Endometrial cancer
BMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d3954 (Published 06 July 2011) Cite this as: BMJ 2011;343:d3954All rapid responses
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Introduction:
Worldwide in 2008, 288,000 women were diagnosed with uterine cancer while the mortality rate from endometrial cancer was 1.7 to 2.4 per 100,000 women (1). Uterine cancer is the fourth most common gynecologic malignancy in Peninsular Malaysia (2). Most current update describes that in the United States 44,717 women were diagnosed with uterine cancer in 2010 and among them 8,402 women died from this deadly disease(3).We read the insightful clinical review article "Endometrial Cancer" and applauded the in-depth discussion on investigative procedures for symptomatic cases.
However,we are concerned that till date there is no screening test available for large scale screening and monitoring for endometrial cancer in asymptomatic average risk population. Therefore, there is an urgent need of a robust, non invasive, cost effective tool for large scale screening, early detection and prognostic monitoring of endometrial carcinoma.
Background:
Modern histopathological diagnostics for endometrial carcinoma includes microscopic cellular and tissue diagnostics, for demonstrating the presence of cancer and precancerous conditions.
Histopathological diagnostics is the gold standard test for endometrial carcinoma in every single step from screening to diagnosis and also in choosing a treatment plan and in monitoring the cancer patient for cure or relapse (4).
MOLECULAR TUMOR MARKERS or BIOMARKERS:
The term tumor marker is used in international literature to mean an organ-specific material of which an elevated amount is present in body fluids of cancer patients, whereas in similar body fluids it would appear in only low concentrations if at all in a healthy person or a person who did not have a tumor. Even though such biomarkers are generally seemed to be not specific, they have become an important tool in the early recognition that a tumor is present or have recurred.
In Hungary, tumor markers are not tested to the extent that international expectations would warrant (5).
Despite incredible advancement in cutting age molecular technologies seen in 21st century, endometrial cancer is perhaps the least studied and understood cancer affecting women. Unfortunately at present no screening tests or tests for early detection and monitoring for recurrence are available for endometrial cancer in women who belong to average risk group but have no symptoms.
microRNA EXPRESSION PROFILING IN ENDOMETRIAL CARCINOMA:
In the past few years, substantial progress has been made in the arenas of clinical trials and translational research. An area of recent interest is the relative expression patterns of microRNAs (miRNAs) in cancer and how these molecules contribute to oncogenesis.
MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) of approximately 22 bp that induce RNA interference with a complementary messenger RNA (mRNA) and act in silencing of mRNA. miRNAs are strongly associated with cancer development and those involved in carcinogenesis are classified into oncogenic miRNAs and tumor suppressor miRNAs (tumor suppressor miRs). Specific miRNAs are expressed in various tissues and changes in regulation of gene expression are thought to cause carcinogenesis. Thus, tissue-specific miRNAs may be biomarkers for cancer diagnosis and prognosis.(4) Earlier Fenshi Zhan et al., reported that MicroRNA-10b (miR-10b) has been positively involved in the migration of a number of tumor cells lineages (5).
In the recent past, we appreciated the clinical application of the MicroRNA signature classifier (MSC) Lung Cancer assay which significantly reduced the false positive rate and the potential side effects associated with repeated LDCT scans or other unnecessary invasive diagnostic follow-ups(6).
In endometrial cancer, miRNAs are associated with regulation of gene expression, epigenetic dysfunction and carcinogenesis. Thus, miRNAs are likely to have key roles in diagnosis, prognostic prediction. Laura Romero-Pérez et al., reported that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis (7).An exploratory study to find a single microRNA or a group of microRNAs which are specific to endometrial cancer tissue may solve this emerging problem.
ADAMs (A Disintegrin And Metalloproteinases) EXPRESSION PROFILING IN ENDOMETRIAL CARCINOMA:
ADAMs is a family of multifunctional proteases ( a disintegrin and metalloproteinases) that direct cellular processes across multiple organ systems via their intrinsic catalytic, cell adhesive and intracellular signaling properties and also promotes cell migration and invasion in several tumor cell lines (8-13).
The metalloprotease family of enzymes is integral to the process of tumor progression, from angiogenesis and cell migration to remodeling of the tumor microenvironment, invasion, and metastasis. In the recent past Sushan E Pories et al., reported that urinary matrix metalloproteinases (MMPs) and ADAM 12 could be detected in the urine of breast cancer patients and these urinary metalloproteinases could be used as biomarkers to predict breast cancer risk status (14). An analysis on ADAMs expression profiling may help us to find a co-biomarker for endometrial carcinoma.
References:
1. World cancer research fund international. Cancer facts and figures: Endometrial cancer rates. http://www.wcrf.org/cancer_statistics/cancer_facts/endometrial_cancer_ra... (Accessed on January 30, 2013).
2. http://www.makna.org.my/PDF/MalaysiaCancerStatistics.pdf
3. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2010 Incidence and Mortality Web-based Report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2013. http://www.cdc.gov/uscs.
4. http://www.cancer.org/cancer/endometrialcancer/detailedguide/endometrial...
5. http://www.iccp-portal.org/sites/default/files/plans/Hungary_National_Ca...
Control_Programme_English.pdf
6. MicroRNAs in endometrial cancer. (2013) Banno K1, Yanokura M, Kisu I, Yamagami W, Susumu N, Aoki D. Int J Clin Oncol. 2013 Apr;18(2):186-92. doi: 10.1007/s10147-013-0526-9. Epub 2013 Feb 5.
7. Laura Romero-Pérez, M Ángeles López-García et al.,ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma:(2013)Modern Pathology 26, 1514-1524 (November 2013) | doi:10.1038/modpathol.2013.93
8. Tanu Pramanik, Lecturer; Hj Abdul Halim Hj Mansar, Professor ; Narazah Mohd. Yusoff, Professor ; Jogenananda Pramanik, Professor : (January 14, 2014 ) Simple, cost effective, minimally invasive or non-invasive molecular screening test for lung cancer- A need of the hour! http://annals.org/article.aspx?articleid=1809422
9. Fenxi Zhang, Suhua Jing, Tongming Ren, Juntang Lin (2013) microRNA-10b promotes the migration of mouse bone marrow-derived mesenchymal stem cells and downregulates the expression of E-cadherin. Molecular Medicine Reports (Impact Factor: 1.17). 08/2013; DOI:10.3892/mmr.2013.1615
10. Lin Juntang, 1 Wang Congrui,2 Jogenananda Pramanik, et al.,(2004) Study on construction of cDNA libraries from rat normal liver and regeneration liver with smart technique; Indian J Clin Biochem. 2004 July; 19(2): 177–180. doi: 10.1007/BF02894281,PMCID: PMC3454212
11.Lin Juntang, Jogenananda Pramanik, Wang Congrui, Zhang Huiyong, Feng Huigen, Yang Baosheng, Li Yuchang, Xu Cunshuan (2004) Study on construction of cDNA library of the treated changliver cell and quality analysis. Indian Journal of Clinical Biochemistry 07/2004; 19(2):181-3.
12. Congrui Wang, Huiyong Zhang, Huigen Feng, Baosheng Yang, Jogenananda Pramanik, Zhikun Guo, Juntang Lin (2010)Molecular characterization and functional analysis of a protease-related protein in Chang-liver cells. BMB reports 05/2010; 43(5):375-81
13. Xin Yan, Juntang Lin, Venkata Ajay Narendra Talabattula, Carolin Mußmann, Fan Yang, Andreas Wree, Arndt Rolfs, Jiankai Luo : ADAM10 Negatively Regulates Neuronal Differentiation during Spinal Cord Development. PLoS ONE (Impact Factor: 3.73). 01/2014; 9(1):e84617. DOI:10.1371/journal.pone.0084617
14. Susan E. Pories, David Zurakowski,Roopali Roy et al., Urinary Metalloproteinases: Noninvasive Biomarkers for Breast Cancer Risk Assessment (2008) Cancer Epidemiol Biomarkers Prev May 2008 17; 1034: doi: 10.1158/1055-9965.EPI-07-0365.
Competing interests: Prof.Dr.J.Pramanik is also the Dean of International students affair in Caribbean Medical University School of Medicine,Curacao,Netherlands Antillies and Dr.Lin Juntang is also employed as Vice Dean in Xinxiang Medical University,Xinxiang City, China.
With ever increasing numbers of endometrial adenocarcinoma being
diagnosed, this is a timely clinical review.
We would like to point out the factual inaccuracies in the classification
of these tumours given in Box 2 of this clinical review. While Bokhman
proposed a model of endometrial carcinogenesis based on the premise that
there are two main pathogenetic mechanisms for the development of
endometrial adenocarcinoma, endometrial adenocarcinomas are usually
classified according to their histopathological type by the WHO or the
modified WHO/IsGYP classification as follows:
Endometrioid
Variant with squamous differentiation
Villoglandular variant
Secretory variant
Ciliated cell variant
Mucinous
Serous
Clear cell
Mixed cell carcinoma
Squamous cell carcinoma
Transitional carcinoma
Small cell carcinoma
Undifferentiated carcinoma
Carcinosarcoma
Bokhman's categorisation of endometrial adenocarcinomas as Type 1 and
Type 2 serves to highlight the main pathogenetic mechanisms underlying the
development of endometrial carcinomas. The Type 1 carcinomas are of
endometrioid type, arise in younger perimenopausal patients in a
background of endometrial hyperplasia with unopposed oestrogen
stimulation, and are usually indolent in their behaviour. Type 2
carcinomas, on the other hand, are prototypically of serous type, tend not
to be associated with unopposed oestrogen stimulation, arise in a
background of atrophic endometrium in older postmenopausal patients and
behave aggressively. Type 1 and Type 2 carcinomas have different
underlying genetic abnormalities.
In addition to endometrioid adenocarcinomas, Type 1 carcinomas
include mucinous, and secretory subtypes of endometrial adenocarcinoma -
mucinous adenocarcinomas are NOT type 2 carcinomas as indicated in box 2
of this publication.
Ref
1.http://info.cancerresearchuk.org/cancerstats/types/uterus/incidence/
2.Bokhman JV (1983) Two pathogenetic types of endometrial carcinomas.
Gynecologic Oncology 15:10-17.
3.Tavassoli FA, Devilee P (eds). World Health Organization
Classification of Tumours. Pathology and Genetics of Tumours of the Breast
and Female Genital Organs. Lyon: IARC Press, 2003
4.Sherman ME, Sturgeon S, Brinton LA, Potischman N, Kurman RJ, Berman
ML, et al (1997) Risk factors and hormone levels in patients with serous
and endometrioid uterine carcinomas. Modern Pathology 10:963-968.
Competing interests: No competing interests
I read with interest the clinical review on endometrial cancer from
Saso et al 1. Endometrial cancer is the most common gynaecological cancer
in the USA and as the authors have pointed out the incidence in the UK is
increasing 1. In my opinion, the authors and other specialists in this
field have failed to recognise the wider health implications associated
with endometrial cancer. Most institutions approach this with blinkered
eyes and manage a cancer that we normally cure. However, endometrial
cancer is often only a side effect of a much more problematic systemic
disorder that involves obesity, diabetes, hypertension, and depression.
The authors have acknowledged this but in their review they have failed to
detail the importance of addressing co-morbidity during routine
management.
In my opinion, all women with endometrial cancer must have their co-morbidity investigated. Often this is of greater importance than their
cancer. Diabetic and hypertensive control can be poor and the presentation
of cancer is an opportunity to address this. Many women with the disease
are depressed and psychological support is essential if lifestyle changes
can be corrected. Women with a Body Mass Index of 40 or greater should be
referred to a bariatric team. Bariatric surgery may help the management of
endometrial cancer. Although there is no evidence to support this directly
it is clear that bariatric support improves the co-morbidity associated
with endometrial cancer.
In summary, those involved with the management of endometrial cancer
must ensure that the multidisciplinary team involves Bariatric,
Hypertensive, Diabetic, and Psychological groups where appropriate.
Thomas Ind MB BS MD FRCOG
Consultant Gynaecological Cancer Surgeon
Royal Marsden & St George's Hospitals, London, UK
1 - Saso S, Chatterjee J, Georgiou E, Ditri AM, Smith JR, Ghaem-
Maghani S. Endometrial Cancer. BMJ 2011; 343: 84 - 89.
Competing interests: No competing interests
Why is there still a rising incidence of endometrial cancer in
postmenopausal women in the developed world when the use of HRT should be
falling? 1
The International Agency for Research on Cancer (IARC) listed
exogenous estrogens and progestins as highest level Group 1 carcinogens in
2007.2 In one study the use of estrogen replacement therapy (ERT) for
5 years or more increased the risk of endometrial cancer 22 times.3
Widespread use of ERT caused a huge epidemic of endometrial cancer in the
1970s and 1980s. The resultant switch to combined exogenous
progestin/estrogen (CHRT), similar or identical to combined hormonal
contraceptives, caused the epidemic of breast cancer. Combined progestins
and oestrogens also increase the risk of endometrial cancer (possibly
unless taken continuously),4 but longer progestin use causes more breast
cancer.
Progestins are used to treat menorrhagia but can also increase
endometrial arteriolar development and cause heavy bleeding from another
wise atrophic endometrium.5 No wonder hysterectomy is needed so often
before the menopause. Weight gain is a common reason for discontinuing
progestins and residual obesity from taking progestins plus treatment of
any breast cancers with tamoxifen may also be important reasons for
increases in postmenopausal endometrial cancer.
It is misleading to believe that taking carcinogenic progestins for one year as contraceptives are protective. These findings are likely to be
due to faulty epidemiology because so few women now have never taken progestins or oestrogens.6 Also smoking carcinogenic cigarettes is likely to be protective of anything but smokers may be thinner or die from
lung cancer instead of endometrial cancer.
The largest increases and decreases in breast and endometrial cancers
have coincided with changes in hormone use but these lessons have still
not been learned it seems. www.harmfromhormones.co.uk
1 Saso S, Chatterjee J, Georgiou E, Ditri AM, Smith JR, Ghaem-
Maghami S. Endometrial cancer. BMJ. 2011 Jul 6;343:d3954. doi:
10.1136/bmj.d3954.
2 IARC Working Group on the Evaluation of Carcinogenic Risks to
Humans. Combined estrogen-progestogen contraceptives and combined estrogen
-progestogen menopausal therapy. IARC Monogr Eval Carcinog Risks Hum.
2007;91:1-528.
3 Jick SS, Walker AM, Jick H. Estrogens, progesterone, and
endometrial cancer. Epidemiology1993;4:20-4.
4 Jaakkola S, Lyytinen HK, Dyba T, Ylikorkala O, Pukkala E.
Endometrial cancer associated with various forms of postmenopausal hormone
therapy: a case control study. Int J Cancer. 2011 Apr 1;128(7):1644-51.
doi: 10.1002/ijc.25762. Epub 2011 Jan 12.
5 Grant ECG. Relation between headaches from oral contraceptives and
development of endometrial arterioles. BMJ 1968 Aug 17;3(5615):402-5.
6 Grant EC. Re: breast cancer risk in relation to the interval
between menopause and starting hormone therapy. J Natl Cancer Inst. 2011
Jul 6;103(13):1069. Epub 2011 Jun 23.
Competing interests: No competing interests
The review by Srdjan Saso et al. (1) on diagnosis and treatment of
endometrial cancer is very interesting. However, I have questions about
the diagnosis, the treatment and the staging of endometrial cancers:
1. Histology of endometrial lesions confirms the diagnosis of
endometrial carcinoma. However, could the hysteroscopy with fluid and
curettage for an endometrial sample disseminate cancerous cells into the
myometrium, the fallopian tubes and then in the peritoneal cavity?
2. Is an oriented biopsy preferable?
3. The question of staging by pelvic lymphadenectomy is discussed in
early stages of endometrial carcinoma as its morbidity is not negligible.
What is the place of sentinel lymph node biopsy as a less invasive
procedure suggested by other studies (2)?
4. What is the place of PET-CT in the staging of endometrial
carcinoma?
5. Are there still many indications for laparotomic management of
endometrial cancers? Indeed, laparotomy is a more historical approach
compared to laparoscopy, a minimally invasive and safe technique (3)
in the treatment and the staging of uterine carcinoma.
References
1.Saso S, Chatterjee J, Georgiou E, Ditri AM, Smith JR, Ghaem-Maghami
S. Endometrial cancer. BMJ. 2011 Jul 6;343:d3954. doi: 10.1136/bmj.d3954.
2.Abu-Rustum NR, Khoury-Collado F, Pandit-Taskar N, Soslow RA, Dao F,
Sonoda Y, Levine DA, Brown CL, Chi DS, Barakat RR, Gemignani ML. Sentinel
lymph node mapping for grade 1 endometrial cancer: is it the answer to the
surgical staging dilemma? Gynecol Oncol. 2009;113:163-9.
3.Alouini S, Rida K, Mathevet P. Cervical cancer complicating
pregnancy: implications of laparoscopic lymphadenectomy. Gynecol Oncol.
2008;108:472-7.
Competing interests: No competing interests
The authors of this article rightly underline that early referral of
women with symptoms suspicious of endometrial carcinoma is indicated.
However they advise referring all pre-menopausal women over the age of 40
with intermenstrual bleeding urgently to a gynaecologist for transvaginal
ultrasound and endometrial biopsy.
UK population studies have shown the self-reported incidence of inter
-menstrual bleedng to be 17%(1). This would result in unmanagebly high
referral levels. The NICE referral guidelines(2) suggest that the
intermenstrual bleeding has to be persistant in the absence of other risk
factors for endometrial carcinoma - 3 months or more. This at least would
seem more viable if a satisfactory level of service is to be maintained.
There is increasing pressure on GPs to keep referrals down in order
to maintain the financial viablity of the NHS.
Any referral guidelines/advice for primary care need to be clear about
the implications of their advice for General Practice and secondary care.
(1)Shapley M, Jordan K, Croft PR; An epidemiological survey of
symptoms of menstrual loss in the community. Br J Gen Pract. 2004
May;54(502):359-63
(2)Referral for suspected cancer, NICE Clinical Guideline (2005)
Competing interests: No competing interests
Did Saso et al (1) mean to advise non-specialists that all "40-50 year
old women with intermenstrual bleeding should be referred, within two
weeks, to a gynaecologist for an urgent Pipelle biopsy and transvaginal
ultrasound?" UK gynaecology departments would come to a grinding halt with
many women over-investigated at a prohibitive cost to the NHS. NICE
guidance states 'an urgent referral should be considered in a patient with
persistent intermenstrual bleeding (IMB) and a negative pelvic
examination' (2) and was further supported by their "Heavy Menstrual Bleeding
guidance3 that 'persistent IMB requires investigation to exclude
malignancy."
Where a referral is indicated, this does not necessarily need to be
to a local hospital gynaecologist. Many parts of the UK now has efficient
primary care and community services providing the necessary expertise to
undertake urgent endometrial assessment - this is both cost effective and
well evaluated as it brings "care closer to home."
Diana Mansour
Consultant in Community Gynaecology and Reproductive Health Care,
Newcastle Hospitals Community Health,
Newcastle upon Tyne
NE1 6ND
Competing interest - none
References
1. Saso S, Chatterjee J, Georgiou E, Ditri AM, Smith JR, Ghaem-
Maghami S. Endometrial cancer. BMJ. 2011 Jul 6;343:d3954. doi:
10.1136/bmj.d3954
2. National Institute for Health and Clinical Excellence. Referral
Guidelines for Suspected Cancer. London: NICE; 2005
http://www.nice.org.uk/nicemedia/live/10968/29814/29814.pdf accessed on 9
July 2011
3. National Institute for Health and Clinical Excellence. Heavy
Menstrual Bleeding. London: NICE; 2007
http://www.nice.org.uk/nicemedia/live/11002/30401/30401.pdf accessed on 9
July 2011
4. National Primary Care Research and Development Centre. Care closer
to home project: evaluation of national demonstration sites
http://www.medicine.manchester.ac.uk/primarycare/npcrdc-
archive/archive/ProjectDetail.cfm/ID/172.htm accessed 9 July 2011
Competing interests: No competing interests
Re: Endometrial cancer
A randomized clinical trial showed that in women with low-risk endometrial cancer undergoing minimally invasive robotic hysterectomy, blood loss, post-operative pain intensity, consumption of analgesics, post-operative symptoms, length of hospital stay, time to meet discharge criteria, did not differ significantly from women operated abdominally.
Only social functioning was in favor of robotic hysterectomy.
Reference
https://ijgc.bmj.com/content/29/4/721
Competing interests: No competing interests