Gynecologic cancer

Question 1

Type I ovarian carcinomas

Answer 1

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

Question 2

Type II ovarian carcinomas

Answer 2

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.

Question 3

Mutational profile of ovarian clear cell carcinoma

Answer 3

ARID1A loss-of-function

PIK3CA exon 9 or exon 20 mutation, or kinase activation of p110alpha

TERT promoter mutation or C228T/C250T

Question 4

ARID1A mutation confers high resistance to. . .

Answer 4

. . . platinum based chemotherapy

Question 5

Mutational profile of endometrioid ovarian carcinoma

Answer 5

CTNNB1 missense mutations

MMR mutations or somatic MLH1 promoter hypermethylation

PTEN loss of heterozygosity

Question 6

Mutational profile of mucinous ovarian carcinomas

Answer 6

KRAS activating mutations

Question 7

Mutational profile of Brenner tumors

Answer 7

KRAS mutation

CCND1 amplification

MYC amplification

Question 8

BRCA deficient tumors are more susceptible to. . .

Answer 8

. . . PARP inhibitors

Which also have a lower side effect profile, making them often preferred therapies.

Question 9

Endometriosis can act as a precursor lesion for. . .

Answer 9

. . . endometrioid carcinoma and clear cell carcinoma.

Question 10

Prognosis in clear cell carcinoma

Answer 10

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.

Question 11

Sex cord tumors with annular tubules (SCTAT)

Answer 11

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-.

Question 12

Small cell carcinoma of the ovary, hypercalcemic type

Answer 12

Characteristically contains a somatic or germline SMARCA4/BRG1 mutation.

Most commonly diagnosed between ages 10-20 with hypercalcemia identified in about 50% of cases.

Question 13

Characteristic mutation in adult granulosa cell tumor

Answer 13

FOXL2 p.C134W

Question 14

Patients with DICER1 mutations have an increased risk of these sex cord stromal tumors

Answer 14

Sertoli-Leydig cell tumors

Tend to be poorly differentiated

Question 15

Features of type 1 endometrial carcinomas

Answer 15

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

Question 16

Type 1 and Type 2 endometrial carcinomas

Answer 16

Type 1: grade 1-2 endometrioid carcinomas

Type 2: grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas

Question 17

Most common gene alterations in type 1 endometrial carcinomas

Answer 17

PTEN, CTNNB1, DNA mismatch repair genes, KRAS, PIK3CA, and POLE

Question 18

Mutation commonly found in endometrial hyperplasia

Answer 18

PTEN

Question 19

Features of type 2 endometrial carcinomas

Answer 19

High-grade cancers

Develop more frequently in postmenopausal women

Question 20

Development of serous carcinomas

Answer 20

Tend to arise from atrophic endometrium or endometrial polyps

Are NOT associated with unopposed estrogen or endometrial hyperplasia.

Question 21

Categories of endometrial carcinomas

Answer 21

1. POLE mutated
2. MMR deficient
3. Copy number high / TP53 mutated
4. Copy number low / TP53 wild-type

Question 22

Hereditary leiomyomatosis and renal cell carcinoma syndrome

Answer 22

FH deficiency

Leiomyomas have characteristic nuclear features

Question 23

Low grade endometrial stromal sarcoma fusions

Answer 23

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.

Question 24

High grade endometrial stromal sarcoma

Answer 24

YWHAE-NUTM2

Question 25

MED12

Answer 25

Hotspot mutations in exon 2 of MED12 are seen in leiomyomas and leiomyosarcomas.

They are more common in benign leiomyomas.

Question 26

Inflammatory myofibroblastic tumor genetics

Answer 26

Involve an RTK rearrangement, most commonly ALK, but sometimes ROS1, RET, or NTRK3.