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Histopathologic diagnosis of antibody-mediated rejection in posttransplant liver biopsies is challenging. The recently proposed diagnostic criteria by the Banff Working Group on Liver Allograft Pathology require positive C4d immunohistochemical staining to establish the diagnosis. However, the reported C4d staining patterns vary widely in different studies. One potential explanation may be due to different antibody preparations used by different investigators. In this study, posttransplant liver biopsies from 69 patients histopathologically diagnosed with acute cellular rejection, chronic rejection, or recurrent hepatitis C were immunohistochemically stained using 2 polyclonal anti-C4d antibodies. On the basis of the distribution of C4d immunoreactivity, 5 different staining patterns were observed: portal vein and capillary, hepatic artery, portal stroma, central vein, and sinusoids. The frequency, extent, and intensity of positive C4d staining with the 2 antibody preparations differed significantly for portal veins/capillaries and central veins, but not for hepatic arteries and portal stroma. Positive sinusoidal staining was seen in only 1 case. There were no significant differences in the frequency, extent, and intensity of positive C4d staining among the acute cellular rejection, chronic rejection, and recurrent hepatitis C groups with the 2 anti-C4d antibodies. These data show that different anti-C4d antibodies can show different staining patterns, which may lead to different interpretation. Caution is thus needed when selecting C4d antibodies for clinical use to aid in the diagnosis of antibody-mediated rejection.

Colonic inertia is a frustrating motility disorder to patients, clinicians, and pathologists. The pathogenesis is largely unknown. The aims of this study were to: (1) characterize the expression of smoothelin, a novel smooth muscle-specific contractile protein expressed only by terminally differentiated smooth muscle cells, in the normal gastrointestinal (GI) tract; and (2) determine whether smoothelin is aberrantly expressed in patients with colonic inertia. A total of 57 resections of the normal GI tract (distal esophagus to left colon) were obtained from patients without GI motor dysfunction. Sixty-one colon resections were obtained from patients with a clinical diagnosis of colonic inertia. Smoothelin immunostaining was conducted on full-thickness tissue sections. In the nondysmotile controls, strong and diffuse cytoplasmic staining for smoothelin was observed in both the inner circular and outer longitudinal layers of the muscularis propria (MP) throughout the entire GI tract. The muscularis mucosae (MM) and muscular vessel walls were either completely negative or only patchily and weakly stained. The 1 exception to this pattern was observed in the distal esophagus, in which the MM was also diffusely and strongly stained. In cases with colonic inertia, a moderate to marked reduction of smoothelin immunoreactivity was observed in 15 of 61 (24.6%) colon resections, selectively seen in the outer layer of the MP. The data demonstrate that smoothelin is differentially expressed in the MP and MM of the normal GI tract and suggest that defective smoothelin expression may play a role in the pathogenesis of colonic inertia in a subset of patients. Copyright © 2012 by Lippincott Williams & Wilkins.

Histopathologic distinction among small-cell carcinoma (SCC), pancreatic endocrine tumor (PET), and gastrointestinal carcinoids metastasized to the liver in needle core biopsies can be extremely challenging because of limited material, crush artifact, and lack of detailed clinical history. In this study, a total of 61 surgically resected or biopsied specimens, including 27 SCCs (lung, 17; colon, 1; gallbladder, 2; stomach, 1; and unknown primary, 6), 18 gastrointestinal carcinoid tumors (GICTs) (stomach, 2; small intestine, 14; colon, 2), and 16 PETs were immunohistochemically examined for the expression of IMP3, TTF-1, CDX2, and NESP55 to evaluate their diagnostic value. The results showed that 24 (89%) of 27 SCCs exhibited strong cytoplasmic staining for IMP3 in 60% to 100% of the tumor cells. Eighteen (67%) SCCs were strongly and diffusely positive for TTF-1. In the remaining 9 TTF-1-negative SCCs (including 4 extrapulmonary cases), 7 showed strong and diffuse IMP3 expression. All SCCs were negative for CDX2 except for 1 case of colonic origin that showed strong CDX2 immunoreactivity. All 16 metastatic PETs were positively stained for IMP3 with 12 cases (75%) showing a diffuse and moderate-to-strong staining pattern while they were negative for TTF-1. Six PETs exhibited moderate-to-strong positivity for CDX2 with nuclear staining in 5% to 40% of tumor cells, and 5 showed a varying degree of positivity for NESP55. Three (17%) of 18 metastatic GICTs showed moderate IMP3 staining in 50% to 90% of the tumor cells, whereas CDX2 was expressed in 17 (94%) cases with moderate-to-strong staining in 50% to 100% of tumor cells. No NESP55 immunoreactivity was detected in metastatic SCCs and GICTs. In conclusion, a panel of these 4 markers is useful in segregating among SCC, PET, and GICT to help determine the primary site of hepatic metastasis.

Histologic evaluation of an endoscopic bile duct biopsy for malignancy is a known challenge. Our prior study has shown that the insulin-like growth factor-II mRNA binding protein-3 (IMP3), S100P, and the von Hippel-Lindau gene product (pVHL) are a useful immunopanel for the distinction between adenocarcinoma and benign biliary epithelium. To further evaluate the usefulness of the IMP3, S100P, and pVHL immunopanel to aid in the interpretation of bile duct biopsies, 16 histologically challenging bile duct biopsies that exhibited atypical histology or features suspicious for malignancy were immunohistochemically stained for IMP3, S100P, and pVHL. Clinical follow-up data were obtained for each case. The results showed that in the 11 cases that showed adenocarcinoma during follow-up, the following staining patterns in atypical/suspicious cells in the initial biopsies were observed: IMP3-positive/S100P-positive/pVHL-negative or reduced (n=6), IMP3-negative/S100P-positive/pVHL-negative or reduced (n=4), and IMP3-positive/S100P-negative/pVHL-negative (n=1). In the 5 follow-up-proven benign cases, 2 biopsies showed an IMP3-negative/S100P-positive/pVHL-positive pattern in atypical cells and 1 was negative for all 3 proteins. The remaining 2 biopsies exhibited an IMP3-positive/S100P-positive/pVHL-negative or reduced pattern in atypical cells that were histologically considered dysplastic on retrospective review. These observations reaffirm that bile duct adenocarcinoma frequently shows positive IMP3 and/or S100P staining with reciprocal negative or reduced pVHL expression. This staining pattern can also be seen in dysplastic epithelium in the absence of invasive carcinoma. On the contrary, benign biliary epithelium typically lacks IMP3 immunoreactivity and may retain normal pVHL expression. However, caution should be exercised when using this immunopanel in the interpretation of challenging bile duct biopsies, because S100P and pVHL stains may give rise to variable patterns that can be difficult to interpret.

Differentiation of primary from metastatic adenocarcinoma in the lung can be challenging, and it demands sensitive and specific biomarkers, especially when the tissue for diagnosis is limited. Thyroid transcription factor-1 (TTF-1) has been considered a reliable marker for adenocarcinoma of lung origin. However, several recent studies have shown that TTF-1 immunostaining is also positive in adenocarcinomas arising in different organs including colon, endometrium, endocervix, and ovary. In addition, approximately 20% of lung primary adenocarcinomas are negative for TTF-1 immunostaining, and napsin A immunostaining has slightly higher sensitivity in detecting lung primary adenocarcinoma. We performed TTF-1 and napsin A immunostaining on 120 cases of primary lung adenocarcinomas and 37 cases of metastatic carcinomas in the lung. The results showed that 95 (79.2%) of 120 lung primary adenocarcinomas showed napsin A+/TTF-1+ double-positive immunostaining pattern. TTF-1⁻/napsin A+, TTF-1+/napsin A⁻, and TTF-1⁻/napsin A⁻ were seen in 8.3%, 3.3%, and 9.2% lung primary adenocarcinomas, respectively. Eight (21.6%) of the 37 metastatic carcinomas were positive for TTF-1 and they include clear-cell renal cell carcinomas completely negative for napsin A although napsin A was detected in 12 (80.0%) of 15 primary papillary and 3 (33.3%) of 9 primary clear-cell renal cell carcinomas. All renal epithelial neoplasms were TTF-1 negative. These findings indicate that double napsin A and TTF-1-positive immunostaining is highly specific for lung primary adenocarcinoma and the combination of these 2 biomarkers is warranted to help segregating primary lung adenocarcinoma from metastatic carcinoma in the lung.

Malignant mesotheliomas occur in the pleura, peritoneum, pericardium, and tunica vaginalis. The majority of tumors are pleural in origin. The typical pattern of spread is usually contiguous or via implantation. Hematogenous or lymphatic metastasis is not uncommon; however, metastasis to bone has rarely been well documented. This is a case report of malignant pleural mesothelioma metastatic to the femur with a pathologic fracture of femoral neck.