Flat adenomas in a colon cancer-prone kindred

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.     

A case of flat elevated type carcinoma in adenoma of the duodenum with gastric cancer

Duodenal adenoma is rare, and there have been very few case reports of flat elevated type adenoma. We report a case of flat elevated type carcinoma in adenoma of the duodenum with gastric cancer. A 58-year-old man was referred to our hospital for gastric cancer. Endoscopic examination revealed the gastric cancer and a flat elevated tumor in the descending part of the duodenum, measuring 6 cm in diameter. The biopsy specimen of the duodenal lesion was diagnosed as adenoma. Distal gastrectomy and segmental partial resection of the duodenum were performed with no complication. Histologically, the gastric cancer was poorly differentiated adenocarcinoma with submcosal invasion and without lymph node metastasis, and the duodenal tumor was a well differentiated carcinoma in villous adenoma. The duodenal adenocarcinoma was limited to the mucosal layer and the resected margins were free of tumor. It is difficult to distinguish a carcinoma from a benign elevated lesion in the duodenum. Therefore, a resection of the whole tumor is necessary. Though endoscopic resection is the first choice of therapy, a surgical partial resection is necessary when it is difficult. Then, a segmental resection may be one of the useful procedures of surgery.     

Patient and tumor characteristics of colon cancers with microsatellite instability: a population-based study.

Molecular screening for microsatellite instability (MSI) in colon cancers has been proposed to identify individuals with hereditary nonpolyposis colorectal cancer. To date, most reports of MSI in colorectal cancer have been based on studies of clinical case series or high-risk families. We examined the proportion of incident colon cancers in the general population that exhibit MSI by patient and tumor characteristics. We interviewed 201 colon cancer cases ascertained by the New Mexico Tumor Registry in the metropolitan Albuquerque area for demographic information, lifestyle factors, medical history, and family cancer history. Paired normal and tumor tissue specimens were obtained for each case. Three microsatellite markers were used; instability was defined as observed alteration at two or more loci. Overall, 37 of 201 (18%) colon cancers exhibited instability. MSI was more common among cases >70 years (26%) and most common among cases >80 years (38%). MSI was significantly associated with tumors in the proximal colon and with later stage and poor differentiation among cases >70 years. MSI was not associated with a history of polyps. Family history of colorectal cancer was associated with MSI only among cases <50 years. When all factors were analyzed jointly in a regression model, proximal subsite and poor differentiation remained significantly associated with MSI. One patient, whose tumor exhibited MSI, fulfilled the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer. Our study provides a population-based estimate of MSI in colon tumors and a representative estimate of the proportion of colorectal cancer patients in the general population who consent to be interviewed for family cancer history and to have biological samples analyzed.     

Screening and surveillance for colorectal cancer.

Colorectal cancer is the second most common cause of cancer death among American men and woman. Currently available screening and surveillance techniques are effective in detecting early-stage colorectal cancer and its premalignant precursor lesion, the adenomatous polyp (adenoma). Removal of adenomas by colonoscopic polypectomy significantly reduces the incidence of colorectal cancer. Appropriate screening and surveillance recommendations should be based on the individual's colorectal cancer risk stratification. High-risk groups, such as patients with hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), should be offered genetic counseling and specialized screening recommendations for colorectal and associated extracolonic malignancies.     

Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability

Inactivation of DNA-mismatch repair underlies the genesis of microsatellite unstable (MSI) colon cancers. hPMS2 is one of several genes encoding components of the DNA-mismatch repair complex, and germline hPMS2 mutations have been found in a few kindreds with hereditary nonpolyposis colorectal carcinoma (HNPCC), in whom hereditary MSI colon cancers develop. However, mice bearing null hPMS2 genes do not develop colon cancers and hPMS2 mutations in sporadic human colon cancers have not been described. Here we report that in Vaco481 colon cancer the hPMS2 gene is inactivated by somatic mutations of both hPMS2 alleles. The cell line derived from this tumor is functionally deficient in DNA mismatch repair. This deficiency can be biochemically complemented by addition of a purified hMLH1-hPMS2 (hMutLalpha) complex. The hPMS2 deficient Vaco481 cancer cell line demonstrates microsatellite instability, an elevated HPRT gene mutation rate, and resistance to the cytotoxicity of the alkylator MNNG. We conclude that somatic inactivation of hPMS2 can play a role in development of sporadic MSI colon cancer expressing the full range of cancer phenotypes associated with inactivation of the mismatch repair system.     

Familial colorectal adenocarcinoma from the Swedish Family-Cancer Database.

Familial risks for colorectal (CRC) adenocarcinoma were characterized from the Swedish Family-Cancer Database covering 9.6 million individuals, whose family relationships and cancers were obtained from registered sources, not sensitive to reporting or ascertainment bias. Cancer cases were retrieved from the Swedish Cancer Registry from years 1958-96. Standardized incidence ratios (SIRs) were calculated based on gender-, age-, period- and tumor type specific rates. A total of 4,794 and 67,925 CRCs were recorded in offspring and parents, respectively. For colon and rectal adenocarcinoma, the SIRs in offspring were 2.28 and 1.68 by parental CRC adenocarcinoma, giving attributable proportions of 6.45 and 3.31%, respectively. The SIR of CRC was over 10 when both offspring and parents were diagnosed at a young age. The risk for parental CRC adenocarcinoma was over 100 when 2 or more children were affected. The risk in siblings was also very high when a parent was affected. The familial cancer sites that associated with CRC were those typical of hereditary nonpolyposis colorectal cancer (HNPCC). This is the largest study published on familial CRC and the only one reporting specifically on adenocarcinoma. The data suggest that HNPCC is the largest single disease entity among CRCs, probably accounting for less than 50% of familial CRC. Other familial components appear heterogeneous, characterized by incomplete penetrance, recessive mode of inheritance and few associated tumor sites.     

Primary minute invasive de novo colonic adenocarcinoma appearing as submucosal tumor

A 4 mm white-yellow submucosal tumor-like lesion was detected in the sigmoid colon of an asymptomatic 52-yr-old Japanese man. Because the lesion was unexpectedly suspicious for adenocarcinoma by pathological examination of the biopsy specimen, it was treated by endoscopic mucosal resection. The specimen obtained demonstrated well-differentiated adenocarcinoma without any adenomatous element, and was located principally in the submucosal layer with a maximum depth of 1600 µm from the muscularis mucosae. The cancer exposed to the luminal surface was pathologically concluded to be diminutive. Intriguingly, aggregation of lymphocytes was found beneath the mucosal layer, which might have compromised the integrity of the muscularis mucosae. Because of deep submucosal infiltration and the latent aggressive nature of de novo cancer, the patient underwent an additional partial sigmoidcolectomy, which demonstrated no residual cancer and no regional lymph node metastasis. The lesion in this patient exhibited a previously undescribed appearance of de novo colon cancer as submucosal tumor in an early phase of growth.     

A case of advanced gastric cancer resembling submucosal tumor of the stomach

We report a case of primary gastric carcinoma with a macroscopic appearance indistinguishable from that of a submucosal tumor. A 48-year-old man visited our hospital with a chief complaint of epigastric discomfort. Endoscopic examination revealed a protruding lesion with a well defined margin on the anterior wall of the gastric antrum. Most of the tumor surface was covered with apparently normal gastric mucosa and a shallow recess with mild erosion was observed on the top. Abdominal ultrasonography showed a hypoechoic lesion with an irregular margin under the gastric mucosa. Laboratory examination revealed an elevated CA19-9 level of 106.9 U/ml. In spite of repeated bouling biopsies, no histological diagnosis could be obtained before surgery. However, gastrectomy with regional lymph node dissection was performed because of the high likelihood of gastric cancer, in view of the markedly elevated CA19-9 level and irregular tumor margin demonstrated by abdominal ultrasonography. The tumor was diagnosed histologically as papillo-tubular adenocarcinoma invasive to the serosa with marked vessel infiltration. No metastasis was found in the regional lymph nodes. Gastric cancer resembling submucosal tumor is rare and often difficult to diagnose. Careful estimation of the possibility of gastric cancer and the informed consent of the patient are critically important, in cases of suspected primary gastric cancer resembling submucosal tumor, in order to decide the form of treatment.      

The ODAC Chronicles: Part 6a. ODAC’s structure and function

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is the most common form of hereditary colorectal cancer. It is characterized by early onset of colorectal cancer and other extracolonic-associated malignancies. This disorder is inherited in an autosomal dominant pattern and is due to a mutation in one of the DNA mismatch repair genes. Although clinical and molecular understanding of the syndrome has progressed dramatically in the last decade, diagnosis of the syndrome is still a clinical challenge. This review summarizes the main features of the syndrome and provides an update of its management.     

Lynch syndrome in colorectal cancer patients

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is the most common form of hereditary colorectal cancer. It is characterized by early onset of colorectal cancer and other extracolonic-associated malignancies. This disorder is inherited in an autosomal dominant pattern and is due to a mutation in one of the DNA mismatch repair genes. Although clinical and molecular understanding of the syndrome has progressed dramatically in the last decade, diagnosis of the syndrome is still a clinical challenge. This review summarizes the main features of the syndrome and provides an update of its management.     

Laryngeal carcinoma in a Lynch syndrome II kindred

Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for about 4% to 6% of the total colorectal cancer burden. It is subdivided into Lynch syndrome I and II. Lynch syndrome I is characterized by an autosomal dominant inheritance pattern for site-specific, early onset, adenocarcinoma of the colon, with proximal predominance and an excess of synchronous and metachronous colonic cancers. Lynch syndrome II (cancer family syndrome) shows these same colon cancer characteristics, but differs in that there is an excess proclivity of other forms of cancer, particularly of the endometrium and ovary. This article documents a family that shows features of Lynch syndrome II. Unique aspects pertain to a patient who is in the direct genetic lineage (whose five brothers manifested colonic cancer), but who developed carcinoma of the uterine cervix at age 34 and laryngeal cancer at 60. The pedigree also shows uterine cervical carcinoma among other patients at genetic risk. Her son, who is a nonsmoker and nondrinker, manifested laryngeal cancer at age 31. These observations appear to add new information about tumor heterogeneity in HNPCC.     

Genetics of hereditary colorectal cancer

Genetic factors can dramatically influence the risk of colorectal cancer, and the molecular bases of many hereditary colorectal cancer syndromes, including familial adenomatous polyposis (FAP), attenuated FAP (AFAP), and hereditary nonpolyposis colorectal cancer (HNPCC) have been elucidated. Additional syndromes continue to be defined as new genes, including MYH , are linked to the development of colonic polyps and cancer. The risks of colorectal cancer are variable and depend on the specific germline alterations. Some mutations are associated with a 100% lifetime risk of developing cancer, while others are associated with only a mild increase in risk. Although there are overlapping clinical features in many of these syndromes, they can be distinguished by the age at cancer diagnosis, inheritance pattern, number and distribution of polyps, specific histologic features of the cancers, and the presence of distinctive extracolonic features. The introduction and refinement of genetic testing has provided a new and invaluable tool for the diagnosis and assessment of cancer risk for suspected cases of hereditary colon cancer.     

Hereditary colorectal cancer syndromes: an overview

Approximately 5% of the 140,000 cases of colorectal cancer diagnosed annually are attributable to an underlying hereditary colorectal cancer syndrome. However, this is likely to be an underestimation. Our understanding of the genetic basis, as well as the guidelines for clinical management of these syndromes, continue to evolve rapidly. Because of the high risk of not only colorectal cancer but also multiple extracolonic tumors, it is crucial for clinicians to recognize the unique features in the diagnosis and management of these high-penetrance syndromes, including familial adenomatous polyposis, MYH-associated polyposis, and hereditary nonpolyposis colon cancer.     

遗传性非息肉病性大肠癌

目的：探讨总结遗传性卢肉病性大肠癌（ＨＮＰＣＣ）的特征,提高早期诊断和治疗水平。方法：复习文献并本结合本组四个家族的临床资料进行总结分析。结果：ＨＮＰＣＣ发病年龄轻,平均发病年龄４４岁,约６５％的患者病变发生在曲近侧结肠;约２５％的患者有多原发大肠癌;２０～７０％的患者可检测到错配修复基因（ＭＭＲ）的突变;病理分化差但有较好的预后。结论：ＨＮＰＣＣ有明显的特征,利用这些特征有助于早期诊断和制定合理     

A case of three malignant tumors of the duodenal bulb and large intestine

A 75-year-old woman with anemia admitted to our hospital and was found to have a polyp in the duodenal bulb. The biopsy specimen was histologically diagnosed as an adenoma. A barium enema examination showed an obstruction in the ascending colon and a biopsy done on a specimen of the ascending colon revealed colonic cancer. A histology of the resected specimen of the duodenal bulb revealed a tubular adenocarcinoma in an adenoma, and a similar examination of a colonic resected specimen revealed a mucinous, papillary carcinoma. A primary malignant tumor in the duodenum is an uncommon tumor and our case is first in Japan showing three malignant tumors with an early duodenal cancer.     

When does MMR loss occur during HNPCC progression?

Inactivation of DNA mismatch repair (MMR) is the hallmark of hereditary nonpolyposis colorectal cancer (HNPCC) and sporadic colorectal cancers with microsatellite instability (MSI+). MMR loss results in a markedly elevated mutation rate, and many MS mutations are found in MSI+ cancers. In theory, it is possible to estimate the interval between MMR loss and cancer removal by counting numbers of cancer MS mutations--the more MS mutations, the longer the intervals since MMR loss. Using this somatic molecular clock approach, MMR loss is estimated to precede transformation (clonal expansion) and likely occurs in normal appearing colon. Surprising, ages at MMR loss are more consistent with MMR loss as a relatively late event during progression to MSI+ cancer.     

Role of <Emphasis Type="Italic">APC</Emphasis> and DNA mismatch repair genes in the development of colorectal cancers

Colorectal cancer is the third most common cause of cancer-related death in both men and women in the western hemisphere. According to the American Cancer Society, an estimated 105,500 new cases of colon cancer with 57,100 deaths will occur in the U.S. in 2003, accounting for about 10% of cancer deaths. Among the colon cancer patients, hereditary risk contributes approximately 20%. The main inherited colorectal cancers are the familial adenomatous polyposis (FAP) and the hereditary nonpolyposis colorectal cancers (HNPCC). The FAP and HNPCC are caused due to mutations in the adenomatous polyposis coli (APC) and DNA mismatch repair (MMR) genes. The focus of this review is to summarize the functions of APC and MMR gene products in the development of colorectal cancers.     

Familial aggregation of colorectal cancer in Egypt

We have investigated the familial aggregation of colorectal cancer and hereditary nonpolyposis colorectal cancer (HNPCC) in Egypt because of the high incidence of colorectal cancer in Egyptian children and young adults and the prevalence of consanguinity there. In a pilot study, we conducted detailed interviews with 111 Egyptian colorectal cancer patients and 111 healthy Egyptian controls about their family histories of colorectal cancer, and other cancers, consanguinity, age at diagnosis, symptoms and recurrence. Eight patients (7.2%) had one or more first- or second-degree relatives under age 40 with colorectal cancer, suggestive of HNPCC by the Amsterdam criteria. One of these families had a typical history of HNPCC, with 4 relatives having colorectal cancer in 3 generations; 3 of these relatives were younger than age 45 at colon cancer diagnosis, and other relatives had extracolonic tumors. Another 14 patients (12.6%) had a first- or second-degree relative with a family history of other neoplasms such as endometrial, urinary and hepatobiliary cancers that could also be related to HNPCC. Four patients with early-onset colon cancer and a family history of other HNPCC-related cancers reported that their parents were first-degree cousins. Int. J. Cancer 77:811–816, 1998.© 1998 Wiley-Liss, Inc.