An update on the pathology of extranodal T-cell lymphomas

Non-cutaneous extranodal NK/T cell lymphoproliferations constitute a heterogenous group of rare neoplasms, occurring primarily in the gastro-intestinal tract, nasal area, spleen and liver. Besides primarily extranodal NK/T-cell lymphoma entities – i.e. extranodal NK/T-cell lymphoma, hepatosplenic T-cell lymphoma, primary intestinal T-cell lymphomas and NK/T-cell lymphoproliferations of the gastrointestinal tract, and breast implant-associated anaplastic large cell lymphoma – extranodal tissues may also be involved by T-cell leukemias, or other entities usually presenting as nodal diseases. Primary extranodal entities are characterized by distinct clinical and pathologic features, implying variable prognosis, ranging from indolent to highly aggressive. Here, we will review the clinico-pathologic features of the pertinent entities including the recent advances in their molecular and genetic characterization, with an emphasis on those newly recognized, and highlight the diagnostic criteria helpful to sort out the distinction with potential mimickers.     

Extranodal diffuse large B cell lymphoma of cutaneous follicle centre lymphoma type: a study of 24 patients with non-cutaneous primary limited stage extranodal diffuse large B cell lymphoma in support of a new concept

Aigner F, Korol D, Schmitt A M & Kurrer M O
(2012) Histopathology  60, 774–784 Extranodal diffuse large B cell lymphoma of cutaneous follicle centre lymphoma type: a study of 24 patients with non‐cutaneous primary limited stage extranodal diffuse large B cell lymphoma in support of a new concept Aims: Follicle centre cell lymphoma of small cell type showing either a follicular or diffuse growth pattern similar to cutaneous follicle centre lymphoma (cFCL) has been recognized in extranodal non‐cutaneous sites. Our aim was (i) to investigate whether diffuse large B cell lymphoma (DLBCL) of cFCL type could be identified in extranodal non‐cutaneous sites and (ii) whether clinical characteristics similar to primary cFCL could be recognized. Methods and results: Of 24 extranodal non‐cutaneous DLBCLs, nine (38%) had large centrocytoid morphology and 15 (62%) were either ‘centrocytoid and centroblastic’ or ‘centroblastic and immunoblastic’. Six centrocytoid cases were Irf‐4 negative, Bcl‐6 positive and at most weakly CD10‐ or Bcl‐2‐positive by immunohistochemistry, consistent with DLBCL of cFCL type. All patients with cFCL type were stage IE and were significantly younger than other patients. Recurrences occurred in two patients and were exclusively extranodal. Conclusion: Our results suggest that DLBCL of cFCL type can be identified in extranodal non‐cutaneous sites and shows clinical characteristics similar to genuine cFCL. We propose to expand the concept of cFCL to encompass large cell lymphomas in extranodal sites.     

Frequent expression of CD30 antigen in the primary gastric non-B, non-Hodgkin lymphomas

Most primary gastric lymphomas are of B-cell origin. Fourteen cases of primary gastric non-B, non-Hodgkin lymphomas were studied to evaluate their clinicopathological and immunophenotypic findings. The cases were comprised of 11 men and three women, with a median age of 56.5 years. Most patients underwent surgery either with or without chemotherapy, exhibiting a 5 year survival rate of 57.5%. Morphologically, the neoplastic cells showed various histological features, such as anaplastic large cell lymphoma (ALCL) (n = 3), peripheral T-cell lymphoma, unspecified, large (n = 4), medium-sized (n = 2) and mixed cell (n = 5). Two cases displayed a non-B, non-T cell phenotype, whereas the remaining cases displayed a T-cell phenotype. Six cases were CD4+, while two were CD8+. The neoplastic cells were CD30+ in 10 cases. TIA-1 was positive in six cases. In one case, anaplastic large cell lymphoma kinase (ALK) was identified with immunostaining and chromosomal rearrangement of ALK was detected by fluorescence in situ hybridization (FISH). In conclusion, although the mechanism of CD30 expression is unknown, primary gastric non-B, non-Hodgkin lymphomas tend to express CD30. We consider that some of the cases in the present study may be derived from cytotoxic T cells, similar to systemic and cutaneous ALCL, the majority of which exhibit TIA-1.     

Primary extranodal marginal zone lymphoma of the endometrium: report of four cases and review of literature

Primary extranodal marginal zone lymphoma of the endometrium (PEMZL-EM) is exceedingly rare and has not been well characterized. Herein, we study the clinicopathological, cytogenetic and molecular features of four cases, the largest case series reported to date. The median age of the four patients was 59 years. Clinical presentations included abnormal vaginal bleeding (three cases) and incidental finding (one case). There were no constitutional symptoms in any of the cases. None of the patients had evidence of lymphoma in any other anatomic sites including bone marrow. Histologically, the lymphoma was characterized by a nodular proliferation of small lymphocytes admixed with occasional immunoblasts and variable number of plasma cells, which was restricted to the endometrium in most cases. Lymphoepithelial lesions were not identified in any of the cases. All cases displayed the immunophenotype of marginal zone B-cell lymphoma. Cytogenetics and FISH studies revealed absence of characteristic chromosomal translocations. Molecular analysis demonstrated immunoglobulin heavy chain gene rearrangement in all cases, two of which were found to use IgVH3-30 gene by DNA sequencing. Three of the four patients were still alive after a median follow-up of three years. PEMZL-EM predominantly affects postmenopausal women and is characterized by distinct histological patterns, lack of specific genomic alterations, and indolent clinical course.     

淋巴结外恶性淋巴瘤外周血T淋巴细胞亚群与免疫指标测定分析

目的：检测原发性淋巴结外恶性淋巴瘤（Primary extranodal lymphoma，PENL）患者外周血T淋巴细胞亚群比例和免疫球蛋白（Ig）水平的变化。方法：分别应用流式细胞术（FCM）和免疫速率比浊法测定T淋巴细胞亚群比例和免疫球蛋白（Ig）以及补体C3、C4含量。结果：PENL组CD3^＋、CD4^＋和CD8^＋明显降低（P〈0．01），原发性结性恶性淋巴瘤（结性组）CD4^＋／CD8^＋比值和NK细胞比较其他两组有显著意义（P〈0．01）；提示PENL组、结性组中CD3^＋、CD4^＋和NK细胞与IgA、IgG、C3比较有显著的相关性（P〈0．01）。结论：结外恶性淋巴瘤患者免疫功能的改变，在其发病机制中的作用不容忽视，可以作为病情进展的免疫学指标。     

Malignant lymphomas and undifferentiated small cell carcinoma of the thyroid: a clinicopathological review in the light of the Kiel classification for malignant lymphomas

The paper reports a re-evaluation--based on the Kiel classification for non-Hodgkin lymphomas--of a group of cases initially diagnosed as undifferentiated small cell carcinomas or primary lymphomas of the thyroid. Twelve such cases were found among the 155 cases of primary malignant tumours of the thyroid recorded at the Institut Jules Bordet between 1955 and 1975. The review of the clinical charts and the histology showed that all the cases were in fact malignant lymphomas fitting easily into one of the groups described in the Kiel classification. These findings support the growing opinion that undifferentiated small cell carcinoma of the thyroid does not exist as a distinctive clinicopathological entity. Furthermore, the Kiel classification proved to be an excellent prognostic indicator, since all the cases classified as highly malignant were indeed fatal, whereas the surviving cases--three of which had shown tumoral extension beyond the thyroid capsule--fell into the group of low malignancy. Lastly, this study acknowledges the frequently observed association of malignant lymphoma of the thyroid with stigmata of Hashimoto's disease, and thus supports the concept that the continuous antigenic stimulation observed in the latter could trigger the development of a malignant lymphoma.     

Differential expression of the HECA-452 antigen (cutaneous lymphocyte associated antigen, CLA) in cutaneous and non-cutaneous T-cell lymphomas

The monoclonal antibody HECA-452 identifies an antigen that is primarily expressed on high endothelial venules, the preferred site of lymphocyte extravasation in lymphoid tissues, and also on a subpopulation of myelomonocytic cells and some T-cells. We investigated the expression of the HECA-452 antigen, also called the cutaneous lymphocyte associated antigen, in primary cutaneous and primary non-cutaneous T-cell non-Hodgkin's lymphomas. The tumour cells of cutaneous T-cell non-Hodgkin's lymphomas were positive in 53% of cases, while only 5% of the non-cutaneous lymphomas were positive. These differences were also present in morphologically identical tumours. Thus, the tumour cells in six out of 10 primary cutaneous anaplastic large cell T-cell lymphomas were positive, while they were positive in none of 24 primary non-cutaneous anaplastic large cell T-cell lymphomas. In general, primary cutaneous and primary nasal T-cell non-Hodgkin's lymphomas were devoid of HECA-452 positive high endothelial venules, whereas most nodal T-cell non-Hodgkin's lymphomas contained HECA-452 positive high endothelial venules. These observations suggest that the HECA-452 antigen might be related to a skin-associated type of lymphoid tissue and to lymphomas originating in the skin. However, the results of HECA-452 expression in secondary sites, and the clinical data of the primary cutaneous large cell lymphomas did not support the concept that HECA-452 is functionally involved in homing to the skin, or that loss of the HECA-452 antigen is related to tumour progression of primary cutaneous T-cell lymphomas.(ABSTRACT TRUNCATED AT 250 WORDS)     

Follicular dendritic cells in extranodal non-Hodgkin lymphomas of MALT and non-MALT type

Extranodal lymphomas of the thyroid (n=19), kidney (n=15) and testis (n=30) were investigated histologically and immunohistochemically for follicular dendritic cell pattern using the monoclonal antibody Ki-FDC1P. This recognizes follicular dendritic cells in paraffin sections. Follicular dendritic cells were most predominant in lymphomas of the thyroid. These thyroid lymphomas showed the morphological features of mucosa-associated lymphoid tissue (MALT) type lymphomas in 18 of 19 cases and were classified as high-grade malignant lymphoma of MALT type with evidence of a low-grade malignant component (n=18). Ten of these cases contained destroyed reactive follicles of follicular dendritic cells. In 6 of these 10 cases follicular dendritic cells occurred in a pattern of tumour-associated abortive follicle type. The remaining lymphoma of the thyroid was an immunoblastic lymphoma of B-cell type showing no detectable follicular dendritic cells. In extranodal lymphomas of non-MALT type follicular dendritic cells occurred in only two cases where immunocytoma involved the kidney. Malignant lymphomas of the kidney (chronic lymphocytic leukaemia,n=2; immunocytoma,n=4; centroblastic lymphoma,n=9) and of the testis (immunocytoma,n=2; centroblastic lymphoma,n=27; immunoblastic lymphoma of B-cell type,n=1) revealed no characteristics of MALT type lymphoma, cytologically or with respect to follicular dendritic cells. Classical lymphoepithelial lesions formed by centrocyte-like cells, a hallmark of MALT, occurred exclusively in thyroid lymphomas of MALT type. Although occurrence of classical lymphoepithelial lesions formed by centrocyte-like cells was limited to thyroid lymphomas of MALT type, a growth pattern of lymphoid blasts, with formation of lesions mimicking lymphoepithelial lesions superficially, was found in 6 of 27 testicular centroblastic lymphomas. Follicular dendritic cells in non-Hodgkin's lymphomas of MALT type show distinct follicular patterns not found in other extranodal lymphomas such as those found in the kidney and testis.     

Malignant lymphomas in HIV-seropositive patients. Frequency,features, and prognosis. Report on 31 cases

Summary In a random HIV-seropositive population, malignant lymphomas were diagnosed in 31 patients, of whom 24 (77%) had non-Hodgkin lymphoma (NHL) and 7 (23%) Hodgkin lymphoma (HL). The prevalence of NHL among AIDS patients was 8% (23/279 cases), with a prevalence of 17% among autopsied patients (16/96 cases). No patient with HL had AIDS at the time of diagnosis. In 7 of 23 AIDS patients with NHL (30%) the diagnosis was made only post mortem; among these were all 5 patients with primary CNS NHL. Median survival from the time of diagnosis was 1 month for patients with NHL and 3 months for those with HL. In individual patients, survival for several years may be possible with chemotherapy. Certain patients with NHL appear to benefit from intensive chemotherapy with a combination of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOPB protocol). Appropriate, therapeutic strategies taking into account the patients' individual conditions, including the overall prognosis, urgently requires development. Metastatic CNS involvement, which was the primary cause of death in 5 of 11 patients with NHL (45%) receiving chemotherapy, represents a serious limitation to successful treatment.Abbreviations AIDS acquired immunodeficiency syndrome - CB centroblastic - CDC Centers for Disease Control - CHOP cyclophosphamide, doxorubicin, vincristine, prednisone - CMV cytomegalovirus - CNS central nervous system - COPBLAM cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, procarbazine - COPP/ABVD cyclophosphamide, vincristine, prednisone, procarbazine/doxorubicin, bleomycin, vinblastine, darcarbazine - CR complete remission - CT computerized tomography - ELISA enzyme-linked immunosorbent assay - HIV human immunodeficiency virus - HL Hodgkin lymphoma - IT intrathecal - IMVP16 ifosfamide, methotrexate, etoposide - KC Kiel classification - MACOP-B methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin - ML malignant lymphoma - NHL non-Hodgkin lymphoma - OI opportunistic infection - PCP Pneumocystis carinii pneumonia - PD progressive disease - PR partial remission - RT radiation therapy - WBC white blood cells - WF Working Formulation     

Malignant lymphomas of true histiocytic origin. A clinical, histological, immunophenotypic and genotypic study

The clinical, histological, immunophenotypic and genotypic properties of four cases of lymphoma of true histiocytic origin are described. The cases were identified by typing 925 non-Hodgkin's lymphomas by immunophenotypic and/or genotypic techniques, and they all presented with skin lesions. The histological and immunophenotypic examination showed dense, diffuse infiltrates of markedly pleomorphic mononuclear cells that were positive for macrophage-associated markers, and negative for B-cell, T-cell and myeloid cell-associated antigens. Staining for Ki-1 and epithelial membrane antigen was also negative. Gene rearrangements studies were performed in three cases, and all of these showed germline configuration of both T-cell receptor and immunoglobulin genes. In all cases, the clinical course was aggressive with rapid and widespread dissemination to internal organs, poor response to conventional chemotherapy, and short survival times (0.5 to 14 months). This suggests that although true histiocytic tumours are very rare, their recognition may be important for clinical and/or prognostic reasons.     

A study of malignant lymphomas in Iran,based on the updated Kiel classification

Summary One hundred and sixty-two consecutive cases of malignant lymphoma were collected from two diagnostic centres in north and south Iran. Tissue samples were examined by immunohistological methods, and the non-Hodgkin's lymphomas were classified according to the updated Kiel classification. The distribution of the different types of malignant lymphoma in this study is compared with the situation in Western countries.     

Primary lymphoma of the thyroid: a clinical, histological and immunohistochemical study of 20 cases

Twenty cases of malignant lymphoma arising in the thyroid gland were studied clinically, histologically and immunohistochemically. Nineteen cases were non-Hodgkin's lymphoma (15 diffuse and four follicular lymphoma) and one was a plasmacytoma. Immunohistochemical analysis of the lymphomas using paraffin-embedded sections disclosed that 17 lymphomas were B-cell type and two were T-cell type. The plasmacytoma was of IgG kappa type. The large majority of the lymphomas were associated with an underlying chronic thyroiditis. The 5-year survival rate of the patients was 70%. An unfavourable diagnosis was more likely when the tumour was diffuse rather than follicular, when it was of diffuse large cell type or of immunoblastic type and when there was cervical lymph node involvement.     

Altered expression of Bcl-2, c-Myc,H-Ras,K-Ras,and N-Ras does not influence the course of mycosis fungoides

Introduction

Data about genetic alterations in mycosis fungoides (MF) are limited and their significance not fully elucidated. The aim of the study was to explore the expression of various oncogenes in MF and to assess their influence on the disease course.

Material and methods

Skin biopsies from 27 MF patients (14 with early MF and 13 with advanced disease) and 8 healthy volunteers were analyzed by real-time polymerase chain reaction (PCR) to detect Bcl-2, c-Myc, H-Ras, K-Ras and N-Ras expression. All PCR reactions were performed using an Applied Biosystems 7900HT Fast Real-Time PCR System and interpreted using Sequence Detection Systems software which utilizes the comparative delta Ct method. The level of mRNA was normalized to GAPDH expression. All data were analyzed statistically.

Results

All evaluated oncogenes were found to be expressed in the skin from healthy controls and MF patients. Bcl-2 (–4.2 ±2.2 vs. –2.2 ±1.1; p = 0.01), H-Ras (–3.0 ±3.3 vs. 0.6 ±2.6; p = 0.01) and N-Ras (–3.6 ±2.0 vs. –1.1 ±2.4; p = 0.03) were expressed at significantly lower levels in MF. No relationships between oncogene expression and disease stage, presence of distant metastases and survival were observed (p > 0.05 for all comparisons).

Conclusions

The pathogenic role and prognostic significance of analyzed oncogenes in MF seem to be limited and further studies are needed to establish better prognostic factors for patients suffering from MF.