Methylation study of tumor suppressor genes in human aberrant crypt foci, colorectal carcinomas, and normal colon.

BACKGROUND: Aberrant crypt foci (ACF) are the earliest preneoplastic lesions in human colon, identifiable on chromoendoscopic screening. Our objective was to evaluate the %methylation of APC, CDKN2A, MLH1, RASSF1, MGMT, and WIF1 tumor suppressor genes (TSG) in ACF, corresponding colorectal carcinomas (CRC), and normal colonic mucosal controls. METHODS: In this study, macroscopically normal-appearing mucosal flaps were sampled 5-10 cm away from the tumor mass from 302 fresh colectomy specimens to identify ACF-like lesions. Thirty-five cases with multiple ACFs were selected (n 35) as the main study group, with corresponding sections from CRC (n 35) as disease controls, and mucosal tissue blocks from 20 colectomy specimens (normal controls), operated for non-neoplastic pathologies. Genomic DNA was extracted, and methylation-specific polymerase chain reaction (PCR) was performed on a customized methylation array model. %Methylation data were compared among the groups and with clinicopathological parameters. Selected target mRNA and protein expression studies were performed. RESULTS: %Methylation of TSGs in ACF was intermediate between normal colon and CRC, although a statistically significant difference was observed only for the WIF1 gene (P < 0.01). Also, there was increased nuclear ß-catenin expression and upregulation of CD44-positive cancer-stem cells in ACF and CRCs than in controls. Right-sided ACFs and dysplastic ACFs had a higher %methylation of CDKN2A (P < 0.01), whereas hyperplastic ACFs had a higher %methylation of RASSF1 (P 0.04). The topographic characteristics of ACFs did not correlate with TSG %methylation. CONCLUSIONS: Early epigenetic methylation of WIF1 gene is one of the mechanisms for ACF development in human colon.

Beyond the Usual Suspects: Primary Premaxilla Sarcoidosis.

Introduction: Sarcoidosis is an idiopathic systemic granulomatous disorder that can affect multiple organs, including rare extrapulmonary sites like the premaxilla. This case report presents a rare occurrence of premaxillary sarcoidosis, a condition scarcely reported in medical literature. Case Report: The patient, a 62-year-old male, presented with a progressively enlarging painless swelling on the right cheek over a three-year period. Despite multiple Fine Needle Aspiration Cytology (FNAC) examinations yielding no conclusive diagnosis, a contrast-enhanced computed tomographic (CT) scan revealed an ill-defined lesion in the premaxillary soft tissue. Biopsy and subsequent excision procedures confirmed the presence of non-caseating granulomas with asteroid bodies, indicative of sarcoidosis. With no systemic involvement and complete excision of the disease, further treatment was not necessary. Conclusion: This case highlights the challenges in diagnosing premaxillary (Extrapulmonary Sarcoidosis) sarcoidosis due to its rarity and resemblance to other dental and maxillofacial conditions and granulomatous lesions. Accurate diagnosis requires a high index of suspicion, multidisciplinary approach, involving clinical assessment, histopathological analysis, and imaging modalities. By deepening our understanding of these uncommon presentations, this report aims to enhance clinical awareness and contribute to improved patient outcomes.

An unusual case of oral sarcoidosis: A diagnostic dilemma.

Sarcoidosis is a rare type of multi-organ granulomatous disease. It is characterised by non-caseating necrotising granulomatous inflammation. The exact mechanism causing the disease is unknown due to its variation of manifestation in patients. The clinical presentation of this disease is protean, and often, patients remain asymptomatic throughout life. The most commonly affected organ by sarcoidosis is the lung accounting for up to 90% of all cases. Oral manifestation is a relatively rare presentation of sarcoidosis, and there are only a few cases reported till date. In this case report, the authors present a case of oral sarcoidosis of the retromolar trigone region.

The rare case of a cystic pancreatic neuroendocrine tumor.

The pancreatic neuroendocrine tumors (PanNETs) most commonly present as solid neoplasms; however, very rarely, they may present primarily as cystic neoplasms. Most of the cystic PanNETs are non-secreting tumors, and the radiological features are not well defined. Hence pre-operative diagnosis is usually challenging and the tumors are misdiagnosed as mucinous cystic neoplasms, intraductal papillary mucinous neoplasms, serous cystic neoplasms, solid pseudopapillary neoplasms, and non-neoplastic cysts. However, the management depends on the accurate diagnosis of these cystic lesions, which poses a dilemma. Herein, we report the case of a cystic PanNET in the tail of the pancreas, which was clinically and radiologically misdiagnosed as a mucinous cystic neoplasm. This case is reported to highlight this issue to the medical community regarding the diagnostic difficulty in such rare non-functioning pancreatic neuroendocrine tumors.

The rare case of a cystic pancreatic neuroendocrine tumor

The pancreatic neuroendocrine tumors (PanNETs) most commonly present as solid neoplasms; however, very rarely, they may present primarily as cystic neoplasms. Most of the cystic PanNETs are non-secreting tumors, and the radiological features are not well defined. Hence pre-operative diagnosis is usually challenging and the tumors are misdiagnosed as mucinous cystic neoplasms, intraductal papillary mucinous neoplasms, serous cystic neoplasms, solid pseudopapillary neoplasms, and non-neoplastic cysts. However, the management depends on the accurate diagnosis of these cystic lesions, which poses a dilemma. Herein, we report the case of a cystic PanNET in the tail of the pancreas, which was clinically and radiologically misdiagnosed as a mucinous cystic neoplasm. This case is reported to highlight this issue to the medical community regarding the diagnostic difficulty in such rare non-functioning pancreatic neuroendocrine tumors.

Tricuspid Valve Hemangioma Associated with Hypoplastic Left Heart Syndrome Presenting as Sudden Infant Death Syndrome.

Primary cardiac tumors are rare in children with a low incidence varying from 0.0017 to 0.28% in autopsy studies. Approximately 90% of the reported primary cardiac tumors in the pediatric population are benign and the most common subtype is rhabdomyomas accounting for approximately 60%, while hemangiomas are rare primary tumors with a 5% incidence. Hypoplastic left heart syndrome is abnormal development of the left-sided cardiac structures, leading to obstruction of blood flow from the left ventricle out-flow tract. Here we report a case of tricuspid hemangioma in association with hypoplastic left heart syndrome, a rare association not previously reported in the literature.

Ambiguous Genitalia Associated with an Extremely Rare Syndrome: A Case Report of XLAG Syndrome and Review of the Literature.

X-linked lissencephaly, absent corpus callosum, and epilepsy of neonatal onset with ambiguous genitalia comprises the XLAG syndrome and only 15 cases have been reported in literature. Due to its rarity, the exact clinical course and outcome are not known. Exact associations of this disease are also elusive. Hereby we are reporting this extremely rare entity and we searched the English literature extensively to get consolidated knowledge regarding this entity that would help the readers. Pre-natal radiological work-up can detect these malformations, which should be followed by medical termination, counseling and karyotyping. Till date the longest survival noted was 4 years only.

Congenital Eccrine Angiomatous Hamartoma: A Rare Entity Revisited.

Eccrine angiomatous hamartoma (EAH) is a rare benign malformation characterized by eccrine and vascular components. It usually presents at birth or during early infancy or childhood on lower extremities as a nodule or plaque. We report a case of asymptomatic tumoral swelling over the left leg in a 5-month-old Indian infant since birth. This was diagnosed as EAH on histopathology and confirmed on immunohistochemistry.

Topographic, histological and molecular study of aberrant crypt foci identified in human colon in different clinical groups.

BACKGROUND/AIMS: Aberrant crypt foci (ACF) are early microscopic lesions of the colonic mucosa, which can be detected by magnified chromoendoscopy. Herein, we have investigated whether ACF identified in different clinical groups can be differentiated based on their characteristics. METHODS: Macroscopically unremarkable mucosal flaps were collected from 270 fresh colectomies and divided into 3 clinical groups: colorectal carcinoma (group A), disease controls having known pre-neoplastic potential (group Bc), and disease controls without risk of carcinoma development (group Bn). Topographic and histologic analysis, immunohistochemistry, and molecular studies (high-resolution melt curve analysis, real-time polymerase chain reaction, and Sanger sequencing) were conducted for certain neoplasia-associated markers. RESULTS: ACF were seen in 107 cases, out of which 72 were left colonic ACF and 35 right colonic ACF (67.2% vs. 32.7%, P=0.02). The overall density of left colonic ACF was 0.97/cm, which was greater than the right colonic ACF density of 0.81/cm. Hypercrinia was present in 41 out of 72 left colonic ACF and in 14 out of 35 right colonic ACF (P=0.01). Immunohistochemical expression of p53 was also greater in left colonic ACF than in right colonic ACF (60.5% vs. 38.2%, P=0.03). However, ACF identified among the 3 clinical groups did not show any distinguishing topographic, histological, or genetic changes. CONCLUSIONS: Left colonic ACF appear to be high-risk based on their morphological and prototypic tumor marker signature. ACF identified in different clinical groups do not show significant genotypic or topographic differences. Further detailed genetic studies are required to elucidate them further.

Identification of High-Risk Aberrant Crypt Foci and Mucin-Depleted Foci in the Human Colon With Study of Colon Cancer Stem Cell Markers.

BACKGROUND: During colonoscopic screening, only macroscopic lesions will be identified, and these are usually the result of multiple genetic abnormalities. Magnification endoscopic detection of aberrant crypt foci (ACF), long before they acquire complex genetic abnormalities, is promising. However, the features of high-risk ACF-like lesions need to be identified. MATERIALS AND METHODS: In the present cross-sectional study, grossly visible normal mucosal flaps were shaved from 152 colectomies, including 96 colorectal cancer (CRC) cases and 56 controls (22 control specimens with disease with malignant potential and 34 without malignant potential). Methylene and Alcian blue stains were performed directly on the unfixed mucosal flaps to identify ACF and mucin-depleted foci (MDF). Detailed topographic analyses, with immunohistochemical staining for ß-catenin and cancer stem cell (CSC) markers (CD44, CD24, and CD166) were performed. RESULTS: ACF, MDF, and ß-catenin-accumulated crypts were detected more in specimens with adjacent CRC. The left colon had ACF with a larger diameter and greater crypt multiplicity, density, and gyriform pit pattern and were considered the high-risk ACF group. MDF, more commonly associated with dysplasia, is also a marker of possible carcinogenesis. The CD44 CSC marker was significantly upregulated in ACF specimens compared with normal controls. Our 3-tier ACF-only pit pattern classification system showed better linearity with mucosal dysplasia than did the 6-tier Kudo classification. CONCLUSION: High-risk ACF, when detected during chromoendoscopic screening, should be followed up. CSCs might play an important role in pathogenesis. Larger studies and genotypic risk stratification for definite identification of high-risk ACF are needed.

Spectrum of hepatobiliary cystic lesions: A 7-year experience at a tertiary care referral center in North India and review of literature.

CONTEXT: Cysts arising from the hepatobiliary tree are a group of heterogeneous lesions with regard to pathogenesis, clinical presentation, and radiological finding. They can be intrahepatic or extrahepatic, developmental, secondary to infective/inflammatory etiologies, as well as neoplastic. This study was conducted to determine the spectrum of hepatobiliary cysts in surgically intervened cases, with regard to their prevalence, histological spectrum, and clinicoradiological correlation, wherever possible. METHODS: In this retrospective observational study, hematoxylin and eosin stained slides of all cases of hepatobiliary cystic lesions, operated between 2009 and 2016 were reviewed. Special stains as reticulin, Masson's trichrome, and periodic acid Schiff were done wherever necessary. Overall prevalence, age-sex distribution, clinical presentation and histopathological patterns were studied. Relevant imaging findings were correlated wherever possible. RESULTS: A total of 312 cases of hepatobiliary cysts were identified, the majority in females. Choledochal cysts (CCs) were the most common type (n = 198,63.5%), followed by hydatid cysts (n = 73,23.3%), simple hepatic cysts (n = 10,3.2%), congenital hepatic fibrosis (n = 10,3.2%), biliary cystadenomas (n = 4,1.2%) hepatic mesenchymal hamartomas (n = 7,2.2%), and cavernous hemangiomas (n = 3,0.9%). Fibropolycystic liver disease (n = 2,0.6%), Caroli's disease (n = 1, 0.3%), liver abscess (n = 2, 0.6%), infantile hemangioendothelioma (n = 1,0.3%), and biliary cystadenocarcinomas (n = 1,0.3%) were rare. Lesions noted mostly in 1st decade of life were: CCs, fibrocystic liver disease, Caroli's syndrome, cystic mesenchymal hamartoma, and infantile hemangioendotheliomas. CONCLUSION: In our cohort of surgically intervened cases of hepatobiliary cystic lesions from a tertiary care hospital in North India, the CCs, followed by hydatid cyst were the most common lesions. Histology can play vital role in characterization, as often clinical findings and radiology can overlap.

Does Hepatocyte Paraffin 1 expression stand a role in determining the site origin of an adenocarcinoma from unknown gastrointestinal primary?

BACKGROUND: Hepatocyte Paraffin 1 (Hep Par 1) was being extensively used to recognize the hepatocellular carcinomas, until recognition of its expression in tumors without hepatocellular differentiation. AIMS AND OBJECTIVES: The aim of this study was to analyze if Hep Par 1 stain can serve as a specific marker of the small intestinal (SI) adenocarcinomas, versus other gastrointestinal tract (GIT) primary tumors. MATERIALS AND METHODS: In this retrospective cross-sectional study, normal GIT mucosa (n - 60), corresponding adenocarcinomas (n - 60) and nodal metastatic foci (n - 60) from the same patients, including 10 cases each from the esophagus, stomach, SI periampullary region, colon, rectum, and gall bladder were included. H-score was calculated by multiplying the stain distribution and intensity scores. The H-scores were compared with other clinical and histological parameters. RESULTS: While normal SI mucosa showed diffuse strong Hep Par 1 staining, normal esophageal and gastric epitheliums were negative and normal colon, rectal, and biliary epithelium showed weak focal positivity. Adenocarcinomas from all these sites, however, showed Hep Par 1 expression, irrespective of the tumor type, site or origin, and tumor stage. The corresponding metastatic sites also showed variable Hep Par 1 positivity, without any site specificity. CONCLUSION: Hep Par 1 stain cannot help to determine the exact site of origin of primary GIT tumors. Its expression in adenocarcinomas across the GIT and their metastatic foci proves that it cannot be regarded as a marker of SI differentiation, especially in malignancy.

Combined presence of multiple gastrointestinal stromal tumors along with duodenal submucosal somatostatinoma in a patient with neurofibromatosis type 1.

Neurofibromatosis type-1 (NF-1) is an autosomal dominant disorder, with increased risk of developing benign and malignant tumors of the gastrointestinal tract (GIT). However, the synchronous presence of multiple GIT stromal tumors and duodenal submucosal somatostatinoma, like in this 50-year-old female NF-1 patient, is very rare. She presented with hematemesis, malena, along with multiple neurofibromas all over the body. Thorough radiological and peroperative work-up revealed multiple ulcerated submucosal and serosal nodules in the proximal small intestine. Histological work-up revealed diagnosis of a duodenal submucosal somatostatinoma with multifocal serosal gastrointestinal stromal tumors. This case is being reported to highlight the rare coincidence of multiple GIT tumors in an NF-1 patient.