Adenocarcinoma of the small bowel in lynch syndrome II

Adenocarcinoma of the small bowel is rare and accounts for about 1% of all gastrointestinal tract cancer. This disorder has been identified in association with Crohn's disease, celiac disease, Peutz-Jegher's syndrome, and familial adenomatous polyposis. We report adenocarcinoma of the small bowel in nine patients from eight Lynch syndrome II extended pedigrees. Each affected patient was in the direct genetic lineage or manifested multiple primary cancers (stomach, colon, endometrium, and ovary) consonant with the tumor spectrum of Lynch syndrome II. The average age of onset for small bowel cancer was 47 years (range 31 to 56 years), versus the general population peak occurrence after the sixth decade. We conclude that small bowel cancer may be an integral component of the tumor spectrum of Lynch syndrome II.     

Sebaceous adenomas in an MYH associated polyposis patient of Indian (Gujarati) origin

MYH associated polyposis is an autosomal recessive polyposis syndrome with a high risk of large bowel cancer, caused by mutations in the DNA repair gene MYH. Founder mutations have been described in different ethnic groups. Muir Torre Syndrome is the association of internal malignancies with sebaceous gland tumours; Lynch Syndrome/Hereditary Non Polyposis Cancer is the best known cause. There has been a previous report of sebaceous gland tumours in an Italian patient with MYH associated polyposis. We describe a man of Indian (Gujarati) descent who has MYH associated polyposis and multiple sebaceous adenomas of the skin.     

An unusual case of Turcot’s syndrome associated with ileal adenocarcinoma,intestinal non-Hodgkin’s lymphoma,and duodenal adenocarcinoma. Review of the classification and genetic basis of Turcot’s syndrome

A 38-year-old man with a history of colonic and small bowel polyposis and glioblastoma was investigated for dyspepsia. Upper GI endoscopy identified an abnormal area in the duodenum, confirmed by histology as high grade non-Hodgkin’s B cell MALT lymphoma. Although cases of Turcot’s syndrome (TS) (colonic polyposis and primary brain tumour occuring in the same patient) have been previously described, association with haematological malignancy is rare. This is the first report of intestinal lymphoma occurring in an adult with TS.     

The liver: another organ involved in Muir Torre syndrome?

Muir Torre syndrome is a rare autosomal dominant cancer-predisposing syndrome characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies that belong to the spectrum of hereditary non polyposis colorectal cancer (HNPCC), i.e., tumors of gastrointestinal and genitourinary tracts. Hepatobiliary malignancy in association with Muir Torre syndrome has rarely been reported. Here, we describe a case of Muir Torre syndrome associated with an hepatocellular-carcinoma in a patient with a non-cirrhotic liver and an HNPCC-family with multiple cases of hepatocellular carcinoma.     

Current status of familial gastrointestinal polyposis syndromes

Because of the rarity of familial gastrointestinal cancer-predisposing syndromes, their exploration in literature is not extensive. In this review, an update of the clinicopathological and molecular criteria of gastrointestinal familial polyposis syndromes with potential malignant transformation is performed. In addition, a guide for screening and surveillance was synthesized and a distribution of gene mutations according to the specific syndromes and geographic distribution was included. The following inherited polyposes syndromes were analyzed: familial adenomatous polyposis, the hamartomatous familial polyposes (Juvenile polyposis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, hereditary mixed polyposis syndrome, Gorlin syndrome, Birt-Hogg-Dube syndrome, neurofibromatosis type I and multiple endocrine neoplasia syndrome 2B), Li-Fraumeni syndrome, and MUTYH-associated adenomatous polyposis. For proper medical care, subspecialization of gastroenterologists, pathologists, and genticists in the field of familial diseases should be introduced in the medical curriculum.     

Diffuse intestinal ganglioneuromatosis an uncommon manifestation of Cowden syndrome

Diffuse intestinal ganglioneuromatosis is a hamartomatous polyposis characterized by a disseminated, intramural or transmural proliferation of neural elements involving the enteric plexuses. It has been associated with MEN II, neurofibromatosis type 1 and hamartomatous polyposis associated with phosphatase and tensin homolog mutation. We report the case of a female patient with a history of a breast and endometrial tumor who presented in a colonoscopy performed for rectal bleeding diffuse ganglioneuromatosis, which oriented the search for other characteristic findings of Cowden syndrome given the personal history of the patient. The presence of an esophagogastric polyposis was also noted. Cowden syndrome is characterized by skin lesions, but it is rarely diagnosed by these lesions, because they are usually overlooked. Intestinal polyposis is not a major diagnostic criterion but it is very useful for early diagnosis. The combination of colonic polyposis and glucogenic acanthosis should orient the diagnosis to Cowden syndrome.     

Synchronous primary carcinomas of the ampulla of vater and ascending colon in a patient with multiple flat adenomas

Multiple primary cancers occurring in the same patients have been reported to represent 1.8–3.9% of all cancers. The majority of all patients reported to have had a combination of simultaneous neoplastic changes in the ampulla of Vater and the colon showed familial adenomatous polyposis (FAP) syndrome. Variants of familial adenomatous polyposis coli are: attenuated adenomatous polyposis coli (AAPC, previously also known as flat adenoma syndrome) and multiple adenoma coli. AAPC is characterized clinically by many, but usually fewer than 100, colonic lesions that are characteristically slightly elevated and plaque-like, with a reddish surface and sometimes central depression. Genetically it represents an extremely rare variant of FAP. Another group of individuals, so-called multiple adenoma patients, have a phenotype similar to AAPC, but most have no demonstrable germ-line adenomatous polyposis coli mutation, as do patients with FAP or AAPC. However, there have been only a few reports that discussed concurrent neoplastic changes in the ampulla of Vater and colon in patients with multiple colonic flat adenomas, but without the florid phenotype of classical FAP. We present rare clinical course of a patient with multiple (more than 60) flat adenomas in the proximal colon and two primary cancers: of the ampulla of Vater and of the ascending colon. This patient and his family history did not show polyposis compatible with FAP or hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.     

Gynecological malignancies, brain tumors, and familial adenomatous polyposis.

The syndrome of familial adenomatous polyposis has a wide spectrum of clinical manifestations including adenomatous polyps of the colon and small bowel, adenocarcinoma of ampulla of Vater, tumors of the central nervous system, bone lesions, and various soft tissue tumors. The one common denominator is colonic polyposis. It is not known whether this phenotypic heterogeneity is due to various genotypes, or if the entire clinical spectrum is due to one genetic defect. We are reporting the association of gynecologic malignancies with familial adenomatous polyposis as an additional variant of this disease. This report is on two sisters from a family with familial polyposis coli who developed adenomatous polyposis of the colon, central nervous system tumors, and cancers of the ovary and uterus. The gynecological malignancies add another variant to this clinical syndrome.     

Genetics of primary brain tumors: a review

Summary In this review we provide evidence for the existence of genes associated with primary malignant brain tumors. We summarize the current knowledge from studies of familial cancer aggregation, hereditary syndromes, and molecular and cytogenetic studies. The epidemiologic evidence is suggestive but inconclusive for an association between brain tumors and cancers in other family members, including cancers of the breast, lung and colon. Central nervous system (CNS) tumors have been associated with several hereditary syndromes including the Li-Fraumeni cancer family syndrome, neurofibromatosis (types 1 and 2), tuberous sclerosis, nevoid basal cell carcinoma syndrome, familial polyposis, and von Hippel-Lindau disease. Significant studies leading to the recognition of molecular and cytogenetic abnormalities in malignant gliomas are described in detail. The genetic studies conducted thus far suggest a role for inherited susceptibility in some CNS tumors.     

The genetics of FAP and FAP-like syndromes

The presence of multiple adenomatous polyps in the large bowel confers a high lifetime risk of colorectal cancer. Although many cases of classical familial adenomatous polyposis (> 100 polyps) can be accounted for by mutations in the adenomatous polyposis coli (APC) gene, a large group of patients remains with multiple (5–100) adenomas and in whom there is no detectable APC mutation. Recently two new genetic variants have been found to be associated with multiple colorectal adenomas and cancer, MYH/MUTYH on chromosome 1p and the HMPS/CRAC1 locus on chromosome 15q13–q14. New information also continues to emerge regarding the less common hamartomatous polyposis conditions, Peutz–Jeghers syndrome and Juvenile Polyposis syndrome. In approximately half to two thirds of these families, germline genetic variants can now be uncovered. In this review we draw together some of the most recent information pertinent to the molecular pathogenesis of colorectal polyposis.     

Torre's syndrome in association with premalignant and malignant tumors and suspected familial polyposis

Torre's syndrome was diagnosed in a patient with the clinical characteristics of familial polyposis coli, an association, that to our knowledge, has not been reported previously.     

Multiple primary cancer of the large intestine in patients with diffuse polyposis

Primary multiple cancer of the colon was diagnosed in 116 out of 636 (18.2%) cases of diffuse polyposis of the organ. Cancer was more likely to develop in patients with proliferative forms of diffuse colonic polyposis (97.4%). Surgical procedure was determined by tumor site and extent of polyposis.     

Patterns of inheritance of colonic polyps

While the inheritance pattern of familial polyposis coli is established as an autosomal dominant pattern, the expression of the various extracolonic manifestations associated with the neoplastic polyposis is less well understood. The discrete polyp cancer syndrome may not be recognized unless both polyps and colon cancer are considered in the inheritance pattern. The hamartomatous polyps follow a Mendelian-dominant inheritance pattern for the Peutz-Jeghers syndrome, while the inheritance pattern for the juvenile polyposis syndromes is less clear. Cowden's disease appears in a Mendelian dominant pattern, but the occurrence of colonic polyps is less well documented. The ganglioneuromas follow a mendelian dominant inheritance pattern, while the relationship and occurrence of colonic polyps in association with Torre's syndrome is uncertain. The Mendelian dominant inheritance pattern for the cancer family syndrome is documented; the role of colon polyps in this syndrome is less well understood. A further understanding of the inheritance patterns of these various colon polyps will lead to more understanding of the basic disease and help in prevention and early detection for treatment and cure.     

Bilateral internuclear ophthalmoplegia associated with pediatric brain tumor progression: a case series and review of the literature

Internuclear ophthalmoplegia (INO) is a rare disorder of conjugate lateral gaze that has been described in a number of neurologic conditions including multiple sclerosis, stroke and less commonly brain tumors. We describe a series of 3 boys (11, 12, 15 years) diagnosed with primary central nervous system tumors (pilomyxoid variant astrocytoma, anaplastic oligoastrocytoma, gliomatosis cerebri) who developed bilateral INO as a manifestation of progressive disease. Time from diagnosis to development of bilateral INO ranged from 13–36 months. All children died of their disease 1–9 months following diagnosis of bilateral INO and had significant dorsal pontine invasion on magnetic resonance imaging at progression. Only one child had brainstem involvement at diagnosis. Our case series highlights this rare ophthalmologic syndrome of bilateral INO in association with tumor progression and provides a literature review of brain tumor associations with INO.     

Adenomatous polyposis coli and multiple endocrine neoplasia type 2b. A pathogenetic relationship

A young man presenting with Cushing's syndrome was found to have multiple endocrine neoplasia type 2b MEN 2b and adenomatous colonic polyposis with duodenal and gastric polyps. The entire syndrome of MEN 2b was present, including metastatic medullary carcinoma of the thyroid, a pheochromocytoma, and peripheral nerve abnormalities. The concurrence of these two inherited multiple neoplasia syndromes may reflect a common pathogenetic step in this patient.     

Phenotypic variation in hereditary nonpolyposis colon cancer syndrome. Association with infiltrative fibromatosis (desmoid tumor).

Familial infiltrative fibromatosis (desmoid tumor) is a recognized complication of familial adenomatous polyposis (FAP) but has not been described in families without colonic polyposis. The authors describe a unique family in which a predisposition to infiltrative fibromatosis and nonpolyposis colon cancer was inherited dominantly through four generations. This report expands the range of phenotypic variation described for the hereditary nonpolyposis colon cancer (HNPCC) syndrome and adds to the extracolonic complications that are common with FAP and HNPCC.     

Genetic risks and familial associations of small bowel carcinoma

Adenocarcinoma of small intestines (SBA) is a relatively rare malignancy with poor outcomes due to delayed diagnosis. Fifty percent of patients have metastases on presentation and therefore early detection and treatment offers the best long term outcomes. Certain genetic polyposis syndromes and familial diseases are associated with increased risks for SBA. These include familial adenomatous polyposis (FAP), Lynch syndromes (LS), Juvenile polyposis syndrome, Peutz-Jeghers syndrome, Crohn’s disease (CD) and celiac disease. Mutations in APC gene, Mismatch repair genes, STK11 gene, and SMAD4 gene have been implicated for the genetic diseases respectively. While there are no specific inherited genetic mutations for CD, genome-wide association studies have established over 140 loci associated with CD. CpG island mutations with defects in mismatch repair genes have been identified in celiac disease. Significant diagnostic advances have occurred in the past decade and intuitively, it would seem beneficial to use these advanced modalities for surveillance of these patients. At present it is debatable and no clear data exists to support this approach except for established guidelines to diagnose duodenal polyps in FAP, and LS. Here we discuss the genetic alterations, cancer risks, signaling mechanisms and briefly touch the surveillance modalities available for these genetic and clinical syndromes. English language articles from PubMed/Medline and Embase was searched were collected using the phrases “small-bowel adenocarcinoma, genetics, surveillance, familial adenomatous polyposis, lynch syndromes, Peutz-Jeghers syndrome, juvenile polyposis syndrome, CD and celiac disease”. Figures, tables and schematic diagram to illustrate pathways are included in the review.     

Constitutional MLH1 methylation presenting with colonic polyposis syndrome and not Lynch syndrome

At least one-third of patients meeting clinical criteria for Lynch syndrome will have no germline mutation and constitutional epimutations leading to promoter methylation of MLH1 have been identified in a subset of these patients. We report the first case of constitutional MLH1 promoter methylation associated with a colonic polyposis syndrome in a 39 year-old man with a family history of colorectal cancer (CRC) and a personal history of 21 polyps identified over 8 years as well as the development of two synchronous CRCs over 16 months who was evaluated for a hereditary cancer syndrome. Immunohistochemistry (IHC) of multiple tumors showed absent MLH1 and PMS2 expression, though germline testing with Sanger sequencing and multiplex ligation-dependent probe amplification of these mismatch repair genes (MMR) genes was negative. A next generation sequencing panel of 29 genes also failed to identify a pathogenic mutation. Hypermethylation was identified in MLH1 intron 1 in tumor specimens along with buccal cells and peripheral white blood cells, confirming the diagnosis of constitutional MLH1 promoter methylation. This case highlights that constitutional MLH1 methylation should be considered in the differential diagnosis for a polyposis syndrome if IHC staining shows absent MMR gene expression.