No abstract

Peutz-Jeghers syndrome is caused by germline mutations in the LKB1/STK11 gene. Peutz-Jeghers syndrome is associated with an increased risk of developing intestinal and extraintestinal cancers, including pancreatic, lung, and breast carcinomas. LKB1 gene inactivation has recently been demonstrated in a subset of sporadic pancreatic and lung carcinomas. The role of the LKB1 gene in sporadic breast carcinomas remains unclear, though recent studies suggest inactivation only within papillary carcinomas. Using a commercially available polyclonal antibody that has been shown to mirror LKB1 genetic status in gastrointestinal and pulmonary carcinomas, the authors performed IHC on a large series of breast cancers using tissue microarrays (TMAs). All abnormal TMA results were confirmed using whole sections; specifically, whole sections from the donor blocks of lesions demonstrating diminished or absent LKB1 protein expression on TMA were evaluated to compare labeling of the lesion with that of the surrounding normal breast. In all cases, normal breast epithelium demonstrated strong cytoplasmic labeling (providing an internal positive control), whereas the stroma was nonreactive. Luminal cells typically labeled more strongly than myoepithelial cells. Among 70 invasive ductal carcinomas, 3 (4.3%) showed complete loss of LKB1 labeling, whereas 6 others (8.6%) showed diminished labeling. Of the eight intraductal carcinoma lesions adjacent to these invasive carcinomas, one (12.5%) showed complete loss of LKB1 labeling and one other (12.5%) showed diminished labeling; these results were identical to those of the adjacent invasive carcinomas. One of 10 (10%) hematogenous metastases of mammary carcinoma showed loss of LKB1 labeling. Nine of the 10 invasive carcinomas and both of the ductal carcinoma in situ (DCIS) cases showing loss of or diminished LKB1 expression were of high grade. In contrast, all 13 pure nonpapillary DCIS lesions, all 5 invasive lobular carcinomas and 3 accompanying lobular carcinoma in situ lesions, all 7 papillary DCIS lesions, and all 3 papillomas evaluated showed intact LKB1 labeling. Therefore, although frequent methylation of the LKB1 gene has been reported in papillary carcinomas of the breast, the authors did not find loss of protein expression in these lesions. Instead, it was found that loss of LKB1 protein expression occurs in a subset of high-grade in situ and invasive mammary carcinomas. The authors found LKB1 gene methylation in several of these invasive carcinomas. Given recent Western blot results indicating that diminished LKB1 expression in breast carcinomas correlates with shorter relapse-free survival, LKB1 IHC merits evaluation as a potential prognostic marker for breast carcinoma.

Most types of sporadic gastrointestinal (GI) polyps vastly outnumber their syndromic counterparts. In contrast, the incidence of sporadic Peutz-Jeghers polyps (PJP) is unknown. We examined all potential PJP seen at our hospital over a 22-year (y) period to assess the incidence of sporadic PJP. The pathology database of a large hospital was searched for "Peutz-Jeghers polyp(s)," yielding 121 polyps from 38 patients. The polyps were reviewed by 3 pathologists to confirm the diagnosis. Clinical information to confirm or refute a diagnosis of Peutz-Jeghers syndrome (PJS) was collected. Of the 102 polyps included after histologic review, 94 polyps arose in patients meeting the World Health Organization criteria for PJS. These PJS polyps were eliminated from further analysis. Clinical information was obtained for the remaining 8 patients with potential "sporadic" PJP (1 to 50 y; mean=14 y; median=4 y). Of the 8 potential sporadic PJP, only 3 polyps from 3 patients had unequivocal PJP histologic features, all from the small intestine. All 3 patients had clinical histories suggesting syndromic PJP although they did not meet World Health Organization criteria, that is, 2 developed pancreatic cancer, 1 had bilateral "ovarian cystic masses" and a glomus tympanicum tumor, and 1 had strong family history of GI malignancies. The 5 remaining patients each had a colonic polyp with features suggestive, but not definitely diagnostic of, PJP. In these cases, prolapse lesions could not be excluded. One patient had a history of high-grade dysplasia in a tubulovillous adenoma in the colon at 53 years, but no family cancer history. Another had a family GI cancer history. Another had a history of pituitary adenoma at age 39, and the last had ductal breast carcinoma diagnosed 4 years before the discovery of the polyp. Our findings suggest that if sporadic PJP exist, they are extremely rare. Moreover, our data suggest that individuals with a single PJP may have a cumulative lifetime risk of cancer similar to those with the syndrome.

Sessile serrated adenomas (SSAs) show serrations typical of hyperplastic polyps but display architectural differences and lack traditional dysplasia. SSAs with foci of low- (LGD) or high-grade dysplasia (HGD) or early invasive carcinoma are seldom biopsied and, thus, are not well studied. Immunohistochemical analysis for MLH1, MSH2, MSH6, and PMS2 (mismatch repair gene products) was performed on colon biopsy specimens from 11 patients (age range, 54-87 years; 4 men and 7 women) showing SSA with LGD (n = 1), HGD (n = 5), or focal invasive carcinoma (n = 5). All 11 cases showed intact nuclear staining for MSH2 and MSH6 in the SSA component; in foci of LGD, HGD, or carcinoma; and in background normal mucosa. In contrast, there was tandem loss of MLH1 and PMS2 in zones of LGD (1/1) or HGD (3/5) and early carcinoma (2/4; with concordant loss in associated HGD) but retention in SSA areas (11/11) and normal mucosa (11/11). No patient was known to have hereditary nonpolyposis colorectal cancer/Lynch syndrome. This study offers additional strong evidence that SSA is truly a precursor to at least a subset of sporadic microsatellite-unstable colorectal cancer.

Invasive colorectal carcinomas (CRCs) with invasion confined to the lamina propria (LP) [intramucosal carcinoma (IMC)] lack access to lymphatics and therefore have no potential for metastases and local intervention (usually polypectomy) should be adequate treatment. For this reason, they are classified as "Tis" in the TNM system. It is believed that carcinomas invading the submucosa with unfavorable histology (tumors at/near the margin, and/or vascular invasion, and/or poor differentiation) require additional intervention after polypectomy, whereas those with favorable histology can be safely treated endoscopically. However, there are few data on poorly differentiated (PD) carcinomas showing invasion confined to the LP. Polypectomy is theoretically curative but in practice this has not been well demonstrated. Thus, the clinicopathologic features of 15 cases of PD CRCs with invasion limited to the LP on initial biopsies were studied to determine the best course of management for this rare subset of carcinomas. A computer search and histologic review of cases seen at Johns Hopkins Hospital was performed. Fifteen cases of PD CRC with invasion limited to the LP were identified. The clinicopathologic features of these tumors were reviewed. All 15 cases showed PD IMC with single cells infiltrating only the LP. Patients were 38 to 79 years (median, 62) of age with a male predominance (M:F=4:1). Three cases had signet ring cell differentiation, 1 had focal small cell features, and another had focal squamous differentiation. Fourteen of the cases were associated with background adenomas or adenomalike lesions including: 7 involving tubulovillous or villous adenomas, 6 involving tubular adenomas, 1 involving dysplasia associated with chronic inflammatory bowel disease. Nine of the lesions had surrounding high-grade dysplasia. One case showed no background dysplasia or adenoma. One patient was lost to follow-up and the remaining 14 were followed for 1 to 96 months (mean, 21.3 mo; median, 13 mo). Seven patients had no residual disease on follow-up colonoscopy, and no resection was performed. The remaining 7 patients were treated with partial colectomy (6) or low anterior resection (1), and of these, 5 had no infiltrating carcinoma and negative lymph nodes. One patient had a separate large colorectal (T3) carcinoma with 8/10 positive regional lymph nodes; the IMC seen on biopsy was presumably a metastasis as it was unassociated with an in situ component. Finally, the resected rectum from which an IMC had been previously detected had no residual invasive carcinoma, but the anal skin was involved by Paget disease. Thus, of the 15 cases of PD CRCs limited to the LP, 1 was a metastasis from a separate CRC and another had associated Paget disease of the anal skin. As such, even in the setting of PD carcinomas, no metastatic disease was seen arising from any of the cases that were confirmed as early primary lesions. These preliminary findings suggest that patients with isolated intramucosal PD CRCs may be managed endoscopically.