Endometrial carcinoma

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Endometrial carcinoma, also endometrial adenocarcinoma, is a common gynecologic malingnancy[1] that often arises from endometrial hyperplasia. The incidence of endometrial carcinoma is increasing, as the proportion of obese individuals is increasing.

An introduction to the endometrium is in the article endometrium.

Clinical

Risk factors

Risk factors for endometrial carcinoma - mnemonic COLD NUT:[2]

  • Cancer Hx (ovarian, breast, colon).
  • Obesity.
  • Late menopause.
  • Diabetes.
  • Nulliparity.
  • Unopposed estrogen (polycystic ovarian syndrome (PCOS), anovulation, hormone replacement therapy (HRT)).
  • Tamoxifen use.
    • Used for breast cancer; the risk is quite small[3] or possibly negligent.[4]

Family history

Several syndromes are seen in association with endometrial cancer:[5]

  • Cowden syndrome (PTEN mutation) - most common.
    • Associated with endometrioid endometrial carcinoma.
  • Lynch syndrome (mutation of a mismatch repair gene - there are several[6]).
    • Associated with non-endometrioid endometrial carcinoma.[5]
    • Autosomal dominant.

Management

  • Hysterectomy is the standard treatment for endometrial carcinoma.
    • In low-grade carcinomas (i.e. low grade endometrioid type), if the woman isn't done with their childbearing, the treatment may be hormones and surveillance biopsies.[7]
    • Endometrial carcinomas with involvement of the endocervical canal are treated with a radical hysterectomy.[8]

Details:

  • Low grade and low stage endometrioid carcinoma: total hysterectomy (includes cervix).
  • Non-endometrioid or high stage endometrioid or high-grade endometrioid: radical hysterectomy (includes cervix, vaginal cuff, parametrial tissue).

Subtypes - overview

They are commonly grouped based on clinicopathologic features:[9][10]

Feature Type I Type II
Histologic types endometrioid endometrial carcinoma, mucinous endometrial carcinoma serous carcinoma of the endometrium, clear cell carcinoma of the endometrium, undifferentiated carcinoma
Clinical
characteristics 		premenopausal, estrogen excess, obesity postmenopausal, no estrogen excess, atrophic endometrium
Prognosis good poor
Genetic
abnormalities 		microsatellite instability, PTEN & KRAS mutations p53 mutations
Precursor lesion(s) endometrial hyperplasia possibly endometrial intraepithelial carcinoma[11] †

Notes:

Grading (FIGO)

Based on gland formation & adjusted by nuclear pleomorphism:[12][13][14][15]

  • Grade 1: <5% solid component.
  • Grade 2: 5-50% solid component.
  • Grade 3: >50% solid component.

Modifiers/adjustment:

  • High grade nuclei upgrades cancer by one; high grade nuclei = increased size, irregular large nucleoli, irregular chromatin pattern (clumped, coarse).[16]

Notes:

Staging

  • Stage I: confined to uterine body.
    • Ia = less than half of myometrium.
    • Ib = greater than half of myometrium.
  • Stage II: uterus + cervix.
    • II = cervical stroma involved.
      • Cervical epithelium involvement does not change stage.
  • Stage III: outside uterus - but inside pelvis.
    • IIIa - involves serosa and/or adnexa (direct extension or metastasis)
    • IIIb - vaginal involvement (direct extension or metastasis) or parametrial involvement
  • Stage IV: outside true pelvis or in mucosa of bladder or GI tract.

References: [17][18][19][20].

Specific types

Endometrioid endometrial carcinoma

  • AKA endometrioid endometrial adenocarcinoma.

General

  • Good prognosis - usually.
  • Women in 40s & 50s.
  • Associated with estrogen excess.
    • Typical patient is obese.

Gross

  • Thickened endometrium.

Microscopic

Features:

  • Atypical (ovoid) glands with - one of the following four:[21][22][23]
    1. Desmoplastic stromal response.
    2. Confluent cribriform growth. †
    3. Extensive papillary growth. †
    4. Severe cytologic atypia. †
  • Squamous metaplasia - very common.
    • Look for squamous morules:
      • Ball of cells with an intensely eosinophilic cytoplasm - key feature.
      • Central nucleus.
      • Intercellular bridges - may be hard to find.
      • +/-Dyskeratotic cells.

Notes:

  • † There is a size cut-off for criteria 2, 3 and 4: > 2.1 mm.[22]
  • Dyskeratosis = abnormal keratinization;[24] classically have intensely eosinophilic cytoplasm +/- nuclear fragmentation (karyorrhexis) - see: several dyskeratotic cells.
  • Squamous metaplasia != neoplastic -- it may occur due to hormones.[25]
  • Squamous morules in endometrioid endometrial carcinoma - not associated with HPV infection.[26]


DDx:

Image:

IHC

  • Vimentin +ve.
  • ER +ve.
  • PR +ve.

Others:

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ENDOMETRIUM, BIOPSY: 
- ENDOMETRIOID ENDOMETRIAL ADENOCARCINOMA, FIGO GRADE I/III.

Micro

The sections show endometrium with complex, fused glands with scant intervening stroma over a region measuring greater than 2.1 millimetres. Focally, a desmoplastic stroma is also identified. No nuclear atypia is appreciated.

Endocervical versus endometrial - biopsy

The foamy histiocytes in the stroma and lack of desmoplasia slightly favour an endometrial origin; however, the lesion would be best classified with an excisional specimen and in conjunction with the clinical impression.

Mucinous carcinoma of the endometrium

  • AKA endometrial mucinous carcinoma.

General

Microscopic

Features:[10]

  • Cells with intracytoplasmic mucin (>50% of tumour).
  • Usu. mild-to-moderate nuclear atypia.

DDx:

IHC

Features:[28]

  • ER-alpha +ve.
  • PR-alpha +ve.
  • PR-beta +ve.

Serous carcinoma of the endometrium

  • AKA serous endometrial carcinoma.
  • AKA serous carcinoma of the uterus.
  • AKA uterine serous carcinoma.
  • AKA uterine papillary serous carcinoma.

General

  • Arising in the setting of atrophy.
  • Usually post-menopausal.
  • Precursor lesion: endometrial intraepithelial carcinoma.[11]
  • Aggressive behaviour - high probability of disseminated disease.

Gross

  • Thin endometrium.
  • +/-Polypoid mass.

Microscopic

Features - serous:

  • Architecture - classically papillary.
    • May be glomeruloid, tubulocystic, solid (uncommon).
  • Cytology:
    • Columnar or cuboidal cells.
      1. Moderate to marked nuclear pleomorphism - variation of size, shape and staining.
        • Large nuclear size variation between cells often esp. prominent.
      2. Singular prominent, classically red, nucleolus.
  • +/-Psammoma bodies.

DDx:

Images:

IHC

  • p16 +ve[27] - should be strong.
  • p53 +ve[29] diffuse & strong > 50% or 75% of the tumour - depending on the paper one reads.
    • Subset is p53 -ve.
  • Ki-67 "high" - no cut-point defined.
  • ER often -ve.[30]
  • PR often -ve.[30]

High-grade endometrioid carcinoma versus serous carcinoma:[31]

  • p53 -ve, PR +ve, PTEN loss -- suggest endometrioid.
  • p16 and PTEN superior to ER, PR, and p53.[32]

Notes:

Clear cell carcinoma of the endometrium

  • AKA clear cell endometrial carcinoma.
  • AKA endometrial clear cell carcinoma.

General

  • Ten-year survival ~ 40%.[35]
  • Uncommon <=5 % of endometrial carcinomas.[36]
  • Type II endometrial cancer - estrogen-independent, usually post-menopausal women.

Microscopic

Features:[36]

  • Clear cells - with moderate nuclear pleomorphism - key feature.
    • Classically clear cells... but not always.
  • Hobnail pattern -- apical cytoplasm > cytoplasm on basement membrane.
  • Usually tubular/cystic, may be solid or papillary.
    • Papillae may be pseudopapillae -- with edema instead of vessels.

Notes:

  • May have psammoma bodies - esp. in papillary area; may lead to confusion with serous carcinoma.

DDx:

DDx weird stuff:[36]

Stains

IHC

Features:[37]

Others:[36]

  • CAM5.2 +ve.
  • CK34betaE12 +ve.

Note:

See also

References

  1. ↑ Fowler W, Mutch D (September 2008). "Management of endometrial cancer". Womens Health (Lond Engl) 4 (5): 479–89. doi:10.2217/17455057.4.5.479. PMID 19072487.
  2. ↑ Greenwald, J.; Heng, M. (2007). Toronto Notes for Medical Students 2007 (2007 ed.). The Toronto Notes Inc. for Medical Students Inc.. pp. GY40. ISBN 978-0968592878.
  3. ↑ Brown, K. (Sep 2009). "Is tamoxifen a genotoxic carcinogen in women?". Mutagenesis 24 (5): 391-404. doi:10.1093/mutage/gep022. PMID 19505894.
  4. ↑ Ashraf, M.; Biswas, J.; Majumdar, S.; Nayak, S.; Alam, N.; Mukherjee, KK.; Gupta, S.. "Tamoxifen use in Indian women--adverse effects revisited.". Asian Pac J Cancer Prev 10 (4): 609-12. PMID 19827879.
  5. ↑ 5.0 5.1 Okuda T, Sekizawa A, Purwosunu Y, et al. (2010). "Genetics of endometrial cancers". Obstet Gynecol Int 2010: 984013. doi:10.1155/2010/984013. PMC 2852605. PMID 20396392. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852605/.
  6. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 120435
  7. ↑ Zivanovic O, Carter J, Kauff ND, Barakat RR (December 2009). "A review of the challenges faced in the conservative treatment of young women with endometrial carcinoma and risk of ovarian cancer". Gynecol. Oncol. 115 (3): 504–9. doi:10.1016/j.ygyno.2009.08.011. PMID 19758691.
  8. ↑ Ware, RA.; van Nagell, JR. (2010). "Radical hysterectomy with pelvic lymphadenectomy: indications, technique, and complications.". Obstet Gynecol Int 2010. doi:10.1155/2010/587610. PMID 20871657.
  9. ↑ Lim, D.; Oliva, E. (Nov 2010). "Nonendometrioid endometrial carcinomas.". Semin Diagn Pathol 27 (4): 241-60. PMID 21309259.
  10. ↑ 10.0 10.1 Nucci, Marisa R.; Oliva, Esther (2009). Gynecologic Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 241. ISBN 978-0443069208.
  11. ↑ 11.0 11.1 Roelofsen, T.; van Kempen, LC.; van der Laak, JA.; van Ham, MA.; Bulten, J.; Massuger, LF. (Mar 2012). "Concurrent endometrial intraepithelial carcinoma (EIC) and serous ovarian cancer: can EIC be seen as the precursor lesion?". Int J Gynecol Cancer 22 (3): 457-64. doi:10.1097/IGC.0b013e3182434a81. PMID 22249577.
  12. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 1087-8. ISBN 0-7216-0187-1.
  13. ↑ URL: http://www.pathologyoutlines.com/uterus.html#endometrialcarc.
  14. ↑ URL: http://www.emedicine.com/med/topic2832.htm.
  15. ↑ Ayhan A, Taskiran C, Yuce K, Kucukali T (January 2003). "The prognostic value of nuclear grading and the revised FIGO grading of endometrial adenocarcinoma". Int. J. Gynecol. Pathol. 22 (1): 71–4. PMID 12496701.
  16. ↑ Tadrous, Paul.J. Diagnostic Criteria Handbook in Histopathology: A Surgical Pathology Vade Mecum (1st ed.). Wiley. pp. 240. ISBN 978-0470519035.
  17. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 1088. ISBN 0-7216-0187-1.
  18. ↑ http://www.emedicine.com/med/topic2832.htm
  19. ↑ Staging with groovy graphics (cancerfacts.com)
  20. ↑ URL: http://en.wikibooks.org/wiki/Radiation_Oncology/Endometrium/Staging. Accessed on: 2 May 2012.
  21. ↑ Nucci, Marisa R.; Oliva, Esther (2009). Gynecologic Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 239. ISBN 978-0443069208.
  22. ↑ 22.0 22.1 Kurman, RJ.; Norris, HJ. (Jun 1982). "Evaluation of criteria for distinguishing atypical endometrial hyperplasia from well-differentiated carcinoma.". Cancer 49 (12): 2547-59. PMID 7074572.
  23. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Endometrium_11protocol.pdf. Accessed on: 12 January 2012.
  24. ↑ URL: http://dictionary.reference.com/browse/dyskeratosis. Accessed on: 5 September 2011.
  25. ↑ Miranda, MC.; Mazur, MT. (May 1995). "Endometrial squamous metaplasia. An unusual response to progestin therapy of hyperplasia.". Arch Pathol Lab Med 119 (5): 458-60. PMID 7748076.
  26. ↑ Chinen, K.; Kamiyama, K.; Kinjo, T.; Arasaki, A.; Ihama, Y.; Hamada, T.; Iwamasa, T. (Sep 2004). "Morules in endometrial carcinoma and benign endometrial lesions differ from squamous differentiation tissue and are not infected with human papillomavirus.". J Clin Pathol 57 (9): 918-26. doi:10.1136/jcp.2004.017996. PMID 15333650.
  27. ↑ 27.0 27.1 Chiesa-Vottero, AG.; Malpica, A.; Deavers, MT.; Broaddus, R.; Nuovo, GJ.; Silva, EG. (Jul 2007). "Immunohistochemical overexpression of p16 and p53 in uterine serous carcinoma and ovarian high-grade serous carcinoma.". Int J Gynecol Pathol 26 (3): 328-33. doi:10.1097/01.pgp.0000235065.31301.3e. PMID 17581420.
  28. ↑ Shabani, N.; Mylonas, I.; Jeschke, U.; Thaqi, A.; Kuhn, C.; Puchner, T.; Friese, K.. "Expression of estrogen receptors alpha and beta, and progesterone receptors A and B in human mucinous carcinoma of the endometrium.". Anticancer Res 27 (4A): 2027-33. PMID 17649817.
  29. ↑ Yemelyanova, A.; Ji, H.; Shih, IeM.; Wang, TL.; Wu, LS.; Ronnett, BM. (Oct 2009). "Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases.". Am J Surg Pathol 33 (10): 1504-14. doi:10.1097/PAS.0b013e3181ac35f5. PMID 19623034.
  30. ↑ 30.0 30.1 Kounelis, S.; Kapranos, N.; Kouri, E.; Coppola, D.; Papadaki, H.; Jones, MW. (Apr 2000). "Immunohistochemical profile of endometrial adenocarcinoma: a study of 61 cases and review of the literature.". Mod Pathol 13 (4): 379-88. doi:10.1038/modpathol.3880062. PMID 10786803.
  31. ↑ Darvishian, F.; Hummer, AJ.; Thaler, HT.; Bhargava, R.; Linkov, I.; Asher, M.; Soslow, RA. (Dec 2004). "Serous endometrial cancers that mimic endometrioid adenocarcinomas: a clinicopathologic and immunohistochemical study of a group of problematic cases.". Am J Surg Pathol 28 (12): 1568-78. PMID 15577675.
  32. ↑ Alkushi, A.; Köbel, M.; Kalloger, SE.; Gilks, CB. (Jul 2010). "High-grade endometrial carcinoma: serous and grade 3 endometrioid carcinomas have different immunophenotypes and outcomes.". Int J Gynecol Pathol 29 (4): 343-50. doi:10.1097/PGP.0b013e3181cd6552. PMID 20567148.
  33. ↑ Horree, N.; Heintz, AP.; Sie-Go, DM.; van Diest, PJ. (2007). "p16 is consistently expressed in endometrial tubal metaplasia.". Cell Oncol 29 (1): 37-45. PMID 17429140.
  34. ↑ Bárcena, C.; Oliva, E. (Nov 2011). "WT1 expression in the female genital tract.". Adv Anat Pathol 18 (6): 454-65. doi:10.1097/PAP.0b013e318234aaed. PMID 21993272.
  35. ↑ Abeler, VM.; Vergote, IB.; Kjørstad, KE.; Tropé, CG. (Oct 1996). "Clear cell carcinoma of the endometrium. Prognosis and metastatic pattern.". Cancer 78 (8): 1740-7. PMID 8859187.
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 36.6 Offman, SL.; Longacre, TA. (Sep 2012). "Clear cell carcinoma of the female genital tract (not everything is as clear as it seems).". Adv Anat Pathol 19 (5): 296-312. doi:10.1097/PAP.0b013e31826663b1. PMID 22885379.
  37. ↑ Nucci, Marisa R.; Oliva, Esther (2009). Gynecologic Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 250. ISBN 978-0443069208.
  38. ↑ Fadare, O.; Liang, SX. (Apr 2012). "Diagnostic Utility of Hepatocyte Nuclear Factor 1-Beta Immunoreactivity in Endometrial Carcinomas: Lack of Specificity For Endometrial Clear Cell Carcinoma.". Appl Immunohistochem Mol Morphol. doi:10.1097/PAI.0b013e31824973d1. PMID 22495362.
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