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.[2] Usually, when cells grow old or get damaged, they die, and new cells take their place.[2] Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should.[2] The buildup of extra cells often forms a mass of tissue called a growth or tumor.[2] These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.[3]
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.[4] Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.[5] 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. 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.[5]
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.[5] FGFR2 mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear.[4] 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.[6]
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.[7] 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.[5]
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. Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so.[8] An atypical hyperplasia is one with visible abnormalities in the nuclei. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia.[9] 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 p53, and develops into a serous carcinoma.[10]
References
- ↑ International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.
- ↑ 2.0 2.1 2.2 2.3 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.
- ↑ 4.0 4.1 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.
- ↑ 5.0 5.1 5.2 5.3 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.