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ABSTRACT: Nonneoplastic signet-ring cell change (SRCC) is a rare but known phenomenon in gastrointestinal and biliary tracts and is always associated with underlying mucosal ulceration/erosion secondary to infection, ischemia, or other etiology. Because nonneoplastic SRCC closely mimics signet-ring cell adenocarcinoma (SRCA), differentiation of these 2 entities is critical because misdiagnosis of nonneoplastic SRCC as SRCA can lead to intense therapeutic interventions such as surgery and/or chemoradiation therapy. In this review, a brief overview on nonneoplastic SRCC in gastrointestinal and biliary tracts, including the spectrum of clinical presentation, important histologic features, and immunohistochemical markers that are useful in differentiating nonneoplastic SRCC from SRCA, is provided. The pathogenesis of nonneoplastic SRCC in gastrointestinal and biliary tracts is discussed.
Annals of diagnostic pathology 12/2011; 15(6):490-6.
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ABSTRACT: Cancer stem cells (CSC) are unique subpopulations that have the capacity to drive malignant progression and mediate radio/chemoresistance. The role of nestin as a CSC marker in gastric adenocarcinoma is largely unknown. Our objective was to evaluate immunoexpression of CSC markers CD44 and nestin in gastric adenocarcinoma versus non-neoplastic gastric mucosae (NNGM) and correlate it with various clinicopathologic factors. Tissue microarray blocks from 174 cases of gastric adenocarcinoma and 41 samples of adjacent NNGM were assembled. Clinical data including patient's age and sex, tumor histologic subtype and grade, and disease stage were obtained. Expression of CD44 and nestin was assessed by immunohistochemistry. Expression of membranous CD44 (51%, 78/152) and cytoplasmic nestin (25%, 43/174) was significantly greater in gastric adenocarcinoma than in NNGM (P<0.001). A subset of cases (n=15) that co-expressed membranous CD44 and cytoplasmic nestin were significantly more frequent in Lauren intestinal histologic subtype than in diffuse subtype (P<0.05). Foci of intestinal metaplasia (n=6) showed either CD44 (3/6) or nestin (2/6) expression. This is the first study to report the clinicopathologic significance of nestin expression in gastric cancers, and to correlate the nestin expression with CD44, another stem cell marker. The study shows that nestin and CD44, are significantly expressed in a subset of gastric adenocarcinoma, particularly co-expression of nestin and CD44 is significantly revealed in Lauren intestinal histologic subtype. Their expression is also increased in intestinal metaplasia, a premalignant lesion. These findings suggest that CSCs may have a pathogenetic role in the pathway of intestinal metaplasia-intestinal type gastric adenocarcinoma.
International journal of clinical and experimental pathology 01/2011; 4(8):733-41. · 1.89 Impact Factor
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ABSTRACT: fibrolamellar hepatocellular carcinoma (FLHCC) has a better prognosis than conventional hepatocellular carcinoma. Nevertheless, FLHCC has a propensity to recur with limited responsiveness to chemotherapy.
The purpose of this study was to provide insight into the cell cycle biology of FLHCC, as it relates to FLHCC's relatively indolent nature and lack of chemoresponsiveness.
in seven cases of FLHCC, we assessed: 1. immunoexpression of protein analytes indicating cell cycle progression including Ki-67 (G1, S, G2 and M phases) and S-phase kinase-associated protein (Skp) 2 along with the mitotic index (MI); 2.immunoreactivity for cyclin-dependent kinase inhibitors of cell cycle progression from G1 to S phase, p27Kip1 and p16INK4.
the mean percentage of Ki-67 nuclear positivity in neoplastic hepatocytes ranged from 1.0% to 29.7%. Nuclear Skp2 immunoexpression was not observed in any of the cases. The mitotic index was very low (0-1 mitotic figure / 10 high-power fields). All cases showed moderate to strong nuclear p16INK4 positivity (diffuse in five and focal in two). Contras-tively, the adjacent non-neoplastic hepatocytes expressed only mild (2 cases) to no (3 cases) p16INK4.
our analysis has revealed that cell cycle arrest in FLHCC occurs in G0G1 phase and is associated with overexpression of the cell cycle regulator, p16INK4 in tumoral cell nuclei compared with non-neoplastic hepatocytes. In conjunction with our previous immunohistochemical demonstration of a constitutively activated nuclear factor (NF)-kappaB pathway and stemness characteristics of FLHCC with limited differentiation, this cell cycle arrest elucidates the biology of FLHCC's indolent nature and relative chemoresistance.
International journal of clinical and experimental pathology 01/2010; 3(8):792-7. · 1.89 Impact Factor
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ABSTRACT: The mammalian target of rapamycin (mTOR) is centrally involved in growth, survival and metabolism. In cancer, mTOR is frequently hyperactivated and is a clinically validated target for therapy and drug development. Biologically, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTOR complex 1 (mTORC1) which is predominantly cytoplasmic in subcellular localization and mTOR complex 2 (mTORC2) which is both cytoplasmic and nuclear. mTORC1 is sensitive to the selective inhibitor rapamycin. By contrast, mTORC2 is relatively resistant to rapamycin. Moreover, its putative downstream effector, Akt phosphorylated on serine 473 represents a signal transduction pathway for tumor survival. Phospholipase D (PLD) and its product, phosphatidic acid (PA) have been implicated as an activator of mTOR signaling, including the direct phosphorylative activation of p70S6K atthreonine 389. The latter promotes cell cycle progression. In this study, we investigated the activation status and subcellular localization of mTOR and the relative expression of PLD1, as well as their downstream effectors in a spectrum of uterine smooth muscle tumors using normal myometria as controls. The results show significant activation with overexpression of phosphorylated mTORC2 complex in uterine leiomyosarcoma (ULMS) and smooth muscle tumors of uncertain malignant potential (STUMP) as evidenced by nuclear localization of p-mTOR (Ser 2448) in ULMS>STUMP>uterine leiomyoma and normal myometria (p<0.05) and with overexpression of PLD1(p<0.05). Cor-relatively, there are overexpressions of nuclear p-Akt (Ser 473) and nuclear p-p70S6K (Thr 389) in ULMS and STUMP (p<0.05). The activation with overexpression of components of the mTORC2-PLD1 pathway in ULMS and to a lesser degree in STUMP provides insight into their tumorigenic mechanisms. Thus the development of therapies designed to target mTORC2 and PLD1 activity may be beneficial in treating ULMS.
International journal of clinical and experimental pathology 01/2010; 4(2):134-46. · 1.89 Impact Factor
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ABSTRACT: The involvement of cancer stem cells (CSC) in tumorigenesis has been studied in several malignancies, but their presence in fibrolamellar hepatocellular carcinoma (FLHCC) has not previously been evaluated. General characteristics of "stemness" include the expression of putative stem cell antigens, reduced cell cycle progression, and limited functional differentiation or dedifferentiation under the influence of the microenvironment. Immunohistochemical probes applied to 8 archival cases of FLHCC vis-à-vis contiguous non-neoplastic parenchyma, which was present in 5 cases, revealed such stemness characteristics by showing: (a) stem cell antigens, with moderate to intense expression of CD133 in the cytoplasm (6 of 8 FLHCC cases and comprising >40% of the tumoral areas) and of CD44 on the plasmalemmal aspect (7 of 8 FLHCC cases and comprising 50 to 95% of the tumor cells), vs foci of such overexpressions in only 1 of 5 of the contiguous liver parenchyma (p = 0.053 and p = 0.015, respectively); (b) limited G1 to S phase progression ( <1 % of tumor cells with nuclear S phase kinase-associated protein [Skp]2 expression); and (c) dedifferentiation or reduced functional differentiation in the form of minimal to absent expression of a differentiation-associated marker, peroxisomal proliferator-activator receptor (PPAR)-gamma in tumoral nuclei and loss of plasmalemmal expression of beta-catenin in 6 of 8 FLHCC cases vs expression of these proteins in the non-neoplastic, differentiated hepatocytes in 5 of 5 and 4 of 5 cases, respectively, in contiguous liver parenchyma (p <0.01 and p = 0.053, respectively). In contrast, only 1 of 11 cases of well-differentiated, conventional hepatocellular carcinoma (HCC) showed mild to moderate expression of CD133 in the cytoplasm, but with the majority (8 of 11) showing occasional nuclear expression. Similarly, only 3 of 11 cases of conventional HCC expressed plasmalemmal CD44. Notably, 11 of 11 cases of conventional HCC expressed beta-catenin on the plasmalemmal aspect of the tumor cells, and 3 of 11 showed nuclear translocation. These findings in conventional HCC were significantly different from those in FLHCC (p = 0.003, 0.009, and 0.0005, respectively). This study provides evidence of stemness in FLHCC and discusses the implications of stemness in the histogenesis of FLHCC vs conventional, well-differentiated HCC.
Annals of clinical and laboratory science 01/2010; 40(2):126-34. · 0.96 Impact Factor
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International Journal of Colorectal Disease 11/2009; 25(4):539-40. · 2.38 Impact Factor
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Uday C Ghoshal,
Shridhar Tiwari, Sadhna Dhingra,
Rakesh Pandey,
Ujjala Ghoshal,
Shweta Tripathi,
Himani Singh,
V K Gupta,
A K Nagpal,
Sita Naik,
Archana Ayyagari
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ABSTRACT: Despite association between H. pylori and gastric neoplasm (GN) from the developed world, studies from India, where infection is more common and acquired early, are scant and contradictory.
Two hundred and seventy-nine patients with GN from two northern and one eastern Indian centers during the period 1997-2005, 101 non-ulcer dyspepsia (NUD), and 355 healthy volunteers (HV) were evaluated for H. pylori [rapid urease test (RUT), histology and anti-H. pylori, and CagA IgG serology].
Patients with GN [263 gastric carcinoma and 16 (6%) primary gastric lymphoma, 208 male] were older than HV (n = 355, 188 male) and NUD (n = 101, 54 male) patients (53 +/- 12 versus 44 +/- 17 and 43 +/- 13 years, respectively; P < 0.001). Eastern Indian patients with GN (n = 145) were younger than those from northern India (n = 134; 52 +/- 12 versus 55 +/- 12 years; P < 0.007, t-test). In GN and NUD patients H. pylori positivity by RUT [86/225 (38%) versus 46/101 (46%)], anti-H. pylori IgG [154/198 (78%) versus 85/101 (84%)], and histology [136/213 (64%) versus 55/101 (55%)] were comparable (chi(2)-test). Serum IgG anti-H. pylori antibody was more common among HV than among GN patients [300/355 (85%) versus 154/198 (78%); P = 0.04, chi(2)-test]. Intestinal metaplasia was more common in GN than in NUD patients [101/252 (40%) versus 2/98 (2%), P < 0.000, chi(2)-test]. CagAIgG was more common in GN than in NUD patients [124/163 (76%) versus 64/101 (63%)] but comparable to that in HV patients [87/98 (89%), P = NS].
Frequency of H. pylori as detected using endoscopy and serology-based tests is not higher among patients with GN as compared with controls in India.
Digestive Diseases and Sciences 05/2008; 53(5):1215-22. · 2.12 Impact Factor
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ABSTRACT: Fine needle aspiration cytology is not a commonly employed diagnostic modality in the diagnosis of parathyroid tumors.
A 28 year old lady being followed-up for 5 years after en bloc resection of a parathyroid carcinoma presented with a nodule in the lower neck, away from the parathyroidectomy scar. The 1 cm isolated nodule was located in the muscular and subcutaneous plane and corresponded to the needle track of FNA performed on a neck nodule before the parathyroidectomy. On evaluation, she had mild hypercalcemia and high normal serum parathyroid hormone levels. FNAC and histology including immunohistochemistry for Chromogranin A after local excision of the nodule confirmed the nodule to be a recurrent parathyroid carcinoma along the needle track.
To the best of the authors' knowledge, this is only the second case of needle track implantation after FNA in parathyroid carcinoma reported to date. This case highlights the risk of engraftment of parathyroid tissue after FNA and cautions against the use of FNA as a preoperative diagnostic modality for the evaluation of parathyroid lesions.
Langenbeck s Archives of Surgery 12/2006; 391(6):623-6. · 1.81 Impact Factor
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ABSTRACT: A case of eosinophilic variant of chromophobe cell renal carcinoma (EVCCRC), an uncommon variety of renal cell carcinoma, occurred in a 72 year old male. The most problematic differential diagnosis was renal oncocytoma, as the two entities share overlapping features on histology, yet differ completely in biological behavior. EVCCRC is a potentially malignant neoplasm whereas renal oncocytoma is totally benign. Staining with Hale's Colloidal Iron using modified Mowry's technique showed granular cytoplasmic positivity. The diagnosis was confirmed by ultrastructural examination of the tumor which revealed unique features of EVCCRC like presence of numerous cytoplasmic microvesicles along with mitochondria displaying tubulo-vesicular cristae. This case delineates the role of electron microscopic examination as the sole means to differentiate EVCCRC from renal oncocytomas.
Indian Journal of Pathology and Microbiology 05/2005; 48(2):255-7. · 0.68 Impact Factor
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ABSTRACT: Dapsone can rarely cause a hypersensitivity reaction called dapsone syndrome, consisting of fever, hepatitis, exfoliative dermatitis, lymphadenopathy and hemolytic anemia. Dapsone syndrome is a manifestation of the DRESS (drug rash with eosinophilia and systemic symptoms) syndrome which is a serious condition that has been reported in association with various drugs. Cholangitis in dapsone syndrome has not been reported so far in the world literature.
We report a patient who presented with fever, exfoliative dermatitis, jaundice and anemia within three weeks of starting of dapsone therapy. These features are typical of dapsone syndrome, which is due to dapsone hypersensitivity and is potentially fatal. Unlike previous reports of hepatitic or cholestatic injury in dapsone syndrome we report here a case that had cholangitic liver injury. It responded to corticosteroids.
We conclude that cholangitis, though unusual, can also form a part of dapsone syndrome. Physicians should be aware of this unusual picture of potentially fatal dapsone syndrome.
BMC Gastroenterology 09/2003; 3:21. · 2.42 Impact Factor
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ABSTRACT: To evaluate the diagnostic accuracy and reliability of preoperative ultrasound (US)-guided fine needle aspiration cytology (FNAC) in the diagnosis of xanthogranulomatous cholecystitis (XGC) and coexistent lesions (carcinoma) and also to evaluate the possibility ofmissing either carcinoma or XGC on cytology.
The cytologic diagnoses of XGC and coexistent lesions were made according to standard criteria. In a prospective, 5-year study, preoperative US-guided FNAC from 42 cases of XGC was compared with follow-up histologic diagnoses, which were available in 31 cases. When FNAC after the first aspiration showed the aspirate to be nondiagnostic, FNAC was repeated under US guidance.
Preoperative US-guided FNAC diagnoses of XGC were made in 31 cases, for which follow-up histology was available in all cases. US-guided FNAC diagnosis ofXGC only was made in 30 cases and coexistent lesions in 1 case. Followup histology revealed 26 cases of XGC, 4 of a coexistent lesion and 1 of squamous cell carcinoma only. The overall diagnostic accuracy of preoperative US-guided FNAC was 96.77%. The overall possibility of missing XGC was 3.33% and that of carcinoma, 12.01%.
Preoperative US-guided FNAC is safe, rapid, reliable, cost-effective and accurate in diagnosing XGC. However, the possibility ofcoexistent carcinoma cannot be definitely ruled out. It is therefore recommended that FNAC be performed from multiple suspicious sites under radiologic guidance. Thus, preoperative US-guided FNAC diagnosis would help in determining the urgency of treatment and also in planning the surgical procedure for gallbladder lesions.
Acta cytologica 51(1):37-41. · 0.49 Impact Factor
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ABSTRACT: Despite a possible role of Helicobacter pylori in gastric carcinoma (GC), its pathogenesis is not clear. There is scanty data on apoptosis in GC in relation to H. pylori and CagA antibody. Therefore, we studied gastric epithelial apoptosis in GC and non-ulcer dyspepsia (NUD) with or without H. pylori infection, and the degree of apoptosis in relation to CagA antibody status.
20 patients each with GC and NUD were investigated for H. pylori using rapid urease test (RUT), IgG anti-H. pylori and anti-CagA antibodies, histology of endoscopically normal-looking mucosa for H. pylori, intestinal metaplasia (IM), and apoptosis using TUNEL assay. Positivity to one tissue-based (RUT or histology) and one serology based (anti-H. pylori or CagA IgG) test was taken as diagnostic of active H. pylori infection, and negative result in both tissue-based tests suggested its absence.
Patients with GC more often had anti-H. pylori IgG (16 of 20 vs. 8 of 20; p=0.02) and a trend towards higher apoptotic index (AI) (48.6 [19.2 to 71.7] vs. 41.4 [11.7 to 63.6]; p=0.06) than NUD. AI was higher in GC (66.7 [57.5 to 71.7] vs. 32.6 [19.2 to 39.8]; p<0.0001) and NUD (58.6 [50.7 to 63.6] vs. 24.4 [11.7 to 32.2]; p<0.0001) infected with H. pylori than in those without infection. AI was also higher in GC than in NUD with H. pylori infection (66.7 [57.5 to 71.7] vs. 58.6 [50.7 to 63.6]; p=0.01). Four of the 20 patients with GC and none with NUD had IM (p=ns). There was no difference in AI in relation to CagA antibody. AI positively correlated with patients' age in presence of H. pylori infection (correlation coefficient=0.5, p=0.03) but not in its absence.
Exaggerated apoptosis may play a role in H. pylori-mediated gastric diseases including carcinogenesis. AI increases with aging in patients infected with H. pylori.
Indian Journal of Gastroenterology 24(5):193-6.
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ABSTRACT: To evaluate the diagnostic efficacy of abdominal fat pad aspiration cytology as a screening procedure for systemic amyloidosis and to assess the clinical usefulness of semiquantitative grading criteria of fat pad amyloid deposits.
Aspiration cytology samples from 297 cases of abdominal fat pad were retrospectively analyzed for amyloid deposits. The smears were graded semiquantitatively. The deposits in the smears were compared with histologic evidence of amyloidosis in deeper tissues in 44 cases.
Retrospective analysis of 297 cases of aspiration cytology revealed amyloid in 90 cases. Follow-up biopsies from deeper tissues in 44 cases showed presence of systemic amyloidosis in 13 cases. The sensitivity and specificity of abdominal fat pad fine needle aspiration cytology was 78% and 93%, respectively. The positive predictive value was 84% and negative predictive value 90%.
Fat pad aspiration cytology is a useful screening procedure for diagnosis of systemic amyloidosis. Patients with grade 1 deposits should not undergo a toxic therapeutic regimen on the basis of fat pad cytology alone; histologic confirmation of visceral amyloid deposition in deeper tissue is advised. Patients with grades 2 and 3 deposits may undergo suitable therapy for amyloidosis.
Acta cytologica 51(6):860-4. · 0.49 Impact Factor
