Loss of alcohol dehydrogenase 1B in cancer-associated fibroblasts: contribution to the increase of tumor-promoting IL-6 in colon cancer.

BACKGROUND: Increases in IL-6 by cancer-associated fibroblasts (CAFs) contribute to colon cancer progression, but the mechanisms involved in the increase of this tumor-promoting cytokine are unknown. The aim of this study was to identify novel targets involved in the dysregulation of IL-6 expression by CAFs in colon cancer. METHODS: Colonic normal (N), hyperplastic, tubular adenoma, adenocarcinoma tissues, and tissue-derived myo-/fibroblasts (MFs) were used in these studies. RESULTS: Transcriptomic analysis demonstrated a striking decrease in alcohol dehydrogenase 1B (ADH1B) expression, a gene potentially involved in IL-6 dysregulation in CAFs. ADH1B expression was downregulated in approximately 50% of studied tubular adenomas and all T1-4 colon tumors, but not in hyperplastic polyps. ADH1B metabolizes alcohols, including retinol (RO), and is involved in the generation of all-trans retinoic acid (atRA). LPS-induced IL-6 production was inhibited by either RO or its byproduct atRA in N-MFs, but only atRA was effective in CAFs. Silencing ADH1B in N-MFs significantly upregulated LPS-induced IL-6 similar to those observed in CAFs and lead to the loss of RO inhibitory effect on inducible IL-6 expression. CONCLUSION: Our data identify ADH1B as a novel potential mesenchymal tumor suppressor, which plays a critical role in ADH1B/retinoid-mediated regulation of tumor-promoting IL-6.

V(alpha)14iNKT cells promote liver pathology during adenovirus infection by inducing CCL5 production: implications for gene therapy.

Replication-defective recombinant adenoviruses are the most widely studied replication-defective vectors for the potential treatment of inherited human diseases. However, broad clinical application of replication-defective adenoviruses in gene therapy is being hindered by the induction of vigorous innate and adaptive immune responses against the vector that cause deleterious effects in the liver. V(alpha)14 invariant natural killer T cells (V(alpha)14iNKT cells) are thymus-derived innate T cells at the interface between the two arms of the immune response and provide full engagement of host defense. The pathophysiological role of intrahepatic V(alpha)14iNKT cells during replication-defective adenovirus infection is not known and is the main focus of our study. Our data showed that intrahepatic V(alpha)14iNKT cells were activated in response to adenovirus infection to induce significant levels of hepatic chemokine (C-C motif) ligand 5 (CCL5) and subsequent liver toxicity. Moreover, intrahepatic CCL5 production was selectively reduced by V(alpha)14iNKT cell deficiency. In vivo studies utilizing CCL5-deficient mice or V(alpha)14iNKT cell-deficient mice demonstrated that CCL5 deficiency or V(alpha)14iNKT cell deficiency was associated with reduced liver pathology. Similar results were seen after blocking the biological effects of the CCL5 receptors. In conclusion, we have identified an important proinflammatory role for activated intrahepatic V(alpha)14iNKT cells in positively influencing hepatic CCL5 production to promote acute liver inflammation and injury. Therefore, our findings highlight the blockade of CCL5 interaction with a cognate receptor(s) as an important potential strategy to alleviate liver pathology associated with replication-defective adenovirus infection.

Eccrine porocarcinoma of the vulva: a case report and review of literature.

A case of a 48-year-old woman with a 5 cm left vulvar mass that grew over a six month period is presented. Histopathologic examination of the excised mass was diagnostic of malignant eccrine poroma (eccrine porocarcinoma) with in-situ component. Due to the rarity of this tumor (only five vulvar cases previously reported) and its heterogeneous non-specific clinical and histologic features, the tumor often presents as a diagnostic challenge to clinicians and pathologists. The tumor may be mistaken for a metastasis in cases where the tumor cells are poorly differentiated or for a squamous cell carcinoma in cases with extensive squamous differentiation. There is a need for correct diagnosis of this rare entity - so that appropriate therapy can be instituted in a timely manner. The pertinent literature is reviewed highlighting the diagnostic histomorphologic features and the immunohistochemical profile for making the correct diagnosis of eccrine porocarcinoma.

Cytomorphology, ultrastructural, and cytogenetic findings in follicular dendritic cell sarcoma: a case report.

BACKGROUND: Follicular dendritic cell (FDC) sarcoma is a rare low-to-intermediate grade malignant dendritic cell neoplasm that often has an indolent clinical course. FDC sarcomas are often misdiagnosed on aspiration cytology. CASE: A 26-year-old woman presented with a solid, slowly growing, painless mass in her right neck for 3 months. Computed tomography revealed a 3.6-cm, well-defined homogenous solid mass located posterior to the mandible and submandibular glands. Fine needle aspiration cytology revealed many large, spindle to ovoid epithelioid cells in singles, small clusters, and syncytial sheets with moderate to abundant cytoplasm, indistinct cell borders, irregular nuclear membrane, fine to vesicular chromatin, and conspicuous nucleoli. The background contained many small mature lymphocytes intimately mixed with large epithelioid tumor cells. Tumor cells were strongly positive for CD21, CD35, CD23, and fascin. Diagnosis of FDC sarcoma was rendered; follow-up surgical resection and ultrastructural study confirmed the diagnosis. The cytogenetic study showed a normal female karyotype 46,XX. CONCLUSION: Although the cytomorphology of FDC sarcoma is characteristic, a preoperative diagnosis of FDC sarcoma based on fine needle aspiration cytology is very challenging, if not impossible. Immunohistochemistry is always necessary for rendering and/or confirming the diagnosis, and ultrastructural studies are helpful.

GammadeltaT cells initiate acute inflammation and injury in adenovirus-infected liver via cytokine-chemokine cross talk.

Emerging studies suggest an important role for the innate immune response in replication-defective adenovirus (Ad)-mediated acute liver toxicity. Specifically, classical innate immune cells (including NK cells, neutrophils, and Kupffer cells) have all been implicated in the development of Ad-mediated acute liver toxicity. The nonclassical innate immune T cell, the gammadeltaT cell, has been implicated in the pathophysiology of several viral infections that predominantly affect the mucosa and brain, but the specific role in the pathology of AdLacZ-mediated acute liver inflammation and injury as well as accompanying vector clearance is largely unknown. In the present study, we demonstrated that a CXCL9-CXCR3-dependent mechanism governed the accumulation of gammadeltaT cells in the livers of mice infected with Ad expressing the Escherichia coli LacZ gene (AdLacZ). We also showed a critical role for gammadeltaT cells in initiating acute liver toxicity after AdLacZ administration, driven in part by the ability of gammadeltaT cells to promote the recruitment of the conventional T cell, the CD8(+) T cell, into the liver. Furthermore, reduced hepatic injury in AdLacZ-infected gammadeltaT-cell-deficient mice was associated with lower hepatic levels of gamma interferon (IFN-gamma) and CXCL9, an IFN-gamma-inducible chemokine. Finally, our study highlighted a key role for IFN-gamma and CXCL9 cross talk acting in a feedback loop to drive the proinflammatory effects of gammadeltaT cells during AdLacZ-mediated acute liver toxicity. Specifically, intracellular IFN-gamma produced by activated hepatic gammadeltaT cells interacts with hepatocytes to mediate hepatic CXCL9 production, with the consequent accumulation of CXCR3-bearing gammadeltaT cells in the liver to cause acute liver damage without vector clearance.

Downregulation of TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L in Barrett's esophagus with dysplasia and adenocarcinoma.

TRAIL/Apo2L is a CD95 ligand-related member of the TNF family that initiates apoptosis in immune and neoplastic cells after binding to specific surface receptors. The authors previously reported a specific topographic pattern of TRAIL expression in the normal colonic mucosa and the loss of TRAIL expression in tubular adenomas as well as in most colon carcinomas. Therefore, they hypothesized that similar changes may occur during the malignant transformation of Barrett's esophagus. The aim of this study was to compare TRAIL/Apo2L expression in normal gastroesophageal (GE) junction, Barrett's esophagus with and without dysplasia, and associated adenocarcinoma. Immunohistochemical evaluation of TRAIL expression was performed on formalin-fixed paraffin-embedded sections from 29 GE junction/esophageal biopsies, 20 gastric biopsies, 6 esophagectomies, 2 small bowel resection specimens, and 5 colon biopsies. The expression was graded semiquantitatively on a 4-point scale (0-3). TRAIL was expressed in the foveolar epithelium of the histologically normal GE junctional mucosa and stomach as well as in the normal intestinal epithelium, with maximal expression in the surface epithelium. TRAIL was always detected in Barrett's metaplasia (21/21, 100%), and the overall expression was similar to that of the columnar portion of the normal GE junction (8/8, 100%). TRAIL was rarely and weakly (1+) expressed in Barrett's esophagus with dysplasia (3/18, 16.7%) and adenocarcinoma (1/10, 10.0%) (P<0.001). Similarities in the topographic pattern of TRAIL expression in the normal GE junction, stomach, small intestine, and colon suggest a common function of TRAIL throughout the gastrointestinal tract. These results show that the downregulation of TRAIL is associated with development of dysplasia in Barrett's esophagus. Thus, the immunohistochemically detected downregulation of TRAIL expression appears to be a promising indicator of dysplasia in Barrett's esophagus.

Metastasis of small cell carcinoma of lung into an ovarian mucinous neoplasm: immunohistochemistry as a useful ancillary technique for diagnosis and classification of rare tumors.

The authors report the first case of ovarian mucinous adenocarcinoma with metastasis from a synchronous small cell neuroendocrine carcinoma of the lung. A 62-year-old white woman presented with weight loss and increased abdominal girth. She was found to have a large, complex cystic mass in the pelvis, and during the staging evaluation, a large, right pulmonary hilar mass was detected. Bronchial brushing as well as transbronchial fine-needle aspiration was diagnostic of small cell carcinoma. The patient received 3 cycles of chemotherapy with carboplatin and subsequently underwent a supracervical hysterectomy and bilateral salpingo-oophorectomy. A large, multiloculated cystic mass was found arising from the right ovary. Microscopic examination disclosed a mucinous neoplasm with both mucinous cystadenoma and mucinous papillary adenocarcinoma components. A microscopic focus of cells with "atypical" cytomorphologic features was detected within the mucinous neoplasm. Immunohistochemistry showed that group of cells to be positive for thyroid transcription factor 1 and chromogranin, confirming them to be metastasis from the pulmonary small cell neuroendocrine carcinoma. This case, in addition to being the first reported case of such metastasis, also highlights the diagnostic utility of immunohistochemistry as a reliable and very useful ancillary technique for the diagnosis of neoplasms with unusual clinical and/or histomorphologic presentations. The clinical and prognostic implications are also discussed.

Diagnostic utility of cell cycle and apoptosis regulatory proteins in verrucous squamous carcinoma.

A major problem in the diagnosis of verrucous squamous cell carcinoma is the lack of readily reproducible objective criteria for distinguishing this malignant lesion from reactive epithelial hyperplasia. Both lesions are characterized by thickened (well-differentiated) squamous epithelium without cellular atypia and subjacent stroma densely infiltrated by lymphocytes and plasma cells. This study was carried out to evaluate the use of cell cycle and apoptosis-related regulatory proteins in the diagnosis of verrucous carcinoma. The study materials consisted of representative formalin-fixed and paraffin-embedded tissue blocks from 19 cases of verrucous carcinoma, 18 classic squamous cell carcinoma, and 14 squamous epithelial hyperplasia (acanthosis). The immunohistochemical expression of the following of cell cycle and apoptosis-related regulatory proteins was evaluated using avidin-biotin complex detection technique: p16, p21, p53, Ki67, and retinoblastoma gene product (RBGP) (also known as retinoblastoma protein [pRb]). Expression of Ki67 was detected only in the single basal layer of the epithelium in all 14 cases of acanthosis. In verrucous carcinoma, Ki67 was detected in basal and suprabasal cells in the lower third of the neoplastic epithelium in 19 of 19 cases (100%). In neoplastic squamous epithelium with frankly invasive squamous cell carcinoma, Ki67 was diffusely expressed throughout the entire thickness of the epithelium as well as in the underlying invasive tumor nests. The pattern of p53 expression was similar to that of Ki67 in all the experimental groups, with a Pearson correlation coefficient of 0.98. In addition, immunohistochemical expression of p53 in the hyperplastic squamous epithelium was very weak, in contrast to the more intense immunoreactivity observed in verrucous carcinoma and classic squamous cell carcinoma. There was an overlapping in the expression of p16, p21, and RGBP in all the experimental groups, being present in more than half the thickness of the epithelium in 50% to 100% cases in each study group. We therefore conclude that the pattern of Ki67 and p53 expression in verrucous carcinoma is readily reproducible and distinctly different from that observed in epithelial hyperplasia and that seen in invasive squamous cell carcinoma. Thus Ki67, and p53 immunostains are reliable adjuncts that may be helpful in resolving diagnostic problems associated with verrucous carcinoma.

Subepithelial myofibroblasts express cyclooxygenase-2 in colorectal tubular adenomas.

PURPOSE: Recent data support the hypothesis that the inducible isoform of cyclooxygenase (COX-2) plays a role in the early stages of colonic carcinogenesis and that nonsteroidal anti-inflammatory drugs (NSAIDs) retard the development of colon cancer by modulating COX-2. However, the cell types responsible for producing COX-2 in colorectal adenomas remain a subject of controversy. EXPERIMENTAL DESIGN: COX-2 expression in normal colonic mucosa (n = 50), hyperplastic polyps (n = 43), sporadic adenomas (n = 67), and invasive colonic adenocarcinoma (n = 39) was studied in formalin-fixed and paraffin-embedded tissue sections from endoscopy biopsy and colonic resection specimens. Immunohistochemistry (avidin-biotin complex technique with double immunolabeling) was used to identify the phenotypes of COX-2-producing cells. RESULTS: In colorectal adenomas, increased expression of COX-2 was detected and localized to alpha smooth muscle actin ( proportional, variant SMA)-positive subepithelial stromal cells (myofibroblasts) in the periluminal region of the lamina propria in 63 (94%) of 67 cases. In contrast, in normal colonic mucosa and in hyperplastic polyps with intact epithelium, COX-2 expression was found only in macrophages and endothelial cells. In areas in which the surface epithelium was ulcerated in normal mucosa as well as hyperplastic or neoplastic polyps, COX-2 expression was increased in granulation tissue (and present in macrophages, endothelium, and myofibroblasts). In invasive carcinoma, COX-2 expression in myofibroblasts was limited to the adenomatous portion of the tumor and was detected in 62% of cases (n = 39). In addition, focal expression of COX-2 by malignant epithelial cells was observed in 23% of invasive adenocarcinoma. CONCLUSIONS: These results show that increased COX-2 expression in sporadic adenoma of the colon is common and is localized specifically to subepithelial intestinal myofibroblasts. These findings further support the hypothesis that myofibroblasts are important target cells for NSAID-mediated chemoprevention of colorectal cancer.

Effect of decalcification on the immunohistochemical expression of ABH blood group isoantigens.

Immunohistochemical stains for ABH blood group antigens were recently shown to be useful ancillary tools for sorting out specimen mix-ups in surgical pathology, irrespective of the fixatives used. However, the effects of decalcification on the expression of these antigens are not known. Therefore, to examine the validity of using ABH blood group immunohistochemistry in decalcified tissues, we studied the immunohistochemical expression of ABH blood group antigens in B5-fixed, decalcified, paraffin-embedded archival bone marrow specimens from 43 consecutive patients (13 blood group A, 6 group B, 20 group O, and 4 group AB). Immunohistochemical staining for A, B, and H blood group antigens was performed with monoclonal antibodies and an avidin-biotin detection method with citrate antigen retrieval. The results of immunohistochemistry were correlated with patients' blood groups as determined by serology. Immunohistochemical expression of the A and B blood group antigens with good staining intensity was detected in erythrocytes and endothelial cells. The immunoreactivity for H blood group antigen was attenuated by the decalcification process and could not be enhanced with citrate antigen retrieval. However, in all 43 cases, the A and B antigen staining pattern was concordant with patients' blood groups as determined with serology. These results show that decalcification does not have adverse effects on immunohistochemical expression of the A and B blood group antigens in tissue sections but may nullify the expression of H isoantigen. However, based on A and B immunoreactivity patterns, immunostaining for ABH blood group antigens can be helpful in resolving problems of specimen mix-ups and tissue floaters in decalcified specimens.

Immunohistochemical expression of cyclooxygenase-2 in normal kidneys.

Cyclooxygenase (COX)-2, the recently described inducible form ofcyclooxygenase, has been shown to be responsible for the inflammatory and tumorigenic effects of prostaglandins; hence the development and expanding clinical use of COX-2 selective inhibitors termed super aspirins. These pharmacologic agents block COX-2 without abrogating the desired physiologic roles of the constitutively expressed isoform COX-1. Therefore, they are now used in place of nonselective COX inhibitors in patients who require prolonged use of nonsteroidal anti-inflammatory agents. However, there are sporadic reports of COX-2-related nephrotoxicity, and the mechanism of this adverse reaction is not known. Also, the pattern of in situ expression of COX-2 in the human kidney is not known. We therefore studied the immunohistochemical expression of COX-2 in normal kidneys obtained from 53 consecutive total nephrectomy specimens. COX-2 immunohistochemistry was performed using affinity purified polyclonal murine antibody and avidin-biotin detection method with citrate antigen retrieval. Also, to localize COX-2 expression to specific cell types, double immunolabeling was performed using avidin-biotin (for COX-2 detection) and alkaline phosphatase (for detection of alpha-smooth muscle actin or factor VIII related antigen). In the cortex, COX-2 was found to be constitutively expressed in the endothelial cells of arteries, arterioles, and glomeruli in all 53 kidneys. COX-2 expression was also found in the cortical thick ascending limb of the loop of Henle (medullary rays and macula densa) in 50 of 53 cases. In the medulla, COX-2 expression was detected in the endothelial lining of the vasa recta in 52 cases and in the collecting ducts in 5 cases. These data show significant constitutive expression of COX-2 in normal kidney and underscore the need for caution in the use of COX-2 selective inhibitors, especially on a long-term basis.

Effect of tissue fixatives on the immunohistochemical expression of ABH blood group isoantigens.

Immunohistochemical analysis of ABH blood group isoantigens has been shown to be a useful ancillary technique for resolving problems associated with specimen mix-ups in the daily practice of surgical pathology. However, the effects of different fixatives on the expression of these antigens in paraffin-embedded tissues are not known. Therefore, the effects of seven different fixatives on the immunohistochemical expression of ABH blood group isoantigens were studied in tissues from several organs. The following fixatives were used: acetone, 70% ethanol, B5, Bouin, Carnoy, methanol, and 10% formalin. After fixation for 6, 12, and 72 hours, the tissue blocks were embedded in paraffin, and immunohistochemistry was performed on 4 microm-thick tissue sections using monoclonal antibodies to blood group isoantigens (A, B, and H) and the avidin-biotin detection method. Also, immunostaining was performed on step tissue sections with and without antigen retrieval using citrate buffer at pH 6.0. The expression of the blood group isoantigens was concordant with the blood group of the patient in all the cases studied, irrespective of the fixative and time of fixation. However, in the absence of antigen retrieval, the intensity of the staining reaction was diminished. These results showed that irrespective of the fixative used, immunohistochemical staining of paraffin-embedded tissue sections with ABH blood group antibodies is a rapid, reliable, and cost-effective method for sorting out interpretative problems of tissue contaminants (floaters) and specimen mix-ups in surgical pathology.

Immunohistochemical study of thyroid transcription factor-1 and HER2/neu in non-small cell lung cancer: strong thyroid transcription factor-1 expression predicts better survival.

The relationship of thyroid transcription factor-1 (TTF-1) and HER2/neu expression in non-small cell lung cancer (NSCLC) with multiple parameters including survival were examined. Patients with primary NSCLC who had surgical resection and follow-up of at least 5 years were included in the study. There were 57 patients (38 men and 19 women), 44 to 75 years old (median age, 61 years); 28 patients had adenocarcinoma (AD) and 29 had squamous cell carcinoma. Tumors were examined for TTF-1 and HER2/neu expression using formalin-fixed, paraffin-embedded tissue. Clinical and follow-up data were obtained from the hospital records and Cancer Center database. Representative tumor sections were stained using standard immunohistochemical technique and commercial antibodies for TTF-1 (clone 8G7G3/1, Dako) and HER2/neu (polyclonal, Dako). Tumors were graded as negative (<5%), weak positive (5-49%), and strong positive (>50%), based on the percentage of positively stained tumor cells. Statistical analyses were performed using log-rank test, Pearson and Spearman correlations, and Kaplan-Meier survival curves. TTF-1 expression was seen in 45.6% of all tumors (80% of ADs and 14% of squamous cell carcinomas). Eighteen patients with tumors showing strong TTF-1 expression had significantly better survival compared with the 39 patients whose tumors showed negative or weak TTF-1 expression, although many more of the higher stage AD had strong TTF-1 staining than stage I AD. The TTF-1 expression did not correlate with tumor differentiation and was considered an independent predictor of survival. Seventeen of the 18 tumors with strong TTF-1 expression were ADs. Only eight of 57 (17%) tumors showed HER2/neu expression; seven of these eight were ADs. Although HER2/neu expression and survival did not show correlation, the majority of those ADs with weak or strong HER2/neu staining also had strong TTF-1 staining, were mostly stage I tumors. and had overall longer survival. All patients with stage I disease showed better 5-year survival compared with those with stages II and III. Hispanic patients had significantly worse survival compared with Caucasians and African Americans. The results of this study suggest that strong expression of TTF-1 is an independent predictor of better survival and may be a useful prognostic tool for evaluation of patients with NSCLC.

Down-regulation of Fas expression in the lymph nodes of patients infected with human immunodeficiency virus.

CONTEXT: The mechanism by which human immunodeficiency virus 1 (HIV-1) infection causes increased rates of apoptosis and gradual chronic depletion of CD4(+) T lymphocytes in patients infected with HIV-1 is not known. Findings from in vitro culture studies and analysis of mononuclear cells in the peripheral blood of HIV-infected patients have led to the hypothesis that abnormal expression and/or interaction of Fas and Fas ligand (FasL) may play significant roles in the derangement of homeostasis of CD4(+) lymphocytes in patients infected with HIV-1. OBJECTIVE: To determine the in situ expression of Fas and FasL in the lymph nodes of patients infected with HIV-1. DESIGN: Immunohistochemical expression of Fas and FasL was studied in the lymph node biopsy specimens from 20 patients infected with HIV-1. As controls, we also studied 120 lymph nodes from 28 HIV-1-seronegative patients with reactive lymphadenopathy. RESULTS: In the reactive lymph nodes of seronegative patients, expression of Fas was diffuse in the germinal centers and also in immunoblast-like cells in the T-cell regions. In the lymph nodes of patients infected with HIV, there was a consistent remarkable decrease in Fas expression in 12 of 20 patients and a total lack of Fas expression in the remaining 8 patients. Expression of FasL was comparable in both patient groups. CONCLUSIONS: There is marked down-regulation of Fas in the lymph nodes of HIV-infected patients, a sharp contrast to what occurs in circulating mononuclear cells in the peripheral blood of these patients. These results indicate the need for further studies of this molecular event for possible therapeutic intervention based on reconstitution of Fas and/or FasL activity in the treatment of HIV infection.

Immunohistochemical study of myofibroblasts in normal colonic mucosa, hyperplastic polyps, and adenomatous colorectal polyps.

CONTEXT: Myofibroblasts are distinct cells with characteristics of both smooth muscle cells and fibroblasts. Through their ability to secrete cytokines, chemokines, prostaglandins, growth factors, and matrix components, they are thought to play critical roles in inflammation, growth, repair, and neoplasia. OBJECTIVE: The goal of this study was to identify the distinct cell populations of the lamina propria of normal colon and colorectal polyps. DESIGN: We studied the expression of alpha-smooth muscle actin (alphaSMA), smooth muscle myosin (SMM), desmin, vimentin, and c-kit by intestinal mesenchymal (stromal) cells in the normal colonic mucosa (n = 5), as well as in hyperplastic polyps (n = 5), sporadic colorectal adenomas (n = 47), and adenomas from patients with familial polyposis (n = 36). RESULTS: In the normal colonic mucosa, the pericryptal stromal cells were alphaSMA+, SMM+, desmin-, and vimentin+, defining them as myofibroblasts. In contrast, cells of the muscularis mucosae were alphaSMA+, SMM+, desmin+, and vimentin-, defining them as smooth muscle cells. alpha-Smooth muscle actin also highlighted direct connections between the muscularis mucosae and the pericryptal myofibroblasts, and vimentin immunostaining showed a network of connections between the alphaSMA+ pericryptal myofibroblasts and the alphaSMA- fibroblasts in the interstitium. In all hyperplastic polyps and adenomatous polyps, the interstitial stromal cells (fibroblasts) now also express alphaSMA and form a syncytium of alphaSMA+ networklike connections throughout the lamina propria. Stromal cells of sporadic adenomas demonstrated the same immunohistochemical staining characteristics displayed by adenomas from patients with familial polyposis and by hyperplastic polyps. Conclusions.-These findings indicate that in normal colon, alphaSMA- fibroblasts are the predominant cell type in the lamina propria. However, the pericryptal (subepithelial) stromal cells are a distinct cell type (alphaSMA+ myofibroblast) that is immunophenotypically different from muscularis mucosae smooth muscle cells and are connected to the interstitial, nonpericryptal fibroblasts with which they exist as a network throughout the lamina propria of the normal colon. Furthermore, in both hyperplastic and neoplastic polyps, there are changes in nonpericryptal fibroblasts from vimentin+, alphaSMA-, and SMM- to vimentin+, alphaSMA+, and SMM+; thus, the interstitial fibroblasts are replaced by myofibroblasts. The factors that cause these changes and the origin of the myofibroblasts need to be determined to clarify the biology of colorectal tumorigenesis.

Angiosarcoma of the of scalp with calvarium involvement in a 50-year-old African-American man.

BACKGROUND: Angiosarcoma of the scalp is a rare, aggressive, and deadly cancer that affects mainly elderly Caucasian men. OBJECTIVES: The insidious and masquerading presentation of angiosarcoma poses enormous diagnostic challenges for primary care providers. PATIENTS/METHODS: We present a case of a 50-year-old black man referred for evaluation of a 3.7-cm-x-5.4-cm ulcerated, fluctuant scalp lesion that had failed to respond to different antibiotics and proper wound care. RESULTS: Surgical excision and subsequent histopathology revealed angiosarcoma. CONCLUSIONS: This case report highlights the importance of high index of suspicion for early diagnosis of cancerous lesions in wounds and stresses the need to include angiosarcoma in the differential diagnosis for all face and scalp lesions, as early detection may save lives. A comprehensive literature review is also presented.

The ROS scavenger, NAC, regulates hepatic Vα14iNKT cells signaling during Fas mAb-dependent fulminant liver failure.

Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18(-/-) mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses.

Stromal expression of actin is a marker of aggressiveness in basal cell carcinoma.

Basal cell carcinoma is a very common malignant skin tumor that rarely metastasizes but is often locally aggressive. In a number of studies conducted by different investigators, Bcl2, beta-catenin, cyclin D1, hMSH2, and alpha-smooth muscle actin have been reported to have potential for predicting basal cell carcinoma aggressiveness. However, these reports were inconclusive and sometimes contradictory. We therefore studied the expression and topographic locations (tumor versus stroma) of all these gene products in a group of clinically proven aggressive basal cell carcinomas (n = 30) and randomly selected control cases of nonaggressive basal cell carcinomas (n = 33). The results were subjected to statistical analysis with Mann-Whitney test and logistic regression. The accuracy of the resulting significant discriminating criteria was further tested using the omnibus tests of model coefficients. With multivariate analysis, differential expression of Bcl-2, beta-catenin, and cyclin D1 was not significantly different between aggressive and nonaggressive tumors. hMSH2 expression was up-regulated in the aggressive tumors (P = .005). Alpha-smooth muscle actin was expressed by tumor cells in both study groups, but stromal expression of alpha-smooth muscle actin was restricted to the aggressive tumors and highly predictive of aggressive behavior (P < .001; accuracy, 87%). Logistic regression combining the expression of alpha-smooth muscle actin and hMSH2 yielded a predictive model with 97% accuracy (P < .001). These data show conclusively that aggressive basal cell carcinomas express alpha-smooth muscle actin in the stroma, whereas nonaggressive basal cell carcinomas express alpha-smooth muscle actin in the tumor cells, and that stromal expression of alpha-smooth muscle actin is an accurate, reliable, and easy to use marker of aggressiveness in basal cell carcinomas and can be used in clinical practice for surgical therapeutic decisions.

Relationship between eosinophils and chronic endometritis.

The histopathologic diagnosis of chronic endometritis is based on the presence of plasma cells in the endometrial stroma. However, many conditions can mimic or interfere with the search for plasma cells, including the plasmacytoid stroma cells and predecidual changes of stroma cells. Eosinophils are another type of chronic inflammatory cells, which can be easily identified with routine hematoxylin and eosin stain by their characteristic eosinophilic granules. This study was conducted to investigate whether eosinophils can be used as diagnostic markers of chronic endometritis. The hematoxylin and eosin-stained glass slides of 422 consecutive endometrial biopsies were reviewed. The biopsies that have eosinophils were subjected to immunohistochemical staining with CD138, a marker for plasma cells. In all, 91 of 422 biopsies contained eosinophils with 72.5% (66/91) showing presence of plasma cells (positive staining with CD138). Of these 66 cases, only 4 cases were previously diagnosed as chronic endometritis. These results suggest the presence of eosinophils in endometrial biopsy specimen indicates a need to search for plasma cells (with immunohistochemical stain if needed) for the diagnosis of chronic endometritis.