NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates normoxic HIF-1α and p27Kip1 expression in malignant melanoma and other human tumors.

NADPH oxidase 5 (NOX5) generated reactive oxygen species (ROS) have been implicated in signaling cascades that regulate cancer cell proliferation. To evaluate and validate NOX5 expression in human tumors, we screened a broad range of tissue microarrays (TMAs), and report substantial overexpression of NOX5 in malignant melanoma and cancers of the prostate, breast, and ovary. In human UACC-257 melanoma cells that possesses high levels of functional endogenous NOX5, overexpression of NOX5 resulted in enhanced cell growth, increased numbers of BrdU positive cells, and increased γ-H2AX levels. Additionally, NOX5-overexpressing (stable and inducible) UACC-257 cells demonstrated increased normoxic HIF-1α expression and decreased p27Kip1 expression. Similarly, increased normoxic HIF-1α expression and decreased p27Kip1 expression were observed in stable NOX5-overexpressing clones of KARPAS 299 human lymphoma cells and in the human prostate cancer cell line, PC-3. Conversely, knockdown of endogenous NOX5 in UACC-257 cells resulted in decreased cell growth, decreased HIF-1α expression, and increased p27Kip1 expression. Likewise, in an additional human melanoma cell line, WM852, and in PC-3 cells, transient knockdown of endogenous NOX5 resulted in increased p27Kip1 and decreased HIF-1α expression. Knockdown of endogenous NOX5 in UACC-257 cells resulted in decreased Akt and GSK3ß phosphorylation, signaling pathways known to modulate p27Kip1 levels. In summary, our findings suggest that NOX5 expression in human UACC-257 melanoma cells could contribute to cell proliferation due, in part, to the generation of high local concentrations of extracellular ROS that modulate multiple pathways that regulate HIF-1α and networks that signal through Akt/GSK3ß/p27Kip1 .

Fibrolamellar carcinomas are positive for CD68.

Fibrolamellar carcinomas are a unique type of liver carcinoma that arise in non-cirrhotic livers of young individuals. Despite their distinctive appearance, recent studies have demonstrated a lack of consistency in how fibrolamellar carcinomas are diagnosed by pathologists. As a potential aide in diagnosis, we investigated the staining properties of CD68. The CD68 gene encodes for a transmembrane glycoprotein located within lysosomes and endosomes. Macrophages as well as other cell types rich in lysosomes/endosomes are CD68 positive. Cases of fibrolamellar carcinoma were collected from four academic centers. Control groups included hepatocellular carcinomas arising in both non-cirrhotic livers and cirrhotic livers. A group of cholangiocarcinomas were also stained. CD68 immunostaining was scored for both intensity and distribution on a scale of 0 to 3+. Twenty-three primary fibrolamellar carcinomas and 9 metastases (total of 24 individuals) were immunostained and showed a distinctive granular, dot-like or stippled pattern of cytoplasmic staining in nearly all cases (31/32), with a median distribution and intensity score of 3+. In control hepatocellular carcinomas that arose in non-cirrhotic livers, 10/39 showed CD68 staining with a median distribution and intensity score of 2+. In hepatocellular carcinomas arising in cirrhotic livers, 3/27 cases showed CD68 positivity, all with stippled dot-like cytoplasmic staining similar to that of fibrolamellar carcinomas. All five cholangiocarcinomas were negative. Overall, CD68 positivity was strongly associated with fibrolamellar carcinomas, P<0.001 and had a sensitivity of 96%, a specificity of 80%, and a negative predictive value of 98%. In sum, tumor positivity for CD68 staining was highly sensitive for fibrolamellar carcinoma and a lack of CD68 staining should suggest caution in making a diagnosis of fibrolamellar carcinoma.

State of the Art: Toward Improving Outcomes of Lung and Liver Tumor Biopsies in Clinical Trials-A Multidisciplinary Approach.

PURPOSE: National Cancer Institute (NCI)-sponsored clinical trial network studies frequently require biopsy specimens for pharmacodynamic and molecular biomarker analyses, including paired pre- and post-treatment samples. The purpose of this meeting of NCI-sponsored investigators was to identify local institutional standard procedures found to ensure quantitative and qualitative specimen adequacy. METHODS: NCI convened a conference on best biopsy practices, focusing on the clinical research community. Topics discussed were (1) criteria for specimen adequacy in the personalized medicine era, (2) team-based approaches to ensure specimen adequacy and quality control, and (3) risk considerations relevant to academic and community practitioners and their patients. RESULTS AND RECOMMENDATIONS: Key recommendations from the convened consensus panel included (1) establishment of infrastructure for multidisciplinary biopsy teams with a formalized information capture process, (2) maintenance of standard operating procedures with regular team review, (3) optimization of tissue collection and yield methodology, (4) incorporation of needle aspiration and other newer techniques, and (5) commitment of stakeholders to use of guideline documents to increase awareness of best biopsy practices, with the goal of universally improving tumor biopsy practices.

Clinical Evolution of Epithelial-Mesenchymal Transition in Human Carcinomas.

The significance of the phenotypic plasticity afforded by epithelial-mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in the clinic. We evaluated epithelial-mesenchymal phenotypic characteristics across a range of tumor histologies using a validated, high-resolution digital microscopic immunofluorescence assay (IFA) that incorporates ß-catenin detection and cellular morphology to delineate carcinoma cells from stromal fibroblasts and that quantitates the individual and colocalized expression of the epithelial marker E-cadherin (E) and the mesenchymal marker vimentin (V) at subcellular resolution ("EMT-IFA"). We report the discovery of ß-catenin+ cancer cells that coexpress E-cadherin and vimentin in core-needle biopsies from patients with various advanced metastatic carcinomas, wherein these cells are transitioning between strongly epithelial and strongly mesenchymal-like phenotypes. Treatment of carcinoma models with anticancer drugs that differ in their mechanism of action (the tyrosine kinase inhibitor pazopanib in MKN45 gastric carcinoma xenografts and the combination of tubulin-targeting agent paclitaxel with the BCR-ABL inhibitor nilotinib in MDA-MB-468 breast cancer xenografts) caused changes in the tumor epithelial-mesenchymal character. Moreover, the appearance of partial EMT or mesenchymal-like carcinoma cells in MDA-MB-468 tumors treated with the paclitaxel-nilotinib combination resulted in upregulation of cancer stem cell (CSC) markers and susceptibility to FAK inhibitor. A metastatic prostate cancer patient treated with the PARP inhibitor talazoparib exhibited similar CSC marker upregulation. Therefore, the phenotypic plasticity conferred on carcinoma cells by EMT allows for rapid adaptation to cytotoxic or molecularly targeted therapy and could create a form of acquired drug resistance that is transient in nature. SIGNIFICANCE: Despite the role of EMT in metastasis and drug resistance, no standardized assessment of EMT phenotypic heterogeneity in human carcinomas exists; the EMT-IFA allows for clinical monitoring of tumor adaptation to therapy.

Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C Trial.

There is relatively little information in the literature on the histopathology of chronic hepatitis C in children. The Peds-C Trial, designed to test the efficacy and safety of peginterferon alfa-2a and ribavirin in children, provided an opportunity to examine liver biopsies from 121 treatment-naïve children, ages 2 to 16 (mean, 9.8 years) infected with the hepatitis C virus (HCV) and with no other identifiable cause for liver disease, signs of hepatic decompensation, or another significant nonhepatic disease. Liver biopsies were scored for inflammation, fibrosis, steatosis, and other histological features. Inflammation in the biopsy was minimal in 42%, mild in 17%, moderate in 38%, and severe in only 3%. Five had bridging fibrosis, and 2 had cirrhosis. Steatosis was absent in 56%, minimal in 34%, and mild in 10%. Inflammation scores correlated with fibrosis scores, serum alanine aminotransferase levels, and duration of infection, but not with age, body mass index z score, or HCV genotype. Fibrosis scores correlated with inflammation but not with age, HCV genotype, body mass index z score, or steatosis parameters. Steatosis correlated with serum alanine aminotransferase levels and body mass index z scores; overweight children had more fibrosis than the non-overweight. In conclusion, in this cohort of HCV-infected children, inflammation, fibrosis, and steatosis were milder than reported for treatment-naïve adults with chronic hepatitis C, but there were several with bridging fibrosis or cirrhosis. The positive correlation of inflammation with duration of infection and fibrosis and of obesity with fibrosis suggest that children with chronic hepatitis C will be at risk for progressive liver disease as they age and possibly acquire other comorbid risk factors.

Synovial sarcoma of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 10 cases.

Only a few synovial sarcomas arising in the gastrointestinal tract have been reported, most of them are from the esophagus. We report clinical, histopathologic, and immunohistochemical features of 10 gastric synovial sarcomas. These tumors occurred in 4 males and 6 females with mean and median age of 52 years (range, 29 to 68 y). None of the patients had evidence of synovial sarcoma elsewhere. The tumor sizes ranged from 0.8 to 15 cm (mean, 3 cm). Two tumors were large transmural masses of 8 and 15 cm, and 8 were 0.8 to 6 cm, ulcerated cuplike or plaquelike or oval lesions predominantly involving the luminal side. Histologically, 9 tumors were monophasic one also having a poorly differentiated round cell component, and one was biphasic. Microscopic calcifications were present in 2 tumors. At least focal keratin (AE1/AE3 cocktail, keratin 7) and/or epithelial membrane antigen-positivity were detected in all tumors, and there was no CD34 or KIT-immunoreactivity. SYT-SSX fusion transcripts were demonstrated in 7 cases studied by a polymerase chain reaction-based fusion transcript assay. Five patients had a partial gastrectomy, and 5 underwent wedge or segmental resections. Two patients had received chemotherapy after surgery, but none had postoperative radiation. Four patients with plaquelike or cuplike tumors < or =3 cm were alive and well 1, 2, 2, and 18.5 years after surgery. Two patients died of tumor 25 and 29 months after surgery. One of them had a large 8-cm tumor, and another had a 2-cm tumor with a poorly differentiated component. Two patients were alive with recurrences 6 and 48 months after diagnosis. Synovial sarcoma rarely occurs as a gastric primary tumor. It has a variable prognosis depending on tumor size and differentiation, and should be considered in the differential diagnosis of KIT-negative gastric spindle cell neoplasms.

Glypican-3 expression in benign liver tissue with active hepatitis C: implications for the diagnosis of hepatocellular carcinoma.

Glypican 3 is an oncofetal antigen that shows great promise as an adjunct to the diagnosis of hepatocellular carcinoma. To investigate whether glypican 3 might also appear in nonneoplastic liver cells, we performed immunostains on 60 biopsies of chronic hepatitis C, 30 with low-grade activity and 30 with high-grade activity. Glypican 3 immunoreactivity was detected in 25 (83.6%) of 30 in the high-grade but in none in the low-grade group. In 20% of the positive cases, glypican 3 produced strong cytoplasmic staining of more than 25% of hepatocytes and could potentially lead to a misdiagnosis of hepatocellular carcinoma. Pathologists should be aware of this phenomenon and exercise caution in interpreting biopsies or other specimens of suspected hepatocellular carcinoma when active necroinflammatory disease is present.

What Can Be Done to Improve Research Biopsy Quality in Oncology Clinical Trials?

PURPOSE:: Research biopsy specimens collected in clinical trials often present requirements beyond those of tumor biopsy specimens collected for diagnostic purposes. Research biopsies underpin hypothesis-driven drug development, pharmacodynamic assessment of molecularly targeted anticancer agents, and, increasingly, genomic assessment for precision medicine; insufficient biopsy specimen quality or quantity therefore compromises the scientific value of a study and the resources devoted to it, as well as each patient's contribution to and potential benefit from a clinical trial. METHODS:: To improve research biopsy specimen quality, we consulted with other translational oncology teams and reviewed current best practices. RESULTS:: Among the recommendations were improving communication between oncologists and interventional radiologists, providing feedback on specimen sufficiency, increasing academic recognition and financial support for the time investment required by radiologists to collect and preserve research biopsy specimens, and improving real-time assessment of tissue quality. CONCLUSION:: Implementing these recommendations at the National Cancer Institute's Developmental Therapeutics Clinic has demonstrably improved the quality of biopsy specimens collected; more widespread dissemination of these recommendations beyond large clinical cancer centers is possible and will be of value to the community in improving clinical research and, ultimately, patient care.

Globular hepatic amyloid: an early stage in the pathway of amyloid formation: a study of 20 new cases.

Only 25 cases of globular hepatic amyloidosis have been reported, mostly from the early 1980s. We reviewed clinical, histopathologic, and immunohistochemical features of 20 cases of hepatic globular amyloid out of 208 cases of liver amyloidosis seen at the Armed Forces Institute of Pathology since 1970. Fourteen (70%) were men and 6 were women with a median age of 67 years (range, 40 to 92 y). More than half of the patients were Hispanic. Ten of 20 patients were diagnosed with systemic amyloidosis. Histologically, all cases revealed round to oval-shaped sometimes laminated globules, 1 to 40 mum in diameter, and 6 cases had evidence of transition from globular to the more usual linear form. In all 20 cases, Congo red and/or Sirius red stained the globules red and showed an apple green birefringence under polarized light. Portal tracts and parenchyma were involved in 15/20 the cases, and sinusoidal deposition alone in 5 cases. Vascular deposition was very common with more than 3/4 of the cases showing mainly perivenular amyloid with both the terminal hepatic venules and portal vein branches being equally involved. A few intrahepatocellular globules were present in half of the cases. In conclusion, hepatic amyloidosis can rarely occur as a globular form, and the finding of intracellular amyloid globules and transitional forms of globular to linear patterns of deposition suggest that this is an early form of hepatic involvement by systemic amyloidosis.

Expression of estrogen and progesterone receptors and inhibin-alpha in hepatobiliary cystadenoma: an immunohistochemical study.

To further characterize the immunohistochemical features of hepatobiliary cystadenoma with mesenchymal stroma, a battery of stains was performed on nine typical cases. All nine tumors had been resected from female patients who ranged in age from 30 to 59 years. Freshly cut sections were stained with antibodies to estrogen receptor (ER), progesterone receptor (PR), alpha-smooth muscle actin (SMA), inhibin-alpha, and cytokeratins (CK) 7, 8, 18, and 19. Nuclear staining of the mesenchymal stromal cells for ER and PR was present in all and seven out of nine cases, respectively. A strong cytoplasmic staining of the mesenchymal stromal cells for SMA was seen in all cases. A patchy pale cytoplasmic staining of the tumor epithelium for ER and PR was seen in five out of nine and four out of nine cases, respectively. Immunoreactivity of luteinized stromal cell for inhibin-alpha was documented in three out of nine cases. All tumors (nine out of nine) demonstrated strong cytoplasmic positivity of the epithelial lining of the cysts to CK7, CK8, CK18, and CK19, typical of biliary-type epithelium. The expression of ER, PR, and inhibin-alpha in the ovarian-like stroma supports the likely hormonal dependence of this tumor and probably explains its almost exclusive occurrence in women.

Decoding NADPH oxidase 4 expression in human tumors.

NADPH oxidase 4 (NOX4) is a redox active, membrane-associated protein that contributes to genomic instability, redox signaling, and radiation sensitivity in human cancers based on its capacity to generate H2O2 constitutively. Most studies of NOX4 in malignancy have focused on the evaluation of a small number of tumor cell lines and not on human tumor specimens themselves; furthermore, these studies have often employed immunological tools that have not been well characterized. To determine the prevalence of NOX4 expression across a broad range of solid tumors, we developed a novel monoclonal antibody that recognizes a specific extracellular region of the human NOX4 protein, and that does not cross-react with any of the other six members of the NOX gene family. Evaluation of 20 sets of epithelial tumors revealed, for the first time, high levels of NOX4 expression in carcinomas of the head and neck (15/19 patients), esophagus (12/18 patients), bladder (10/19 patients), ovary (6/17 patients), and prostate (7/19 patients), as well as malignant melanoma (7/15 patients) when these tumors were compared to histologically-uninvolved specimens from the same organs. Detection of NOX4 protein upregulation by low levels of TGF-ß1 demonstrated the sensitivity of this new probe; and immunofluorescence experiments found that high levels of endogenous NOX4 expression in ovarian cancer cells were only demonstrable associated with perinuclear membranes. These studies suggest that NOX4 expression is upregulated, compared to normal tissues, in a well-defined, and specific group of human carcinomas, and that its expression is localized on intracellular membranes in a fashion that could modulate oxidative DNA damage.

Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in Adults and Children.

Nonalcoholic fatty liver disease (NAFLD) is the liver disease associated with obesity, diabetes, and the metabolic syndrome. Although steatosis is a key histologic feature, liver biopsies of patients with NAFLD can show a wide range of findings. Nonalcoholic steatohepatitis (NASH) is a progressive subtype of NAFLD first defined by analogy to alcoholic hepatitis. Young children may have an alternate pattern of progressive NAFLD characterized by a zone 1 distribution of steatosis, inflammation, and fibrosis. Several grading and staging systems exist, but all require adequate biopsies. Although NASH generally shows fibrosis progression over time, some patients show regression of disease.

The root causes of pharmacodynamic assay failure.

Robust pharmacodynamic assay results are valuable for informing go/no-go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable to fulfill this role. Our experience suggests that variable reagent and specimen quality are two major contributors to this problem. Minimizing all potential sources of variability in procedures for specimen collection, processing, and assay measurements is essential for meaningful comparison of pharmacodynamic biomarkers across sample time points. This is especially true in the evaluation of pre- and post-dose tumor biopsies, which suffer from high levels of tumor insufficiency due to variations in biopsy collection techniques and significant specimen heterogeneity within and across patients. Developing methods to assess heterogeneous biopsies is necessary in order to evaluate a majority of tumor biopsies collected for pharmacodynamic biomarker studies. Improved collection devices and standardization of methods are being sought in order to improve the tumor content and quality of tumor biopsies. In terms of reagent variability, we have found that stringent initial reagent qualification and quality control of R&D-grade reagents is critical to minimize lot-to-lot variability and prevent assay failures, especially for clinical pharmacodynamic questions, which often demand assay performance that meets or exceeds clinical diagnostic assay standards. Rigorous reagent specifications and use of appropriate assay quality control methodologies help to ensure consistency between assay runs, laboratories and trials to provide much needed pharmacodynamic insights into the activity of investigational agents.

Diagnosis of focal nodular hyperplasia of the liver by needle biopsy.

Focal nodular hyperplasia (FNH) of the liver can be a difficult diagnosis to establish in limited diagnostic samples such as a needle-core tissue biopsy, especially for pathologists with limited experience with the lesion. To characterize the features that can be used to make the diagnosis, we reviewed and analyzed the clinicopathologic features of 100 consecutive cases submitted for consultation in which we were confident of the diagnosis of FNH in needle biopsy material. A diagnosis of FNH was correctly made by the contributing pathologist in 24 of the 100 referred cases. Most of the patients (81%) were women of childbearing age with a mean age of 36.75 +/- 9.82 years. Most of the patients (70%) were asymptomatic at diagnosis. The most consistent diagnostic histological feature of FNH in needle biopsy was the presence of ductular reaction with varied intensity at the junction of the fibrous septa with the hepatocellular component, which was present in all 100 cases. Thick abnormal arteries were seen in all but 2 cases (n = 98). Features of chronic cholestasis with cholate stasis and accumulation of copper (demonstrable by the rhodanine stain) and copper-binding protein (demonstrable with the Victoria blue stain) were nearly as common (n = 94). A confident diagnosis of FNH can be made with a needle biopsy, especially if the biopsy is known to come from a mass, and the lesion contains characteristic fibrosis with ductules at the interface between hepatocytes and the fibrous region, prominent arteries, and benign hepatocytes with features of chronic cholestasis.

Expression of KIT (CD117) in angiomyolipoma.

Angiomyolipoma is a unique mesenchymal tumor postulated to arise from perivascular epithelioid cells. Immunohistochemical studies have shown that angiomyolipomas express the melanocytic markers HMB-45, MART-1 (Melan A), microphthalmia transcription factor, and tyrosinase, in addition to smooth muscle actin. KIT (CD117) is a transmembrane growth factor receptor expressed in cells of melanocytic and a variety of other cell lineages. To date, KIT immunoreactivity has not been systematically studied in angiomyolipoma. In this study we immunohistochemically analyzed a series of 21 angiomyolipomas (15 hepatic, six renal) with KIT. All were KIT positive: 14 of 21 (67%) with 3+ staining (>50% of tumor cells), 4 of 21 (19%) with 2+ staining (25-50% of tumor cells), and 3 of 21 (14%) with 1+ staining (<25% of tumor cells). In comparison, the percent of angiomyolipomas showing 3+ staining with HMB-45 was 62% and with Melan A was 52%. Positive KIT staining was detected in the epithelioid, spindle, and intermediate small round cells. Most cases showed diffuse cytoplasmic positivity. Strong perinuclear staining was present in the vacuolated clear epithelioid cells. There was focal KIT staining of fat cells. KIT was not detected in the endothelial cells lining blood vessels within the tumor. KIT may be a useful ancillary marker for the diagnosis of angiomyolipoma. Angiomyolipoma should be included in the differential diagnosis of KIT-positive tumors.

Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases.

In this study we analyzed the clinicopathologic features of duodenal smooth muscle or stromal tumors, including 156 GISTs, 6 leiomyomas (LMs), and 5 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. GISTs were documented as KIT positive (n = 109); 47 tumors were also included because of their histologic identity to KIT-positive cases. GIST-specific c-kit gene mutations were documented in exon 11 in 9 of 30 cases (30%) and exon 9 in 4 of 30 cases (13%). The GISTs occurred in patients with an age range of 10-88 years (median 56 years); 54% were male. Ten patients had neurofibromatosis type I; six of them had multiple GISTs. The GISTs ranged from small asymptomatic intramural or external nodules to large masses that extended into the retroperitoneum (median size 4.5 cm). They were mostly spindle cell tumors; three malignant GISTs had an epithelioid morphology, and 81 cases had skeinoid fibers. The tumors often coexpressed CD34 and KIT (54%) and were variably positive for smooth muscle actin (39%) and S-100 protein (20%) but never for desmin. A total of 86% of patients with tumors >5 cm with >5 mitoses/50 high power fields (HPF) (n = 21) died of disease, whereas no tumor <2 cm with <5 mitoses/50 HPF (n = 12) recurred or caused death. Long latency was common between primary operation and recurrences or metastases; either one occurred in 49 of 140 patients with follow-up (35%). No formula could accurately predict metastases, which occasionally developed even if mitotic activity was <5/50 HPF and size <5 cm. Metastases were in the abdominal cavity, liver, and rarely in bones and lungs but never in lymph nodes. Four actin- and desmin-positive and KIT-negative benign intramural LMs were similar to those more often seen in the esophagus. There were five LMSs, one of which formed a polypoid intraluminal mass; all were actin positive and KIT negative. The great majority of duodenal mesenchymal tumors are GISTs, which have a spectrum from small indolent tumors to overt sarcomas. LMs and LMSs are rare.

Inflammatory myofibroblastic tumors (inflammatory pseudotumors) of the gastrointestinal tract: how closely are they related to inflammatory fibroid polyps?

Inflammatory myofibroblastic tumors (inflammatory pseudotumors) and inflammatory fibroid polyps of the gastrointestinal tract both feature prominent inflammatory infiltrates admixed with spindle-shaped fibroblasts/myofibroblasts set in a collagenous, fibrovascular, or myxoid stroma. Erroneously, some have considered inflammatory fibroid polyps to be intraluminal manifestations of inflammatory myofibroblastic tumors. In this study, we have characterized the histopathology of inflammatory myofibroblastic tumors, tumors that have only rarely been reported in the gastrointestinal tract, and have focused on whether inflammatory myofibroblastic tumors and inflammatory fibroid polyps in the gastrointestinal tract are distinct or similar. Clinical, histopathologic, and immunohistochemical features of 38 inflammatory myofibroblastic tumors limited to the wall of the gastrointestinal tract were compared with those of 45 inflammatory fibroid polyps. Compared to patients with inflammatory fibroid polyps, those with inflammatory myofibroblastic tumors were younger (mean age 41 years vs. 53 years); had larger tumors (mean 8 +/- 5.2 cm vs. 3.6 +/- 4.6 cm); presented with abdominal pain, fever, and weight loss more frequently and less frequently had bowel obstruction. Inflammatory fibroid polyps had more eosinophils and fibrosis and fewer lymphoid cell infiltrates than inflammatory myofibroblastic tumors. A regular vascular pattern was a feature of inflammatory fibroid polyps but not of inflammatory myofibroblastic tumors. Most (82%) inflammatory fibroid polyps were positive for CD34 versus none of the inflammatory myofibroblastic tumors. Smooth muscle actin was more frequently positive in inflammatory myofibroblastic tumors than in inflammatory fibroid polyps (86% versus 13%). Inflammatory myofibroblastic tumors were much less frequent and were more evenly distributed in the gastrointestinal tract than inflammatory fibroid polyps. Both appear to be benign processes. Inflammatory myofibroblastic tumors, but not inflammatory fibroid polyps, had a tendency to recur. In conclusion, inflammatory myofibroblastic tumors of the gastrointestinal tract are extremely rare and differ clinically, histologically, and immunohistochemically from inflammatory fibroid polyps.

Melanoma markers in angiomyolipoma of the liver and kidney: a comparative study.

CONTEXT: Melanoma markers, especially the new microphthalmia transcription factor (mitf), have not been previously compared in hepatic and renal angiomyolipomas. OBJECTIVES: To evaluate expression of the novel melanocytic markers mitf and tyrosinase in angiomyolipomas, and to compare these markers with the established markers HMB-45 and melan-A in both hepatic and renal tumors. DESIGN: Clinical, histopathologic, and immunohistochemical features of 15 hepatic angiomyolipomas were compared with those of 10 renal angiomyolipomas. RESULTS: No significant differences between patients with hepatic angiomyolipomas and renal angiomyolipomas were found with respect to age, gender, race, and tumor size. Hepatic angiomyolipomas exhibited a predominance of the epithelioid smooth muscle cell component, in contrast to their renal counterparts, which were predominantly spindled. The smooth muscle cells expressed HMB-45 in 100% of cases in both groups, melan-A in 14 of 15 hepatic angiomyolipomas and 8 of 9 renal angiomyolipomas, mitf in 5 of 12 hepatic angiomyolipomas versus 6 of 10 renal angiomyolipomas, and tyrosinase in 3 of 12 and 2 of 10 hepatic angiomyolipomas and renal angiomyolipomas, respectively. The extent and intensity of immunostaining with HMB-45 and melan-A were dependent on whether spindled or epithelioid cells predominated; the epithelioid cells showed stronger and more widespread reactivity than the spindled cells. CONCLUSION: We believe that the best immunohistochemical marker for confirming the diagnosis of angiomyolipoma is HMB-45, followed by melan-A. Routine use of mitf and/or tyrosinase is not indicated.

Fibrolamellar hepatocellular carcinoma: an immunohistochemical comparison with conventional hepatocellular carcinoma.

The fibrolamellar variant of hepatocellular carcinoma (FLC) differs from conventional hepatocellular carcinoma (HCC) in some clinical and pathological features. The authors investigated possible differences in reactivity between FLCs and HCCs using glypican-3 (GPC3), an oncofetal protein, and survivin, an antiapoptotic protein. They also compared staining of FLC and HCC with antibodies to cytokeratins 7 (CK7) and 19 (CK19) and CD34. GPC3 was significantly more often and more strongly expressed in HCCs (72%) than in FLCs (17%). Survivin nuclear translocation in tumor cells did not differ between HCCs (10%) and FLCs (9%). There was more abundant expression of CK7 in FLCs (92%) than in HCCs (33%), whereas CK19 was more often found in HCCs (20%) than in FLCs (5%). All tumors had CD34-positive sinusoids. This study shows that FLCs and HCCs differ in the expression of GPC3, CK7, and CK19 and that there is a lack of difference as regards survivin and CD34.

Tumors of the liver and intrahepatic bile ducts: radiologic-pathologic correlation.

Primary tumors of the liver can be classified pathologically based on their cell of origin into epithelial tumors, arising from hepatocytes or biliary epithelium, and nonepithelial tumors, including mesenchymal tumors and lymphoma. Characteristic findings on MR imaging can be seen in many cases. This article reviews the MR imaging appearance of these tumors with pathologic correlation.