Henry T. Lynch

Hereditary nonpolyposis colorectal cancer (Lynch syndrome): An updated review

Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Aldred Warthins description of Family G a century ago. The phenotype features an excess of early onset colorectal carcinoma (CRC) with a propensity to involve the proximal colon, and a variety of extracolonic cancers, particularly carcinoma of the endometrium, ovary, stomach, small bowel, ureter, and renal pelvis. The recent discovery that HNPCC patients carry germline mutations in DNA mismatch repair genes has engendered great interest in the syndrome.

Pathologic features of endometrial carcinoma associated with HNPCC: A comparison with sporadic endometrial carcinoma

Endometrial carcinoma is a common malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC). Like colon carcinoma, endometrial carcinoma is diagnosed at an earlier age in women with HNPCC. In contrast to colon carcinoma, the pathologic features of endometrial carcinoma in HNPCC have not been studied in detail. It was the purpose of this study to pathologically characterize a series of HNPCC associated endometrial carcinomas.

Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome.

The hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome is an autosomal dominant genetic disorder caused by the inheritance of a mutation in one of a family of genes encoding DNA mismatch repair (MMR) proteins. HNPCC manifests as genetic instability in linked tumors. Clinically, the syndrome is characterized by early onset malignancies, primarily of the colon and endometrium, with an increased incidence of tumors at other gastrointestinal sites, upper urologic tract, ovary, and pancreas as well. However, the inclusion of breast cancer as an integral tumor of this syndrome is controversial.

Characteristics of small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma

Small bowel carcinoma is uncommon. However, hereditary nonpolyposis colorectal carcinoma (HNPCC) patients are at increased risk of small bowel carcinoma. The purpose of this study was to characterize small bowel tumors in HNPCC patients.

Rectal cancer after prolonged sulindac chemoprevention. A case report

Background. Sulindac is reported to induce regression of colonic adenomas. However, its role as a chemoprophylactic agent for people with familial adenomatous polyposis (FAP) is under consideration.

Loss of surface and cyst epithelial basement membranes and preneoplastic morphologic changes in prophylactic oophorectomies

The authors suggested that the loss of collagen IV and laminin‐containing basement membrane and the loss of Disabled‐2 (Dab2) expression were two critical events associated with morphologic dysplastic changes of the ovarian surface epithelium as a step in tumorigenicity. Both the basement membrane and Dab2, a candidate tumor suppressor of ovarian carcinoma, were involved in epithelial cell surface positioning and organization. The authors speculated that the purging of the basement membrane may be similar to the proteolysis during gonadotropin‐stimulated ovulation, a cyclooxygenase 2 (Cox‐2)‐mediated process.

Family information service and hereditary cancer

There has been a groundswell of interest in hereditary forms of cancer during the past 2 decades. This interest has been driven heavily by the attention given by the press to rapidly emerging knowledge about hereditary cancer risk, coupled with news about an increasing number of culprit germ-line mutations predisposing humans to a variety of hereditary cancer-prone disorders. The greatest attention has been fueled by the discovery of BRCA1 and BRCA2 mutations in the mid-1990s and by the response of women who have actively sought greater attention to the early diagnosis of breast cancer in the interest of obtaining life-saving solutions. This surge of attention has prompted physicians to attend education programs and to pay greater attention to the prolific literature on hereditary cancer that has emerged so rapidly. Noteworthy is the formidable responsibility that the American Society of Clinical Oncology (ASCO) has taken in developing education programs on hereditary cancer for oncologists throughout the United States. A significant problem is that, for the most part, practicing physicians are not prepared to obtain sufficient family histories of cancer to establish a hereditary cancer syndrome diagnosis when it may be occurring in their patients. The attainment of a precise family history of cancer, inclusive of detailed information on the clinical and pathologic findings on the proband, on all of the proband’s siblings, progeny, parents, aunts and uncles, and on both sets of grandparents (referred to as the modified nuclear pedigree), will, in most cases, provide sufficient information for the physician to consider cancer proneness and, in certain circumstances, to enable establishment of a hereditary cancer syndrome diagnosis. When examining aunts and uncles and grandparents, the physician is investigating older individuals who have passed through the cancer risk age and, therefore, will be more genetically informative. Further, once the physician has established an hereditary cancer diagnosis, a major challenge is to educate effectively the at-risk members of the extended family. In this setting, the family information service (FIS) can become extremely valuable to the needs of the family. For example, the family will need to understand the importance of well targeted screening procedures that are melded to the family history and to the natural history of the particular hereditary cancer syndrome. For example, in familial adenomatous polyposis (FAP), family members need to understand the colonic phenotype of multiple adenomatous polyps and the consequence of an extraordinarily high rate of cancer susceptibility, which, when a patient is affected, ultimately requires prophy625

Characterization of the neoplastic phenotype in the familial atypical multiple-mole melanoma-pancreatic carcinoma syndrome

Previous studies suggest that the familial atypical multiple‐mole melanoma (FAMMM) syndrome may predispose affected families to nonmelanoma carcinomas, including adenocarcinoma of the pancreas. It has been found that many of these families harbor mutations in the CDKN2A gene on chromosome 9p21. The phenotypic expression of CDKN2A mutations in these families has not been characterized fully.

Hereditary cancer: Ascertainment and management

in genetically predisposed families with or without polyposis, the mean age at onset is 45 years,2-4 (2) a marked ex cess of bilateral cancer occurrence in paired organs, e.g., breasts, adrenal (pheochromocytomas) and thyroid glands, carotid body, kidney (Wilms tumor), acoustic neurinoma;56 (3) in nonpaired organs, multiple primary or multicentnc cancer occurs with a fre quency many times greater than other wise expected.7 Tumor registry data have shown that the risk of other cancer in patients with certain histologic vari eties is significantly higher than in cancer free patients of the same age.8 While these studies did not evaluate specific etiologies, many of the most frequently occurring multiple primary tumor asso ciations in cancer registry data were con sidered consistent with a genetic etiol ogy; (4) although there are well estab lished autosomal recessive, sex-linked, and cytogenetic cancer and precancerous disorders, in many cases vertical trans mission in consecutive generations of families has been identified with segre gation patterns consistent with autoso mal dominant inheritance.2 These characteristics can be utilized as familial cancer selection criteria when identified in isolated patients and nuclear family cancer clusters, with or without an immediate impression as to the spe cific hereditary cancer or precancer syn Generalities in Family Cancer

The genetic epidemiology of male breast carcinoma

Carcinoma of the male breast accounts for 0.5–1% of all breast carcinoma cases in the U.S. and 1300 cases annually. Female and male breast carcinoma share several clinical and biologic features. The epidemiology of male breast carcinoma is also similar to that of female breast carcinoma, particularly pertaining to the role of hormonal status (namely, relative hyperestrogenism) and family history. Conditions associated with increased estrogen or decreased androgen (such as Klinefelter syndrome), benign breast conditions (including gynecomastia), testicular disorders, liver disease, medications (particularly exogenous estrogens), and radiation exposure predispose to male breast carcinoma. Hill et al. found that familial and sporadic male breast carcinoma were similar with respect to natural history, survival, and pathology. Previous investigations yielded similar results. Male breast carcinoma commonly presents as a painless, firm, subareolar mass or a mass in the upper outer quadrant of the breast. Men are generally diagnosed at an older age and with a more advanced stage of breast carcinoma than are women. Breast tumors in men are more often beneath the nipple. The male-to-female ratio of male breast carcinoma patients is higher among black patients than among white patients. Hsing et al. compared 178 men who died of breast carcinoma with 512 men who died of other causes. Increased risks were found for men who were described by their next-of-kin as very overweight (OR 5 2.3, 95% confidence interval [CI] 5 1.1–5.0). Consumption of red meat was associated with an increased risk and consumption of fruits and vegetables was protective, although neither association was significant. These investigators concluded that obesity increased the risk of male breast carcinoma through hormonal mechanisms. The predominant histologic type of male breast carcinoma is infiltrating ductal carcinoma. Treatment is similar to that for female breast carcinoma. When axillary lymph node metastasis is present, males are candidates for adjuvant systemic combination chemotherapy, hormonal (tamoxifen) therapy, or both, following primary surgical extirpation. Most males with breast carcinoma have estrogen receptor and progesterone receptor positive tumors. Hill et al. found 744