Immunohistochemical investigation of tumorigenic pathways in sinonasal intestinal-type adenocarcinoma. A tissue microarray analysis of 62 cases.

AIMS: Sinonasal intestinal-type adenocarcinoma (ITAC) is an uncommon neoplasm morphologically similar to colorectal adenocarcinoma, with a well-recognized association with occupational exposure to wood or leather dusts. Here, we analyse several gene products with pivotal roles in tumorigenesis, including p53, p16, deleted in colon cancer (DCC), retinoblastoma, adenomatous polyposis coli, ß-catenin, E-cadherin and CD10, and discuss their relation to clinical behaviour and to similar pathways in colorectal adenocarcinomas. METHODS AND RESULTS: Immunohistochemical analysis of 62 ITACs was conducted on a tissue microarray. Aberrant expression of p53 and p16 were the most commonly observed alterations (61.3% and 64.5% of cases, respectively). Analysis according to the histological subtype showed that p53 overexpression was less frequent in mucinous ITACs (35.3% versus 71.1%, P = 0.018), while loss of DCC and E-cadherin were observed more frequently in this subtype (76.5% versus 31.1%, P=0.002 and 82.4% versus 31.1%, P<0.001, respectively). No correlation was found between the aberrant expression of these and clinical behaviour while mucinous adenocarcinomas had a significantly worse prognosis, with shorter disease-free interval and overall survival (P=0.005 and P<0.001, respectively). CONCLUSIONS: Mucinous ITACs appear to follow a distinct molecular pathway(s) from the non-mucinous variants, and pursue an aggressive clinical behaviour.

Increase in FOXP3+ regulatory T cells in GVHD skin biopsies is associated with lower disease severity and treatment response.

In animal models, CD4+/CD25+ T-regulatory cells (Tregs) have been reported to prevent/delay the onset of graft-versus-host disease (GVHD). Recently, an insufficient upregulation of Tregs was found in target organ (intestinal) biopsies from patients with GVHD. We have analyzed by immunohistochemistry the number of CD3+ T lymphocytes and FOXP3+ Tregs in skin biopsies from (1) recipients of allogeneic hematopoietic stem cell transplantation (HSCT, n = 26), (2) nontransplanted patients diagnosed with cutaneous drug reaction (n = 12), and (3) healthy donors (n = 10). Infiltrating CD3+ cells were significantly higher in both transplanted patients showing acute GVHD (aGVHD) and drug reaction when compared to healthy donors and patients without GVHD. Tregs number in aGVHD was higher than in patients without GVHD or healthy subjects and lower than in drug reaction. Interestingly, the number of infiltrating FOXP3+ Tregs was significantly higher in patients responding to GVHD treatment and with a low GVHD grade. Increase in FOXP3+ Tregs in GVHD skin biopsies correlates with less severe GVHD and is associated with response to GVHD treatment. Larger studies are required to confirm that evaluation of Tregs in minimally invasive skin biopsies assists the diagnosis and prognosis of GVHD patients.

Definition of bone necrosis by the pathologist.

Osteonecrosis is a common disorder that may go clinically unrecognized or may result in the collapse of the architecture of bone, determining severe anatomic alterations of the involved site. Osteonecrosis is not a specific disease entity, but rather the result of a number of conditions ultimately leading to an impairment of blood supply to the bone tissue, although there is evidence that modifications of bone remodelling activity and weakening of bone structure with formation of microfractures are implicated as well. According to the site involved and to the factors promoting its development, the morbid anatomy and histopathology of osteonecrosis show a different appearance. This review discusses the main skeletal manifestations of osteonecrosis, including subarticular avascular necrosis of the femoral head and of the knee, as well as osteonecrosis of the jaw.

The impact of histopathologic examination of graft-versus-host disease in the era of reduced-intensity conditioning regimen: a study from the Gruppo Italiano Trapianto di Midollo Osseo.

Reduced-intensity conditioning regimens have reshaped the clinical presentation of graft-versus-host disease after hematopoietic stem cell transplants. However, histopathologic features of graft-versus-host disease following reduced-intensity conditioning regimens have not been fully characterized. In a series of 112 biopsies (skin, n = 60; gastrointestinal [GI] tract, n = 44; liver, n = 8), we described the morphologic profile of graft-versus-host disease following reduced-intensity conditioning and investigated whether histopathologic changes of graft-versus-host disease following reduced-intensity conditioning have a diagnostic and/or prognostic value. Forty-four patients (49.5%) experienced acute graft-versus-host disease, 2 (2.2%) late-onset acute graft-versus-host disease (grade I, n = 13; grade II-IV, n = 33), 24 (27.0%) chronic graft-versus-host disease (de novo n = 12, progressive n = 12) and 19 (21.3%) overlap syndrome. In the skin, we observed: (i) phase-nonspecific changes, such as acute graft-versus-host disease features in chronic graft-versus-host disease patients (n = 4/24; 16.6%), (ii) subtle alterations such as superficial fibrosis in widened dermal papillae (n = 8), in acute graft-versus-host disease/late-onset graft-versus-host disease (n = 6/46; 13.0%) or chronic graft-versus-host disease (n = 2/24, 8.3%) patients, and (iii) features of chronic and acute graft-versus-host disease coexisting in the same specimen in overlap syndrome (n = 3/19; 15.7%). In the GI tract, we did not demonstrate peculiar features differing from those commonly observed in the myeloablative setting. By univariate analysis, a reduced overall survival was associated with graft-versus-host disease type (chronic graft-versus-host disease P = .006, acute graft-versus-host disease P = .03), older age (P = .04), and histopathologic diagnosis of "consistent with" + definite graft-versus-host disease (P = .02). Histopathologic diagnosis retained an independent prognostic value by multivariate analysis (P = .01). The present study indicates that pathologists should be aware of the peculiar morphologic changes of cutaneous graft-versus-host disease following reduced-intensity conditioning and further recommends histopathology in the diagnostic workup of graft-versus-host disease in patients undergoing reduced-intensity conditioning regimen.

Clear cell carcinoma of the bladder in a patient with a earlier clear cell renal cell carcinoma: a case report with morphologic, immunohistochemical, and cytogenetical analysis.

Clear cell transitional carcinoma of the bladder is a subtype of transitional carcinoma that morphologically resembles a clear cell renal cell carcinoma. Although kidney tumors do not frequently metastasize to the bladder, the recurrence after a clear cell renal cell carcinoma has been reported even several years after nephrectomy. We report the case of a male patient to whom radical nephrectomy for a clear cell renal cell carcinoma has been done, with a bladder tumor featuring polygonal cells with abundant clear cytoplasm deeply infiltrating the vesical wall. We discuss the morphologic features, the immunohistochemical staining with a new marker and the UroVysion FISH analysis to achieve a definitive diagnosis.

Epidermal growth factor receptor expression and gene copy number in sinonasal intestinal type adenocarcinoma.

Sinonasal intestinal type adenocarcinoma (ITAC) is a rare subtype of adenocarcinoma strongly associated with professional exposure to wood or leather dusts. It is an aggressive tumor, with an estimated 5-year survival of 40%. Herein, we report a series of 55 cases tested for epidermal growth factor receptor protein expression and epidermal growth factor receptor gene copy gains, through immunohistochemistry and fluorescence in situ hybridization. Eighteen tumors (32.7%) showed EGFR positivity, seven of which exhibited high expression levels of the receptor. The frequency of EGF-R overexpression was significantly higher in tumors from woodworkers (6 of 14, 42.8%) than in tumors from leatherworkers (2 of 21, 9.5%), or arising in subjects with no known occupational history (0 of 8) (P=0.015, Pearson chi square). No correlation was found with other clinico-pathological parameters, including histologic subtype, stage, overall, and disease free survival. In cases with EGFR overexpression, fluorescent in situ hybridization analysis revealed disomy in three adenocarcinomas, chromosome 7 polysomy in two, and EGFR gene amplification in three. In conclusion, a subset of ITAC, mostly occurring in woodworkers, express high levels of EGFR and this is often associated with either gene amplification or chromosome 7 polysomy. EGFR targeted therapies could therefore be investigated prospectively in this group of tumors.