Uterine cancer pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Pathophysiology
Pathophysiology
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Endometrial cancer forms when there are errors in normal endometrial cell growth.[3] Usually, when cells grow old or get damaged, they die, and new cells take their place.[3] Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should.[3] The buildup of extra cells often forms a mass of tissue called a growth or tumor.[3] These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.[4]
In 10–20% of endometrial cancers, mostly Grade 3 (the highest histologic grade), mutations are found in a tumor suppressor gene, commonly p53 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.[5] Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.[6] The p53 pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of p53 is overexpressed, the cancer tends to be particularly aggressive.[5] P53 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.[6]
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.[5] Beta-catenin mutations are commonly found in endometrial cancers with squamous cells.[6] FGFR2 mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear.[5] 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.[7]
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.[8] Mutations in tumor suppressor genes are common in Type II endometrial cancer.[1] PIK3CA is commonly mutated in both Type I and Type II cancers.[2] In women with Lynch syndrome-associated endometrial cancer, microsatellite instability is common.[6]
Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasias can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia.[9] Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so.[10] An atypical hyperplasia is one with visible abnormalities in the nuclei. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia.[11] Mutations in the KRAS gene can cause endometrial hyperplasia and therefore Type I endometrial cancer.[5] Endometrial hyperplasia typically occurs after the age of 40.[12] Endometrial glandular dysplasia occurs with an overexpression of p53, and develops into a serous carcinoma.[13]
References
- ↑ 1.0 1.1
- ↑ 2.0 2.1
- ↑ 3.0 3.1 3.2 3.3 Kong A, Johnson N, Kitchener HC, Lawrie TA (2012). "Adjuvant radiotherapy for stage I endometrial cancer". Cochrane Database Syst Rev. 4: CD003916. doi:10.1002/14651858.CD003916.pub4. PMC 4164955. PMID 22513918.
- ↑ What You Need To Know: Endometrial Cancer".NCI. National Cancer Institute. Retrieved 6 August 2014.
- ↑ 5.0 5.1 5.2 5.3 5.4 Thaker, PH; Sood, AK. "Molecular Oncology in Gynecologic Cancer". In Lentz, GM; Lobo, RA; Gershenson, DM; Katz, VL. Comprehensive Gynecology (6th ed.). Mosby. ISBN 978-0-323-06986-1.
- ↑ 6.0 6.1 6.2 6.3 Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C; et al. (2013). "Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Ann Oncol. 24 Suppl 6: vi33–8. doi:10.1093/annonc/mdt353. PMID 24078661.
- ↑ Mani, RS (September 2014). "The emerging role of speckle-type POZ protein (SPOP) in cancer development". Drug Discovery Today. 19 (9): 1498–1502. doi:10.1016/j.drudis.2014.07.009. PMID 25058385.
A recent exome-sequencing study revealed that 8% of serious endometrial cancers and 9% of clear cell endometrial cancers have SPOP mutations
- ↑ International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.
- ↑
- ↑ Luo, L; Luo, B; Zheng, Y; Zhang, H; Li, J; Sidell, N (5 June 2013). "Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia". The Cochrane database of systematic reviews. 6: CD009458. doi:10.1002/14651858.CD009458.pub2. PMID 23737032.
- ↑ Hoffman, BL; Schorge, JO; Schaffer, JI; Halvorson, LM; Bradshaw, KD; Cunningham, FG, eds. (2012). "Endometrial Cancer". Williams Gynecology (2nd ed.). McGraw-Hill. p. 820. ISBN 978-0-07-171672-7.
- ↑
- ↑ Saso, S; Chatterjee, J; Georgiou, E; Ditri, AM; Smith, JR; Ghaem-Maghami, S (2011). "Endometrial cancer". BMJ. 343: d3954–d3954. doi:10.1136/bmj.d3954. PMID 21734165.