Strong correlation between molecular changes in endometrial carcinomas and concomitant hyperplasia.

OBJECTIVE: Endometrial cancer (EC) results from the accumulation of numerous genetic abnormalities contributing to the progression from hyperplasia to EC. Information on these various genetic changes has been primarily derived from studying groups of either hyperplasias or cancers.We evaluated both hyperplastic and EC tissue obtained from the same surgical specimens for KRAS mutations, microsatellite instability (MSI), and mismatch repair gene methylation, and results were correlated between the paired hyperplastic tissue and EC. The aim was to determine if molecular alterations appearing in ECs might also be present in the premalignant (hyperplastic) region of the tumor. METHODS: One hundred ninety-seven cases of EC with associated hyperplasia were evaluated. DNA samples were studied using primer sets for KRAS gene codons 12/13 and for MSI utilizing the Bethesda panel. Methylation testing was performed on specimens that were microsatellite unstable using the MRC Holland SALSA MS-MLPA methylation-specific DNA detection kit. RESULTS: Forty-one (20.8%) of 197 cancers demonstrated a KRAS mutation, with 35 (85.4%) of 41 accompanying hyperplasias also containing a KRAS mutation. Forty-five cancers (22.8%) were microsatellite unstable, with 38 (84.4%) of 45 accompanying hyperplasias also demonstrating instability. Of the 45 microsatellite unstable cancers, 28 (62.2%) demonstrated methylation in both the cancer and the accompanying hyperplasia, whereas 9 pairs (20%) showed no methylation for either the cancer or hyperplasia. CONCLUSIONS: Approximately 95% of endometrial specimens demonstrated identical molecular findings regarding KRAS mutation and microsatellite stability in the paired cancer and hyperplastic tissue. The same methylation pattern was found in 82.2% of the studied paired samples. Our findings strongly suggest that the molecular changes of KRAS mutation, MSI, and methylation occur early in the neoplastic process. We propose that endometrial biopsies revealing only hyperplasia should be studied for these molecular alterations as an indicator of possible early carcinogenesis.

Rapid spontaneous regression of acute-onset vulvar intraepithelial neoplasia 3 in young women: a case series.

OBJECTIVE: Vulvar intraepithelial neoplasia 3 (VIN 3)/vulvar carcinoma in situ is currently treated by surgical excision, laser ablation, or topically with 5-fluorouracil or imiquimod. The rate of progression of untreated VIN 3/vulvar carcinoma in situ to invasive cancer is significant, although difficult to assess, because most patients undergo treatment. The peak incidence of invasive carcinoma of the vulva occurs in the sixth decade, which may indicate that human papillomavirus (HPV)-related preinvasive disease in the younger population has a lower progression rate. However, the risk of invasive disease cannot be disregarded. METHODS: This is a case series of complete spontaneous resolution of untreated VIN 3/vulvar carcinoma in situ in 5 healthy women aged 20 to 36 years from a single community gynecologic oncologist practice from 2006 to 2010. RESULTS: Complete spontaneous regression of acute VIN 3/vulvar carcinoma in situ was reported in 6 healthy young women aged 20 to 36 years. New sexual partners were reported in 2 of the 6 patients preceding the onset of vulvar lesions within 6 months. All patients were nonsmokers, healthy without known immunocompromise, and noted the acute onset of vulvar lesions. Vulvar intraepithelial neoplasia 3/vulvar carcinoma in situ was diagnosed on biopsy and confirmed on independent review. All lesions were multifocal in nature. Time to spontaneous regression was 6, 6, 8, 12, 18, and 20 weeks after initial biopsy. No patient received the HPV vaccine. Recurrence has not been noted in any of the patients within the follow-up period of 6 to 60 months. CONCLUSIONS: Short-term follow-up with conservative management of acute-onset VIN 3/vulvar carcinoma in situ in this young patient population correlates with similar treatment strategies for HPV-related cervical intraepithelial neoplasia of the cervix and may prevent disfigurement, pain, and complications associated with the current recommended therapeutic modalities. The timing of intervention for VIN 3/vulvar carcinoma in situ in the young population needs clarification. Future studies are in order.

Microsatellite instability and DNA methylation of endometrial tumors and clinical features in young women compared with older women.

INTRODUCTION: Molecular genetic changes in endometrial cancers are important to identify possible family cancer syndromes and thus, to facilitate appropriate screening. Most studies in this regard have focused primarily on young women. We have assayed cancers for microsatellite instability (MSI) and DNA methylation from a large group of patients younger than 50 years and a comparable group of older women. We obtained personal and medical histories of the patients and their family cancer histories. METHODS: The Bethesda panel of markers was used for the detection of MSI. Methylation status of mismatch repair genes was ascertained using the methylation-specific DNA detection kit SALSA MS-MLPA No. ME011. RESULTS: There were 101 patients younger than 50 years and 112 older women. The 2 age groups did not differ in the percentage of patients who were obese, carried a diagnosis of diabetes, or previously had another cancer. The younger patients were more likely to be nulliparous, whereas the older patients were more likely to have hypertension. Among the younger group, 21 (20.8%) tumors revealed MSI, and 13 (61.9%) of these were unmethylated. For the older women, 35 (31.2%) had MSI tumors, and only 6 (17.1%) of these were unmethylated. Young women with a family history of a hereditary nonpolyposis colorectal cancer-related cancer were more likely to have a tumor revealing MSI and no methylation, but family history was less helpful in older women in this regard. CONCLUSION: We did not find personal risk factors or a history of an additional cancer to be different between the 2 age groups. The combination of MSI testing and DNA methylation studies resulted in the identification of presumptive hereditary nonpolyposis colorectal cancer syndrome in approximately 13% of women with endometrial cancer presenting at age younger than 50 years and in approximately 5% of older women. Family history was more helpful with younger women than with older women.

Krukenberg tumor: metastasis of Meckel's diverticular adenocarcinoma to ovaries.

A 56-year-old female presented with abdominal pain, weight loss and fatigue. Computed tomography revealed an abdominopelvic mass and ascites. At surgery she had carcinomatosis and bilateral ovarian metastases arising from a cancer in a Meckel's diverticulum. Histology identified the primary to be a signet-ring cell adenocarcinoma within the Meckel's with ovarian metastases. This is the first report of a Krukenberg tumor from a Meckel's diverticulum. A discussion of malignancies within a Meckel's diverticulum is provided.