Pathology and genetics of tumors of soft tissue and bone

The regulation of cell growth and survival can be subverted by a variety of genetic defects that alter transcriptional programs normally responsible for controlling cell number. High throughput analysis of these gene expression patterns should ultimately lead to the identification of minimal expression profiles that will serve as common denominators in assigning a cancer to a given category. In the course of defining the common denominators, though, we should not be too surprised to find that cancers within a single category may nevertheless exhibit seemingly disparate genetic defects. The wnt pathway has already provided an outstanding example of this. We now know of three regulatory genes in this pathway that are mutated in primary human cancers and several others that promote experimental cancers in rodents (Fig. 1). In all of these cases the common denominator is the activation of gene transcription by -catenin. The resulting gene expression profile should provide us with a signature common to those cancers carrying defects in the wnt pathway. In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.

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Wnt signaling and cancer

/pdf/pathology-and-genetics-of-tumours-of-the-digestive-system-3xy9cwrc3c.pdf

Pathology and genetics of tumours of the digestive system

https://www.nejm.org/doi/pdf/10.1056/NEJMra012242

Hereditary Colorectal Cancer

Background Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and multiple colorectal adenomas. We attempted to define the syndrome at the molecular level. Methods Fourteen families with Turcot's syndrome identified in two registries and the family originally described by Turcot and colleagues were studied. Germ-line mutations in the adenomatous polyposis coli (APC) gene characteristic of familial adenomatous polyposis were evaluated, as well as DNA replication errors and germ-line mutations in nucleotide mismatch-repair genes characteristic of hereditary nonpolyposis colorectal cancer. In addition, a formal risk analysis for brain tumors in familial adenomatous polyposis was performed with a registry data base. Results Genetic abnormalities were identified in 13 of the 14 registry families. Germ-line APC mutations were detected in 10. The predominant brain tumor in these 10 families was medulloblastoma (11 of 14 patients, or 79 percent), and the relative risk of cer...

https://www.nejm.org/doi/pdf/10.1056/NEJM199503303321302

The Molecular Basis of Turcot's Syndrome

The authors identified 132 patients who died with a documented diagnosis of familial adenomatous polyposis (FAP). A review of the medical records, autopsy reports, and in-depth discussion with local physicians and well-informed family members was performed. It was impossible, even after the review, to ascertain the exact cause of death in 22 patients. In the remaining patients, the cause of death was as follows: metastatic colorectal carcinoma, 64 patients (58.2 percent), (colon, 49 [44.5 percent], rectal, 15 [13.6 percent]); desmoid tumors, 12 (10.9 percent); periampullary carcinoma, 9 (8.2 percent); brain tumors, 8 (7.3 percent); perioperative mortalities, 5 (4.5 percent); adrenal carcinoma, 1 (0.9 percent); and abdominal carcinomatosis, 1 (0.9 percent). Ten patients died of causes not related to FAP. The major causes of death in 36 patients who underwent prophylactic colectomy were desmoid tumor and periampullary malignancy. This finding underscores the importance of lifelong surveillance and periodic endoscopic evaluation in patients with FAP.

Mortality in patients with familial adenomatous polyposis

Desmoid tumors are locally invasive, nonmetastasizing fibrous tumors most frequently seen in patients with familial polyposis coli (FPC). Of 325 patients with FPC treated at the Cleveland Clinic, 29 (8.9%) were found to have a total of 36 desmoid tumors. These tumors occur in young patients (mean age: 29.8 years), particularly women (ratio 3:1), and most appeared after previous colectomy (86%). The majority (72% of all desmoids, 90% of patients) were located within the abdomen, specifically within the mesentery of the small intestine. In most cases, attempts at surgical resection were followed by recurrence, and other previous treatments were similarly ineffective. Six of the 29 patients (21%) died from the desmoid and three died from other causes. The recent use of sulindac (Clinoril) has produced some early encouraging results in four patients with these tumors that have proven so difficult to treat in the past.

Desmoid tumors in familial polyposis coli.

ObjectiveThis study was performed to examine the relation between phenotypic expression in patients with familial adenomatous polyposis (FAP) and the site of mutations in the APC (adenomatous polyposis coli) gene. The ability of APC mutations to predict surgical outcome was also investigated.Summary

APC genotype, polyp number, and surgical options in familial adenomatous polyposis.

Forty of 416 patients with familial adenomatous polyposis were noted to have intra-abdominal desmoid tumors, and a subgroup of 16 were treated with noncytotoxic drug therapy. Drugs used were sulindac (14 patients), sulindac plus tamoxifen (3 patients), indomethacin (4 patients), tamoxifen (4 patients), progesterone (DEPO-PROVERA; Upjohn Co., Kalamazoo, MI) (2 patients), and testolactone (1 patient). Therapy with these drugs for continuous periods of six months or more resulted in three complete and seven partial remissions. When treated patients were compared with untreated patients (n = 12), there were significant benefits for the treated group, both in reduction of desmoid size and in improvement of symptoms, despite the inherent selection bias against this. Sulindac was the only drug used in enough patients to permit independent evaluation of its effect, with one complete and seven partial reductions of tumor size. Some patients had a delayed response to sulindac, with tumor shrinkage occurring after an initial period of tumor enlargement. When using sulindac for the treatment of desmoid tumors, this phenomenon should be considered.

Noncytotoxic drug therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis.

A review of the endoscopy reports and pathology results from esophagogastroduodenoscopy (EGD) of all patients with familial adenomatous polyposis (FAP) undergoing such an examination was performed Two hundred fortyseven patients were identified, with an overall prevalence of duodenal adenomas of 66 percent and of fundic gland polyps of 61 percent Analysis of our more recent experience (1986 to 1990) shows the prevalence to be 88 percent and 84 percent, respectively A normal-appearing papilla was adenomatous in 50 percent of cases No case of periampullary carcinoma developed in patients under surveillance Routine EGD is indicated for patients with FAP Duodenal adenomas and fundic gland polyps will occur in the majority of patients

Ellen McGannon

Papers

Mortality in patients with familial adenomatous polyposis

Desmoid tumors in familial polyposis coli.

APC genotype, polyp number, and surgical options in familial adenomatous polyposis.

Noncytotoxic drug therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis.

Gastroduodenal polyps in patients with familial adenomatous polyposis.