Endometrial cancer pathophysiology

Endometrial cancer
A histologic view of an endometrial adenocarcinoma showing many abnormal nuclei

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Monalisa Dmello, M.B,B.S., M.D. [2]

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Overview

Development of endometrial cancer is the result of multiple genetic mutations. Genes involved in the pathogenesis of endometrial cancer include TP53, KRAS, and PTEN. The pathophysiology of endometrial cancer depends on the histological subtype.

Pathogenesis

• Endometrial cancer forms when there are errors in normal endometrial cell growth.
• Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasia can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia. Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so.
• Mutations in the KRAS gene can cause endometrial hyperplasia and therefore type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of TP53, and develops into a serous carcinoma (type II endometrial cancer).
• Endometrial cancer frequently metastasizes to the ovaries and fallopian tubes when the cancer is located in the upper part of the uterus and the cervix when the cancer is in the lower part of the uterus.
• The cancer usually first spreads into the myometrium and the serosa, then into other reproductive and pelvic structures. When the lymphatic system is involved, the pelvic lymph nodes and para-aortic lymph nodes are usually first to become involved, but in no specific pattern, unlike cervical cancer.
• More distant metastases are spread by the blood and often occur in the lungs, as well as the liver, brain, and bone.

Genetics

Mutations found in Type I and Type II endometrial cancers Gene mutated Mutation type Type I prevalence Type II prevalence ARID1A point mutation 40% unknown CTNNB1 point mutation 14–44% unknown FGFR2 point mutation 16% unknown KRAS point mutation 10–20% unknown PIK3R1 point mutation 43% unknown TP53 point mutation 10–20% 90% PTEN point mutation 37–61% unknown MLH1 epigenetic silencing 30% unknown RASSF1A epigenetic silencing 48% unknown SPRY2 epigenetic silencing 20% unknown PPP2R1A point mutation unknown 17–41% CDH1 loss of heterozygosity unknown 80–90% CDKN2A loss of heterozygosity and/or epigenetic silencing 20% 40% PIK3CA (oncogene) amplification 24–39% 20–30% PIK3R1 (oncogene) point mutation unknown 12% STK15 (oncogene) amplification unknown 60% CCNE1 (oncogene) amplification unknown 55% ERBB2 (oncogene) amplification unknown 30% CCND1 (oncogene) amplification unknown 26%

Genes involved in pathogenesis of endometrial cancer involve:

• In 10–20% of endometrial cancers, mostly grade 3 (the highest histologic grade), mutations are found in a tumor suppressor gene, commonly TP53 or PTEN.
• In 20% of endometrial hyperplasias and 50% of endometrioid cancers, PTEN suffers a loss-of-function mutation or a null mutation, making it less effective or completely ineffective. Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.
• The TP53 pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of TP53 is overexpressed, the cancer tends to be particularly aggressive. TP53 mutations and chromosome instability are associated with serous carcinomas, which tend to resemble ovarian and fallopian carcinomas. Serous carcinomas are thought to develop from endometrial intraepithelial carcinoma.
• PTEN and p27 loss of function mutations are associated with a good prognosis, particularly in obese women. The Her2/neu oncogene, which indicates a poor prognosis, is expressed in 20% of endometrioid and serous carcinomas. CTNNB1 (beta-catenin; a transcription gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear. Beta-catenin mutations are commonly found in endometrial cancers with squamous cells.
• FGFR2 mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear.
• SPOP is another tumor suppressor gene found to be mutated in some cases of endometrial cancer: 9% of clear cell endometrial carcinomas and 8% of serous endometrial carcinomas have mutations in this gene.
• Type I and type II cancers (explained below) tend to have different mutations involved. ARID1A, which often carries a point mutation in type I endometrial cancer, is also mutated in 26% of clear cell carcinomas of the endometrium, and 18% of serous carcinomas. Epigenetic silencing and point mutations of several genes are commonly found in type I endometrial cancer.
• Mutations in tumor suppressor genes are common in type II endometrial cancer. PIK3CA is commonly mutated in both type I and type II cancers. In women with Lynch syndrome-associated endometrial cancer, microsatellite instability is common.
• The genetic mutations most commonly associated with endometrioid adenocarcinoma are in the genes PTEN, a tumor suppressor; PIK3CA, a kinase; KRAS, a GTPase that functions in signal transduction; and CTNNB1, involved in adhesion and cell signaling. The CTNNB1 (beta-catenin) gene is most commonly mutated in the squamous subtype of endometrioid adenocarcinoma.
• The genetic mutations seen in serous carcinoma are chromosomal instability and mutations in TP53, an important tumor suppressor gene.
• The p53 cell signaling system is not active in endometrial clear cell carcinoma.

Microscopic Pathology

On microscopic histopathological analysis, endometrial cancer is characterized by:

1. Endometrioid (most common; 75%–80%)

• Ciliated adenocarcinoma
• Secretory adenocarcinoma
• Papillary or villoglandular
• Adenocarcinoma with squamous differentiation

• Adenoacanthoma
• Adenosquamous (Adenosquamous tumors contain malignant elements of both glandular and squamous epithelium)

2. Uterine papillary serous (<10%)

3. Mucinous (1%)

4. Clear cell (4%)

5. Squamous cell (<1%)

6. Mixed (10%)

7. Undifferentiated

Characteristic/Parameter	Type I endometrial cancers	Type II endometrial cancers
Time of onset	Occur most commonly before and around the time of menopause	Occur in older, post-menopausal
Race	White	Black
Grade of tumor	Low-grade	High-grade
Invasive	Minimally invasive into the underlying uterine wall myometrium	Deep invasion into the underlying myometrium
Estrogen	Dependent	Independent
Type	Endometrioid	Uterine papillary serous carcinoma, clear cell carcinoma
Prognosis.	Good	Poor

Endometrioid adenocarcinoma

• In endometrioid adenocarcinoma, the cancer cells grow in patterns reminiscent of normal endometrium, with many new glands formed from columnar epithelium with abnormal nuclei.
• Low-grade endometrioid adenocarcinomas have well differentiated cells, have not invaded the myometrium, and are seen alongside endometrial hyperplasia. The tumor's glands form very close together, without the stromal tissue that normally separates them.
• Higher-grade endometrioid adenocarcinomas have less well-differentiated cells, have more solid sheets of tumor cells no longer organized into glands, and are associated with an atrophied endometrium. There are several subtypes of endometrioid adenocarcinoma with similar prognoses, including villoglandular, secretory, and ciliated cell variants. There is also a subtype characterized by squamous differentiation. Some endometrioid adenocarcinomas have foci of mucinous carcinoma.

Serous carcinoma

• Serous endometrial carcinoma is aggressive and often invades the myometrium and metastasizes within the peritoneum seen as omental cake or the lymphatic system.
• Histologically, it appears with many atypical nuclei, papillary structures, and, in contrast to endometrioid adenocarcinomas, rounded cells instead of columnar cells. Roughly 30% of endometrial serous carcinomas also have psammoma bodies.
• Serous carcinomas spread differently than most other endometrial cancers; they can spread outside the uterus without invading the myometrium.

Clear cell carcinoma

• Clear cell carcinoma, histologically, it is characterized by the features common to all clear cells: the eponymous clear cytoplasm when H&E stained and visible, distinct cell membranes.

Mucinous carcinoma

• Mucinous endometrial carcinomas, typically have well-differentiated columnar cells organized into glands with the characteristic mucin in the cytoplasm.
• Mucinous carcinomas must be differentiated from cervical adenocarcinoma.

Mixed or undifferentiated carcinoma

• Histologically, these tumors show sheets of identical epithelial cells with no identifiable pattern.

Other carcinomas

• Non-metastatic squamous cell carcinoma and transitional cell carcinoma are very rare in the endometrium.
• For primary squamous cell carcinoma of the endometrium (PSCCE) to be diagnosed, there must be no other primary cancer in the endometrium or cervix and it must not be connected to the cervical epithelium. The common genetic causes remain uncharacterized.
• Histologically, TCCE resembles endometrioid carcinoma and is distinct from other transitional cell carcinomas.

References

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