Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1.

Twelve to 15% of sporadic colorectal cancers display defective DNA mismatch repair (MMR), manifested as microsatellite instability (MSI). In this group of cancers, promoter hypermethylation of the MMR gene hMLH1 is strongly associated with, and believed to be the cause of, MSI. A subset of colorectal neoplastic lesions arising in inflammatory bowel disease (IBD) is also characterized by MSI. We wished to determine whether hMLH1 hypermethylation was associated with diminished hMLH1 protein expression and MSI in IBD neoplasms. We studied 148 patients with IBD neoplasms, defined as carcinoma or dysplasia occurring in patients with ulcerative colitis or Crohn's disease. MSI was evaluated using multiplex fluorescent PCR to amplify loci D2S123, BAT-25, BAT-26, D5S346, and D17S250 in all cases. Lesions were characterized as high-frequency MSI (MSI-H) if they manifested instability at two or more loci, low-frequency MSI (MSI-L) if unstable at only one locus, or MS-stable (MSS) if showing no instability at any loci. Methylation-specific PCR was performed to determine the methylation status of the hMLH1 promoter region. hMLH1 protein expression was also evaluated by immunohistochemistry. Thirteen (9%) of 148 neoplasms arising in IBD were MSI-H, comprising 11 carcinomas and 2 dysplastic lesions. Sixteen additional lesions (11%) were MSI-L, comprising 11 carcinomas and 5 dysplastic lesions. The remaining 118 neoplasms (80%) were MSS. Six (46%) of 13 MSI-H, 1 (6%) of 16 MSI-L, and 4 (15%) of 27 MSS lesions showed hMLH1 hypermethylation (P = 0.013). Diminished hMLH1 protein expression in neoplastic cell nuclei relative to surrounding normal cell nuclei was demonstrated immunohistochemically in four of four (100%) hypermethylated lesions tested. In IBD neoplasia, hMLH1 promoter hypermethylation occurs frequently in the setting of MSI, particularly MSI-H. Furthermore, hMLH1 hypermethylation and MSI are strongly associated with diminished hMLH1 protein expression in IBD neoplasms. These findings suggest that hMLH1 hypermethylation causes defective DNA MMR in at least a subset of IBD neoplasms.

Low prevalence of the APC I1307K sequence in Jewish and non-Jewish patients with inflammatory bowel disease.

A germline sequence alteration at codon 1307 of the APC gene (I1307K) has been reported in 6-7% of the Ashkenazi Jewish population in the United States. This alteration is believed to predispose the APC gene to a secondary mutation at the same locus, resulting in an increased risk of colorectal carcinoma. There is an increased risk of colorectal carcinoma in patients with inflammatory bowel disease (IBD), a relatively large proportion of whom are Ashkenazi Jews. We therefore sought to determine whether the I1307K sequence variant occurred in the germline DNA of IBD patients. To our surprise, we found this sequence in only two of 267 patients with IBD (0.7%), occurring in only 1.5% of Jewish IBD patients. The I1307K sequence variant was not found in 67 patients with esophageal cancer, 53 patients with gastric carcinoma (13 MSI-H and 44 MSI-negative), or ten patients with sporadic MSI-H colon cancer. These findings suggest that the I1307K sequence is relatively rare in the germline of Jewish as well as non-Jewish IBD patients. It does not appear to contribute to the increased colorectal cancer risk present in these patients.

Epithelioid cells in myoid hamartoma of the breast: a potential diagnostic pitfall for core biopsies.

OBJECTIVE: We report six cases of myoid hamartoma of the breast, a rare benign lesion in which the characteristic smooth muscle cells may have epithelioid histology. We emphasize the importance of radiographic correlation and immunohistochemical studies to diagnosis, particularly on stereotactic core biopsies, to avoid potential confusion with infiltrating lobular carcinoma. DESIGN: Case studies. Prospective and retrospective analysis of six cases, including stereotactic biopsy of two. SETTING: Academic medical center-based pathology practice. PATIENTS: Six postmenopausal women, aged 50 to 59 years, with palpable or nonpalpable mammographically evident breast masses. RESULTS: All the lesions were radiographically well circumscribed, most showing heterogeneous radiodensity. Histologically variable amounts of glandular, fibrous, and adipose tissue were admixed with smooth muscle cells, which occasionally had prominent epithelioid features. All the lesions' myoid cells stained for smooth muscle markers as well as steroid receptor proteins. Stereotactic core biopsy was diagnostic in one case, making excision unnecessary. CONCLUSIONS: With proper radiographic correlation and immunohistochemical confirmation, myoid hamartoma can be confidently diagnosed even on the limited tissue samples yielded by stereotactic core biopsy.