abstract: Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤ 70 years.

Blogger's Note: age >50 yrs will be at issue

Gynecol Oncol. 2012 Feb 1.

Abstract

OBJECTIVE:

Lynch syndrome (LS) is a hereditary syndrome that predisposes to multiple malignancies including endometrial cancer (EC). We aimed to evaluate a diagnostic strategy for LS based on routine analysis of microsatellite instability (MSI) and immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in tumor tissue of all newly diagnosed EC patients ≤70years.

METHODS:

Consecutive EC patients ≤70years were included prospectively in eight Dutch centers. EC specimens were analyzed for MSI, IHC of four MMR proteins, MMR gene methylation status and BRAF-mutations. Tumors were classified as; 1) likely to be caused by LS, 2) sporadic MSI-H, or 3) microsatellite stable (MSS).

RESULTS:

Tumor specimens of 179 patients (median age 61years, IQR 57-66) were analyzed. In our study 92% of included patients were over 50 years of age. Eleven EC patients were found likely to have LS (6%; 95% CI 3-11%), including 1 patient suspected of an MLH1, 2 of an MSH2, 6 of an MSH6 and 2 of a PMS2 gene defect. Germline mutation analyses revealed 7 MMR gene germline mutations. Ten patients likely to have LS (92%) were older than 50years. In addition, 31 sporadic MSI-H tumors with MLH1 promoter hypermethylation (17%; 95% CI 13-24%) were identified.

CONCLUSIONS:

Molecular screening for LS in patients with EC diagnosed≤70years, leads to identification of a profile likely to have LS in 6% of cases. New screening guidelines for LS are needed, including recommendations for EC patients older than 50years of age.

open access: Archives of Pathology & Laboratory Medicine Online - Squamous Lesions of the Ovary

Defining:
Coelomic metaplasia is defined as some of the cells of the peritoneum (also known as the abdominal wall) developing into endometrial cells instead of normal peritoneal cells. Studies of pelvic peritoneal tissue from women undergoing laparotomy suggests that before endometriosis has become established in the peritoneum, there might be a metaplastic change by peritoneal mesothelial cells into endometrial glandular cells. In this article, we will discuss how coelomic metaplasia causes endometriosis.

Defining: Metaplasia:
....When cells are faced with physiological or pathological stresses, they respond by adapting in any of several ways, one of which is metaplasia......

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Article:

"When encountered in the ovary, a diagnosis of squamous cell carcinoma can pose a challenging differential diagnosis. Although squamous cell carcinoma is a frequent entity encountered in the female genital tract, it is rare in primary form in the ovary and, hence, when identified therein, it is incumbent on the pathologist to explore other potential entities or primary sites. Primary squamous cell carcinoma has been identified in the ovary, however, and as such, demonstrates the vast histologic heterogeneity that may be seen in ovarian lesions. This is a review of the literature pertaining to ovarian squamous lesions, including a number of diagnostic pearls."

"COMMENT

Although squamous elements in the ovary are relatively common, squamous cell carcinoma is distinctly rare, especially in pure form. Debate continues on the pathogenesis of primary squamous cell carcinoma without an associated dermoid. Most authors suggest squamous cell carcinoma in association with endometriosis arises from neoplastic transformation of preexisting endometrial epithelium.7,11 This may be in keeping with the varied metaplasia and neoplasia that may be seen within endometrial glands. Cases of pure primary squamous cell carcinoma of the ovary are an even greater etiologic conundrum; some authors suggest that these lesions may arise because of seeding from occult premalignant or fully malignant squamous lesions located outside the ovary.7,11 These lesions may also serve as examples of the broad potential of coelomic metaplasia."

abstract: Synchronous gynecologic malignancy and preliminary results of Lynch syndrome (Korean women)

METHODS:

Thirty six women with synchronous gynecologic tumors of endometrial and ovarian cancer were identified among patients being treated at our institution.

CONCLUSION:

In this study, the frequency of Lynch syndrome associated immunohistochemical staining (MLH1, MSH2, and MSH6) group was estimated as 9% (3/32) among Korean women with synchronous gynecologic tumors.

open access: Jan 2012 - Assessing the malignant potential of ovarian inclusion cysts in postmenopausal women within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a prospective cohort study

Objective  To evaluate the malignant potential of ultrasound-detected ovarian inclusion cysts in the development of ovarian cancer (OC) in postmenopausal women.

Design  Prospective cohort study.

Setting  UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Population  Postmenopausal women.

Conclusions  Postmenopausal women with ultrasound-detected inclusion cysts do not seem to be at increased risk of ovarian or breast/endometrial (hormone-dependent) cancers.

see also 

Table 1.   Details of ovarian cancers detected in the cohort of women with inclusion cysts in year 1 

Table 2.   Details of ovarian cancers detected in the cohort of women with normal scans in year 1 

Table 3.   Relative risks of developing gynaecological cancers in women with inclusion cysts

Incidence and Factors Associated with Synchronous Ovarian and Endometrial Cancer: A Population-Based Case–control Study

abstract: Mitochondrial DNA genotyping reveals synchronous nature of simultaneously detected endometrial and ovarian cancers.

Abstract

Simultaneous independent primary tumors of the female genital tract occur in 1-2% of gynecological cancer patients, 50-70% of which are synchronous tumors of the endometrium and ovary. 

Guidelines for determining the nature of simultaneously detected tumors, based on surgical and histopathological findings, are often ambiguous and may require further molecular analyses.

Such approach is necessary to indicate correct prognosis and hence treatment.

We here demonstrate how mitochondrial DNA sequencing may provide a cheap and useful tool to contribute to indisputably recognize the synchronous nature of simultaneously detected endometrial and ovarian carcinomas. We further confirm our findings by means of Comparative Genomic Hybridization array analysis, which strengthens the informative potential of mitochondrial DNA genotyping in diagnosing synchrony.

Lynch Syndrome Hereditary Cancers Public Awareness Day | Fight Colorectal Cancer

Increased Risk of Cancer

If a parent carries a Lynch mutation there is a 50-50 chance that their child will inherit Lynch syndrome with

• 60 to 80 percent increased lifetime risk of colorectal cancer.
• 40 to 70 percent increased risk of endometrial cancer (cancer of the uterus lining).
• 13 percent increased risk for stomach cancer
• 12 percent increased risk of ovarian cancer.
• smaller, but significant risk of small intestine, urinary tract, heptobiliary (liver, gall bladder and bile ducts), skin, and brain cancers.
• Some families may also have increased risk for breast cancer.

Note: 
Lynch Syndrome is also noted for multiple primary cancers (different cancers in one person)

abstract: Mutation and Loss of Expression of ARID1A in Uterine Low-grade Endometrioid Carcinoma

Abstract:

ARID1A is a recently identified tumor suppressor gene that is mutated in approximately 50% of ovarian clear cell and 30% of ovarian endometrioid carcinomas. The mutation is associated with loss of protein expression as assessed by immunohistochemistry.

In this study, we evaluated ARID1A immunoreactivity in a wide variety of carcinomas to determine the prevalence of ARID1A inactivation in carcinomas. Mutational analysis of ARID1A was carried out in selected cases. Immunoreactivity was not detected (corresponding to inactivation or mutation of ARID1A) in 36 (3.6%) of 995 tumors.

Uterine low-grade endometrioid carcinomas showed a relatively high-frequency loss of ARID1A expression, as 15 (26%) of 58 cases were negative. The other tumor that had a relatively high-frequency loss of ARID1A expression was gastric carcinoma (11%). Mutational analysis showed 10 (40%) of 25 uterine endometrioid carcinomas; none of 12 uterine serous carcinomas and none of 56 ovarian serous and mucinous carcinomas harbored somatic ARID1A mutations. All mutations in endometrioid carcinomas were nonsense or insertion/deletion mutations, and tumors with ARID1A mutations showed complete loss or clonal loss of ARID1A expression.

In conclusion, this study is the first large-scale analysis of a wide variety of carcinomas showing that uterine low-grade endometrioid carcinoma is the predominant tumor type harboring ARID1A mutations and frequent loss of ARID1A expression. These findings suggest that the molecular pathogenesis of low-grade uterine endometrioid carcinoma is similar to that of ovarian low-grade endometrioid and clear cell carcinoma, tumors that have previously been shown to have a high-frequency loss of expression and mutation of ARID1A.

full free access: Absence of microsatellite instability in mucinous carcinomas of the breast (Lynch Syndrome)

Note: some key excerpt; see also Supplemental Tables 1-4

"Microsatellite instability (MSI) is a form of genetic instability that results from defects in DNA mismatch repair. MSI is reported to be rare in unselected breast cancers, however it is a common feature in subsets of colorectal, ovarian and endometrial cancers. In these anatomical sites, MSI-high carcinomas often display a mucinous histology. The aim of this study was to determine whether mucinous carcinomas of the breast would more frequently display MSI-high than invasive ductal carcinomas of no special type (IDC-NSTs). The expression of four MSI markers (i.e. MSH2, MSH6, MLH1 and PMS2) was immunohistochemically assessed in 35 mucinous breast carcinomas and 35 histological grade- and oestrogen receptor (ER) status-matched IDC-NSTs, and in a series of 245 invasive breast cancers...........
........
Subsets of colorectal [24], gastric [31], pancreatic [31], ovarian [32] and endometrial tumours [22,31,33], and particularly those occurring in the hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome [31], are characterised by microsatellite instability. Interestingly, however, MSI-H appears to be vanishingly rare in breast cancer [21,34]. Likewise, breast cancers displaying an MSI-L status are remarkably rare, whereas in tumours from other anatomical sites, such as colorectal, endometrial or ovarian cancers [27], this phenomenon is not as uncommon. Of note, in some anatomical sites (e.g. colorectal and ovarian), tumours displaying microsatellite instability often display a mucinous histology [32,35,36]. However, the prevalence of MSI in mucinous carcinomas of the breast has not yet been systematically addressed........
...........All 35 pure mucinous carcinomas of the breast analysed were positive for MLH1 and MSH6 as determined by IHC, and 33 out of 35 (94.2%) and 32 out of 34 cases (94.1%) showed expression of MSH2 and PMS2, respectively (Table 2 and Figure 1)............cont'd

abstract: CA 125 normalization with chemotherapy is independently predictive of survival in advanced endometrial cancer

Abstract

OBJECTIVE: Changes in CA 125 with chemotherapy predict outcome for epithelial ovarian cancer. There is no such data for advanced endometrial cancer.
CONCLUSION: As with epithelial ovarian cancer, changes in CA 125 are highly predictive of outcome for advanced, chemotherapy treated endometrial cancer.

Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study : The Lancet Oncology

Interpretation

EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.

Does the time interval between first and last birth influence the risk of endometrial and ovarian cancer?

CONCLUSION: Our findings suggest that the risk of endometrial cancer is significantly decreased for women having at least a difference of 10 years between their first and last birth. Ovarian cancer does not seem to be influenced by the time interval between first and last birth.

Prognostic value of microsatellite instability (MSI) and PTEN expression in women with endometrial cancer: results from studies of the NCIC Clinical Trials Group (NCIC CTG)

Abstract

AIM: The impact of PTEN status and microsatellite instability (MSI) on the prognosis of women with endometrial cancer is controversial. The aim of this study was to investigate MSI and PTEN expression in two patient populations using data from NCIC CTG studies.
METHODS: Archival paraffin embedded tumour from women with endometrial cancer enrolled in NCIC CTG studies: EN5 (stage I/II) and IND 126, 148 and 160 (advanced/recurrent disease) were examined for MSI using BAT25/26 and for PTEN expression using immunohistochemistry. PTEN and MSI status were correlated with clinicopathologic variables and survival using data from NCIC CTG trial databases.
RESULTS: PTEN and MSI results were available from 128 and 163 patients, respectively. MSI+ tumours were more common in women enrolled in EN5 compared to the IND studies (p=0.01). PTEN negative tumours were associated with improved survival in both univariate (hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.32-0.94; p=0.03) and multivariate (adjusted HR 0.54, 95% CI 0.30-0.96; p=0.03) analyses in women enrolled in IND studies. Microsatellite stable tumours were associated with an improved prognosis in univariate (HR 0.18, 95% CI 0.06-0.51; p<0.0001)>
CONCLUSIONS: PTEN negative tumours in women with advanced disease are associated with improved survival. MSI+ tumours are more common in early stage disease and in this group of women are associated with a worse prognosis

Menopause, hormone replacement and gynaecological cancers -- Menopause International

Note: abstract, full access via subscription ($$$)

Reviews

Menopause, hormone replacement and gynaecological cancers

Lynsey Hinds and John Price
Belfast City Hospital, Northern Ireland
Correspondence: Dr Lynsey Hinds, 1 Strawhill Manor, Donaghcloney, Belfast BT66 7GH Northern Ireland. Email: hindslynsey@hotmail.co.uk
 
Approximately 18,000 women are diagnosed with a gynaecological cancer in the UK each year. Predisposing risk factors for some of these gynaecological cancers include an early menarche/late menopause and hormone replacement therapy (HRT). Furthermore, treatment of gynaecological malignancies often induces an iatrogenic menopause, which may be more severe than a natural onset. HRT is an extremely effective treatment that may dramatically improve physical and psychological symptoms and ultimately quality of life in patients with cancer. However, the safety of using HRT in patients with gynaecological cancer is a controversial issue and not entirely clear. The main concern is the theoretical risk of the stimulation of residual cancer cells by estrogen replacement. The review of the evidence in this article found that for most gynaecological cancers this hypothesis was not proven. No study to date has found HRT to have a detrimental effect on survival in patients with early stage endometrial cancer, epithelial ovarian cancer, cervical cancer and vulval tumours. HRT is only an absolute contraindication in low-grade endometrial stromal sarcomas and is best avoided in granulosa cell ovarian tumours. Therefore, HRT should not be withheld in the majority of patients with gynaecological cancer. If quality of life is being adversely affected by symptoms of the menopause, then patients with cancer should be counselled regarding the known risks and benefits of HRT to enable them to make an informed decision on their treatment.

A prospective study of dietary acrylamide intake and the risk of breast, endometrial, and ovarian cancers — Cancer Epidemiology, Biomarkers & Prevention

WHO website: What is acrylamide?

Abstract

Background
Acrylamide is a probable human carcinogen formed during cooking of many common foods. Epidemiological studies of acrylamide and breast cancer risk have been null; however, positive associations with ovarian and endometrial cancers have been reported. We studied acrylamide intake and risk of breast, endometrial, and ovarian cancers in a prospective cohort study.

Methods
We assessed acrylamide intake among 88,672 women in the Nurses' Health Study using food frequency questionnaires administered every four years. Between 1980 and 2006 we identified 6301 cases of invasive breast cancer, 484 cases of invasive endometrial adenocarcinoma, and 416 cases of epithelial ovarian cancer. We used Cox proportional hazards models to study the association between acrylamide and cancer risk.

Results
We found no association between acrylamide intake and breast cancer overall or according to estrogen and progesterone receptor status. We found an increased risk of endometrial cancer among high acrylamide consumers (adjusted relative risk [RR] for highest versus lowest quintile=1.41, 95% CI: 1.01-1.97, p-value for trend=0.03). We observed a non-significant suggestion of increased risk for ovarian cancer overall (RR 1.25, CI: 0.88-1.77, p-trend=0.12), with a significantly increased risk for serous tumors (RR 1.58, CI: 0.99-2.52, p-trend=0.04). Associations did not differ by smoking status.

Conclusions
We observed no association between acrylamide and breast cancer. Risk of endometrial cancer and possibly ovarian cancer was greater among high acrylamide consumers.

Impact
This is the second prospective study to report positive associations with endometrial and ovarian cancers. These associations should be further evaluated to inform public health policy.

abstract: Hormone prevention strategies for breast, endometrial and ovarian cancers

"Prospective, randomized trials, designed to control for all known variables, are mandatory to fully assess the potential for hormonal chemoprevention in breast, endometrial and ovarian cancers."

Characteristics and prognosis of coexisting adnexa malignancy with endometrial cancer: a single institution review of 51 cases

CONCLUSION:
Our results showed that OS and PFS of synchronous primary ovarian cancer in patients with endometrial cancer is better than those with ovarian metastasis patients. Pre- and intra-operative, intensive and careful assessment, and strict and continuous postoperative surveillance should pay attention to the endometrial cancer patients who preserved ovary for having possibility of coexisting occult ovarian lesions.

Personal history of breast cancer as a significant risk factor for endometrial serous carcinoma in women aged 55 years old or younger

Note: suggestive of Lynch Syndrome (unresolved connection between breast cancer/Lynch Syndrome??)

Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma

Note: this issue is important as early-age diagnoses in Lynch Syndrome is common

"Approximately one quarter of women diagnosed with Lynch syndrome-associated CRC (colorectal cancer) developed EC within 10 years. This supports the sentinel cancer concept and suggests that active and early management is important for these women."

abstract: The inherited genetics of ovarian and endometrial cancer

"Endometrial and epithelial ovarian cancers are the fourth and fifth most common cancers in women in developed countries, after breast, lung, and colorectal cancer. In the United States alone, in 2008 there were about 40000 new diagnoses of endometrial cancer and 7500 disease-related deaths. For ovarian cancer, there were about 22000 new diagnoses and 15000 deaths over the same period. The purpose of this article is to review the recent developments in the inherited genetics of ovarian and endometrial cancer, with particular attention to recent progress in identifying common low-penetrance susceptibility genes and their clinical implications."