Sanjay Kakar

University of California, San Francisco, San Francisco, California, United States

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Publications (91)348.02 Total impact

  • Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 01/2015; 28(1):159-60.
  • Source
    Human pathology 12/2014; · 2.81 Impact Factor
  • Archives of pathology & laboratory medicine 10/2014; · 2.88 Impact Factor
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    ABSTRACT: The data used for the World Health Organization (WHO) classification of hepatocellular adenoma (HCA) is largely based on cases from tertiary level centers in Europe. This study examines the distribution of HCA subtypes in a large community population and determines the impact of immunohistochemistry (IHC) on reclassification, diagnosis, and management. All cases diagnosed as HCA in a large community hospital network from 2000–2010 were reviewed. The following immunohistochemical stains were evaluated in cases where paraffin-embedded tissue was available (n = 35): β-catenin, glutamine synthetase (GS), serum amyloid A (SAA), C-reactive protein (CRP), liver fatty acid binding protein (LFABP). 28 of 35 cases were confirmed to be HCA, 5 cases were reclassified as well-differentiated hepatocellular carcinoma (HCC), and 2 cases were reclassified as focal nodular hyperplasia (FNH). The HCA cases were further subclassified into hepatocyte nuclear factor 1α (HNF1α) inactivated (29%), inflammatory (32%), inflammatory with β-catenin activation (3%), non-inflammatory β-catenin activated (0%), and unclassified (36%). Long-term follow-up was available on 33 of 35 cases and there were no cases of recurrence or distant metastasis. Immunohistochemistry can provide a definite HCA subtype in two-thirds of cases. HCA subtypes in this large community-based population differed from the prior large French studies, in that there were a greater proportion of unclassified adenomas and a virtual absence of β-catenin activated adenomas. It is likely that most β-catenin activated hepatocellular tumors show morphologic and reticulin staining abnormalities indicative of well-differentiated HCC. Immunohistochemistry for GS and SAA can identify cases with β-catenin activation, and aid in the distinction of inflammatory adenoma and FNH.
    Human pathology 05/2014; · 2.81 Impact Factor
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    ABSTRACT: Well-differentiated hepatocellular carcinoma in non-cirrhotic liver can show morphological features similar to hepatocellular adenoma. In rare instances, hepatocellular carcinoma can arise in the setting of hepatocellular adenoma. This study compares the immunohistochemical and cytogenetic features of the hepatocellular adenoma-like and hepatocellular carcinoma portions of these tumors. Immunohistochemistry for β-catenin, glutamine synthetase, serum amyloid A protein, glypican-3, and heat-shock protein 70 was done in 11 cases of hepatocellular carcinoma arising in hepatocellular adenoma in non-cirrhotic liver. Tumors with nuclear β-catenin and/or diffuse glutamine synthetase were considered β-catenin activated. Fluorescence in situ hybridization (FISH) was done in nine cases for gains of chromosomes 1, 8 and MYC. There were seven men (33-75 years) and four women (29-65 years). Focal atypical morphological features were seen in hepatocellular adenoma-like areas in 7 (64%) cases. Hepatocellular adenoma-like areas showed features of inflammatory hepatocellular adenoma in 7 (64%) cases; 4 of these were also serum amyloid A-positive in the hepatocellular carcinoma portion. β-Catenin activation, heat-shock protein 70 positivity, and chromosomal gains on FISH were seen in the hepatocellular adenoma portion in 55%, 40%, and 56% of cases, and 73%, 60%, and 78% of cases in the hepatocellular carcinoma portion, respectively. In conclusion, the hepatocellular adenoma-like portion of most cases of hepatocellular carcinoma arising in hepatocellular adenoma shows features typically seen in hepatocellular carcinoma such as focal morphological abnormalities, β-catenin activation, heat-shock protein 70 expression, and chromosomal gains. Hepatocellular adenoma-like areas in these tumors, especially in men and older women, may represent an extremely well-differentiated variant of hepatocellular carcinoma, whereas the morphologically recognizable hepatocellular carcinoma portion represents a relatively higher grade component of the tumor.Modern Pathology advance online publication, 18 April 2014; doi:10.1038/modpathol.2014.50.
    Modern Pathology 04/2014; · 6.36 Impact Factor
  • Human pathology 03/2014; 45(3):660–661. · 2.81 Impact Factor
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    ABSTRACT: Inflammatory hepatocellular adenoma can show overlapping histological features with focal nodular hyperplasia, including inflammation, fibrous stroma, and ductular reaction. Expression of serum amyloid-associated protein in inflammatory hepatocellular adenoma and map-like pattern of glutamine synthetase in focal nodular hyperplasia can be helpful in this distinction, but the pitfalls and limitations of these markers have not been established. Morphology and immunohistochemistry were analyzed in 54 inflammatory hepatocellular adenomas, 40 focal nodular hyperplasia, and 3 indeterminate lesions. Morphological analysis demonstrated that nodularity, fibrous stroma, dystrophic blood vessels, and ductular reaction were more common in focal nodular hyperplasia, while telangiectasia, hemorrhage, and steatosis were more common in inflammatory hepatocellular adenoma, but there was frequent overlap of morphological features. The majority of inflammatory hepatocellular adenomas demonstrated perivascular and/or patchy glutamine synthetase staining (73.6%), while the remaining cases had diffuse (7.5%), negative (3.8%), or patchy pattern of staining (15%) that showed subtle differences from the classic map-like staining pattern and was designated as pseudo map-like staining. Positive staining for serum amyloid-associated protein was seen in the majority of inflammatory hepatocellular adenomas (92.6%) and in the minority of focal nodular hyperplasia (17.5%). The glutamine synthetase staining pattern was map-like in 90% of focal nodular hyperplasia cases, with the remaining 10% of cases showing pseudo map-like staining. Three cases were labeled as indeterminate and showed focal nodular hyperplasia-like morphology but lacked map-like glutamine synthetase staining pattern; these cases demonstrated a patchy pseudo map-like glutamine synthetase pattern along with the expression of serum amyloid-associated protein. Our results highlight the diagnostic errors that can be caused by variant patterns of staining with glutamine synthetase and serum amyloid-associated protein in inflammatory hepatocellular adenoma and focal nodular hyperplasia.Modern Pathology advance online publication, 28 June 2013; doi:10.1038/modpathol.2013.114.
    Modern Pathology 06/2013; · 6.36 Impact Factor
  • Sanjay Kakar, Dhanpat Jain
    Surgical Pathology Clinics 06/2013; 6(2):ix-x.
  • Nafis Shafizadeh, Sanjay Kakar
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    ABSTRACT: This review discusses the various histologic subtypes of hepatocellular carcinoma (HCC), focusing on their clinical features, pathologic features, immunohistochemical profiles, differential diagnosis, prognosis, and clinical relevance of diagnosis. The WHO recognized variants of scirrhous HCC, fibrolamellar carcinoma, combined HCC-cholangiocarcinoma (HCC-CC), sarcomatoid HCC, undifferentiated carcinoma, and lymphoepithelioma-like HCC are discussed in detail. Other subtypes including clear cell HCC, diffuse cirrhosis-like HCC, steatohepatitic HCC, transitional liver cell tumor, and CAP carcinoma are also reviewed.
    Surgical Pathology Clinics 06/2013; 6(2):367-384.
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    ABSTRACT: Scirrhous hepatocellular carcinoma is a rare ill-defined morphological subtype of hepatocellular carcinoma characterized by marked stromal fibrosis. This variant can be difficult to distinguish from intrahepatic cholangiocarcinoma and metastatic adenocarcinoma, especially on needle biopsies. We performed immunohistochemistry for hepatocellular and adenocarcinoma-associated markers on 20 scirrhous hepatocellular carcinoma cases and compared the results with classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Scirrhous hepatocellular carcinomas were significantly less likely to be HepPar-1 positive than classical hepatocellular carcinomas (26% and 74%, respectively; P<0.001) and were significantly more likely to express adenocarcinoma-associated markers such as epithelial cell adhesion molecule (63 vs 11%; P<0.001), cytokeratin 19 (26 vs 2%; P<0.001), and cytokeratin 7 (53 vs 2%; P<0.001). At least one of these adenocarcinoma-related markers was positive in 80% of scirrhous hepatocellular carcinoma cases. Glypican 3 and arginase were positive in 79% and 85% of cases of scirrhous hepatocellular carcinoma, respectively; the combined use of these two markers yielded 100% sensitivity for scirrhous hepatocellular carcinoma. In conclusion, the scirrhous morphology, absence of HepPar-1 staining, and frequent positivity with adenocarcinoma-related markers in scirrhous hepatocellular carcinoma can lead to an erroneous diagnosis of adenocarcinoma. Glypican 3 and arginase are the most reliable markers for identifying hepatocellular differentiation in this setting.Modern Pathology advance online publication, 25 January 2013; doi:10.1038/modpathol.2012.243.
    Modern Pathology 01/2013; · 6.36 Impact Factor
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    ABSTRACT: Purpose:To evaluate the feasibility of using contrast material-enhanced computed tomographic (CT) measurements of hepatic fractional extracellular space (fECS) and macromolecular contrast material (MMCM) uptake to measure severity of liver fibrosis.Materials and Methods:All procedures were approved by and executed in accordance with University of California, San Francisco, institutional animal care and use committee regulations. Twenty-one rats that received intragastric CCl(4) for 0-12 weeks were imaged with respiratory-gated micro-CT by using both a conventional contrast material and a novel iodinated MMCM. Histopathologic hepatic fibrosis was graded qualitatively by using the Ishak fibrosis score and quantitatively by using morphometry of the fibrosis area. Hepatic fECS and MMCM uptake were calculated for each examination and correlated with histopathologic findings by using uni- and multivariate linear regressions.Results:Ishak fibrosis scores ranged from a baseline of 0 in untreated animals to a maximum of 5. Histopathologic liver fibrosis area increased from 0.46% to 3.5% over the same interval. Strong correlations were seen between conventional contrast-enhanced CT measurements of fECS and both the Ishak fibrosis scores (R(2) = 0.751, P < .001) and the fibrosis area (R(2) = 0.801, P < .001). Strong negative correlations were observed between uptake of MMCM in the liver and Ishak fibrosis scores (R(2) = 0.827, P < .001), as well as between uptake of MMCM in the liver and fibrosis area (R(2) = 0.643, P = .001). Multivariate linear regression analysis showed a trend toward independence for fECS and MMCM uptake in the prediction of Ishak fibrosis scores, with an R(2) value of 0.86 (P = .081 and P = .033, respectively).Conclusion:Contrast-enhanced CT measurements of fECS and MMCM uptake are individually capable of being used to estimate the degree of early hepatic fibrosis in a rat model.© RSNA, 2012Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112452/-/DC1.
    Radiology 11/2012; · 6.21 Impact Factor
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    ABSTRACT: The distinction of hepatocellular adenoma from well-differentiated hepatocellular carcinoma (HCC) arising in noncirrhotic liver can be challenging, particularly when tumors histologically resembling hepatocellular adenoma occur in unusual clinical settings such as in a man or an older woman or show focal atypical morphologic features. In this study, we examine the morphologic, immunohistochemical, and cytogenetic features of hepatocellular adenoma-like neoplasms occurring in men, women 50 years or older or younger than 15 years, and/or those with focal atypia (small cell change, pseudogland formation, and/or nuclear atypia), designated atypical hepatocellular neoplasms, where the distinction of hepatocellular adenoma versus HCC could not be clearly established. Immunohistochemistry was performed for β-catenin, glutamine synthetase, and serum amyloid A in 31 hepatocellular adenomas, 20 well-differentiated HCCs, and 40 atypical hepatocellular neoplasms. Chromosomal gains/losses had previously been determined in 37 cases using comparative genomic hybridization or fluorescence in situ hybridization. β-Catenin activation was observed in 35% of atypical hepatocellular neoplasms compared with 10% of typical hepatocellular adenomas (P < .05) and 55% of well-differentiated HCCs (P = .14). Cytogenetic changes typically observed in HCC were present in all atypical hepatocellular neoplasms with β-catenin activation. β-Catenin activation in atypical hepatocellular neoplasms was also associated with atypical morphologic features. Follow-up data were limited, but adverse outcome was observed in 2 atypical hepatocellular neoplasms with β-catenin activation (1 recurrence, 1 metastasis); transition to areas of HCC was observed in 1 case. The similarity in morphologic and cytogenetic features of β-catenin-activated hepatocellular adenoma-like tumors and HCC suggests that the former tumors represent an extremely well-differentiated variant of HCC.
    Human pathology 10/2012; · 2.81 Impact Factor
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    ABSTRACT: Reticulin stains are commonly used in surgical pathology to assess mass lesions for the possibility of hepatocellular carcinoma. The loss of normal reticulin staining can help support a diagnosis of hepatocellular carcinoma, and this stain has proven to be particularly helpful on limited biopsies and fine-needle aspirates. However, an underappreciated diagnostic pitfall is that non-neoplastic liver tissue can also show reticulin loss when there is fatty change. To further characterize this important diagnostic pitfall, reticulin staining was studied in cases of nonalcoholic steatosis, nonalcoholic steatohepatitis, and hepatic adenomas with fatty change. A total of 112 cases with varying degrees of steatosis were collected from 4 academic centers, including 49 cases of steatosis, 49 cases of steatohepatitis, and 14 hepatic adenomas with fatty change. Steatosis was graded as mild (5% to 30% macrovesicular steatosis), moderate (31% to 60%), and marked (>60%). Reticulin stains were scored as the number of foci with diminished reticulin staining in 10 hpf. A focus of diminished reticulin was scored when the extent of reticulin loss was similar to that seen in hepatocellular carcinomas. In the total study set, 28 cases showed mild steatosis, 40 cases showed moderate steatosis, and 44 cases showed marked steatosis. Interestingly, increasing amounts of fat were associated with decreased reticulin staining. For mild steatosis, reticulin loss was rare, with the number of foci of reticulin loss per 10 hpf averaging 0.8 (range, 0 to 3); however, this increased for moderate steatosis, which showed a mean of 3.0 foci per 10 hpf (range, 0 to 5), and was most prominent with marked steatosis, which showed an average of 5.8 foci of reticulin loss per 10 hpf (range, 5 to 8). An almost identical pattern was seen in cases of nonalcoholic steatohepatitis. Overall, reticulin loss was not associated with the degree of inflammation or with the presence or absence of balloon cell change. Reticulin loss also did not correlate with fibrosis stage. In hepatic adenomas, reticulin loss was seen only in areas of fatty change, and decreased reticulin again paralleled the amount of steatosis, with more prominent reticulin loss in those cases with marked steatosis. In conclusion, reticulin loss that reaches levels seen in hepatocellular carcinoma can be seen focally in benign liver tissues with fatty change. Overall, loss of reticulin is more common and more extensive with marked fatty change and does not seem to be linked to inflammation or fibrosis stage. Loss of reticulin can also be seen in hepatic adenomas with fatty change. Increased awareness of this important diagnostic pitfall will help prevent overcalling of reticulin loss when evaluating biopsies and resections of hepatic neoplasms with fatty change.
    The American journal of surgical pathology 05/2012; 36(5):710-5. · 4.59 Impact Factor
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    ABSTRACT: The relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with high-level microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotype-positive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors, but not in high-level microsatellite-unstable tumors. The high frequency of methylation and BRAF V600E mutation suggests that many signet ring cell carcinomas may be related to the serrated pathway of carcinogenesis.
    Modern Pathology 04/2012; 25(7):1040-7. · 6.36 Impact Factor
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    ABSTRACT: PURPOSE To evaluate the possibility of using contrast-enhanced CT measurements of the fractional extracellular space (fECS) and macromolecular contrast material (MMCM) retention in the liver to quantify the severity of hepatic fibrosis. METHOD AND MATERIALS Twenty-one rats were treated with intragastric CCl4 for 2 to 12 weeks in order to induce a wide range of hepatic fibrosis. Three rats were imaged every two weeks by respiratory-gated micro-CT using both a conventional contrast material and a novel polyethylene glycol-derived polylysine dendrimer as an iodinated macromolecular contrast material (MMCM). Immediately after scanning, the livers were removed, fixed in formalin, and stained with Picrosirius Red. Hepatic fibrosis was graded qualitatively using the Ishak fibrosis score (0-6) and quantitatively by morphometry. All measurements of liver fibrosis were made in a blinded fashion. The hepatic fECS and MMCM retention were calculated for each animal scan and correlated with the histopathological measurements using bivariate and multivariate linear regressions. RESULTS Rats developed progressive hepatic fibrosis over the 12-week study interval, with Ishak scores rising from a baseline of 0 in untreated animals to a maximum of 5. Liver fibrosis area, measured as a percent of total tissue area, rose from 0.9% to 5.9% over the same interval. Strong correlations were seen between conventional contrast CT scan estimates of fECS and both the Ishak fibrosis score (r2=0.81, p<0.001) and the fibrosis area (r2=0.79, p<0.001). In addition, strong negative correlations were observed between the retention of MMCM in the liver and the Ishak fibrosis scores (r2=0.83, p<0001) as well as the fibrosis area (r2=0.64, p<0.001). Multivariate linear regression showed a trend toward independence for fECS and MMCM retention for the prediction of Ishak fibrosis scores, with an adjusted r2 = 0.86 (p-values of 0.081 and 0.033). CONCLUSION Contrast-enhanced CT measurements of fECS and MMCM retention are individually capable of quantifying early hepatic fibrosis in a rat model and, when combined, show an even greater correlation to fibrosis severity. Further study is merited to assess translation to clinical hepatic CT imaging. CLINICAL RELEVANCE/APPLICATION CT measurements of hepatic fECS and MMCM retention may be useful quantitative markers of liver fibrosis and could allow for non-invasive monitoring of liver disease severity and progression.
    Radiological Society of North America 2011 Scientific Assembly and Annual Meeting; 12/2011
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    Nafis Shafizadeh, Sanjay Kakar
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    ABSTRACT: There is considerable overlap in morphologic features in well-differentiated hepatocellular lesions necessitating the use of immunohistochemistry and other techniques for diagnosis. Map-like pattern with glutamine synthetase in focal nodular hyperplasia and cytoplasmic staining with serum amyloid associated protein in inflammatory hepatocellular adenoma (HA) are useful for this distinction. The distinction of well-differentiated hepatocellular carcinoma (HCC) and HA in noncirrhotic liver is facilitated by demonstrating glypican-3 and cytogenetic changes like gains of chromosomes 1 and 8. Nuclear staining with β-catenin and/or diffuse staining with glutamine synthetase strongly favors well-differentiated HCC or HA with high risk for HCC. In a cirrhotic liver, separation of early HCC from high-grade dysplastic nodule requires identification of stromal invasion, which can be highlighted by absence of keratin 7-positive ductular reaction. Combined use of heat shock protein 70, glutamine synthetase, and glypican-3 can be useful as positivity for 2 or more of these markers has shown high specificity for HCC in early studies.
    Advances in anatomic pathology 11/2011; 18(6):438-45. · 3.22 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide, is most commonly caused by chronic hepatitis B virus (HBV) infection. However, whether HBV plays any direct role in carcinogenesis, other than indirectly causing chronic liver injury by inciting the host immune response, remains unclear. We have established two independent transgenic mouse lines expressing the complete genome of a mutant HBV ("preS2 mutant") that is found at much higher frequencies in people with HCC than those without. The transgenic mice show evidence of stress in the endoplasmic reticulum (ER) and overexpression of cyclin D1 in hepatocytes. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice develop hepatocellular neoplasms, including HCC. Unexpectedly, we also found a significant increase in hepatocarcinogenesis independent of necroinflammation in a transgenic line expressing the entire wildtype HBV. As in the mutant HBV mice, HCC was found only in aged--2-year-old--mice of the wildtype HBV line. The karyotype in all the three transgenic lines appears normal and none of the integration sites of the HBV transgene in the mice is near an oncogene or tumor suppressor gene. The significant increase of HCC incidence in all the three transgenic lines--expressing either mutant or wildtype HBV--therefore argues strongly that in absence of chronic necroinflammation, HBV can contribute directly to the development of HCC.
    PLoS ONE 10/2011; 6(10):e26240. · 3.53 Impact Factor
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    ABSTRACT: MiR-145 is downregulated in various cancers including prostate cancer. However, the underlying mechanisms of miR-145 downregulation are not fully understood. Here, we reported that miR-145 was silenced through DNA hypermethylation and p53 mutation status in laser capture microdissected (LCM) prostate cancer and matched adjacent normal tissues. In 22 of 27 (81%) prostate tissues, miR-145 was significantly downregulated in the cancer compared with the normal tissues. Further studies on miR-145 downregulation mechanism showed that miR-145 is methylated at the promoter region in both prostate cancer tissues and 50 different types of cancer cell lines. In seven cancer cell lines with miR-145 hypermethylation, 5-aza-2'-deoxycytidine treatment dramatically induced miR-145 expression. Interestingly, we also found a significant correlation between miR-145 expression and the status of p53 gene in both LCM prostate tissues and 47 cancer cell lines. In 29 cell lines with mutant p53, miR-145 levels were downregulated in 28 lines (97%), whereas in 18 cell lines with wild-type p53 (WT p53), miR-145 levels were downregulated in only 6 lines (33%, P < 0.001). Electrophoretic mobility shift assay showed that p53 binds to the p53 response element upstream of miR-145, but the binding was inhibited by hypermethylation. To further confirm that p53 binding to miR-145 could regulate miR-145 expression, we transfected WT p53 and MUT p53 into PC-3 cells and found that miR-145 is upregulated by WT p53 but not with MUTp53. The apoptotic cells are increased after WT p53 transfection. In summary, this is the first report documenting that downregulation of miR-145 is through DNA methylation and p53 mutation pathways in prostate cancer.
    Carcinogenesis 02/2011; 32(5):772-8. · 5.27 Impact Factor
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    Guoren Deng, Sanjay Kakar, Young S Kim
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    ABSTRACT: MicroRNAs (miRs) are a class of small RNAs that regulate gene expression at the post-transcriptional and/or translational level by interacting with their target mRNAs. miRs are down-regulated or up-regulated in various cancer types, triggering abnormal cell differentiation, proliferation and apoptosis. miR-124a and miR-34b/c have been reported to be expressed at lower levels in colorectal cancer (CRC) due to methylation of these genes. The present study aimed to determine the methylation status of miR-124a and miR-34b/c in CRCs and polyps of various histological types, adjacent normal mucosa and ulcerative colitis. The colon cancer cell line study showed an association of the lower expression of miR-124a and miR-34b/c with the methylation of these genes and induction of the expression of these genes with the treatment by 5-aza-2'-deoxycytidine. Among nine different cancer types examined, CRC showed the highest frequency of methylation of miR-124a (cell lines 88% and tissues 99%) and miR-34b/c (cell lines 89% and tissues 93%). Mucinous and non-mucinous CRCs and all the histological types of colorectal polyps showed a high frequency of methylation of miR-124a and miR-34b/c. Notably, methylation of miR-124a (59%) and miR-34b/c (26%) was observed in the adjacent normal mucosa of CRC patients, but not in colonic mucosa from patients without cancer or with ulcerative colitis. The methylation of miR-124a in the adjacent normal mucosa was associated with the microsatellite instability of CRC, while the methylation of miR-34b/c was associated with an older age at diagnosis of CRC. The results showed that the methylation of miR-124a and miR-34b/c occured early in colorectal carcinogenesis and certain CRCs may arise from a field defect defined by the epigenetic inactivation of miRs.
    Oncology letters 01/2011; 2(1):175-180. · 0.99 Impact Factor
  • Rageshree Ramachandran, Sanjay Kakar
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    ABSTRACT: Fibrolamellar hepatocellular carcinoma (FLM) is a rare tumour that typically presents in young adults. It occurs in non-cirrhotic liver and is usually associated with normal serum alpha-fetoprotein. It is defined by a triad of morphological features: polygonal tumour cells with eosinophilic cytoplasm, prominent macronucleoli and lamellar fibrosis. A central scar can be present. The principal differential diagnosis is conventional hepatocellular carcinoma (HCC), especially the scirrhous variant. Acinar differentiation and focal mucin production are common and can be confused with adenocarcinoma. Focal neuroendocrine differentiation can occur and can be mistaken for neuroendocrine tumours. FLM also shows distinctive features at the molecular level; many of the commonly observed abnormalities in conventional HCC like p53 and β-catenin mutations are not observed in FLM. The extent of cytogenetic changes and CpG island methylation is low in FLM compared to conventional HCC. FLM is an aggressive neoplasm with 5-year survival of around 50%. Although the outcome in FLM has been considered more favourable compared to conventional HCC, this is likely to be related to absence of cirrhosis rather than unique morphological features of the tumour.
    Diagnostic Histopathology 08/2010; 16(8):388–396.

Publication Stats

2k Citations
348.02 Total Impact Points

Institutions

  • 2004–2014
    • University of California, San Francisco
      • • Department of Pathology
      • • Veterans Affairs Medical Center
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2008–2011
    • CSU Mentor
      Long Beach, California, United States
  • 2008–2010
    • Vanderbilt University
      Nashville, Michigan, United States
  • 2004–2008
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2002–2003
    • Mayo Clinic - Rochester
      • Department of Gastroenterology and Hepatology
      Rochester, Minnesota, United States
    • Mayo Foundation for Medical Education and Research
      • Department of Pathology
      Scottsdale, AZ, United States
  • 2000
    • University of Illinois at Chicago
      • Department of Pathology (Chicago)
      Chicago, IL, United States