Sanjay Kakar

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

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Publications (101)435.14 Total impact

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    ABSTRACT: Background: Adenocarcinomas of the appendix represent a heterogeneous disease depending on the presence of mucinous histology, histologic grade, and stage. In the current study, the authors sought to explore the interplay of these factors with systemic chemotherapy in a large population data set. Methods: Patients in the National Cancer Data Base (NCDB) who were diagnosed with mucinous, nonmucinous, and signet ring cell-type appendiceal neoplasms from 1985 through 2006 were selected. Multivariable Cox proportional hazards regression models were developed. Results: A total of 11,871 patients met the inclusion criteria for the current study: 50.3% had mucinous neoplasms, 40.5% had nonmucinous neoplasms, and 9.2% had signet ring cell-type neoplasms. The 5-year overall survival (OS) stratified by grade was similar among patients with American Joint Committee on Cancer stage I to stage III disease but not for those with stage IV disease. The median OS for patients with stage IV mucinous and nonmucinous tumors was 6.4 years and 2.3 years, respectively, for those with well differentiated histology (P<.0001) and was 1.5 years and 0.8 years, respectively, for those with poorly differentiated histology (P<.0001). In multivariable modeling for stage I to III disease, adjuvant chemotherapy improved OS for both mucinous and nonmucinous histologies, with hazard ratios (HRs) of 0.78 (95% confidence interval [95% CI], 0.68-0.89 [P = .0002]) and 0.83 (95% CI, 0.74-0.94 [P = .002]), respectively. For patients with stage IV disease, systemic chemotherapy significantly improved OS for those with nonmucinous (HR, 0.72; 95% CI, 0.64-0.82 [P<.0001]) but not mucinous (HR, 0.95; 95% CI, 0.86-1.04 [P = .2) histologies, although this was grade-dependent. The median OS for chemotherapy versus no chemotherapy was 6.4 years versus 6.5 years (P value not significant) for patients with mucinous, well-differentiated tumors and 1.6 years versus 1.0 years (P = .0007) for patients with mucinous, poorly differentiated tumors. Conclusions: Adjuvant chemotherapy demonstrated a significant OS benefit regardless of histology. However, for patients with stage IV disease, the benefit of systemic chemotherapy varied by tumor histology and grade, with patients with well-differentiated, mucinous, appendiceal adenocarcinomas deriving no survival benefit from systemic chemotherapy. Cancer 2015. © 2015 American Cancer Society.
    Cancer 10/2015; DOI:10.1002/cncr.29744 · 4.89 Impact Factor
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    ABSTRACT: Context .- Several immunohistochemical markers are available to establish the diagnosis of hepatocellular carcinoma. Judicious selection is essential to achieve a reliable diagnosis in limited tissue provided by liver biopsy. Objective .- To compare the efficacy of 5 hepatocellular markers for the diagnosis of hepatocellular carcinoma across various levels of differentiations. Design .- Immunohistochemistry for hepatocyte paraffin antigen 1 (Hep Par 1), polyclonal carcinoembryonic antigen (CEA), glypican-3, arginase-1, and bile salt export pump transporter was performed in 79 hepatocellular carcinomas, yielding 93 observations (13 well-differentiated [14%], 41 moderately differentiated [44%], and 39 poorly differentiated [42%] tumors). Results .- Arginase-1 and Hep Par 1 had the highest sensitivity for well-differentiated hepatocellular carcinoma, whereas arginase-1 and glypican-3 had the highest sensitivity for poorly differentiated hepatocellular carcinoma. When staining of more than 50% of the tumor was considered a positive result, arginase-1 remained the most sensitive marker for all differentiations, whereas sensitivity for Hep Par 1 in poorly differentiated hepatocellular carcinoma dropped to 30% and that of glypican-3 in well-differentiated hepatocellular carcinoma was 15%. The addition of Hep Par 1 and/or polyclonal CEA to arginase-1 did not lead to an increase in sensitivity for any differentiation. The combined use of arginase-1 and glypican-3 yielded 100% sensitivity for poorly differentiated hepatocellular carcinoma. Conclusion .- Arginase-1 was the most sensitive marker in all differentiations of hepatocellular carcinoma. Glypican-3 had high sensitivity for poorly differentiated cases and its combined use with arginase-1 enabled identification of nearly all cases of poorly differentiated hepatocellular carcinoma. Although bile salt export pump transporter has good overall sensitivity, it has a limited role in establishing hepatocellular differentiation when added to a panel of arginase-1 with either glypican-3 or Hep Par 1.
    Archives of pathology & laboratory medicine 08/2015; 139(8):1028-1034. DOI:10.5858/arpa.2014-0479-OA · 2.84 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. The search for targeted treatments has been hampered by the lack of relevant animal models for the genetically diverse subsets of HCC, including the 20-40% of HCCs that are defined by activating mutations in the gene encoding β-catenin. To address this chemotherapeutic challenge, we created and characterized transgenic zebrafish expressing hepatocyte-specific activated β-catenin. By 2 months post fertilization (mpf), 33% of transgenic zebrafish developed HCC in their livers, and 78% and 80% of transgenic zebrafish showed HCC at 6 and 12 mpf, respectively. As expected for a malignant process, transgenic zebrafish showed significantly decreased mean adult survival compared to non-transgenic control siblings. Using this novel transgenic model, we screened for druggable pathways that mediate β-catenin-induced liver growth and identified two c-Jun N-terminal kinase (JNK) inhibitors and two antidepressants (one tricyclic antidepressant, amitriptyline, and one selective serotonin reuptake inhibitor) that suppressed this phenotype. We further found that activated β-catenin was associated with JNK pathway hyperactivation in zebrafish and in human HCC. In zebrafish larvae, JNK inhibition decreased liver size specifically in the presence of activated β-catenin. The β-catenin-specific growth-inhibitory effect of targeting JNK was conserved in human liver cancer cells. Our other class of hits, antidepressants, has been used in patient treatment for decades, raising the exciting possibility that these drugs could potentially be repurposed for cancer treatment. In support of this proposal, we found that amitriptyline decreased tumor burden in a mouse HCC model. Our studies implicate JNK inhibitors and antidepressants as potential therapeutics for β-catenin-induced liver tumors.
    PLoS Genetics 07/2015; 11(7):e1005305. DOI:10.1371/journal.pgen.1005305 · 7.53 Impact Factor

  • Gastroenterology 04/2015; 148(4):S-997. DOI:10.1016/S0016-5085(15)33406-5 · 16.72 Impact Factor
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    ABSTRACT: Modern Pathology features diagnostic anatomic pathology and contains original scientific papers, selected short courses, appropriate special lectures, reviews, editorials, letters to the editor, and Academy News. In many ways, it reflects the instructive and informative composition of the Academy's annual meeting. Publication is monthly.
    Modern Pathology 01/2015; 28(1):159-60. DOI:10.1038/modpathol.2014.121 · 6.19 Impact Factor
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    Human pathology 12/2014; 46(4). DOI:10.1016/j.humpath.2014.10.029 · 2.77 Impact Factor
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    ABSTRACT: Albumin, widely recognized as a highly sensitive and specific marker of hepatocellular carcinoma (HCC), is currently unavailable in the diagnostic laboratory because of the lack of a robust platform. In a prior study we detected albumin mRNA in the majority of intrahepatic cholangiocarcinomas using a novel branched chain RNA in situ hybridization (ISH) platform. We now explore the utility of albumin ISH as a marker of hepatocellular differentiation in HCCs, and compare its sensitivity with Hep Par 1 and Arginase-1. We evaluated 93 HCCs and its mimics including neuroendocrine tumors of the gastrointestinal tract (n=31), neuroendocrine tumors of the pancreas (n=163), melanoma (n=15), and gallbladder carcinoma (n=34). We performed ISH for albumin and immunohistochemistry for Hep Par 1 and Arginase-1. Five previously uncharacterized hepatic neoplasms from our files were also evaluated. Immunohistochemistry for Arginase-1 was performed on 59 intrahepatic cholangiocarcinomas. In addition, 43 HCCs evaluated on the manual platform were also examined on the automated instrument. Fifty-five percent of HCCs were moderately differentiated and 39% poorly differentiated. The sensitivity of ISH for albumin was 99%, with 92 of 93 HCCs staining positive for albumin. In contrast to ISH, the sensitivity of immunohistochemistry for Hep Par 1 and Arginase-1 was 84% and 83%, respectively. The sensitivity of albumin for poorly differentiated HCCs was 99%, whereas that for Arginase-1 and Hep Par 1 was 71% and 64%, respectively. Ninety-seven percent of the HCCs showed albumin positivity in >50% of tumor cells using the ISH platform, as compared with 76% and 70% for Hep Par 1 and Arginase-1 immunohistochemistry, respectively. Three of the 5 previously uncharacterized neoplasms were positive for albumin ISH. Automated albumin ISH platform performed equivalently to the manual format, with albumin reactivity in >50% of tumor cells in all 43 cases that were tested on both platforms. All non-HCCs were negative for albumin. All 59 intrahepatic cholangiocarcinomas were negative for Arginase-1. In conclusion, branched chain ISH performed on manual and automated mode is a robust assay for detecting albumin with sensitivity for poorly differentiated HCCs superior to Arginase-1 and Hep Par 1. When interpreted in conjunction with Arginase-1, albumin ISH offers a high level of sensitivity and specificity.
    American Journal of Surgical Pathology 10/2014; 39(1). DOI:10.1097/PAS.0000000000000343 · 5.15 Impact Factor

  • Archives of pathology & laboratory medicine 10/2014; 139(5). DOI:10.5858/arpa.2014-0395-CP · 2.84 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; 45(5). DOI:10.1016/j.humpath.2013.12.011 · 2.77 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; 27(11). DOI:10.1038/modpathol.2014.50 · 6.19 Impact Factor
  • Sanjay Kakar · Kimberley J. Evason · Linda D. Ferrell ·

    Human pathology 03/2014; 45(3):660–661. DOI:10.1016/j.humpath.2013.09.019 · 2.77 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; 27(1). DOI:10.1038/modpathol.2013.114 · 6.19 Impact Factor
  • 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. DOI:10.1016/j.path.2013.03.007
  • Sanjay Kakar · Dhanpat Jain ·

    Surgical Pathology Clinics 06/2013; 6(2):ix-x. DOI:10.1016/j.path.2013.03.009
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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; 26(6). DOI:10.1038/modpathol.2012.243 · 6.19 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 CCl4 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. (C) RSNA, 2012
    Radiology 11/2012; 266(1). DOI:10.1148/radiol.12112452 · 6.87 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; 44(5). DOI:10.1016/j.humpath.2012.07.019 · 2.77 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. DOI:10.1097/PAS.0b013e3182495c73 · 5.15 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. DOI:10.1038/modpathol.2012.44 · 6.19 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

Publication Stats

3k Citations
435.14 Total Impact Points


  • 2004-2015
    • University of California, San Francisco
      • • Department of Pathology
      • • Department of Laboratory Medicine
      • • Veterans Affairs Medical Center
      San Francisco, California, United States
  • 2004-2014
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2010
    • Vanderbilt University
      • Department of Medicine
      Nashville, Michigan, United States
  • 2008
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 2001-2003
    • Mayo Clinic - Rochester
      • Department of Gastroenterology and Hepatology
      Rochester, Minnesota, United States
  • 2000
    • University of Illinois at Chicago
      • Department of Pathology (Chicago)
      Chicago, Illinois, United States