Specific molecular characteristics of Tumors (not soft tissue) Flashcards
NR4A3 fusion/activation
Acinic Cell Carcinoma
*also DOG1
The majority of cases have t(4,9) resulting in NR4A3 upregulation
Acinic Cell Carcinoma
*also DOG1
t(4;9)
Acinic Cell Carcinoma
*also DOG1
Salivary gland; acinic cell carcinoma; molecular
The majority of cases have t(4,9) resulting in NR4A3 upregulation
Secretory Carcinoma
secretory carcinoma harbor ETV6::NTRK3 fusion
t(12;15)(p13;q25)
Salivary gland; secretory carcinoma; molecular
secretory carcinoma harbor ETV6::NTRK3 fusion
t(12;15)(p13;q25)
CRTC1::MAML2 fusion is seen in 40-90% of….
mucoepidermoid carcinoma
mucoepidermoid carcinoma; molecular
CRTC1::MAML2 fusion is seen in 40-90%
MYB fusion /activation is seen in 80% of…
adenoid cystic carcinoma
adenoid cystic carcinoma; molecular
MYB fusion /activation
Gains (especially trisomy) of chromosome 7, 17 and loss of Y chromosome
Papillary RCC (foam cells, look for tubulopapillary features)
Papillary or tubule-papillary architecture, lined by cuboidal cells (low-grade tumors); cells can have abundant basophilic, eosinophilic, clear +/- cytoplasm, hemosiderin pigment –> FOAM CELLS
Papillary RCC (2nd most common RCC)
Gains of chromosome 7, 17 and loss of Y chromosome,
*while majority unilateral, these of all RCCs are most inclined to be b/l and multifocal
Stains for Papillary RCC
- IHC: Positive: PAX8, CK7 (but negative in eosinophilic tumors), AMACR, vimentin, CD10, FH; Negative: CAIX (can be focal positive)
- Gains of chromosome 7, 17 and loss of Y chromosome,
MET germline mutation and kidney
Papillary RCC
don’t forget the Gains of chromosome 7, 17 and loss of Y chromosome,
t(6;9)(q22-23;p23-24) …salivary gland….
Adenoid Cystic Carcinoma
MYBL1-NFIB fusion → t(6;9)(q22-23;p23-24)
PLAG1-HMGA2 fusion…
pleomorphic adenoma
PAX8/PPAR gamma rearrangement, a translocation (2;3)(q13;p25)
This is the second most common mutation found in follicular carcinomas, being present in approximately 30% of follicular carcinomas and approximately 5% of oncocytic (Hurthle cell) carcinomas.
Thyroid and RAS mutations
These are the most common somatic mutations found in follicular thyroid carcinoma.
RET/PTC1 and PTC3 rearrangements on chromosome 10 (10q11. 2)
This is the second most common molecular abnormality seen in papillary thyroid carcinomas (PTC), being present in approximately 20% of cases.
TRK rearrangement of the NTRK1 gene of chromosome 1q22
This rearrangement is found in less than 5% of PTCs.
Thyroid and BRAF.
Point mutation in the BRAF gene at codon 600 (BRAFT1799A [V600E])
BRAF mutations are the most commonly detected abnormality in PTC, present in around 45% of adult cases. Ninety percent of these mutations show Valine to Glutamate point mutation BRAFT1799A (V600E).
granulomatous stuff on cytology of a lymph node…
If not medical…
Squamous cell carcinoma, seminoma, and thymoma are the most common metastatic tumors associated with granuloma formation in lymph nodes. Granulomas may also be found in lymph nodes harboring primary or secondary malignant diseases, including Hodgkin lymphoma and T cell-type non-Hodgkin lymphoma.
Molecular analysis often shows mutations of SMAD4 and KRAS genes
KRAS mutations are present in 95% of pancreatic adenocarcinomas. Mutation of SMAD4 (DPC4) is also seen.
Atrial myxoma has been linked to which gene?
Atrial myxoma has been linked to the PRKAR1-alpha gene.
80% of SPORADIC colorectal carcinomas have what mutation?
APC.
This is why a germline mutation in APC has 100% chance of colon cancer
*normally, APC product inhibits WNT pathway (B-catenin)
*a mutation of APC will result in abnormal B-catenin nuclear localization
*this is the CHROMOSOMAL instability pathway
10-15% of SPORADIC colorectal carcinomas are NOT related to some APC mutation…which mutations are these carrying?
somewhere in the hMLH1 realm
*95% are MLH1
*more rarely seen are MSH2 and MSH6
MOST rare: PMS2
If you lose MLH1 by IHC, what does that mean?
*you have more work to do
*MLH1 loss alone (and then it’s dimer) can happen in sporadic tumors
*MSH2, MSH6 and PMS2 loss are essentially lynch diagnostic
If you lose MSH2, MSH6 orPMS2, what does that mean?
*MSH2, MSH6 and PMS2 loss are essentially lynch diagnostic
*MLH1 loss alone (and then it’s dimer) can happen in sporadic tumors
KRAS mutations in a colorectal carcinoma…
EGFR-targeted antibody therapy
*RAS mutations confer resistance to this therapy
*bad prognosis
*Cetuximab
What are the genetic mutations that you need to think about for Lung cancer?
EGFR/HER1
KRAS
EML4-ALK fusion (Inv(2))
*these are mutually exclusive and are done to predict EGFR targeted agents
*Gefitinib
*Erlotinib
*Gefitinib and Erlotinib are what?
Lung cancer specific treatments
EGFR/HER1
KRAS
EML4-ALK fusion (Inv(2))
*these are mutually exclusive and are done to predict EGFR targeted agents
*Gefitinib
*Erlotinib
Which of the three families of genetic mutations is the strongest predictor of EGFR inhibitor therapy RESISTANCE?
KRAS mutations (lung cancer, 30% of cases), strongly predict RESISTANCE to EGFR inhibitor therapy
*Gefitinib
*Erlotinib
A smoker has lung cancer with mucinous histology. What is the most likely mutation?
KRAS mutation.
predicts lack of response to EGFR inhibitors
A small % of lung cancers have an inversion. What’s the inversion, fusion, and why do we care?
EML4-ALK fusion (Inv(2))
these are in young, non-smokers with higher stage tumors and solid histology
*signet ring cells
*there is a specific treatment: Crizotinib
Most common PTC mutation in children
RET-PTC1/3
*look for RET
*second most common in adults, but most common in kids
*10q (either inversion or translocation)
Thyroid nodule, t(2;3)
PAX8-PPARy1
*less than half of follicular carcinomas
*think ‘follicular lesion’
RAS mutations in thyroid
Follicular carcinoma
*more than half of follicular carcinomas
RET mutation in thyroid
Activating RET mutations in MEDULLARY
*also, RET-PTC fusion in children for PTC
*most commonly sporadic (70% of cases), with the remaining 30% of cases being arising in patients with multiple endocrine neoplasia type 2 (MEN2)
Clear cell renal cell carcinoma cytogenetics
3p deletion
*results in de-regulation of VHL gene
*de-regulation of ubiquitin pathway
*in 70% of sporadic CCRCC
t(X;17)
translocation associated RCC (stain for TFE)
ASPL-TFE3
*papillary with psammoma bodies
t(X;1)
translocation associated RCC (stain for TFE)
EITHER:
*PSF-TFE3
*PRCC-TFE3
*papillary with psammoma bodies
t(6;11)
translocation associated RCC
Alpha-TFEB
*NOT papillary, NO psammoma bodies
*eosinophilic, younger patients, nests, tubules
BRAF in melanoma
NOT in mucosal melanomas
most common mutation overall, found in skin melanomas
*target of directed therapy
you see NUT and you think…
Head and neck
midline carcinoma, next to respiratory tract (including mediastinum) in children and young people that is fatal and ugly
*BRD4-NUT
*BRD3-NUT
t(15;19)
BRD4-NUT
NUT midline carcinoma
*midline carcinoma, next to respiratory tract (including mediastinum) in children and young people that is fatal and ugly
t(9;15)
BRD3-NUT
*3 is less than 4, NUT is on 15
NUT midline carcinoma
*midline carcinoma, next to respiratory tract (including mediastinum) in children and young people that is fatal and ugly
t(11;19)
MECT1-MAML2
mucoepidermoid carcinoma
PLAG1
Pleomorphic adenoma
8q12
FOXL2 mutation
Granulosa cell tumor
ADULT type
specific for this entity
t(12;15)
ETV6-NTRK
*cellular CMN
*infantile fibrosarcoma
*secretory carcinoma of salivary gland and breast
ETV6-NTRK
t(12;15)
*cellular CMN
*infantile fibrosarcoma
*secretory carcinoma of salivary gland and breast
why is DSRCT in abdomen positive for WT1 IHC?
t(11;22)
EWS-WT1 fusion
GYN case, t(7;17)
endometrial stromal sarcoma
JAZF1-JJAZ1
PTEN for GYN tumors…
PTEN is one of the most frequently mutated genes in endometrioid adenocarcinoma
DICER1 mutations in GYN tumors
sertoli leydig
isochromosome 12p or 12p amplification
Dysgerminoma
*ovarian mass, young girl
*look for gonadoblastoma part with calcifications
*most common malignant germ cell tumor in ovary
Hairy Cell Leukemia
*bone marrow fibrosis
*splenomegaly
*villi all around the cell
*fried egg bone marrow HandE
*monocytopenia
BRAV V600E and annexin POSITIVE
(vs splenic marginal zone, which is BRAF V600E NEGATIVE and annexin 1 negative)
isochromosome 12p and testicular tumors
spertamotyic seminoma (3 cell types) is NOT isochromosome 12p associated
*normal seminoma IS i12p associated
*does not have ITGCN component, and is not mixed with other germ cell tumors
Molecular of polymorphous adenocarcinoma salivary gland
OTHER HIGH YIELD POINTS
* Usually seen in elderly females and most common site is the palate
* Presents as an asymptomatic slow growing mass
* Gross: Well circumscribed, unencapsulated yellow or tan mass
* Prognosis excellent and has a low recurrence rate about 10%
* IHC: positive for cytokeratin, S100, SOX10, vimentin; variable p63; P40 (-)
* Molecular: Activating hotspot mutations in PRKD1 in nearly 75% of cases
genetics of anaplastic thyroid carcinoma
p53 and TERT
*From a genetic perspective, inactivating mutations in TP53 are considered a hallmark of anaplastic carcinoma, and reported in most cases.
*TERT promoter mutations are also present in up to 73% of anaplastic carcinomas.
infantile hemangioma
glut1
*present at birth
*rapid phase of growth, then slow involution
always has glut1
t(11;19) (q21;p13)
chimeric CRTC1-MAML2 fusion gene
*mucoep
t(12;15) (p13;q25)
ETV6-NTRK3 chimeric gene.
This translocation is considered a defining feature of mammary analogue secretory carcinoma.
sinonasal papilloma molecular
(classic inverted type)
RNA in situ hybridization: Positive for low-risk HPV6/11
* Molecular:
➢ More than 90% of cases will have a somatic EGFR Exon 20 mutation
*oncocytic has KRAS mutations
*exophytic type still has HPV association, but LACKS the egfr and kras mutations
sinonasal papilloma differential
exophytic is best prognosis and midline
the other two (oncocytic and inverted) are lateral or sinuses and have some risk of malignant transformation
*TP53 mutations portend malignant transmoration
*there is some association with low risk HPVs
Dysembryoblastic neuroepthelial tumor molecular
FGR1 activating mutations
*overlying cortical dysplasia
*neurons floating in mucin
*columns of small tumor cells perpendicular to cortical surface
*olig2 IHC
Pleomorphic xanthoastrocytoma, pilocytic astrocytoma and ganglioneuroma have what mutation in common?
BRAF V600E (MAPK pathway)
*if not that they have CDKN2A homozygoous deletions
Pleomorphic xanthoastrocytoma
grade 2,3 (5 mitoses cutoff)
*kids in temporal lobe
*pleomorphic cells but still eosinophilic granular bodies
dense reticulin network
Pilocytic astrocytoma most common fusion
A tandem duplication at 7q34 leading to a fusion between the poorly characterized gene KIAA1549 and BRAF is common and found in approximately 66% of pilocytic astrocytomas.
(MAPK pathway)
*most common glioma in kids, cerebellum
*midline structures like optic pathway? –> NF1
BAP 1 loss meningioma
grade 3
*BAD
grading criteria meningioma
Grade 2: more than 4 mit/HPF,
*3 or more FEATURES: (sheet-like growth, small cell change, big nucleoli, necrosis, increased cellularity)
*clear cell type (SMARCE1)
*chordoid type
Grade 3: any more than 20 mit/HPF
*anaplastic histology (sarcomatoid, carcinomatous, atypical mitoses)
*TERT promoter mutation
*CDKN2A homozygous deletion
*papillary subtype
*rahabdoid subtype (look for BAP1 loss)
PBRM1 in meningioma
papillary subtype, grade 3 by definition
CDKN2A deletion in meningioma
grade three
*BAD
4 and 20 mits/HPF in the world of neuropath…
meningioma criteria, 1-2 and then 3-4
