PATHOLOGY 1 Flashcards

Question

2. What is the definition of emphysema A. Irreversible enlargement of the airspaces distal to the terminal bronchiole B. X C. Persistent cough with sputum production for at least 3 months in at least 2 consecutive years. D. Episodic bronchoconstriction due to increased airway sensitivity. E.

Answer 1

Emphysema is pathologically defined as: an abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls and without obvious fibrosis.

Answer 2

I think B CLINICAL PRESENTATION Ovarian hyperthecosis, a disorder characterized by severe hyperandrogenism and insulin resistance, is seen primarily in postmenopausal women [1-3] but occasionally in premenopausal women [4]. Women typically present with slowly progressive acne and hirsutism (eg, excessive male-pattern hair growth), and they are likely to be virilized [5]. Thus, many have clitoral enlargement, male-pattern baldness, deepening of the voice, and a male habitus. In almost all cases, insulin resistance and hyperinsulinemia are present [3,6], and women are at increased risk for type 2 diabetes and cardiovascular disease [2]. Additional physical findings may include central obesity, skin tags, and acanthosis nigricans. The ovarian secretion of large amounts of testosterone in women with hyperthecosis means that peripheral estrogen production is increased. As a result, the risk of endometrial hyperplasia and endometrial carcinoma is increased, especially in postmenopausal women [2,7]. ROBINS Non-Neoplastic and Functional Cysts FOLLICLE AND LUTEAL CYSTS Cystic follicles in the ovary are so common that they are considered virtually normal. They originate in unruptured graafian follicles or in follicles that have ruptured and immediately sealed. Morphology. These cysts are usually multiple. They range in size up to 2 cm in diameter, are filled with a clear serous fluid, and are lined by a gray, glistening membrane. On occasion, larger cysts exceeding 2 cm (follicle cysts) may be diagnosed by palpation or ultrasonography; these may cause pelvic pain. Granulosa lining cells can be identified histologically if the intraluminal pressure has not been too great. The outer theca cells may be conspicuous due to increased amounts of pale cytoplasm (luteinized). As discussed subsequently, when this alteration is pronounced (hyperthecosis), it may be associated with increased estrogen production and endometrial abnormalities. Granulosa luteal cysts (corpora lutea) are normally present in the ovary. These cysts are lined by a rim of bright yellow tissue containing luteinized granulosa cells. They occasionally rupture and cause a peritoneal reaction. Sometimes the combination of old hemorrhage and fibrosis may make their distinction from endometriotic cysts difficult. POLYCYSTIC OVARIES AND STROMAL HYPERTHECOSIS Polycystic ovarian disease (PCOD; formerly termed SteinLeventhal syndrome) affects 3% to 6% of reproductive-age women. The central pathologic abnormality is numerous cystic follicles or follicle cysts, often associated with oligomenorrhea. Women with PCOD have persistent anovulation, obesity (40%), hirsutism (50%), and, rarely, virilism.[72,][73] Morphology. The ovaries are usually twice normal size and have a smooth, gray-white outer cortex studded with subcortical cysts 0.5 to 1.5 cm in diameter. On histologic examination, there is a thickened, fibrotic superficial cortex beneath which are innumerable follicle cysts associated with hyperplasia of the theca interna (follicular hyperthecosis) ( Fig. 22-34 ). Corpora lutea are frequently but not invariably absent. FIGURE 22-34 Polycystic ovarian disease and cortical stromal hyperplasia. A, The ovarian cortex reveals numerous clear cysts. B, Sectioning of the cortex reveals several subcortical cystic follicles. C, Cystic follicles seen in a low-power microphotograph. D, Cortical stromal hyperplasia manifests as diffuse stromal proliferation with symmetric enlargement of the ovary. The initiating event in PCOD is not clear. Increased secretion of luteinizing hormone may stimulate the theca-lutein cells of the follicles, to produce excessive androgen (androstenedione), which is converted to estrone. For years, these endocrine abnormalities were attributed to primary ovarian dysfunction because large wedge resections of the ovaries sometimes restored fertility. It is now believed that a variety of enzymes involved in androgen biosynthesis are poorly regulated in PCOD. Recent studies link PCOD, like type 2 diabetes, to insulin resistance. Treatment of the insulin resistance sometimes results in resumption of ovulation.[74] Stromal hyperthecosis, also called cortical stromal hyperplasia, is a disorder of ovarian stroma most commonly seen in postmenopausal women, but it may blend with PCOD in younger women. The disorder is characterized by uniform enlargement of the ovary (up to 7 cm), which has a white to tan appearance on sectioning. The involvement is usually bilateral and microscopically shows hypercellular stroma and luteinization of the stromal cells, which are visible as discrete nests of cells with vacuolated cytoplasm. The clinical presentation and effects on the endometrium are similar to those of PCOD, although virilization may be striking.[72] A physiologic condition mimicking the above syndromes is theca lutein hyperplasia of pregnancy. In response to pregnancy hormones (gonadotropins), proliferation of theca cells and expansion of the perifollicular zone occurs. As the follicles regress, the concentric theca-lutein hyperplasia may appear nodular. This change is not to be confused with true luteomas of pregnancy (see below).

Answer 3

4. Which of the following is most likely a cause of diabetes insipidus **A. Craniopharyngioma Based of Stat Dx.** B. Rathke cleft cyst C. Lymphocytic hypophysitis D. Macroadenoma E. Empty sella D insipidus from ADH deficiency is designated as central to differentiate it from nephrogenic diabetes insipidus, which is a result of renal tubular unresponsiveness to circulating ADH. The clinical manifestations of the two diseases are similar and include the excretion of large volumes of dilute urine with an inappropriately low specific gravity. Serum sodium and osmolality are increased as a result of excessive renal loss of free water, resulting in thirst and polydipsia. Patients who can drink water can generally compensate for urinary losses; patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration. Lymphocytic hypophysitis Dr Mostafa El-Feky◉ and Assoc Prof Frank Gaillard◉◈ et al. Lymphocytic hypophysitis is an uncommon non-neoplastic inflammatory condition that affects the pituitary gland. It is closely related to other inflammatory conditions in the region, namely orbital pseudotumour and Tolosa-Hunt syndrome. Epidemiology Lymphocytic hypophysitis is seen most frequently in women, with a F:M of ~ 9:1, and often in the postpartum period or the third trimester of pregnancy. Clinical presentation Clinical presentation is varied depends on the part of the pituitary affected and the size of the lesion. Lymphocytic hypophysitis can thus be classified as: anterior pituitary: lymphocytic adenohypophysitis most common mimics a pituitary adenoma endocrine hormone deficits are common, including hypopituitarism mass effects on adjacent structures (e.g. optic chiasm) posterior pituitary: lymphocytic infundibular neurohypophysitis rare diabetes insipidus both anterior and posterior pituitary: lymphocytic infundibular panhypophysitis Pathology It is characterised by infiltration of the pituitary stalk with lymphocytes, as the name would suggest. Importantly, there is a paucity of plasma cells or granulomas, differentiating it from IgG4-related hypophysitis and granulomatous hypophysitis (e.g. due to neurosarcoidosis) respectively. Associations autoimmune conditions such as autoimmune thyroiditis pernicious anaemia ipilimumab: monoclonal antibody drug Radiographic features CT Coronal CT and multiplanar reconstructions can visualise the pituitary region reasonably well. Lymphocytic hypophysitis appears as an enhancing soft tissue mass involving the pituitary and extending into the suprasellar region. MRI MRI, as is the case with other pituitary lesions, is the best modality for assessing this condition which appears as a pituitary region mass. T1 affected area is isointense with slight signal heterogeneity normal posterior pituitary bright spot may be absent 8 T1 C+ (Gd) can variably enhance, usually homogeneously 7 dural enhancement may be present 8 infundibulum may be thickened 8 T2 hypointensity in parasellar region can be present and may be useful in differentiating from a pituitary adenoma 4 Treatment and prognosis Lymphocytic hypophysitis is usually self-limiting and spontaneous recovery can occur. Corticosteroids are sometimes given and deficient hormones can be replaced 8. Differential diagnosis The differential diagnosis is primarily that of other pituitary region masses. Considerations include: pituitary adenoma macroadenomas are expected to enlarge the sella turcica craniopharyngioma (papillary type) suprasellar meningioma dural-based usually follows the cerebral cortex intensity pituitary metastasis Langerhans cell histiocytosis (LCH) IgG4-related hypophysitis granulomatous hypophysitis (idiopathic or secondary to systemic illness e.g. sarcoidosis, syphilis, and tuberculosis) xanthomatous hypophysitis necrotising hypophysitis

Answer 4

* Least likely to have a phaeochromocytoma = MEN 1 * MEN2B * **Phaeo** * Mucosal neuormas * Medullary thyroid * Marfanoid habitus * MEN 2A * **P Phaeo** * P arathydoid hyperplasia * Medullary Thyroid * MEN 1 - tumour supressor gene 11q. AD. PPP or PiParPanc * **Pituitary adenomas** (prolactinoma most common)\_ * **Parathyroid** (parathyroid hyperplasia most common) hyperparathyroidism is seen in 80-95% of patients. * **PANCREAS** islet cell tumours (gastrinoma, glucagonoma) * VHL "hipple" * *Haemangioblastoma* * *Increased Risk RCC* * *Pancreatic tumours (cystadenomas, Cysts, cystadenocarcinoma)* * ***Phaeo*** * *Endolymphatic sac tumour, Retinal haemangioma.* * *Liver, pancreas and renal cysts.* * Clear cell RCC 70% * Renal cysts * Renal AML * Hemangioblastomas 70% (cerebellar, spinal chord, brainstem. * Choroid plexus papilloma * Retinal haemangioblastomas * Endolymphatic sac tumours * Phaeo 25-30 * paragangliomas * pNETs * Pancreatic Cysts * Pancreatic Cystadenoma * Renal Cysts * Liver cysts * NF1 - NF1 Gene 17q. Tumour suppressory of the ras/Mapk pathway. * Gliomas (pilocytic, optic nerve glioma, diffuse brainsetm glioma, spinal astrocytoma, spinal pilocytic astrocytoma). * Gangliogliomas * Leiomyosarcoma * Leukaemia * carcinoid tumours. * **Phaeo** * malignant peripheral nerve sheath tumour * Wilms * Rhabdomyo * Renal AML

Answer 5

Rathke cleft cyst Dr Mohamed Saber and Associate Professor Donna D'Souza◉ et al. Rathke cleft cysts, also known as pars intermedia cysts, are non-neoplastic, sellar or suprasellar epithelium-lined cysts arising from the embryologic remnants of Rathke pouch in the pituitary gland. They are common lesions and usually incidentally identified. Epidemiology common, found in ~15% (range 11-22%) of autopsies 2,6 rare in childhood; mostly seen in adults since the underlying substrate is congenital, lesions thought to enlarge throughout life 2 recognised female preponderance (~2:1 female to male ratio) Clinical presentation The vast majority of Rathke cleft cysts are asymptomatic and incidentally found. If large, they may cause: visual disturbances: due to compression of the optic chiasm pituitary dysfunction due to compression of adjacent pituitary tissue and distortion of the pituitary stalk present in up to 69% of symptomatic cases 10 headaches 3 Pathology Rathke pouch forms during the 4th week of embryologic development as a rostral outpouching from the roof of the primitive oral cavity. The anterior wall of the pouch gives rise to the anterior lobe of the pituitary (pars distalis). The posterior wall of the pouch does not proliferate and remains as the intermediate lobe of the pituitary (pars intermedia). The lumen of the pouch narrows to form a cleft (Rathke cleft) that normally regresses. Persistence of this cleft with the expansion is believed to be the origin of a Rathke cleft cyst. The wall of the cyst is typically lined by a single columnar cell layer of epithelium, often containing goblet cells, and is often ciliated. An intraluminal nodule which macroscopically appears white and is often adherent to the cyst wall (although it may be free-floating) is composed of solid tissue that represents desquamated cellular debris 3,10. Radiographic features On imaging, a Rathke cleft cyst is seen as a well defined non-enhancing midline cyst within the sella arising between the anterior and intermediate lobes of the pituitary. 40% are purely intrasellar and 60% have suprasellar extension. Purely suprasellar location, although reported, is rare. Plain radiograph On lateral skull x-ray, it can rarely cause sellar enlargement if reaches large size 12. CT non-contrast typically non-calcified and of homogenous low attenuation uncommonly it may be of mixed iso- and low-attenuation, or contain small curvilinear calcifications in the wall (seen in 10-15% of cases) postcontrast typically non-enhancing, although the cyst wall may enhance in some cases 8 MRI The signal characteristics vary according to the cyst composition, which may be mucoid or serous. T1 50% are hyperintense (high protein content) 50% are hypointense T2 70% are hyperintense 30% are iso or hypointense T1 C+ (Gd) no contrast enhancement of the cyst is seen; however, a thin enhancing rim of surrounding compressed pituitary tissue may be apparent 9,10 In ~75% of cases, a small non-enhancing intracystic nodule can be identified which is virtually pathognomonic of a Rathke cleft cyst. When seen, it is hyperintense to surrounding fluid on T1 and hypointense on T2. Depending on the signal of the surrounding fluid, it may be inapparent on one sequence or the other. Occasionally, a fluid-fluid level may be seen (particularly if there has been a haemorrhage). Treatment and prognosis Surgical treatment is indicated for symptomatic cases. A case series showed 18% recurrence rate after surgical resection, supporting the theory that a relationship exists between symptomatic Rathke cleft cyst and craniopharyngioma 11. Differential diagnosis The main differential diagnoses are: cystic pituitary adenoma can show fluid-fluid level or haemorrhagic debris; Rathke cleft cysts almost never bleed 11 craniopharyngioma no gender difference similar age group usually suprasellar or have a suprasellar component tend to calcify arachnoid cyst older patients no gender difference epidermoid cyst usually suprasellar restriction on DWI teratoma usually has solid components often fatty signal

Answer 6

EBV least associated with: * Hodgkin lymphoma * **Oral cancer in a young person** * Endemic nasopharyngeal carcinoma - True * Endemic Burkitts * X https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554094/ Epstein-Barr Virus in the Pathogenesis of Oral Cancers Joseph T. Guidry, Christine E. Birdwell, and Rona S. Scott\* Author information Copyright and License information Disclaimer The publisher's final edited version of this article is available at Oral Dis See other articles in PMC that cite the published article. Go to: Abstract Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that establishes a lifelong persistent infection in the oral cavity and is intermittently shed in the saliva. EBV exhibits a biphasic life cycle, supported by its dual tropism for B lymphocytes and epithelial cells, which allows the virus to be transmitted within oral lymphoid tissues. While infection is often benign, EBV is associated with a number of lymphomas and carcinomas that arise in the oral cavity and at other anatomical sites. Incomplete association of EBV in cancer has questioned if EBV is merely a passenger or a driver of the tumorigenic process. However, the ability of EBV to immortalize B cells and its prevalence in a subset of cancers has implicated EBV as a carcinogenic cofactor in cellular contexts where the viral lifecycle is altered. In many cases, EBV likely acts as an agent of tumor progression rather than tumor initiation, conferring malignant phenotypes observed in EBV-positive cancers. Given that the oral cavity serves as the main site of EBV residence and transmission, here we review the prevalence of EBV in oral malignancies and the mechanisms by which EBV acts as an agent of tumor progression. Keywords: Epstein-Barr virus (EBV), lymphoma, carcinoma, tumor Go to: EBV life cycle in the oral cavity Epstein-Barr virus is a gammaherpesvirus that establishes life-long persistent infections in the oral cavity in the majority of adults worldwide. Infection typically begins in early childhood, with 50% of children infected by the age of five (Porter et al., 1969). Acquisition of the virus continues through adulthood with greater than 90% of adults becoming infected (Cohen et al., 2011). Early EBV infections are generally mild or asymptomatic; but primary infection in adolescence carries an increased risk for developing infectious mononucleosis (IM), a self-limited lymphoproliferative disease with a clinical triad of fever, pharyngitis, and swollen lymph nodes (Henle et al., 1968, Niederman et al., 1976). The symptoms of IM are primarily due to a massive T cell response to the EBV-infected B cell blasts with replication of the virus in the oropharynx (Murray et al., 1992, Schendel et al., 1992). Other viral and parasitic pathogens can cause IM-like symptoms, but IM caused by EBV is typically associated with a heterophile-positive antibody response that is the basis for the Monospot clinical mononucleosis test. IM patients have high viral loads in blood and saliva for 6 months after convalescence (Fafi-Kremer et al., 2005). Following primary infection, EBV establishes a lifelong infection, with periodic, asymptomatic EBV shedding. The oral cavity is a primary site for transmission and persistence of EBV. EBV disseminates to other anatomical sites, and is found in blood circulating B cells in healthy carriers at a frequency of 1 to 50 in 106 B lymphocytes (Khan et al., 1996). EBV is periodically shed in the saliva throughout the lifetime of infected individuals and can be transmitted to naïve individuals (Ling et al., 2003, Yao et al., 1985). Lifelong carriage of EBV is achieved by the biphasic nature of the viral life cycle. Transmission via the oral cavity targets epithelial cells and naïve B lymphocytes for infection. Lymphoid rich regions in the oral cavity such as tonsils and adenoids that constitute Waldeyer’s ring juxtapose epithelial and B lymphocytes for efficient entry and egress of the virus (Hadinoto et al., 2009, Niederman et al., 1976). Indeed, EBV is frequently detected in adenoids and tonsils, but not the hard palate (Berger et al., 2007, Jiang et al., 2015). Epithelial cells support the amplification of the virus shed in saliva, while B lymphocytes, specifically memory B cells, are the primary reservoir for long term persistence of EBV (Babcock et al., 1998, Hadinoto et al., 2009, Jiang et al., 2006). The EBV virion consists of an enveloped capsid that carries a linear, double-stranded DNA genome approximately 170 kilobase pairs in length. Entry into naïve B lymphocytes and epithelial cells is mediated by engagement of viral glycoproteins on the viral envelope with cellular receptors on the cell’s plasma membrane (reviewed in (Chesnokova et al., 2015)). The virus enters cells by either endocytosis in B lymphocytes or direct fusion of the viral envelope with the plasma membrane of epithelial cells. Inside the virion, the linear EBV genome carries few epigenetic marks being mostly devoid of DNA methylation or histones (Fernandez et al., 2009, Szyf et al., 1985). Following entry, the virus delivers its linear genome to the nucleus where the genome undergoes a circularization event through recombination of terminal repeats present at the ends of the linear DNA (Lindahl et al., 1976). Each circularization event results in a fused terminal repeat fragment that has a unique number of repeats, and is used as a marker for viral clonality (Raab-Traub & Flynn, 1986). Furthermore, the EBV genome in cells is replicated and maintained as an extrachromosomal episome. The EBV genome also rapidly associates with nucleosomes and the viral DNA is methylated having a similar chromatin structure as the host genome (Kalla et al., 2010). DNA methylation and histone modifications are epigenetic marks that regulate gene expression. Depending on the cellular context, EBV establishes various viral gene expression states that are integral to completion of the viral lifecycle. EBV infection of B cells supports the latent phase of the viral life cycle and long term viral persistence (Qu & Rowe, 1992, Rooney et al., 1989, Tierney et al., 1994). Memory B cells are the lifelong reservoir for EBV. EBV reaches memory B cells by direct infection or by navigating short-lived B cells through their differentiation program into long-lived memory B cells (Kurth et al., 2003, Thorley-Lawson & Gross, 2004). Several EBV latency programs, characterized by a set of increasingly restricted viral gene expression patterns, have been observed at different points in the B cell differentiation program (Table 1). The EBV latency programs result from silencing of viral gene expression to avoid elimination by cytotoxic T cells as an immune evasion strategy required for viral persistence in the B cell compartment (Murray et al., 1992, Schendel et al., 1992). Epigenetic modifications, such as DNA methylation and histone modifications, on viral promoters regulate various viral gene expression states. In naïve B cells, six Epstein-Barr virus nuclear antigens (EBNA) 1, 2, 3A, 3B, 3C, and LP, and three latent membrane proteins (LMP) 1, 2A, and 2B are expressed. Known as latency III or the growth program, these viral factors promote B cell growth and are required for in vitro B cell immortalization (Reviewed in (Kang & Kieff, 2015)). The EBNA proteins are involved in transcriptional regulation while LMP1 mimics CD40 signaling and LMP2 mimics B cell receptor signaling, together providing signals necessary for B cell activation, proliferation, and cell survival (Reviewed in (Kang & Kieff, 2015)). In germinal center B cells, four latency proteins are expressed: EBNA1, LMP1, LMP2A, and LMP2B (known as Latency II or the default program). In dividing memory B cells, the latency I program is limited to expression of EBNA1, which is required for the maintenance of the viral episome during cell division (Yates et al., 1984), and LMP2A (Babcock et al., 2000). Latency 0 is the absence of all viral gene expression and has been reported in non-dividing memory B cells (Decker et al., 1996, Ruf & Sample, 1999). In addition, EBV has non-coding RNAs that are expressed in the latency programs that include the EBV-encoded RNAs (EBERs), BamH1 fragment A rightward transcripts (BARTs), and viral microRNAs (Qu & Rowe, 1992, Tierney et al., 1994). Rescue from latency and induction of the productive phase of the viral life cycle (termed viral reactivation) occurs upon terminal differentiation of memory B cells into plasma cells, which is induced upon antigen stimulation of the cognate B cell receptor (Crawford & Ando, 1986, Laichalk & Thorley-Lawson, 2005). Virus released from the B cell can then infect epithelial cells where the virus is amplified for cell-to-cell spread or infection of a new host. Epithelial differentiation also regulates the viral lifecycle, with viral replication occurring in the upper differentiated layers (Greenspan et al., 1985, Sixbey et al., 1984, Tugizov et al., 2003). Epithelial cells may also harbor latent EBV infection, but the nature of EBV epithelial latency is less understood than in B cells (Reusch et al., 2015). Table 1 EBV gene expression programs EBV Gene Expression ProgramCell compartmentPhenotypeEBV Genes ExpressedAssociated Diseases Latency IIINaïve B cellsEBV-induced B cell growth and survival B cell immortalizationEBNA1, 2, 3A,3B, 3C and EBNA LP LMP1, 2A, 2B EBV BART EBV miRNAs EBER 1 and 2DLBCL, PTLD, IM Latency IIGerminal Center B cellsB cell survivalEBNA1 LMP1, 2A, 2B EBV BARTs EBV miRNAs EBER 1 and 2DLBCL, HL, NPC and GC Latency IDividing Memory B cellsEBV episome maintenanceEBNA1 EBV BARTs EBV miRNAs EBER 1 and 2BL Latency 0Non-dividing memory B cellsQuiescent stateNone LyticPlasma B cells, Epithelial CellsViral replicationAll viral genes in an ordered cascade of viral gene expressionOHL BART: BamH1 fragment A rightward transcript; BL: Burkitt’s lymphoma; DLBCL: Diffuse large B cell lymphoma; EBER: EBV-encoded RNA; EBNA: EBV nuclear antigen; GC: Gastric carcinoma; HL: Hodgkin’s lymphoma; IM: Infectious mononucleosis; LMP: Latent membrane protein; miRNA: microRNA; NPC: Nasopharyngeal carcinoma; OHL: Oral hairy leukoplakia; PTLD: Post-transplant lymphoproliferative disease Go to: EBV in the tumor context EBV infections typically have no pathogenic consequences despite long term carriage of the virus. However, in some cases, EBV has been associated with a number of lymphoid and epithelial malignancies arising in the oral cavity and at other anatomical sites. The viral oncogenic potential is demonstrated by the ability of EBV-infected B lymphocytes to proliferate indefinitely as immortalized lymphoblastoid cell lines in vitro (Gerper et al., 1969, Henle et al., 1967). EBV was originally discovered in Burkitt’s lymphoma (BL), and EBV’s association with malignancies has expanded to include associations with Hodgkin’s lymphoma, natural killer/T cell lymphoma, nasopharyngeal carcinoma (NPC), gastric carcinoma, and oropharyngeal squamous cell carcinoma (OSCC) (Burke et al., 1990, Epstein et al., 1964, Henle & Henle, 1970, Jiang et al., 2012, Levine et al., 1971, Tao et al., 2002). As a persistent infection, EBV is tightly controlled by cell mediated innate and adaptive responses to prevent disease. In cases of immunosuppression, such as in transplant recipients or those living with acquired immunodeficiency syndrome (AIDS), there is an increased risk for developing an EBV-associated malignancy that includes post-transplant lymphoproliferative disease, oral plasmablastic lymphoma, primary effusion lymphoma coinfected with Kaposi’s sarcoma herpesvirus, primary central nervous system lymphoma, smooth muscle tumors, and oral hairy leukoplakia (OHL). The mechanisms governing how EBV contributes to the tumorigenic process likely differ in each of its associated malignancies, but some common features are noted. In all EBV-associated malignancies, EBV is in a latent state. Viral latency allows for sustained expression of viral oncogenes while avoiding immune detection and cytopathic effects from the replicative phase of the viral lifecycle. Yet, high viral loads have also been correlated with tumor development as individuals with IM have 4-fold greater risk of developing Hodgkin’s lymphoma (Bernard et al., 1987, Carter et al., 1977, Connelly & Christine, 1974, Gutensohn & Cole, 1981, Hjalgrim et al., 2000, Kvale et al., 1979, Levine et al., 1998, Munoz et al., 1978, Rosdahl et al., 1973, Serraino et al., 1991). In addition, high EBV antibody titers have been detected in patients with BL, Hodgkin’s lymphoma, and NPC and precede tumor onset by a short period of only a few years (de-The, 1982, Levine et al., 1971, Mueller et al., 1989, Ji et al., 2007). As such, monitoring EBV antibody titers is used for the clinical detection of NPC (Lee et al., 1997, Zhong et al., 2006). The reasons behind such increased viral titers are unknown, but aberrant viral reactivation would increase the virus pool and the likelihood of infecting existing pre-neoplastic cells. Confounding EBV’s role in cancer is an incomplete association of the virus in cancers of similar histogenetic phenotypes. However, EBV infection can also result in epigenetic reprogramming of lymphoid and epithelial cells (Birdwell et al., 2014, Hansen et al., 2014, Saha et al., 2015, Vockerodt et al., 2008). Epigenetic changes are defined as heritable changes in gene expression that do not result from DNA mutations. EBV-associated malignancies display altered DNA methylation states from EBV-negative tissues (Cancer Genome Atlas Research, 2014, Chang et al., 2006, Dai et al., 2015, Hansen et al., 2014). Viral factors have been shown to manipulate the host epigenetic machinery affecting the host epigenome as well, suggesting that EBV-induced epigenetic alterations can contribute to tumor progression in the absence of the virus or viral gene expression in a “hit-and-run” manner (Birdwell et al., 2014, Hino et al., 2009, Paschos et al., 2012, Skalska et al., 2010, Tsai et al., 2002). EBV also participates as co-factor that likely replaces the need for additional genetic and epigenetic alterations during cancer progression. The oral cavity where EBV is routinely shed is a key site to address some questions about EBV-associated malignancies. The sections that follow review the incidence of EBV-associated malignancies in the oral cavity and how EBV contributes to tumor progression of oral cancers. Go to: EBV and Oral Lymphoproliferative Diseases In general, the occurrence of lymphomas in the oral cavity is rare accounting for less than 5% of all lymphoma (Silva et al., 2016). However, oral lymphomas are the third most frequent oral cancers following OSCC and salivary gland carcinomas (Silva et al., 2016). Hodgkin’s lymphoma, which is EBV-associated in approximately 50% of tumors, rarely presents in the oral cavity with only a handful of reported cases that involved the tongue, palate and tonsil (Darling et al., 2012). Diffuse large B-cell (DLBCL) and Burkitt’s lymphomas are the most common EBV-associated non-Hodgkin’s lymphomas that occur in the oral cavity (Silva et al., 2016). Despite a continual presence of EBV in the oral cavity, the incidence of EBV-associated oral non-Hodgkin’s lymphoma, regardless of immune status, is comparable to non-Hodgkin’s lymphoma arising at other anatomical sites (Gulley et al., 1995, Hummel et al., 1995, Leong et al., 2001, Solomides et al., 2002). It is important to note that oral lymphomas are often misdiagnosed. Common manifestations of intraoral non-Hodgkin’s lymphoma include swelling and ulceration at various regions throughout the oral cavity (involving the tonsils, gingiva, tongue, palate, and buccal mucosa), tooth mobility, and pain (Ardekian et al., 1999, Richards et al., 2000). As the manifestation of oral lymphomas mimic symptoms of periodontal disease, osteomyelitis, or other diseases (Richards et al., 2000), misdiagnosis often delays initiation of proper treatment resulting in worsened disease outcome (Dodd et al., 1992, Nittayananta et al., 1998, Spatafore et al., 1989). Thus, understanding how EBV contributes to oral lymphomagenesis will be important in uncovering virally derived biomarkers for early diagnosis and treatment. EBV and Oral Diffuse Large B-Cell Non-Hodgkin’s Lymphoma EBV has been associated with DLBCL of the elderly, a clonal B cell lymphoma occurring more commonly in older patients (\> 50 years of age) from Asia (Reviewed in (Ok et al., 2013)). Though less frequently, these tumors can also occur in younger persons, as well as in North America or Europe. Determination of EBV status is based on in situ hybridization detection of the EBERs. The EBER transcripts are an abundantly expressed set of viral noncoding RNAs that are frequently used for the clinical detection of EBV. Assignment of EBV positivity is usually based on all tumor cells being positive for EBV. However, the percentage of EBER-positive cells varies in DLBCL. The incomplete association of EBER in DLCBL suggests that EBV in a few cells may be sufficient to support the oncogenic phenotype. EBV viral proteins and RNAs have been shown to be transferred in exosomal vesicles with phenotypic effects transferred to the uninfected cells (Meckes et al., 2013, Pegtel et al., 2011). Alternatively, EBERs may not be the most robust marker for EBV detection in theses tumors, and a stronger correlation with EBV infection may be missed. The EBV status in oral DLBCL is not well defined due to the rarity of these tumors. In general, EBV-positive DLBCL has been shown to carry a lower frequency of p53 mutations and increased macrophage infiltration in contrast to EBV-negative DLBCL (Courville et al., 2016, Morscio et al., 2017). EBV-positive DLBCL display a type II or III latency pattern. The oncogenic phenotype of EBV-positive DLBCL is thought to be regulated by the EBV oncoprotein LMP1, an integral membrane protein that promotes cell proliferation and survival. LMP1 signals in a ligand-independent manner and mimics CD40 signaling with activation of a number of signaling pathways that include NF-kB, JNK/AP-1, MAPK, and PI3K-Akt. A phenotype of DLBCL is activation of the NF-kB pathway, which is known to also be activated by LMP1. EBV-positive DLBCL carry a poorer prognosis than EBV-negative DLBCL. EBV and Oral Burkitt’s Lymphoma BL is a rapidly proliferating tumor that arises at extranodal sites in children and adults. The hallmark of BL is a chromosomal translocation involving MYC and the immunoglobulin gene locus, resulting in high levels of MYC expression (Zech et al., 1976). BL is categorized into three subtypes: endemic or African, sporadic, and AIDS-associated. These BL forms share clinical and histological presentation, but differ in geographical region and prevalence of EBV infection. Endemic BL occurring mainly in children in the equatorial belt of Africa is very highly associated with EBV infection, with a nearly 100% association, while sporadic BL and HIV-associated BL exhibit a lower prevalence of EBV-positivity at approximately 10–20% and 30–60%, respectively (Magrath, 1990, Mbulaiteye et al., 2014). Oral BL is more prominent in the endemic BL form where about half appear in the jaw, while most sporadic BL present as an abdominal mass (Silva et al., 2016). EBV is thought to play an early role in the development of BL. Some BL tumors are a clonal expansion of a single EBV-infected cell (determined by the terminal repeat number as a marker of clonality), suggesting that infection occurred prior to proliferation and expansion of the tumor cells. High EBV titers are a risk factor for development of BL. In addition to EBV, malaria has been implicated as a co-factor in endemic BL. Parasite burden has been shown to correlate with the incidence of EBV-positive BL in geographic regions endemic for malaria (Morrow, 1985). It has been suggested that malaria-induced immunosuppression of T cells or T cell exhaustion allows for greater expansion of EBV-positive proliferating B cells, which in turn increases the probability of a MYC translocation event and subsequent BL formation (Ho et al., 1986, Whittle et al., 1984). Constitutive c-Myc expression drives B cell proliferation but also induces apoptosis through the p53 pathway or the BCL2-like protein 11 (BIM) apoptotic activator (Harrington et al., 1994). However, EBV-positive BL show resistance to apoptosis compared to EBV-negative BL suggesting that EBV confers protection from c-Myc-mediated apoptosis (Kelly et al., 2006, Piccaluga et al., 2015). Most EBV-positive BL display a latency I viral gene expression program, with EBNA1, LMP2A, and viral microRNAs detected (Rowe et al., 1987). These viral factors have been shown to provide survival advantages to B cells by various mechanisms (Kennedy et al., 2003, Lu et al., 2011, Riley et al., 2012). Mapping of the mutation spectrum of BL has uncovered a number of mutations in addition to the defining MYC-immunoglobulin gene translocation. TP53 mutations occur in approximately 40% of BL tumors (Bhatia et al., 1992, Giulino-Roth et al., 2012). Other common mutations include the negative transcriptional regulator ID3 (in 34% of BL), anti-apoptotic gene MCL1 (in 17% of BL) and chromatin remodelers ARID1A and SMARCA4 (in 25% of BL) (Giulino-Roth et al., 2012, Love et al., 2012). Importantly, EBV-positive BL have a lower number of mutations than EBV-negative BL (Giulino-Roth et al., 2012, Vockerodt et al., 2008). In addition, DNA hypermethylation of the B-Lymphocyte-Induced Maturation Protein 1 promoter, involved in B cell terminal differentiation with putative tumor suppressor activity, is more frequent in EBV-positive BL than EBV-negative BL (Zhang et al., 2014). The observations support the notion that EBV may substitute the requirement for mutation during lymphomagenesis. EBV and Oral Lymphomas in the Immunocompromised Host Secondary immune suppression due to AIDS or transplantation carries an increased incidence for lymphoma. Prior to antiretroviral therapy, AIDS patients showed a 60 to 200-fold increase in lymphoma compared to HIV-negative individuals (Bower et al., 2006). Many of these lymphomas were linked to EBV (Carbone, 2003, Shibata et al., 1993). Plasmablastic lymphomas are an aggressive oral lymphoma that frequently occur in the jaw and oral mucosa of AIDS patients. Plasmablastic lymphoma is a variant DLBCL with immunoblastic morphology and plasma cell immunophenotype that is associated with latent EBV infection in approximately 70% of cases (Colomo et al., 2004, Delecluse et al., 1997, Gaidano et al., 2002). Introduction of antiretroviral therapies decreased the incidence of HIV-associated non-Hodgkin’s lymphomas (Hishima et al., 2006). In transplant patients, Post-Transplant Lymphoproliferative Disease (PTLD) is a life-threatening complication (Nalesnik et al., 1988). PTLD consists of a spectrum of disorders that range from a benign polyclonal lymphoid proliferation to a malignant/clonal lymphoma. PTLD mainly occurs in the gastrointestinal tract, and a few cases of oral PTLD have been reported (Amorim Pellicioli et al., 2016, Lones et al., 1995, Ojha et al., 2008). Intraoral PTLDs have been observed in the gingiva, hard palate, and tongue (Broudy & Sabath, 1995, Chang et al., 1994, Hanto et al., 1981, Johnson et al., 2007, Oda et al., 1996, Ojha et al., 2008, Raut et al., 2000). The risk of PTLD is dependent on the organ transplant, the age and EBV status of the patient, and type and duration of immune suppression, with PTLD incidence ranging from 1 to 20%. Latent EBV is associated with 80% of PTLD cases, predominating in early PTLD which appear within the first year following immune suppression. Furthermore, EBV-seronegative transplant recipients are 20 times more likely to develop PTLD (Haque et al., 1996). Thus, PTLD is associated with primary EBV infection where EBV latency III/growth program stimulates B cell growth that goes unchecked in the absence of immune control. Restoration of immune function through adoptive T cell therapy with EBV-specific cytotoxic T cells or reduction of immunosuppression results in regression of the tumor in many cases (Bollard et al., 2012). Go to: EBV and Oral Carcinoma Given its tropism for epithelial cells and lifelong residence in the oral cavity, EBV has also been linked to carcinomas arising in the oral cavity. Although not an oral carcinoma per se, EBV association with NPC is well established and has provided correlates for EBV’s role in carcinoma. NPC is an aggressive, highly invasive squamous cell carcinoma with prominent lymphoid infiltrates that arises in the nasopharynx. NPC is prevalent in Southern China, Southeast Asia, and Inuit populations accounting for 20% of all cancers in these endemic regions, but NPC is rare in Western populations. NPC has been classified into 3 groups according to the differentiation state and keratinizing tumor morphology. Nearly all undifferentiated NPC are associated with EBV. Increased EBV antibody titers have been reported approximately three years prior to NPC detection (Ji et al., 2007). EBV infection has also been shown to follow early genetic changes in the premalignant epithelium to facilitate a stable latent infection. NPC tumors display a type II latent EBV infection which is defined by expression of viral oncogenes LMP1, LMP2, EBNA1, and viral noncoding RNAs. Importantly, EBV infection of epithelial cells has been shown to confer phenotypes observed in NPC tumors. EBV infection is able to delay differentiation, likely reprogramming epithelial cells with features of basal or progenitor stem cells (Birdwell et al., 2014). LMP2A has been shown to induce a delay in epithelial differentiation (Scholle et al., 2000), while LMP1 can induce a cancer stem cell/progenitor phenotype in nasopharyngeal epithelial cells (Kondo et al., 2011). In addition, EBV infection has been shown to confer a metastatic phenotype to EBV-infected cells (Queen et al., 2013, Kassis et al., 2002). Thus, EBV infection in the context of carcinoma may promote tumor progression conferring the salient phenotypes that are associated with the morbidity and mortality of NPC. EBV and Oropharyngeal Squamous Cell Carcinoma Epidemiological studies have revealed variable rates of EBV infection in OSCC, ranging from no association to 100%. Geographic and ethnic differences are one explanation for the varied EBV association in OSCC. (Bagan et al., 2008, Cruz et al., 1997, D’Costa et al., 1998, Iamaroon et al., 2004, Kobayashi et al., 1999, Sand et al., 2002, Tsang et al., 2003). However, inconsistencies in detection methods and the prevalence of EBV in the oral cavity, in particular EBV-positive lymphoid tumor infiltrates, have obscured the ability to definitively associate EBV with OSCC. In addition, epithelial tissues exhibiting severe dysplasia show a more pronounced EBER expression than OSCC, suggesting that EBERs may not be a reliable marker for assigning EBV-positivity in OSCC (Kikuchi et al., 2016). In addition to EBER, LMP1 and EBNA2 have been detected in OSCC (Kikuchi et al., 2016, Shimakage et al., 2002). LMP1 in particular has been detected in the absence of EBER expression, consistent with the possibility of an EBER-negative latent EBV infection in OSCC (Gonzalez-Moles et al., 2002, Bonnet et al., 1999, Kobayashi et al., 1999, Sugawara et al., 1999). Fewer than one EBV genome per cell has been detected in OSCC, further raising the question of whether EBV serves as a factor in tumor progression or is simply a passenger (Goldenberg et al., 2004). However, several studies have demonstrated considerably higher levels of EBV infection in OSCC versus healthy tissues of the same cohort (Bagan et al., 2008, Cruz et al., 1997, D’Costa et al., 1998, Jiang et al., 2015, Kobayashi et al., 1999, Sand et al., 2002). An epidemic rise in OSCC has been observed over the past several decades that is associated with human papillomavirus, specifically HPV16 (Ramqvist & Dalianis, 2010). HPV is a small DNA tumor virus more traditionally associated with cancers arising in the anogenital tract. EBV and HPV co-infection have been detected in 15–20% of carcinomas occurring in the oropharynx (Jalouli et al., 2012, Polz-Gruszka et al., 2015). Interestingly, the vast majority of OSCC occurs in the tonsils and the base of tongue, lymphoid-rich regions where EBV resides (Dahlstrand & Dalianis, 2005, Licitra et al., 2002). Specific analysis of EBV/HPV co-infection in tonsillar and base of tongue squamous cell carcinoma has shown co-infection rates of 25% and 70%, respectively (Jiang et al., 2015). This study also showed that all tumors harbored integrated HPV, suggesting that when EBV was detected it was likely in a cell harboring an integrated HPV (Jiang et al., 2015). OSCC prognosis has been shown to vary depending on a number of factors, particularly age, with older patients exhibiting poorer prognosis (Jadhav & Gupta, 2013). However, HPV-positive OSCC exhibit a better prognosis compared to HPV-negative OSCC with treatment de-escalation being recommended to reduce the extensive morbidity following chemotherapy (Benson et al., 2014). A better understanding of the etiology of HPV-positive OSCC is critical for the development of effective treatment regimens. HPV-positive OSCC exhibits distinct characteristics when compared to other HPV-associated cancers. HPV-positive OSCC are poorly differentiated, highly invasive, and exhibit a more rapid onset, developing within a matter of years as opposed to decades. A correlation between EBV infection and poor differentiation status in OSCC has been demonstrated (Gonzalez-Moles et al., 1998). Experimentally, EBV infection has been shown to delay epithelial differentiation and promote an invasive phenotype, further enhancing the invasiveness of epithelial cells expressing HPV16 E6 and E7 oncogenes (Birdwell et al., 2014, Jiang et al., 2015, Kassis et al., 2002, Queen et al., 2013). Furthermore, delayed differentiation and enhanced invasiveness were retained in epithelial cells even after loss of EBV, indicating that a stable epigenetic reprogramming followed EBV infection (Birdwell et al., 2014, Queen et al., 2013). EBV could therefore contribute to OSCC pathogenesis via epigenetic reprogramming of infected tumor cells, and help explain the inconsistent detection of EBV in OSCC. How EBV might contribute to the pathogenesis of HPV-positive OSCC still needs to be defined, but may reflect the influence of HPV and EBV on one another’s viral lifecycles. One study showed that EBV/HPV co-infection increased both EBV and HPV replication in organotypic raft culture (Makielski et al., 2016). Alternatively, HPV infection may alter the EBV life cycle to favor latency, which was observed when EBV infected HPV-immortalized organotypic raft cultures (Guidry and Scott, unpublished observations). In either case, increased viral outputs or latency are consistent with clinical manifestations of EBV-associated carcinomas. EBV and Salivary Gland Epithelioma EBV infection is also linked to salivary gland epithelioma, a rare carcinoma endemic to southern Chinese and Arctic Inuit populations (Albeck et al., 1993, Kuo & Hsueh, 1997, Leung et al., 1995). salivary gland epithelioma exhibits histological similarities of non-keratinizing, undifferentiated NPC and most commonly occurs in the parotid gland with lymphoid infiltrates (Ambrosio et al., 2013). Endemic areas have a salivary gland epithelioma incidence of 5.9% (Abdulla & Mian, 1996), with an almost complete association with EBV infection (Abdulla & Mian, 1996, Iezzoni et al., 1995, Jen et al., 2003). EBV in salivary gland epithelioma has been characterized as a clonal latent EBV infection (Leung et al., 1995) specifically detected in carcinoma cells and not in infiltrating lymphocytes or in surrounding benign tissues (Hamilton-Dutoit et al., 1991, Huang et al., 1988, Iezzoni et al., 1995, Jen et al., 2003, Lanier et al., 1991). LMP1 protein has been detected in a subset of EBV-positive salivary gland epithelioma (Jen et al., 2003, Leung et al., 1995), in which a considerable portion of tumors exhibited C-terminal mutations in LMP1, including a 30bp C-terminal deletion characteristic of EBV-associated NPC in Chinese populations, as well as various C-terminal point mutations. The C-terminal deletion/mutations are thought to promote cellular proliferation, and may enhance the oncogenic effects of EBV in salivary gland epithelioma (Jen et al., 2003). EBV and Oral Hairy Leukoplakia Particularly seen in AIDS patients, OHL is another disease manifestation in the oral epithelium associated with EBV infection (Braz-Silva et al., 2008, Mabruk et al., 1994, Mabruk et al., 1996, Schmidt-Westhausen et al., 1993). OHL itself is not necessarily associated with significant morbidity or mortality, but instead serves as sign of immunodeficiency, particularly in the context of HIV infection (Chattopadhyay et al., 2005, Cherry-Peppers et al., 2003, Greenspan et al., 2004). OHL presents as elevated white lesions typically at the lateral borders and dorsum of the tongue, though lesions have also been described at the soft palate, floor of mouth, and buccal and oral mucosa (Triantos et al., 1997). OHL directly results from EBV replication, and is not related to a latent EBV infection (Greenspan et al., 1985, Greenspan & Greenspan, 1989, Walling, 2000). Treatment with the herpesvirus antiviral nucleoside analog acyclovir, which inhibits EBV replication, was shown to resolve OHL lesions within a matter of weeks (Resnick et al., 1988). Antiretroviral therapies and reconstitution of immune function have reduced OHL in HIV-infected individuals. The presence of permissive EBV replication makes OHL unique compared to EBV-associated malignancies; however, latency-associated genes are also concomitantly expressed in OHL (Sandvej et al., 1992, Thomas et al., 1991, Webster-Cyriaque & Raab-Traub, 1998, Webster-Cyriaque et al., 2000), which may influence regulation of cell proliferation and apoptosis and likely contribute to its histopathologic features (Walling, 2000). EBV replication in OHL does not culminate in cell lysis, likely due to the expression of anti-apoptotic viral genes, such as LMP1, which induces anti-apoptotic cellular gene expression, and BHRF1, which acts as a viral Bcl-2 homologue (Henderson et al., 1993). EBV oncogenic gene expression and the consequential cell survival in the face of extensive viral replication likely contribute to acanthosis, a hypertrophy of the infected epithelium at the spinous layer with EBV replication itself contributing to the koilocytic changes characteristic of OHL (Becker et al., 1991, Dawson et al., 1995, Triantos et al., 1997, Webster-Cyriaque & Raab-Traub, 1998). OHL may also exhibit a heterogeneous EBV infection characterized by co-infection of different EBV types and strain variants (Walling et al., 1992, Walling et al., 1994, Walling et al., 1995, Walling et al., 1999, Walling & Raab-Traub, 1994). Similar heterogeneous EBV infections have also been detected in immunocompetent individuals and could potentially enhance EBV pathogenicity in OHL (Burrows et al., 1996, Gan et al., 2002, Kelly et al., 2002, Midgley et al., 2000, Walling, 2000). Go to: Summary Although the oral cavity serves as the site of EBV residence and transmission, EBV-associated oral cancers are relatively rare, but are often misdiagnosed as symptoms mimic those of less severe diseases. In general, EBV-associated cancers do not seem to predominate in the oral cavity, but the oral cavity likely serves as a primary site of persistence that seeds cancers at other sites such as the nasopharynx and stomach. The role of EBV in its associated cancers is co-factorial requiring other genetic alterations and is associated with other infections (malaria and HPV). However, EBV infection is a critical oncogenic event that correlates with a rapid tumor progression and metastatic phenotype. Standard techniques for EBV detection are not always reliable as EBV gene expression may vary in different settings. Incomplete viral associations are often reported, but may reflect bystander oncogenic effects of EBV in the microenvironment or loss of EBV during tumor evolution. EBV-induced epigenetic reprogramming provides a mechanism for viral “hit-and-run” where maintenance of oncogenic phenotypes occurs in the absence of the virus or viral gene expression. Thus, additional studies will continue to define the contributions of EBV to oral tumor initiation and progression and provide virus-associated biomarkers for diagnosis, prognosis, and treatment.

Answer 7

* Small and large bowel Pneumatosis LEAST associated with (two questions on pneumatosis) * Cystic fibrosis * Asthma * **AMI** * SMA thrombus * Diverticulosis * * Benign pneumatosis can be caused by a variety of reasons such as \ * pulmonary disease, * systemic disease (scleroderma, lupus, AIDS), * intestinal inflammation, * iatrogenic/procedures, * medications (steroids, chemotherapeutic drugs, Lactulose, sorbitol and voglibose), * and organ transplation4. * Life-threatening pneumatosis can be caused by * intestinal ischaemia, * obstruction, * enteritis/colitis, * toxic caustic ingestion, * toxic megacolon, * organ transplantation, and * collagen vascular disease4.

Answer 8

1. Most likely to have bilateral phaeochromocytoma? 1. **VHL** 1. TS 1. MEN 1 1. ?? 1. ?? Pathology Spontaneous mutations account for 50-86% of cases 3, with the remainder inherited as an autosomal dominant condition. In the majority of such cases (80%) the mutation has been narrowed down to two tumour suppressor genes, both part of the mTOR pathway 3,13: TSC1: encoding hamartin, on chromosome 9q32-34 TSC2: encoding tuberin, on chromosome 16p13.3 (accounts for most cases) Radiographic features Tuberous sclerosis has a significant number of manifestations, involving many organ systems. The most common radiographic manifestations are: cortical or subependymal tubers and white matter abnormalities renal angiomyolipomas cardiac rhabdomyoma(s)

Answer 9

1. Testicular tumour most likely to cause elevated AFP? 1. **Endodermal sinus tumour** 1. Leydig 1. Seminoma - cant have elevated AFP by definition. May have mildly elevated bhcg 1. Sertoli Alpha-fetoprotein AFP can be secreted by NSGCT that contain embryonal carcinoma, yolk sac tumor or teratoma. By definition, seminoma or choriocarcinoma do not secrete AFP. Therefore any patient with an elevated AFP must have a nonseminomatous component of testis cancer. 1. **Endodermal sinus tumour AKA Yolk Sac tumour** * **most common childhood testicular tumour (80%),** * **most cases occurring before the age of two years** 1. * In adults, pure yolk sac tumour is extremely rare, however mixed germ cell tumour is commonly seen. * Pathology * **Totipotent cells**, which later form extraembryonic fetal membranes, give rise to yolk sac tumours. * Features * Perivascular structures called Schiller-Duval bodies can be found in 50% of tumours and are pathognomonic. * Markers * **AFP (alpha fetoprotein) is elevated in \>90% cases** of yolk sac tumour. * Radiographic features * heterogeneous testicular mass favours non-seminomatous germ cell tumour (NSGCT), * **and at age \<2 years,** yolk sac tumour is the favoured diagnosis. * Ultrasound * Diffusely enlarged heterogeneous testis. B. Leydig * 1-3% of all testicular tumours, * Bimodal, 5-10years, 20-30years * 10% malignant * Leydig cell tumours arise from the interstitial cells of Leydig adjacent to the seminiferous tubules * present with serum hormonal imbalance (~30%). * Virilization (including precocious puberty) may occur. * Hyperestrogenism may also occur and patients may demonstrate gynaecomastia. * Ultrasound * small, hypoechoic, round intratesticular mass * may demonstrate cystic areas * most often unilateral * difficult to differentiate from other testicular tumours 1. Seminoma * Testicular seminomas are the most common testicular tumours and account for ~45% of all primary testicular tumours. * Approximately 50% of all germ cell tumours are seminomas * seminomas can arise outside of the testicle; most often within the anterior mediastinum * Testicular germ cell tumours account for around 1-3% of all malignancies in males in Western populations and are the most common nonhematologic malignancy in males 15-49 years old. * Risk factors * undescended testis is the major risk factor for testicular germ cell tumours 10-40 times increased risk * ~10% of tumours are associated with undescended testis * increased risk in the contralateral normally descended testis * a previous tumour in the contralateral testis * a family history of testicular germ cell tumour * testicular microlithiasis: controversial risk factor, although some sources claim approximately 8 times increased risk 2 * other risk factors include infections such * as HIV, mumps, orchitis, and * history of trauma or * organ transplant immunosuppression * Seminoma by definition must be pure seminoma on histology and not associated with an elevated serum alpha-fetoprotein (AFP). * If either of these criteria is not met, the tumour must be classified as non-seminomatous and managed accordingly. * Uncommonly (15%), b-HCG may be slightly elevated. Pure seminomas are subdivided into three histological subtypes: * classic: 85%, infrequent mitoses; monotonous sheet of large cells with abundant cytoplasm and round hyperchromatic nuclei, prominent nucleoli * anaplastic: 10%, ≥3 mitotic figures per high-power field * spermatocytic: 5%, older male patients above 60 years old, rarely metastasise; well-differentiated with cells resembling secondary spermatids 1. Sertoli * Sertoli cell tumours of the testis are uncommon sex cord stromal tumours. * They are less common than Leydig cell tumours of the testis. * May present in both paediatric and adult males, depending on the histologic subtype.n * Testicular mass or firmness. May occasionally present with precocious pseudopuberty or gynaecomastia. * Can occur in four histologic types: * large-cell calcifying (paediatric) * intratubular large cell hyalinizing Sertoli cell neoplasia (LCCSCT) * associated with paediatric males with Peutz-Jegher syndrome * sclerosing Sertoli cell tumour (adults) * Sertoli cell, not otherwise specified * Sertoli cell tumours are less likely to be hormonally active (aromatase) than Leydig cell tumours. * Sertoli cell tumours of the testis are associated with the **Carney complex (cardiac myxomas, sertolic testicular tumours, skin pigmentation)** * Radiographic feature * Ultrasoun * ill-defined hypoechoic intratesticular lesio * usually solitary, unless part of a syndrome * large cell subtype may present with multiple and bilateral mass with large areas of calcification * MRI * limited characterisation in the literature, nonspecific appearance T2: homogeneously hypointense T1 C+ (Gd): homogeneous enhancement Treatment and prognosis Unfortunately, although most are benign, the ultrasound appearance overlaps with malignancy, and the majority are diagnosed after orchidectomy. There are a few case reports of malignant Sertoli cell tumours, but the majority appear benign. There are no known cases of malignant LCCSCT 2, but data is limited. Testicular germ cell tumours account for 90% of primary tumours of the testes. They are the most common nonhaematologic malignancy in men 15-49 years old. * They are divided into: * testicular seminoma: 40% of germ cell tumours 1 * non-seminomatous germ cell tumour: 60% of germ cell tumours * testicular embryonal cell carcinoma * testicular choriocarcinoma * testicular yolk sac tumour * testicular teratoma * testicular mixed germ cell tumour: 15% (typically one or more NSGCT and seminoma) 2 * testicular non-germ cell tumour: 10% of primary tumours Testicular germ cell tumours may "burn out" after metastasising, only leaving a small calcific intratesticular focus behind. Sex cord stromal tumours of the testis Dr Matt A. Morgan◉ et al. Sex cord stromal tumours of the testis are uncommon testicular neoplasms. Although ~90% of these tumours are benign, they cannot be differentiated from testicular malignancies on imaging, and are therefore usually discovered after orchidectomy. Leydig cell tumour of the testis (most common, ~30% hormonally active) Sertoli cell tumour of the testis juvenile granulosa cell tumour of the testis fibroma-thecoma of the testis mixed sex cord stromal tumours gonadoblastoma Epidemiology Uncommon testicular neoplasms with mildly increased incidence in paediatric patients 4% of all testicular neoplasms 11%, if \<12 years old. Pathology These tumours arise from cells that form the sex cords (Sertoli cells) and those that form the testicular stroma (Leydig cells).

Answer 10

1. Multiple endocrine neoplasm Type 1, LEAST associated with 1. **Phaeochromocytoma** 1. Pituitary adenoma 1. Parathyroid hyperplasia 1. Carcinoid 1. Gastrinoma MEN1 * Multiple endocrine neoplasia syndrome * Pituitary adenomas * Pancreas islet cell tumours * gastrinoma * Glucagonoma * Parathyroid hyperplasia * Carcinoid tumours Handy mnemonics for recalling MEN type I: PPP or PiParPanc Associations In addition to the aforementioned characteristic lesions involving the pituitary, parathyroid, and pancreas, numerous other lesions are encountered with greater frequency in patients with MEN1. These include: lipomas angiofibromas adrenal cortical lesions adrenal adenomas adrenocortical hyperplasia cortisol-secreting adenomas adrenal carcinomas (rare) carcinoid tumours hepatic focal nodular hyperplasia 5

Answer 11

1. Aortic dissection 1. 5-10% dissection flap not seen - false 1. **Contrast tracks between the intima and inner (third) media -true** 1. If tear seen, 80% are located at the distal aspect of the aortic arch -false 1. X 1. X 1. CTC p319 vol 2 * Acute aortic syndromes * There are 3 acute aortic syndromes * aortic dissection * intramural haematoma * penetrating ulcer * anatomy review * 3 layers * intima * media * externa * **Penetrating ulcer** * ulceration of an atheromatous plaque that has eroded the inner elastic layer of the aortic wall. * when it reaches the media, it procudes a hematoma within the media. * 1# risk factor = Atherosclerosis * Classic scenario: elderly patient with hyperteniona and atherosclerosis usually involving the descending thoracic aorta * Genesis: * eating like a pig and smoking results in atherosclerosis. * Nasty atherosclerotic plaque erodes through the intima * Hematoma forms in the media * intramural haematoma * With severe disease can eventually progress to a pseuedo aneurysm and maybe rupture * Look for a gap in the intimal calcificaiton * that's how you know its truly penetrated through the intima and not just a contour abnormality. * Classification: * all 3 AASs can be classified as type A or B stanford * Type a before the take off of the left subclavian * Type B, after the take off of the left subclavian * These things often result in a saccular morphology around the arch. * in general sac like aneurysm above the diaphragm is related to penetrating ulcer. Sac like aneurysm below the diaphragm is going to be septic - mycotic * Relationship between penetrating ulcer and dissection * Controversila which usually means it wont be tested * if forced to answer I would go with the following * penetrating ulcers are used by atherosclerosis * Penetrating ulcers can lead to dissection (this is probably true in some cases) * atherosclerosis does NOT cause dissection * Which is confusing, may or may not be true, and is unlikely to be tested. * What is true is that the presence of dense calcified plaque can stope extension of a dissection tear. * dissections often occur in the aortic root which you have the higher flow pressures * Penetrating ulcers nearly never occur in the root, as these flow pressures prevent atherosclerosis (which those cheese burger crumbs away). * Treatment of a penetrating ulcer * medical = similar to type B dissections * if they do get treated (grafted etc) they tend to WORSE than dissections (on average) * When are they surgical? * hemodynamic instability, pain, rupture, distal emboli, rapid enlargement. * **Dissection** * _The most common cause of aortic Syndrome 70%_ * HYPERTENSION is the main factor. * leads to an intimal tear resulting in two lumens * Marfans, turners and CTDs increase risk * CT, especially with arterial contrast enhancement (CTA) is the investigation of choice, able not only to diagnose and classify the dissection but also to evaluate for distal complications. It has reported sensitivity and specificity of nearly 100% * Classic testable scenarios * Pregnancy known to increase risk * Cocaine use in a young otherwise healthy person * Patient with hypertension and a substernal tearing sensation * Chicken vs Egg * some people say that hypertensive pressures kill the vasa vasorum (the little vessels inside the vessel walls) * leading to the development of intramural hematoma which then reptures into the intima * This is INSIDE OUT thinking * Other people think the hypertensive forces tear the inner layer directly (OUTSIDE IN THINKING) * There are two general ways to classify things * Time: Acute (\<2 weeks) or chronic * Location * Stanford A: account for 75% of dissections and involves the ascending aorta and arach proximal to the Left subclavian artery. Needs to be treated surgically * Standford B: occur distal to the take off of the left subclavian and are treated medically unless there are complications (organ ischaemia etc) * Intramural Haematoma * this can occur as primary even secondary to HTN * HTN * blasted vasovasorum * IMH * serosal rupture * pseudoaneurysm * Intima tears * dissection * Secondary event usually from atherosclerosis, but as as a focal hematoma on the road to dissction * Atherosclerosis * focal plaque rupturs * focal IMH * dissection * sereosal rupture * pseudo aneurysm * For the purpose of mcq, the cause is hypertension. * Treatment * also uses the Stanford a vs B idea * Type A surgery * Type B medical * this is controversial and unlikely to be tested. * Predictors of a shitty outcome * most IMHs will spontaneously regress. These are the thing that make that less likely * hematoma thickness greater than 2cm * A/w aneurysmal dilation of the aorta 5cm or more * progression to direction or penetrating ulcer * IMH and Penetrating ulcer has a worse outcome cf IMG and Dissection.

Answer 12

1. HCC, least likely risk factors 1. Alcohol 1. NASH 1. **Hep A** 1. Hep B 1. Hep C Hepatocellular Carcinoma (p. 870 Robins) * HCC accounts for approximately 5% of all cancers worldwide, * with a 3 to 8:1 male predominance. * It occurs most commonly in developing countries with high rates of HBV infection, particularly where infection starts in infancy and there is a high associated carrier rate. * **Half of such cases are not associated with cirrhosis;** rather there may be important adjunct exposure to aflatoxin (a mycotoxin produced by Aspergillus species that contaminates staple food crops). * In Western populations, increased rates of hepatitis C infection are also driving HCC incidence. * **Pathogenesis (p. 870)** * HCC usually arises in the background of chronic liver disease. * Major etiologic factors are * chronic viral infection (HBV or HCV), * chronic alcoholism, * NASH, * and food contaminants (e.g., aflatoxins); * lesser causes include * hemochromatosis, * tyrosinemia, and * α1-AT deficiency. * Activating mutations of β-catenin occur in 40% of HCC, and p53 inactivation is present in 60% of HCC. * Chronic inflammation is associated with genotoxic products, cytokine production, and hepatocyte regeneration; such changes—along with an underlying genetic susceptibility—presumably underlie tumorigenesis. * L-6 can suppress hepatocyte differentiation and promote hepatocyte proliferation by regulating the function of the transcription factor HNF4-α. * Morphology (p. 872) * HCC can present as * a solitary mass, * multifocal nodules, or * a diffusely infiltrative cancer with massive liver enlargement, * often (although not necessarily) in a background of cirrhosis; * intrahepatic spread and vascular invasion are common. * Histologically lesions may range from well differentiated to highly anaplastic and undifferentiated. * A distinctive variant is **fibrolamellar carcinoma.** * Constituting 5% of HCC, it usually presents as a single scirrhous, **hard tumor occurring in 20- to 40-year-olds in the absence of chronic liver disease.** * The cells are well-differentiated cells in cords or nests separated by dense lamellar collagen bundles. * Clinical Features (p. 873) * Features include * hepatomegaly, * right upper-quadrant pain, * weight loss, and * elevated serum α-fetoprotein. * Prognosis depends on * the resectability of the tumor; * mortality is secondary to cachexia, * GI or esophageal variceal bleeding, * liver failure with hepatic coma, or * tumor rupture and fatal hemorrhage. * Hepatitis A Virus (p. 831) Hepatitis A virus (HAV) is a single-stranded RNA virus that causes a benign, self-limited disease; fulminant HAV is rare (fatality rate 0.1% to 0.3%). It is not directly cytopathic; hepatocyte damage is due to CD8+ T-cell responses. HAV accounts for 25% of acute hepatitis worldwide; it has a fecal-oral route of spread. Acute infection is marked by anti-HAV immunoglobulin M (IgM) in serum; IgG appears as IgM declines (within a few months) and persists for years, conferring long-term immunity. An effective vaccine is available. * Hepatitis B Virus (p. 831) Hepatitis B virus (HBV) can cause the following (Fig. 18-3): * Acute, self-limited hepatitis * Nonprogressive chronic hepatitis * Progressive chronic disease culminating in cirrhosis (and increased risk of HCC) * Fulminant hepatitis with massive liver necrosis * Asymptomatic carrier state

Answer 13

1. Sarcoid. Least likely involvement: 1. Spleen and liver 1. Gastrointestinal tract 1. **Bone marrow (effects bone cortex**) 1. Eyes 1. Lymph nodes - common dahnert p669 Intro * immune, multisystem granulomatous disease * unknown eitiology * variable presentation * noncaseating non-necrotic epithelioid cell granumlomas Presentation * bilateral hilar LAD most common Rad finding * pulmonary infiltrates Epid * 10/100000 * higher in African americans * blood group A * 20-40 years * M:F 1:3 Path Phases: * Acute phase: Lymphocytes and scattered macrophages giant cells and small granulomas * Intermediate phase: formed granulomas and minimal scarring * late phase: fibrosis and granulomas and chronic inflammation Histo: * Noncaeseous granulomas composed of a central core surrounded by lymphocytes, scattered plasma cells, fibroblasts, and collagen * occasional minimal central coagulative necrosis. NONCASEATING GRANULOMA * Sarcoidosis is characterized by noncaseating granulomas. These are different than the caseating granulomas produced by other diseases, especially tuberculosis. Caseous necrosis is destruction of cells which are converted to amorphous greyish debris located centrally in granulomas. The term caseous ( L. caseus, cheese) refers to the gross appearance of caseous necrosis which resembles clumped, friable cheese. Acute * Lofgren Syndrome * fever, malaise, arthraliga chronic * Inisidous onset * lungs, skin and eyes abdominal * 30% * increased ACE levels in 91% * scattered hypoattenuating nodules involvinggliver and spleen suggest a dx of sarcoid or lymphoma * Cardiac saroid * 5% clinically 20-50% at autopsy * hypokinesis and systolic dysfunction * cardiomyopathy * GIT * \<1% * Oesophagus to Rectum * Stomach most common * COlon second most common * Genitourinary * 0.2-5% * interstiial nephritis * MSK * 6-20% * usually accompanied by cutaneous manifestations * Joints, muscle and bone. * medullary granulomas infiltrate cortical bone. bone destruction and reactive sclerosis. * heads and feet, vertebra skull. * Neurosarcoid * 9% * dural leptomeningeal noncaseating granulomas * ophthalmic 25-80% * bilateral uveitis, photophobia, blurred vision, glucoma * commonly bilateral uveitis, bilateral enlarged enhancing lacrimal gladsphotophobia and burred vision

Answer 14

1. Which is true regarding pituitary adenomas 1. Thyrotroph is the most common microadenoma - false its rare. 1. Microadenoma is usually non-functioning - ? True. Clinically silent. From Robbins: *The prevalence of pituitary adenomas is 14%, with a peak incidence from age 35 to 60 years; the vast majority are clinically silent microadenomas.* 1. X 1. Somatotrophs can lead to Cushing’s disease - false 1. Lactotrophs are more readily identified in males due to galactorrhea - False * Lactotroph Adenoma (p. 1078) * Prolactinomas are the most common functional pituitary tumor (30%). * Even microadenomas can secrete sufficient PRL to cause hyperprolactinemia; * moreover, serum PRL concentrations tend to correlate with adenoma size. * Hyperprolactinemia can produce amenorrhea (25% of cases), galactorrhea, loss of libido, and infertility. * Hyperprolactinemia is normal during pregnancy. * In addition to adenomas, pathologic hyperprolactinemia can be caused by lactotroph hyperplasia, occurring when the normal dopamine inhibition of PRL secretion is blocked. * This can result from damage to the hypothalamic dopaminergic neurons, pituitary stalk transsection (e.g., head trauma), or drugs that block dopamine receptors; any suprasellar mass can potentially disturb the normal hypothalamic inhibitory pathways. * Consequently, mild PRL elevations—even in the presence of a pituitary adenoma—do not necessarily indicate a PRL-secreting tumor. * Somatotroph Adenomas (p. 1079) * **GH-secreting tumors are the second most common** functioning adenoma. * Hypersecretion of GH stimulates hepatic production of insulin-like growth factor 1 (IGF-1), which causes many of the clinical manifestations; the effects depend on the age of onset. * If somatotroph adenomas appear before epiphyseal closure, elevated GH results in gigantism characterized by a generalized increase in body size and disproportionately long arms and legs. * If increased GH appears after epiphyseal closure, patients develop acromegaly, with enlargement of head, hands, feet, jaw, tongue, and soft tissues. * GH excess is also associated with * gonadal dysfunction, * diabetes mellitus, * muscle weakness, * hypertension, * arthritis, * congestive heart failure, and * increased risk of gastrointestinal (GI) cancers. * Diagnosis relies on documenting elevated serum GH and IGF-1 levels; failure to suppress GH production by an oral glucose load is the most sensitive assay. * Tumors can be surgically removed, or GH secretion can be reduced by drug therapy with somatostatin analogues or GH receptor antagonists. * Effective control of GH levels leads to gradual recession of the tissue overgrowth and resolution of the metabolic abnormalities. * Corticotroph Adenomas (p. 1079) * Corticotroph cell adenomas are typically microadenomas at the time of diagnosis because ACTH production leads to early symptoms related to adrenal hypercortisolism (Cushing disease). * In addition to adenomas, a wide variety of conditions can also cause elevated cortisol levels (Cushing syndrome, discussed under adrenal pathology). * Surgical removal of the adrenals results in loss of inhibitory feedback to the pituitary corticotrophs and can induce the formation of large, destructive adenomas (Nelson syndrome); * these can also cause hyperpigmentation through effects on melanocytes of other products of the ACTH precursor. * Other Anterior Pituitary Adenomas (p. 1080) •Gonadotroph adenomas * (10% to 15% of pituitary adenomas) * typically occur in middle-aged men and women. * Because they produce hormones somewhat variably and the secretory products do not cause recognizable symptoms, most tumors are detected only when they become large enough to cause neurologic symptoms. * Impaired LH production is the most common gonadotroph deficiency; in men the resulting low serum testosterone manifests as decreased energy and libido, whereas in premenopausal women the outcome is amenorrhea. * Thyrotroph adenomas * (1% of pituitary adenomas) are rare causes of hyperthyroidism. * Nonfunctioning pituitary adenomas * (25% to 30% of pituitary adenomas) * include nonsecretory (“silent”) variants of functioning adenomas, as well as true hormone-negative adenomas; the latter are unusual. * Patients with nonfunctioning adenomas typically present with mass effects. * Pituitary carcinomas * are quite rare (\<1%); * most are functional (secreting PRL or ACTH most commonly). * Diagnosis of carcinoma requires the demonstration of metastases. * CLINICAL PRESENTATION * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853872/ The predominant physiologic consequence of hyperprolactinemia is hypogonadotropic hypogonadism (HH) which is due to suppression of pulsatile GnRH. The clinical manifestations of conditions vary significantly depending on the age and the sex of the patient and the magnitude of the prolactin excess. Clinical presentation in women is more obvious and occurs earlier than in men. Women can present with symptoms of oligomenorrhea, amenorrhea, galactorrhea, decreased libido, infertility, and decreased bone mass. It is worth noting that many premenopausal women with hyperprolactinemia do not have galactorrhea, and many with galactorrhea do not have hyperprolactinemia. This is because galactorrhea requires adequate estrogenic or progesterone priming of breast. Conversely, isolated galactorrhea with normal prolactin levels occurs due to increased sensitivity of the breast to the lactotrophic stimulus.[14,15,16] Thus, galactorrhea is very uncommon in postmenopausal women. Approximately 3-10% women with PCOS have coexistent modest hyperprolactinemia.[17] Prolonged hypoestrogenism secondary to hyperprolactinemia may result in osteopenia.[18] Spinal bone mineral density (BMD) is decreased by approximately 25% in such women and is not necessarily restored with normalization of prolactin levels.[19] Women with hyperprolactinemia and normal menses have normal BMD.[20,21] Hyperprolactinemic women may present with signs of chronic hyperandrogenism such as hirsutism and acne, possibly due to increased dehydroepiandrosterone sulfate secretion from the adrenals,[22] as well as reduced sex hormone binding globulin leading to high free testosterone levels. Men with hyperprolactinemia may present with erectile dysfunction, decreased libido, infertility, gynecomastia, decreased bone mass, but rarely galactorrhea. Over time, the patient may have diminished energy, reduced muscle mass, and increased risk of osteopenia.[23]

Answer 15

1. Lung changes. Anaerobic Bacteroides grown. 1. Reflux of gastric contents 1. **Aspiration of oral contents** 1. Haematogenous spread of extrathoracic abscess 1. X 1. X Aspiration Pneumonia Robbins Anaerobic oral flora (Bacteroides, Prevotella, Fusobacterium, Peptostreptococcus), admixed with aerobic bacteria (S. pneumoniae, S. aureus, H. influenzae, P. aeruginosa)

Answer 16

1. Regarding the prostate which is true? (may not actually be Q22 recall) 1. Prostate cancer rarely involves the peripheral zone - false 1. **Nodule related to BPH typically arise in the transitional and periurethral zone - true** 1. X 1. X 1. BPH typically elevated PSA more than prostate cancer - false * * * Morphology (p. 985) * **Most cases (70%) arise in the peripheral zone** of the prostate, usually in the posterior prostate. * Gross: Primary lesions characteristically are * poorly demarcated, * gritty, * firm, and yellow. * Locally advanced cases may infiltrate the * seminal vesicles and * urinary bladder; * invasion of the rectum is uncommon * Microscopic: * Most are well-differentiated adenocarcinomas with small, crowded glands lined by a single layer of epithelium (lacking the outer basal layer of cells); * nuclei are large and often exhibit nucleoli. Perineural invasion is a sign of malignancy * High-grade PIN consisting of architecturally benign but cytologically atypical cells is associated with 80% of prostate carcinomas. * The Gleason system stratifies prostate cancers into five grades based on their glandular patterns * (1 = closest to normal; 5 = no glandular differentiation), * without regard to cytologic features. * The scores of the dominant grade and the second most common grade are added (e.g., Gleason grade 3 + 4; the most well-differentiated tumor has a score of 2 [1 + 1], and the least well-differentiated tumor has a score of 10 [5 + 5]). * Low-to-moderate-grade Gleason scores (2 to 6) suggest treatable disease, whereas higher-grade scores portend a grave prognosis. * Clinical Course (p. 988) * The treatment and prognosis of prostatic carcinoma are influenced primarily by the stage and Gleason grade of the disease. * Localized (clinical stage T1 or T2) disease is treated primarily with surgery or radiotherapy with a 15-year survival rate of 90% * Many prostate cancers have a relatively indolent course; thus it may take 10 years to see benefit from surgery or radiotherapy, and watchful waiting is an appropriate treatment for many older men (or those with significant comorbidity). * Metastases occur initially in **obturator nodes**, followed by spread to other nodal groups. * Hematogenous dissemination occurs primarily to bone, most often in the form of **osteoblastic metastases.** * External beam radiotherapy can be used to treat prostate cancer that is too locally advanced to be cured by surgery. * Hormonal therapy for metastatic disease can include orchiectomy, administration of synthetic analogues of luteinizing hormone-releasing hormone, or pharmacologic blockade of the AR; tumors often become refractory to antiandrogen therapies. * Prostate-Specific Antigen (p. 988) * Prostate-specific antigen (PSA) is the most important test used in the diagnosis and management of prostate cancer. * PSA is a product of prostatic epithelium and is normally secreted in the semen; serum levels are elevated to a lesser extent in BPH than prostate cancer, although there is considerable overlap. * Important points include the following: * PSA is organ-specific yet not cancer-specific. * Other factors such as * BPH, * prostatitis, * infarct, and * instrumentation of the prostate can increase serum PSA levels. * As men age, their prostates tend to enlarge with BPH, with corresponding higher serum PSA levels. * Furthermore, 20% to 40% of patients with organ-confined prostate cancer have PSA below the thresholds usually set for screening for malignancy. * PSA velocity (rate of change of PSA) may be a more useful measurement than just a single PSA value. * This reflects the finding that PSA levels rise faster in prostate cancer than for age-related hyperplasia. * Multiple measurements need to be made over a period of 1 to 2 years. * In the setting of known prostatic carcinoma, PSA monitoring is useful in assessing response to therapy or progression of disease. * In addition to PSA, PCA3 is a noncoding RNA which is overexpressed in 95% of prostate cancers and can be quantified in urine, serving as an additional biomarker. * The combination of urinary PCA3 plus urine TMPRSS2-ERG fusion DNA may have increased sensitivity and specificity compared to PSA screening alone. * Benign Prostatic Hyperplasia or Nodular Hyperplasia (p. 982) * Benign prostatic hyperplasia (BPH) is an extremely common disorder caused by periurethral epithelial and stromal hyperplasia that compresses the urethra; symptoms are related to urinary flow obstruction. * Histologic evidence of BPH is present * in 20% of men by age 40, * 70% of men by age 60, * and 90% by age 70; * only half will have clinically detectable prostate enlargement, and of those, only 50% develop clinical symptoms. * Some 30% of white American males over 50 years of age have moderate-to-severe symptoms. * Etiology and Pathogenesis (p. 982) * The critical mediator in this process is dihydrotestosterone (DHT)—synthesized by the stromal cells of the prostate from circulating testosterone via 5α-reductase, type 2 (Fig. 21-2). * DHT binds to the nuclear androgen receptor (AR) in stromal and epithelial cells, activating the transcription of androgen-dependent genes. * DHT is not a direct mitogen but does increase the production of secondary growth factors and their receptors, in particular fibroblast growth factor (FGF)-7 by stromal cells. * FGF-7 acts in a paracrine manner to stimulate stromal cell proliferation and inhibits epithelial apoptosis * Augmented FGF-1 and -2, and TGF-β production also contribute by driving fibroblast proliferation. * Morphology (p. 982) * Gross: The gland is enlarged by nodules primarily in the **transitional and periurethral zones** (Fig. 21-1); * the cut surface demonstrates well-demarcated nodules that can vary from firm and pale-gray (predominantly fibromuscular stromal) to yellow-pink and soft (mostly glands). * Microscopic: Nodules are composed of variable mixtures of proliferating glands and fibromuscular stroma; * glands are lined by two layers of cells—a basal layer of low cuboidal epithelium covered by a layer of columnar secretory cells. * Other changes include squamous metaplasia and infarcts. * Clinical Features (p. 983) * The symptoms of lower urinary tract obstruction are due to the increased size of the prostate, the extrinsic compression of the urethra, and smooth muscle-mediated contraction of the prostate. * In turn the increased resistance to urinary outflow leads to bladder hypertrophy and distention, with urinary retention. * Patients manifest with the following: * Urinary frequency, nocturia, and difficulty starting and stopping the stream of urine. * Chronic urinary stasis with resultant bacterial overgrowth and UTIs * Urinary bladder diverticula and hydronephrosis * Therapy can include * α-blockers that inhibit the α1-adrenergic receptors mediating prostate smooth muscle tone. * In addition, 5α-reductase inhibitors can reduce the underlying DHT-mediated stimulation, and—for recalcitrant prostates— * surgical (e.g., transurethral resection of the prostate [TURP]) and various other debulking approaches are available.

Answer 17

Aplasia is a condition in which an organ, limb, or other body part does not develop. In most cases, aplasia is obvious at birth. However, certain types of aplasia may sometimes not be apparent until later in life. https://www.medicalnewstoday.com/articles/aplasia#:~:text=Aplasia%20is%20a%20condition%20in,of%20different%20types%20of%20aplasia.

PATHOLOGY 1 Flashcards

(41 cards)