Mucinous cystic neoplasms of the mesentery: a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Mucinous cystic neoplasms arise in the ovary and various extra-ovarian sites. While their pathogenesis remains conjectural, their similarities suggest a common pathway of development. There have been rare reports involving the mesentery as a primary tumour site.</p> <p>Case presentation</p> <p>A cystic mass of uncertain origin was demonstrated radiologically in a 22 year old female with chronic abdominal pain. At laparotomy, the mass was fixed within the colonic mesentery. Histology demonstrated a benign mucinous cystadenoma.</p> <p>Methods and results</p> <p>We review the literature on mucinous cystic neoplasms of the mesentery and report on the pathogenesis, biologic behavior, diagnosis and treatment of similar extra-ovarian tumors. We propose an updated classification of mesenteric cysts and cystic tumors.</p> <p>Conclusion</p> <p>Mucinous cystic neoplasms of the mesentery present almost exclusively in women and must be considered in the differential diagnosis of mesenteric tumors. Only full histological examination of a mucinous cystic neoplasm can exclude a borderline or malignant component. An updated classification of mesenteric cysts and cystic tumors is proposed.</p

Pathology of incipient pancreatic cancer

An understanding of incipient pancreatic neoplasia is an essential foundation for the future development of effective screening tests for pancreatic cancer. Only when we understand early pancreatic neoplasms will we be able to detect tumors that are curable with surgical resection. Two approaches have helped define incipient pancreatic neoplasia. First, the histologic examination of pancreata has helped identify the most common histologic lesions in pancreatic tissues adjacent to infiltrating carcinomas. The assumption is that some of these lesions represent the precursors to the infiltrating cancers. Second, advances in molecular genetics now make it possible to define the genetic alterations present in small lesions. The demonstration that a suspected precursor lesion and an infiltrating pancreatic carcinoma share the same genetic alterations would help establish that the lesion is indeed a precursor to infiltrating pancreatic carcinoma. A spectrum of intraductal proliferations in the pancreas has been found associated with infiltrating adenocarcinoma of the pancreas. These lesions, called "duct lesions," have even been identified in pancreata years before patients develop infiltrating carcinoma. Molecular genetic analysis of these lesions has revealed that they frequently harbor many of the same alterations present in infiltrating carcinoma of the pancreas. These alterations include activation of K-ras and inactivation of p16, p53 and, rarely BRCA2. From these morphologic and molecular observations, we can now develop a progression model for the development of infiltrating carcinoma of the pancreas. Infiltrating carcinomas of the pancreas may arise from pancreatic duct lesions, and the progression of duct lesions to infiltrating cancer is associated with the accumulation of generalized and specific genetic alteration

Loss of Smad4 function in pancreatic tumors: C-terminal truncation leads to decreased stability.

At early stages of tumorigenesis, the transforming growth factor-beta (TGF-beta) signaling pathway is thought to have tumor suppressor activity as a result of its ability to arrest the growth of epithelial cells. Smad4 plays a pivotal role in the TGF-beta signaling pathway and has been identified as a tumor suppressor, being mutated or deleted in approximately 50% of pancreatic carcinomas and 15% of colorectal cancers. A nonsense mutation generating a C-terminal truncation of 38 amino acids in the Smad4 protein has been identified in a pancreatic adenocarcinoma (Hahn, S. A., Schutte, M., Hoque, A. T., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H., and Kern, S. E. (1996) Science 271, 350-353), and here we investigate the functional consequences of this mutation. We demonstrate that the C-terminal truncation prevents Smad4 homomeric complex formation and heteromeric complex formation with activated Smad2. Furthermore, the mutant protein is unable to be recruited to DNA by transcription factors and hence cannot form transcriptionally active DNA-binding complexes. These observations are supported by molecular modeling, which indicates that the truncation removes residues critical for homomeric and heteromeric Smad complex formation. We go on to show that the mutant Smad4 is highly unstable compared with wild type Smad4 and is rapidly degraded through the ubiquitin-proteasome pathway. Consistent with this, we demonstrate that the pancreatic adenocarcinoma harboring this mutated allele, in conjunction with loss of the other allele, expresses no Smad4 protein. Thus we conclude that these tumors completely lack Smad4 activity

Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression

Pancreatic adenocarcinoma develops from histologically identifiable intraductal lesions that undergo a series of architectural, cytological, and genetic changes. Limited genetic evidence recently suggested that the p16 gene plays a role in the progression of these "duct lesions." Duct lesions were identified in pancreata from 33 pancreaticoduodenectomies performed for infiltrating adenocarcinoma. All of these infiltrating adenocarcinomas were previously shown to contain alterations in the p16 gene or its promoter. Monoclonal and polyclonal anti-p16 antibodies were used for histological immunodetection. One hundred twenty-six duct lesions were identified. Nine (30%) of 30 flat, 4 (27%) of 15 papillary, 37 (55%) of 67 papillary with atypia, and 10 (71%) of 14 carcinoma in situ duct lesions showed loss of p16 expression. These included 30% of the flat lesions versus 53% of the nonflat lesions and 29% of the nonatypical lesions versus 58% of the atypical lesions. For both comparisons, the differences were statistically significant (P = 0.036 and P = 0.003, respectively). Loss of p16 expression occurs more frequently, but not exclusively, in higher-grade duct lesions. These data support the hypothesis that pancreatic duct lesions are neoplastic and that they represent the precursors of infiltrating adenocarcinoma. Immunohistochemical detection of p16 provides a new technology to study the genetic alterations in and stages of progression of large numbers of morphologically defined pancreatic duct lesion

K-ras mutations in the duodenal fluid of patients with pancreatic carcinoma

Many patients with carcinoma of the pancreas die because their disease is not detected until late in its course. Methods that detect these cancers earlier will improve patient outcome. Over 80% of pancreatic carcinomas contain mutations in codon 12 of the K-ras gene. Screening duodenal fluid for these mutations may lead to early detection of these cancers and assist in establishing a diagnosis of pancreatic carcinoma. Polymerase chain reaction (PCR), with and without restriction enzyme-mediated mutant enrichment, was performed on DNA isolated from duodenal fluid specimens from 61 patients who underwent pancreaticoduodenectomy (Whipple's operation) for either periampullary cancer or a benign condition of the pancreas. Representative sections of pancreas pathology (primary carcinoma, benign tumor, or chronic pancreatitis) from the patients with duodenal fluid specimens containing amplifiable DNA were also analyzed for K-ras mutations. Wild-type and mutant K-ras were detected by hybridization of the PCR products with K-ras codon 12 mutant and wild-type specific probes. Seven of the 61 duodenal fluid specimens contained DNA that did not amplify. Thirteen (24% of the 54 duodenal fluid specimens with amplifiable DNA and 21% of the total of 61 specimens) contained activating point mutations at codon 12 of the K-ras gene. Mutations were detected in 13 of the 51 duodenal fluid specimens from patients with cancer (sensitivity, 25%), whereas mutations were not detected in any of the 9 amplifiable duodenal fluid specimens from patients with benign conditions of the pancreas (specificity, 100%). One duodenal fluid specimen from a patient with adenocarcinoma of the pancreas had two different K-ras mutations. DNA from three of the primary carcinomas did not amplify or was not available. Twenty-nine (69%) of the 42 primary tumors with amplifiable DNA contained K-ras mutations, whereas 3 (30%) of the 10 pancreata with benign conditions harbored mutations. Twenty-two (65%) of 34 ductal adenocarcinomas of the pancreas with amplifiable DNA had K-ras mutations. It is noteworthy that the same mutation was present in both the duodenal fluid and the primary carcinomas of 11 (92%) of the 12 patients who had primary tumors with amplifiable DNA as well as K-ras mutations in their duodenal fluid specimens. The identification of genetic alterations in cancer-causing genes in duodenal fluid may form the basis for the development of new approaches to the detection of carcinoma of the pancreas. Some pancreata without cancer, however, may also harbor K-ras mutations, potentially limiting the specificity of K-ras-based test

Immunohistochemical labeling for the Dpc4 gene product is a specific marker for adenocarcinoma in biopsy specimens of the pancreas and bile duct

We immunohistochemically labeled 72 biopsy specimens from the extrahepatic biliary tree and pancreas for Dpc4 protein and correlated expression with histologic diagnosis and patient follow-up. Specimens were classified histologically as follows: nonneoplastic, 35; neoplastic, 22; atypical, 15. Loss of expression of Dpc4 protein was identified in 12 specimens; 11 were histologically diagnostic of carcinoma. The 12th specimen was from a patient whose biopsy specimen initially was diagnosed as "atypical," but clinical follow-up revealed adenocarcinoma. Of the 12 atypical biopsy specimens with intact expression for Dpc4, follow-up later revealed that 10 were adenocarcinoma. Loss of expression of Dpc4 protein was never identified in a benign specimen. Immunohistochemical labeling for the Dpc4 gene product is a specific marker of carcinoma in biopsy specimens of the pancreas and extrahepatic bile ducts and is marginally helpful in classifying atypical specimens. The sensitivity for carcinoma is low. This latter finding is not unexpected, because the DPC4 tumor suppressor gene is inactivated in only about half of pancreatic and biliary malignant neoplasms. Importantly, loss of Dpc4 expression has been reported in in situ carcinomas, suggesting that loss of expression should not be equated with invasive carcinom

Can K-ras codon 12 mutations be used to distinguish benign bile duct proliferations from metastases in the liver? A molecular analysis of 101 liver lesions from 93 patients.

It can be difficult to distinguish benign bile duct proliferations (BDPs) from well-differentiated metastatic peripancreatic adenocarcinomas on histological grounds alone. Most peripancreatic carcinomas harbor activating point mutations in codon 12 of the K-ras oncogene, suggesting that K-ras mutational status may provide a molecular basis for distinguishing BDPs from liver metastases. The ability of tests for mutations in codon 12 of K-ras to make this distinction was examined in a two-part study. In the first part we determined the K-ras mutational status of 56 liver lesions and 48 primary peripancreatic adenocarcinomas obtained from 48 patients. In the second part of this study an additional 45 liver lesions were studied. In the first 48 patients, activating point mutations in codon 12 of K-ras were detected in 28 (61%) of the 46 primary carcinomas, in 8 (100%) of 8 liver metastases, in 2 (6.5%) of 31 BDPs, and in none (0%) of 14 liver granulomas. Three BDPs and two primary carcinomas did not amplify. To further estimate the prevalence of K-ras mutations in BDPs we analyzed an additional series of 45 mostly incidental BDPs for K-ras mutations. Three (6.7%) of these 45 harbored K-ras mutations. These results suggest that K-ras mutations may be useful in distinguishing BDPs from metastases in the liver; however, there is some overlap in the mutational spectra of BDPs and pancreatic carcinomas

Clinical significance of K-ras oncogene activation in ampullary neoplasms

AIMS: To investigate the prevalence of K-ras codon 12 point mutations in ampullary neoplasms, to explore their clinical usefulness, and to test whether the detection of these mutations could be used to identify ampullary malignancies at an early stage. METHODS: Forty one tumour specimens from 28 patients with ampullary neoplasms were analysed for activating point mutations in K-ras codon 12 using a sensitive polymerase chain reaction (PCR) based assay. RESULTS: Eleven (39%) of the 28 primary tumours harboured point mutations in K-ras. Mutations were identified in seven (41%) of the 17 carcinomas and four (36%) of the 11 adenomas. Four of the possible six permutations in codon 12 were found in these 11 samples. This spectrum of mutations is different from pancreatic carcinoma but resembles that of colorectal neoplasms. Cytological brush specimens were available in 11 cases, and in all of these specimens, the K-ras status in the primary tumour and brush specimens was identical. CONCLUSIONS: K-ras codon 12 point mutations occur in about 40% of ampullary neoplasms at a relatively early stage in tumorigenesis. The pattern of mutations in these tumours resembles that of the adenoma-carcinoma sequence in the colorectum. These results indicate that ampullary neoplasms can be detected at an early stage by searching for genetic alterations in the K-ras oncogene in cytological brush specimen

Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer

It has been estimated that familial aggregation and genetic susceptibility play a role in as many as 10% of patients with pancreatic cancer (PC). The quantified prospective risk of PC among first-degree relatives of PC patients has not been investigated. Families enrolled in the National Familial Pancreas Tumor Registry (NFPTR) prior to September 1, 1998 were followed to estimate the risk and incidence of PC among first-degree relatives of patients with PC. Analyses were performed separately on kindreds with at least two first-degree relatives with PC (familial pancreatic carcinoma (PC); n = 150) at the time the kindred was enrolled in the NFPTR and on kindreds without a pair of affected first-degree relatives (sporadic PC; n = 191). A subanalysis was performed on familial PC kindreds containing three or more affected members at the time of enrollment in the NFPTR (n = 52). Risk was estimated by comparing observed new cases of PC during the observation period with expected numbers based on the United States population-based Surveillance, Epidemiology and End Results program data. Incidence was estimated using person-years risk analyses. During the observational period, six incident PCs developed in the first-degree relatives: two in the sporadic PC kindreds, and four in the familial PC kindreds. The PC risk in the sporadic PC kindreds was not significantly greater than expected [observed/expected = 6.5 (95% CI = 0.78-23.3)] with an incidence rate of 24.5/10(5)/ year. There was a significantly increased 18-fold risk (95% CI = 4.74-44.5) of PC among first-degree relatives in familial PC kindreds, with an incidence of 76.0/10(5)/year. In the subset of familial PC kindreds with three or more affected family members at the time of enrollment, there was a 57-fold (95% CI = 12.4-175) increased risk of PC and an incidence of 301.4/10(5)/year compared with the Surveillance, Epidemiology and End Result age-adjusted incidence of PC in the U.S. (8.8/10(5)/year). When stratified by age, the risk was largely confined to relatives over the age of 60. This study is the first analysis of incident PC occurring in familial PC kindreds. The risk and incidence of PC is exceptionally high among at-risk first-degree relatives in familial PC kindreds in which at least three first-degree relatives have already been diagnosed with PC. Familial PC kindreds are a reasonable high-risk group for PC screening and chemoprevention researc