RET and BRAT mutations.
Pathology:
Macroscopy – solitary or multifocal, greyish-white, with papillary projections on cut section, and incomplete fibrous septa.
Microscopy:
Papillae – composed of fibrovascular stalks covered by the neoplastic follicular epithelium.
Characteristic nuclear features of tumor cells – very important – the diagnosis of papillary carcinoma is based on these features:
Orphan Annie eye nuclei – empty appearance of nuclei.
Intranuclear grooves – straight lines due to membrane invaginations.
Psammoma bodies – within the cores of papillae. Almost never found in follicular and medullary carcinomas.
There are different variants of papillary carcinoma:
Follicular variant.
Tall-cell variant – with tall columnar cells. Older individuals.
Diffuse sclerosing variant – papillae + areas of squamous metaplasia. Occurs in young people and children.
Papillary microcarcinoma – papillary carcinoma < 1 cm.
Complications – lymphatic invasion - often spreads to cervical lymph nodes.
Clinically – initially asymptomatic, later – hoarseness, dysphagia, cough.
Diagnosis – FNA.
Treatment – thyroidectomy with sampling of cervical nodes. Complications include - hoarseness (due to recurrent laryngeal nerve damage), and hypocalcemia (due to removal of parathyroid glands).
Prognosis – excellent – even when spread to the cervical nodes. 5-year survival > 95%.
2. Follicular carcinoma – malignant proliferation of the follicles, surrounded by a fibrous capsule (like follicular adenoma), but invades through the capsule.
Epidemiology – females > males, 40-60 years old, more in areas with dietary iodine deficiency.
Pathogenesis – RAS mutation.
Pathology:
Macroscopy – single nodule that invades through the capsule, grey-pink on cut section with cysts.
Microscopy:
Neoplastic follicles – that may spreads through the capsule.
Neoplastic follicles invade blood vessels.
Complication – hematogenous spread – metastases to bones, lungs, and liver. No via lymph. (remember that generally carcinomas spread via lymph, but 4 important exceptions are – renal cell carcinoma – to renal vein, hepatocellular carcinoma – to hepatic veins, follicular carcinoma, and choriocarcinoma).
Diagnosis – FNA can’t differentiate between follicular adenoma and follicular carcinoma because it penetrates through the middle and doesn’t take the capsule – which is the most important diagnostic feature to be tested. Thus a section that contains the capsule has to be taken.
Treatment – similar to papillary carcinoma.
Prognosis – excellent.
3. Medullary carcinoma – malignant proliferation of parafollicular C cells (neuroendocrine), characterized by high levels of calcitonin produced by the tumor that may lead to hypocalcemia.
Epidemiology – occur in adults. Two types:
Sporadic – 80%.
Familial – associated with autosomal dominant MEN 2A or 2B:
MEN 2A – medullary carcinoma, primary hyperparathyroidism (adenoma), and pheochromocytoma.
MEN 2B – medullary carcinoma, mucosal neuromas (lips/tongue), pheochromocytoma, and Marfan like habitus.
Familial type has better prognosis than the sporadic type.
Pathogenesis – RET oncogene mutations – when suspecting familial predisposition, we test the patient for RET mutation, and if it’s positive – we perform prophylactic thyroidectomy.
Pathology:
Macroscopy – firm, pale-gray with possible areas of necrosis and hemorrhage:
Sporadic type – has a unilateral solitary nodule.
Familial type – has bilateral multiple nodules.
Microscopy – malignant cells in an amyloid stoma.
Nests and trabeculae of polygonal cells – which lie in amyloid stroma:
Amyloid deposits – derived from calcitonin (example of localized amyloidosis).
C cell hyperplasia – presents only in the familial form and is believed to be a precursor lesion for the carcinoma.
Cytological types:
Large cells.
Small cells.
Fusocellular.
Plasmocytoid.
Diagnosis – FNA + serum calcitonin.
Treatment – genetic screening for familial cases + thyroidectomy.
4. Anaplastic carcinoma – aggressive, undifferentiated malignant tumors of the follicular epithelium.
Epidemiology – elderly.
Risk factors – history of follicular cancer, and multinodular cancer.
Pathology:
Macroscopy – large and irregular mass – invades local structures, leading to dysphagia or respiratory compromise.
Microscopy – highly anaplastic cells, variable in morphology and include:
Pleomorphic giant cells.
Spindle cells.
Clinically – symptoms related to compression and invasion – hyperplastic goiter, dysphagia, dyspnea, and hoarseness.
Treatment – no effective therapy.
Prognosis – very poor – the disease is uniformly fatal, with motility approaching 100%.
5. B-cell lymphoma – associated with Hashimoto thyroiditis.
6. Metastasis into the thyroid - from the – kidneys, lungs, breast, and others.

Question 36

Neoplasms of adrenal cortex

Answer 36

167. Neoplasms of the Adrenal Cortex: Robbins – 1132, Harsh – 799, F.A - 325 5/5/2017
     Adrenocortical neoplasms are wither adenomas or carcinomas. Each can be either:
     Functional – result in hyperadrenalism.
     Non-functional – not associated with hyperadrenalism.
     Functional adenomas are most commonly associated with hyperaldosteronism and Cushing syndrome, whereas virilizing neoplasm is more likely to be a carcinoma.
     Functional and non-functional neoplasms can’t be distinguished on the basis of morphological features.
     Epidemiology:
     Frequency – in adults adenomas and carcinomas are equally common, while in children carcinomas predominate.
     Most are sporadic – however, 2 familial cancer syndromes are associated with a predisposition for developing adrenocortical carcinomas:
     Li-Fraumeni syndrome – in patients who harbor germline TP53 mutations.
     Beckwith-Wiedemann syndrome – a disorder of epigenetic imprinting.

Benign:
Adenomas:
Benign, slow-growing tumors, usually clinically silent (nonfunctional) and are incidental finding at autopsy.
1. Adenoma
Pathology:
Macroscopy – small (up to 2.5 cm), well-circumscribed, nodular lesion that expands the adrenal, yellow in cut section (due to the presence of lipids).
Functional adenomas – are associated with atrophy of the adjacent cortex.
Nonfunctional adenomas – the adjacent cortex is normal.
Microscopy – tumor cells resemble normal cells (mostly of the zona fasciculate).
Vacuolted cytoplasm – due to presence of lipids - the amount of vacuoles and the eosinophilia depend on the amount of lipids within the cells.
“Endocrine atypia” – some degree of nuclei pleomorphism even in benign lesions.
2. Oncocytoma - Adrenal cortical adenoma comprised of cells (oncocytes) with abundant eosinophilic cytoplasm. Cases usually diagnosed incidentally. Most are nonfunctional.
Pathology:
Macroscopy - 3-15 cm, dark tan to brown.
Microscopy – oncocytes (granular cytoplasm).
Myelolipoma:
3. Myelolipoma – rare benign tumor composed of mature adipose tissue and normal hematopoetic cells which occur mostly in the adrenal glands (but also other locations are possible). Usually found as incidental findings.
Macroscopy – yellow-red-brown masses, depending on the amount of fat and blood cells.
Microscopy – mature lymphocytes admixed with hematopoetic cells of all 3 lineages.

All adenomas found incidentally are known as “incidetilomas”.

Adrenocortical carcinomas:
Rare, occur at any age, usually functional, associated with virilism and other features of hyperadrenalism.
Epidemiology – rare, with 2 peaks of incidence:
Preschool children.
Middle to old age.
Pathology:
Macroscopy – large (may exceed 20 cm), poorly demarcated, with areas of necrosis, hemorrhage, and cysts on cut section.
Microscopy – vary from well-differentiated (resemble cells in adenoma) to anaplastic.
Invasion – predominantly into veins and adrenal capsule.
Metastasis to the adrenals are more common than primary neoplasms (especially from the lungs). It’s difficult to differentiate between metastasis and primary carcinomas macroscopically, but microscopically different cells can be seen – for example from the lungs, we can see small cells of the small cell carcinoma of the lungs.

Clinically – mostly functional  hormonally active:
Androgens only.
Androgens + glucocorticoids.
Androgens + glucocorticoids + mineralocorticoids.
Estrogens (exceptional).
Complications – metastases – adrenal cancers have strong tendency to invade the adrenal vein, vena cava, and lymphatics. Spread vie the blood to the lungs and other viscera.
Prognosis – median survival ⁓ 2 years.

Question 37

Diseases of Adrenal medulla and related syndromes

Answer 37

169. Diseases of the Adrenal Medulla and Related Syndromes: Robbins – 1132, Harsh – 799, F.A - 325
     The adrenal medulla, It’s composed of:
     Chromaffin cells – neuroendocrine cells originating from neural crest cells.
     Sustentacular cells – supporting cells.
     The adrenal medulla is the major source of catechoamines in the body
     Paraganglion system – the adrenal medulla + extra-adrenal parganglia - neuroendocrine cells similar to chromaffin cells that are widely dispersed in the body as clusters and nodules.
     The extra-adrenal paraganglia are associated with the autonomic nervous system, and can be divided into 3 groups based on their anatomic distribution:
     Branchiomeric paraganglia – associated with the parasympathetic system, and located along the great vessels of head and neck, and include the – carotid bodies, aortic bodies and many others.
     Intravagal paraganglia – associated with the parasympathetic system, and distributed along the vagus nerve, e.g., ganglion nodosum of the vagus nerve.
     Aorticosympathetic paraganglia – associated with the sympathetic system, distributed along the paravertebral sympathetic paragnanglia  thus mainly along the abdominal aorta. An example for these is the organs of Zuckerkandle close to the aortic bifurcation.

The most important diseases of the adrenal medulla are neoplasms
Based on this, the WHO classifies tumors of the adrenal glands into:
1. Adrenal cortical tumors – adenomas + carcinomas (question 167).
2. Adrenal medullary tumors – contain most of the neuroendocrine tumors that are associated with the autonomic nervous system, and include:
Pheochromocytoma – benign or malignant. Intraadrenal paraganglioma.
Neuroblastoma – tumors of the sympathetic ganglia and adrenal medulla (postganglionic sympathetic neurons)
3. Extra-adrenal paraganglioma – neuroendocrine tumors of the extra-adrenal paraganglion system, at the locations noted above.

Adrenal medullary tumors:
1. Pheochromocytoma – tumors (mostly benign) arising from chromaffin cells, secreting cathecolamines.
Epidemiology – most common tumor of adrenal medulla in adults.
“rule of 10s” – summarize the Features of pheochromocytoma:
10% malignant – defined by the presence of metastatic disease.
10% bilateral – 90% unilateral.
10% extra-adrenal – e.g., organ of Zuckerkandle, bladder wall.
10% calcify.
10% in children.
10% are not associated with hypertension.
Associations – 25% of the patients with pheochromocytoma have a germline mutation, which results in having pheochromocytoma as a feature of the following syndromes:
Neurogibromatosis type 1 – NF-1 mutation - pheochromocytome + neurofibromas  Café-au-lait + optic nerve glioma.
MEN 2A and 2B – RET mutation – A: pheochromocytome + medullary thyroid carcinoma + parathyroid adenoma, B: pheochromocytome + medullary thyroid carcinoma and mucosal ganglioneuromas especially in the oral mucosa. Medullary carcinoma of the thyroid is what kill the patient (thus its removal is considered).
Von Hippel Lindau disease – VHL mutation - pheochromocytoma + renal cell carcinoma + hemangioblastoma + pancreatic endocrine neoplasms.

Pathology:
Macroscopy – the mass varies in size, averaging 100 gm, but can reach 4000 gm.
Solid and well demarcated by a connective tissue.
Color changes:
White-yellow – smaller ones.
Reddish – larger ones, because they tend to have necrosis and hemorrhages.
Brown – when fixated with dichromate, stored catecholamines become brown. Hence the term chromaffin.
Compressed cortex – seen as the small yellow mass (due to lipids).
Microscopy:
Zellballen pattern – characteristic well-defined nests of tumor cells separated by septa, and supplied by abundant vascular network.
“Salt and pepper” nuclei – characteristic to neruroendocrine tumors.
Histologic findings are not reliable to predict clinical behavior – benign tumors may be very dysplastic, with high levels of pleomorphisms and mitotic figures, while paradoxically malignant ones can have less malignant features. Hence, the definitive diagnosis of malignancy is based only on the presence of metastases.
Clinically – the most important manifestation is hypertension - most tumors secrete epinephrin, norepinephrin, and dopamin, which cause episodic hyperadrenergic symptoms – 5 P’s:
Pressure - ↑BP.
Pain – headache.
Perspiration – sweating.
Palpitations – and tachycardia.
Pallor.
Complications:
Catecholamine cardiomyopathy – myocardial damage due to catecholamine-induced constriction of blood vessels or direct catecholamine toxicity  may lead to CHF.
Diagnosis – based on increase in catecholamines breakage products:
↑ serum metanephrines
↑ 24-hours urine metanephrines and VMA (vanillylmandelic acid).
** PAAS score – pheochromocytoma of the adrenal gland coring scale – creating a score based on morphological changes, which helps to determine whether a tumor is benign or malignant.
Treatment - surgical excision – but very important to be treated with Phenoxybenzamine (irreversible blocker of α receptors) followed by β-blockers before removing the tumor. This is impotant because during the surgery the surgeon may press the tumor and squeeze out catecholamines that may lead to massive hypertension in the patient and death.
2. Neuroblastoma – malignant neoplasm arising from the primordial postganglionic sympathetic neurons within the adrenal medulla. It’s the most common neuroblastic tumor – tumors of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells.
Epidemiology – most common tumor of adrenal medullar in children < 4 years old, and the 3rd most common cancer in children. Mean age of onset ⁓18 months.
Pathogenesis – overexpression of N-myc oncogene.
Pathology:
Macroscopy – irregular mass that can cross the midline (in contrast to Wilms tumor).
“In situ” neuroblastomas – minute nodules, silent, which spontaneously regress.
Large masses – of more than 1 kg, soft, gray-tan, or with necrosis + hemorrhage.
Microscopy – undifferentiated cells.
Homer-Wright’s rosettes – tumor cells arranged in a circle around a core of neutropil – fibrillary material from processes of primitive neuroblasts.
Clinically – produce catecholamines.
Less likely to develop hypertension – than phechrmocytoma (despite the cathecolamines).
Opsoclonus-myoclonus syndrome – “dancing eyes-dancing feet” – paraneoplastic syndrome characterized by:
Myoclonic jerks of the extremities.
Chaotic eye movements – in all directions.
Complications – metastases – to skin, bones, liver, lungs. 70% have metastases at time of diagnosis.
Diagnosis:
↑HVA and VMA in urine – homovanillic acid and vanillylmandelic acid.
Prognosis – done by staging,and depends on age – children < 1 year old have good prognosis.

Paraganglioma: - from the extra-adrenal paraganglia (not medulla, but related system. Optional):
Neoplasms arising from cells of the paraganglion system. 70% of the extra-adrenal paragangliomas occur in the head and neck region (however don’t forget that the most important paragangliomas are pheochromocytomas in the adrenal medulla).
1. Carotid body tumor – a parasympathetic paraganglioma, arising from the carotid body cells at the aortic bifurcation.
Pathology:
Macroscopy – red-pink to brown mass.
Microscopy – Zellballen arrangement (characteristic to all paragangliomas).

Question 38

Benign AND MALIGNANT neoplasms of the skin (epithelial and mesenchymal)

Answer 38

1. Epithelial lesions:

1.1 Benign lesions:
Common, and probably arise from stem cell residing in the epidermis and hair follicles.
These tumor usually grow to a limited size and generally do not undergo malignant transformation.
1.1 Seborrheic keratosis: also called a senile wart (altohogh not a real wart cause not caused by HPV)
● Epidemiology:
common non-cancerous (benign) skin tumor that originates from squamous cells in the outer layer of the skin (keratinocytes), occur most frequently in middle aged or older people.
● Etiology and pathogenesis:
- Many of the tumors have mutations in FGF receptor 3 → autoactivation of this receptor.
- In rare cases multiple lesions may appear suddenly as paraneoplastic syndrome (sign of Lesser Trelat) → Patient has multiple internal malignancies (most commonly in the GIT), and these malignancies produce growth factors that stimulate epidermal proliferation.
● Morphology:
Seborrheic keratoses are round, exophytic, coin-like plaques varying in diametrs.
They are tan to dark brown and have a granular appearing surface. In micro can see proliferation of squamous cells with pseudocysts (spaces with keratin) in between them:
▪ Location: They arise spontaneously and are particularly numerous on the trunk, although the extremities, head, and neck also may be sites of involvement.
● Clinical features:
Except for cosmetic concerns, they are usually of little clinical importance.
They may be mistaken for melanomas due to their dark color → leading to surgical removal.
Complications: sometimes seborrheic keratosis progresses to basal cell carcinoma
1.2. Actinic keratosis:
● Epidemiology:
Actinic keratoses are very common in fair-skinnedעור בהיר people and increase in incidence with age and increasing sun exposure
● Etiology:
The lesions are result of chronic exposure to sunlight.
- A high fraction of these lesions are associated with TP53 mutations caused by UV light–induced DNA damage.
● Morphology:
Actinic keratoses usually are less than 1 cm in diameter, tanbrown or red in color, and rough (sandpaper-like) to the touch.
▪Location: there is a predilection for sun-exposed areas (face, arms, dorsum of the hands)
● Clinical features:
These are precancerous lesion that has high frequency to progress to malignant tumor → mainly squamous cell carcinoma.
The lesions can be treated with local cryotherapy (superficial freezing) or topical agents.
1.3 Acanthosis nigricans: (acanthosis- mean thickening of the epidermis and nigricans means dark)
Acanthosis nigricans may be an important cutaneous sign of several underlying a disease (e.g diabetes malitus) and malignant tumor(e.g gastric carcinoma) conditions:
● Etiology and pathogenesis:
It is divided into two types based on the underlying condition:
1. In association with benign conditions:
In 80% of cases, acanthosis nigricans is associated with benign conditions and develops gradually, usually during childhood or puberty.
It may occur (1) as an autosomal dominant trait with variable penetrance, (2) in association with obesity or endocrine abnormalities (particularly with pituitary or pineal tumors and diabetes), and (3) as part of several rare congenital syndromes. The most common associations are with obesity and diabetes.
2. As paraneoplastic phenomenon:
acanthosis nigricans arises in association with cancers, most commonly gastrointestinal adenocarcinomas, usually in middle-aged and older individuals.
● Morphology:
marked by thickened, hyperpigmented skin with a “velvet-like” texture that most commonly appears in the flexural areas (axillae, skin folds of the neck, groin, and anogenital regions).
1.4 Fibroepithelial polyp (also called acrochordon):
▪ Epidemiology:
- one of the most very common benign cutaneous lesions-prevalenceof 46% in the general population.
-one of the most common oral mucosal lesions, it is a reactive focal fibrous and epithelial hyperplasia, with 66% female predilection, mainly at the age of 40-60. can be due to local iritation and trauma.
- are harmless, are typically painless and usually do not grow or change over time.
- Microscopically, an acrochordon consists of a fibrovascularcore, sometimes also withfat cells, covered by an unremarkableepidermis.
- majority of cases are sporadic.
▪ Location:
on the neck, trunk, face, and intertriginous areas
▪ Morphology:
Fibroepithelial polyps are soft, flesh-colored, bag-like tumors that are often attached to the surrounding skin by a stalk.
▪ Clinical features:
Fibroepithelial polyps are usually inconsequential, but can occasionally be associated with systemic disease, mainly: diabetes, obesity, and intestinal polyposis.
They often become more numerous or prominent during pregnancy, presumably related to hormonal stimulation.
1.5 Squamous cell papilloma - benign papilloma that arises from the stratified squamous epithelium of the skin, lip, oral cavity, tongue, pharynx, larynx, esophagus, cervix, vagina or anal canal. result of infection with HPV. Tumor cells proliferate and produce finger-like or warty projections.
1.2 Malignant epithelial lesions
Squamous cell carcinoma:
Most common is acantholytic squamous cell carcinoma1.
● Epidemiology:
Common tumor arising on sunexposed sites in older people.
These tumors have higher incidence in men than women.
Other predisposing factors are: industrial carcinogens, chronic ulcers, old burn scars, ionizing radiation osteomyelitis fistula → chronic inflammation.
● Etiology and pathogenesis:
The mostly common exogenous cause of cutaneous squamous cell carcinoma is UV light exposure, which causes DNA damage →mainly TP53 mutations.
- In addition UV light has transient immunosupressive effect on skin by impairing antigen presentation by langerhans cells.
- Patients who are immunosuppressed as a result of chemotherapy or organ transplantation, or who have xeroderma pigmentosum (rareautosomalrecessivegenetic disorderofDNA repairin which the ability to repair damage caused byultraviolet(UV) light is deficient), are at increased risk.
● Morphology:
- Squamous cell carcinomas in situ appear as sharply defined, red, scaling plaques; many arise from prior actinic keratoses.
- More advanced, invasive lesions are nodular, show variable scale, and ulcerate. Mainly involve lower lip!
● Clinical features:
Invasive squamous cell carcinomas of the skin often are discovered while small and resectable.
The likelihood of metastasis is related to the thickness of the lesion and degree of invasion into the subcutis- but generally metastasis in uncommon and have excellent prognosis.
Tumors arising in the context of actinic keratoses may be locally aggressive but generally metastasize only after long periods of time, while those arising in burn scars, ulcers, and non–sun-exposed skin behave less predictably.
* Mucosal squamous cell carcinomas (oral, pulmonary, esophageal, etc.) generally are much more aggressive then epidermal.
**keratoacanthoma: well differentiated SCC (squamous cell carc. Low grade) which develop rapidly and regress spontaneously (within weeks). Present as a cup shaped tumor filled with keratin debris in the center.
1.2. Basal cell carcinoma:
● Epidemiology:
It is the most common type of malignancy of skin, seen in lighltyבהירי עור pigmented indeviduals.
- more common in warm southern regions of the United States, and its incidence is 40-fold higher in sunny climates near the equator, such as Australia
● Etiology and pathogenesis:
Occur due to chronic exposure to sun.
risk factors: prolonged UVB sunlight exposure, Albinism and xeroderma pigmentosum.
● Morphology:
- manifest as pearly papules, often with prominent dilated subepidermal blood vessels (telangiectasias).
- Some tumors contain melanin pigment and thus appear similar to melanocytic nevi or melanomas. Very common location is on the upper lip.
Micro: many nodules in dermis with peripheral palisading cells (cells are laying up against some space)- in the periphery of a nodule
▪ Two common growth patterns are seen:
i. Multifocal growths (superficial) originating from the epidermis.
ii.nodular lesions – growing downward into the dermis as cords and islands of variably basophilic cells
▪ Location:
- Because they may arise from either the epidermis or the follicular epithelium, they are not encountered on mucosal surfaces
● Clinical features:
- It is a slow-growing cancer that rarely metastasizes- excellent prognosis.
- Individual tumors usually are cured by local excision, but approximately 40% of patients will develop another basal cell carcinoma within 5 years (recurance).
- Advanced lesions may ulcerate, and extensive local invasion of bone or facial sinuses may occur if the lesions are neglected for many years.
2. Mesenchymal tumors:
2.1 Benign tumors:
2.1 Benign fibrous histoicytoma (Dermato-fibroma):
composed of two cell types, namely atypical fibroblasts and histiocytes, arranged in a storiform pattern. Lipid-filled cells may be conspicuous and occasionally are the major component These types of benign fibrous histiocytomas are known as xanthomas (yellowishcholesterol-rich material that can appear anywhere in the body in various disease states) or fibroxanthomas.
● Epidemiology:
These tumors are usually seen in adults and often occur on the legs of young and middle-aged women
● Etiology and pathogenesis:
The cause of fibrous histiocytomas remains a mystery.
Many cases have a history of trauma, suggesting an abnormal response to injury and inflammation.
● Morphology:
These neoplasms appear as firm, tan to brown papules.
Most are less than 1 cm in diameter, but actively growing lesions may reach several centimeters in diameter; with time they often become flattened.
● Clinical features:
Lesions are asymptomatic or tender and may increase and decrease slightly in size over time.
Their biologic behavior is indolent (benign)
2.2. Malignant tumors:
2.1 Dermato-fibro-sarcoma Protuberans (DFSP):
well-differentiated, primary fibrosarcoma of the skin. relatively uncommon soft tissue neoplasm of intermediate- to low-grade malignancy. Metastasis rarely occurs. The cellular origin of DFSP is not clear. Evidence supports the cellular origin being fibroblastic, histiocytic, or neuroectodermal. usually occurs in adults aged 20-50 years.
● Morphology:
- appears as a “protuberant” nodule, most often on the trunk, within a firm plaque that may sometimes ulcerate.
- In contrast to dermatofibroma, the overlying epidermis is generally thinned.
- Deep extension from the dermis into subcutaneous fat, produce a characteristic “honeycomb” pattern.
- These neoplasms are composed of closely packed fibroblasts arranged radially.
● Clinical features:
- These tumors are slow growing, and although they are locally aggressive and can recur, they rarely metastasize.
- These tumors may extend down into the subcutis and thus require wide excision to prevent local recurrence
- While the primary mode of treatment is wide local excision, rare cases that are unresectable due to their location or because of metastatic spread can be treated with inhibitors of the PDGFβ receptor tyrosine kinase.
- As in CML patients, withdrawal of the drug is followed by regrowth of the tumor, so use of this agent is lifelong.

Question 39

Pigmented nevi and melanoma

Answer 39

Melanocytes: in basal layer of epidermis, they produce melanin via melanosomes which passed off to the keratynocytes which result in skin pigmentation (as we see as skin color). Originate from neural crest in embryonology. Vitiligo- localized loss of skin pigmentation due to autoimmune destruction of melanocytes. Albinism- enzyme defect result in impossible production of melanin- have increase risk for basal cell ca, squamous cell ca and even melanoma!. Freckeles- have increased number of melanosomes (not melanocytes!).
♦ Benign melamocytic tumors:
1. Melanocytic nevi (moles):
the term nevus: any congenital lesion of the skin/ benign neoplasm of melanocytes (pathoma).
Melanocytic nevus, however, refers to any benign congenital or acquired neoplasm of melanocytes.
▪ Definition:
Melanocytic nevi are benign neoplasms derived from melanocytes →highly dendritic, pigment-producing cells that are normally interspersed among basal keratinocytes.
● Epidemiology:
There are several types of melanocytic nevi, but acquired melanocytic nevi are the most common type and are found in virtually all individuals.
- Melanocytic nevi tend to occur in sun exposed areas of the body.
● Morphology:
Common acquired melanocytic nevi are tan to brown, uniformly pigmented, small (usually less than 6 mm across), relatively flat macules or elevated papules with well-defined, rounded borders.
▪ Morphological changes in an acquired nevus:
B. Junctional nevi – earliest lesions which consist of aggregates or nests of round cells that grow along the dermoepidermal junction. Common in children.
C. Compound nevi - Eventually, most junctional nevi grow into the underlying dermis as nests or cords of cells to form compound nevi.
D. intradermal nevi - In older lesions the epidermal nests may be lost entirely to form pure intradermal nevi. Common in adults.
* Clinically, compound and dermal nevi are often more elevated than junctional nevi.
* Whereas the superficial cells of the nevus are larger, tend to produce melanin, and grow in nests, deeper nevus cells are smaller, produce little or no pigment, and appear as cords and single cells.
* This sequence of morphologic changes is of diagnostic importance, since they are absent from melanomas
● Clinical features:
- There are numerous types of melanocytic nevi, with varied appearances. Although these lesions usually are of only cosmetic concern, they can become irritating or mimic melanoma, requiring their surgical removal.
* melanocytic nevi may become more prominent during pregnancy, indicating a degree of hormone sensitivity.

 Lentigo:
The term lentigo refers to a common benign localized hyperplasia of melanocytes occurring at all ages, but often initiated in infancy and childhood. There is no sex or racial predilection, and the cause and pathogenesis are unknown.
● Morphology:
Lentigines may involve mucous membranes as well as the skin and consist of small (5 to 10 mm across), oval, tan-brown macules or patches.
* Unlike freckles, lentigines do not darken when exposed to sunlight.
▪ Histology:
The essential histologic feature is linear (nonnested as in nevus) melanocytic hyperplasia restricted to the basal layer of the skin.
* Lentigous pattern can appear also in dysplastic nevi, and melanomas.

A – normal skin, B – lentiginous (linear growth) C – melanocytic nevus (nests)
2. Dysplastic nevi:
A specific type of nevus (mole) that looks different from a common mole. Dysplastic nevi are mostly flat and often larger than common moles and have borders that are irregular. A dysplastic nevus can contain different colors, which can range from pink to dark brown. Parts of the mole may be raised above the skin surface. A dysplastic nevus may develop into melanoma, and the more dysplastic nevi a person has, the higher the risk of melanoma. A dysplastic nevus is sometimes called an atypical mole.
● Epidemiology:
Dysplastic nevi may be sporadic or familial.
▪ Familial form:
dysplastic nevus syndrome, an autosomal dominant disorder charactarized by a tendency to develop multiple dysplastic nevi (up to hundreds) and correspondingly are at higher risk of developing melanoma.
The probability that a person with dysplastic nevus syndrome will develop melanoma is over 50% by age 60, and at-risk individuals sometimes develop several melanomas at multiple sites.
● Morphology:
Dysplastic nevi are larger than most acquired nevi (often greater than 6 mm across) → appear as flat macules, slightly raised plaques with a “pebbly” surface, or target-like lesions with a darker raised center and irregular flat periphery.
They can be recognized by their size, variability in pigmentation (variegation), and irregular borders. Most seem to be acquired rather than congenital.
▪ Histology:
Microscopically, dysplastic nevi usually involve both the epidermis and the dermis and exhibit architectural and cytologic atypia.
- As part of this process, single nevus cells begin to replace the normal basal cell layer along the dermoepidermal junction, producing lentiginous (in a linear broad way) hyperplasia
▪ Location:
Unlike ordinary moles, dysplastic nevi occur on both sunexposed and protected body surfaces.
● Clinical features:
Dysplastic nevi are important because they may be direct precursors of melanoma!! and when multiple in number are a marker of an increased risk for melanoma.
- However the vast majority of lesions are clinically stable and never progress.

3. Blue naevi:
   blue naevus (BN) is a benign, usually intradermal melanocytic lesion characterized by pigmented dendritic spindle-shaped melanocytes and, more rarely, epithelioid melanocytes.
   Most of these tumors are acquired, and most of them occur in the distal upper limbs.
   The most common presentation consists of a single asymptomatic, relatively well circumscribed, dome-shaped blue or blue-black papule less than 1 cm in diameter. The characteristic blue colour is produced by the Tyndall effect.
   Benign rarely malignant transformation.
4. Halo nevus:
   A halo naevus presents as a small circumscribed symmetrical, usually papular pigmented lesion with the appearance of a common benign compound naevus, surrounded by a symmetrical area of depigmentation, representing the “halo”.
   Halo naevi often present during the summer, perhaps because the halo contrasts better with tanned skin.
   They are most common in teenagers and young adults.
5. Spitz nevus:
   Spitz naevus is a benign proliferation of large spindled, oval or large round (=called epithelioid melanocytes) melanocytes that begins in the epidermis, and evolves into compound or intradermal stages. This distinguishes it from some forms of blue naevus, in which the lesion is wholly intradermal from the outset.
   Most common in the first two decades of life.
   Most Spitz naevi are lightly pigmented.
   The classic lesion is a pink to red papule, with an even round border and a domed shape.
   There is slight scale.
   The degree of erythema is often such that the clinician considers the diagnosis of haemangioma.
   ♦ Malignant melanocytic tumors:
   Melanoma:
   ● Epidemiology:
   Melanoma is a relatively common neoplasm related to sun exposure.
   lightly pigmented individuals are at higher risk than are darkly pigmented individuals
   ● Etiology and pathogenesis:
   - About 10% to 15% of melanomas are inherited as an autosomal dominant trait with variable penetrance →dysplastic nevous syndrome.
   - The majority of melanomas are sporadic and have major predisposing environmental factor → UV radiation, albinism and xeroderma pigmentosum.
   - Melanoma may arise in a stepwise fashion from precursor dysplastic nevi- although majority develop de novo with no precursor nevi.
   ▪ Growth of melanoma:
6. Radial growth:
   describes the initial tendency of a melanoma to grow horizontally within the epidermis (in situ), often for a prolonged period. (very thin Breslow thickness!  low risk to metatsize- See below)
   During this stage, melanoma cells do not have the capacity to metastasize, and do not induce angiogenesis.
7. Vertical growth:
   With time the vertical growth supervenes in which the tumor grows downward into the deeper dermal layers as an expansibleנרחב mass lacking cellular maturation.
   This event often seen as development of a nodule in a previously flat lesion.

● Moprhology:
“A,B,C,D” rule- A- asymmetric, B- borders are irregular, hair canot grow on it- if it grow- it’s a nevus!, C- color- not uniform, D- diameter >6mm!!- there are couple of exceptions, see below types of melanomas
Unlike benign nevi, melanomas show striking variations in color, appearing in shades of black, brown, red, dark blue, and gray.
On occasion, zones of white or flesh-colored hypopigmentation also appear, sometimes due to focal regression of the tumor. The borders of melanomas are irregular and often notched, unlike the smooth, round, and uniform borders of melanocytic nevi.
▪ Location:
The great preponderance of melanoma arises in the skin on areas exposed to the sun; other sites of origin include the oral and anogenital mucosal surfaces esophagus, meninges, and the uvea of the eye (but more rare).
● Clinical features:
- Melanoma is the most deadly of all skin cancers and is strongly linked to acquired mutations caused by exposure to UV radiation in sunlight.
- Melanoma of the skin usually is asymptomatic, although pruritus may be an early manifestation.
- The most important clinical sign is a change in the color or size of a pigmented lesion.
▪ The main clinical warning signs are:
1. Rapid enlargement of a preexisting nevus
2. Itching or pain in a lesion
3. Development of a new pigmented lesion during adult life
4. Irregularity of the borders of a pigmented lesion
5. color changes within a pigmented lesion
▪ Metastasis:
- The probability of metastasis is predicted by Breslow thickness- thickness is measured from the top of the granular layer to the deepest invasive tumour cell.
- When metastases occur, they involve not only regional lymph nodes but also liver, lungs, brain, and virtually any other site that can be seeded hematogenously.
- In some cases, metastases may appear for the first time many years after complete surgical excision →suggesting a long phase of dormancy, during which time the tumor may be held in check by the host immune response
▪ Treatment:
- can be cured if it is detected and treated (surgically removal) when it is in its earliest stages. Melanoma has no cure once metastasize!!!!
♦ Prognosis:
Prognostic factor
Most favorable when
Breslow thickness
Thin (<1.51 mm)
Histology
Superficial spreading melanoma
Age
Young
Sex
Female
Body site
Not on the trunk, hands, feet
Ulceration
Absent
Mitotic index
Low
♦ Classification: main 4 types of melanoma: (the fifth written is probably more rare..)
1 Superficial spreading melanoma:
This type of melanoma dominant early radial growth before vertical invasion develops. Most common subtype.
Increasingly, this is the most common type of melanoma in Caucasians, and has a relatively good prognosis being frequently observed in young patients, and on body sites that are intermittently exposed to sunlight
2 Nodular melanoma:
It usually presents as a early rapid vertical phase (amelanotic nodular melanomas are rarely observed), which bleeds or ulcerates. → exclusively grows vertically. it push the epidermis up while it grows down- thus called nodular melanoma. Poor prognosis.
This is the most aggressive type of melanoma.
It often presents on body sites that are intermittently exposed to sunlight →trunk, head and neck, and lower legs.
▪ Morphology:
present as a rapidly expanding papule, nodule or plaque. They are occasionally polypoidal and even pedunculated.
They are usually well circumscribed and symmetric and frequently reach a size of approximately 1 cm before diagnosis. The skin markings are often obliterated with frequent ulceration and crust.
The colour is often black or blue, although a subset of NM is amelanotic.
The amelanotic variety frequently has a subtle blush or peripheral rim of pigment
3 Lentigo maligna melanoma:
This type of melanoma develops when an invasive tumour arises in a lentigo maligna- “radial” grow.
* Lentigo maligna (LM) is a form of melanoma in situ that occurs on the sun exposed skin of elderly people, mainly on the face but also, less often, at extrafacial sites including the neck, upper back and forearm.
Relatively good prognosis.

4. Acral lentigo melanoma:
   Acral lentiginous melanoma (ALM) is a distinct variant of cutaneous melanoma, which occurs on the palms, soles, and subungual sites, and has a characteristic histologic picture
   They often present late and represent the most common type of melanoma in heavily pigmented people. not related to UV light exposure!
   In general, the prognosis is poor of invasive acral melanoma.

(5. Desmoplastic melanoma:- לא מוגדרת כאחת מהארבעה אבל מעניינת
Desmoplastic melanoma (DM) is a spindle cell melanoma in which the malignant cells are separated by collagen fibres or fibrous stroma.→sun exposed areas mainly head and neck.
Most present as a painless indurated plaque but some begin as a small papule or nodule.
Almost half lack pigmentation. This is an exception of the ABCD rule!!!!.
Pale lesions are often mistaken for basal cell carcinoma, dermatofibroma or a scar. Pigment is usually due to an associated lentigo maligna.
The tumours usually infiltrate deeply into the reticular dermis but local spread may involve subcutaneous tissue, deep fascia including periosteum and pericranium, bone and salivary gland.
▪ Prognosis:
Recurrences are common especially after incomplete excision. survival rates are similar to other melanomas of comparable thickness.
DM patients have poorer prognosis).