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Uterus

Endometrial carcinoma

General


Reviewer: Nat Pernick, M.D. (see Reviewers page)
Revised: 10 December 2011, last major update December 2011
Copyright: (c) 2002-2011, PathologyOutlines.com, Inc.

Clinical features
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● Most common gynecologic malignancy in US (33K cases/year, 4K deaths); incidence is increasing
● 80% arise in postmenopausal women, with symptoms of bleeding
● Associated with complex endometrial hyperplasia (J Clin Oncol 2010;28:788), diabetes, dysfunctional uterine bleeding, hypertension, infertility, Muir-Torre syndrome (Am J Surg Pathol 2001;25:936, OMIM), obesity, prolonged estrogen use, tamoxifen use
● Stein-Leventhal syndrome: often have hyperplasia that regresses with medical therapy; rarely have a non-lethal, well differentiated carcinoma with minimal muscular invasion
● Turnerís syndrome: rarely have well differentiated adenocarcinoma, often with prolonged estrogen therapy; 2/3 have squamous differentiation
● Tamoxifen use for breast cancer: may have high-grade endometrial tumors with poor prognosis
● Major types of endometrial carcioma are endometrioid and serous
● Must distinguish muscular invasion (should be deep or have granulation tissue response) from expansion of endometrial-myometrial junction or involvement of adenomyosis (no granulation tissue response, residual normal glands and stroma; glands are surrounded by hyperplastic myometrium)
● Poorly differentiated tumors are associated with paraneoplastic syndrome of bilateral diffuse uveal melanocytic proliferation and blindness (Am J Surg Pathol 2001;25:212)

Spread / metastases
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● Cervix (direct extension or implantation after D & C), ovary, vagina; also bone, CNS, liver, lung, skin
● Nodal metastases to pelvic and para-aortic nodes
● Recurs in vaginal vault, pelvis
● 8% accompanied by simultaneous ovarian carcinoma, usually with same histology; consider as endometrial metastasis if ovarian tumor is small, bilateral and multinodular with surface implants and angiolymphatic invasion within ovarian stroma; consider as simultaneous primaries if both tumors are FIGO grade 1/well differentiated and endometrial tumor is not myoinvasive
● Rarely see foreign body granulomas in peritoneum in response to desquamated keratin; not considered metastatic disease

FIGO grading
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● FIGO 1: resembles microglandular hyperplasia; composed primarily of well formed glands; <5% nonsquamous solid component
● FIGO 2: 6-50% nonsquamous solid component
● FIGO 3: more than 50% nonsquamous solid component; lacks well formed glands, which differentiates it from serous endometrial carcinoma
● FIGO grading excludes serous or clear cell, which are considered high grade (grade 3)
● Raise grade from 1 to 2 or from 2 to 3 if notable nuclear atypia inappropriate for grade (particularly pleomorphism and prominent nucleoli); others say marked atypia
● If marked atypia, tumor may be serous without typical papillary architecture (usually p53+)
Alternative grading: divide endometrioid tumors into low grade or high grade based on solid growth (50% or less vs. 50%+), pattern of invasion (infiltrative vs. expansive) and presence of tumor cell necrosis (yes vs. no); high grade if 2 of these features: <50% solid growth, infiltrative invasion, tumor cell necrosis (Am J Surg Pathol 2000;24:1201)

Prognostic factors
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● Histologic type, FIGO stage (includes depth of invasion, regional nodal metastases and tumor spread), tumor grade, angiolymphatic invasion (particularly for stage 1 tumors), ER, p53 / HER2 (may not be independent) and ploidy

Treatment
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● Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO), possibly with nodal dissection
● Progesterone causes regression in well differentiated tumors, although not curative (Obstet Gynecol Int 2010;2010:431950)
● Chemotherapy for high risk early-stage and advanced-stage disease, and recurrences (Oncologist 2010;15:1026)

Gross description
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● Lush, polypoid endometrium with yellow necrotic areas

Gross images
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Endometrial adenocarcinoma

Micro description
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● Stromal invasion is required for diagnosis; usually is present as stromal disappearance (i.e. back to back, cribriform or confluent glands), stromal desmoplasia (stroma has myofibroblasts, edema, inflammatory cells and myxoid change), stromal necrosis (stroma replaced by necrotic and inflammatory debris) or combinations of these findings between adjacent glands
● May have prominent atypia in high grade lesions or minimal atypia in low grade lesions
● Stromal foam cells between glands are altered endometrial stromal cells; this is suggestive but not diagnostic of carcinoma
● Myometrial invasion: often overdiagnosed due to uneven endomyometrial junction or involvement of adenomyosis (foci of adenomyosis are usually rounded not angulated, adenomyosis involved by carcinoma often has residual benign glands, is surrounded by normal myometrium and other foci are uninvolved)
● Assessment of cervical involvement is inconsistent between gynecologic pathologists (Am J Surg Pathol 2011;35:289)
● Vascular pseudoinvasion is associated with laparoscopic hysterectomy (Am J Surg Pathol 2009;33:298)

Micro images
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Cribriform pattern of well-differentiated endometrioid adenocarcinoma

   
Involvement of adenomyosis vs. myometrial invasion

   
Tamoxifen associated tumors


In this pretherapy curettage specimen, only rare neoplastic cells (center) were seen in voluminous necrotic debris. Better microscopic evidence must be sought before making a definitive diagnosis of carcinoma


Bulky or pushing pattern of myometrial invasion. This tumor (left) invades deeply into the myometrium (right), but the junction between tumor and subjacent myometrium is well demarcated. It is difficult to determine the depth of myometrial invasion without adjacent endometrial-myometrial junction available on the same slide for comparison


This poorly differentiated tumor stimulates a marked stromal response of loose edematous or myxoid tissue with fibroblastic proliferation, which separates the nests of carcinoma from the surrounding myometrium. This is the most common pattern of myometrial invasion by carcinoma


Well-differentiated endometrial glands infiltrate singly through the myometrium, with minimal surrounding reactive stroma


No muscular invasion - this pattern should not be confused with true myometrial invasion, with its attendant unfavorable prognostic implications. The focus of carcinoma in adenomyosis (long arrow) is characterized by its sharply defined rounded border, the lack of a stromal response around it, and the persistence of a benign gland at the arrow. A focus of adenomyosis without carcinoma is present deeper in the myometrium (short arrow)


Carcinoma invading endocervical stroma, a feature necessary for the diagnosis of true cervical invasion

Cytology description
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● Only 50% sensitive for adenocarcinoma, 60% with cervical scrapings and 75% with vaginal pool material
● Normal endometrial cells in a cervical cytologic specimen suggests hyperplasia or carcinoma

Cytology images
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Vaginal smear from postmenopausal woman shows a cluster of small adenocarcinoma cells on the background of numerous superficial cells, indicating estrogenic activity

Positive stains
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● CK7, CK8/18, CK19
● Also vimentin (65%), CEA (areas of squamous metaplasia), CA125, ER, PR, PTEN (80%), cyclin D1 (40%)

Molecular
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● K-ras mutations in infiltrative tumors with desmoplastic stroma
● 25% aneuploid (usually high stage and grade)

Differential diagnosis
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Endometrial hyperplasia: carcinoma favored if marked pleomorphism with loss of polarity, complex ramification of disorderly arranged glands, extensive papillary formations, confluent glandular pattern with solid or cribriform appearance and desmoplastic stroma; intraglandular cellular bridges without stromal support; neutrophils and nuclear debris within glandular lamina (Mod Pathol 2000;13:309)
Serous carcinoma: papillary architecture plus high grade features; high grade endometrioid carcinomas lack well formed glands or tubules; endometrioid carcinoma may be papillary but has low grade nuclear features; superficial portions of tumor may show microglandular patterns resembling hyperplasia and other metaplastic patterns

End of Uterus > Endometrial carcinoma-General


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