Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.

Hodgkin lymphoma (HL) is characterized by the abnormal expression of multiple cytokines, accounting for its unique clinicopathologic features. We have previously shown that interleukin-13 (IL-13) is secreted by HL cell lines and may serve as an autocrine growth factor. To determine the frequency of IL-13 expression in lymphoma patients, tissue sections from 36 patients with classical HL, 5 patients with nodular lymphocyte predominance HL (NLPHL), and 23 patients with non-Hodgkin lymphoma (NHL) were subjected to in situ hybridization. In 31 of 36 cases (86%) of classical HL patients of all histologic subtypes, between 25% to almost 100% of Hodgkin and Reed Sternberg (HRS) cells were positive for IL-13 expression. In contrast, in no case of NLPHL and in only 4 of 23 NHL cases (1 of 5 T-cell-rich B-cell lymphomas, 2 of 5 anaplastic large cell lymphomas, and 1 of 5 peripheral T-cell lymphomas) did the neoplastic cells express IL-13. The expression of the IL-13 receptor chain alpha1 (IL-13Ralpha1) was also analyzed by in situ hybridization. In 24 of 27 (89%) cases of classical HL, between 25% to 75% of HRS cells, as well as a high frequency of lymphocytes and histiocytes, were positive for IL-13Ralpha1 expression. These results were confirmed by the construction of complementary DNA libraries from single HRS cells, followed by polymerase chain reaction analysis, in which IL-13Ralpha1 transcripts were found to be present in all 6 cases of HL. These data indicate that expression of IL-13 and IL-13Ralpha1 is a common feature of HRS cells in HL, consistent with the hypothesis that IL-13 may play a role in autocrine growth in classical HL.

Interleukin 13: a growth factor in hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is a malignant disorder of lymph nodes with distinctive clinical and pathologic features. These features are thought to be primarily due to the abnormal production of multiple cytokines by the malignant cell population of HL, the Reed-Sternberg (RS) cells. We have previously demonstrated that interleukin (IL)-13 expression is a common feature of HL and have studied its role as an autocrine growth factor for RS cells. IL-13 and IL-13R(alpha)1, the IL-13-specific receptor chain, are frequently expressed by HL-derived cell lines and by RS cells from biopsy material of tissues involved by HL. Neutralization of IL-13 in cultures of the HL-derived cell lines HDLM-2 and L-1236 leads to a dose-dependent inhibition of proliferation, and is associated with increased apoptosis in L-1236 cells. Signal transducer and activator of transcription (STAT) 6 is an important mediator of IL-13 signaling. STAT6 is constitutively activated in HL cell lines due to autocrine secretion of IL-13. STAT6 is also phosphorylated (P-STAT6) in RS cells from many primary HL samples, supporting the hypothesis that IL-13 signaling occurs in these malignant cells in vivo. Coexpression of IL-13, IL-13R(alpha)1 and P-STAT6 is uncommon in non-Hodgkin lymphomas. Following a description of the clinical and pathologic features of HL, this review will discuss the function of IL-13 as an autocrine growth factor for RS cells in HL and its potential role in mediating other features of this disease.

Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities.

The bcl-2 gene on chromosome 18 at q21 and the bcl-6 gene on chromosome 3 at q27 are both highly regulated during B-cell differentiation and show an inverse relationship of expression in the normal secondary lymphoid follicle. The objective of this study was to investigate the relationship between bcl-2 and bcl-6 protein expression and the relationship between protein expression and the corresponding chromosomal alterations in malignant lymphomas, including those associated with the germinal center. Expression of bcl-2 and bcl-6 proteins was studied in 55 cases of diffuse large B-cell lymphoma (DLBCL) and 21 cases of follicular lymphoma (FL), and the results correlated with the presence of t(14;18) and 3q27 abnormalities in a subset of 52 cases with cytogenetic analysis. These cases were selected to represent a spectrum of nodal and extranodal lymphomas, including those with and without a t(14;18). It was shown that the neoplastic cells in 71% of DLBCLs and 100% of FLs expressed bcl-6 protein. Expression of bcl-6 was seen more frequently in diffuse large B-cell lymphomas with large noncleaved morphology compared with immunoblastic morphology (82% v 27%, P = .0015), but failed to correlate with 3q27 abnormalities. Thirty-eight percent of cases with 3q27 abnormalities were bcl-6 protein negative, whereas 85% of cases without a 3q27 abnormalities were bcl-6 protein positive. Expression of bcl-2 protein was shown in 51% DLBCLs (nodal v extranodal, 71% v 30%, P = .012). bcl-2 protein was expressed in 89% of FLs with t(14;18), in contrast to 25% of FLs without t(14;18) (P = .016). In DLBCL and FL with t(14;18), the most common pattern of expression was bcl-2+/bcl-6+. In lymphomas without t(14;18), there was not an inverse relationship between bcl-2 and bcl-6 protein expression. In conclusion, these data suggest that mechanisms other than gene rearrangements can deregulate bcl-2 and bcl-6 expression in lymphomas, and there does not appear to be an inverse relationship between these two proteins as seen in the normal germinal center.

Primary non-Hodgkin's lymphoma and malakoplakia of the vagina: a case report.

The vagina is a rare site for both primary non-Hodgkin's lymphoma and malakoplakia. We report a case of concurrent diffuse large B-cell lymphoma and malakoplakia of the vagina in a 67-year-old woman presenting with a vaginal discharge and a vaginal mass. The patient had two biopsy specimens reported as showing malakoplakia only, followed by a third biopsy specimen 10 months later which was diagnosed as diffuse large B-cell lymphoma. Review of the first two biopsy specimens showed areas of histiocytes with Michaelis-Gutman bodies merging with areas of cells with slightly larger nuclei and more amphophilic cytoplasm. Immunohistochemistry for the B-cell marker L-26 (CD20) and polymerase chain reaction analysis of the immunoglobulin heavy chain gene were helpful in retrospectively distinguishing the population of diffuse large B-cell lymphoma from the areas of malakoplakia. The third biopsy specimen showed sheets of large atypical lymphoid cells characteristic of a large cell lymphoma. Malakoplakia has been described in association with a variety of cancers, and this is only the second report of malakoplakia associated with non-Hodgkin's lymphoma. Considering the rarity of these two entities in the vagina, it is unlikely that the association in this case is coincidental, raising the possibilities of an unusual reaction to the presence of lymphoma or a common pathogenesis such as underlying chronic inflammation. Epstein-Barr virus DNA was detected in the second biopsy specimen, suggesting a possible role in the pathogenesis of this lymphoma.

Renal oncocytoma and chromophobe renal cell carcinoma. A comparison of colloidal iron staining and electron microscopy.

Chromophobe renal cell carcinoma (RCC) is characterized by diffuse cytoplasmic staining with Hale colloidal iron (HCI) and the presence of numerous microvesicles. The eosinophilic variant morphologically may resemble renal oncocytoma. The latter commonly shows focal cytoplasmic HCI reactivity, but microvesicles have not been previously reported. We examined 19 chromophobe RCCs and 28 oncocytomas for their HCI staining patterns. Electron microscopy was performed on 13 chromophobe RCCs and 10 oncocytomas. In all cases of chromophobe RCC, more than 75% of cells showed a diffuse cytoplasmic HCI positivity, whereas a variable proportion of cells in 20 oncocytomas showed focal cytoplasmic staining, in a perimembranous, apical, or perinuclear pattern. Ultrastructurally, chromophobe RCCs contained abundant microvesicles with varying numbers of mitochondria, whereas all oncocytomas contained abundant mitochondria with focal collections of microvesicles. The microvesicles, in perimembranous, apical, or perinuclear clusters or singly scattered throughout the cytoplasm, were morphologically indistinguishable from those in chromophobe RCCs. In most cases, the microvesicle location and HCI staining pattern correlated. Chromophobe RCC and oncocytoma have distinctive morphologic features that usually allow their recognition. In difficult cases, HCI staining and electron microscopy may help, but the presence of HCI positivity or microvesicles in an eosinophilic renal tumor does not rule out oncocytoma.

Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is an aggressive lymphoma that is frequently associated with the t(2;5)(p23;q35), resulting in expression of a fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which can be detected by either monoclonal or polyclonal antibodies to the ALK protein. The clinical features of adults with ALCL are incompletely described, and the prognostic factors that are useful for predicting survival remain unclear. This report describes the clinical and laboratory findings in 70 adults with systemic ALCL who were treated with curative intent. We attempted to identify the clinical and pathological factors of prognostic importance, including the International Prognostic Index (IPI), immunophenotype, and expression of the ALK protein. The median age of the patients was 49 years (range, 15 to 75). There were 26 women and 44 men with a median follow-up of 50 months for living patients. Advanced stage was present in 56% and B symptoms were noted in 70% of the patients. Immunostains showed that 46% of the cases had a T-cell phenotype, 36% a null phenotype, and 18% a B-cell phenotype. The expression of ALK protein was found in 51% of the cases. The IPI factors were evenly distributed between the ALK+ and ALK- groups, except that the ALK+ patients were younger (median age, 30 v 61 years; P <.002). The ALK+ cohort included cases with null (44%), T-cell (42%), and B-cell (14%) phenotypes. All 10 cases with cytogenetic or molecular evidence of a t(2;5) were ALK+. The 5-year overall survival (OS) of the entire cohort was 65%. The 5-year OS of the ALK+ and ALK- cases was 79% and 46%, respectively (P <.0003). Analysis of only the T-cell/null cases (n = 57) showed a 5-year OS of 93% for the ALK+ cases and only 37% for the ALK- cases (P <.00001). Univariate analysis of the clinical features showed that age

Concurrent chromosomal alterations at 3q27, 8q24 and 18q21 in B-cell lymphomas.

Recurrent chromosomal translocations in malignant lymphomas most commonly involve 18q21(bcl-2), 8q24 (c-myc) and 3q27 (bcl-6), with an incidence of 27%, 11% and 6%, respectively. Individual cases concurrently harbouring two of these three rearrangements have been previously reported. This report describes four patients with cytogenetic alterations affecting all three loci, which was confirmed by molecular analysis in one case. Clinically, each patient had aggressive B-cell lymphoma with disseminated disease often involving the central nervous system, poor response to chemotherapy and short survival. Activation of c-myc in association with deregulation of bcl-2, bcl-6 or both confers high-grade disease with a poor prognosis.

Anaplastic large cell lymphoma: a clinicopathologic analysis.

The clinicopathologic features of anaplastic large cell lymphoma (ALCL) are reviewed. ALCL is a heterogeneous group of tumours, and histologic examination alone is not adequate in providing useful prognostic information. However, using a combination of clinical, phenotypic, and genotypic features, several distinct clinicopathologic entities have been identified. A subset of ALCL as presently defined is characterized by a balanced translocation, t(2;5)(p23;q35), resulting in a novel fusion protein (NPM-ALK) that can be readily detected by immunohistochemical methods using antibodies against the ALK protein. Detection of ALK protein, along with other methods for demonstrating the t(2;5), has assisted in identifying a distinct biologic entity within the heterogeneous group of ALCL with significant prognostic implications. It is important to separate these from cases of ALK-negative ALCL, which have a poorer prognosis, and cases of primary cutaneous ALCL, which have an excellent prognosis.

Bone marrow involvement in T-cell-rich B-cell lymphoma.

We describe the histologic and immunohistochemical findings in specimens from bone marrow (BM) biopsies performed for staging purposes in 13 patients with a previous tissue-based diagnosis of T-cell-rich B-cell lymphoma (TCRBCL). Bone marrow involvement was found in 8 (62%) of 13 cases and was often paratrabecular. The histologic appearance was not pathognomonic of TCRBCL, with the differential diagnosis including Hodgkin's disease and peripheral T-cell lymphoma. The infiltrates typically had a pale low-power appearance (due to histiocytic infiltration, relative hypocellularity, or both) that, in conjunction with the presence of a polymorphous infiltrate of scattered large atypical cells amid a mixed infiltrate of small lymphocytes and histiocytes, was suggestive of Hodgkin's disease. Immunohistochemistry revealed CD20 reactivity of the large atypical cells with the absence of CD15 and CD30 reactivity, supporting the diagnosis of TCRBCL. A prominent small T-cell infiltrate accompanying the large atypical cells was observed in all positive BM biopsy specimens. The increased incidence of BM involvement in TCRBCL is significantly higher than that found in de novo B-cell diffuse large cell lymphoma, suggesting a possible biologic difference between the two entities. Our cases share some similar clinicopathologic features with histiocyte-rich B-cell lymphoma and with diffuse lymphocyte-predominant Hodgkin's disease, paragranuloma type. We discuss the possible relationship to these two entities.