Carcinoma ex pleomorphic adenoma is subdivided into what 3 prognostic subtypes?
Noninvasive, minimally invasive, and invasive. Noninvasive carcinomas arising in PA are sometimes referred to as in situ or intracapsular carcinomas. These tumors are characterized by relatively abrupt transitions between histologically bland PA and areas with obviously malignant cytologic features but are limited to the confines of the PA without extracapsular invasion. The noninvasive carcinoma may invade the matrix of the preexisting PA but is not considered clinically invasive until it penetrates beyond the capsule of the PA. Minimally invasive CaExPA is defined as a carcinoma that invades no more than 1.5 mm beyond the capsule of the PA. Distinguishing between a benign pseudopod and true invasion may be difficult. A desmoplastic reaction, if present, is helpful. So-called lateral extension (mushroom-type invasion) into and through the capsule, akin to that seen in some thyroid carcinomas, also implies malignancy, as does perineural invasion. In addition, the invasive component should demonstrate atypical cytologic and architectural features.
Discuss the 3 growth patterns seen in adenoid cystic carcinoma.
Cribriform, tubular, and solid. The cribriform subtype is the MC. It is composed of islands of basaloid cells surrounding variably sized cystlike spaces forming a “Swiss cheese” or sievelike pattern. The cystlike spaces are referred to as “pseudocysts” b/c they do not represent true glandular lumina and are contiguous with the surrounding stroma. The pseudocysts contain basophilic glycosaminoglycans and/or eosinophilic, PAS-positive basal lamina material. Rare, true glandular lumina composed of cuboidal cells showing ductal differentiation can also be found scattered throughout and their presence greatly aids in diagnosis. The tubular pattern shows similar cytology with the tumor cells arranged in nests surrounded by variable amounts of eosinophilic, often hyalinized stroma. Occasionally, the stromal component is increased, compressing the tumor cells into thin strands, forming a “trabecular” pattern. Well-formed ducts with recognizable inner epithelial and outer myoepithelial layers are more prominent than in the cribriform pattern. The continuity of the pseudocysts with the surrounding stroma is also more prominent. The solid pattern contains aggregates of basaloid cells without tubular or cystic formation. Although the basaloid cytology of the tumor cells is retained, the tumor cells may be larger and nuclear pleomorphism may be more pronounced. Mitoti figures and comedonecrosis may also be seen. As in the cribriform pattern, true ducts will occasionally be seen scattered among the sheets of cells. This feature, along with accompanying areas of cribriform or tubular growth, can aid in differentiation from other basaloid neoplasms. A combination of patterns can be seen, which could be considered a fourth pattern.
Malignant mixed tumors of the salivary glands can be classified as what 3 types?
- Carcinoma ex pleomorphic adenoma. 2. “Benign” metastasizing pleomorphic adenoma. 3. Carcinosarcoma. >90% of all malignant mixed tumors are CaExPAs and most are high grade, with salivary duct carcinoma; adenocarcinoma NOS; undifferentiated carcinoma; and myoepithelial carcinoma being the most common subtypes.
Myoepithelial neoplasms of the salivary glands.
Some authors believe these should be purely myoepithelial, while some believe a minor ductal component can be present (typically <5%). Myoepithelial neoplasms can be benign (myoepithelioma) or malignant (myoepithelial carcinoma or malignant myoepithelioma). 10-20% are malignant. MC sites are parotid gland and palate. Most myoepitheliomas occur in the 5th and 6th decades of life and most myoepithelial carcinomas occur in the 6th and 7th decades of life. Myoepithelial tumors can be difficult to recognize histologically because of variety in their architectural and cytologic appearances. 6 characteristic growth patterns of myoepithelial tumors: solid, nodular, mucinous, trabecular, pseudoglandular, reticulated. 5 characteristic cell types of myoepithelial tumors: spindled, plasmacytoid-hyaline, clear, epithelioid, oncocytic.
Nasolabial cysts.
The nasolabial cyst is a benign, slow-growing, locally expansile lateral extraosseous lesion below the nasal ala and the medial nasolabial fold. Although often classified as a jaw cyst, the nasolabial cyst is purely a cyst of soft tissue. Alternative, older, or less common names for this lesion include Klestadt cyst, nasal vestibule cyst, nasal wing cyst, and mucoid cyst of the nose. Because the cyst does not involve the dental alveoli, the sometimes also encountered term nasoalveolar cyst is not recommended. Nasolabial cysts can be observed at any age, but MC in 30-50 yo, and F:M = ~3:1. They are typically unilateral and slow-growing. They are found near the distal portion of the nasolacrimal duct and its opening into the inferior nasal meatus. It is believed that nasolabial cysts are hamartomatous developmental lesions, arising from the lower anterior portion of the nasolacrimal duct. Grossly, nasolabial cysts are pink to tan, soft to rubbery-firm, and have variably cystic and fibrous areas filled with clear viscous fluid. Histologically, there is a bilayered epithelium with a cuboidal basal layer and a columnar luminal layer that contains interspersed scattered mucinous goblet cells. To variable extents, nasolabial cysts can also be lined by multilayered or pseudostratified, cuboidal to columnar epithelium. Focal squamous metaplasia or apocrine changes may also be present. Ciliated cells are not present. Cyst wall stroma is composed of hypocellular, collagen-rich fibrovascular tissue with variable amounts of chronic inflammatory cells.
Osteoblastomas associated with a tooth root are called ___.
Osteoblastomas associated with a tooth root are called cementoblastomas. Osteoblastoma occurs more often in the mandible than the maxilla. It is often associated with the root of a tooth, where it forms an ossified, well-demarcated tumor. Microscopically, the bony matrix tends to be abundant in these tumors and to radiate from the tooth root in parallel arrays.
Papillary thyroid carcinoma, cribriform morular variant. What stains can be helpful? This variant is associated with (syndrome) ~25% of the time.
This variant’s unique histology and reactivity with thyroglobulin, TTF-1, and beta-catenin help to distinguish it. This variant is associated with FAP ~25% of the time.
Papillary thyroid carcinoma, diffuse sclerosing variant. In what age group does it occur? What is the histologic appearance?
A rare variant that occurs in children and young adults. It has conventional papillary architecture and PTC nuclear features, but has squamoid changes and abundant psammoma bodies, a dense lymphocytic and sclerotic background, and extensive lymphatic permeation.
Papillary thyroid carcinoma, oncocytic variant. What is the gross and histologic appearance?
This variant is grossly mahogany brown. Microscopically, while it has conventional papillary architecture, it is oncocytic with focally prominent nucleoli and often has psammoma bodies (about 33 %).
PIOLs?
Primary Intraocular Lymphomas. Is a subset of PCNSL. Is usually a DLBCL. They arise from the retina (a suggested renaming for PIOL is primary retinal lymphoma) and rarely from the uvea. Usually presents as a chronic intermediate uveitis unresponsive to corticosteroids in a median age in the 60s. The Dx is based on ID of atypical lymphoid cells in the eye, but b/c PIOL is a subset of PCNSL, the Dx can be made if the lymphoma cells are found in CSF, and an LP is less invasive than a diagnostic vitrectomy or a vitreous or aqueous aspiration anyway. The atypical lymphoid cells are usually large and pleomorphic, with scant basophilic cytoplasm and large nuclei. Other findings include hypersegmented, round, or clover-shaped nuclei with prominent nucleoli and rare mitoses.
Pleomorphic adenoma of salivary gland?
AKA benign mixed tumor. MC salivary gland tumor, accounting for almost 2/3 of all salivary gland tumors. PAs are composed of both epithelial cells and myoepithelial cells, which produce a mesenchymal stromal component that is often myxoid or chondromyxoid. Varying amounts and arrangements of the epithelial, myoepithelial, and stromal components give rise to a broad degree of morphologic diversity. The distinction between a cellular PA, basal cell adenoma, or myoepithelioma can be subjective. An acellular PA can resemble a soft tissue chondroma or myxoma. ~6% of PAs harbor malignancy. PAs are usually well circumscribed and encapsulated in the major salivary glands and nonencapsulated in the minor salivary glands.
Polymorphous low-grade adenocarcinoma of the salivary glands?
PLGA occurs almost exclusively in the minor salivary glands of the oral cavity and oropharynx. They tend to be nonpainful and slow growing, M:F = 1:2, and occurs over a broad age range (average 50-60). Histologically, PLGA is characterized by a triad of infiltrative growth, multiple architectural growth patterns, and cytologic uniformity. Characteristic growth patterns include solid, trabecular, glandular, cribriform, fascicular, cordlike and papillary, with the first 3 patterns being the MC. Typically, the central portion consists of the more solid growth patterns, with the glandular and cordlike elements seen more often at the periphery. Mitoses are rare and necrosis is unsually not seen. PNI is common and can have a targetoid arrangement which is very characteristic of PLGA. The tumor cells are cytologically bland and can be cuboidal, columnar, or spindled, with a mixture being most common.
Salivary duct carcinoma.
SDC is one of the most aggressive salivary gland carcinomas and histologically resembles HG ductal adenocarcinoma of breast. Can be seen in a wide age range but most are in >50 (mean of 60-79). M:F = 3-4:1. It can arise de novo or in the setting of a pleomorphic adenoma (SDCExPA). Parotid gland is the MC tumor site. Microscopically, SDCs are characterized by both infiltrative and intraductal carcinoma resembling breast ductal carcinoma. The most characteristic histologic feature is variably sized, rounded nodules with a cribriform, solid, cystic, or papillary architecture. These so-called ductal lesions frequently demonstrate comedo necrosis, which may undergo calcification. Cytologically high grade and numerous mitoses. The cells have moderate to abundant amounts of eosinophilic to amphophilic cytoplasm, fequently imparting an apocrine-like phenotype. For IHC, most tumors are positive for androgen receptor and SDC is now virtually defined by expression of this. SDCs are often positive for BRST-2 and CEA and >2/3 are positive for HER-2 overexpression, but almost all are negative for ER and PR. Prognosis is dismal.
The most common primary lymphoma subtype occuring in the ocular adnexa?
Low-grade, malignant, extranodal, marginal zone B-cell lymphoma of MALT type.
Uveal malignant melanoma?
… is the most common primary intraocular malignancy in the adult population. It comprises ~5% of all melanomas, and 85% of ocular melanomas are uveal in origin. Mortality, principally from liver metastasis, has historically been ~50%. Features correlating with poor prognosis include: large size, epithelioid cell type, presence of PAS positive vascular mimicry patterns (or extracellular matrix patterns), and ciliary body involvement. Chromosomal changes of prognostic significance include monosomy 3, and alterations of 8q and 6p.
What is HPT-JT syndrome?
HPT-JT (hyperparathyroidism-jaw tumor) syndrome is an inherited disorder with incomplete penetrance. The disorder may be characterized by parathyroid adenoma or carcinoma, benign fibro-osseous lesions of the mandible or maxilla, and renal cysts or tumors. Approximately 80% of patients have hyperparathyroidism and up to 15% of these patients have parathyroid carcinoma. The HRPT2 gene (for ‘‘hyperparathyroidism 2’’) is a putative tumor suppressor gene that was identified and has been mapped to 1q25–q31. The gene encodes a protein named parafibromin for its relationship to parathyroid disease and fibro-osseous jaw lesions. While HPT-JT syndrome is an exceedingly uncommon entity, with an unknown incidence or prevalence, like MEN, it should be considered in the differential diagnosis for the adolescent presenting with hyperparathyroidism.
What is the most common tumor of the paranasal sinuses?
Osteoma. Osteomas are benign, generally slow-growing, bone-forming tumors limited almost exclusively to craniofacial and jaw bones. They can be subdivided into bone surface tumors (or exostoses) that primarily involve the cranial vault, mandible, and external auditory canal and the more common sino-orbital (or paranasal sinus) osteomas that arise from bones that define the paranasal sinuses, nasal cavity, and orbit. Frontal, ethmoid, maxillary, and sphenoid sinuses are most frequently affected in that order. Histologically, while surface exostoses are usually formed of compact bone, sino-orbital osteomas are composed of variable amounts of compact and cancellous bone. Some osteomas have been designated as “osteomas with osteoblastoma-like features” and are difficult to distinguish from osteoblastomas or osteoid osteomas. Osteoblastoma is most commonly located in the vertebrae and long bones, but mandible is also a relatively common location, where it is often associated with the root of a tooth and referred to as cementoblastoma. However, primary osteoblastoma of the paranasal sinuses is very rare. Osteoid osteomas are vary rare in the craniofacial and jaw bones. They are distinguished from osteoblastoma only by size with a nidus usually less than 1 cm, since the histologic features are essentially indistinguishable. Microscopically, although focally indistinguishable from osteoblastoma, osteoma with osteoblastoma-like features has much more mature bone in the form of solid/compact (ivory osteoma) and dense cancellous (mature osteoma) bone. In addition, the outer contour of an osteoma has a smooth rounded surface, often lined by respiratory mucosa, representing the outer surface of its polypoid growth within the sinus cavity. True osteoblastomas, in contrast, will from an expansible intramedullary or periosteal bone tumor.
What HPV types (in order of frequency) are seen mostly commonly in the following lesions? Plantar wart, common wart, flat (juvenile) wart, oral squamous papilloma, oral focal epithelial hyperplasia (Heck disease), epidermodysplasia verruciformis, laryngeal papillomas, condyloma acuminatum, cervical LSIL, cervical HSIL, cervical AIS and invasive cervical adenocarcinoma.
Plantar wart: 1, 2. Common wart: 2, 1, 4, (HPV 7 in fish and meat handlers). Flat (juvenile) wart: 3, 10. Oral squamous papilloma: 6, 11. Oral focal epithelial hyperplasia (Heck disease): 13, 32. Epidermodysplasia verruciformis: 2, 3, 10, 5, 8. Laryngeal papillomas: 6, 11. Condyloma acuminatum: 6, 11. Cervical LSIL: 6, 11. Cervical HSIL: 16, 18, 31, 33, 35. Cervical AIS: 18. Invasive cervical adenocarcinoma: HPV 16 and 18 are detected with equal prevalence in most subtypes of cervical adenocarcinoma.
What are 2 risk factors for development of ameloblastoma?
Dentigerous cyst. Impacted teeth.
___% of medullary thyroid carcinomas occur in a relatively young population in association with MEN2 syndrome; the remainder are sporadic and may occur at any age.
15-20% of medullary thyroid carcinomas occur in a relatively young population in association with MEN2 syndrome; the remainder are sporadic and may occur at any age.
How does medullary thyroid carcinoma appear on FNA?
FNA biopsy yields neoplastic neuroendocrine cells and amyloid in variable proportions. The cellularity of the smears is usually inversely proportional to the amount of amyloid produced by the tumor. The neoplastic cells are dispersed or form loose clusters, rarely forming microfollicles or papillae. MTC is a great mimicker. The tumor cells may have spindly, plasmacytoid, polygonal, hurthloid or giant cells appearances; may demonstrate mild pleomorphism; and may be bi- or multinucleated. The nuclei often have a “salt-and-pepper” or “speckled” chromatin pattern on Pap stain. Nucleoli may be seen, but are usually inconspicuous. Intranuclear cytoplasmic inclusions are frequently identified, and are morphologically identical to those seen in papillary thryoid cancer. Mitotic figures are present in 15% of cases. On Diff-Quik staining, red cytoplasmic granules, corresponding to neurosecretory granules containing calcitonin, may be seen.
What is seen on FNAs in Hashimoto thyroiditis?
Smears from Hashimoto’s thyroiditis show a polymorphous lymphoplasmacytic infiltrate with germinal center formation. Lymphoid tangles, lymphohistiocytic aggregates, tingible body macrophages, and background lymphoglandular bodies may be the overwhelming findings on the smears. Multinucleated histiocytes may be seen. Oncocytic (Hurthle cell) metaplasia is usually prominent. Hurthle cells are epithelial cells with abundant, finely granular cytoplasm and enlarged, variably sized, typically round nuclei that may display prominent nucleoli.
Warthin’s tumor epidemiology.
Warthin’s tumor AKA papillary cystadenoma lymphomatosum AKA adenolymphoma is the second most common benign neoplasm of salivary glands. It arises from ducts trapped during embryologic development of lymph nodes in the parotid glands, explaining why Warthin’s tumor almost always occurs in or around the parotid gland. It often affects people in the fourth to seventh decades of life, with M:F=5:1. Smokers have a higher risk of developing Warthin’s tumors. Warthin’s tumor are multifocal in ~25% of patients and are bilateral in ~5-7.5%. Most of them are cystic, feel “doughy” upon palpation, and yield cloudy fluid on FNA.
How does Warthin’s tumor appear on FNA?
Most of them are cystic, feel “doughy” upon palpation, and yield cloudy fluid on FNA. Smears are hypocellular, but scattered flat sheets of oncocytic cells and lymphocytes are likely to be found. Corpora amylacea and mast cells may be seen. Aspiration of more peripheral solid regions of the lesion may yield more cells. Oncocytic metaplasia is common in elderly males. Therefore, identification of all three components - oncocytic cells, lymphocytes, and cyst contents - is important for diagnosis.
How does pleomorphic adenoma/benign mixed tumor appear on FNA?
BMTs present as painless, slowly growing masses, and are the most common type of salivary gland tumor, especially in the parotid. Aspirates of BMT contain a combination of myxoid matrix, sheets and clusters of epithelial cells, and mesenchymal cells. The mesenchymal cells are of myoepithelial origin and are spindle shaped. “Hyaline cells” are modified myoepithelial cells which appear plasmacytoid with dense, glassy cytoplasm. They tend to present singly and may also be embedded within the fibrillary chondromyxoid stroma. Their presence is quite characteristic of BMT. Electron microscopy demonstrates that intermediate prekeratin filaments account for the dense, glassy appearance of the cytoplasm of hyaline cells. The chondromyxoid stroma is believed to be produced by myoepithelial cells. Tyrosine-rich crystals with radiating, flower-shaped or “daisy head” appearances stain orangeophilic on Pap stain and are not pathognomonic but, when present, support the diagnosis of BMT. They are detectable in less than 10% of BMTs. BMTs may show considerable epithelial atypia, but the atypia is limited and focal. If an aspirate contains features of BMT, but with readily identifiable, highly atypical epithelial cells, high mitotic activity, atypical mitotic figures and necrosis, malignant transformation should be suspected.
What tumors are seen in the subtypes of MEN syndrome?
MEN1: Pancreatic tumors (gastrinoma 50%, insulinoma 20-30%, VIPoma 12%, glucagonoma 33%. MEN 2B: Medullary thyroid carcinoma 85%, pheochromocytoma 50%, mucosal neuroma 100%, marfanoid body habitus 80%. FMTC: Medullary thyroid carcinoma 100%.
The granularity of oncocytes is due to __.
The granularity of oncocytes is due to an excessive amount of mitochondria, resulting in an abundant acidophilic, granular cytoplasm.
Benign lymphoepithelial cystic lesions in the salivary gland are seen in association with HIV infection. Describe.
Salivary gland enlargement associated with a significant lymphoid infiltrate is recognized in HIV-positive patients. Because the lymphoid tissue usually exhibits morphologic and immunophenotypic features similar to those seen in florid follicular hyperplasia and the lesions often occur in association with enlarged lymph nodes, benign lymphoepithelial cystic lesions are thought to represent a manifestation of persistent, generalized lymphadenopathy. AKA benign lymphoepithelial lesion, benign lymphocpithelial cyst, cystic lymphoid hyperplasia, and HIV-related salivary gland disease. The lesion most commonly arises in the parotid gland where it occurs in 3-6% of adults and 1-10% of children with HIV. Overall, benign lymphoepithelial cystic lesions account for ~25% of enlarged salivary glands in the HIV positive patient population. The lesions are often cystic, bilateral, multiple, and associated with lymphadenopathy. Morphologically, they are characterized by epithelial-lined cysts, often with squamous metaplasia, follicular hyperplasia, glandular atrophy, and in some cases epimyoepithelial islands. In many patients, treatment with HAART results in smaller lesions or their complete resolution.
The HIV-related plasmablastic lymphomas characteristically arise in what location?
The HIV-related plasmablastic lymphomas characteristically arise in the oral cavity (60% of cases); however, they can also occur in other mucosal sites, such as the sinonasal cavity and the GI tract, and in nonmucosal sites, such as the skin, soft tissue, and lymph nodes.
What lymphoid proliferations are seen in association with HIV?
Progressive HIV-related lymphadenopathy/HIV-related benign lymphadenopathy. Benign lymphoepithelial cystic lesions. Multicentric Castleman disease. Lymphomas associated with HIV can be subcategorized as those occuring (1) also in immunocompetent patients (most cases), (2) more specifically in HIV+ patients (~5% of cases), and (3) in other immunodeficiency states (<5% of cases). The main entities in (1) are BL (~30% of HIV-related lymphomas), DLBCL (~40%), and cHL (~5-15%). These neoplastic entities account for most of the HIV-related lymphoma, although only the first 2 entities are AIDS-defining diseases. The neoplasms in (2) are highly associated with infection by EBV, KSHV/HHV8, or both. They include: Plasmablastic lymphoma. KSHV+/HHV8+ large B-cell lymphoma associated with MCD. Primary effusion lymphoma/Extracavitary primary effusion lymphoma. In (3), the HIV polymorphic lymphoid proliferations, which resemble the polymorphic poasttransplant-associated lymphoproliferative disorders seen in solid organ transplant recipients, comprise thie category of HIV-related lymphoma/lymphoma-like lymphoproliferative disorders.
What entities are in the differential diagnosis of adenomyoepithelioma of the breast?
Papilloma with prominent myoepithelial cells (the cases with only myoepithelial cells lining the papillae and forming the basal layer below the epithelial elements and without nests, nodules, or an increased proportion of myoepithelial cells are categorized as such). Nipple adenoma (favored by the presence of florid ductal hyperplasia and the pseudoinfiltrative pattern of stromal sclerosis entrapping glandular epithelium without an entrapped fibrous tissue or supporting fibrovascular cores). Clear cell carcinoma (can confirm AME by positive IHC for both epithelial and myoepithelial cell types). Metaplastic tumors associated with papilloma. The adenosis variant of AME has an infiltrative growth pattern that resembles microglandular adenosis (the latter is characterized by an absence of myoepithelial layer and S100 positivity). If the AME predominantly displays a spindle cell component, it may morphologically be mistaken for myoid hamartoma or leiomyoma (AMEs will have strong positivity for S100 and p63, and are negative for actin and cytokeratin). Lesions composed exclusively of benign myoepithelial cells suggest myoepithelioma (do thorough sampling to identify a luminal epithelial component). Adenoid cystic carcinoma (ACC has infiltrative borders, cribriform architecture, and the myoepithelial cells of ACC tend to be smaller, more hyperchromatic, basaloid appearing, and have much less cytoplasm than do those of an AME). Pleomorphic adenoma (hyaline matrix with chondroid areas and distinct encapsulation are more prominent in PA).
How is an adenomatoid hyperplastic nodule of the thyroid defined?
Adenomatoid hyperplastic nodule on the other hand is defined by a follicular nodule that lacks a capsule but otherwise resembles a follicular adenoma.
Papillary thyroid carcinoma metastasizes via (hematogenous/lymphatic) spread. Follicular thyroid carcinoma metastasizes vie (hematogenous/lymphatic) spread.
PTC usually spreads via lymphatics and metastasizes first to lymph nodes. In comparison, FTC usually metastasizes directly to distant organs by hematogenous routes.
What additional histologic features are seen in follicular variant of papillary thyroid carcinoma, in addition to the nuclear features of usual papillary thyroid carcinoma?
In addition to the nuclear features of PTC, FVPTC is frequently associated with other morphologic abnormalities. Other secondary or “soft” features of FVPTC include irregularly shaped, elongated and branching follicles with hypereosinophilic colloid within the lumens, and multinucleated giant cells within the lumen of the follicles. Stromal sclerosis is another feature that is often encountered in these tumors, as well as psammoma bodies. Approximately 33% of cases are encapsulated. Occasionally, abortive papillary structures can also be identified focally in these tumors. The diagnosis of FVPTC is notoriously difficult to make on fine needle aspiration cytology or on frozen section examination. When in doubt, it is better to defer to permanent sections for a more definitive diagnosis.
Primary ciliary dyskinesia AKA immotile cilia syndrome is associated in ~50% of patients with ___ syndrome.
Primary ciliary dyskinesia AKA immotile cilia syndrome is associated in ~50% of patients with Kartagener syndrome AKA situs inversus totalis. Chronic bronchitis, recurrent pneumonia, and atelectasis is virtually pathognomonic for Kartagener syndrome, and in this situation, cilia evaluation is not required for diagnosis.
What is a white sponge nevus?
AKA Cannon disease AKA familial white folded mucosal dysplasia AKA hereditary leukokeratosis. An AD disease with incomplete penetrance and variable expressivity. Prominent parakeratosis, acanthosis, and spongiosis of nonkeratinized squamous mucosa. Rete are blunted. Inflammation is usually not present. Pathognomonic: Pap stain of exfoliative cytology shows a characteristic perinuclear eosinophilic condensation of keratin tonofilaments. Most commonly intraoral, with buccal mucosa most common intraoral site. DDx: hereditary benign intraepithelial dyskeratosis, leukoedema, oral hairy leukoplakia.
What is hairy leukoplakia AKA oral hairy leukoplakia?
An EBV-associated epithelial hyperplasia usually on the lateral tongue in immunocompromised patients, most commonly HIV+ males. The disease correlated with viral load and CD4 counts. Although not an AIDS-defining disease, is a marker of HIV disease progression. Micro: Marked acanthosis and parakeratosis. Epithelial hyperplasia with elongation of rete ridges. Viral cytopathic effect (balloon cells) in spinous layer. Candida can be seen in superficial keratin - coinfection is a common finding in OHL. Very little if any inflammation. No dysplasia. DDx: Frictional keratosis. Hyperplastic candidiasis. Leukoplakia. Lichen planus.
Is oral hairy leukoplakia an AIDS-defining illness?
No. OHL is an EBV-associated epithelial hyperplasia usually on the lateral tongue in immunocompromised patients, most commonly HIV+ males but seen in transplant patients as well. The disease correlated with viral load and CD4 counts. Although not an AIDS-defining disease, is a marker of HIV disease progression.
What is herpangina?
Herpangina is a common viral infection of young children associated with blisters of soft palate or tonsillar pillars. It is caused by viruses belonging to the Enterovirus group (coxsackievirus, poliovirus, echovirus). Coxsackie A16 virus is the most common cause. Transmission is direct contact, usually oral-fecal route.
What virus is the most common cause of herpangina?
Herpangina is a common viral infection of young children associated with blisters of soft palate or tonsillar pillars. It is caused by viruses belonging to the Enterovirus group (coxsackievirus, poliovirus, echovirus). Coxsackie A16 virus is the most common cause, but other coxsackie viruses usually associated include A1 to A6, A8, A10, or A22.
What is hand, foot, and mouth disease?
A common viral illness of infants and children, which causes fever and blister eruptions of mouth and/or skin. Caused by virus belonging to Enterovirus group. Transmission is by direct contact. Virus is found in secretions, including saliva, nose and throat secretions, blister fluid, and stools.
What is Heck disease?
AKA focal epithelial hyperplasia AKA multifocal epithelial hyperplasia. A benign, virus-induced epithelial proliferation of oral mucosa associated with HPV types 13 and 32. Majority of cases are in children. Micro: Prominent acanthosis and elongated broad rete ridges (since the thickened epithelium extends upward, elongated rete are at same depth as adjacent normal rete ridges). May see papillary surface. Mitosoid cells (represents ballooning and nuclear degeneration; represents an altered nucleus resembling a mitosis in an otherwise normal stratified squamous epithelium; can be seen throughout epithelium); do not misinterpret mitosoid cells as atypia. Koilocytic change in superficial keratinocytes can be seen. No dyskeratosis and/or atypia. DDx: Papilloma. Condyloma acuminatum. Oral verruca vulgaris.
What HPV types cause Heck disease (focal epithelial hyperplasia/multifocal epithelial hyperplasia)?
HPV types 13 and 32.
What sites are affected in pemphigus vulgaris?
PV is an autoimmune mucocutaneous disease characterized by intraepithelial blistering. Etiology is circulating autoantibodies to desmoglein 1 and 3 adhesion molecules of squamous epithelium, which inhibit cell-cell adhesion resulting in acantholysis and blister formation. Mucous membranes: oral, nasal, esophagus, larynx, nasopharynx, conjunctivae, genitalia, anal mucosa. Cutaneous sites are mostly on intertriginous areas, trunk, head, and neck. Mucosal PV may be the only manifestation of disease or may precede cutaneous PV by an average of 5 months. >90% of patients will have oral involvement during disease course.
What is the etiology of pemphigus vulgaris?
PV is an autoimmune mucocutaneous disease characterized by intraepithelial blistering. Etiology is circulating autoantibodies to desmoglein 1 and 3 adhesion molecules of squamous epithelium, which inhibit cell-cell adhesion resulting in acantholysis and blister formation (suprabasal bullae formation with intraepithelial clefting).
What is the characteristic direct immunofluorescence finding in pemphigus vulgaris?
Homogenous staining (“fishnet” pattern) of IgG in intercellular desmosomal areas at all levels of the epidermis.
What sites are affected in mucous membrane pemphigoid AKA cicatricial pemphigoid?
MMP is a chronic, blistering mucocutaneous autoimmune disease generally presenting in 6th or 7th decade and M:F=1:2. Oral cavity is frequently affected, with gingival involvement seen in >60%. Ocular lesions occur in ~40% of patients with oral MMP. Upper aerodigestive tract can also be affected. Micro shows subepithelial clefting, intact basal cells, and a sparse inflammatory cell infiltrate in superficial lamina propria.
What is the characteristic direct immunofluorescence finding in mucous membrane pemphigoid (cicatricial pemphigoid)?
Micro shows subepithelial clefting, intact basal cells, and a sparse inflammatory cell infiltrate in superficial lamina propria. Direct immunofluorescence shows a continuous linear band of IgG and C3 at basement membrane zone (can also see IgM and IgA).
What is seen in direct immunofluorescence of lichen planus?
DIF is not specific or diagnostic. May show linear or granular deposits of fibrin or fibrinogen. Deposits of C3, IgM, IgG, and IgA occasionally seen.
What is Riga-Fede disease?
AKA traumatic ulcer, traumatic ulcer with stromal eosinophilia, eosinophilic granuloma of tongue, traumatic granuloma, atypical histiocytic granuloma. It is a chronic traumatic ulceration of oral mucosa with unique histopathologic features. Riga-Fede disease specifically refers to trauma to the soft tissue (ventral tongue or inner lower lip) in newborns or infants from natal or neonatal teeth. In children, traumatic ulcer is often due to thermal or electrical burns or parafunctional habits. In adults, traumatic ulcer is often due to fractured and/or malposed teeth or parafunctional habits. Micro: Ulcer bed composed of granulation tissue with mixed inflammatory cell infiltrate of lymphocytes, histiocytes, neutrophils, and occasionally plasma cells. Inflammation including scattered eosinophils extends into underlying muscle.
What oral lesions are associated with pseudoepitheliomatous hyperplasia?
Granular cell tumor. Hyperplastic candidiasis. Inflammatory papillary hyperplasia. Median rhomboid glossitis. Necrotizing sialometaplasia. Mucosal ulcers (traumatic ulcers, aphthous ulcers, herpetic ulcers, nonhealing extraction sockets). Although PEH can have rete deeply extending into lamina propria, anastamosing of rete, and keratin pearl formation, there will be no or very little cytologic atypia, and while mitotic figures can be present, they will not be atypical.
What is necrotizing sialometaplasia?
A reactive, self-healing inflammatory condition of salivary glands leading to coagulative necrosis of salivary acini and squamous metaplasia of ductal structures. Likely due to vascular compromise leading to ischemic necrosis; associated with trauma due to dental treatment, surgery, or other iatrogenic events. Majority of lesions affect minor salivary glands, especially of hard and soft palate. DDx: Squamous cell carcinoma (In spite of necrosis and possible pseudoepitheliomatous hyperplasia, in NSM the lobular architecture of salivary gland is maintained, and nests of metaplastic squamous cells are round to ovoid with no cytologic atypia). Mucoepidermoid carcinoma (Although mucin pools and squamous epithelium may suggest MEC, in NSM there is a maintained lobular salivary gland architecture, no invasion, minimal cyst formation, no intermediate or clear cell proliferation, and there is formation of true squamous cells (rather than the epidermoid cells of MEC)).
What is the microscopic appearance of, and differential diagnosis of amalgam tattoo in oral tissues?
Amalgam tattoo is a localized area of blue, gray, or black pigmentation caused by amalgam (commonly used dental amalgam contains silver, tin, mercury, and other materials) embedded into oral tissues, usually during dental procedures. Microscopically, is fine black granules scattered within superficial connective tissue. Pigment can be seen in collagen, histiocytes, fibroblasts, elastic fibers, and around blood vessel walls. Usually no inflammation associated with the pigment. Foreign body multinucleated giant cell reaction seen in ~40%. DDx: Pigmented intraoral lesions such as intraoral melanocytic nevus, oral melanotic macule, and oral melanoma. Varicosities. Unintentional mucosal tattoos, such as from accidental placement of foreign material (eg pencil graphite).
What are Fordyce granules?
AKA ectopic sebaceous glands AKA Fordyce condition AKA Fordyce spots. Are benign, ectopic sebaceous glands most common on lateral margins of upper and lower lips and buccal mucosa. Considered a normal variant and thought to arise from ectoderm inclusions during fusion of mandible and maxilla. Micro: Normal sebaceous glands lacking hair follicles. May consist of only 1 lobules but usually multiple acinar lobules in superficial lamina propria. Central duct extending to surface epithelium can be seen. Sebaceous hyperplasia can occur, particularly with advanced age. Glands can become obstructed, forming pseudocysts with the lumen containing keratin, sebum, or mucin.
What is the juxtaoral organ of Chievitz?
A normal anatomic structure located in buccotemporalis fascia bilaterally along medial surface of ascending ramus. It persists throughout life and has no known function. Rare reports of hyperplasia of the juxtaoral organ of Chievitz, but none of carcinoma arising from it. Size ranges from 0.7-1.7 cm in length and 0.1-0.2 cm in width. Is composed of circumscribed nests of squamous cells within fibrous stroma. No mitoses, no or little pleomorphism, no keratinization, no desmoplasia, no inflammation. Duct-like lumina may be present. Stroma is rich in nerves (small nerve branches of buccal nerve), and epithelial islands are often intimately associated with them (intra- and perineural involvement). DDx: Invasive neurotropic squamous cell carcinoma. Mucoepidermoid carcinoma. Adenoid cystic carcinoma. Odontogenic carcinoma.
What is a ranula?
A ranula is a mucocele found on the floor of the mouth. When it is confined to the floor of the mouth it is a simple/oral ranula. A variant is the cervical/diving/plunging ranula, which can dissect the mylohyoid muscle, produce neck swelling, and large lesions may need sublingual gland excision. The term ranula is derived from the Latin word rana, meaning frog, and describes a blue translucent swelling in the floor of the mouth reminiscent of the bulging throat or underbelly of a frog.
What are the definitions of squamous papilloma, verrucae vulgaris, and condyloma accuminatum?
SP: Benign proliferation of squamous epithelium in exophytic pattern with branching fibrovascular tissue cores exhibiting papillary pattern causally related to HPV infection (subtypes 6 and 11 detected in ~50% of cases, rarely HPV 16 detected). VV (AKA common wart or oral wart): Benign HPV-induced (subtypes 2, 4, 6, 40, or 57 detected in 100% of cases) proliferation of squamous epithelium, usually on skin, but also in oral cavity. CA (AKA veneral wart): HPV-related (subtypes 2, 6, 11, 53, or 54 in oral area, rarely 16, 18, or 31 (usually anogenital)) proliferation of squamous epithelium of genitalia, perianal region, oral cavity, or larynx.
What is an Abrikossoff tumor?
AKA granular cell tumor AKA granular cell myoblastoma AKA granular cell nerve sheath tumor AKA granular cell schwannoma.
What is a gingival granular cell tumor of infancy?
AKA Neumann tumor AKA congenital epulis of the newborn. A rare, benign congenital growth on alveolar mucosa in neonates. M:F = 1:8-10. Maxilla:mandible = 3:1. Can be histologically indistinguishable from granular cell tumor, but unlike GCT, develops in newborns to infants only and is S100 negative. Also, while ~50% of GCTs of the oral cavity have pseudoepitheliomatous hyperplasia, congenital epulis never has it. Not to be confused with “nonneural granular cell tumor,” which is a tumor in adults that is S100 negative.
What are etiologies for pyogenic granuloma in the oral cavity? What is the epidemiology?
Pyogenic granuloma AKA lobular capillary hemangioma AKA epulis granulomatosus AKA pregnancy tumor (epulis gravidarum). Etiologies include poor oral hygiene, local irritants (fractured tooth, poor restoration), localized trauma (biting), and hormones (increased in pregnancy and oral contraceptive use. Most common in children and young adults. In up to age 18, M>F but in adults M:F = 1:2. About 1% of pregnant women develop PG, and is related to hormonal influences on vessels. Gingiva is the most common site of oral cavity PG.
What is the cell of origin for pyogenic granuloma/lobular capillary hemangioma?
Bicellular origin from endothelial and pericyte cells.
Peripheral ossifying fibroma.
AKA peripheral fibroma with calcification. Is a reactive proliferation of fibrous tissue with mineralization exclusive to gingiva. May be associated with chronic irritation. Origin is cells from periosteum and/or periodontal ligament. Micro: Cellular fibroblastic stroma with a mineralized component (trabecular bone, woven bone, dystrophic calcification, cementum, or a combination of the above). Surface may be ulcerated.
Mucosal neuroma. What syndromes are associated with it?
Multiple endocrine neoplasia, specifically MEN2B. Most cases of multiple mucosal neuromas are associated with MEN2B. Also, mucosal neuromas are associated with PTEN hamartoma tumor syndrome (PHTS), including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome.
Mucosal neuroma.
Proliferation of nerves, often in a plexiform pattern. Seen on tongue and lips most commonly. Most cases of multiple lesions are seen in patients with MEN2B. Micro: Nonencapsulated, with a haphazard distribution. Hyperplasia of nerve bundles. Prominent thickening of perineurium. DDx: Neurofibroma (may blend with surrounding tissue, has spindle cells with variable collagen). Traumatic neuroma (lacks the prominent perineurium seen in mucosal neuroma). Palisaded encapsulated neuroma (encapsulated at least partially, has spindle cells). Schwannoma (neurilemoma) (characteristic Antoni A and B areas, Verocay bodies, and hyalinized vessels).
What is an epignathus?
A teratoma that arises in the oral cavity. Most common sites are palate and tongue.
Teratomas of the oral cavity.
AKA epignathus. Rare; 1 in 4000 live births have teratoma, and 1-2% of those involve head and neck. Most common sites of teratoma of the oral cavity are palate and tongue. Prenatally, can have polyhydramnios due to impaired fetal swallowing, and AFP concentrations are increased. At birth, can have significant respiratory distress. Top DDx: dermoid cyst or encephalocele.
What is oropharyngeal carcinoma?
Basically is a squamous cell carcinoma of oropharynx, the sites including soft palate, tonsils, uvula, base of tongue, and oropharyngeal wall comprising Waldeyer ring. Is also called oropharyngeal squamous cell carcinoma (OPSCC). What is typically called oral squamous cell carcinoma involves the sites of tongue (lateral and ventral), floor of mouth, lip, retromolar trigone, gingiva, buccal mucosa, and palate. HPV+ OPSCC is nonkeratinizing, while HPV- OPSCC is keratinizing. Other subtypes include: Hybrid-type OPSCC, which has features of both nonkeratinizing OPSCC and keratinizing SCC; is HPV+ most of the time. Lymphoepithelial-like OPSCC, which is similar in histology to EBV-related nasopharyngeal carcinoma; is HPV+. Papillary OPSCC, which is an uncommon variant; most are HPV+.
What are the top 3 most common metastatic tumors to the oral cavity in males and females?
Males: lung > kidney > prostate. Females: breast > genital organs > kidney.
What entities are in the differential diagnosis of osteomyelitis in the head and neck region?
Osteomyelitis AKA osteitis is inflammation or infection of bone and bone marrow. Top differential diagnoses include inflammatory reaction (inflammation part of fracture repair; present at tumor borders; lack of acute inflammation and dead bone), lymphoma (atypical lymphoid infiltrate with bone remodeling and dense fibrosis), sarcoid (noncaseating, tight, well-formed granulomas), bisphosphonate therapy (bone necrosis with death, followed by active remoderling; more often a chronic process), and radiation osteitis (bone necrosis and death with chronic inflammation).
What is cherubism?
Cherubism is an inherited disease characterized by progressive, painless, symmetrical expansion of the jaws, resulting in a cherubic facial appearance. M:F = 2:1, with 100% penetrance in males and 50-70% penetrance in females. Mutations in the SH3BP2 gene have been identified in about 80 percent of people with cherubism. In most of the remaining cases, the genetic cause of the condition is unknown. There are germline point mutations in the SH3BP2 gene on chromosome 4p16.3.
What is the most common type of rhabdomyosarcoma?
Embryonal rhabdomyosarcoma is the most common type (65% of RMS cases) and usually occurs in children ages 3-10 in the head and neck (nasal and oral cavities, orbit, ear), prostate or paratesticular regions. Subtypes of embryonal rhabdomyosarcoma include embryonal NOS, anaplastic, botryoid, and spindle cell, with embryonal NOS being the most common subtype (75%).
What is the most common subtype of embryonal rhabdomyosarcoma?
Embryonal rhabdomyosarcoma is the most common type of rhabdomyosarcoma (65% of RMS cases) and usually occurs in children ages 3-10 in the head and neck (nasal and oral cavities, orbit, ear), prostate or paratesticular regions. Subtypes of embryonal rhabdomyosarcoma include embryonal NOS, anaplastic, botryoid, and spindle cell, with embryonal NOS being the most common subtype (75%).
What is a central giant cell lesion?
AKA central giant cell granuloma AKA giant cell reparative granuloma AKA giant cell tumor. A potentially locally aggressive osteolytic lesion of gnathic bones. Neoplastic process is favored over reactive. The mandible is most commonly affected, with the anterior region more common. It frequently crosses the midline. Histologically, the tumor is composed of giant cells and stroma. The giant cells are most likely related to osteoclasts, can be focal collections or diffusely distributed, have variable size and shape, and can have up to 20 nuclei per cell. The stroma can be loosely arranged to fibrous, is cellular, and can have erythrocyte extravasation with hemosiderin. Do not confuse this entity with the other “giant cell tumor” which is thought to occur exclusively in long bones.
What is osteitis deformans?
Osteitis deformans is a synonym for Paget disease of bone, which is a localized skeletal disorder characterized by osteoclasts of increased number and size containing multiple nuclei. There is excessive breakdown and formation of bone tissue. Most common sites of involvement are: pelvis (70%) > femur (55%) > lumbar spine (50-55%) > skull (40%) > tibia (30%).
True or false. In Paget disease of bone, serum calcium is elevated.
False. Total serum alkaline phosphatase is elevated in over 85% of patients, and may be useful in monitoring the disease. Serum calcium, phosphorus, and aminotransferase are normal in Paget disease of bone.
Risk of secondary sarcoma is __% in Paget disease of bone.
Risk of secondary sarcoma is 4-10% in Paget disease of bone. Secondary sarcomas are generally high grade. The most common types are osteosarcoma and malignant fibrous histiocytoma, but fibrosarcoma and giant cell tumor of bone may also be seen.
What is the etiology of Paget disease of bone?
Unknown. Infectious agents have been proposed based on electron microscopy data, but there is no conclusive proof. The disease occurs in familial clusters and sporadically. 15-40% of patients have a positive family history. Familial cases display an autosomal dominant pattern of inheritance with variable penetrance. Cytogenetic studies of families with Paget disease of bone have identified numerous involved chromosomal loci. Nongenetic factors are also involved in the appearance of the disease, as there is variable penetrance in families, and the fact that the disease has a highly localized nature.
What are the histologic features of Paget disease of bone?
Findings reflect the stage of disease. The initial stages are reflective of osteoclastic activity: numeous osteoclasts, increased vascularity, and numerous resorptive surfaces. Mid-stage shows a mix of patterns: osteoclastic resorption, increased vascularity, and numerous surfaces covered with active osteoblasts. End stage is primarily sclerotic.
What is a simple bone cyst of the head and neck region?
Simple bone cyst AKA traumatic bone cyst AKA traumatic bone cavity AKA solitary bone cyst AKA hemorrhagic cyst. Is a benign empty or fluid-filled cavity within bone most commonly in the mandible. Histologically, will have small fragments of fibrovascular connective tissue, small fragments of bone that are reactive with cellular trabeculae, red blood cells, rare giant cells, dystrophic calcifications, and no epithelial lining. The differential diagnosis includes developmental odontogenic cysts such as dentigerous cyst or lateral periodontal cyst (both have a cyst lining), or reactive odontogenic lesions such as radicular cyst (has a cyst lining) or periapical granuloma (dense inflammatory infiltrate).
Dentigerous cyst. Definition, etiology, and epidemiology.
AKA follicular cyst. Is a developmental cyst surrounding the crown of an impacted tooth and attached to cemento-enamel junction. It develops by accumulation of fluid between reduced enamel epithelium and crown of a tooth. It is the most common developmental cyst (25% of all jaw cysts). Peak incidence 2nd to 3rd decade. Slight male predilection. Most commonly associated with mandibular 3rd molars or maxillary canines.
Dentigerous cyst. Microscopic appearance. DDx.
AKA follicular cyst. It a developmental cyst surrounding the crown of an impacted tooth and attached to the cemento-enamel junction. Dentigerous cysts can be noninflamed or inflamed. Noninflamed: fibrous to fibromyxoid connective tissue; 2-3 layers of cuboidal to ovoid epithelium; occasional mucous cells; rare ciliated cells; occasional dystrophic calcifications; odontogenic epithelial rests. Inflamed: fibrous connective tissue; proliferative epithelium; hyperplastic rete ridges; chronic inflammatory cells; acute inflammatory cells, usually associated with oral communication; cholesterol clefts; Rushton bodies (AKA hyaline bodies in odontogenic cysts feature as eosinophilic, straight or curved, irregular or rounded structures within the epithelial lining of odontogenic cysts); rare mucous cells; rare ciliated cells; rare sebaceous cells. DDx: enlarged dental follicles (has no cystic epithelium).
What are Rushton bodies?
Rushton bodies AKA hyaline bodies in odontogenic cysts feature as eosinophilic, straight or curved, irregular or rounded structures within the epithelial lining of odontogenic cysts. They are present exclusively within odontogenic cysts, and are found almost always within the epithelial lining and only rarely in the fibrous capsule. Rushton bodies may show up in examination of the gross specimen as small, white, dome-shaped swellings measuring up to 0.1 mm on the epithelial surface and protruding into the cyst cavity. In microscopic sections, they appear as eosinophilic, linear, straight or curved or hairpin shaped, circular or polycyclic forms, often with a granular core and sometimes concentrically laminated. They were thought to be of hematogenous origin, but it has been found that Rushton bodies are a secretory product of odontogenic epithelium deposited on the surface of particulate matter like cell debris or cholesterol crystals.
Periapical cyst/granuloma.
Periapical cyst AKA periradicular cyst AKA apical periodontal cyst. Periapical granuloma AKA periradicular granuloma AKA periradicular periodontitis. Definition: inflamed tissue associated with apex or root surface of nonvital tooth. Natural history: caries causes cavitation of tooth; bacterial invasion of pulp tissue; toxins are generated; pulp tissue becomes devitalized. Periapical cysts make up ~75% of periapical lesions, and are the most common cyst of the jaw; periapical granulomas are less common. Microscopic: fibrous tissue; variable inflammation (chronic and acute: lymphocytes, plasma cells, multinucleated giant cells, histiocytes, eosinophils, and neutrophils); dystrophic calcifications; cholesterol clefts; foreign material if previously endodontically treated; periapical cyst will have stratified squamous epithelial lining.
Ameloblastoma. Definition. Epidemiology. Treatment. Transformation?
Definition: Benign, slowly growing, locally aggressive neoplasm of odontogenic epithelium. Most common odontogenic tumor excluding odontomas. 80-85% occur in the posterior mandible. Peripheral ameloblastoma (found on gingiva, usually anterior mandible) is the most common peripheral odontogenic tumor. Intraosseous type - average age 36; unicystic type - 75% found in 2nd to 3rd decade; peripheral type - average age 51. Equal gender distribution. Conventional ameloblastomas generally require en bloc resection. Unicystic lesions are treated with local enucleation. Peripheral lesions are easily treated with local excision. Rare transformation to ameloblastic carcinoma (destructive growth, cytologic features of malignancy including pleomorphism and increased mitoses) or malignant ameloblastoma (required development of metastatic deposits, which are usually in lung).
Ameloblastoma. Microscopic appearance. Variants.
Odontogenic epithelial islands: centrally, stellate reticulum composed of loosely arranged angular cells; surrounded by single layer of ameloblast-like cells; nuclei are located away from basement membrane (reverse polarity AKA Vickers-Gorlin change); basal cytoplasmic vacuolization. Stroma is variable and can be loose or dense. Numerous patterns can be seen (a single pattern may predominate, or a combination of patterns can be seen). Invasive. Variants: plexiform, follicular, desmoplastic, basaloid, granular cell, acanthomatous, unicystic.
Molecular genetics of ameloblastoma.
ING family of tumor suppressor gene has high frequency loss of heterozygosity (ING5 locus LOH correlated to solid tumor type). Notch signaling molecules may be associated with specific tumor phenotypes. Dysregulation of a number of genes involved in normal tooth development may play a role: FOS oncogene most overexpressed gene; underexpressed genes include SHH, TRAF3, DCC, CDH12, TDGF1, TGFB1.
What is a squamous odontogenic tumor? What entities are in the differential diagnosis?
A very rare benign odontogenic neoplasm of squamous epithelium that may demonstrate locally aggressive behavior. Age range 2nd to 7th decades. Sites include anterior maxilla, posterior mandible, or rarely as peripheral lesion in gingiva. Microscopic appearance: Epithelial nests and islands (varying shapes, bland, single cell keratinization may be seen, microcysts, laminated calcifications) and stroma (fibrous connective tissue, hyalinization may be seen around islands). DDx: ameloblastoma, squamous cell carcinoma, metastatic carcinoma, odontogenic epithelial rests, organ of Chievitz.
What is a calcifying epithelial odontogenic tumor? What entities are in the differential diagnosis?
AKA Pindborg tumor. A rare epithelial odontogenic neoplasm with local invasion, characterized by amyloid-like material and calcification. Age range 20-60, average 40. Vast majority are intraosseous and in the mandible. Microscopic: Epithelial cells (sheets, cords, or islands of cells; polyhedral cells with abundant eosinophilic cytoplasm; intracellular bridges are well developed; prominent, well-defined cell borders; pleomorphism usually present, and giant tumor nuclei occasionally seen; mitotic figures rare), matrix (hyalinized or fibrous connective tissue stroma; eosinophilic and homogeneous, positive with Congo red and thioflavin T), and calcification (Liesegang rings (basophilic concentric layers)); usually adjacent to tumor cells. DDx: Clear cell odontogenic carcinoma, squamous cell carcinoma, metastatic squamous cell carcinoma, metastatic renal cell carcinoma. However, all of the entities in the ddx lack amyloid and calcifications.
What is an adenomatoid odontogenic tumor? What entities are in the differential diagnosis?
Formerly known as adenoameloblastoma, but confusion with ameloblastoma should be avoided. AOT is a benign tumor of odontogenic epithelium with distinct duct-like appearance embedded in mature connective tissue stroma. “Tumor of 2/3”: 2/3 are in women, 2/3 are in 2nd decade, 2/3 in anterior maxilla, 2/3 are in associated with impacted tooth. Grossly usually have a thick, well-defined capsule. Micro: Nodules of odontogenic epithelium (duct-like nests or cords lined by cuboidal to columnar cells; reversed nuclear polarity away from central lumen-like space; duct-like spaces are pseudolumina containing eosinophilic secretions) and stroma (spindle to polyhedral eosinophilic cells; swirling to nodular pattern; contains amorphous amyloid-like material (tumor droplets); mineralizations; small vessels. DDx: Ameloblastoma (lacks gland-like structures; usually larger and more invasive; lacks capsule), salivary gland tumor (rare location, usually without calcifications; lacks reverse polarity and stroma is not prominent).
What is the origin of the word “transthyretin”?
Transthyretin (TTR) is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine (T4) and retinol binding protein bound to retinol. This is how transthyretin gained its name, TRANSports THYroxine and RETINol. It is synthesized in the liver, choroid plexus and retinal pigment epithelium for secretion into the bloodstream, cerebrospinal fluid and the eye, respectively. TTR was originally called prealbumin (or Thyroxine-binding prealbumin) because it ran faster than albumin on electrophoresis gels.
Keratocystic odontogenic tumor. Microscopic appearance. DDx.
AKA odontogenic keratocyst AKA odontogenic keratocystoma AKA primordial cyst. Micro: Epithelial lining (6-8 cells thick; lacks rete ridges and epithelium is often detached from fibrous wall, creating cleft; basal layer shows palisading and hyperchromicity; parakeratotic epithelial cells; wavy or corrugated surface keratinization; keratineceous debris in lumen) and fibrous connective tissue (may be detached from overlying epithelium). When inflamed, epithelium is altered and rete ridges are noted. Epithelial hyaline bodies (Rushton bodies) may be seen. By IHC, high Ki-67 confirms proliferation, and TP53 is overexpressed. By molecular genetics, there are mutations in the PTCH gene (chromosome 9q22.3-q31), a tumor suppressor gene, with loss of function. The mutation results in overexpression of BCL-1 and TP53. DDx: Orthokeratinized odontogenic cyst. Dentigerous cyst. Periapical cyst.
How does the microscopic appearance of odontogenic keratocysts differ in those with Gorlin syndrome (nevoid basal cell carcinoma syndrome)?
Patients with Gorlin syndrome develop multiple odontogenic keratocysts. There are more satellite cysts, daughter cysts, budding, and proliferative odontogenic epithelial rests.
Ameloblastic fibroma and ameloblastic fibro-odontoma. Definitions. Micro. DDx.
Ameloblastic fibroma is a true neoplasm composed of a mixture of odontogenic epithelial and mesenchymal tissues. Ameloblastic fibro-odontoma is a tumor composed of a mixture of odontogenic epithelial and mesenchymal tissues that also contains dentin and enamel; may represent a stage of developing odontoma or a hamartoma. Posterior mandible is most common location for both. Micro: Epithelial component (small islands, cords, or strands of odontogenic epithelium; peripheral cells are columnar and ameloblast-like; scant central areas of stellate reticulum-like tissue) and stroma (cellular, myxoid tissue resembling developing dental papilla; cytologically bland round to angulated cells; few to no mitotic figures. Also, in ameloblastic fibro-odontoma only, mineralized tissue (enamel, dentin, calcified material). DDx: Ameloblastoma. Odontoma. Ameloblastic fibrosarcoma.
Odontoma. Definition. Micro. DDx.
Odontomas are hamartomas of odontogenic epithelium and ectomesenchyma. Compound odontomas are small tooth-like structures, which complex odontomas have a haphazard aggregate of enamel and dentin. Compound and complex odontomas can also be in combination. Most occur during the first 2 decades of life. Compound odontomas are most common in anterior maxilla. Complex odontomas are most common in posterior mandible. Micro: Compound odontomas have architecture similar to normal tooth (mature tubular dentin; enamel matrix, but mature enamel is lost during decalcification process; cementum, pulp tissue, dental follicular tissue; occasional dentigerous cyst). Complex odontomas have haphazard arrangement (haphazardly arranged tubular dentin; dentin often surrounds islands of enamel/matrix; thin layer of cementum may surround mass; epithelial ghost cells are frequently seen; dental follicular tissue; occasional dentigerous cyst). Odontomas may be found in conjunction with other odontogenic cysts or tumors, such as odontoameloblastoma. DDx: Hyperdontia (supernumerary teeth). Root tip. Impacted tooth.
What is ossifying fibroma? Epidemiology?
A rare benign neoplasm of bone with lamellar bone formation, osteoblastic rimming, and connective tissue stroma. When cementum is present, the term cementifying fibroma or cemento-ossifying fibroma is used. It is a true neoplasm within fibro-osseous group, rather than a developmental anomaly. Considered on spectrum with fibrous dysplasia and osseous dysplasia. Peak in 2nd to 4th decades, with mean 31 years. M:F = 1:5. Mandible is most common site.
Ossifying fibroma microscopic appearance, ancillary tests, and DDx.
A rare benign neoplasm of bone considered on spectrum with fibrous dysplasia and osseous dysplasia, most common in mandible. Composed of variable amounts of fibrous tissue proliferation and calcifications. Evenly spaced spicules of woven bone with lamellar transformation at periphery and osteoblasts and osteoclasts surrounding spicules (osteoblastic rimming is prominent). Prominent calcified structures (ossicles, cementicles), which are eosinophilic or basophilic spherules of osteoid. Cellular, spindled cell stroma. Multinucleated giant cells can be seen. IHC is unnecessary, but Runx2 nuclear positivity in spindled cells and osteocalcin distributed throughout calcified structures. Molecular genetics: mutations in HRPT2 gene reported. DDx: Fibrous dysplasia (polyostotic helps to exclude OF; irregularly shaped trabeculae of immature woven bone without osteoblastic rimming). Active ossifying fibroma (AKA (aggressive) psammomatoid ossifying fibroma AKA juvenile active ossifying fibroma; highly cellular stroma with mitoses and psammomatous calcifications). Cemento-osseous dysplasia (African-Americans commonly affected, involves periodontal ligament; lacks osteoblastic rimming).
Multiple odontogenic keratocysts are associated with ___ syndrome.
Multiple odontogenic keratocysts are associated with Gorlin syndrome (nevoid basal cell carcinoma syndrome). Mutations in PTCH gene (chromosome 9q22.3-q31), a tumor suppressor gene, with loss of function.
Keratocystic odontogenic tumor. Epidemiology.
AKA odontogenic keratocyst (old term) AKA odontogenic keratocystoma AKA primordial cyst. Is a distinct developmental odontogenic cyst that may be locally aggressive. Age range 10-40 years, with cysts found at an earlier age in those with Gorlin syndrome. 60-80% in mandible.
Polycystic disease of the parotid.
AKA dysgenetic polycystic parotid gland disease. Marked dilation and cystic change within intercalated ducts of parotid gland; striated and excretory ducts unaffected. Rare developmental anomaly not associated with polycystic disease of other organ systems. Typically becomes evident in childhood. F»>M. No malignant transformation.
HIV salivary gland disease.
AKA AIDS-related parotid cyst. HIV-SGD includes HIV-infected individuals with xerostomia, enlargement of one or more major salivary glands, or both. Mostly adult men 20-60 yo. M:F = 9:1. 98% in parotid, 2% in submandibular gland. Bilateral involvement in 60%. Early phases include florid follicular hyperplasia, attenuated to absent mantle lymphocytes, disruption of germinal centers (follicle lysis). MGCs localized to inter-/intrafollicular and periepithelial areas commonly seen. Multiple squamous epithelial-lined cysts and epimyoepithelial islands present.
Chronic sclerosing sialadenitis.
AKA Kuttner tumor AKA IgG4-associated sialadenitis AKA punctate parotitis. A chronic fibroinflammatory salivary gland disease with characteristic morphology that may represent IgG4-associated disease. Most often in 4th to 7th decades. Primarily submandibular gland. Micro: Preservation of lobular architecture. Dense lymphoplasmacytic infiltrate within lobules. Large irregular lymphoid follicles with expanded geographic geminal centers. Sheets of mature plasma cells. Acinar atrophy. Lobules separated by fibrosis composed of fibroblasts and chronic inflammatory cells. Phlebitis may or may not be identified.
Benign lymphoepithelial cyst.
A benign, cystic epithelial lesion intimately associated with lymphocytic proliferation within cyst wall, almost always in parotid and unilateral. If bilateral, HIV salivary gland disease should be considered. Occurs over wide age range but average is 5th to 6th decades.
How can benign lymphoepithelial cyst be differentiated from HIV-associated salivary gland disease?
HIV-SGD is typically multiple, possibly bilateral, and also contain lymphoepithelial islands. Their germinal centers are larger and more irregular, with interfollicular tissue containing numerous plasma cells, neutrophils, histiocytes, and large, irregular mononuclear or multinuclear cells.
Benign lymphoepithelial lesion.
AKA lymphoepithelial sialadenitis AKA myoepithelial sialadenitis. A reactive, focal to diffuse lymphoid infiltrate of salivary glands leading to parenchymal atrophy and degeneration of glandular elements into irregular epithelial complexes. Strong association with Sjogren syndrome; the majority of patients with SS also have BLEL of parotid glands, and are typically bilateral. BLEL occasionally seen independent of SS are usually unilateral and may be secondary to obstruction. Mean age 5th to 6th decade. M:F = 1:3. Potential evolution to extranodal marginal zone B-cell lymphoma.
Oncocytosis (oncocytic hyperplasia) in salivary glands.
Oncocytes are altered epithelial cells whose cytoplasm contains vast numbers of abnormal mitochondria. They are large, polygonal cells with well-defined borders and abundant finely granular acidophilic/eosinophilic cytoplasm. Oncocytosis AKA oncocytic hyperplasia is a nonneoplastic proliferation of oncocytes, which may be localized, multifocal, or diffuse (diffuse oncocytosis), or can produce unencapsulated nodules (nodular oncocytic hyperplasia) in a lobular distribution. Oncocytic metaplasia is non-mass-forming alteration/transformation of glandular epithelial cells into oncocytes. Oncocytic change in salivary gland is associated with normal aging and is normally seen after age 50 and is almost universal after age 70. May be seen in any salivary gland but parotid most frequent. Oncocytic metaplasia and oncocytosis are generally asymptomatic, but nodular oncocytic hyperplasia may present as a clinically evident mass. Oncocytic changes may involve salivary acini, intercalated ducts, or striated ducts. Nuclei are round to oval (or can be shrunken and pyknotic), centrally placed, and may contain one or more prominent nucleoli. Binucleated cells may be seen. Oncocytic metaplasia shows intimate, direct apposition of oncocytic cells with normal salivary gland parenchyma and stroma. Oncocytic hyperplasia may range from small collections of cells to larger unencapsulated nodules. Diffuse oncocytic hyperplasia (diffuse oncocytosis) involves nearly all of salivary gland parenchyma with no nodule or tumor formation.
What is clear cell oncocytosis?
Oncocytes are altered epithelial cells whose cytoplasm contains vast numbers of abnormal mitochondria. They are large, polygonal cells with well-defined borders and abundant finely granular acidophilic/eosinophilic cytoplasm. Cytoplasmic glycogen accumulation may peripheralize intracytoplasmic mitochondria, resulting in clear cytoplasm (clear cell oncocytosis). Or, it may be a fixation artifact.
How can oncocytosis (oncocytic hyperplasia) and oncocytoma in salivary gland be differentiated?
The differences between oncocytoma and clinically evident nodular oncocytic hyperplasia are vague, but features favoring oncocytoma include partial or full encapsulation, and lack of included ductal structures.
Oncocytic change may be seen in many salivary gland neoplasms, including ___.
Oncocytic change may be seen in many salivary gland neoplasms, including Warthin tumor, pleomorphic adenoma, and mucoepidermoid carcinoma. Oncocytic metaplasia/hyperplasia lacks papillary cystic architecture and dense lymphoid infiltrate. Presence of other cell types (myoepithelial, mucocytes, epidermoid cells) favors other neoplasms.
Sialoliths are more common in (Wharton duct/Stensen duct).
Sialoliths are more common in Wharton duct (duct of submandibular gland), likely due to higher content of mucinous saliva. Stone formation in Stensen duct (duct of parotid gland) is less common, and formation in sublingual or minor salivary glands is rare. Sialoliths are formed by accumulation of calcium salts around central focus of bacteria, inspissated mucus, or foreign material.
Pleomorphic adenoma of salivary gland. Epidemiology.
AKA benign mixed tumor AKA mixed tumor. The term chondroid syringoma is used only is skin/dermis based primary. PAs are benign epithelial tumors that show both epithelial and modified myoepithelial elements mixed with mesenchymal myxoid, mucoid, or chondroid appearing material. It has significant architectural diversity rather than cytologic pleomorphism. Incidence: Most common neoplasm of salivary gland origin (45-75% of all salivary gland neoplasms). Comprises ~75% of all major salivary gland neoplasms, and ~40% of all minor salivary gland neoplasms. Wide age range, with peak in 4th to 6th decade. It is the most common benign salivary gland tumor in children. Female > Male (slightly) in adults, and Male > Female in <18 yo. Parotid gland is the most common site (~80%), and most commonly superficial lobe. Minor salivary glands is second most common site (most commonly junction of hard and soft palate, buccal mucosa, or upper lip). Parotid gland tumors have recurrence rate as high as 8%, while minor salivary gland and submandibular gland tumors rarely recur.
Pleomorphic adenoma in salivary gland. What % can have malignant transformation, and what are risk factors for malignant transformation?
Malignant transformation in up to 7% of cases. Risk factors: long history of untreated tumor, multiple recurrences, age of patient (usually >40 yrs), male gender, tumors >2 cm, deep lobe tumors, more common in parotid gland.
Pleomorphic adenoma. Micro.
Immunerable architectural patterns (solid, tubular, trabecular, cystic). Epithelial tissue shows variable morphology (spindle, clear, squamous, basaloid, plasmacytoid). Mesenchymal-like tissue (myxoid stroma, myxochondroid, hyaline stroma, rarely lipomatous, bone). Duct structures (lined by cuboidal or columnar epithelium). Rarely, crystals are present: collagenous crystalloids (eosinophilic needle shapes arranged radially), tyrosine-rich crystalloids (eosinophilic bunted shapes arranged tubularly), crystalloids resembling oxalate crystals. Occasionally squamous metaplasia is identified. Rare necrosis. Rarely sebaceous cells. IHC is sensitive but not specific: panel of CK, p63, GFAP, S100, and SMA recommended (all will be variably positive).
Cytogenetics of pleomorphic adenoma.
4 major cytogenetic abnormalities, with rearrangements involving: 8q12 (39%), 12q13-15 (8%), sporadic clonal rearrangements of other genes (23%), normal karyotype (30%). Currently identified 5 PLAG1 (8q12) and HMGA2 (12q13-15) -containing fusion genes are tumor specific.
Myoepithelioma of salivary gland. Micro. IHC. DDx.
Well circumscribed but variably encapsulated. Broad range of appearances due to multiple architectural patterns (solid, myxoid, reticular, nested, cord-like). Typically composed of spindled or plasmacytoid cells; may have dominant cell type or mixed morphology; plasmacytoid cells with hyperchromatic, round to oval nuclei and abundant, eccentric eosinophilic cytoplasm (characteristic but not pathognomonic, as also seen in pleomorphic adenoma of palate). Although not common, clear, polygonal (epithelioid), or stellate cells may be seen. Background with variable collagenization; may contain abundant acellular mucoid stroma. Lacks chondroid or myxochondroid matrix. Lacks infiltration, perineural invasion, profound pleomorphism, necrosis, increased mitotic figures. IHC: Reactive with pan-CK, CK7, CK14, p63, GFAP, and S100. Variable reactivity with actin-sm, actin-HHF-35, SMHC, and calponin (actins reactive in spindled cells but typically nonreactive in plasmacytoid cells). Mutations of p53 have been observed. DDx: pleomorphic adenoma, myoepithelial carcinoma, spindled soft tissue neoplasm, plasmacytoma.
Basal cell adenoma in salivary gland. Epidemiology. Micro. IHC. DDx.
A benign salivary epithelial neoplsm composed of basaloid cells lacking chondromyxoid stroma. ~2-3% of all salivary gland neoplasia. Wide age range, peak in 6th to 7th decades. M:F = 1:2. ~75% in parotid gland. Micro: All subtypes are composed of basaloid cells (may display 2 cell morphologies). Squamous eddies, drop-like eosinophilic hyaline material, and small ductal structures possible. Multiple architectural subtypes (solid, trabecular, tubular, and membranous patterns). All patterns demonstrate stroma of variable amount and collagenous density. IHC: Keratin variably reactive in all epithelial cells (strongest in inner, larger basaloid cells). Actin-sm, p63, and calponin reactivity in peripheral, smaller basaloid cells. S100 may be variably reactive in both epithelial cell types. DDx: Basal cell adenocarcinoma. Canalicular adenoma. Adenoid cystic carcinoma.
Myoepithelioma of salivary gland. Epidemiology.
AKA myoepithelial adenoma AKA benign myoepithelial tumor. A benign salivary gland neoplasm composed entirely of myoepithelial differentiated cells (no ductal cells allowed). Incidence is ~2% of all salivary gland neoplasms and ~6% of minor salivary gland neoplasms. Wide age range affected, with peak in 3rd to 4th decade and average 44 yrs. Equal gender distribution. ~50% occur in parotid gland, with hard or soft palate affected next most frequently.
Warthin tumor. Epidemiology.
AKA papillary cystadenoma lymphomatosum AKA adenolymphoma AKA cystadenolymphoma. Strong link between WT and cigarette smoking. 2nd most common benign salivary gland tumor following pleomorphic adenoma, accounting for ~5% of all salivary gland tumors, and represents up to 12% of benign parotid gland tumors. Wide age range, but most common in 5th to 7th decades. M>F. Almost exclusively in parotid, particularly in superficial lobe. Bilateral tumors seen in up to 10% of cases, and multifocal tumors seen in up to 12% of cases. Bilateral or multifocal tumors may occur synchronously or metachronously. It may also occur synchronously or metachronously with other salivary gland tumors, including pleomorphic adenoma (most common).
Warthin tumor. Micro. IHC. Cytogenetics. DDx.
Micro: Papillary and cystic lesion composed of epithelial and lymphoid components. Epithelial component lining the papillary projections composed of double layer of granular eosinophilic cells (referred to as oncocytic epithelia). Inner or luminal cells: Nonciliated, tall columnar cells with nuclei aligned toward luminal aspect. Outer or basal cells: Round, cuboidal, or polygonal cells with vesicular nuclei. Lymphoid component predominantly composed of mature lymphocytes containing lymphoid follicles with germinal centers. Epithelioid and lymphoid components are sharply demarcated from one another. Other imflammatory cells may be seen, including plasma cells, histiocytes, mast cells, and occasional multinucleated (Langhans-type) giant cells. Lumens of cysts may contain thick secretions, cholesterol crystals, cellular debris, or corpora amylacea-like laminated bodies. Squamous metaplasia and focal necrosis may be seen in association with secondary inflammation. Due to presence of oncocytic cells, WT is subject to degenerative alterations occuring spontaneously or following manipulation. Metaplastic or infarcted variant of WT accounts for <10% of all WT. IHC: All epithelial cells are panCK positive. Luminal (or inner) epithelial cells are CK7, CK8, CK18, and EMA positive. S100, p63, calponin, GFAP, and actin negative. Lymphoid cells reactive for CD20, CD3, CD56, CD4, and CD8. Cytogenetics: t(11;19) translocation and CRTC1/MAML2 fusion transcript identified. DDx: Cystadenoma. Other numerous slivary gland tumors with oncocytic cells.
Warthin tumor and many mucoepidermoid carcinomas have a similar translocation and fusion transcript, suggesting evidence for a common genetic association. What is it?
t(11;19) translocation and CRTC1/MAML2 fusion transcript.
Warthin tumors may have malignant transformation into ___.
Transformation of WT to malignant WT is exceedingly rare (incidence of <0.1%), with squamous cell carcinoma being most common.
Canalicular adenoma of salivary gland. Epidemiology. Micro. IHC. DDx.
AKA monomorphic adenoma. ~2% of all salivary gland tumors, ~4% of all benign tumors, and ~20% of all lip salivary gland tumors. Wide age range, mean 65 yrs. M:F = 1:2. Vast majority in upper lip. Micro: Encapsulated. Canalicular pattern with cords and ribbons showing connection points between opposing columnar cells within spaces (Beading: columnar cells abutting one another within tubules. This beading of columnar cells is characteristic). Tubules interconnect in lattice-like architecture. CUboidal to columnar cells. Basaloid cells with round to oval nuclei. Scant, slightly eosinophilic cytoplasm. No mitotic figures. Loose, fibrillar stroma; rich in hyaluronic acid and chondroitin sulphate. Calcifications may be seen (microliths). IHC: Various keratins are positive, as well as S100 and CD117. SMA, calponin, SMMHC, p63, GFAP negative. DDx: Basal cell adenoma. Adenoid cystic carcinoma.
What is lymphadenoma and sebaceous lymphadenoma of salivary gland? Definitions. Epidemiology.
Sebaceous lymphadenoma: Rare salivary gland neoplasm composed of epithelial nests and cysts with focal sebaeous differentiation distributed within dense hyperplastic lymphoid tissue. Lymphadenoma: Histologically similar to sebaceous lymphadenoma but devoid of sebaceous elements. >90% occur in parotid gland or surrounding tissues, but is a very rare neoplasm and is <1% of all parotid neoplasms. Average age 6th to 8th decades. Equal gender distribution.
Lymphadenoma and sebaceous lymphadenoma of salivary gland. Micro. IHC. DDx.
Micro: Well circumscribed, well encapsulated, pushing yet noninfiltrative border. Epithelial element: Evenly dispersed solid epithelial nests with bland cytology and cysts of variable size (squamoid, columnar, or cuboidal lining; may contain secreted material). SLA: sebaceous cells in solid nests or within cyst walls. LA: lack of sebaceous component. Lymphoid component: Uniformly dense. Germinal centers may be focal to numerous. No infiltration/invasion of epithelial component. Foreign body reaction may be present due to cyst rupture. IHC: PanCK pos in epithelial component. p63 pos in basal layer of sebaceous nests. Lymphoid markers (CD3, CD20, Bcl-2, etc) confirm reactive, hyperplastic lymphoid population. DDx: Warthin tumor. Tumor-associated lymphoid proliferation. Metastatic carcinoma.
What are the 3 types of ductal papillomas in salivary gland?
Ductal papillomas are a group of uncommon benign epithelial salivary gland neoplasms. The 3 types are: Sialadenoma papilliferum, intraductal papilloma, and inverted ductal papilloma. SP has an exophytic and endophytic proliferation of squamous and ductal epithelium. IP has a unicystic cavity lined by cuboidal to columnar epithelial cells giving rise to papillary fronds filling the cavity. IDP is unencapsulated but well demarcated, endophytic, basaloid and squamous/epidermoid cell growth with interspersed mucous cells. Top ddx include mucoepidermoid carcinoma, papillary cystadenoma, and verrucous carcinoma.
Brown tumors of bone, which are non-neoplastic mass lesions, arise out of the setting of (primary/secondary/tertiary) hyperparathyroidism.
Brown tumors of bone, which are non-neoplastic mass lesions, can arise out of the setting of primary, secondary, and tertiary hyperparathyroidism.
Brown tumors of bone. Age. Gender. Locations.
Brown tumors are non-neoplastic mass lesions that develop as a complication of hyperparathyroidism. They usually develop in adults in the 3rd to 4th decades. M<F. They may be solitary or multiple and commonly arise in the pelvis, ribs, clavicles, and extremities.
Brown tumors of bone. Micro.
Histologically, they have a lobular architecture defined by fibrous septa that may contain trabeculae of reactive woven bone. The lobules are composed of an admixture of plump fibroblasts, extravasated RBCs, hemosiderin-laden macrophages and scattered osteoclast-type giant cells, which freuently cluster around areas of hemorrhage. This bloody mass of reactive tissue erodes the endosteum, thinning and expanding the cortex as the periosteum deposits new bone. In sever cases, large blood-filled cysts develop, resulting in a lesion known as osteitis fibrosa cystica. Bone not involved by the tumor shows evidence of increased osteoclastic activity in the form of dissecting osteitis (osteoclasts boring through the center of bony trabeculae), cortical cutting cones (groups of osteoclasts tunneling into and expanding Haversian canals) and subperiosteal excavation. Treatment of the underlying abnormality abates the osteoclastic activity ad the lesion eventually regresses as it is filled in by newly deposited bone.
What entities are in the DDx of brown tumor of bone?
Giant cell reparative granuloma and giant cell tumor of bone. Giant cell reparative granuloma and brown tumor may have similar morphologic features and may be impossible to distinguish from one another by light microscopy alone. In giant cell tumor of bone, the mononuclear cells are not as spindled as the fibroblasts of a brown tumor and in contrast to a brown tumor, the nuclei of the mononuclear cells are morphologicallly identical to those in the osteoclasts.
Cystadenoma of salivary gland. Epidemiology. Micro. DDx.
AKA cystic duct adenoma. ~4% of all benign epithelial salivary gland neoplasms. Wide age range, average 6th to 7th decades. M:F = 1:2-3. Parotid gland most common (50% of cases), minor salivary glands second most common. Micro: Well circumscribed but variable encapsulation. Cysts of variable number and size separated by fibrous connective tissue. Focal to spotty inflammatory element may be present in connective tissues. Epithelial lining typically composed of cuboidal to columnar cells; occasional mucinous or oncocytic epithelial lining, which may be focal or diffuse; squamoid lining rare and typically focal. Intraluminal papillary proliferation may be evident and especially common in unicystic lesions. Cysts may contain eosinophilic fluid and/or scattered detached cells. Cytology bland with rare mitotic figures. A variant, papillary oncocytic cystadenoma, is a cystadenoma with significant intraluminal papillary projections surfaced by a single or bilayered oncocytic epithelial lining, with the epithelial component resembling Warthin tumor. DDx: mucoepidermoid carcinoma, salivary duct cyst, cystadenocarcinoma, Warthin tumor.
Mesenchymal tumors account for ~3.5% of salivary gland tumors. What are the top 3 mesenchymal salivary gland tumors?
Schwannoma > lipoma > hemangioma.
Hemangiomas in salivary gland.
All histologic variants of hemangioma occur in salivary glands, but capillary (juvenile) hemangioma is most common. Hemangiomas account for 90% of parotid gland tumors in infants <1 yo are hemangioma. Capillary (juvenile) hemangiomas have M:F = 1:3, while cavernous hemangiomas tends to be seen more frequently in older males. Parotid gland involved in 90%, and up to 25% are bilateral. Pediatric tumors initially grow rapidly, but 75-95% spontaneously involute before 7 yo, and many earlier. Pharmacological therapy (corticosteroids and interferon) yields a response in up to 98% of cases. IHC: Endothelial cells pos for CD31, CD34, FVIIIRAg. Residual salivary ducts are keratin pos. GLUT1 pos in juvenile hemangiomas.
Mucoepidermoid carcinoma in salivary gland. Epidemiology. Prognosis.
A malignant epithelial tumor with variable components of mucous, epidermoid, and intermediate cells. Environmental exposure: ioning radiation (latent period varies, and long-term f/u is required). Most common malignant salivary gland tumor, ~16% of all salivary gland tumors, most common salivary gland tumor to arise in gnathic bones. Wide age range. Most common malignant salivary gland tumor in children. M<F. Parotid gland most common location. Central (primary intraosseous) type has predilection for mandible. Prognosis: LG tumors rarely met and only 2.5% result in death; for HG tumors, 55-80% met or result in death. Mets go to lung, bone, brain. Sites of aggressive tumors regardless of grade: submandibular gland, tongue, floor of mouth. Primary intraosseous rarely met.
Mucoepidermoid carcinoma of salivary gland. Micro. IHC. Cytogenetics.
Cystic spaces: often filled with mucin, occ papillary projections present. Epidermoid cells: nests or scattered; polygonal cells. Intermediate cells: large polygonal epidermoid cells; small basal cells; often in nests or sheets. Mucous cells: intracytoplasmic mucin; large or ovoid; vacuolated or clear cytoplasm; in groups or individual cells. Clear cells: usually <10% of cells but can be a dominant finding; contain glycogen or mucin. Spilled mucus: incites inflammatory response. Tumor-associated lymphoid proliferation: lymphoid cells with occ germinal centers; may be confused with met disease to a lymph node. Necrosis, anaplasia, and mitoses variably present. PNI and ALI can be seen. Sarcomatoid transformation rarely seen. IHC: p63 has strong basal cell nuclear pos, and may highlight intermediate as well as epidermoid cells. CK5/6 highlights epidermoid-type cells but is often neg in transitional cells. Ki-67 high expression seen with increased proliferation, usually indicative of HG tumor. HER2 tends to be strongly reactive in HG tumors. Cytogenetics: t(11;19)(q21-22;p13) fuses mucoepidermoid carcinoma translocated 1 (MECT1) with Mastermind-like gene family (MAML2); is identified in LG to IG tumors only. Other abnormalities include variable losses of 2q, 5p, 12p, and 16p. Aneuploid tumors have a higher recurrence rate, higher cervical LN involvement, and decreased survival.
Adenoid cystic carcinoma in salivary gland. Epidemiology. Prognosis.
Outdated names include cylindroma (may be confused with benign dermal tumor of same name) and adenocystic carcinoma (may be confused with carcinoma of eccrine origin). 4th most common malignant salivary gland tumor. Seen in adults with peak in 6th decade. Rare in children. M:F = 2:3. Found with essentially equal frequency in major and minor salivary glands. In major salivary gland, parotid most common; in minor salivary gland, palate most common. Prognosis: High incidence of recurrence. Characterized by late onset metastases (5 yr survival rate is good, and 20 yr survival rate is poor). Mets to lung and bone. Solid pattern tumors have worse prognosis. Surgical margin status does not affect survival, but anatomic site does affect outcome, with palatal lesions having best outcome and parotid lesions having better prognosis than submandibular gland lesions.
Most common malignant salivary gland tumor.
Mucoepidermoid carcinoma.
Most common benign salivary gland tumor.
Pleomorphic adenoma.
Adenoid cystic carcinoma in salivary gland. Micro. HC and IHC. DDx. Cytogenetics.
Micro: Infiltrative (PNI commonly seen; infiltrative edges into fat, skeletal muscle, soft tissue). Combinations of patterns usually present, although one predominates. Patterns: cribriform, tubular, and solid. Cytologic features: small to medium cells with eosinophilic to clear cytoplasm; nuclei are oval to sharply angulated with coarse, basophilic chromatin and occasional small nucleoli; mitotic figures are rare except for in the solid pattern. HC: Alcian blue and PAS highlight basement membrane material of pseudolumina. IHC: May have limited practical use, as tumors in DDx often react similarly. DDx: PLGA, PA, basal cell adenocarcinoma, basal cell adenoma, epithelial-myoepithelial carcinoma, CExPA, basaloid SCC, cylindroma, sialoblastoma, NEC. Cytogenetics: No particular gene profile identified. 30% have translocations involving 6q and 9p (MYB-NFIB translocation). ~50% have loss of chromosome 12q12. LOH at 6q23-25 is associated with poorer prognosis. Alteration of p53 is associated wtih tumor recurrence and progression to solid type.
Acinic cell carcinoma in salivary gland. Epidemiology. Prognosis.
AKA acinic cell adenocarcinoma AKA acinous cell carcinoma AKA acinic cell tumor (discouraged, as malignancy is well established). A malignant epithelial salivary gland neoplasm demonstrating serous acinar cell differentiation with cytoplasmic zymogen secretory granules. It is not exclusively, nore even necessarily predominantly, serous type cells. Salivary ductal cells are also part of this neoplasm. Environmental exposure: radiation exposure a possible factor. Epidemiology: Represents ~10-12% of all malignant salivary gland tumors, and is 2nd to mucoepidermoid carcinoma in frequency. Wide age range with even distribution from 2nd to 7th decades, with mean in mid-40s. M:F = 2:3. 80% in parotid, with minor salivary glands 2nd most common site. Prognosis: Generally good prognosis; 5 yr survival 80-90% and 10 yr survival 65%.
Acinic cell carcinoma in salivary gland. Micro. HC. IHC. Cytogenetics.
Micro: Tumor extension into normal tissue is common, although “apparent” encapsulation is present. Although one pattern and cell type dominate, combination and spectrum is common. Patterns: solid/lobular > microcystic > papillary-cystic > follicular. Several cell types are present: serous acinar cells > intercalated duct type cells > vacuolated cells > nonspecific glandular cells > clear cells. Lymphoid infiltrate, sometimes prominent with germinal center formation, can be seen. Stromal fibrosis or desmoplasia is uncommon. HG transformation (dedifferentiation) into HG carcinoma (including small cell carcinoma) is rare and heralds poor prognosis. HC: PAS+, diastase-resistant zymogen granules (reaction can be patchy and limited). Neg or only focally pos granules with mucicarmine. IHC: Immunoprofile is nonspecific and unpredictable, so seldom of diagnostic value. Cytogenetics: No consistent or specific structural chromosomal alterations. DDx: normal salivary gland, papillary cystadenocarcinoma, mucoepidermoid carcinoma, metastatic thyroid carcinoma, clear cell tumors (epithelial-myoepithelial CA, clear cell adenoCA, clear cell oncocytoma, met RCC), PLGA.
Most common causes of primary hyperparathyroidism?
Parathyroid adenoma > parathyroid hyperplasia > parathyroid carcinoma.
80-90% of hypercalcemia is due to what 2 conditions?
Hyperparathyroidism or malignancy (often with the paraneoplastic expression of PTHrP).
Polymorphous low-grade adenocarcinoma. Epidemiology. Prognosis.
AKA terminal duct carcinoma AKA lobular carcinoma. PLGA is a malignant epithelial tumor characterized by infiltrative growth of cytologically uniform cells arranged in architecturally diverse patterns. Uncommon; ~2% of all salivary gland tumors. Wide age range at 16-95 yrs, mean is 60 yrs, vast majority are 50-70 yrs, exceedingly rare in children. M:F = 1:2. Predilection for blacks. Almost always in minor glands: palate 60%, buccal mucosa 15%, lip 10%. Prognosis: Overall excellent long-term prognosis, with ~95% 10 yr survival.
Polymorphous low-grade adenocarcinoma. Micro. IHC. Cytogenetics.
Micro: Infiltrative growth, architectural diversity, and cytologic uniformity, set in characteristic matrix. Infiltrative growth: Unencapsulated, but usually well circumscribed. Encased, entombed, incarcerated, or completely surrounded minor salivary glands. Invades into soft tissues, especially fat. Bone invasion can be seen. Significant PNI. Patterns of growth: Striking variety of growth patterns. Low power gives “eye of the storm,” “streaming” or “whorled” appearance. Characteristic concentric layering of cells around central nidus, creating targetoid tableau. Periphery often shows linear, single-file cell infiltration. Arranged in lobules, theques, glandular profiles, tubules, trabeculae, and cribriform nests. Papillae, if identified, are focal and not dominant pattern. Cellular features: Uniformly bland round to polygonal or fusiform tumor cells. Small to medium, with indistinct cellular borders. Ample pale to eosinophilic cytoplasm. Round to oval nuclei with open, vesicular nuclear chromatin. Inconspicuous to small nucleoli. Matrix material: Slate gray-blue stroma usually only focal. Hyalinized, slightly eosinophilic stroma separates cells. Inconspicuous mitoses. Tyrosine-like crystals are identified in <5%. Rare metaplastic changes: squamous, sebaceous, mucous, clear, oncocytic. IHC: Variable expression of epithelial and myoepithelial markers. Cytogenetics: Chromosome 12 abnormalities are most common: p or q arms (12q22 and 12p12.3).
Salivary duct carcinoma. Epidemiology. Prognosis.
AKA cribriform salivary carcinoma of excretory ducts AKA high-grade salivary duct carcinoma AKA cribriform carcinoma. SDC is a HG adenocarcinoma resembling HG breast ductal carcinoma thought to be derived from intralobular and interlobular excretory ducts. LG cribriform cystadenocarcinoma is a unique entity, perhaps not a LG variant of SDC. SDC is a common tumor in CaExPA. Up to 9% of malignant salivary gland neoplasms. Age peak 7th decade. M:F = 3:1. Parotid involved in 70-95% of cases. Prognosis: One of the most aggressive salivary gland malignancies, with poor prognosis overall (<35% 5 yr survival).
Salivary duct carcinoma. Micro. HC. IHC. Cytogenetics.
Micro: Variably sized, rounded, solid or cystic nodules of tumor cells that resemble intraductal or infiltrating ductal carcinoma of the breast. Small nodules are filled with neoplastic cells. Larger cystic nodules with irregular shape. Comedonecrosis is conspicuous. PNI and LVI frequent. Marked, dense, desmoplastic (hyalinized) fibrosis is conspicuous. Lymphoplasmacytic inflammator cell infiltrate is frequently present. Cells are arranged in cribriform, band-like solid, and papillary patterns. Small tumor nests infiltrate between larger nodules. Epithelial cells have moderate to marked pleomorphism, are cuboidal to polygonal, with ample eosinophilic granular, oncocytic cytoplasm. Nuclei are round, centrally located, with large, prominent nucleoli and hyperchromatic chromatin. Mitotic figures, including atypical forms, are usually easily identified. Uncommonly, psammoma bodies and areas of squamous differentiation seen. Variants: sarcomatoid, micropapillary, mucin-rich, osteoclast-type giant cell, low-grade SDC (controversial entity). HC: Nonreactive with mucicarmine and Alcian blue. IHC: Pos for epithelial markers, androgen receptor, HER-2/neu. Cytogenetics: Frequent LOH involving 9p21, 6q, 16q, 17p, and 17q regions.
Direct detection of the mutations of thyroid cancer is feasible because only about 7 genes are mutated in the vast majority of thyroid cancers. The mutations in these genes are almost always mutually exclusive. The various mutations correlate closely with tumor type: Mutations in ___, ___ and ___ are restricted to papillary thyroid carcinomas, ___ is strongly associated with the follicular variant of papillary thyroid carcinoma, ___ is largely restricted to follicular neoplasms, and ___ and ___ (less common) are more likely in follicular neoplasms than papillary thyroid carcinomas.
Direct detection of the mutations of thyroid cancer is feasible because only about 7 genes are mutated in the vast majority of thyroid cancers. The mutations in these genes are almost always mutually exclusive. The various mutations correlate closely with tumor type: Mutations in B-RAF, RET and TRK are restricted to papillary thyroid carcinomas, N-RAS is strongly associated with the follicular variant of papillary thyroid carcinoma, PAX8/PPARgamma is largely restricted to follicular neoplasms, and H-RAS and K-RAS (less common) are more likely in follicular neoplasms than papillary thyroid carcinomas.
What are issues and problems with mutation testing of thyroid cancers?
Though only 7 genes appear involved in initiation of the vast majority of thyroid cancers of follicular origin, testing is complicated by the presence of multiple potential point mutations in RAS and B-RAF genes, and many different translocations of RET and TRK (at least 11 and 5, respectively). Testing for point mutations (eg, B-RAF, N-RAS, H-RAS, and K-RAS) requires only a small amplicon size, an assay that works on the relatively poor substrates of FFPE material. Detecting translocations is much more challenging. The translocations of RET and TRK are mostly intrachromosomal, making them relatively difficult to detect by FISH. Studies using FISH to detect RET translocations have found alternating positive and negative areas within morphologically malignant cells of papillary thyroid carcinoma—a finding that may reflect insensitivity of the FISH technique rather than the implausible alternative of multiple independent RET translocations. Polymerase chain reaction–based detection of the translocations is also difficult because the translocations can take place over a large distance. Use of messenger RNA as the basic substrate makes the translocations easier to detect, because relatively long introns are spliced out of the messenger RNAs, though working with RNA requires special attention to the method of preservation.
What conditions is ACD associated with?
ACD appears to be due to defective iron utilization/metabolism and is associated with chronic nonhematologic disorders such as chronic infections, connective tissue disorders, malignancy, and renal, thyroid, and pituitary disorders.
What is the PTEN gene? In what tumors is it often mutated?
Phosphatase and tensin homolog (PTEN) gene is on chromosome band 10q23.31. In addition to its role as a tumor suppressor, it has important roles in embryogenesis and maintenance of physiologic functions in many organ systems and is constitutively expressed in normal tissues. It is one of the most frequently inactivated genes in sporadic cancer. Sporadic mutations of PTEN occur frequently in many tumors such as glioblastoma, breast carcinoma, endometrial carcinoma, thyroid neoplasms, skin neoplasms, and advanced prostate cancer.
Nasal chondromesenchymal hamartoma. Epidemiology? Histologic appearance? DDx?
A rare, often cystic lesion that typically fills the nasal cavity and extends into the ethmoid sinuses. It is considered an upper respiratory tract analogue of chest wall mesenchymal hamartoma. Although benign, it may erode the cribriform plate, and have an intracranial component. It is more common in males (2/3), and typically affects children, with a mean age of 14 months. Histologically, there is well demarcated mature cartilage, myxoid stroma and spindle cells. There may also be focal osteoclast-like giant cells, aneurysmal bone cyst-like formations, and collagen fibers. DDx: aneurysmal bone cyst, chondroblastoma, chondromyxoid fibroma, fibrous dysplasia, osteochondromyxoma.
What are the 3 morphologic types of lymphangiomas?
Capillary, or simple, lymphangiomas are usually found in superficial skin and composed of capillary-sized, thin-walled vessels. Cavernous lymphangiomas are subcutaneous lesions composed of mildly dilated large spaces that are larger than those seen in capillary lymphangiomas. Cystic hygromas are most common in the neck and composed of large, dilated, cystic lymphatic spaces. Combinations of the 3 types can sometimes be found in a single lesion. Differentiating lymphangiomas on the basis of histologic type appears without clinical implications.
> 90% of all lymphangiomas occur in what region?
Head and neck. Most are found in the skin and subcutaneous tissues, but they have also been described in the larynx, parotid gland, mouth, tongue, and tonsils.
HPV-related head and neck squamous cell carcinomas are restricted in distribution to which of the following sites: tonsils, nose, hard palate, buccal mucosa, oral tongue, base of tongue, lip, oropharynx?
Oropharynx, tonsils, and base of tongue.
What are the 2 isoenzymes of serum amylase?
Pancreatic and salivary. But when subjected to electrophoresis, 6 bands result, with the first three being salivary and the slowest three being pancreatic.
How many bands form when serum amylase is subjected to electrophoresis?
When serum amylase is subjected to electrophoresis, 6 bands result, with the first three being salivary and the slowest three being pancreatic.
Other than electrophoresis and monoclonal antibody assays, how can salivary and pancreatic amylase be differentiated?
An inhibition test: Salivary amylase is sensitive to inhibition by the wheat germ lectin, triticum vulgaris.
List non-pancreatic causes of hyperamylasemia.
Diabetic ketoacidosis, peptic ulcer disease, acute cholecystitis, ectopic pregnancy, salpingitis, bowel ischemia, intestinal obstruction, renal insufficiency, salivary gland pathology, and macroamylasemia. Amylase may also be raised somewhat by the administration of opioid analgesics, due presumably to contracture of the sphincter of Oddi.
What tumors are seen in patients with vHL disease?
Hemangioblastomas (CNS and retinal), pheochromocytoma, clear cell RCC, pancreatic cysts, islet cell tumors, epididymal and ovarian cystadenomas, endolymphatic sac tumors.
What tumors are seen commonly in tuberous sclerosis (the “major features” as set forth in a consensus statement from the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association)?
Facial angiofibromas (adenoma sebaceum) or forehead plaque. Nontraumatic ungual or periungual fibroma. >3 hypomelanotic macules. Shagreen patch (connective tissue nevus). Multiple retinal nodular hamartomas. Cortical tuber. Subependymal nodule. SEGA. Cardiac rhabdomyoma, single or multiple. LAM. Renal AML. Definite TSC is either 2 major features or one major plus 2 minor features.
MEN1 manifests with pituitary adenomas, parathyroid adenomas, and pancreatic islet cell tumors. What are nonendocrine lesions associated with MEN1?
Facial angiofibromas, collagenomas, lipomas, and meningiomas.
There are 3 subtypes of MEN2: MEN 2A, MEN 2B, and FMTC. All are autosomal dominant, all are due to a mutation in RET, and all have a high risk for medullary thyroid carcinoma. While the histology of the medullary thyroid carcinoma in the syndrome is not distinctive, the appearance of the background thyroid is. What is seen?
C-cell hyperplasia and numerous small foci of medullary carcinoma.
What tumors occur in Carney complex?
Cutaneous lentigenes (simple lentigos). Blue nevi, particularly the cellular blue nevus. Cardiac myxomas (as well as myxomas of breast, female genital tract, and skin (especially on eyelid and external ear)). Endocrine tumors including thyroid follicular adenomas, pituitary adenomas (GH-secreting), and the so-called primary pigmented nodular adrenocortical disease (a form of multinodular hyperplasia of the adrenal cortex that causes Cushing syndrome). Large-cell calcifying Sertoli cell tumor. Psammomatous melanotic schwannoma.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): juvenile periodontitis.
Actinobacillus actinomycetemcomitans.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): visceral and ocular larva migrans.
Toxocara canis/cati.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): bacterial pharyngitis.
S. pyogenes (GAS), C. diphtheriae.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): acute epiglottitis.
H. influenzae type B.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): rhinoscleroma.
Klebsiella rhinoscleromatosus.
T4 and T3 circulate in the blood bound to what 3 different binding proteins?
T4 and T3 circulate in the blood bound to 3 different binding proteins: thyroxine-binding globulin (TBG), prealbumin (AKA thyroxine-binding prealbumin (TBPA) AKA transthyretin (TTR)), and albumin. TBG carries 70% of the circulating T4 and T3 due to its high affinity. Prealbumin binds to ~10-15% of the hormones (mostly T4), and albumin binds to the remaining 10-15%.
What is Ramsay Hunt syndrome?
AKA herpes zoster oticus. It is caused by reactivation of latent VZV infection in the geniculate ganglion of the facial nerve with subsequent spread of the inflammatory process to involve the eighth cranial nerve. The syndrome typically includes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle. Vertigo, tinnitus, and hearing loss can also occur.
What is Alagille syndrome (AGS) AKA syndromic paucity of interlobular bile ducts AKA arteriohepatic dysplasia?
AGS is a multisystem disorder with AD inheritance and variable penetrance and expressivity. The traditional diagnostic criteria have consisted of paucity of the interlobular bile ducts in association with 3 of 5 major findings, including chronic cholestasis, cardiac disease (most frequently peripheral pulmonary artery stenosis), skeletal manifestations (short stature, butterfly vertebrae), ocular abnormalities (most commonly posterior embryotoxon, a circular opacity of the posterior peripheral cornea), and characteristic facial features (triangular face with a prominent forehead, deep-set eyes, a pointed chin, and a straight nose with a bulbous tip). Mutations are in the JAGGED1 (JAG1) gene.
For bone tumors, metastases are far more common than primary bone tumors in a ratio of __:1. The 5 most common primary sites are ___.
For bone tumors, metastases are far more common than primary bone tumors in a ratio of 25:1. The 5 most common primary sites are lung, breast, prostate, kidney, and thyroid. After lungs and liver, skeleton is 3rd most frequent site of metastatic disease.
Patients with familial adenomatous polyposis develop juvenile nasopharyngeal angiofibromas __x more frequently than an age-matched population.
Patients with familial adenomatous polyposis develop juvenile nasopharyngeal angiofibromas 25x more frequently than an age-matched population.
IHC staining pattern for juvenile nasopharyngeal angiofibromas?
Positive for androgen receptors (75%), rarely for PR, and negative for ER. Other positive stains include beta-catenin, MSA, CD31 and CD34 in the vascular endothelium, and CD117 in mast cells.
In addition to colorectal polyps, ~__% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (__%), congenital hypertrophy of the retinal pigment epithelium (__%), desmoid-type fibromatosis (__%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (__x), duodenal carcinoma (__x), ampullary carcinoma (__x), nasopharyngeal adenofibroma (__x), thyroid carcinoma (__x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (__x), and pancreatic carcinoma (__x).
In addition to colorectal polyps, ~90% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (80%), congenital hypertrophy of the retinal pigment epithelium (70-80%), desmoid-type fibromatosis (15%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (847x), duodenal carcinoma (330x), ampullary carcinoma (123x), nasopharyngeal adenofibroma (25x), thyroid carcinoma (7.6x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (7x), and pancreatic carcinoma (4x).
What are causes of hypocalcemia?
Low PTH (hypoparathyroidism): genetic disorders, post-surgical (thyroidectomy, parathyroidectomy, radical neck dissection), autoimmune, infiltration of the parathyroid gland (granulomatous, iron overload, metastases), radiation-induced destruction of parathyroid glands, hungry bone syndrome, HIV infection. High PTH (secondary hyperparathyroidism in response to hypocalcemia): vitamin D deficiency or resistance, parathyroid hormone resistance, renal disease, loss of calcium from the circulation (hyperphosphatemia, tumor lysis, acute pancreatitis, osteoblastic metastases, acute respiratory alkalosis, sepsis or acute severe illness. Drugs. Disorders of magnesium metabolism.
Is lymphangioma of the orbit or hemangioma of the orbit more common?
Hemangioma of orbit. Most cases occur in adults, and most are cavernous.
Adenoid cystic carcinoma. Epidemiology. It accounts for __% of all malignant tumors of the oral and maxillofacial region, and accounts for __% of all salivary gland malignancies.
ACC is a malignant tumor with a deceptively benign histologic appearance characterized by indolent, locally invasive growth with high propensity for local recurrence and distant metastasis. It accounts for 1% of all malignant tumors of the oral and maxillofacial region, accounts for 22% of all salivary gland malignancies, and is one of the MC malignant tumors of the minor salivary and seromucinous glands. The MC site is the minor salivary glands of the oral cavity, but involvement can occur in almost any site with a secretory gland component and has been reported in sites such as lacrimal gland, esophagus, lung, breast, uterine cervix, and prostate. ACC can occur in any age, but is MC in the 5th and 6th decades of life.
Adenoid cystic carcinoma. Gross and microscopic appearances, IHC staining.
Grossly, ACC is typically a firm, poorly circumscribed, and unencapsulated mass. The cut surface is white to gray-white with a solid appearance. Hemorrhage and necrosis are rare features and should raise the suspicion of high-grade transformation into dedifferentiated ACC. The microscopic appearance is heterogeneous, consisting of varying amounts of 3 distinct growth patterns: cribriform, tubular, and solid. The cytology of the tumor cells is relatively uniform, showing a basaloid appearance with angulated, hyperchromatic nuclei and scant, clear to eosinophilic cytoplasm. The tumor cells represent 2 populations of cells showing either myoepithelial or intercalated duct cell differentiation. On IHC, SMA, SMMHC, and S100 will highlight cells showing myoepithelial differentiation surrounding the pseudocysts. The lumens of the pseudocysts are positive for BM components such as type IV collagen and laminin. ACC of the salivary gland is strongly positive for CD117.
Why is hypocalcemia seen only in some patients with medullary thyroid carcinoma, despite high circulating calcitonin levels?
This has been attributed to a secondary increase in PTH, as well as resistance of the tissues to the effect of calcitonin.
True or false. Ocular complications (proliferative retinopathy) occurs with greater frequency in SC disease and sickle cell-beta+-thalassemia than in SS.
True.
What diseases can be caused by EBV in the primary stage of infection, and in the latent stage of infection?
Primary: Infectious mononucleosis. X-linked lymphoproliferative disorder. Hepatitis. Latent: Burkitt lymphoma (100% of endemic BL, 25% of sporadic BL). Hodgkin lymphoma (EBV in 50-70% of cases). Primary effusion lymphoma (EBV in 70% of cases, HHV8 in 100% of cases). Lymphomatoid granulomatosis. Post-transplant lymphoproliferative disorder (EBV in >95%). Oral hairy leukoplakia. Nasopharyngeal carcinoma (nearly 100% EBV positive in Chinese and Inuit populations, 75% EBV positive in US).
EBER (EBV-encoded RNA) is positive in all EBV-related tumors except for which one?
Oral hairy leukoplakia is the only EBV-related lesion that is negative for EBER by ISH.
The various SS-associated complications are about half as frequent in SC disease, but what 2 conditions are equally common or more common in SC disease?
Avascular necrosis of bone and proliferative retinopathy.
Low grade myofibroblastic sarcoma AKA low grade myofibrosarcoma is a rare, low to intermediate grade tumor composed predominantly of malignant myofibroblasts. Locations? Microscopic appearance?
It typically occurs in the head and neck (tongue and oral cavity) and extremities.
Microscopically, it is circumscribed to diffusely infiltrative with fascicles or storiform growth of spindled tumor cells. Cells have ill defined, pale eosinophilic cytoplasm, fusiform nuclei that are either elongated or wavy with evenly distributed chromatin or round and vesicular with indentations and small nucleoli. There is usually at least focal nuclear atypia with hyperchromasia and irregular nuclear membranes. The stroma is collagenous with prominent hyalinization, and numerous thin walled capillaries may be present. There are no histiocytic giant cells, or prominent inflammation. Mitotic activity is 1-6 mitoses/10 HPF. IHC: At least one myogenic marker is positive, and tumor cells are negative for h-caldesmon.
What are some extrahepatic manifestations of HCV infection?
Hematologic diseases such as essential mixed cryoglobulinemia, lymphoma, and aplastic anemia. Renal disease, particularly membranoproliferative glomerulonephritis. Autoimmune disorders such as thyroiditis and the presence of autoantibodies. Dermatologic conditions such as porphyria cutanea tarda and lichen planus. Diabetes mellitus.
What are symptoms of mumps infection?
Mumps infection is frequently accompanied by a nonspecific prodrome consisting of low-grade fever, malaise, HA, myalgias, and anorexia. These symptoms are generally followed within 48 hrs by the development of parotitis, a classic feature of mumps infection seen in 95% of symptomatic cases. The parotitis is due to direct infection of ductal epithelium and local inflammation. Symptomatic infection in adults is usually more severe than in children.
Coxsackie A virus causes (conditions). Coxsackie B virus causes (conditions).
Coxsackie A virus causes hand-foot-mouth disease and herpangina. Coxsackie B virus causes myocarditis, pericarditis, and epidemic pleurodynia (the grippe).
Rubella virus causes German measles, which is only really consequential in pregnancy. Which trimester infections have the most serious fetal implications?
First trimester infections have the most serious fetal implications. Defects in neonates infected in the first trimester include hearing impairment (60%), heart defects (45%) (PDA in 20% and peripheral pulmonic stenosis in 12%), microcephaly (27%), cataracts (25%), low birth weight (<2500 g) (23%), hepatosplenomegaly (19%).
What conditions are caused by mutations in the PTCH1/patched 1 gene?
More than 225 mutations in PTCH1 have been found to cause Gorlin syndrome/nevoid basal cell carcinoma syndrome. Somatic mutations are associated with sporadic basal cell carcinoma, medulloblastoma, breast cancer, colon cancer, and keratocystic odontogenic tumors. At least seven mutations in PTCH1 have been found to cause nonsyndromic holoprosencephaly.
What are some secondary causes of a predominant hypercholesterolemia?
Hypothyroidism, DM, nephrotic syndrome, cholestasis, cyclosporine, thiazide diuretics, or loop diuretics.
What are some secondary causes of a predominant hypertriglyceridemia?
Heavy alcohol consumption, obesity, DM, hepatitis, pregnancy, renal failure, beta blockers, isotretinion, corticosteroids, nephrotic syndrome, and gout.
What are some secondary causes of a mixed hypertriglyceridemia and hypercholesterolemia?
Severe examples of DM, hypothyroidism, or nephrotic syndrome. Also, type III hyperlipidemia, thiazides, loop diuretics, and beta blockers.
Tangier disease is an autosomal recessive disorder of lipid metabolism characterized by what lipid values?
Low cholesterol, normal to increased TG, absent HDL, and absence of APO-A1. Cholesterol esters deposit in the tonsils, lymph nodes, vasculature, and spleen, and corneal opacities develop.
In Hashimoto’s disease, __% have anti-thyroglobulin Ab and __% have anti-thyroid peroxidase Ab. In Graves disease, __% have anti-thyroglobulin Ab and __% have anti-thyroid peroxidase Ab.
In Hashimoto’s disease, 90% have anti-thyroglobulin Ab and 95% have anti-thyroid peroxidase Ab. In Graves disease, 50% have anti-thyroglobulin Ab and 90% have anti-thyroid peroxidase Ab.
C1 esterase inhibitor (C1 Inh) deficiency is an autosomal dominant disorder also called hereditary angioedema. What parts of the body are affected?
Swelling is seen most consistently in the skin (upper extremity more than lower) and intestinal tract (abdominal pain episodes). Laryngeal edema, though classic and potentially lethal, is present in only about 1% of episodes but has a lifetime incidence of 50%. Facial swelling is rare, and while there is swelling of the soft palate and uvula, it spares the tongue. Acute episodes are treated with androgenic agents.
What is the procedure for detecting anti-thyroid antibodies?
Incubate serum with cryostat sections of thyroid. Add fluorescein-labeled AHG. Examine: Fluorescence that highlights follicular epithelial cell cytoplasm is anti-thyroid microsomal, while fluorescence that highlights follicular contents is anti-thyroglobulin.
What is the clinical utility of anti-microsomal antibody AKA anti-thyroid microsomal antibody?
High specificity (90%) and sensitivity (95%) for Hashimoto disease, although up to 50% of patients with Graves disease will have antibodies. Note: Anti-liver kidney microsomal type 1 antibody is different, and is found in autoimmune hepatitis.
What is the clinical utility of anti-thyroglobulin antibodies?
Hashimoto disease.
What is the clinical utility of anti-thyroid-stimulating antibodies?
Also called LATS, it is present in 90% of individuals with Graves disease.
What auto-antibodies are associated with Hashimoto disease, and how are they detected?
Anti-microsomal and anti-thyroglobulin. IIF on cryostat sections of thyroid tissue; latex agglutination.
What auto-antibodies are associated with Graves disease, and how are they detected?
Anti-TSH (TSI/LATS). Detected by bioassay.
Warthin’s tumor (papillary cystadenoma lymphomatosum and adenolymphoma) is the second most common benign neoplasm of salivary glands. What does it arise from?
It arises from ducts trapped during embryologic development of lymph nodes in the parotid glands. This may explain why Warthin’s tumor almost always occurs in or around the parotid gland.
What is seen on FNA of a branchial cleft cyst?
These cysts usually arise in the lateral neck, anterior to the sternocleidomastoid muscle. FNA shows turbid material composed of proteinaceous material; histiocytes; and nucleated and anucleated squamous cells, which may be sparse or numerous. Multinucleated giant cells and epithelioid histiocytes, indicating a granulomatous reaction, may also be present. Inflamed lesions may come to clinical attention because of a sudden increase in size. FNAs of inflamed branchial cleft cysts show inflammatory cells, and squamous cells may display significant cytologic atypia.
What is seen on FNA of parathyroid cysts?
Aspirates of parathyroid cysts characteristically yield thin, clear, watery fluid. Epithelial cells are typically sparse, relatively uniform and bland, resembling thyroid follicular cells. Immunocytochemical staining for PTH and analysis of cyst fluid for PTH may be diagnostically helpful.
For the following thyroid disorders, what are %s for the presence of anti-thyroglobulin Ab, anti-microsomal Ab, and LATS/TSI (Long-Acting Thyroid-Stimulating/Thyroid-Stimulating Immunoglobulin, AKA TSH receptor) Ab: Hashimoto thyroiditis, other thyroiditis (de Quervain and lymphocytic), Graves disease, thyroid carcinoma?
Hashimoto thyroiditis: 60-100%, 80%, 0%. Other thyroiditis (de Quervain and lymphocytic): 30-50%, 50%, 0%. Graves disease: 30%, 60-80%, 100%. Thyroid carcinoma: 20-50%, 15%, 0%.
Intraocular medulloepithelioma. Epidemiology.
Intraocular medulloepithelioma is a congenital tumor of the nonpigmented ciliary epithelium, usually diagnosed in childhood. Rare in comparison to retinoblastoma, medulloepithelioma is still the second most common primary intraocular neoplasm during the first decade of life. Intraocular medulloepithelioma shares many histopathologic feature with medulloepithelioma of the CNS, but its overall prognosis is considerably better. There is no gender or race predilection, and it is not associated with any congenital malformation or cytogenetic abnormality.
Intraocular medulloepithelioma. Microscopic appearance.
Microscopically, the tumor is characterized by cords of primitive pseudostratified neuroepithelial cells that resemble the embryonic retina or neural tube, surrounded by a loose mesenchymal tissue rich in hyaluronic acid. The neuroepithelial surface facing the stroma is lined by a thin basement membrane, corresponding to the internal limiting membrane of the neurosensory retina. The opposite surface is lined by a series of terminal bars, which corresponds to the external limiting membrane of the neurosensory retina. When the medullary epithelium folds so that the vitreous surface faces inwards, it creates cysts rich in hyaluronic acid. Such proliferating cysts can detach from the main tumor and appear as free-floating cysts in the anterior or posterior segment of the eye. The spaces between anastomosing cords of neuroepithelial cells may be filled in with sheets of undifferentiated neuroblasts, indistinguishable microscopically from from cells seen in retinoblastoma. Both Homer Wright and Flexner-Wintersteiner rosettes can be observed among undifferentiated neuroblasts. Neuroepithelial tubules and absence of calcifications are also features of medulloepithelioma not found in retinoblastoma. The designation teratoid medulloepithelioma applies when heteroplastic tissue is present. More than a third of medulloepitheliomas contain heteroplastic elements. Mature hyaline cartilage is the most common heteroplastic element, but neuroglial tissue resembling disorganized brain and rhabdomyoblasts also can be seen. Nonteratoid and teratoid medulloepitheliomas can both be either benign or malignant. The diagnosis of malignant medulloepithelioma is based on the presence of undifferentiated neuroblastic cells, high mitotic rate, and tissue invasion. IHC has different patterns of reactivity depending on whether the tissue of interest is neuroepithelial or heteroplastic. The nonteratoid component is typically positive for vimentin and NSE.
Which thyroid tumors are galectin-3 pos, CK19 pos, HBME-1 pos?
Papillary carcinoma (92% positive for galectin-3, 86% positive for CK19, 77% positive for HBME-1). Papillary carcinoma, macrofollicular variant (100%, 86%, 100%). Papillary carcinoma, follicular variant (90%, 89%, 90%). Follicular adenocarcinoma (66%, 59%, 62%).
Which thyroid tumors are galectin-3 pos, CK19 neg, HBME-1 neg?
Atypical follicular adenoma (90% positive for galectin-3, 14% positive for CK19, 29% positive for HBME-1). Hyalinizing trabecular tumor (86%, 38%, 0%). Hurthle cell adenocarcinoma (86%, 39%, 20%). Anaplastic carcinoma (74%, 25%, 7%). Hurthle cell adenoma (60%, 0%, 33%).
How does Hashimoto’s thyroiditis stain with galectin-3, CK19, and HBME-1?
Galectin-3 positive in 20%, CK19 positive in 87%, and HBME-1 positive in 19%.
Which thyroid tumors are galectin-3 neg, CK19 neg, HBME-1 neg?
Well differentiated thyroid tumor of uncertain malignant potential (37% positive for galectin-3, 33% positive for CK19, 40% positive for HBME-1). Nodular goiter (19%, 37%, 3%). Follicular adenoma (18%, 32%, 11%). Papillary hyperplastic nodule (13%, 25%, 0%). Thyroid nodule hyperplasia (10%, 24%, 0%). Thyrotoxic hyperplasia (7%, 9%, 0%).
How does normal thyroid tissue stain with galectin-3, CK19, and HBME-1?
0% positive for galectin-3, 20% positive for CK19, 0% positive for HBME-1.
What is RET/PTC?
The RET proto-oncogene on chromosome 10q11.2 encodes a cell membrane receptor tyrosine kinase. In some papillary thyroid carcinomas, the tyrosine kinase domain of RET is fused with a heterologous gene that provides the promoter and the 5’-coding region. The product of this rearrangement is a chimeric oncogene named RET/PTC. Since the original report, at least 11 types of RET/PTC variants have been isolated.
RET/PTC. The RET proto-oncogene on chromosome 10q11.2 encodes a cell membrane receptor tyrosine kinase. In some PTCs, the tyrosine kinase domain of RET is fused with a heterologous gene that provides the promoter and the 5’-coding region. The product of this rearrangement is a chimeric oncogene named RET/PTC. Since the original report, at least 11 types of RET/PTC variants have been isolated. What variants are most common?
Most of these rearrangements are between RET on chromosome 10 and genes located on different chromosomes. By contrast, RET/PTC1 and RET/PTC3 are intrachromosomal paracentric inversions because the genes involved H4 and RFG (also designated ELE1/ARA70/NCOA4) are also all located on chromosome 10. RET/PTC1 and RET/PTC3 account for the vast majority of the variants, while the others are very rare and have little clinical significance.
