endometrial adenocarcinoma

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Definition: Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Most endometrial cancers are carcinomas (usually adenocarcinomas), meaning that they originate from the single layer of epithelial cells that line the endometrium and form the endometrial glands.

Endometrial carcinomas are traditionally divided into two types:

 Type 1: endometrial endometrioid carcinoma

• 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: endometrial serous carcinoma

• 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

Images

 https://twitter.com/dozing_dog/status/733527740435992576

Microscopy

The histopathology of endometrial cancers is highly diverse. There are many microscopic subtypes of endometrial carcinoma, including the common "endometrioid type", in which the cancer cells grow in patterns reminiscent of normal endometrium, and the far more aggressive "papillary serous carcinoma" and "clear cell endometrial carcinomas".

The most common finding is a well-differentiated endometrioid adenocarcinoma, which is composed of numerous, small, crowded glands with varying degrees of nuclear atypia, mitotic activity, and stratification. This often appears on a background of endometrial hyperplasia.

Frank adenocarcinoma may be distinguished from atypical hyperplasia by the finding of clear stromal invasion, or "back-to-back" glands which represent nondestructive replacement of the endometrial stroma by the cancer. With progression of the disease, the myometrium is infiltrated.

However, other subtypes of endometrial cancer exist and carry a less favorable diagnosis such as the "uterine papillary serous carcinoma" and the "clear cell carcinoma".

FIGO Staging

Endometrial carcinoma is surgically staged using the FIGO cancer staging system.

The 2010 FIGO staging system is as follows: Carcinoma of the Endometrium

 IA Tumor confined to the uterus, no or @<@ ½ myometrial invasion
 IB Tumor confined to the uterus, > ½ myometrial invasion
 II Tumor involves the uterus and the cervical stroma

• IIIA Tumor invades serosa or adnexa
• IIIB Vaginal and/or parametrial involvement
• IIIC1 Pelvic lymph node involvement
• IIIC2 Para-aortic lymph node involvement, with or without pelvic node involvement
• IVA Tumor invasion bladder mucosa and/or bowel mucosa
• IVB Distant metastases including abdominal metastases and/or inguinal lymph nodes

Pathogenesis

Some authorities have proposed that endometrial carcinomas be classified into two pathogenetic groups:

 Type I: These cancers occur most commonly in pre- and peri-menopausal women, often with a history of unopposed estrogen exposure and/or endometrial hyperplasia. They are often minimally invasive into the underlying uterine wall, are of the low-grade endometrioid type, and carry a good prognosis.

 Type II: These cancers occur in older, post-menopausal women, are more common in African-Americans, are not associated with increased exposure to estrogen, and carry a poorer prognosis. They include:

• the high-grade endometrioid cancer
• the uterine papillary serous carcinoma
• the uterine clear cell carcinoma.

FIGO grading of Endometrial Carcinoma

 G1: Highly differentiated (composed of glands and 5% of lesion is of solid growth pattern).
 G2: Moderately differentiated ( 6%-50% of lesion composed of solid sheets of cells).
 G3: Undifferentiated ( > 50% of lesion composed of solid sheets of cells).

Variants

 endometrial giant cell carcinoma (20588176)

Targeted therapy

 Molecular targets

• PI3K-AKT-mTOR
  • temsirolimus
  • everolimus

• EGFR
  • EGFRI: erlotinib

• HER2
  • trastuzumab

• tyrosine kinases
  • TKIs : sorafenib

• VEGF
  • anti-VEGF-A: bevacizumab
  • VEGF trap: aflibercept

• Focal adhesion kinase (FAK)
• Enhancer of zeste homolog 2 EZH2
• Delta-like ligand 4 (DLL4)

Open access reviews

 http://www.ncbi.nlm.nih.gov/pubmed/23886121
 http://www.ncbi.nlm.nih.gov/pubmed/23819113
 http://www.ncbi.nlm.nih.gov/pubmed/23346316
 http://www.ncbi.nlm.nih.gov/pubmed/23291663

See also

 type 3 intermediate filaments
 * vimentin (MIM.193060)
 * GFAP (MIM.137780) (mutations in Alexander disease MIM.203450)
 * peripherin

References

 Immunohistochemistry and HPV in situ hybridization in pathologic distinction between endocervical and endometrial adenocarcinoma: a comparative tissue microarray study of 76 tumors. Jones MW, Onisko A, Dabbs DJ, Elishaev E, Chiosea S, Bhargava R. Int J Gynecol Cancer. 2013 Feb;23(2):380-4. doi : 10.1097/IGC.0b013e31825cc8ee PMID: 23318908

 A panel of 3 markers including p16, ProExC, or HPV ISH is optimal for distinguishing between primary endometrial and endocervical adenocarcinomas. Kong CS, Beck AH, Longacre TA. Am J Surg Pathol. 2010 Jul;34(7):915-26. doi : 10.1097/PAS.0b013e3181e3291e PMID: 20534993

 Intermediate filaments in endometrial and endocervical carcinomas. The diagnostic utility of vimentin patterns. Dabbs DJ, Geisinger KR, Norris HT. Am J Surg Pathol. 1986 Aug;10(8):568-76. PMID: 2426982

 Significant variation in the assessment of cervical involvement in endometrial carcinoma: an interobserver variation study. McCluggage WG, Hirschowitz L, Wilson GE, Oliva E, Soslow RA, Zaino RJ. Am J Surg Pathol. 2011 Feb;35(2):289-94. PMID: 21263250

 Endometrial giant cell carcinoma: a case series and review of the spectrum of endometrial neoplasms containing giant cells. Mulligan AM, Plotkin A, Rouzbahman M, Soslow RA, Gilks CB, Clarke BA. Am J Surg Pathol. 2010 Aug;34(8):1132-8. PMID: 20588176

 Molecular pathology of endometrial carcinoma: practical aspects from the diagnostic and therapeutic viewpoints. D Llobet, J Pallares, A Yeramian, M Santacana, N Eritja, A Velasco, X Dolcet, and X Matias-Guiu. J Clin Pathol 2009; 62: 777-785. PMID: 18977806

 Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma. Garg K, Soslow RA. J Clin Pathol. 2009 Aug;62(8):679-84. PMID: 19638537

 Ellenson LH. Early molecular changes in endometrial cancer. Int J Gynecol Cancer. 2005 Mar-Apr;15(2):399-400. PMID: 15823134