Genetics and Syndromes Flashcards
Ewing sarcoma/PNET
5 translocations, all involving EWS gene at 22q12
- t(11;22)(q24;q12) Most common (>80%)
- EWS/Fli-1
- t(21;22)(q22;q12) Most of the remaining
- t(7;22)(p22;q12) Rare
- t(17;22)(q12;q12) Rare
- t(2;22)(q33;q12) Rare
Neuroblastoma
Neuroblastoma
- MYCN oncogene amplification
- PCR or FISH
- MYCN amplified tumors worse prognosis
Mesenchymal chondrosarcoma
Mesenchymal chondrosarcoma
- sheets and clusters of uniform, small round cells
- multiple foci of well-differentiated cartilage
- t(11;33) (q24;q12) translocation
- expression of Sox9
- master regulator of cartilage differentiation
Immunohistochemistry to Detect Transforming Mutations?
Immunohistochemistry to Detect Transforming Mutations
- The point mutation from arginine to histidine in codon 132 (R132H) of isocitrate dehydrogenase 1 (IDH1) is commonly found in astrogliomas and is not present in gliosis. The test can be performed with an antibody specific to the mutant IDH1.
- Mutations of TP53 commonly lead to a protein with a longer half-life than the short-lived wild type p53 protein; thus accumulation of this protein can be studied by IHC.
- Integrase interactor 1 (INI-1) is deleted in rhabdoid tumors and epitheloid sarcomas; thus absence of the protein aids making the diagnosis of these entities.
- HER-2/NEU amplification is studied by Herceptest assessed according to ASCO-CAP or treatment of gastric cancer (ToG) guidelines for breast and gastric carcinoma, respectively
Thyroid Mutations
PTC
- BRAF (BRAFV600E)
- RAS genes (HRAS and NRAS)
- RET/PTC translocations (RET/PTC1 and RET/PTC3)
- TRK translocations (
Follicular thyroid carcinomas
- RAS (HRAS and NRAS codon61)
- PAX8/PPAR gamma translocations
Follicular adenomas
- RAS mutations
Medullary thyroid carcinoma
- Activating RET mutations
- Germ line mutations are seen in >95% of familial cases (MEN2 or familial medullary thyroid carcinoma).
Thyroid Mutations
BRAF
- PTC
RAS
- PTC
- Follicular carcinoma
- Follicular adenoma
RET
- PTC
- Medullary (MEN2 & familial medullary thyroid carcinoma)
TRK translocations
- PTC
PAX8/PPAR gamma translocations
- Follicular thyroid carcinomas
Mutations in PTC
Most common -> least common?
Pathway?
Associations?
Mutations in PTC
Activate the mitogen-activated protein kinase (MAPK) pathway
- BRAF point mutations
- 40-50%
- mainly BRAFV600E
- a/w classical and tall cell
- predict more aggressive behavior even in pT1 tumors
- only in 10% of follicular variant PTC
- RAS genes
- 10% to 20%
- mainly HRAS and NRAS codon 61 mutations
- mainly in the follicular variant
- RET/PTC translocations
- 10% to 20%
- fusions of RET with 11 different partners
- mainly RET/PTC1 [fusion partner CCDC6] and RET/PTC3 [fusion partner NCOA4]
- a/w classical histologic appearance, a younger age at diagnosis, lymph node metastasis, and radiation exposure (RET/PTC2)
- TRK translocations
*
Follicular Thyroid Mutations
Follicular Thyroid Mutions
RAS mutations
- up to 50% follicual carcinoma
- HRAS and NRAS codon61
- +/- follicular adenomas (precuresor?)
PAX8/PPAR gamma translocations
- 30-35% follicular carcinoma
Medullary Thyroid Carcinoma Mutations
Medullary Thyroid Carcinoma Mutations
- Activating RET mutations
- Germ line mutations un > 95% of familial cases
- MEN2
- familial medullary thyroid carcinoma
Thyroid FNA
Testing of thyroid fine needle aspirates
- BRAF V600E mutations, NRAS and HRAS codon 61 mutations, and RET/PTC translocations help manage thyroid nodules
- BRAF V600E mutation or RET/PTC translocationhas a high PPV for malignancy
- provided the LOD of the test is not
- BRAF V600E mutation or RET/PTC translocationhas a high PPV for malignancy
- PAX8-PPAR gamma translocation is strongly a/w invasion in a follicular neoplasm
- In specimens with indeterminate cytology, having 1 mutations is a/w an increased risk of malignancy
- 88% follicular lesion of uncertain significance
- 87% follicular neoplasm
- 95% suspicious for malignancy
- versus no mutation: 6%, 14%, and 28%
- the high PPV can allow total thyroidectomy instead of lobectomy in positive cases
Translocations in MALT lymphoma
Translocations in MALT lymphoma
t(11;18)
- API2 and MALT1 genes
- gastric and pulmonary
t(14;18)
- IgH and MALT1 genes
- ocular adnexa/orbit and salivary gland
Trisomy 3
- nonspecific abnormality frequently detected in MALT lymphomas
t(3;14)
- IgH and FOXP1 genes
- thyroid, ocular adnexa/orbit, and skin
Trisomy 18
- nonspecific abnormality frequently detected in MALT lymphomas
Associated mutation?
Trisomy 13
- least common of the viable autosomal trisomy syndromes (the others being Trisomy 18 and 21)
- phenotype typically includes cleft palate, polydactyly, microcephaly, and anomalies of the heart and kidneys
Adenoid cystic carcinoma (ACC) of the breast
- Incidence?
- Age?
- Hormone receptor profile?
- Clinical course?
- More aggressive behavior can be seen in the __ variant
- Morphologically, ACCs of the breast are similar to those seen in salivary glands, composed of two cell types
- one which stains with luminal epithelial markers ____ (4)
- the other staining with ___ (4) and ___(4)
- ACCs of the salivary gland and breast consistently harbor the hallmark __ fusion gene resulting from a __ translocation.
Adenoid cystic carcinoma (ACC) of the breast
- rare tumor accounting for less than 0.1% of all breast carcinomas
- occurs predominantly in postmenopausal women (mean age of 60)
- triple negative (ER/PR/HER2) receptor profile
- indolent clinical course, presenting with localized disease
- more aggressive behavior can be seen in the solid variant
- Morphologically, ACCs of the breast are similar to those seen in salivary glands, composed of two cell types
- one which stains with luminal epithelial markers CK7, EMA, CEA, and CD117
- the other staining with high molecular weight/basal cytokeratins CK5, CK5/6, CK14, CK17 and myoepithelial markers p63, S100, actin, calponin
- ACCs of the salivary gland and breast consistently harbor the hallmark MYB–NFIB fusion gene resulting from a t(6;9)(q22–23;p23–24) translocation.
- Prognosis?
- Location?
- Age?
- Clinical presentation?
- Frequency of recurrence?
- Cell of origin?
- Genetics?
- Most helpful diagnostic marker? caveat?
- Best way to detect mutation?
DDx:
Dermatofibrosarcoma Protuberans
- slow-growing dermal spindle cell tumor of intermediate malignancy
- typically occurs on the trunk and proximal extremities of young and middle-aged adults
- solitary lesion or multiple polypoid nodules arising in an indurated plaque
- Local recurrence is common, occurring in one third of all cases.
- immunohistochemical and ultrastructural evidence indicates a fibroblastic origin
- t(17;22) translocation in > 90% –> pathogenic COL1A1-PDGFB fusion gene
- most helpful diagnostic marker is CD34, which stains 50% to 100% of the cells
- CD34 is negative or focally positive in dermatofibromas
- PCR may be used to identify the COL1A1-PDGFB fusion gene
DDx:
Giant cell fibroblastoma
- considered a variant of dermatofibrosarcoma protuberans that often manifests in childhood
- may exhibit the same immunogenetic and cytogenetic profile as DFSP
Fibrosarcomatous change in DFSP
- characterized by a fascicular or herringbone growth pattern, represents malignant transformation
- fibrosarcomatous areas express CD34 in less than 50% of cases
Stains?
EM?
Mutation?
Acute disseminated form?
2 other types?
Langerhans Cell Histiocytosis
- Langerhans cell histiocytosis previously was divided into multiple clinical subtypes, but there is much overlap. The different forms of Langerhans cell histiocytosis have similar pathology in that there is a proliferation of Langerhans cells, which can be identified by the distinctive reniform, or kidney-shaped, nuclei.
- Langerhans cells stain positively with S-100 protein and CD1a immunohistochemical stains. Langerhans cells do not stain with CD68.
- With electron microscopy, characteristic Birbeck granules are seen within Langerhans cells. The Birbeck granules resemble a tennis racquet.
- BRAF V600Emutation
Letterer-Siwe disease
- acute disseminated form of Langerhans cell histiocytosis
- usually seen in infants and has many systemic manifestations
- skin lesions are characterized by hyperpigmented scaly patches, which can coalesce and form a seborrheic dermatitis–like eruption
- unresponsive dermatitis in the diaper area
- hyperpigmented papules with associated hemorrhage at the periphery of the dermatitis area
Hand-Schüller-Christian disease
- a form of Langerhans cell histiocytosis that is characterized by the triad of bone lesions, exophthalmos, and diabetes insipidus
Eosinophilic granuloma
- a form of Langerhans cell histiocytosis that usually consists of either a few lesions or one lesion and most commonly affects the bone
- skin and oral mucosa occasionally can be involved.
Congenital self-healing reticulohistiocytosis
- also known as Hashimoto-Pritzker disease
- a variant of Langerhans cell histiocytosis with a very good prognosis
- lesions are often present at birth but can manifest within the first few weeks of life as well
- most commonly, there are scattered papules and nodules over the skin
- occasionally, only a single lesion is present
Located in lateral ventricle
a/w?
grade?
histology?
Subependymal giant cell astrocytoma (SEGA)
- Associated with Tuberous Sclerosis
- most common CNS neoplasm in TS patients
- typically present in the wall of the lateral ventricles and are predominantly exophytic
- benign, slow-growing, discrete neoplasms and are graded as WHO grade I tumors
- many large plump cells with abundant glassy eosinophilic cytoplasm and large eccentric nuclei are present accompanied by elongated cells with smaller nuclei and fibrillar processes, forming a nodular appearance
Tuberous sclerosis
CNS lesions?
Gross?
Histology?
Most common?
Genes?
Tuberous sclerosis lesions in CNS
- cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas
- patients can present with seizures, mental retardation, behavioral problems and raised intracranial pressure
Cortical tubers
- effacement of the neocortex with collections of large, bizarre cells and extensive fibrillary gliosis beneath the pia
- Grossly, the cortical tubers are firm and scattered over the brain blurring the gray-white matter junction
Subependymal nodules
- firm or calcified protrusions, single or in rows, more commonly in the walls of the lateral ventricles
Subependymal giant cell astrocytomas (SEGA)
- most common CNS neoplasm in TS patients
- typically present in the wall of the lateral ventricles and are predominantly exophytic
- benign, slow-growing, discrete neoplasms
- WHO grade I tumors
- many large plump cells with abundant glassy eosinophilic cytoplasm and large eccentric nuclei are present accompanied by elongated cells with smaller nuclei and fibrillar processes, forming a nodular appearance
TSC1 gene: hamartin, 9q34
TSC2 gene: tuberin, 16p13.3
Tuberous sclerosis cutaneous lesions
Tuberous sclerosis cutaneous lesions
- hypomelanic macules (ash-leaf)
- facial angiofibromas
- periungal or subungal fibromas
- shagreen patches
- fibrous hamartomas
Two different genes are associated with tuberous sclerosis:
- TSC1 gene: hamartin, 9q34
- TSC2 gene: tuberin, 16p13.3
Tuberous sclerosis
Inheritance pattern?
Lesions?
Presentation?
Genes?
Tuberous sclerosis
- autosomal dominant
- lesions in the CNS
- cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas
- patients can present with seizures, mental retardation, behavioral problems and raised intracranial pressure
- cutaneous lesions
- hypomelanic macules, facial angiofibromas, periungal or subungal fibromas, and shagreen patches or fibrous hamartomas
- cardiac rhabdomyomas
- pulmonary lymphagioleiomyomatosis
- renal angiomyolipomas, and renal cysts
- Two different genes are associated with tuberous sclerosis:
- TSC1 gene: hamartin located in chromosome 9q34
- TSC2 gene: tuberin located in chromosome 16p13.3