Vishal Chandan

Collagenous gastritis: histopathologic features and association with other gastrointestinal diseases.

Collagenous gastritis (CG) characterized by the deposition of a subepithelial collagen band and accompanying inflammatory infiltrate is a rare disorder. The natural history and pathogenesis of CG remain unclear. We describe the histologic features (23 gastric, 18 duodenal, and 4 colonic biopsies) and clinical findings of an additional 12 cases. Histologic features including active or chronic inflammation, surface epithelial injury, intraepithelial lymphocytosis, intestinal metaplasia, and Helicobacter pylori, and measurement of thickness of subepithelial collagenous band were evaluated in gastric biopsies. The clinical features, endoscopic findings, and follow-up were obtained and correlated with histologic features. There was an even number of males (n=6) and females (n=6). Four patients were children/young adults, 3 of whom (75%) presented with anemia and gastric nodularity. Eight patients were adults, 6 of whom (75%) had an associated autoimmune disease (1 with Hashimoto thyroiditis and polymyositis) or other intestinal disease (3 with celiac sprue, 1 with collagenous colitis, 1 with collagenous sprue), in contrast to none in the 4 children/young adults, P=0.06. The range of subepithelial collagen thickness was 15 to 120u2009μm in CG. The collagenous layer showed surface epithelial injury and entrapped inflammatory cells. On presentation, the thickened collagen distribution in the antrum and body was variably patchy and diffuse. Four (33%) patients showed lymphocytic gastritis (3 within the same biopsy); one of these patients also had celiac sprue and another had collagenous sprue. Three (25%) patients had celiac sprue (2 had duodenal biopsy proven and 1 had a clinical diagnosis of celiac sprue). An additional patient had duodenal biopsies showing collagenous sprue. Four patients had follow-up biopsies during a 3 to 119-month period after the diagnosis of CG. CG persisted on the follow-up gastric biopsies in 3 (75%) of the 4 patients, and the other patient had lymphocytic gastritis, a finding not seen in previous biopsies. CG is a rare disorder with a distinct presentation and association in pediatric and adult patients. An absence of associated intestinal and autoimmune diseases characterizes the pediatric population. Association with lymphocytic gastritis, celiac or collagenous sprue, collagenous colitis, and autoimmune disorders are frequently seen in adult patients.

Leukocyte cell-derived chemotaxin 2 (LECT2)–associated amyloidosis is a frequent cause of hepatic amyloidosis in the United States

Using laser microdissection and mass spectrometry (MS)-based proteomics, we subtyped amyloid deposits from 130 cases of hepatic amyloidosis. Although we confirmed that immunoglobulin light chain amyloidosis was the most frequent cause of hepatic amyloidosis, leukocyte cell-derived chemotaxin 2 (LECT2) amyloidosis (ALect2) accounted for 25% of cases. This novel finding was associated with Hispanic ancestry, incidental discovery of amyloid in liver specimens sampled for other unrelated conditions, and a characteristic pattern of hepatic amyloid deposition. Although ALect2 patients had a common LECT2 polymorphism, pathogenic mutations were not discovered, suggesting that constitutive or compensatory LECT2 overexpression led to ALect2 deposition. These findings indicate that ALect2 is a common cause of hepatic amyloidosis in the population of the United States, and subtyping hepatic amyloid deposits by an accurate analytic method such as MS is required for optimal clinical management of hepatic amyloidosis patients and to avoid incorrect and unnecessarily toxic therapies.

Patchy distribution of pathologic abnormalities in autoimmune pancreatitis: Implications for preoperative diagnosis

Autoimmune pancreatitis (AIP) is a distinctive form of chronic pancreatitis that can mimic pancreatic carcinoma. In the past, AIP accounted for up to 27% of Whipple resections performed for suspected adenocarcinoma. More recently, with increased awareness of AIP and reports of its steroid responsiveness, tru-cut needle biopsies are increasingly used as an aid in preoperative diagnosis. We noticed a distinctive patchy distribution to the pathologic abnormalities in many cases of resected AIP that could potentially interfere with preoperative diagnosis by needle biopsy. We studied 39 pancreatic resections with AIP, defined by the following triad of features: (1) lymphoplasmacytic infiltrates around ducts, (2) acinar lymphoplasmacytic inflammation with atrophy and fibrosis, and (3) obliterative phlebitis. Criteria for inclusion in the study included either submission of the entire resection specimen (n=21) or extensive histologic sampling (n=18) defined as submission of ≥10 sections. We reviewed all hematoxylin and eosin-stained sections and (1) mapped areas of sparing and involvement by AIP, (2) classified the AIP as lobulocentric, ductocentric, or mixed, and (3) tabulated numbers of immunoglobulin (Ig) G4+ plasma cells in areas of involvement and sparing. To be included as an area of sparing, both duct and acinar parenchyma had to be free of lymphoplasmacytic inflammation, and the focus had to be at least 0.5u2009cm in diameter. Our results demonstrate a high prevalence of patchiness in AIP. Thirty-two (82%) specimens had areas of sparing (mean of 22% of each specimen spared, range 0.8% to 80%). The largest focus of uninvolved pancreas varied from 0.5 to 8.8u2009cm2 (mean: 1.8u2009cm2). In the remaining 7 (18%) cases, the changes of AIP were diffuse, with involvement of the entire submitted specimen. Number of IgG4+ plasma cells correlated highly with areas of involvement versus sparing by AIP; there were ≥5 IgG4+ plasma cells/20× field in 34 of 35 (97%) involved foci, but in only 1 of 26 (4%) histologically uninvolved foci (P<0.001). Classification as lobulocentric AIP (n=11), ductocentric AIP (n=15), and mixed AIP (n=12) did not correlate with extent of patchiness (P=0.92) or with the volume of spared parenchyma (P=1.0). These results demonstrate patchy involvement by AIP in a majority of resected pancreata. In specimens containing large areas of uninvolved parenchyma, this raises the potential for underdiagnosis by tru-cut biopsy. In patients with radiologic and serologic features (eg, elevated serum IgG4 level) suspicious for AIP, this potential pitfall in pathologic diagnosis should be considered before proceeding to surgery. IgG4 immunostaining of apparently negative biopsies may be helpful, but only in a small minority of cases.

Esophageal lichen planus.

Esophageal lichen planus is an underrecognized condition, with fewer than 50 cases reported to date. Unlike cutaneous lichen planus, esophageal lichen planus occurs almost exclusively in middle-aged or older women who also have oral involvement. It commonly involves the proximal esophagus and manifests as progressive dysphagia and odynophagia. Endoscopic findings can include lacy white papules, pinpoint erosions, desquamation, pseudomembranes, and stenosis. Histologic features of esophageal lichen planus have only rarely been illustrated. They differ from those of cutaneous disease in several respects, including the presence of parakeratosis, epithelial atrophy, and lack of hypergranulosis. Correct diagnosis of esophageal lichen planus is difficult but bears important therapeutic implications. It is typically a chronic and relapsing condition that can require systemic or local immunosuppressive therapy and repeated endoscopic dilatations for esophageal strictures. Esophageal lichen planus may have malignant potential, as evidenced by 3 patients who developed squamous carcinoma of the esophagus after longstanding disease.

Liver Masses: A Clinical, Radiologic, and Pathologic Perspective

Liver masses present a relatively common clinical dilemma, particularly with the increasing use of various imaging modalities in the diagnosis of abdominal and other symptoms. The accurate and reliable determination of the nature of the liver mass is critical, not only to reassure individuals with benign lesions but also, and perhaps more importantly, to ensure that malignant lesions are diagnosed correctly. This avoids the devastating consequences of missed diagnosis and the delayed treatment of malignancy or the unnecessary treatment of benign lesions. With appropriate interpretation of the clinical history and physical examination, and the judicious use of laboratory and imaging studies, the majority of liver masses can be characterized noninvasively. Accurate characterization of liver masses by cross-sectional imaging is particularly dependent on an understanding of the unique phasic vascular perfusion of the liver and the characteristic behaviors of different lesions during multiphasic contrast imaging. When noninvasive characterization is indeterminate, a liver biopsy may be necessary for definitive diagnosis. Standard histologic examination usually is complemented by immunohistochemical analysis of protein biomarkers. Accurate diagnosis allows the appropriate selection of optimal management, which is frequently reassurance or intermittent follow-up evaluations for benign masses. For malignant lesions or those at risk of malignant transformation, management depends on the tumor staging, the functional status of the uninvolved liver, and technical surgical considerations. Unresectable metastatic masses require oncologic consultation and therapy. The efficient characterization and management of liver masses therefore requires a multidisciplinary collaboration between the gastroenterologist/hepatologist, radiologist, pathologist, hepatobiliary or transplant surgeon, and medical oncologist.

MR elastography of hepatocellular carcinoma: Correlation of tumor stiffness with histopathology features—Preliminary findings

PURPOSEnTo determine if tumor stiffness by MR Elastography (MRE) is associated with hepatocellular carcinoma (HCC) pathologic features.nnnMATERIAL AND METHODSnA retrospective review was undertaken of all patients with pathologically confirmed HCC who underwent MRE prior to loco-regional therapy, surgical resection or transplant between 1/1/2007 to 12/31/2015. An independent observer measured tumor stiffness (kilopascals, kPa) by drawing regions of interest (ROI) covering the HCC and in the case of HCCs with non-enhancing/necrotic components, only the solid portion was included in the ROI. HCC tumor grade (WHO criteria), vascular invasion and tumor encapsulation were assessed from retrievable pathology specimens by an expert hepatobiliary pathologist. Tumor stiffness was compared by tumor grade, size, presence of capsule and vascular invasion using Students t-test (or Exact Mann-Whitney test).nnnRESULTSn21 patients were identified who had pathologically confirmed HCCs and tumor MRE data. 17 patients (81.0%) had underlying chronic liver disease. The mean±SD tumor size (cm) was 5.3±3.9cm. The mean±SD tumor stiffness was 5.9±1.4kPa. Tumors were graded as well differentiated (N=2), moderately differentiated (N=11) and poorly differentiated (N=8). There was a trend toward increased tumor stiffness in well/moderately differentiated HCCs (6.5±1.2kPa; N=13) compared to poorly differentiated HCCs (4.9±1.2kPa; N=8) (p<0.01). There was no significant correlation between tumor stiffness and liver stiffness or tumor size. There was no significant difference in tumor stiffness by presence or etiology of chronic liver disease, vascular invasion or tumor encapsulation.nnnCONCLUSIONnPreliminary data suggest that tumor stiffness by MRE may be able to differentiate HCC tumor grade.

Increased immunoglobulin G4-positive plasma cells in collagenous sprue.

Collagenous sprue is a rare enteropathy whose etiology is unknown, but immune-mediated mechanisms are one of several possibilities. However, the role of immunoglobulin G4 (IgG4)-positive plasma cells has not been studied in collagenous sprue. Endoscopic biopsies from the duodenum with a histologic diagnosis of collagenous sprue (n = 40 from 35 patients), celiac disease (n = 25), peptic duodenitis (n = 15) and normal duodenum (n = 25) were immunohistochemically stained with IgG4 and CD138 antibodies. For each case, the quantities of IgG4- and CD138-positive plasma cells in the lamina propria were estimated by averaging the number in 3 high-power fields (hpf) that showed the highest concentration. Nine of forty collagenous sprue samples showed a mean of 10 or more IgG4 plasma cells per hpf, whereas none of the duodenal control biopsies showed 10 or more IgG4 plasma cells per hpf: celiac disease (P = .01), peptic duodenitis (P = .05), and normal duodenum (P = .01). Our study demonstrates that increased IgG4-positive plasma cells are present in a subset (23%) of collagenous sprue and may play a role in its pathogenesis.

Arginase-1 is frequently positive in hepatoid adenocarcinomas

Hepatoid adenocarcinoma is a rare extrahepatic tumor, which shows morphological and immunohistochemical similarities to hepatocellular carcinoma (HCC). Hence, hepatoid adenocarcinoma can cause diagnostic confusion with HCC. Arginase-1 immunostain has been recently shown to be an excellent marker of normal hepatocytes and is a sensitive and specific marker for HCC. However, the expression of Arginase-1 in hepatoid adenocarcinoma has not been evaluated in detail. Eight cases of hepatoid adenocarcinoma were immunostained with Arginase-1, Hepar-1, Glypican-3, CK7, CK20, CK19, polyclonal carcinoembryonic antigen, ɑ-fetoprotein, CDX2, and TTF-1. Albumin in situ hybridization was performed in 4 cases. All 8 cases were positive for Hepar-1. Arginase-1 was positive in 5 (62.5%) of 8 cases; 2 of these cases showed diffuse staining, while 3 showed patchy staining. Glypican-3, CK7 and ɑ-fetoprotein were each positive in 4 (50%) of 8 cases. CK19 was positive in 3 (37.5%) of 8 cases. polyclonal carcinoembryonic antigen showed canalicular staining in 3 (37.5%) of 8 cases and albumin in situ hybridization was positive in 3 (75%) of 4 cases. CDX2 was positive in 2 (25%) of 8 cases, both arising from the stomach. CK20 was positive in 1 (12.5%) of 8 case while TTF-1 was negative in all cases. Hepatoid adenocarcinoma has a similar immunostaining profile as HCC. Arginase-1 expression is common (62.5%) in hepatoid adenocarcinoma and hence it is not useful in distinguishing HCC from hepatoid adenocarcinoma.

Globular hepatic amyloid is highly sensitive and specific for LECT2 amyloidosis

Globular hepatic amyloid (GHA) is rare, and its clinical significance remains unclear. Recently, leukocyte chemotactic factor–associated amyloidosis (ALECT2) has been reported to involve the liver, showing a globular pattern. We reviewed 70 consecutive cases of hepatic amyloidosis to determine the prevalence and morphology of hepatic amyloid subtypes, especially ALECT2 and its association with GHA. Each case was reviewed for amyloid subtype (immunohistochemistry and/or mass spectrometry), its pattern (linear or globular), and distribution (vascular, perisinusoidal, or stromal). In addition, 24 cases of confirmed hepatic ALECT2 on mass spectrometry from our consultation files were also reviewed. LECT2 immunostaining was performed in 49 cases. Of the 70 cases, immunoglobulin light chain (AL) type was most common with 41 cases (59%), followed by transthyretin (ATTR) 15 cases (22%), 3 cases each of fibrinogen A (AFib) (4%), serum amyloid A (AA) (4%), and ALECT2 (4%), 2 cases of apolipoproteins (AApoA1) (3%), and 3 cases (4%) were unclassified. Three of our 70 cases (4%), with ALECT2, and all 24 cases (100%) of mass spectrometry–confirmed hepatic ALECT2 showed only GHA deposits in the hepatic sinusoids and portal tracts. Three (4%) other cases of AL type showed a focal globular pattern admixed with prominent linear amyloid. None of the other amyloid subtypes showed GHA. LECT2 immunostain was positive in all 27 cases (100%) of ALECT2 and negative in the other 22 non-ALECT2 cases (100%) (14 AL, 5 ATTR, 1 AA, 1 AFib, 1 AApoA1). Pure GHA is uncommon (4%) but is highly specific for ALECT2, and LECT2 immunostain is helpful in confirming this amyloid type.

A subset of well-differentiated hepatocellular carcinomas are Arginase-1 negative

Hepatocellular carcinoma (HCC) is a common malignancy both in the United States of America and worldwide. Despite the refinement of imaging techniques in at-risk populations, a needle biopsy diagnosis remains an important diagnostic tool for HCC in many cases. Various immunohistochemical markers have been developed to facilitate this diagnosis, such as HepPar-1, glypican-3 and, most recently, arginase-1. Amongst them, arginase-1 has been shown to have superior sensitivity and specificity than the others. Performance of arginase-1 has been reported to be excellent for diagnosis of well-differentiated HCCs, with some tail-off in sensitivity for poorly differentiated tumors. Our experience has suggested that a subset of well-differentiated HCCs can be negative for arginase-1. We examined 68 consecutive confirmed cases of well-differentiated HCC diagnosed on needle biopsy, and found 7 (10%) to be completely negative for arginase-1. This finding is of fundamental clinical importance in view of previous studies that have shown arginase-1 to be always positive in well-differentiated HCC.