Immunohistochemically detected p53 protein accumulation was an independent marker of shortened survival and was seen more often in familial than in sporadic carcinomas. Our findings also suggest a correlation between p53 protein accumulation and p53 gene mutation.

BACKGROUND The purpose of this investigation was to determine if there are pathobiologic differences between BRCA1‐related and BRCA2‐related hereditary breast cancer (HBC) and non‐HBC. METHODS On the basis of linkage to chromosomes 17q or 13q and/or the presence of ovarian and male breast cancer, HBC families were classified as either “BRCA1‐related” (26 families, 90 breast cancer pathology cases) or “Other” (26 families, 85 cases), in which most BRCA2 cases were likely to reside. Cases were compared with 187 predominantly non‐HBC cases. Tumors were assessed for histologic type, grade, and ploidy and S‐phase fraction by quantitative DNA flow cytometry. Clinical presentation and available follow‐up data were obtained. RESULTS BRCA1‐related and Other HBC patients each presented at lower stage (P = 0.003) and earlier age than non‐HBC patients (mean, 42.8 years and 47.1 years vs. 62.9 years, P < 0.0001). Compared with non‐HBC, invasive BRCA1‐related HBC had a lower diploidy rate (13% vs. 35%; P = 0.002), lower mean aneuploid DNA index (1.53 vs. 1.73; P = 0.002), and strikingly higher proliferation rates (mitotic grade 3; odds ratio [OR] = 4.42; P = 0.001; aneuploid mean S‐phase fraction 16.5% vs. 9.3%, P < 0.0001). Other HBC patients, including patients in two BRCA2‐linked families, had more tubular‐lobular group (TLG) carcinomas (OR = 2.56, P = 0.007). All trends were independent of age. A nonsignificant trend toward better crude survival in both HBC groups was age‐ and stage‐dependent. Compared with Other HBC, BRCA1‐related HBC patients had fewer recurrences (P = 0.013), a trend toward lower specific death rates, and fared no worse than breast cancer patients at large. Other HBC patients, despite neutral prognostic indicators, fared worse. CONCLUSIONS BRCA1‐related HBCs are more frequently aneuploid and have higher tumor cell proliferation rates compared with Other HBC. Despite these adverse prognostic features, BRCA1‐related HBC patients have paradoxically lower recurrence rates than Other HBC patients. The excess of TLG cancers in the “Other” HBC group may be associated with BRCA2 linkage. Cancer 1996; 697‐709.

Existing Roux-en-Y bile diversion procedures for duodenogastric reflux coupled with distal gastric resection or antrectomy and vagotomy have varied success due to interruption of the physiologic relationships between stomach and duodenum, the reduction of the gastric reservoir, the side effects of vagotomy, and the effect of the Roux limb on gastric emptying. A new bile diversion procedure, suprapapillary Roux-en-Y duodenojejunostomy, was studied, which eliminates the need for gastric resection to prevent jejunal ulcers by preserving duodenal inhibition of gastric acid secretion and the protective effects of duodenal secretion on the surrounding mucosa. Experimentally, the incidence of jejunal ulceration was significantly decreased by the preservation of the proximal duodenum. Clinically, bile diversion by suprapapillary Roux-en-Y duodenojejunostomy alleviates symptoms of duodenogastric reflux disease without being ulcerogenic (in the presence of normal gastric secretion) or prolonging gastric emptying.

Primary genetic factors are etiologic in at least 5-10% of patients with colon cancer. The polyposis syndromes (FPC) are easily identified examples because of the spectacular number of polyps. The hereditary nonpolyposis syndromes (HNPCC), although five times more common than FPC, are usually not recognized because they do not have such a distinctive clinical, premonitory genetic marker. Colorectal cancer expression was surveyed in 10 extended, thoroughly documented HNPCC kindreds. One hundred sixteen patients were found to have 183 colorectal cancers. Despite the striking family history, less than 5% were correctly treated by subtotal colectomy. This provided a unique opportunity to study the natural history. Five findings differed significantly (p less than 0.05) from patients with sporadic colon cancer: (1) mean age of initial colon cancer diagnosed was 45.6 years; (2) 69.1% of first colon cancers were located proximal to the splenic flexure of the colon; (3) 18.1% had synchronous colon cancer; (4) 24.2% had metachronous colon cancer develop with life table analysis showing the risk for a metachronous lesion at 10 years to be 40%; and (5) only 23.3% of cancers were located in the sigmoid colon or rectum. Based on this data, it is recommended that the family history of all patients with a newly diagnosed colon cancer be evaluated for evidence of this syndrome. If an autosomal dominant inheritance pattern emerges, an in-depth genetic investigation is indicated. When HNPCC is confirmed, the following recommendations apply: a subtotal abdominal colectomy is indicated at the time of the initial colon cancer because of the risk of synchronous and metachronous lesions. The rectum should be spared in favor of careful lifetime surveillance because of the proclivity for proximal colon cancer involvement. As yet unaffected members of a newly diagnosed HNPCC kindred who are in the "direct genetic line" should be cautioned that they are at 50% risk and must begin an intensive surveillance program beginning in the third decade with careful attention to the right colon. Patients from newly diagnosed HNPCC families who have had a previous conventional colectomy for colon cancer should, at the very least, enter an intensive surveillance program; a prophylactic completion subtotal colectomy should be considered for patients who are less than totally compliant.

Approximately 5 to 6 percent of the total colorectal cancer burden is accounted for by hereditary nonpolyposis colorectal cancer (HNPCC). Because clinical premonitory signs such as those seen in familial polyposis coli (FPC) are lacking, the clinician must recognize clinical findings and family history typical of HNPCC. The authors have described colorectal cancer expression from a survey of ten HNPCC kindreds. Kindred members with colorectal cancer differed significantly (P less than .05) from patients with sporadic colorectal cancer: 1) mean age of initial colon cancer diagnosis was 44.6 years; 2) 72.3 percent of first colon cancers were located in the right colon, and only 25 percent were in the sigmoid colon and rectum; 3) 18.1 percent had synchronous colon cancers; and 4) 24.2 percent developed metachronous colon cancer, with a risk for metachronous lesions in ten years of 40 percent. Affecteds and their first-degree relatives should undergo early intensive education and surveillance. In families with an early age of onset, colonoscopy should begin at age 25, and biannually thereafter, with fecal occult blood testing of the stool semiannually. Third-party carriers must become more responsive to the costly surveillance measures required for these otherwise healthy patients.

Melanin production by a medullary thyroid carcinoma (MTC) is reported and discussed. Immunohistochemically, the tumor cells contained calcitonin; by electron microscopy, they bore numerous, heterogeneous granules similar to those described previously in MTCs. One small focus of tumor was pigmented. Here, melanosomes in different stages of maturation were found in dendritic cells that ramified among granule‐bearing cells. The remarkable phenotypic divergence in this solitary, nongerm cell neoplasm is unusual but not so surprising in light of the APUD nature and neural crest origin of both the melanocyte and the thyroid C cell, which gives rise to MTC. The authors view the calcitonin and melanosome phenotypes as closely related tumor clones evolving from a common precursor neoplastic cell. This unique “experiment of nature” adds to the set of rare human tumors that make melanin “ectopically”.

We describe new pathologic findings in a hereditary nonpolyposis colorectal cancer family. Affected family members developed multiple small adenomas with right-sided predominance; many adenomas had an unusual appearance featuring slightly elevated lesions with adenomatous changes confined to the upper regions of the colonic crypts. We have adopted the previously established term "flat adenoma" for these lesions. This phenotype may be a morphologic marker for at least one subset of hereditary nonpolyposis colorectal cancer.

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