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Papalas J.A.,Pathology Section | Papalas J.A.,Duke University | Wang E.,Duke University
American Journal of Dermatopathology | Year: 2013

The use of anaplastic lymphoma kinase antibodies (ALK1) as a diagnostic aid has expanded since becoming a routinely available immunohistochemical stain. Because the skin may be the site of a wide variety of hematolymphoid and fibroblastic proliferations, dermatopathologists commonly use ALK1 as part of a broader staining panel in diagnosing soft tissue and cutaneous hematolymphoid neoplasms. Furthermore, new entities and differential diagnostic contexts are emerging, which broaden the utility of ALK1 immunohistochemistry. We review the expanding role of ALK1 immunohistochemistry in contemporary dermatopathology. © 2013 Lippincott Williams & Wilkins.


Lopez-Beltran A.,University of Sfax | Amin M.B.,Cedars Sinai Medical Center | Oliveira P.S.,Hospital da Luz | Montironi R.,Marche Polytechnic University | And 6 more authors.
American Journal of Surgical Pathology | Year: 2010

In this report, we present the clinicopathologic features of 27 cases of the lipid cell variant of urothelial bladder carcinoma. This is a rare variant of bladder cancer recognized by the current WHO classification of urologic tumors. The lipid cell component varied from 10% to 50% of the tumor specimen; in 11 cases the lipid cell component composed greater than 30% of the tumor. The architectural pattern of the tumor varied from solid expansile to infiltrative nests. The large epithelial tumor cells had an eccentrically placed nucleus and abundant vacuolated cytoplasm resembling signetring lipoblasts. Mucin stains were negative in all the cases. Typical features of high grade conventional urothelial carcinoma were present in all the cases with micropapillary or plasmacytoid carcinoma in 2 and 1 cases, respectively; extensive squamous or glandular differentiation was present in 2 additional cases. Most neoplastic cells had nuclei of intermediate nuclear grade with occasional nuclear pleomorphism. Immunohistochemical staining showed that the lipid cell component was positive for cytokeratins 7, 20, CAM 5.2, high molecular weight (34ßE12) and AE1/AE3, epithelial membrane antigen, and thrombomodulin; vimentin and S100 protein were negative. The loss of heterozygosity (LOH) analysis was done on 8 cases using 4 polymorphic microsatellite markers (D9S171, D9S177, IFNA, and TP 53); LOH at least in 1 marker was present in 6 cases. The LOH results were the same for lipid variant and conventional urothelial carcinoma. Pathologic stage was Ta (n=1), T1 (=2), T2, at least (n=7), T3a (n=4), T3b (n=8), and T4a (n=5). Electron microcopy analysis based on 2 cases supported lipid content in tumor cells. Follow-up information was available in all the cases, ranging from 6 to 58 months (mean, 28mo). Sixteen of the patients died of disease at 16 to 58 months (mean, 33mo) and 8 patients were alive with disease at 8 to 25 months (mean, 22mo). Another 3 patients died of other causes at 6 to 15 months (mean, 10mo). In summary, lipid cell urothelial bladder carcinoma is typically associated with advanced stage high-grade urothelial carcinoma, in which the prognosis is poor and clonally related to the concurrent conventional urothelial carcinoma. In limited samples, it may be misdiagnosed as liposarcoma, sarcomatoid carcinoma (carcinosarcoma), or signetring cell carcinoma. Morphologic distinction from other malignant neoplasms with lipid cell phenotype is critical for its clinical management. © 2010 by Lippincott Williams & Wilkins.


Lopez-Beltran A.,University of Cordoba, Spain | Montironi R.,Marche Polytechnic University | Patriarca C.,Melegnano Hospital | Blanca A.,University of Cordoba, Spain | And 3 more authors.
Human Pathology | Year: 2011

We present the clinicopathologic and immunonohistochemical features of 25 cases of flat urothelial carcinoma in situ with glandular differentiation. Previously, cases on this category have been reported as in situ adenocarcinoma (a term not currently preferred). Fourteen of 25 cases had concurrent conventional urothelial carcinoma in situ. Five of the cases were primary carcinoma in situ with glandular differentiation; twenty cases of secondary carcinoma in situ with glandular differentiation were associated with urothelial carcinoma alone (n = 11) or with glandular differentiation (n = 7), discohesive (n = 1) or micropapillary carcinoma (n = 1). The individual tumor cells were columnar. The architectural pattern of the carcinoma in situ with glandular differentiation consisted of 1 or more papillary, flat or cribriform glandular patterns. Univariate statistical analysis showed no survival differences between urothelial carcinoma in situ with glandular differentiation and conventional urothelial carcinoma in situ (log-rank 0.810; P =.368). Carcinoma in situ with glandular differentiation showed high ki-67 index and p53 accumulation, high nuclear and cytoplasmic p16 expression and diffuse PTEN expression, a phenotype that also characterized concurrent conventional carcinoma in situ. MUC5A, MUC2, CK20, and c-erbB2 were positive in all 25 cases of urothelial carcinoma in situ with glandular differentiation, and CDX-2 was present in 19 cases; MUC1, CK7, or 34βE12 was focally present in 21, 19, and 18 cases, respectively. MUC1core was negative in all cases. We concluded that urothelial carcinoma in situ with glandular differentiation is a variant of carcinoma in situ that follows the natural history of conventional urothelial carcinoma in situ. The immunophenotype suggests urothelial origin with the expression of MUC5A and CDX2 as signature for glandular differentiation. © 2011 Elsevier Inc.


PubMed | University of Perugia, Perugia General Hospital, Pathology Section and University of Rome Tor Vergata
Type: | Journal: Cellular and molecular life sciences : CMLS | Year: 2016

Clostridium difficile causes nosocomial/antibiotic-associated diarrhoea and pseudomembranous colitis. The major virulence factors are toxin A and toxin B (TcdB), which inactivate GTPases by monoglucosylation, leading to cytopathic (cytoskeleton alteration, cell rounding) and cytotoxic effects (cell-cycle arrest, apoptosis). C. difficile toxins breaching the intestinal epithelial barrier can act on underlying cells, enterocytes, colonocytes, and enteric neurons, as described in vitro and in vivo, but until now no data have been available on enteric glial cell (EGC) susceptibility. EGCs are crucial for regulating the enteric nervous system, gut homeostasis, the immune and inflammatory responses, and digestive and extradigestive diseases. Therefore, we evaluated the effects of C. difficile TcdB in EGCs. Rat-transformed EGCs were treated with TcdB at 0.1-10ng/ml for 1.5-48h, and several parameters were analysed. TcdB induces the following in EGCs: (1) early cell rounding with Rac1 glucosylation; (2) early G2/M cell-cycle arrest by cyclin B1/Cdc2 complex inactivation caused by p27 upregulation, the downregulation of cyclin B1 and Cdc2 phosphorylated at Thr161 and Tyr15; and (3) apoptosis by a caspase-dependent but mitochondria-independent pathway. Most importantly, the stimulation of EGCs with TNF- plus IFN- before, concomitantly or after TcdB treatment strongly increased TcdB-induced apoptosis. Furthermore, EGCs that survived the cytotoxic effect of TcdB did not recover completely and showed not only persistent Rac1 glucosylation, cell-cycle arrest and low apoptosis but also increased production of glial cell-derived neurotrophic factor, suggesting self-rescuing mechanisms. In conclusion, the high susceptibility of EGCs to TcdB in vitro, the increased sensitivity to inflammatory cytokines related to apoptosis and the persistence of altered functions in surviving cells suggest an important in vivo role of EGCs in the pathogenesis of C. difficile infection.


Galimberti S.,University of Pisa | Nagy B.,Semmelweis University | Palumbo G.A.,University of Catania | Ciancia E.,Pathology Section | And 6 more authors.
Acta Haematologica | Year: 2010

In this study, we determined the allele and genotype frequencies of vascular endothelial growth factor (VEGF) G+405C, C-460T, C+936T and C-2578A single nucleotide polymorphisms (SNPs) in 32 patients affected by mantle cell lymphoma (MCL) and 58 healthy controls. Real-time PCR combined with melting curve analysis was used for the determination of SNP alleles. A significant difference in the allele frequency of VEGFC-460T and C+936T SNPs in MCL and healthy cases was not observed. On the contrary, VEGF G+405C and C-2578A SNP allele distribution was significantly lower in the patient group than among normal controls (p = 0.014, p = 0.001). This observation suggests that further investigation is warranted, both in vitro and in a larger series of patients, to further examine the role of VEGF polymorphisms in the pathogenesis of MCL. In addition, the use of quantitative real-time PCR combined with a melting curve analysis method in the detection of the 4 VEGF SNPs may have the potential to replace older and more time-consuming PCR-RFLP methods and bears further investigation. Copyright © 2009 S. Karger AG, Basel.


Bassotti G.,University of Perugia | Villanacci V.,Pathology Section | Bernardini N.,University of Pisa | Dore M.P.,University of Sassari
Journal of Clinical Gastroenterology | Year: 2016

Colonic diverticular disease is a frequent finding in daily clinical practice. However, its pathophysiological mechanisms are largely unknown. This condition is likely the result of several concomitant factors occurring together to cause anatomic and functional abnormalities, leading as a result to the outpouching of the colonic mucosa. A pivotal role seems to be played by an abnormal colonic neuromuscular function, as shown repeatedly in these patients, and by an altered visceral perception. There is recent evidence that these abnormalities might be related to the derangement of the enteric innervation, to an abnormal distribution of mucosal neuropeptides, and to low-grade mucosal inflammation. The latter might be responsible for the development of visceral hypersensitivity, often causing abdominal pain in a subset of these patients. © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Hoang M.P.,Harvard University | Reuter J.,NC Associates | Papalas J.A.,Pathology Section | Edwards L.,Carolinas Medical Center | Selim M.A.,Duke University
American Journal of Dermatopathology | Year: 2014

Currently, urogenital complaints are among the most common problems encountered by family practitioners, gynecologists, and dermatologists. In response to the intricacy of vulvar disorders, the International Society for the Study of Vulvovaginal Disease was created to facilitate the exchange between clinicians and pathologists involved in the care of these patients. Recent classifications for inflammatory disorders and intraepithelial neoplasm have been proposed. In addition, vulvar skin biopsies are the most common source of intradepartmental consultation during dermatopathology sign-out. The purpose of this article is to review the various inflammatory dermatoses of the vulva and to update readers with new advances regarding these entities. © 2014 Lippincott Williams &Wilkins.


Bassotti G.,University of Perugia | Villanacci V.,Pathology Section
Internal and Emergency Medicine | Year: 2013

Chronic constipation is a frequently complained condition in clinical practice and may be primary (idiopathic) or due to secondary causes. The definition of the various forms of constipation is presently made according to the Rome III criteria, which recently incorporated also specific diagnostic algorithms. The diagnosis of constipation relies on the patient's history, including use of drugs, physical examination, and specific investigations (transit time, anorectal manometry, balloon expulsion test, defecography). These will often be useful to start a targeted therapeutic schedule that may include fibres, laxatives, biofeedback training and, in extreme cases, a surgical approach. This review will analyse the clinical and diagnostic aspects of chronic constipation in adult patients, with emphasis on recent therapeutic approaches. © 2011 SIMI.


Papalas J.A.,Pathology Section | Papalas J.A.,Duke University | Sangueza O.P.,Wake forest University | Puri P.K.,LabCorp | And 2 more authors.
American Journal of Dermatopathology | Year: 2013

The subepidermal hormonally sensitive tissue of the vulva is anatomically unique and may give rise to a wide variety of vascular tumors. As a consequence, classifying vulvar vascular lesions has been challenging due both to the wide variety of lesions that may be encountered and the heterogeneity in reporting across several disciplines. The purpose of this study is to present an institutional experience of vulvar vascular lesions. Overall, 85 patients were identified over a 26-year period. Vascular lesions belonging to the following classes included (n, %total) benign vascular tumors (32, 38%), dilatations of preexisting vessels (31, 36%), hyperplasia/reactive (7, 8%), tumors with significant vascular component (11, 13%), malformations (3, 4%), and malignant vascular tumors (1, 1%). Two reaction patterns based on vulvar lymphatic pathology were identified: one is a stromal dominant pattern and the other is a vascular dominant pattern. Vulvar vascular malformations and true vascular malignancies, although rare, may have associated high morbidity. To accurately classify vulvar lymphatic lesions, the pathologist must carefully consider the patient's clinical history taking into account features such as preexisting lymphedema. Copyright © 2013 by Lippincott Williams & Wilkins.


PubMed | Pathology Section
Type: Journal Article | Journal: The American Journal of dermatopathology | Year: 2013

The subepidermal hormonally sensitive tissue of the vulva is anatomically unique and may give rise to a wide variety of vascular tumors. As a consequence, classifying vulvar vascular lesions has been challenging due both to the wide variety of lesions that may be encountered and the heterogeneity in reporting across several disciplines. The purpose of this study is to present an institutional experience of vulvar vascular lesions. Overall, 85 patients were identified over a 26-year period. Vascular lesions belonging to the following classes included (n, %total) benign vascular tumors (32, 38%), dilatations of preexisting vessels (31, 36%), hyperplasia/reactive (7, 8%), tumors with significant vascular component (11, 13%), malformations (3, 4%), and malignant vascular tumors (1, 1%). Two reaction patterns based on vulvar lymphatic pathology were identified: one is a stromal dominant pattern and the other is a vascular dominant pattern. Vulvar vascular malformations and true vascular malignancies, although rare, may have associated high morbidity. To accurately classify vulvar lymphatic lesions, the pathologist must carefully consider the patients clinical history taking into account features such as preexisting lymphedema.

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