Gynecologic cancer Flashcards
Type I ovarian carcinomas
Develop from indolent precursor lesions
(ie, atypical proliferative serous tumor to low-grade serous carcinoma)
Tend to involve classical adenocarcinoma drivers like KRAS and BRAF
Type II ovarian carcinomas
Genetically unstable, highly aggressive tumors
(ie, high grade serous carcinoma, carcinosarcoma, undifferentiated carcinoma)
Develop de novo, from STIC, or from a prior carcinoma.
Harbor TP53 mutations or have a loss-of-function in BRCA1 or BRCA2.
Mutational profile of ovarian clear cell carcinoma
ARID1A loss-of-function
PIK3CA exon 9 or exon 20 mutation, or kinase activation of p110alpha
TERT promoter mutation or C228T/C250T
ARID1A mutation confers high resistance to. . .
. . . platinum based chemotherapy
Mutational profile of endometrioid ovarian carcinoma
CTNNB1 missense mutations
MMR mutations or somatic MLH1 promoter hypermethylation
PTEN loss of heterozygosity
Mutational profile of mucinous ovarian carcinomas
KRAS activating mutations
Mutational profile of Brenner tumors
KRAS mutation
CCND1 amplification
MYC amplification
BRCA deficient tumors are more susceptible to. . .
. . . PARP inhibitors
Which also have a lower side effect profile, making them often preferred therapies.
Endometriosis can act as a precursor lesion for. . .
. . . endometrioid carcinoma and clear cell carcinoma.
Prognosis in clear cell carcinoma
Clear cell carcinoma tends to present at a lower stage, like type 1 tumors, however the clinical course is often more aggressive with a worse prognosis and poor response to platinum-based chemotherapeutics, like type 2 tumors.
This may reflect the effects of ARID1A loss, which is the most common mutation in clear cell carcinoma.
Sex cord tumors with annular tubules (SCTAT)
Exceedingly rare ovarian tumors that can present as a result of sporadic or germline mutations in STK11/LKB1. Remember, STK11 mutation is the cause of Peutz-Jeghers syndrome.
Sporadic tumors tend to be larger and have greater propensity to behave aggressively. SCTATs in Peutz-Jeghers patients are less likely to present with clinical symptoms and usually have a benign clinical course.
SCTATs have sharply delineated, bland nests of tumor cells which are variable in size. Calretinin+, Inhibin+, WT1+, SF1+, CD10-.
Small cell carcinoma of the ovary, hypercalcemic type
Characteristically contains a somatic or germline SMARCA4/BRG1 mutation.
Most commonly diagnosed between ages 10-20 with hypercalcemia identified in about 50% of cases.
Characteristic mutation in adult granulosa cell tumor
FOXL2 p.C134W
Patients with DICER1 mutations have an increased risk of these sex cord stromal tumors
Sertoli-Leydig cell tumors
Tend to be poorly differentiated
Features of type 1 endometrial carcinomas
More common in perimenopausal and menopausal women
More common in women with hyperestrogenic states, including elevated BMI
Tend to be lower grade and stage at diagnosis
Type 1 and Type 2 endometrial carcinomas
Type 1: grade 1-2 endometrioid carcinomas
Type 2: grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas
Most common gene alterations in type 1 endometrial carcinomas
PTEN, CTNNB1, DNA mismatch repair genes, KRAS, PIK3CA, and POLE
Mutation commonly found in endometrial hyperplasia
PTEN
Features of type 2 endometrial carcinomas
High-grade cancers
Develop more frequently in postmenopausal women
Development of serous carcinomas
Tend to arise from atrophic endometrium or endometrial polyps
Are NOT associated with unopposed estrogen or endometrial hyperplasia.
Categories of endometrial carcinomas
- POLE mutated
- MMR deficient
- Copy number high / TP53 mutated
- Copy number low / TP53 wild-type
Hereditary leiomyomatosis and renal cell carcinoma syndrome
FH deficiency
Leiomyomas have characteristic nuclear features
Low grade endometrial stromal sarcoma fusions
JAZF1-SUZ12
PHF1-JAZF1
EPC1-PHF1
MEAF6-PHF1
So, either a fusion involving JAZF1 or PHF1. These are seen in about 50% of cases. If all these are negative, sending for a broader or unbiased fusion panel is still likely to detect some sort of fusion (>90% of cases). Send it to Kyle Devins.
High grade endometrial stromal sarcoma
YWHAE-NUTM2
MED12
Hotspot mutations in exon 2 of MED12 are seen in leiomyomas and leiomyosarcomas.
They are more common in benign leiomyomas.
Inflammatory myofibroblastic tumor genetics
Involve an RTK rearrangement, most commonly ALK, but sometimes ROS1, RET, or NTRK3.