Endometrial carcinoma

Topic Completed: 1 September 2016

Minor changes: 1 May 2020

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PubMed Search: endometrial carcinoma[title] uterus

See also: specific carcinoma subtypes

Carlos Parra-Herran, M.D.
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Cite this page: Parra-Herran C. Endometrial carcinoma-general. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/uterusendometrialcarc.html. Accessed July 5th, 2020.
Clinical features
  • Most common gynecologic malignancy in US (33K cases / year, 4K deaths); incidence is increasing
  • 80% arise in postmenopausal women, and manifest with symptoms of bleeding
  • Endometrial carcinomas are traditionally divided into two types:
    • Type 1: includes endometrioid and mucinous carcinoma; tumors are associated with long term unopposed estrogen stimulation (obesity, polycystic ovarian syndrome / Stein-Leventhal syndrome, exogenous estrogen use, tamoxifen use); PTEN, KRAS and PAX2 gene alterations are common; endometrial intraepithelial neoplasia (EIN) / atypical hyperplasia is regarded as the precursor lesion (J Clin Oncol 2010;28:788, Cancer 2005;103:2304)
    • Type 2: includes serous, clear cell, undifferentiated carcinoma and carcinosarcoma; these tumors have a lesser association with unopposed estrogen exposure; serous carcinoma is characterized by early alterations in TP53; serous intraepithelial carcinoma has been proposed as the preinvasive precursor
  • The classification of endometrial carcinoma is evolving towards a molecular based grouping (see Molecular section below)
  • Other associations include diabetes, dysfunctional uterine bleeding, hypertension, infertility, Muir-Torre syndrome (Am J Surg Pathol 2001;25:936, OMIM - Muir-Torre syndrome), Turner syndrome (usually well differentiated adenocarcinoma; 2/3 have squamous differentiation), tamoxifen use for breast cancer (increased risk for endometrioid, serous carcinoma and carcinosarcoma)
  • 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:
  • 10-30% of patients present at advanced stage (FIGO stage III-IV), typically with involvement of cervix (direct extension or "drop-down" / skip metastasis), fallopian tube, ovary or vagina
  • Metastases also occur to bone, brain, liver, lung, skin
  • Nodal metastases are most common to pelvic and para-aortic nodes
  • Most recurrencess are local (vaginal vault, pelvis)
  • A synchronous ovarian carcinoma is present in up to 30% of women (Int J Womens Health 2014;6:691, Obstet Gynecol 2005;106:693)
    • When present, synchronous ovarian and endometrial carcinomas have the same histologic type (vast majority are endometrioid)
    • Distinguishing these examples of endometrial and ovarian involvement is relevant for staging and treatment:
      • Synchronous ovarian and endometrial tumors
      • Primary endometrial with metastatic ovarian involvement
      • Primary ovarian with metastatic endometrial involvement
    • However, histopathologic assessment may be inadequate to distinguish these examples, and may only suggest one possibility over the others
    • Features that support two synchronous carcinomas include:
      • Different histologic types or tumor grades
      • Endometrial carcinoma has absent or only superficial myometrial invasion
      • Ovarian carcinoma is confined to the ovary
      • Absence of lymphovascular space invasion
      • Different patterns of MMR or hormone receptor expression by IHC
    • Conversely, secondary ovarian involvement by a primary endometrial tumor should be considered when:
      • Endometrial tumor has deep myometrial invasion, lymphovascular space invasion, serosal or parametrial involvement
      • Bilateral ovarian involvement
      • Ovarian tumor involves surface and has extensive lymphovascular space invasion
      • Both tumors show similar MMR and hormone receptor expression by IHC
    Histologic grading:
  • Endometrioid and mucinous carcinomas are graded with a three tier system developed by the International Federation of Gynecology and Obstetrics (FIGO):
    • FIGO 1: predominant glandular growth and < 5% nonsquamous solid component; glandular architecture is identified by the presence of patent lumina within the gland, relatively preserved polarity of the epithelium and absent to mild epithelial stratification
    • FIGO 2: 6-50% nonsquamous solid component
    • FIGO 3: more than 50% nonsquamous solid component
    • Architectural grading described above is upgraded by one if there is severe nuclear atypia (pleomorphism, enlargement, prominent nucleoli)
    • In general, a two tier system can be also applied, with FIGO1 and FIGO2 being considered low grade, and FIGO 3 being considered high grade
  • Other carcinoma types (serous, clear cell, carcinosarcoma, undifferentiated, mixed) are by definition HIGH GRADE
Prognostic factors
  • 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 and ploidy
  • Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO) is standard treatment
  • Regional nodal dissection is performed in patients with: endometrioid carcinoma FIGO 2 or 3, high grade histologic type, tumor size > 2 cm or with myometrial invasion on imaging, or suspicious lymph nodes
  • Medical treatment with exogenous progestin is a valid option in patients who desire to preserve fertility or are not eligible for surgery, have a FIGO 1 endometrioid carcinoma and no or superficial myometrial invasion on imaging (Obstet Gynecol Int 2010;2010:431950)
  • Radiation therapy is usually indicated in patients with FIGO stage Ib or greater or with local (vaginal, pelvic) recurrence
  • Chemotherapy is indicated for high risk early stage or advanced stage disease, recurrences and distant metastases (Oncologist 2010;15:1026)
Gross description
  • Lush, polypoid endometrium with yellow necrotic areas
Gross images

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Endometrial adenocarcinoma

Microscopic (histologic) description
  • The diagnosis of carcinoma is based on features indicative of invasion into the surrounding mesenchyma (endometrial stroma or myometrium)
    • Stromal invasion is typically seen in the form of glandular confluence and complex architecture: loss of individual glandular contours with gland fusion, lack of intervening stroma and back to back architecture
    • Invasion usually presents in cribriform, microacinar and solid architectural patterns; other helpful features are 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
    • Stromal foam cells between glands are altered endometrial stromal cells; this is suggestive but not diagnostic of carcinoma
  • Myometrial invasion is often overdiagnosed or difficult to establish, since uteri frequently have an uneven endomyometrial junction or adenomyosis involved by carcinoma
  • Carcinoma is confined to the endometrium / adenomyosis when:
    • Focus of carcinoma has a round or ovoid shape with a smooth and convex outer contour (regardless of its size), and is entirely or mostly composed of neoplastic glandular epithelium
    • Outer contour smoothly continues with adjacent uninvolved endomyometrial interface
    • Residual endometrial type stroma or benign endometrial glands are present in the periphery or within the focus
    • There is no significant desmoplastic reaction
  • Assessment of cervical involvement is inconsistent between gynecologic pathologists (Am J Surg Pathol 2011;35:289)
  • Artificial tumor intrusion into vascular spaces (vascular pseudoinvasion) can be seen in laparoscopic, robotic assisted hysterectomies (Am J Surg Pathol 2009;33:298)
    • Real vascular invasion is seen in lymphatics and venous vessel and it is commonly seen in the vicinity of the myoinvasive tumor; intravascular foci are round and conform to the shape of the vessel; sometimes they are partially adherent to the vessel wall
    • Artificial intrusion should be considered if the intravascular tumor retains a glandular shape or stromal elements within it, has a large ("chunky") size and involves arterial vessels, or other elements are identified within vascular spaces (benign endometrium, surface necrotic material or exudates)
Microscopic (histologic) images

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Images hosted on PathOut server:

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
    Cervico-vaginal cytology:
  • 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
Molecular / cytogenetics description
  • Determination of the tumor histologic type is critical for patient risk stratification and management
  • However, there is poor interobserver reproducibility in tumor type and grade among expert pathologists (Mod Pathol 2013;26:1594, Am J Surg Pathol 2013;37:874, Int J Gynecol Cancer 2011;21:654)
  • Recent studies have provided a comprehensive characterization of the genomic profiles of endometrial carcinoma:
    • In 2013, the Cancer Genome Atlas (TCGA) Research Network published an integrated genomic characterization of endometrial carcinoma based on genomic data from array and sequencing based technologies (Nature 2013;497:67)
    • It proposed a classification that separates endometrial carcinomas in four groups:
      • Copy number - high (frequently involving mutations of TP53); this group includes the vast majority of serous carcinomas and 25% of high grade endometrioid tumors
      • Copy number - low (frequently involving mutations of PTEN, PIK3CA, ARID1A and KRAS); this group is mostly composed of low grade endometrioid carcinomas
      • Microsatellite instability hypermutated (frequently involving alterations of mismatch repair protein genes)
      • Polymerase ɛ (POLE) ultramutated; this group is mostly composed of endometrioid cancers, which despite having a dramatically increased transversion mutation frequency, and newly identified hotspot mutations in the POLE gene (which encodes the central catalytic subunit of DNA polymerase epsilon), appear to have a better prognosis than other groups (J Natl Cancer Inst 2014;107:402, Cancer 2015;121:386)
    • These molecular based classification correlates with clinical outcomes: survival rates are best in POLE mutated tumors, followed by copy number-low, microsatellite instability and copy number-high carcinomas (Nature 2013;497:67); thus, the molecular fingerprint can better assist in patient risk stratification and management
    • Ancillary testing using formalin fixed, paraffin embedded tumoral tissue can serve as a surrogate to detect its molecular alterations, and determine the molecular group (J Pathol 2012;228:20)
    • A recent study proposed an algorithm using POLE mutational analysis and immunohistochemistry for p53 and mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) as a valid surrogate to determine the molecular group (Br J Cancer 2015;113:299); when combined with clinicopathologic features, the molecular classifier highly correlated with outcome and survival curves
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