Loss of TCR-beta F1 and/or EZRIN expression is associated with unfavorable prognosis in nodal peripheral T-cell lymphomas.

Nodal peripheral T-cell lymphoma (nodal PTCL) has an unfavorable prognosis, and specific pathogenic alterations have not been fully identified. The biological and clinical relevance of the expression of CD30/T-cell receptor (TCR) genes is a topic under active investigation. One-hundred and ninety-three consecutive nodal PTCLs (89 angioimmunoblastic T-cell lymphomas (AITL) and 104 PTCL-unspecified (PTCL-not otherwise specified (NOS)) cases) were analyzed for the immunohistochemical expression of 19 molecules, involving TCR/CD30 pathways and the associations with standard prognostic indices. Mutually exclusive expression was found between CD3 and TCR-beta F1 with CD30 expression. Taking all PTCL cases together, logistic regression identified a biological score (BS) including TCR molecules (TCR-beta F1 and EZRIN) that separates two subgroups of patients with a median survival of 34.57 and 5.20 months (P<0.001). Multivariate analysis identified BS and the prognostic index for PTCL (PIT) score as independent prognostic factors. This BS maintained its significance in multivariate analysis only for the PTCL-NOS subgroup of tumors. In AITL cases, only a high level of ki67 expression was related to prognosis. A BS including molecules involved in the TCR signaling pathway proved to be an independent prognostic factor of poor outcome in a multivariate analysis, specifically in PTCL-NOS patients. Nevertheless, validation in an independent series of homogeneously treated PTCL patients is required to confirm these data.

Versatilidad clínica del pseudotumor inflamatorio en Urología / Clinical Versatility of the Inflammatory Pseudotumor in Urology

Objetivo: El pseudotumor inflamatorio es una lesión rara, de comportamiento benigno y cierta heterogeneidad histológica que aparece en el tracto genitourinario. Se revisan una serie de pseudotumores inflamatorios urogenitales poniendo especial énfasis en sus características clínico-patológicas e inmunohistoquímicas. Material y métodos: Análisis retrospectivo de la casuística tratada entre enero de 1981 y diciembre de 2010 que identifica los casos de pseudotumor inflamatorio de localización urogenital. Se analizan las variables edad, sexo, clínica, topografía y tratamiento, y las características anatomopatológicas e inmunohistoquímicas de cada caso. Resultados: Se describen un total de 8 casos de pseudotumor inflamatorio de localización urogenital, de los cuales 6 se localizaron en la vejiga, uno en el riñón y uno en el epidídimo. La edad media de los pacientes fue 46,75 (± 19,84) años. Los síntomas de presentación tumoral fueron hematuria macroscópica, monosintomática o acompañada de sintomatología del tracto urinario inferior y masa inguino-escrotal. En cuanto al tratamiento en los casos de localización vesical se realizó resección transuretral± cistectomía; el caso de localización renal se trató mediante pielotomía y exéresis y el de localización epididimaria mediante exéresis simple. El estudio anatomopatológico evidenció pseudotumor inflamatorio en todos los casos, de aspecto mesenquimal y mixoide con células fusiformes de citoplasma eosinófilo, con presencia de frecuentes células inflamatorias. El patrón inmunohistoquímico más común mostró positividad para actina músculo-específica (HHF-35), vimentina y negatividad para proteína S-100. ALK-1 resultó positivo en el 87,5% de los casos. Conclusión: El pseudotumor inflamatorio es una entidad de buen pronóstico que, con un buen diagnóstico histopatológico e inmunohistoquímico, todo urólogo debe conocer y distinguir para realizar un tratamiento quirúrgico tan conservador como sea posible (AU)

Objective: The inflammatory pseudotumor is a rare lesion, having benign behavior and some histological heterogeneity that appears in the genitourinary tract. A series of urogenital inflammatory pseudotumors are reviewed with emphasis on their clinicopathological and immunohistochemical characteristics. Material and methods: A retrospective study the causistics treated between January 1981 in December 2010 was performed. It identified the cases of inflammatory pseudotumor with urogenital localization. The variables age, gender, symptoms, topography, treatment and anatomopathological and immunohistochemical characteristics of each case were analyzed. Results: A total of 8 cases of the urogenital-located inflammatory pseudotumor are described. Of these, 6 were located in the bladder, one in the kidney and one in the epididymis. Mean age of the patients was 46.75 (±19.84) years. Tumor presentation symptoms were macroscopic hematuria, single symptom or accompanied by symptoms of the lower urinary tract and inguinoscrotal mass. In regards to treatment in the cases of bladder localization, transuretheral ± cystectomy were performed. In the case of kidney localization, treatment was made by means of pyelotomy and exeresis, and in the case of epididymis localization, simple exeresis was performed. The anatomopathological study showed inflammatory pseudotumor in every cases, having a mesenchymal and myxoid appearance, with fusiform cells of eosinophil cytoplasm, with presence of frequent inflammatory cells. The most common immunohistochemical pattern shows positivity for the muscle-specific actin (HHF-35), vimentin and negativity for protein S-100. ALK-1 was positive and 87.5% of the cases. Conclusion: The inflammatory pseudotumor is a condition having good prognosis which, when there is a good histopathological and immunohistochemical diagnosis, every urologist should recognize and distinguish in order to carry out as conservative a surgical treatment as possible (AU)

[Clinical versatility of the inflammatory pseudotumor in urology]. / Versatilidad clínica del pseudotumor inflamatorio en Urología.

OBJECTIVE: The inflammatory pseudotumor is a rare lesion, having benign behavior and some histological heterogeneity that appears in the genitourinary tract. A series of urogenital inflammatory pseudotumors are reviewed with emphasis on their clinicopathological and immunohistochemical characteristics. MATERIAL AND METHODS: A retrospective study the causistics treated between January 1981 in December 2010 was performed. It identified the cases of inflammatory pseudotumor with urogenital localization. The variables age, gender, symptoms, topography, treatment and anatomopathological and immunohistochemical characteristics of each case were analyzed. RESULTS: A total of 8 cases of the urogenital-located inflammatory pseudotumor are described. Of these, 6 were located in the bladder, one in the kidney and one in the epididymis. Mean age of the patients was 46.75 (± 19.84) years. Tumor presentation symptoms were macroscopic hematuria, single symptom or accompanied by symptoms of the lower urinary tract and inguinoscrotal mass. In regards to treatment in the cases of bladder localization, transuretheral ± cystectomy were performed. In the case of kidney localization, treatment was made by means of pyelotomy and exeresis, and in the case of epididymis localization, simple exeresis was performed. The anatomopathological study showed inflammatory pseudotumor in every cases, having a mesenchymal and myxoid appearance, with fusiform cells of eosinophil cytoplasm, with presence of frequent inflammatory cells. The most common immunohistochemical pattern shows positivity for the muscle-specific actin (HHF-35), vimentin and negativity for protein S-100. ALK-1 was positive and 87.5% of the cases. CONCLUSION: The inflammatory pseudotumor is a condition having good prognosis which, when there is a good histopathological and immunohistochemical diagnosis, every urologist should recognize and distinguish in order to carry out as conservative a surgical treatment as possible.

Progression to large B-cell lymphoma in splenic marginal zone lymphoma: a description of a series of 12 cases.

Splenic marginal zone lymphoma (SMZL) is considered to be an indolent extranodal B-cell lymphoma. Despite its low aggressivity, histologic progression has been described in sporadic reports, although the frequency, characteristics, and underlying molecular abnormalities of this phenomenon are largely unknown. We review here the clinical, morphologic, immunohistochemical, and molecular features of a series of 12 SMZL cases that showed progression to large B-cell lymphoma (LBCL). The most frequent location of secondary LBCL was in peripheral lymph node. This occurred between 12 and 85 months after diagnosis of SMZL. However, in two cases LBCL was diagnosed at the initial stage of the disease (one spleen tumoral nodule and one hilar lymph node). The histologic and immunophenotypic features of these cases were similar to those of transformed LBCL at other sites. In four cases the immunoglobulin heavy chain gene polymerase chain study revealed the same rearrangement pattern in both primary and secondary tumors, thereby confirming their identity and excluding the possibility of a second malignancy. As is the case with other low-grade lymphoproliferative disorders, SMZL may undergo high-grade transformation. These 12 cases represent 13% of our series of SMZL with adequate follow-up. The incidence of large cell transformation in SMZL seems to be lower than in follicular lymphoma (25-60%) and mantle cell lymphoma (11-39%), although it is similar to the frequency of transformation in B-chronic lymphocytic lymphoma/small lymphocytic lymphoma (1-10%). The mean proliferative index (MIB1 staining) in initial SMZL specimens of cases with LBCL transformation was 28.6%, higher than that of MIB1 staining in the overall SMZL series (21.8%), although not statistically significantly so. p53 or p16INK4a inactivation in this series was observed in only one case, in contrast with the situation observed in chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. It seems that progression in SMZL is mainly independent of p53 or p16INK4a inactivation. The frequency of the 7q deletion in this series was 3 of 7 (42%). 7q loss may play an alternative role in the inactivation of the p53 and p16INK4a pathway, thereby favoring tumoral progression.

Cutaneous presentation of follicular lymphomas.

The description of primary cutaneous follicular lymphoma has raised interest in the differential diagnosis of this versus disseminated follicular lymphoma involving the skin. We report here on four cases of Stage IV follicular lymphoma, diagnosed in skin biopsy, in which cutaneous lesion was the most noticeable feature of clinical presentation. In all cases, the morphological features were superimposed over typical nodal follicular lymphoma. Apart from classic B-cell markers, they were characterized by CD10 and bcl6 positivity, markers of follicle germinal center cells; and bcl2 expression, with a corresponding t(14;18) translocation in three of three cases examined. In all four cases, bone marrow study and clinical staging revealed disease that had disseminated since diagnosis. Follow-up showed relapsing cutaneous and nodal disease in two cases. The only difference observed with a control group of 10 cases of primary cutaneous follicular lymphoma was the absence in this group of t(14; 18). Disseminated classical follicular lymphoma has to be considered in the differential diagnosis of follicular lymphoma presenting in the skin. This series of cases suggests that the presence of t(14;18) could imply the existence of disease that has disseminated beyond the skin and that cases harboring this translocation could be candidates for systemic polychemotherapy.

Unique phenotypic profile of monocytoid B cells: differences in comparison with the phenotypic profile observed in marginal zone B cells and so-called monocytoid B cell lymphoma.

Monocytoid B cells (MBCs) are a subset of B cells that may be recognized in several reactive and tumoral lymph node conditions, including toxoplasmic lymphadenitis, infectious mononucleosis, and Hodgkin's lymphoma. Although this is a commonly observed cell population, which has even given its name to a type of lymphoma, MBC lymphoma, scarcely any information is available about the function and characteristics of this cell type. A relationship with marginal zone (MZ) B lymphocytes has been claimed for MBCs, but this has not yet been fully proven. Indeed, specific markers for MBCs are still lacking, which has made it difficult to analyze their relationship with other B cell subpopulations and confirm the existence of tumors deriving from this B cell subset. We used a panel of cell cycle markers to explore the characteristics of MBCs and their relationship with MZ B cells, nodal MZ lymphoma, and splenic MZ lymphoma. We therefore compared the phenotypic profile of MBCs in different conditions with normal MZ B cells within the spleen and mesenteric lymph nodes, with a group of seven cases of nodal MZ/MBC lymphoma and another group of five cases of splenic MZ lymphoma. MBCs were mainly in the G(0) to G(1) phases, as deduced from the presence of a proportion of between 10 and 35% Ki67-positive cells, whereas very low expression was observed with cyclin A and cyclin B staining. Nests of MBCs were clearly labeled by the expression of p21(WAF1), a cyclin-dependent kinase inhibitor (CKI), rarely detectable in benign lymphocytes, and by cyclin E. Basically all MBCs were bcl-2-negative, and high cyclin D2 and cyclin D3 were also detected in these cells, at proportions and intensities above expected levels, when the percentage of proliferating cells was taken into account. p27(KIP1) expression was characterized by homogeneous reactivity, higher than that observed in other B cell populations with a relatively high-growth fraction. Immunoglobulin staining showed undetectable light and heavy chains. However, splenic MZ cells, nodal MZ lymphoma, and splenic MZ lymphoma showed a distinct expression of IgM and bcl-2, with high p27 (KIP1) nuclear expression and undetectable or low levels of cyclin A, B, E, or D, or p21(WAF1) expression. The data from this study show an unexpected immunophenotype in MBCs, different from the one observed in splenic and lymph node MZ B cells. This suggests that either MBCs are a unique B cell population from a distinct cell lineage, or if related to MZ cells, they would represent a definite differentiation stage characterized by a distinctive immunophenotype. They also show so-called MZ/MBC lymphoma to be more closely related to lymph node and splenic MZ B cells, as they do not share the most distinctive features of MBCs.

Primary cutaneous large B-cell lymphoma: the relation between morphology, clinical presentation, immunohistochemical markers, and survival.

The histogenesis, morphology, immunophenotype, and clinical behavior of cutaneous large B-cell lymphomas (CLBCL) are largely a matter of controversy. We performed an investigation to determine whether CLBCL have features that differentiate them from other large B-cell lymphomas and whether CLBCL is itself a heterogeneous group. To this end, we reviewed the main characteristics of a series of 32 cases of LBCL found in the skin. We reviewed the clinical findings and paraffin sections of the tumors from these 32 patients. The immunohistochemical study performed included p53, MIB1, Bcl2, Bcl6, and CD10 markers. We carried out statistical analysis of these data (univariate and multivariate), seeking an association between the features of the tumors and clinical outcome, as defined by failure-free survival time. Only one patient died as a consequence of the lymphoma. Nevertheless, the accumulated probability of survival without failure at 48 months was 0.46. The number, type, and localization of the lesions were not associated with variations in either survival or failure-free survival. The expression of p53 was negative in this group of CLBCL, whereas Bcl-2 expression or localization in the lower leg did not relate to any other significant feature. Histologic examination of the cases disclosed three different groups: Grade III follicular lymphomas (FLs), monomorphous large B-cell lymphomas (LBCL type I), and LBCL with an admixed component of small B-lymphocytes (LBCL type II). Grade III FL (11 cases) tended to be found in the head and neck and showed CD10 expression in a majority of cases. A higher probability of lymph node relapses was associated with cases located in the head and neck and with CD10+ tumors. Cutaneous large B-cell lymphomas are indolent tumors, but follow an insidious course. Our data support the interpretation that CLBCL is a heterogeneous condition; comprises some LBCL derived from CD10+ germinal center cells which manifests more frequently as tumors in the head and neck region, with an increased probability of relapse in lymph nodes [1] and has some distinctive morphologic features. The existence of a component of small B-cells within the other CLBCL could lend support to the theory that some of these tumors, more than arise de novo, may have originated in preexistent small B-cell lymphomas, but no firm evidence of this is provided in this study.

Rib metastasis revealing hepatocellular carcinoma.

Bone metastasis infrequently appears as the first manifestation of hepatocellular calcinoma (HCC), and in any case in most patients the primary tumour is detected a few months after its development. We report the case of a patient with alcoholic liver disease, increased levels of alpha-fetoprotein, and no evidence of hepatic lesion in the different imaging modalities, in whom metastasis of HCC was detected in the ribs, whereas the primary tumour was not diagnosed until 15 months later. We believe that all patients with increased levels of alpha-fetoprotein should be tested in an intensified search for HCC and possible metastases, given that hepatic lesions may not be detected until many months alter the diagnosis of metastatic disease.

CD44v6 expression in inflammatory bowel disease is associated with activity detected by endoscopy and pathological features.

AIMS: Overexpression of CD44v6 in colon crypt epithelial cells has been suggested to have diagnostic potential in differentiating ulcerative colitis from other forms of colon inflammation, including Crohn's disease. Our aim was to determine the value of CD44v6 expression in inflammatory bowel disease (IBD) and to look for possible associations between CD44v6 expression and activity of this disease. METHODS AND RESULTS: CD44v6 expression was studied using immunohistochemical techniques in 100 surgical and endoscopic colon samples of ulcerative colitis (n = 71) and Crohn's disease (n = 29), and in every case disease activity was studied by endoscopy and microscopic examination. Fifty-five of 71 (77.5%) samples of ulcerative colitis showed monoclonal antibody 2F10 stained colon epithelium, as did 16 of 29 (55.2%) samples of Crohn's disease. CD44v6 was detected in 88.2% (15 of 17) of cases of IBD with severe disease activity and in 100% of eight cases of severe ulcerative colitis. Our study showed a strong association between CD44v6 expression and the activity of IBD (P = 0.007). CONCLUSIONS: CD44v6 expression in IBD is significantly associated with activity detected by means of endoscopy and pathological features. Our data suggest that CD44v6 expression may have some usefulness in conjunction with other factors as a means of evaluating the disease activity. Moreover, CD44v6 expression was higher in ulcerative colitis than Crohn's disease (P = 0.02), although this does not confirm the utility of monoclonal antibody 2F10 in differential diagnosis between ulcerative colitis and Crohn's disease, as there was a notable percentage of positive samples of Crohn's disease.

p27KIP1 is abnormally expressed in Diffuse Large B-cell Lymphomas and is associated with an adverse clinical outcome.

Cell cycle progression is regulated by the combined action of cyclins, cyclin-dependent kinases (CDKs), and CDK-inhibitors (CDKi), which are negative cell cycle regulators. p27KIP1 is a CDKi key in cell cycle regulation, whose degradation is required for G1/S transition. In spite of the absence of p27KIP1 expression in proliferating lymphocytes, some aggressive B-cell lymphomas have been reported to show an anomalous p27KIP1 staining. We analysed p27KIP1 expression in a series of Diffuse Large B-cell Lymphoma (DLBCL), correlating it with the proliferative index and clinical outcome, to characterize the implications of this anomalous staining in lymphomagenesis in greater depth. For the above mentioned purposes, an immunohistochemical technique in paraffin-embedded tissues was employed, using commercially available antibodies, in a series of 133 patients with known clinical outcomes. Statistical analysis was performed in order to ascertain which clinical and molecular variables may influence outcome, in terms of disease-free survival (DFS) and overall survival (OS). The relationships between p27KIP1 and MIB-1 (Ki-67) were also tested. An abnormally high expression of p27KIP1 was found in lymphomas of this type. The overall correlation between p27KIP1 and MIB-1 showed there to be no significant relationship between these two parameters, this differing from observations in reactive lymphoid and other tissues. Analysis of the clinical relevance of these findings showed that a high level of p27KIP1 expression in this type of tumour is an adverse prognostic marker, in both univariate and multivariate analysis. These results show that there is abnormal p27KIP1 expression in DLBCL, with adverse clinical significance, suggesting that this anomalous p27KIP1 protein may be rendered non-functional through interaction with other cell cycle regulator proteins.

Anomalous high p27/KIP1 expression in a subset of aggressive B-cell lymphomas is associated with cyclin D3 overexpression. p27/KIP1-cyclin D3 colocalization in tumor cells.

p27 cyclin-dependent kinase inhibitor downregulation is essential for transition to the S phase of the cell cycle. Thus, proliferating cells in reactive lymphoid tissue show no detectable p27 expression. Nevertheless, anomalous high p27 expression has been shown to be present in a group of aggressive B-cell lymphomas with high proliferation index and adverse clinical outcome. This suggests that abnormally accumulated p27 protein has been rendered functionally inactive. We analyzed the causes of this anomalous presence of p27 in a group of aggressive B-cell lymphomas, including 54 cases of diffuse large B-cell lymphomas and 20 Burkitt's lymphomas. We simultaneously studied them for p27, cyclin D3, cyclin D2, cyclin D1, and cyclin E expression, because it has been stated that high levels of expression of cyclin D1 or E lead to increased p27 levels in some cell types. A statistically significant association between p27 and cyclin D3 expression was found for the group as a whole. Additionally, when dividing the cases according to the level of expression of cyclin D3 by reactive germinal centers, it was observed that cases with stronger cyclin D3 expression also show higher p27 expression. The relationship between both proteins was also shown at a subcellular level by laser confocal studies, showing that in cases with high expression of both proteins there was a marked colocalization. Additional evidence in favor of p27 sequestration by cyclin D3 was provided by coimmunoprecipitation studies in a Burkitt's cell line (Raji) showing the existence of cyclin D3/p27 complexes and the absence of CDK2/p27 complexes. These results could support the hypothesis that there are cyclin D3/p27 complexes in a subset of aggressive B-cell lymphomas in which p27 lacks the inhibitory activity found when it is bound to cyclin E/CDK2 complexes. This interaction between both proteins could lead to an abnormal nuclear accumulation, detectable by immunohistochemical techniques.