Loss of Mismatch Repair Protein Expression in Unselected Endometrial Adenocarcinoma Precursor Lesions.

OBJECTIVE: The benefit of evaluating the precursor of endometrial carcinoma, endometrial hyperplasia (intraepithelial neoplasia [EIN]), for loss of mismatch repair (MMR) protein expression and Lynch syndrome has yet to be determined. The present study aims to establish the incidence and type of loss of MMR protein expression in unselected premalignant lesions of endometrial adenocarcinoma, as well as the agreement of immunohistochemical staining in pretreatment endometrial biopsy (EMB) specimens with subsequent uterine resections. METHODS: A retrospective review identified 112 endometrial biopsies meeting criteria for endometrial EIN. Slides made from tissue microarray blocks were evaluated using antibodies against MLH1, PMS2, MSH2, and MSH6. Cases with a deficit in MLH1 were evaluated for gene promoter hypermethylation by polymerase chain reaction analysis. Fifty-four subsequent hysterectomy specimens were retrieved and assessed for MMR protein expression. RESULTS: Of the 112 endometrial biopsies with EIN, 4.5% (5/112) exhibited loss of MMR protein expression. The majority (4/5) demonstrated a deficit of MLH1, of which all exhibited inactivation via promoter hypermethylation. A single case displayed an absence of MSH6. Age was not significantly associated with MMR deficiency. There was no significant association between MMR status in the EMB and a subsequent diagnosis of cancer. Immunohistochemical staining in all successive hysterectomy cases was concordant with the pattern observed in the EMB specimen. CONCLUSIONS: Sporadic hypermethylation of MLH1 seems to be the primary mechanism underlying defective MMR protein expression in EIN. Among our cohort, only 1 patient (<1%) had a mutation suggestive of a hereditary inheritance. Hence, the utility of evaluating EIN for MMR protein expression as a screen for Lynch syndrome is limited, regardless of age.

Lynch Syndrome in patients with clear cell and endometrioid cancers of the ovary.

OBJECTIVE: Patients with Lynch Syndrome are at an increased risk for a variety of malignancies, including ovarian cancer. Ovarian cancers associated with Lynch Syndrome are predominantly clear cell or endometrioid in histology. Lynch Syndrome is characterized by germline mutations in mismatch repair (MMR) genes. The current study aims to assess the prevalence of loss of MMR expression in patients with endometrioid and clear cell ovarian carcinoma. METHODS: A retrospective review identified 90 patients with endometrioid and/or clear cell carcinomas. Slides made from tumor tissue microarray blocks were evaluated using immunohistochemical stains with antibodies against MLH1, PMS2, MSH2, and MSH6. Statistical analysis was performed. RESULTS: Seven of the 90 cases (7.8%) had loss of MMR expression. The mean age of patients with loss of MMR expression (47 years) was significantly younger than those with retained MMR expression (p=0.014). Loss of MMR expression was present in 20% of patients under the age of 53 with clear cell or endometrioid cancers. Genetic studies found that 3 of the 5 patients with loss of MMR expression carried mutations consistent with Lynch Syndrome; acquired hypermethylation of MLH1 was noted in one patient. Six of 7 patients (86%) whose tumors lacked MMR expression had synchronous or metachronous primary malignancies, a significantly greater prevalence than those with retained MMR expression (p<0.001). CONCLUSION: Patients under the age of 53 with clear cell or endometrioid ovarian carcinomas are at a clinically significant risk for loss of MMR expression and Lynch Syndrome; routine screening with immunohistochemical staining should be considered.

Survival of endometrial cancer patients with lymphatic invasion and deficient mismatch repair expression.

OBJECTIVE: This study examines patients under the age of 70 with endometrial cancer and lymphatic invasion or lymph node metastases. Survival of patients with loss of tumor mismatch repair expression is compared to survival of patients with normal mismatch repair expression. METHODS: This is a retrospective review of patients treated from 1998-2009 for carcinoma of the endometrium. All patients with lymphatic invasion, including lymph node metastases, had immunohistochemical staining of the primary tumor for loss of expression of the mismatch repair genes MLH1, PMS2, MSH6, and MSH2. Overall survival and disease specific survival were compared using Kaplan-Meier plots. RESULTS: Sixty-six patients were identified for inclusion; 26 demonstrated loss of mismatch repair expression and 40 demonstrated normal mismatch repair expression. Overall survival and disease specific survival were significantly better in the group with defective mismatch repair expression. Subgroup analysis of FIGO stage 3C patients also showed significantly better survival in patients with deficient mismatch repair expression. CONCLUSION: For patients with endometrial cancer and lymphatic invasion, patients demonstrating loss of mismatch repair expression in the primary tumor appear to have a significantly better survival than patients with normal mismatch repair expression. Further investigation appears warranted to examine a possible role of mismatch repair expression as a prognostic marker for high risk patients with endometrial cancer.

Clinical and pathologic features of young endometrial cancer patients with loss of mismatch repair expression.

OBJECTIVE: This study examines premenopausal and early menopause patients in a unique population with endometrial cancer and loss of mismatch repair (MMR) gene expression. The purpose is to compare clinical and pathologic differences in patients with loss of expression (LOE) to those with normal expression (NE). METHODS: Endometrial cancer patients under age 60 in-between 1998 and 2008 were identified from a single tumor registry. Clinical and pathologic data were abstracted from records. Staining for expression of MSH6, MSH2, MLH1, and PMS2 were performed on archived tissue blocks. Statistical analysis was performed. RESULTS: 158 patients were analyzed; 58% Asian, 34% Pacific Islander, and 8% Caucasian. 31 demonstrated LOE of at least one MMR gene; 127 retained NE. 50% Caucasian, 21.9% Asian, and 12.5% Pacific Island populations had LOE of one or more MMR genes. LOE was found to have a higher incidence of Grade III (p=0.0013) and stage 3-4 tumors (p=0.0079), mean depth of myometrial invasion (p=0.0019), lymphovascular space invasion (p=0.0020), nodal metastases (p=0.0157), and a lower incidence of Grade I (p=0.0020) and stage 1A tumors (p=0.0085). LOE had a significantly lower mean BMI (p=0.0001). 35% of patients in the NE vs zero in the LOE group had a BMI greater than 40. CONCLUSION: Younger patients with LOE endometrial cancer appear to represent a clinically significant subgroup of patients without features characteristically found in classic type 1 endometrial cancer generally demonstrating lower BMI and tumors associated with poor prognostic characteristics. It is unclear if the distinctive ethnicity found in Hawaii has a significant impact on outcome. Further investigation is necessary to identify appropriate treatment strategies.

Hereditary diffuse gastric cancer associated with E-cadherin germline mutation: a case report.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominate cancer syndrome that leads to an increased risk of developing invasive diffuse type (signet ring cell) gastric carcinoma. Approximately 30% of HDGC cases are caused by a germline mutation involving the E-cadherin (CDH1) gene. Those with the CDH1 mutation have an 80% and 60% cumulative lifetime risk of developing diffuse type gastric carcinoma and lobular breast carcinoma respectively. Due to the focal nature of early diffuse type gastric carcinoma, identifying early lesions with surveillance endoscopy is limited. As a result, elective risk-reducing total gastrectomy is currently recommended. In this report, the clinical, intraoperative, and pathologic work-up is reviewed regarding a patient with known CDH1 germline mutation.

Outcomes for patients with T1 squamous cell cancer of the vulva undergoing sentinel node biopsy.

OBJECTIVE: This retrospective review was undertaken to evaluate survival in patients with T1 squamous cell carcinoma of the vulva treated with radical local excision and sentinel node dissection. METHODS: Patients with T1 cancers underwent pre-operative lymphoscintigraphy and sentinel lymph node dissection using technetium sulfur colloid and isosulfan blue dye. The primary tumor was removed with radical local excision. Patients with negative sentinel nodes did not receive any additional treatment. Survival was calculated using life table analysis. RESULTS: There were 21 patients who underwent 27 sentinel node dissections. Three patients were found to have positive sentinel nodes. At a median follow-up of 4.6 years, two patients have died of cancer, and three patients have died of intercurrent illness. None of the patients with negative sentinel nodes has died of cancer. There were no groin or distant recurrences in patients with negative sentinel nodes. Three-year disease-free survival for all patients and for patients with negative sentinel nodes were 90% and 100% respectively. CONCLUSION: The survival for patients with early vulvar cancer treated with sentinel node dissection and radical local excision appears excellent.