Mixed AP for me Flashcards
Neurofibromatosis type 1 (NF1)
NF1 is most common inherited disease associated with neurofibromas
Autosomal dominant
NF1 on chromosome 17q11.2, encoding neurofibromin
Multiple neurofibromas, café au lait spots, freckling of axilla &/or groin, bone dysplasia, brainstem gliomas, malignant peripheral nerve sheath tumors (MPNST), pheochromocytomas, duodenal neuroendocrine tumors, and gastrointestinal stromal tumors
NF1 diagnosis
≥ 6 café au lait macules, greatest diameter of which is > 5 mm in prepubertal patients and > 15 mm in postpubertal patients
≥ 2 neurofibromas of any type or 1 plexiform neurofibroma
Axillary or inguinal freckling (Crowe sign)
Optic glioma
≥ 2 Lisch nodules
Distinctive osseous lesion, such as sphenoid dysplasia or pseudoarthrosis
1st-degree relative with NF1 according to these criteria
NF1 DDx
McCune-Albright Syndrome:
Consists of polyostotic fibrous dysplasia, café au lait spots, and endocrinopathies caused by GNAS mutation
Café au lait spots are larger than in NF1 and have “coast of Maine” border
Neurofibromatosis Type 2:
Autosomal dominant disorder caused by mutation of NF2, located on chromosome 22q12; encodes merlin
Bilateral vestibular schwannomas, cutaneous schwannomas, meningiomas, and juvenile posterior subcapsular cataracts
Hereditary Nonpolyposis Colon Cancer:
Multiple café au lait spots, axillary freckling, and cutaneous neurofibromas are similar to NF1
Colonic cancer at unusually young age
Multiple Endocrine Neoplasia Type 2B:
Autosomal dominant tumor syndrome pattern caused by mutations of RET gene
High risk of pheochromocytoma but can be differentiated based on other clinical features
Neurofibromatosis type 2 (NF2)
Germline mutations in NF2 encoding for merlin/schwannomin, 22q12.2
NF2 mutations inherited in 1/2 of patients and new germline mutation in remaining 1/2
More severe phenotype in patients with frameshift or nonsense mutations
Germline mosaicism occurs in 20-30% of patients without family history
Bilateral vestibular schwannomas are hallmark of NF2 (90-95% of patients)
Neurofibroma, meningioma, ependymoma, retinal hamartomas, Glial microhamartomas, Café au lait spots but at lesser frequency than NF1
Schwannomatosis
Germline mutations of either SMARCB1 or LZTR1
Tumorigenesis in schwannomatosis must involve mutation of at least 2 different tumor suppressor genes
Occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harboring not only SMARCB1 and LZTR1 but also NF2
Onset is usually in 2nd and 3rd decades
Unilateral vestibular schwannomas may occur at low frequency and do not exclude diagnosis
Chronic pain is most common symptom
Lack of family history in majority of patients
Meningiomas occur at low frequency
Ependymoma not feature
Ophthalmologic manifestations not present (in contrast to NF2)
Schwannomatosis diagnosis
Lack of bilateral vestibular schwannoma; lack of NF2 in 1st-degree relative; lack of germline NF2 mutation
Schwannomas or meningiomas (≥ 2 pathologically proven) and
≥ 2 tumors with chromosome 22 loss of heterozygosity + 2 different NF2 mutations or schwannoma or meningioma + germline SMARCB1 mutation
Adenoid cystic carcinoma
Combination of patterns: Cribriform, tubular, solid
Cells are usually small with limited eosinophilic to clear cytoplasm
Nuclei are oval to sharply angulated (peg-shaped) with coarse chromatin and small nucleoli
Mitotic figures are rare
t(6;9)/MYB-NFIB
High MYB expression (worse patient survival)
Perineural invasion is very commonly present
High-grade transformation to poorly differentiated cells; necrosis; increased mitoses, conventional ACC must be identified concurrently
Salivary duct carcinoma
Perineural and lymph-vascular invasion common
Comedonecrosis conspicuous
Rounded to irregular, solid or cystic nodules of tumor cells
Arranged in solid, band-like, papillary, and cribriform patterns; Roman bridge architecture classic
Polygonal cells with moderate/marked pleomorphism, ample eosinophilic, granular cytoplasm (apical snouts)
Numerous mitoses, including atypical forms
Variants: Sarcomatoid, micropapillary, mucin-rich, osteoclast-type giant cell
Positive: Androgen receptor, CK7; negative: CK5/6, p63
Breast epithelial markers (HER2/neu) positive in many
PTEN loss in 50%: Homozygous or hemizygous deletion, chromosome 10 monosomy
ERBB2 (HER2/neu) gene amplification
PLAG1 and HMGA2 FISH rearrangement/amplification common
Epithelial-Myoepithelial Carcinoma (EMC)
EMC frequently has evidence of preexisting pleomorphic adenoma
Classic features of biphasic (bilayered) tubular histology, which predominates
Inner layer: Single row of cuboidal to columnar epithelial cells
Outer layer: Syncytium of large, polygonal myoepithelial cells in layers clear cytoplasm, surrounding vesicular nucleus, rich in glycogen (PAS+)
Basement membrane-like hyalinized material may separate duct-like structures
Epithelial and myoepithelial markers highlight dual population
Presumed to be of intercalated duct origin (biphasic)
Perineural and vascular invasion is common. Bone invasion is uncommon
Mitotic rate is low (1-2/2 mm²)
High-grade transformation (dedifferentiation) (~ 20%), parotid most common, epithelial > > myoepithelial, and poor prognosis. Sheets and nests of markedly atypical cells showing necrosis, increased mitoses. Areas of typical EMC still identified
Cytology EMC
1 of tumors with high false-negative rate
Biphasic smears with ductal cells and larger pale to clear myoepithelial cells
Larger cells are fragile, creating many naked nuclei
Hyalinized basal lamina can create globules
Localized-Type Tenosynovial Giant Cell Tumor
Synonyms :
Giant cell tumor of tendon sheath
Nodular tenosynovitis
Localized pigmented villonodular synovitis (PVNS), Intraarticular forms
Balanced translocation involving 1p13 (CSF1 gene):
CSF1 overexpression by neoplastic stromal cells
Autocrine activation of neoplastic cells via CSF1R
Recruitment and activation of macrophages and giant cells via CSF1R
Mostly in digits as painless slow-growing mass, benign but recurs locally (10-20%), recurrence risk higher in distal phalanx, interphalangeal of thumb, osseous erosion
Microscopic: Well demarcated Multinodular with fibrous septa Stromal fibrosis Can be extensive Can mimic osteoid Hemosiderin deposits Discohesive areas render pseudoglandular appearance Cleft-like spaces lined by synoviocytes Distal tumors can invade dermis
Diffuse-Type Tenosynovial Giant Cell Tumor
Synonym: Pigmented villonodular synovitis (PVNS)
Generally benign, locally aggressive neoplastic proliferation of synovial origin
Balanced translocation involving 1p13 (CSF1)
Most of synovial surface affected
Villous, nodular, or villonodular
Extraarticular tumors form multinodular masses
Large, usually > 5 cm
Painful mass with decreased range of motion, commonly in knee, high rate of relapse
Poorly demarcated from adjacent soft tissue
Thin, delicate villi and broad papillary structures
Solid cellular areas with multinodular architecture
Heterogeneous cell population
Large epithelioid cells
Osteoclastic giant cells
Macrophages/xanthoma cells
Hemosiderin, fibrosis
Common bland spindle cell DDx
Fibromatosis Inflammatory myofibroblastic tumor Neurofibroma Nodular fasciitis Solitary fibrous tumor
Desmoid-Type Fibromatosis
Large, painless, slow-growing mass, rare in hands and feet
Fascicles of spindle cells with interspersed collagen and usually negligible inflammation
Small-caliber vessels often with perivascular edema
SMA(+) Negative for ALK-1 by IHC Nuclear β-catenin (+) in majority CD34, h-caldesmon, S100 protein, CD117, STAT6 (-) CTNNB1 (β-catenin) or APC mutations
Inflammatory myofibroblastic tumor
Mesentery common location in and more common pediatric and young adults
ALK(+) or ALK gene rearrangments in 50%
SMA(+), nuclear β-catenin (-)
Subset of ALK-negative tumors harbor fusions involving ROS1, RET, PDGFRB, or NTRK3
Expansile or infiltrative peripheral border
Myofibroblastic cells:
Usually spindled, ovoid, or stellate, rarely epithelioid
Vesicular nuclei with 1 or 2 conspicuous nucleoli
Occasional cells have enlarged nuclei with macronucleoli or “smudgy” chromatin
Usually abundant inflammatory cells (plasma cells, lymphocytes)
