Shu-Yuan Xiao

Arginase-1: a new immunohistochemical marker of hepatocytes and hepatocellular neoplasms.

The distinction of hepatocellular carcinoma (HCC) from metastatic tumor in the liver often presents a diagnostic challenge that carries significant impact on prognostication and therapy. The number of diagnostically useful immunohistochemical markers of hepatocytes is limited to hepatocyte paraffin antigen (HepPar-1), polyclonal carcinoembryonic antigen, and CD10, with α-fetoprotein and glypican-3 labeling HCCs. Arginase-1 (Arg-1) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of arginine to ornithine and urea. We used immunohistochemistry to compare the sensitivity of Arg-1 to that of HepPar-1 in 151 HCCs. We found that the overall sensitivities of Arg-1 and HepPar-1 are 96.0% and 84.1%, respectively. The sensitivities of Arg-1 in well, moderately, and poorly differentiated HCCs are 100%, 96.2%, and 85.7%, respectively, whereas, in comparison, HepPar-1 demonstrated sensitivities of 100%, 83.0%, and 46.4% for well, moderately, and poorly differentiated tumors, respectively. There were no HCCs in our study that were reactive for HepPar-1 but nonreactive for Arg-1. We also examined Arg-1 expression in nonhepatocellular tumors, including many that are potential mimics of HCC (renal cell carcinomas, neuroendocrine tumors, melanomas, gastric adenocarcinomas, and adrenocortical carcinomas) and found that only 2 non-HCC tumors were reactive for Arg-1. Arg-1 represents a sensitive and specific marker of benign and malignant hepatocytes that may ultimately prove to be a useful diagnostic tool in routine surgical pathology practice.

Durable Complete Response of Metastatic Gastric Cancer with Anti-Met Therapy Followed by Resistance at Recurrence

UNLABELLEDnA 48 year-old female with chemo-refractory metastatic gastric cancer to the liver was treated on a Phase I clinical trial with MetMAb, a monoclonal antibody targeting the Met tyrosine kinase receptor. The primary tumor had high MET gene polysomy and evidence for an autocrine production of HGF, the growth factor ligand of Met. A complete response was obtained lasting two years; the cancer recurred as a peritoneal deposit invading into the transverse colon and a gastrohepatic ligament node. Compassionate use of MetMAb therapy at recurrence achieved a mixed response--a partial response of the two initial lesions, but with development of multiple new foci of carcinomatosis. Tissue and serum studies evaluating the Met signaling pathway did correlate with MetMAb treatment response initially and at the time of recurrence.nnnSIGNIFICANCEnThis research brief is the first to describe a durable complete response obtained with a molecularly targeted monoclonal antibody, MetMAb, to the receptor tyrosine kinase, Met, in a patient with chemorefractory metastatic gastric cancer. It is also the first to report biomarkers that predicted therapeutic response to Met inhibition.

Marked gastric foveolar hyperplasia associated with active cytomegalovirus infection

Transient protein-losing gastropathy with marked gastric rugal hypertrophy, a Menetriers disease-like process, is an uncommon condition of unknown etiology. Most of these cases have been reported in pediatric patients; the clinical course is usually favorable. Cytomegalovirus infection has been implicated as a possible etiology in many of the reported cases. This type of Ménétriers-like disease has not been well documented in adult patients. We describe here an elderly man who presented with severe protein-losing gastropathy and large polypoid nodules in the stomach. Gastric mucosal biopsies revealed marked gastric foveolar hyperplasia with morphological evidence of cytomegalovirus (CMV) infection. Immunohistochemical analysis demonstrated an aberrant topographic distribution of staining for transforming growth factor-α and transforming growth factor-β receptor II, as described in other cases of Ménétriers disease in the literature. This transient Ménétriers-like disease associated with CMV infection should be considered in the differential of both pediatric and adult patients with GI protein loss.

Histological evaluation in ulcerative colitis

This review summarizes diagnostic problems, challenges and advances in ulcerative colitis (UC). It emphasizes that, although histopathological examination plays a major role in the diagnosis and management of UC, it should always be interpreted in the context of clinical, endoscopic, and radiological findings. Accurate diagnosis requires knowledge of the classic morphological features of UC, as well as a number of atypical pathological presentations that may cause mis-classification of the disease process, either in resection or biopsy specimens. These atypical pathological presentations include rectal sparing and patchiness of disease at initial presentation of UC in pediatric patients or in the setting of medically treated UC, cecal or ascending colon inflammation in left-sided UC, and backwash ileitis in patients with severe ulcerative pancolitis. Loosely formed microgranulomas, with pale foamy histiocytes adjacent to a damaged crypt or eroded surface, should not be interpreted as evidence of Crohn’s disease. Indeterminate colitis should only be used in colectomy specimens as a provisional pathological diagnosis. Patients with UC are at risk for the development of dysplasia and carcinoma; optimal outcomes in UC surveillance programs require familiarity with the diagnostic criteria and challenges relating to UC-associated dysplasia and malignancy. Colon biopsy from UC patients should always be evaluated for dysplasia based on cytological and architectural abnormalities. Accurate interpretation and classification of dysplasia in colon biopsy from UC patients as sporadic adenoma or UC-related dysplasia [flat, adenoma-like, or dysplasia-associated lesion or mass (DALM)] requires clinical and endoscopic correlation. Isolated polypoid dysplastic lesions are considered to be sporadic adenoma if occurring outside areas of histologically proven colitis, or adenoma-like dysplasia if occurring in the diseased segment. Recent data suggest that such lesions may be treated adequately by polypectomy in the absence of flat dysplasia in the patient. UC patients with DALM or flat high-grade dysplasia should be treated by colectomy because of the high probability of adenocarcinoma. The natural history of low-grade dysplasia (LGD) is more controversial: while multifocal LGD, particularly if detected at the time of initial endoscopic examination, is treated with colectomy, unifocal flat LGD detected during surveillance may be managed by close follow-up with increased surveillance. The surveillance interval and treatment options for UC patients with dysplasia are reviewed in detail.

Complete Endoscopic Mucosal Resection Is Effective and Durable Treatment for Barrett's-Associated Neoplasia

BACKGROUND & AIMSnBarretts esophagus (BE) with high-grade dysplasia (HGD) or intramucosal carcinoma (IMC) is treated by complete eradication of areas of BE by endoscopic mucosal resection (EMR). By using this approach, histologic analysis also can be performed. We investigated the effectiveness, safety, and durability of this approach, as well as its use in diagnosis after a single referral.nnnMETHODSnWe collected data from 107 patients who were referred to the Center for Endoscopic Research and Therapeutics at the University of Chicago for BE (mean length, 3.6 cm) with suspected HGD or IMC, from August 2003 through December 2012. All patients underwent EMR and were followed up through January 2014 (mean follow-up time, 40.6 mo). The primary outcome was treatment efficacy (complete eradication of BE and associated neoplasia); secondary outcomes included safety, durability, and accuracy of diagnosis.nnnRESULTSnBE was eradicated completely by EMR in 80.4% (86 of 107) of patients based on intention-to-treat analysis, and in 98.8% (79 of 80) of patients based on per-protocol analysis. The diagnosis was changed for 25% of patients after EMR, including 4 cases that initially were diagnosed as HGD by biopsy analysis and subsequently were found to have evidence of submucosal invasion when EMR specimens were assessed. Strictures and symptomatic dysphagia developed in 41.1% and 37.3% of patients, respectively, with an average of 2.3 dilations required. Perforations occurred in 2 patients after EMR and in 1 patient after dilation. HGD and IMC recurred in 1 patient each; both were treated successfully with EMR. Based on pathology analysis of the most recently collected specimens, 71.6% of patients (53 of 74) were in complete remission from intestinal metaplasia and 100% were in complete remission from HGD (74 of 74) or cancer (74 of 74).nnnCONCLUSIONSnFor patients with BE with HGD or neoplasia, complete EMR is an effective and durable treatment and is a relatively safe technique. Specimens collected by EMR also can be analyzed histologically to aid in diagnosis. The common complication of EMR is esophageal stricture, which can be addressed with endoscopic dilation.

Basaloid Squamous Cell Carcinoma of the Esophagus With or Without Adenoid Cystic Features

CONTEXTnBasaloid squamous cell carcinoma (BSCC) of the esophagus is a rare malignant tumor that morphologically could bear some resemblance to adenoid cystic carcinoma (ACC) originating from salivary glands.nnnOBJECTIVEnThe purpose of this study is to describe the histologic, immunohistochemical, and ultrastructural findings of BSCCs of the esophagus, with an emphasis on comparing tumors with or without adenoid cystic features.nnnDESIGNnWe reviewed 239 cases of primary esophageal carcinoma and detected 12 cases (5%) of BSCC. The light and electron microscopic findings and immunocytochemical localization of various antigens, including cytokeratins (AE1, AE3), carcinoembryonic antigen, epithelial membrane antigen, S100, smooth muscle actin, and p53, were examined in these BSCC cases.nnnRESULTSnHistologically, all BSCCs were composed of solid lobules or nests of basaloid cells with well-demarcated outlines surrounded by a fibrous stroma. Seven of 12 tumors showed areas of ACC-like features, that is, cribriform-like pseudoglandular lumina formation and hyaline material surrounding the tumor nests, whereas the remaining 5 tumors were apparently pure basaloid carcinomas. These 2 groups of tumors were histologically and immunohistochemically identical in many aspects, namely, high-grade nuclei of the tumor cells with frequent mitoses, abundant comedo-type necrosis, focal areas of concomitant squamous differentiation, consistent immunoreactivity for cytokeratins, and poor or absent staining for S100 and smooth muscle actin. Ultrastructurally, the basaloid tumor cells exhibited relatively undifferentiated cellular characteristics and undeveloped cell organelles.nnnCONCLUSIONnBasaloid squamous cell carcinomas of the esophagus frequently have an intimate association with ACC-like patterns, but their histologic, immunocytochemical, and ultrastructural features correspond more to poorly differentiated squamous cell carcinoma than to salivary gland ACC. This distinction is important because genuine ACC is much less aggressive than BSCC.

Benign papillary mesothelioma of the tunica vaginalis testis.

We report a case of benign mesothelioma of the tunica vaginalis testis in a 69-year-old man who presented with a 4-month history of scrotal swelling. A polypoid pedunculated nodule, 1.5 cm in diameter, was found near the head of the right epididymis. Histologically, the tumor exhibited features characteristic of a well-differentiated papillary mesothelioma. The mesothelial origin of this tumor was further supported by immunohistochemical analysis. The tumor cells exhibited nuclear p53 protein accumulation, despite the benign histologic findings and a 3-year uneventful follow-up after resection. A polymerase chain reaction analysis for simian virus 40 DNA was negative. The papillary configuration seen in this tumor is uncommon for this site, inasmuch as benign mesotheliomas of the tunica vaginalis testis usually exhibit an adenomatous pattern. One should be aware of this pattern, and benignity should be mentioned in the pathologic report to prevent overtreatment. In addition, positive p53 immunohistochemical staining should not be taken automatically as evidence for malignancy in this type of lesion.

Absolute Quantitation of Met Using Mass Spectrometry for Clinical Application: Assay Precision, Stability, and Correlation with MET Gene Amplification in FFPE Tumor Tissue

Background Overexpression of Met tyrosine kinase receptor is associated with poor prognosis. Overexpression, and particularly MET amplification, are predictive of response to Met-specific therapy in preclinical models. Immunohistochemistry (IHC) of formalin-fixed paraffin-embedded (FFPE) tissues is currently used to select for ‘high Met’ expressing tumors for Met inhibitor trials. IHC suffers from antibody non-specificity, lack of quantitative resolution, and, when quantifying multiple proteins, inefficient use of scarce tissue. Methods After describing the development of the Liquid-Tissue-Selected Reaction Monitoring-mass spectrometry (LT-SRM-MS) Met assay, we evaluated the expression level of Met in 130 FFPE gastroesophageal cancer (GEC) tissues. We assessed the correlation of SRM Met expression to IHC and mean MET gene copy number (GCN)/nucleus or MET/CEP7 ratio by fluorescence in situ hybridization (FISH). Results Proteomic mapping of recombinant Met identified 418TEFTTALQR426 as the optimal SRM peptide. Limits of detection (LOD) and quantitation (LOQ) for this peptide were 150 and 200 amol/µg tumor protein, respectively. The assay demonstrated excellent precision and temporal stability of measurements in serial sections analyzed one year apart. Expression levels of 130 GEC tissues ranged (<150 amol/µg to 4669.5 amol/µg. High correlation was observed between SRM Met expression and both MET GCN and MET/CEP7 ratio as determined by FISH (nu200a=u200a30; R2u200a=u200a0.898). IHC did not correlate well with SRM (nu200a=u200a44; R2u200a=u200a0.537) nor FISH GCN (nu200a=u200a31; R2u200a=u200a0.509). A Met SRM level of ≥1500 amol/µg was 100% sensitive (95% CI 0.69–1) and 100% specific (95% CI 0.92–1) for MET amplification. Conclusions The Met SRM assay measured the absolute Met levels in clinical tissues with high precision. Compared to IHC, SRM provided a quantitative and linear measurement of Met expression, reliably distinguishing between non-amplified and amplified MET tumors. These results demonstrate a novel clinical tool for efficient tumor expression profiling, potentially leading to better informed therapeutic decisions for patients with GEC.

Lymphocytic colitis and collagenous colitis: a review of clinicopathologic features and immunologic abnormalities.

Lymphocytic colitis (LC) and collagenous colitis (CC), 2 histologic forms of microscopic colitis, were recognized as rare disease entities 4 decades ago. An increasing body of evidence accumulated in the past 40 years reveals increasing incidence and prevalence rates, a wide spectrum of clinical presentations, and several histologic variants. Although several recent randomized clinical trials confirmed the efficacy of oral budesonide in treating LC and CC, disease relapse after a short-duration treatment is common. Despite their common clinical presentations and well-defined histologic diagnostic criteria, there are only few studies on the immunologic abnormalities in colonic tissue. The aim of this review is to (1) familiarize the pathologists in general practice with histomorphology of LC and CC, including the rare histologic variants and the clinical implication associated with these 2 diagnoses, (2) summarize the data from recent randomized clinical trials of oral budesonide, and (3) review immunological studies on colonic tissue. Overall, immunologic abnormalities of colonic tissue seem to explain for the histomorphologic features and the clinical symptomatology of LC and CC. Advances in the understanding of the underlying immunologic abnormalities in the colonic tissue may help develop novel and effective therapies for these 2 diseases.

Comparing morphometric, biochemical, and visual measurements of macrovesicular steatosis of liver.

The degree of macrovesicular steatosis is typically evaluated in liver biopsies by visual estimation, which is subject to intraobserver and interobserver variations. Computer morphometry and biochemical measurement may provide more accurate results. Our aim was to develop a morphometry method and compare its results with visual and biochemical measurements. Twenty-six fresh frozen liver specimens were each divided into 4 aliquots. Three aliquots were processed biochemically to extract fat, and the fat content was defined as the weight percentage of fat. One aliquot was fixed in formalin, from which hematoxylin and eosin slides were made and reviewed by 3 pathologists to estimate fat content. Digital images of slides were analyzed by computer morphometry, which defined fat content as the percentage of area occupied by fat droplets. The results showed that individually, each method produced highly precise and reproducible measurements. Compared with each other, they showed very strong correlations (correlation coefficient r = 0.81-0.95). The range of fat content in all 26 specimens was 2.2% to 15% by biochemical, 0.8% to 82.5% by visual, and 0.3% to 19.6% by morphometry method. Visual estimation appeared to have a systematic bias, giving results nearly 4-fold higher than other methods. This may be because visual estimation denotes the fraction of hepatocytes containing fat droplets, instead of the true fraction of fat. Strong correlations between different methods suggest that all 3 are valid methods for measuring steatosis. Computer morphometry is easy to implement and not affected by the bias seen in visual estimation. It may serve as a potential supplemental or alternative method.