Mantle cell lymphoma of the cecum.

The authors have read with great interest the recently published article "Colon lymphomas: an analysis of our experience over the last 23 years" by Martín Domínguez V et al., a single center retrospective review of 29 patients diagnosed with colon lymphoma. The present report describes a case of mantle cell lymphoma (MCL) of the cecum that aims to improve the knowledge regarding this unusual clinical and endoscopic entity.

A prognostic analysis of 895 cases of stage III colon cancer in different colon subsites.

PURPOSE: Stage III colon cancer is currently treated as an entity with a unified therapeutic principle. The aim of the retrospective study is to explore the clinicopathological characteristics and outcomes of site-specific stage III colon cancers and the influences of tumor location on prognosis. METHODS: Eight hundred ninety-five patients with stage III colon cancer treated with radical operation and subsequent adjuvant chemotherapy (5-fluorouracil/oxaliplatin) were divided into seven groups according to colon segment (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon). Expression of excision repair cross-complementing group 1 (ERCC1) and thymidylate synthase (TS) was examined by immunohistochemistry. We assessed if differences exist in patient characteristics and clinic outcomes between the seven groups. RESULTS: There were significant differences in tumor differentiation (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) stage (P < 0.001), metachronous liver metastasis (P < 0.001), metachronous lung metastasis (P < 0.001), and ERCCI expression (P < 0.001) between the seven groups. Both 5-year recurrence-free survival (RFS) and 5-year overall survival (OS) exhibited significant differences (both P < 0.001) with survival gradually decreasing from cecum to sigmoid colon. Cox regression analyses identified that tumor location was an independent prognostic factor for RFS and OS. CONCLUSIONS: Stage III colon cancer located proximally carried a poorer survival than that located distally. Different efficacies of FOLFOX adjuvant chemotherapy may be an important factor affecting survival of site-specific stage III colon cancers.

Genetic mechanisms in interval colon cancers.

BACKGROUND AND AIM: The factors underlying the development of interval colon cancers are not well defined and are likely heterogeneous. We sought to determine whether there are distinct molecular properties associated with interval colon cancers. METHODS: Colon cancers diagnosed within 5 years of a complete and well-prepped colonoscopic examination were identified over a 7-year period at a single institution. The clinical and pathological features of the tumors were defined. Analysis of DNA mismatch repair (MMR) and genotyping of a panel of oncogenes associated with colon cancer were performed. RESULTS: Forty-two interval colon cancers were diagnosed at an average age of 70 years. 69 % of tumors were located in the right colon. 41 % of tumors exhibited DNA microsatellite instability (MSI). Loss of staining of DNA MMR proteins by immunohistochemistry (IHC) was confirmed in 82 % of the MSI-positive tumors. Among tumors with abnormal MSI and IHC, 54 % exhibited somatic methylation of the MLH1 promoter, but the remaining 43 % exhibited molecular features indicative of underlying Lynch syndrome (LS). The frequency of somatic mutations in the KRAS, BRAF, NRAS, and PIK3CA oncogenes was similar between interval cancer cases and controls. CONCLUSIONS: Interval colon cancers are not distinguished by the activation of the KRAS, NRAS, BRAF, or PIK3CA oncogenic pathways. However, MSI pathway defects are present in a significant proportion of interval colon cancers. Underlying LS may explain nearly half of these MSI-positive cases, and the remaining cases appear to represent sporadic serrated pathway tumors.

Multifocal in situ mantle cell neoplasia of the ileocecal region: a case report with simultaneous nodal and extranodal involvement.

In situ mantle cell neoplasia (ISMCN) is a rare entity of disputed clinical significance. We report an additional case, unusual by its presentation in the large intestine and its multifocal involvement of several nodal and extranodal sites. The diagnosis was made in a 46-year-old male patient from a surgical specimen resected for cecal adenocarcinoma. Gross examination showed multiple small polypoid lesions surrounding the ileocecal valve, corresponding to lymphoid aggregates with hyperplastic follicles. Numerous cyclin D1/SOX11+ lymphoid cells, harboring the t(11;14)(q13;q32) translocation, were present in the inner layers of mantle zones. The same lesions were found in the ileum, the appendix, and the regional lymph nodes. The final diagnosis was multifocal ISMCN of the ileocecal region, with both nodal and extra-nodal involvement. A simple surveillance was decided. Our observation expands the clinical spectrum of the disease and underlines the necessity to closely examine even normal-appearing reactive lymphoid tissues.

A comprehensive study of nondysplastic and dysplastic serrated polyps of the vermiform appendix.

Serrated colorectal polyps often show DNA hypermethylation and/or BRAF mutations and have been implicated in the "serrated neoplastic pathway." Although similar lesions occur in the appendix, they have never been systematically investigated. We evaluated a study group of 56 serrated polyps, a control group of 17 mucinous cystadenomas, and 4 adenocarcinomas with adjacent serrated polyps of the appendix to better understand their pathogenesis. The study cases were classified as nondysplastic or dysplastic serrated polyps and evaluated for MLH-1, MSH-2, MGMT, beta-catenin, p53, and Ki-67 expression, BRAF and KRAS mutations, and microsatellite instability. Serrated polyps usually occurred in older adults with no sex predilection. Most (59%) lacked dysplasia, but all showed similar molecular features, regardless of the degree of dysplasia present. Decreased MLH-1 (50%, P<0.001) and/or MGMT (59%, P<0.001) expression and BRAF (29%, P=0.007) mutations were significantly more common in serrated polyps, but BRAF mutations were detected in a minority of the extracted DNA in 15/16 cases. Of the 28 cases with decreased MLH-1 expression, none showed high-frequency microsatellite instability. Loss of MLH-1 (25%) or MGMT (50%) expression and BRAF or KRAS mutations (50%) were inconsistently present in adenocarcinomas and were not identified in combination in any cases. We conclude that molecular features of the "serrated neoplastic pathway" are present with similar frequencies among dysplastic and nondysplastic serrated appendiceal polyps and are not highly prevalent in adjacent carcinomas. These features, including BRAF mutations, may be more closely related to a serrated morphology in appendiceal polyps rather than biologically important changes.

Cecal adenocarcinoma with prominent rhabdoid feature: report of a case with immunohistochemical, ultrastructural, and molecular analyses.

Colorectal adenocarcinoma with rhabdoid phenotype is extremely rare, and only 1 case of adenocarcinoma showing rhabdoid dedifferentiation has been reported. The authors present another case of cecal adenocarcinoma with prominent rhabdoid feature in a 66-year-old man. The 13-cm sized tumor consisted mainly of rhabdoid cells and partly of adenocarcinoma, and transition from adenocarcinoma to rhabdoid areas was noted. Ultrastructural analysis revealed intracytoplasmic aggregates of intermediate filaments in the rhabdoid cells. Adenocarcinoma cells were diffusely immunoreactive to cytokeratin 7 and AE1/3, but occasionally positive for vimentin. The rhabdoid cells were negative for cytokeratin 7, weakly/focally immunoreactive to AE1/3, and diffusely positive for vimentin. These results suggested that the rhabdoid cells were dedifferentiated adenocarcinoma. Analysis of the rhabdoid cells with molecular techniques is also presented.

Are all RAS mutations the same? Coexisting KRAS and NRAS mutations in a caecal adenocarcinoma and contiguous tubulovillous adenoma.

Mutations of the human Kirsten rat sarcoma viral oncogene homologue (KRAS) and the highly homologous human neuroblastoma RAS viral oncogene homologue (NRAS) are associated with resistance to antiepidermal growth factor receptor therapies in patients with colorectal cancer. In this report, we describe a caecal adenocarcinoma that contains both KRAS c.35G>T (G12V) and NRAS c.34G>A (G12S) mutations. The adenocarcinoma arises from a contiguous high-grade tubulovillous adenoma, which also carries the identical KRAS and NRAS mutations, supporting their common origin. While KRAS mutations are common in colorectal cancers, NRAS mutations are relatively rare and the coexistence of multiple RAS mutations is not documented, presumably reflecting similar functions of wild-type and mutant forms of RAS. Recent experimental evidence has suggested that KRAS and NRAS may in fact mediate distinct biological processes in the colon, and this unusual case potentially illustrates the hypothesis clinically. Characterisation of the diverse and divergent functions of RAS family members and mutant forms of RAS in the colon form important considerations for the development of RAS-targeting therapeutics.

Mixed adenoneuroendocrine carcinoma of gastrointestinal tract: report of two cases.

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare tumor of the gastrointestinal tract that consists of a dual adenocarcinomatous and neuroendocrine differentiation, each component representing at least 30% of the tumor. To date, only seven cases have been reported in the cecum, and less than 40 in the stomach. Our first case was diagnosed in a 74-years-old female as a polypoid lesion of the cecum with direct invasion in the transverse colon, without lymph node metastases. The second case was diagnosed in the stomach of a 46-years-old male as a polypoid tumor of the antral region that invaded the pancreas and presented metastases in 22 regional lymph nodes. The metastatic tissue was represented by the glandular component. In both cases, the tumor consisted of a moderately-differentiated tubular adenocarcinoma (with mucinous component in Case 1) intermingled with neuroendocrine carcinoma. Ki67 index was lower than 20% in Case 1, respectively higher than 20% in Case 2. The neuroendocrine component was marked by synaptophysin and neuron specific enolase, being negative for Keratins 7/20. The neuroendocrine component represented 60% in Case 1, and 40% in Case 2, respectively. The glandular components were marked by carcinoembryonic antigen, maspin and keratin 20/7 (Case 1/2). Both cases were proved to be microsatellite stable. Independently by the localization and tumor stage, MANECs appear to be highly malignant tumors, with high risk for distant metastases. The aggressiveness seems to depend on the endocrine component, independent of its proportion. The neuroendocrine component could be a dedifferentiated adenocarcinoma with a neuroendocrine phenotype.

DOME/GALT type adenocarcimoma of the colon: a case report, literature review and a unified phenotypic categorization.

Several types of colorectal cancers are associated with a prominent lymphoid component, which is considered a positive prognostic factor. We report a case of a dome-type carcinoma of the cecum in a 57 year old female. The sessile, non-polypoid lesion histologically consisted of a tubulovillous adenoma with low-grade dysplasia. The submucosal invasive component showed low-grade architectural features that included cystically dilated glands containing eosinohilic debris. Immunohistochemical studies displayed retention of the four mistmach repair proteins, consistent with a stable phenotype. After 3 years, the patient remains free of recurrence. A literature review highlighted striking similarities between dome-type carcinoma and the gut-associated lymphoid tissue carcinoma, the two sharing an intimate association with the gut associated lymphoid tissue.The two variants might therefore be grouped into a unified category.

Histomorphometric characteristics and cellular kinetics of colorectal polyps with epithelial serrated proliferation adjacent to carcinoma.

Four cases of colorectal polyps with epithelial serrated proliferation (CP-ESP) with malignant transformation were studied. In CP-ESP adjacent to carcinoma, if the nuclear size in the surface layer was significantly smaller than those in the bottom and the middle layers of the crypts, the specimen was defined as zone formation positive. If there was no significant difference among the layers, the specimen was defined as zone formation negative. Cell kinetics were evaluated using Ki-67 immunostaining. The CP-ESP regions of cases 1 and 2 showed zone formation with inferior and lateral glandular branching, and were qualitatively hyperplastic on cell kinetics. Cases 3 and 4 showed inferior and lateral glandular branching with no zone formation, and were kinetically neoplastic (adenoma). The histogenesis of hyperplastic polyps with atypia (cases 1 and 2) involves the hyperplastic polyp-carcinoma sequence. In contrast, the development of tubulovillous adenoma or serrated adenoma (cases 3 and 4) may involve the tubulovillous adenoma-carcinoma or serrated adenoma-carcinoma sequence.

Immunoscintigraphy using 99mTc-labeled anti-CEA monoclonal antibody for patients with colorectal cancer.

Immunoscintigraphy by 99mTc labeled mouse CEA antibody, BW 431/26, was done for 14 patients with colorectal cancer. All patients underwent body scan 6 and 24 hours after administration of 99mTc antibody, 30 mCi/1mg. In 13 out of 14 cases (92.9%) with colorectal cancer, the specific accumulation of 99mTc was shown. The count ratio between the lesion and normal tissue indicating the accumulation of labeled antibody was calculated as 2.6 to 12.8. The hepatic metastasis could be demonstrated as cold spots in one case and as hot spots in the other case. No adverse reaction was noticed in any of patients examined. These results indicate that immunoscintigraphy by 99mTc-CEA antibody detects carcinoma of the colon excellently, and is quite useful clinically. With SPECT, it is possible to localize the site of the lesion more distinctly and to predict the accumulation of the antibody in the tumor as a treatment application.

Primary small cell carcinoma of the cecum.

Cecal extrapulmonary small cell carcinoma (cESC) is extremely rare, with only single previous report of occurrence in a child. We report a 76-year-old man admitted for evaluation of a cecal mass seen in colonoscopy. Histology revealed small cell carcinoma with classic immunohistochemical profile similar to those seen in the colon. Further clinical survey documented absence of any other masses or abnormality. To the best of our knowledge, this is the first case of primary cESC occurring in an adult. Awareness of the pathologist and clinician of the cecum as a potential site of cESC may help to prevent misdiagnosis as poorly differentiated adenocarcinoma. This is crucial because extrapulmonary small cell carcinomas usually have worse prognosis.

Neonatal gastrointestinal stromal tumor. Report of a case and review of literature.

Gastrointestinal stromal tumor (GIST) is very rare in infancy. Most of the reported cases in the literature are in adults; some are in children but there are a few reported cases in the literature. The present case is a 6-day-old female neonate presenting with lethargy, poor feeding, constipation, abdominal distention, and rectal bleeding. She was operated on with the impression of intestinal obstruction, and right hemicolectomy was performed on her. Surgical specimen showed a well-defined and round 3-cm mass in the cecal area. Diagnosis was made by histologic and immunohistochemical studies which showed a GIST. The tumor showed positive vimentin and c-kit but negative for all other markers (desmin, actin, S100, NSE, and CD-34). So the case was an undifferentiated GIST. After 1 year of follow-up the patient was completely normal.

Malignant fibrous histiocytoma of the cecum: report of a case and review of the literature.

Malignant fibrous histiocytoma (MFH) of the gastrointestinal tract is extremely rare. Here we report a case of MFH of the cecum and review other cases of large bowel MFH in the literature. A 64-year-old man had a large tumor mass in the cecum associated with multiple small peritoneal implants. Histologically, most of the lesion showed inflammatory pseudotumor-like appearance; that is, a mixed proliferation of fibroblasts and myofibroblasts loosely arranged in sweeping fascicles or whorled structures and an admixture of chronic inflammatory cell infiltrate. The myofibroblastic nature of the spindle-shaped cells was confirmed by their immunohistochemical and ultrastructural findings. In addition, there was atypical histiocytic cells infiltrate in some areas and marked lymphatic involvement and lymph node metastasis by such histiocytic cells. These features were interpreted as MFH, although it had to be distinguished from inflammatory fibrosarcoma and leiomyosarcoma. The differential diagnosis is discussed here.

Caecal adenocarcinoma with rhabdoid phenotype: an immunohistochemical and ultrastructural analysis.

A polypoid caecal adenocarcinoma in a 72-year-old female was found microscopically to be composed mainly of rhabdoid cells. Deposits in the liver and lymph nodes had a similar histological appearance to the primary tumour. The rhabdoid cells were typified by abundant eosinophilic cytoplasm, eccentric nuclei and prominent nucleoli. The differential diagnosis included rhabdomyosarcoma, metaplastic carcinoma (carcinoma with sarcomatoid dedifferentiation), carcinosarcoma and extra-renal rhabdoid tumour. The rhabdoid cells showed strong immunoreactivity with cytokeratin, epithelial membrane antigen and vimentin. Ultrastructurally, cytoplasmic whorls of intermediate filaments were noted. Multiple sections, immunohistochemistry and ultrastructural examination all revealed an adenocarcinomatous component which blended with the rhabdoid areas. In one area a rhabdoid cell was present within a malignant gland. This case illustrates that the rhabdoid appearance of many tumours can be misleading and is merely a non-specific morpho-phenotypic pattern seen in extra-renal sites. In the extra-renal setting, careful search for evidence of differentiation should be undertaken.

Large bowel adenomas: markers of risk and endpoints.

In many large bowel chemoprevention trials adenomas have a double duty: they are used to identify subjects at risk for large bowel neoplasia, and also serve as endpoints. Many features of adenomas make them suitable for these tasks. Patients with adenomas are fairly numerous and easy to identify; further, the 'adenoma-carcinoma' sequence suggests that adenomas are logical endpoints. The high recurrence risk among adenoma patients means that a relatively modest number of subjects will suffice for adequate statistical power. The are some limitations to the use of adenomas, however. There is clearly heterogeneity of risk for subsequent cancer. Patients with only small adenomas may have rates of colorectal cancer that are not much greater than those of the general population. Certainly subjects with large adenomas, and those with villous or highly dysplastic adenomas have a higher risk. Often, one would chose the high-risk patients for preventive interventions. Such a strategy makes sense from a risk-benefit point of view. However, from a population perspective, such a strategy may well have only a minor impact on the overall colorectal cancer burden. For more complete population-based prevention, efforts will have to be directed to the numerous individuals who are each at small risk, but who collectively account for most colorectal cancer. For this preventive approach, patients with any adenoma would certainly be part of the target population, and so are sensible subjects in chemoprevention trials. There are similar complexities in consideration of the use of adenomas as endpoints of chemoprevention trials. The adenomas that occur in prevention trials are generally small, and may not be associated with a greatly increased cancer risk. The issue for chemoprevention trials however, is not whether the endpoints are truly intermediate in the causal chain-but whether the intervention under study alters the adenoma recurrence risk to the same extent as it does for colorectal cancer risk. This is a difficult matter to verify, but the limited data available are encouraging. The epidemiology of colorectal adenomas (largely small adenomas) is similar in many regards to that for colorectal cancer itself. Thus to the extent that data are available, one can tentatively conclude that external influences affect adenomas and colorectal cancer similarly. To date, more than ten adenoma prevention trials have reported results. The data have been fairly consistent. Vitamin C (with or without vitamin E) has provided at most a modest protective benefit, except in one small trial in which it was combined with vitamin E and preformed vitamin A. beta-Carotene seems to be without any effect, and interventions to increase fiber and decrease fat intake have not indicated substantial effects. On the other hand, trials among familial polyposis patients have provided evidence for an impact of nonsteroidal anti-inflammatory drugs. Studies in progress have the potential to clarify greatly the preventive potential of the currently promising-but yet unproven-chemopreventive regimens.