Intraductal papillary mucinous neoplasm of the pancreas and associated lesions.
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Adenocarcinoma, Mucinous↗
Biomedical subjects
Runjan Chetty
Publications and source records attributed to Runjan Chetty.
Microsatellite analysis of the APC gene and immunoexpression of E-cadherin, catenin, and tubulin in esophageal squamous cell carcinoma.
The histological features that accompany the development and progression of solid tumors are known to be controlled by a distinct cascade of molecular events. One such event is the inactivation of tumor suppressor genes, such as the adenomatous polyposis coli (APC) gene. Disruption of the cadherin-catenin cell adhesion complex also plays a role in the initial steps of cancer invasion and metastasis whereas alterations in cell structural molecules, such as tubulin, may contribute to the cancer phenotype. The understanding of the status of these molecules in ESSC may provide novel markers that could impact on management of the disease. The present study examined alterations in the microsatellite sequence of the APC gene via fluorescent-based polymerase chain reaction in 100 cases of primary esophageal squamous cell carcinoma. In addition, the expression of E-cadherin, alpha- and beta-catenin, and alpha- and beta-tubulin was analyzed using immunohistochemistry. These data were then statistically compared with each other as well as the relevant clinicopathologic data. Although the APC markers (D5S210, D5S346, D5S299, and D5S82) tested did show an overall high frequency of allelic imbalance/loss of heterozygosity (62.48%) and microsatellite instability (41.27%), they did not show prognostic significance in the study cohort and were not correlated with the immunohistochemical data. The tubulin proteins showed no significant change in expression in the tumor tissue The decreased immunoreactivity of E-cadherin was statistically correlated with the presence of lymph node metastases (P = .0180). Although alpha- and beta-catenin as well as E-cadherin showed no direct prognostic value, E-cadherin may warrant further investigation as an indirect prognostic indicator by allowing more accurate prediction of lymph node metastases.
Cadherins↗
Expression of Wnt-signaling pathway proteins in intraductal papillary mucinous neoplasms of the pancreas: a tissue microarray analysis.
Abrogation of the Wnt-signaling pathway is implicated in the carcinogenesis of several malignancies, especially colorectal cancer where up to 90% of cases are thought to have impaired Wnt signaling. It is less frequently involved in conventional ductal pancreatic adenocarcinoma. This pathway has not been explored in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas previously and formed the basis of this study. A tissue microarray of 18 cases of IPMN was stained for proteins involved in the Wnt pathway: adenomatous polyposis coli (APC), pan-beta-catenin, axin 2, glycogen synthase 3alphabeta and 3beta, c-myc, E-cadherin, and cyclin D1. The IPMNs were classified as 8 adenomas, 3 borderline, and 7 cases with carcinoma in situ and/or invasive carcinoma, occurring in 13 females, and the overall age range was 45 to 73 years. Immunohistochemical analysis showed nuclear beta-catenin staining in 7 (39%) of the 18 cases. The cases with nuclear beta-catenin localization included 1 adenoma, 2 borderline IPMN, and 4 carcinomas in situ and/or invasive carcinomas. Seven cases showed absence of APC immunostaining and these included 4 cases with nuclear beta-catenin localization. Fourteen cases displayed marked diffuse up-regulation of c-myc protein, and 12 cases also showed diffuse cyclin D1 protein overexpression. E-cadherin expression was intense and membrane in location (comparable to normal tissue) in 6 of 8 adenomas (no tissue was available in 1 case). Decreased E-cadherin staining was noted in 8 cases where tissue was available for assessment. There was progressive decrease in membrane staining of E-cadherin in 2 of 3 borderline lesions, 1 of 2 carcinomas in situ, and 4 of 5 invasive carcinomas. All other immunostains were either normal in distribution or did not show any correlation with beta-catenin or clinicopathologic parameters. In conclusion, 7 (39%) of 18 cases of IPMN in this study demonstrated abnormal localization of beta-catenin, 4 of which also lacked APC expression. Of 5 carcinomas arising in IPMN, 4 displayed a decrease in E-cadherin expression. There was also a trend for the higher grades of IPMN to show nuclear localization of beta-catenin. These findings suggest that a proportion of cases of IPMN may show abnormalities in the Wnt-signaling pathway with consequent altered expression of downstream related proteins.
Adenoma↗
Pancreatic endocrine tumour with ductules: further observations of an unusual histological subtype.
AIMS: Pancreatic endocrine tumours (PET) containing ductules are an uncommon histological variant. Considerable conjecture surrounds the origin and histogenesis of the ductules. Opinions range from the ductules being an inherent part of the tumour, to others who feel they are merely entrapped. A study of 21 cases of this variant was undertaken with particular attention paid to the distribution and morphology of the ductules, the presence of entrapped acinar tissue and the surrounding uninvolved pancreatic tissue. METHODS AND RESULTS: Twenty-one cases were detailed occurring in either gender equally and with a wide age range (19-85 years). All cases, except one, were sporadic, the vast majority were located in the tail and were of small size (less than 2.0 cm). All cases were typified by stromal fibrosis, either diffuse (15) or in the form of septae (6). Embedded within the fibrous tissue were ductular structures, some of which were dilated and ectatic. The ductules were centrally located (5), at the periphery of the tumour (9) or diffusely scattered throughout the lesion (7). All cases showed ductulo-insular complexes. Insulin was demonstrated in 15 immunohistochemically. CONCLUSIONS: It is likely that in some cases the ductules are entrapped as the tumour grows into surrounding normal pancreatic tissue and the ductular proliferation is a secondary phenomenon. In a proportion of cases, the ductules are likely to be a part of the tumour arising as part of focal chronic inflammation or as a result of the growth factor effects of insulin, in cases associated with insulin production. There is nothing to suggest that the ductules confer any special biological characteristics to the PET and are merely a histological nuance. However, some cases may have a dominant tubular component, which could present problems at frozen section where the association with fibrosis may invoke a mistaken diagnosis of pancreatic ductal adenocarcinoma or chronic pancreatitis.
Adenocarcinoma↗
Lipid-rich variant of pancreatic endocrine neoplasms.
Most pancreatic endocrine neoplasms (PENs) show characteristic and well-recognized endocrine morphology; however, a lipid-rich pattern, which can present a diagnostic problem in biopsies, has been reported, mostly as individual cases. Some have been included in descriptions of the rare clear-cell variant associated with von Hippel-Lindau (VHL) syndrome. The histogenesis, clinicopathologic characteristics, and significance of this lipid-rich pattern have not been unraveled. In this study, 11 PENs exhibiting foamy, microvesicular cytoplasm were analyzed. In some cases, the nuclei were distorted by the vesicles, and the usual endocrine chromatin pattern was not evident. The growth pattern was relatively diffuse, with vague compartmentalization of the cells by a delicate vasculature; prominent nesting was noted in only 4 cases. Pathology reports indicated substantial diagnostic challenge in these cases; on biopsies, 1 case was originally diagnosed as adrenal cortical carcinoma, another as renal cell carcinoma, a third as solid-pseudopapillary tumor, and a fourth had a fine needle aspiration cytologic diagnosis of adenocarcinoma. All cases were chromogranin and synaptophysin positive. Electron microscopy in 3 cases confirmed the cytoplasmic vesicles to be lipid vacuoles. Neurosecretory granules were also evident. Clinically, as in conventional PENs, there appeared to be two distinct subsets: Two cases were familial or functional/syndromic (1 with VHL and the other with MEN-1 and glucagonoma syndrome) and occurred in younger adults (ages 41 and 47 years); the majority (n = 9) were nonfunctional/nonsyndromic and nonfamilial. The latter group was mostly represented by elderly males (mean age: 65 vs. 58 years in conventional sporadic PENs). Immunohistochemically, markers implicated in VHL-associated neoplasia, including HIF-1alpha, inhibin, and Melan-A (in clear-cell PENs) and MUC6 (in serous cystadenomas) were mostly negative in lipid-rich PENs (1 of 10, 1 of 10, 0 of 10 and 0 of 10, respectively). In conclusion, the lipid-rich pattern, reminiscent of adrenal cortical cells, represents a distinct subset of PENs. It presents a diagnostic challenge for surgical pathologists, especially in biopsies. EM supports the name lipid-rich for this variant. The findings suggest that the pathogenesis of lipid-rich tumors may be different from the VHL-associated clear-cell variants of PENs.
Adenocarcinoma↗
Lymphedematous HIV-associated Kaposi's sarcoma.
BACKGROUND: Advanced Kaposi's sarcoma is frequently associated with chronic lymphedema (cLO). The histopathological features of lymphedematous HIV-associated KS (KS) are poorly documented and the co-existence of fibroma-like nodules in lymphedematous KS is under-recognized. The aims of this study were to assess the clinicopathological spectrum and diagnostic difficulties associated with lymphedematous KS and to highlight the clinicopathological profile of fibroma-like nodules. In addition, the pathogenesis of fibroma-like nodules and cLO is revisited. MATERIALS AND METHODS: Prospective 17-month clinicopathological study of all biopsies from patients with lymphedematous KS. RESULTS: Seventy-four biopsies, the majority from the lower limbs, from 41 patients were evaluated. Nineteen, 14, five and three patients had one, two, three or four biopsies each, respectively. In 14 biopsies, there was poor clinicopathological correlation of KS stage. Exclusive lesional KS (patch, plaque, nodule or lymphangioma-like) was identified in 29 biopsies; 23 and eight biopsies demonstrated KS or fibroma-like morphology and the adjacent dermis demonstrated cLO. There was variable intratumoral and peritumoral venous compression and lymphatic dilatation. Fourteen biopsies demonstrated cLO exclusively. Smaller fibroma-like nodules lacked KS spindle cells, whereas >5 mm nodules demonstrated focal KS spindle cell proliferation and aggregation on extensive sectioning. The subcutis of 42 biopsies demonstrated variable fibrosis, hemosiderin deposits, lymphocytes, plasma cells, KS, interstitial granular material and pools of lymph fluid. Subcutaneous abscesses were identified in six biopsies. All biopsies had variable epidermal features of cLO. CONCLUSIONS: cLO influences clinicopathological correlation of KS stage and may also mask the presence of KS and the co-existence of subcutaneous abscesses. Smaller fibroma-like nodules are hypothesized to be a manifestation of cLO that have the potential to acquire the characteristics of KS. Lymphatic and venous obstruction, protein-rich interstitial fluid, tissue hemosiderin and subcutaneous infection are hypothesized to play a combined role in the evolution and perpetuation of cLO.
Acquired Immunodeficiency Syndrome↗
Intracytoplasmic inclusions (including the so-called "rhabdoid" phenotype) in pancreatic endocrine tumors.
The cytoplasm of pancreatic endocrine tumors (PET) can show a diverse range of appearances from clear, to oncocytic, to intracellular mucin accumulation, and the presence of intracytoplasmic inclusions. Intracytoplasmic eosinophilic inclusions can vary morphologically and the spectrum ranges from small, dot-like hyaline inclusions, to deeply acidophilic/eosinophilic ones that occupy almost the whole cytoplasm and displace the nucleus eccentrically: the so-called "rhabdoid" phenotype. The aim of this study was to analyze the frequency, morphology, behavior, and relationship to clinicopathological features of large intracytoplasmic inclusions, including the rhabdoid phenotype, in a large number of PET. The morphological features of 84 cases were assessed for the presence of large, globular intracytoplasmic inclusions. Fourteen of 84 cases contained intracytoplasmic inclusions with 5 cases containing cells conforming to the characteristic rhabdoid morphology. The remaining nine cases showed pale intracytoplasmic inclusions. Four of the five cases with rhabdoid cells had spread to lymph nodes and/or peripancreatic fatty tissue. This study confirms that a spectrum of large intracytoplasmic inclusions is encountered in PET, ranging from lightly eosinophilic intracytoplasmic globules to the more typical rhabdoid phenotype (deeply eosinophilic inclusions). This phenotype, in particular the rhabdoid cells, is worthy of attention as a proportion may show lymphovascular invasion with evidence of metastasis at the time of presentation, irrespective of size, mitotic rates, or necrosis.
Adenoma, Islet Cell↗
A 60-year-old woman with lymphoma and postchemotherapy thickening of the urinary bladder wall. Cytomegalovirus cystitis associated with immunosuppression.
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Antineoplastic Agents, Alkylating↗
Differential gene expression profile reveals deregulation of pregnancy specific beta1 glycoprotein 9 early during colorectal carcinogenesis.
BACKGROUND: APC (Adenomatous polyposis coli) plays an important role in the pathogenesis of both familial and sporadic colorectal cancer. Patients carrying germline APC mutations develop multiple colonic adenomas at younger age and higher frequency than non-carrier cases which indicates that silencing of one APC allele may be sufficient to initiate the transformation process. METHODS: To elucidate the biological dysregulation underlying adenoma formation we examined global gene expression profiles of adenomas and corresponding normal mucosa from an FAP patient. Differential expression of the most significant gene identified in this study was further validated by mRNA in situ hybridization, reverse transcriptase PCR and Northern blotting in different sets of adenomas, tumours and cancer cell lines. RESULTS: Eighty four genes were differentially expressed between all adenomas and corresponding normal mucosa, while only seven genes showed differential expression within the adenomas. The first group included pregnancy specific beta-1 glycoprotein 9 (PSG9) (p < 0.006). PSG9 is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy, mainly by syncytiotrophoblasts. Further analysis of sporadic and familial colorectal cancer confirmed that PSG9 is ectopically upregulated in vivo by cancer cells. In total, deregulation of PSG9 mRNA was detected in 78% (14/18) of FAP adenomas and 75% (45/60) of sporadic colorectal cancer cases tested. CONCLUSION: Detection of PSG9 expression in adenomas, and at higher levels in FAP cases, indicates that germline APC mutations and defects in Wnt signalling modulate PSG9 expression. Since PSG9 is not found in the non-pregnant adult except in association with cancer, and it appears to be an early molecular event associated with colorectal cancer monitoring of its expression may be useful as a biomarker for the early detection of this disease.
Adenomatous Polyposis Coli↗
Bizarre stromal cells in ischemic bowel disease.
The presence of bizarre stromal cells has been reported in gastrointestinal and extraintestinal lesions. We describe, for the first time, the presence of bizarre stromal cells with a cytomegalovirus (CMV)-like appearance or ganglion-like cells in 3 cases of ischemic colitis. The 3 patients were males ranging in age from 62 to 78 years, showed varying degrees of cardiovascular insufficiency, and were diagnosed with ischemic colitis. Colonic biopsies showed changes of ischemic colitis of variable severity. Common to all 3 cases, within the granulation tissue, stromal cells showed a broad spectrum of morphologic alterations, ranging from just nuclear enlargement to striking atypical features, large pleomorphic, hyperchromic nuclei, and eccentric prominent nucleoli. Occasionally, these cells displayed an eosinophilic oval nuclear inclusion, surrounded by a clear halo, resembling CMV inclusions. In conclusion, the etiopathogenesis of these cells can be partially explained by hypoxia, inflammation, regeneration/repair, and cell turnover alone or, more probably, in combination in the granulation tissue response to injury. The morphologic spectrum of bizarre stromal cells and ganglion-like cells suggests an obvious differential diagnosis, which includes carcinoma and sarcoma. The finding of enlarged cells with eccentric intranuclear eosinophilic inclusions requires the exclusion of CMV. However, immunohistochemistry, together with an awareness of those atypical stromal cells, can occur in the setting of ulceration and/or polypoid lesions, preventing an incorrect diagnosis.
Aged↗
Pancreatic endocrine tumors with ductules.
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Carcinoma, Islet Cell↗
Basaloid squamous carcinoma of the anal canal with an adenoid cystic pattern: histologic and immunohistochemical reappraisal of an unusual variant.
Two cases of a distinctive variety of basaloid squamous carcinoma (BSC) of the anal canal are described. Both occurred in female patients who presented with bleeding per rectum. Histologic evaluation of the tumors showed lobules and aggregates of medium-sized basaloid cells with distinctive peripheral palisading and focal areas of central, comedo-necrosis. Accompanying dysplasia of the overlying squamous mucosa was absent. However, the microscopic pattern was dominated by the presence of eosinophilic, hyaline, paucicellular basement membrane-like material around and within tumor nests. This appearance together with microcystic spaces simulated that of an adenoid cystic carcinoma. Immunohistochemistry of the tumors revealed the following profile: CK7, CK5/CK6, 34betaE12 positive, CK14 focally positive but CK20 negative. The following were all negative: EMA, CEA, smooth muscle and muscle-specific actin, calponin, and S-100. The tumor cells exhibited diffuse nuclear positivity with p63. The eosinophilic basement membrane hyaline material was positive for collagen type IV and also for laminin. BSC of the anal canal with an adenoid cystic pattern is an infrequently encountered and reported variant, although it is seen more often in the aerodigestive tract. There may be an increased propensity for BSC with an adenoid cystic pattern to metastasize to the liver, but the number of cases encountered are too small to be definitive. The histologic differential diagnosis is true salivary gland-type adenoid cystic carcinoma and basal cell adenocarcinoma. Immunohistochemistry and awareness of this unusual pattern of BSC will facilitate the correct diagnosis being reached.
Anal Canal↗
Epidermal growth factor receptor expression in anal canal carcinoma.
Most anal canal carcinomas (ACCs) are squamous cell carcinomas (SCCs). SCCs in other tumor sites strongly express epidermal growth factor receptors (EGFRs), the inhibition of which might result in favorable changes in tumor growth. A review of the published scientific literature reveals no information regarding the expression of EGFR in ACCs. Therefore, we obtained archived pathology samples from ACC biopsies and examined the frequency and level of expression of EGFR and other cell surface and cell cycle markers. The 21 samples studied universally and strongly expressed EGFR and were negative for HER-2. Clinical studies of EGFR inhibitors in advanced ACC are warranted.
Aged↗
Low sensitivity of a nested polymerase chain reaction in oropharyngeal washings for the diagnosis of pneumocystis pneumonia in HIV-infected patients.
STUDY OBJECTIVE: To compare the relative yield and diagnostic utility of the polymerase chain reaction (PCR) analysis for Pneumocystis jirovecii DNA in oropharyngeal washings using transbronchial biopsy (TBBx) and BAL as "gold standards." DESIGN: Prospective study. SETTING: Academic tertiary center. PATIENTS: Oropharyngeal washes were obtained in 50 consecutive patients with clinical pneumocystis pneumonia (PCP). Because of varying clinical severity, not all patients tolerated bronchoscopy. Thirty-five patients underwent TBBx, and 48 patients underwent BAL. METHODS: DNA extracted from oropharyngeal washings and BAL was subjected to a nested PCR test using primers for the large subunit mitochondrial ribosomal RNA of P jirovecii. Oropharyngeal washings were compared with BAL PCR and TBBx. RESULTS: Sixteen of the 35 TBBx procedures had positive results for PCP (46%). Oropharyngeal washings yielded positive results for pneumocystis in 7 of the 16 patients (sensitivity, 44%; specificity, 79%). Thirty-five of 48 patients (73%) had positive PCR results on BAL analysis. The relative yield of the PCR in oropharyngeal washes compared with BAL fluid was 40% (14 of 35 washes), giving a sensitivity of 40% and specificity of 77%. CONCLUSION: PCR DNA amplification of oropharyngeal washings in HIV-seropositive subjects has a low sensitivity and specificity for the diagnosis of PCP.
AIDS-Related Opportunistic Infections↗
Spindle cell pancreatic endocrine tumor associated with Cushing's syndrome.
A 59-yr old female presented with Cushing's syndrome due to ectopic ACTH production. At the time of initial diagnosis an obvious source for the Cushing's syndrome was not found and the patient was treated with bilateral adrenalectomy. Three years later she presented with hyperpigmentation and evidence of ACTH overproduction. This time a CT scan localized a mass to the tail of the pancreas and a distal pancreatectomy was performed. The mass was composed of compact plump spindle cells arranged in interlacing fascicles, was well circumscribed, and did not display angioinvasion. Although isolated punctate foci of necrosis were noted, the overall mitotic count was 1 per 10 high power fields. Immunohistochemistry showed the tumor to be positive for chromogranin, synaptophysin, and ACTH. This case highlights an unusual histological variant of pancreatic endocrine tumor (PET), namely, one composed almost exclusively of interlacing spindle-shaped cells. This raises a wide differential diagnosis and the use of immunohistochemistry is required to arrive at the correct diagnosis. ACTH-producing PET are usually aggressive lesions with metastases at the time of presentation and aggressive biological behavior. However, this case was characterized by an indolent clinical course.
Adrenocorticotropic Hormone↗
Expression profiling by microarrays in colorectal cancer (Review).
Genome-wide gene profiling studies using microarrays have the potential to improve diagnosis and treatment of human cancers. Microarrays have identified many genes that are deregulated in colorectal cancer compared to normal tissue. Groups of genes that are predictive of tumor stage or presence of metastases, hence putatively associated with cancer progression have also been revealed. Microarray studies have identified genes whose expression are impacted by chemotherapies for colorectal cancer, thus could potentially be used to predict response to treatments. Unique gene expression profiles have also been used to classify metastases of uncertain origin. The wide application of microarrays generates exciting prospects in translational research. However, to date overlaps of candidate gene lists associated with specific clinical/biological phenotypes remain disturbingly poor between studies. Overfitting, bias, reporting of only the best results, and fidelity of probe annotations could present limitations for the interpretation of results shown in microarray publications. Making raw data from these microarray experiments publicly available for analysis by other investigators using different analytical algorithms or for in silico studies may facilitate the most thorough mining of data from these expensive studies. Validations of the results using other more precise techniques and at the biological level represent critical follow-up goals for microarray studies.
Adenoma↗
Microsatellite analysis of the DCC gene in nephroblastomas: pathologic correlations and prognostic implications.
Microsatellite instability has been reported in a wide variety of cancer types. Inactivation or loss of tumour suppressor genes has been shown to result in cell cycle deregulation and neoplastic growth. We conducted a microsatellite study using fluorescent-based DNA technology to determine whether mutations in the microsatellite sequences of the deleted in colorectal cancer (DCC) gene, a tumour suppressor at 18q21.1, have any pathologic correlation or prognostic significance in nephroblastomas. Normal and tumour DNA was isolated from 106 cases of nephroblastoma using the standard proteinase K digestion and phenol-chloroform extraction method from paraffin wax-embedded tissue. Polymerase chain reaction using three microsatellite markers; D18S21, D18S34 and D18S58, for the DCC gene were performed. The polymerase chain reaction products were analysed on the ALF Express Automated DNA sequencer. The results were correlated with age at diagnosis, preoperative chemotherapy, clinicopathological stage, histological classification and patient outcome using chi(2) test. Allelic imbalance/loss of heterozygosity appeared to be a more frequent genetic aberration than microsatellite instability with 20% of cases showing allelic imbalance/loss of heterozygosity and only 9% of cases showing microsatellite instability. Genetic aberrations were more frequent in unfavourable histology tumours compared to favourable histology tumours (P=0.012). All patients with genetic aberrations for more than one DCC marker died independent of histological classification and stage (P=0.016). There was no statistically significant difference when DCC aberrations were compared with age at diagnosis, preoperative chemotherapy and clinicopathological stage. In conclusion, this study has found that multiple aberrations involving the DCC locus may play a role in the progression of nephroblastomas, and hence confer a poorer prognosis.
Adolescent↗