Morphological characteristics of malignant T-cell lymphomas in baboons

Fifteen cases of generalized peripheral T-cell non-Hodgkin's lymphoma in baboons were phenotyped immunologically and morphologically. Using the updated Kiel classification the cases included low-grade and high-grade lymphomas and low-grade lymphomas that had transformed into high-grade lymphomas. In the low-grade group there were seven cases of lymphocytic type, partly corresponding to chronic lymphocytic leukaemia of T type and to T-zone lymphoma in man. In addition there were four cases of prolymphocytic-lymphocytic type, which show large nodules (proliferation centres) and which have no equivalent in the Kiel classification. In four cases there was a progression to an immunoblastic lymphoma and in one case to a large cell anaplastic lymphoma. In addition, three cases of large cell anaplastic lymphoma without a low-grade component were found. Both the immunoblastic lymphomas and the large cell anaplastic lymphomas corresponded well with the same types in the Kiel classification. The cases of large cell anaplastic lymphoma were also CD30 positive. Most of these lymphomas were CD4 positive, but there were rare cases that were either CD8 positive, showed both CD4 and CD8 positivity or had lost both antigens. Antigens associated with cell activation were often revealed. All but one baboon had antibodies in the blood against the retrovirus STLV-1 (simian T-cell leukaemia virus 1), which is very similar to human T-cell leukaemia virus 1 (HTLV-1) in man. Despite this virological resemblance, the morphology of these T-cell lymphomas does not resemble that of the HTLV-1-positive Japanese T-cell lymphomas but is like that of the HTLV-1-negative European cases.     

T-cell lymphoma in Hashimoto's thyroiditis

An elderly Caucasian woman with a 2-year-history of hypothyroidism, treated with thyroxine, presented with a rapidly growing mass in the thyroid. The morphological and immunological features of this thyroid tumour were those of a peripheral T-cell lymphoma with an immunophenotype commonly associated with HTLV-1 positive-adult T-cell leukaemia/lymphoma, although serology for HTLV1 antibody was negative. Monoclonal gene rearrangements were demonstrated with T-cell receptor beta- and gamma-specific primers. There are several interesting features in this case (i): although primary B-cell lymphomas (MALT-associated lymphomas) of thyroid are a well-recognized sequel to thyroiditis, primary T-cell lymphomas are rare, even in areas of the world where adult T-cell lymphomas predominate; (ii) the tumour showed the typical immunophenotype of an HTLV-1 positive T-cell lymphoma but the patient is English, has not visited endemic areas, and is serologically negative for HTLV–1; (iii) the residual thyroid gland showed a florid lymphocytic thyroiditis with Hu¨rthle cell change, typical of Hashimoto's thyroiditis; (iv) unlike other reports of thyroid T-cell lymphoma, which have presented with stage III-IV disease, this tumour presented in the favourable clinical stage of IE.     

Non-HTLV-1-associated primary gastric T-cell lymphomas show cytotoxic activity: clinicopathological,immunohistochemical characteristics and TIA-1 expression in 31 cases

AIMS: Most primary gastrointestinal lymphomas are of B-cell origin and T-cell origin is very rare. Recent studies have suggested that human T-cell lymphotrophic virus type 1 (HTLV-1) may be involved in the development of primary gastric T-cell lymphoma. We analysed 31 patients with primary gastric T-cell lymphoma in south-west Japan, an area endemic for HTLV-1, and determined their phenotypes, genotypes, and HTLV-1 status. METHODS AND RESULTS: Here we present 31 cases of primary gastric T-cell lymphoma in a HTLV-1-endemic area in Japan and analyse the clinical status, histology, phenotype and virus status. The median age at onset of primary gastric T-cell lymphoma was 57 years with a gender ratio of M:F = 1.58:1. Six of the 31 primary gastric T-cell lymphoma cases had HTLV-1 proviral DNA (five males, one female), nine of the 31 cases were positive for anti-adult T cell leukaemia antibody, without examination of HTLV-1 proviral DNA (five males, four females), eight were non-HTLV-1-associated primary gastric T-cell lymphoma (four males, four females) and the other eight cases were unknown. Primary gastric T-cell lymphoma usually presented as a large ulcerated tumour at the corpus to the antrum and histologically consisted of anaplastic large cell type (n = 2), pleomorphic large cell type (n = 3), pleomorphic medium and large cell type (n = 14), pleomorphic medium cell type (n = 11), and angioimmunoblastic T-cell lymphoma type (n = 1). There were no clear macroscopic and microscopic differences between HTLV-1-associated and non-HTLV-1-associated primary gastric T-cell lymphoma. Most patients died within 2 years of diagnosis, and both types of primary gastric T-cell lymphoma (with and without HTLV-1) were associated with poor prognosis. Cytotoxic marker analysis showed that HTLV-1-associated lymphomas were negative for TIA-1, while non-HTLV-1-associated lymphomas were positive for TIA-1. CONCLUSIONS: Our results suggest that in HTLV-1-endemic areas, patients with HTLV-1-associated primary gastric T-cell lymphoma should be managed carefully and that TIA-1 seems to be useful for identifying the aetiology of this lesion.     

Monoclonal antibody HML-1 reactivity with adult T-cell leukaemia/lymphoma and other lymphomas

Human T-cell leukaemia/lymphoma virus type 1 (HTLV-1), a causative virus of adult T-cell leukaemia/lymphoma (ATLL), is known to be transmitted by breast-feeding. Using a monoclonal antibody HML-1 which labels human intestinal intra-epithelial T lymphocytes, we have immunohistochemically examined ATLL tissues in order to evaluate the possibility that HTLV-1 infected intestinal T cells are the origin of ATLL cells. Previously this antibody was reported to react with intestinal T-cell malignant lymphomas but not with peripheral tumours, or any B-cell lymphomas. We investigated 181 patients with malignant lymphomas and found that 19 out of 113 ATLLs were positive for HML-1. T-cell malignant lymphomas excluding ATLL also reacted with HML-1 (7/24), but all the B-cell lymphomas 0/33) and non-neoplastic lymph node and skin lesions (0/10) were negative for HML-1. In patients with ATLL and other T-cell malignant lymphomas, the positivity level of HML-1 was relatively higher in stomach (3/7) and tonsil (2/6) than that in lymph nodes (15/100) and skin (8/47). We observed one HML-1 positive ATLL patient with tumour formation in the skin and lymphadenopathy and marked infiltration of the large intestine but minimal involvement of other organs. Although HML-1 was frequently expressed in gastric infiltration of ATLL, the level of positivity was too low in lymph nodes to support the hypothesis that HTLV-1 infected intestinal T cells are the origin of ATLL cells. Some of the HML-1 positive ATLL cases co-expressed CD30. Furthermore, three of six cases of Ki-1 lymphoma (large anaplastic cell lymphoma) were positive for HML-1. We conclude that expression of HML-1 in ATLL reflects an activated state of the lymphoma cells, but not the intestinal origin of ATLL cells.     

The World Health Organization classification of malignant lymphoma: incidence and clinical prognosis in HTLV-1-endemic area of Fukuoka

New insights into the pathogenesis of lymphoid malignancies have been gained through novel genetic, molecular and immunological techniques. A new classification system for lymphoid malignancies, known as the new World Health Organization (WHO) classification, has been proposed recently based on these findings. The relative incidence of the subtypes of malignant lymphoma is known to differ according to geographic location. Adult T-cell leukemia/lymphoma (ATLL) is a human malignancy associated with human T-cell leukemia virus type 1 (HTLV-1), and the Kyushu islands are an HTLV-1 endemic area. To clarify the relationship between the histological classification and prognosis of lymphoid malignancies, we reclassified previous cases in our department and summarized our previous reports using the WHO classification. Of 933 cases of lymphoid malignancies, 471 (50%) were B-cell lymphoma, 396 (42%) T/natural killer (NK)-cell lymphoma and 41 (4%) Hodgkin lymphoma (HL). Analysis of clinical outcome showed favorable prognosis for HL, intermediate for B-cell lymphoma and poor prognosis for T-cell lymphoma. Among B-cell lymphomas, the commonest type was diffuse large B-cell lymphoma (n = 281; 60%). Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) was diagnosed in 82 cases (17%), follicular lymphoma in 52 (11%) and mantle cell lymphoma in 24 (5%). Other less common lymphomas were Burkitt lymphoma (n = 9; 2%) and lymphoblastic lymphoma (n = 5; 1%). Using overall survival rates, the various B-cell lymphoma types could be divided into three broad groups for prognostic purposes: (i) low-risk group comprising follicular lymphoma and MALT; (ii) intermediate-risk group comprising diffuse large B-cell lymphoma and Burkitt lymphoma; and (iii) high-risk group comprising mantle cell lymphoma and lymphoblastic lymphoma. Among the T/NK-cell lymphomas, the commonest type was ATLL (n = 191; 48%), followed by peripheral T-cell lymphoma, unspecified (n = 83; 21%), angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) (n = 38; 10%), anaplastic large cell lymphoma (ALCL) (n = 22; 6%). Less common types were lymphoblastic lymphoma (n = 17; 4%), nasal and nasal-type NK/T-cell lymphoma (n = 17; 4%), mycosis fungoides (MF) (n = 9; 2%) and other rare types. With respect to clinical prognosis, T/NK-cell lymphomas fell into three groups: (i) relative low-risk group comprising ALCL, AILD, MF and lymphoblastic lymphoma; (ii) relative intermediate-risk group comprising NK/T-cell lymphoma and unspecified lymphoma; and (iii) extremely high-risk group comprising ATLL. Among the lymphoblastic lymphomas, B-cell type and T-cell type lymphomas exhibited different clinical outcomes. We conclude that the histological, phenotypic and genotypic classification of the new WHO system should be beneficial for the clinical approach to these tumors.     

Adult T-cell leukemia/lymphoma in Jujuy,north-west Argentina

Human T-cell leukemia virus type 1 (HTLV-1) infection is prevalent in native Americans living in the Andes. Some of their malignant lymphomas (ML) show a peculiar histology suggestive of adult T-cell leukemia/lymphoma (ATLL). To determine whether ML resembling ATLL are indeed ATLL, re-analysis of 34 cases occurring in Jujuy, a province of Argentina, was conducted, concentrating on immunological phenotype, integration of HTLV-1 proviral DNA, expression of HTLV-1 p40Tax and p27Rex, and infection of Epstein-Barr virus (EBV). The ML were 22 cases of mature peripheral T-cell and natural killer (NK)-cell neoplasm (mT/NKN), 11 B-cell malignant neoplasms and one Hodgkin's lymphoma. Polymerase chain reaction against the HTLV-1 proviral DNA, using DNA extracted from paraffin sections, indicated integration of the HTLV-1 proviral DNA in three cases of eight mT/NKN. Two other cases of mT/NKN were positive for anti-HTLV-1 antibodies. Expression of p40Tax and p27Rex was detected in all five of these mT/NKN cases associated with HTLV-1. As such, these five mT/NKN were rediagnosed as ATLL. In situ hybridization signals for EBV-encoded small nuclear early region-1 were detected in nine cases of mT/NKN, of which five cases of NK-cell lymphoma were found to have cytoplasmic CD3 expression, a CD56 phenotype and positivity of TIA1. According to the new World Health Organization classification, the mT/NKN class includes five cases of ATLL and five cases of NK-cell lymphomas. The five cases of ATLL were of native American extraction from an HTLV-1-endemic area around Jujuy, north-west Argentina.     

‘Grey zones’ in the differential diagnosis of lymphoma pathology

The 2016 World Health Organization classification of lymphoid malignancies has further improved basis for pathological diagnosis and better characterization of lymphoproliferative conditions. It includes a range of new entities and expanded requirements for molecular analysis, but reliance on close integration of the clinical, pathological and molecular features still remains the cornerstone for diagnosis. Despite the advances in knowledge and refined diagnostic criteria, certain areas of lymphoma pathology remain difficult and contentious. We provide a review of some entities which continue to represent diagnostic “grey zones”, with potentially overlapping pathological, molecular or clinical features, but in most instances require specific treatments to achieve best clinical outcomes. We focus on: clarifying diagnostic ambiguity between nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte rich B-cell lymphoma, including the relevant differential diagnoses; key features and differential diagnosis of mediastinal grey zone lymphoma; characteristics of high grade B-cell lymphomas, with particular reference to their genetic features as defining diagnostic parameters; pathological overlaps of EBV-positive lymphoproliferations and their differential diagnosis with EBV-positive classic Hodgkin lymphoma.     

Nodal T/NK-cell lymphoma of nasal type: a clinicopathological study of six cases

Aims:  To investigate the clinicopathological features of six unusual cases of nodal CD56+ and Epstein–Barr virus (EBV)+ T/natural killer (NK)-cell lymphoma, a putative nodal counterpart of nasal NK/T-cell lymphoma (nodal T/NK-cell lymphoma of nasal type) in comparison with nasal NK/T-cell lymphoma with secondary lymph node involvement ( n  = 24) and peripheral T-cell lymphoma (PTCL) of cytotoxic molecule (CTM)+ and EBV+ type ( n  = 21).
Methods and results:  All cases of nodal T/NK-cell lymphoma of nasal type exhibited diffuse infiltration of pleomorphic medium-sized to large tumour cells, reminiscent of those in CTM+ EBV+ PTCL. The tumour cells had a typical phenotype of nasal NK/T-cell lymphoma: CD2+, CD3ε+, CD4−, CD5−, CD56+, T-cell intracellular antigen-1+, granzyme B+, perforin+ and EBV+. However, four of six cases demonstrated clonal T-cell receptor γ-gene rearrangement on polymerase chain reaction analysis, unlike nasal NK/T-cell lymphoma. Comparison of clinical parameters and overall survival among the three groups demonstrated only minor differences.
Conclusions:  Nodal T/NK-cell lymphoma may occupy the grey zone between extranodal nasal-type NK/T-cell lymphoma and nodal CTM+ PTCL in a spectrum of NK to T-cell lymphomas that are EBV+. The close relationship between NK/T-cell lymphomas and cytotoxic T-cell lymphomas was also substantiated.     

Pitfalls in diagnostic hematopathology �C Part II

The overlapping features of malignant lymphomas create a diagnostic “grey zone” , and lead to the invention of “grey zone lymphomas”. There are several major grey zone lymphomas: 1) Lymphomas with overlapping features of Hodgkin lymphoma and large B-cell lymphoma; 2) Lymphomas with overlapping features of Burkitt lymphoma and diffuse large B-cell lymphoma; 3) Lymphomas with overlapping features of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte rich large B-cell lymphoma; 4) Lymphomas with overlapping features of Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL) and peripheral T-cell lymphoma (PTCL); 5) T-cell classical Hodgkin lymphoma and ALCL-HL. The second review of this series will be dedicated to discussion of the “grey zone” features of the lymphomas and how to narrow down the “grey zone” between those lymphomas.     

Leu-M1 antigen expression in acute leukaemias

Leu-M1 is a differentiation antigen present in human myelomonocytic cells. Seventy-seven acute leukaemias were retrospectively stained with anti-Leu-M1 using the immunoperoxidase technique on Bouin-fixed paraffin-embedded sections. The subjects were 44 acute lymphoblastic leukaemias (ALL) and 33 acute myeloid leukaemias (AML) previously characterized by cytochemical and immunologic (cell suspension) methods. Leu-M1 was positive in all the AML and in half of the ALL cases. These results suggest that Leu-M1 does not allow differentiation between AML and ALL. For the ALL cases Leu-M1 was positive in 15/28 B-cell types, 4/12 T-cell type and 3/4 'null'-cell type cases. Thus, this antibody is of no assistance in defining types B, T, or 'null' in ALL. Leu-M1 was also studied on paraffin sections of 34 high grade malignant lymphomas. The antibody was negative in all 13 B-cell lymphomas (lymphoblastic: 6; immunoblastic: 7) and in all 4 'null' cell lymphomas. It was positive in 4/9 peripheral T-cell type, the other T-cell lymphomas (lymphoblastic: 5; immunoblastic: 3) remaining negative. Thus, Leu-M1 may be positive in T-cell lymphomas but it is negative in B-cell lymphomas and is always negative in B or T lymphoblastic types. It seems that lymphoblasts are Leu-M1 negative in non-Hodgkin's lymphoma and may be Leu-M1 positive in leukaemias.     

The world health organization classification of malignant lymphomas in japan: incidence of recently recognized entities. Lymphoma Study Group of Japanese Pathologists

New insights into the immunology and genetics of malignant lymphomas have allowed the recognition of new entities and the refinement of previously recognized disease categories. The relative incidence of these subtypes of malignant lymphoma is also known to differ according to geographic location. In order to clarify the current status of malignant lymphomas in Japan and the relative incidences of their subtypes, 3194 patients were classified according to the new World Health Organization (WHO) classification. Among these were 3025 cases (94.71%) of non-Hodgkin's lymphoma (2189 cases (68.53%) of B-cell lymphoma, 796 cases (24.92%) of T-cell lymphoma) and 141 cases (4.41%) of Hodgkin's lymphoma. The incidences of the major subtypes of non-Hodgkin's lymphoma were 33.34% for diffuse large B-cell lymphoma, 8.45% for marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, 8.05% for plasma cell myeloma, 7.45% for adult T-cell leukemia/lymphoma (ATLL), 6.7% for follicular lymphoma, 6.67% for peripheral T-cell lymphoma of unspecified type, 2.79% for mantle cell lymphoma, 2.6% for nasal and nasal-type T/NK cell lymphoma, 2.35% for angioimmunoblastic T-cell lymphoma, and 2.35% for precursor B-cell lymphoblastic leukemia/lymphoma, in decreasing order. The other subtypes comprised less than 2%, mainly precursor T-cell lymphoblastic lymphoma/leukemia (1.72%), anaplastic large-cell lymphoma of T- and null-cell types (1.53%), and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (1.31%). The incidence of ATLL was influenced by its high percentage (19.20%) in the south-western Japanese island, Kyushu, an endemic area of human T-cell leukemia virus type 1 (HTLV-1), but which appeared to be lower than that in a previous study. The nodular sclerosis and mixed cellularity types of Hodgkin's disease occupied 1.78% and 1.63%, respectively. These data are distinct from those in Western countries and similar in several ways to those in the East, although the relatively high rate of ATLL was attributed to the geographical difference in the etiologic factor, HTLV-1.     

T-cell lymphomas in children

T-cell lymphomas in children are rare and compromise a rather limited spectrum of entities. Relatively frequently observed are precursor T-cell lymphomas mainly presenting as mediastinal tumors with or without leukemia and ALK-positive anaplastic large cell lymphomas (ALCL) with nodal or extra nodal manifestations. In contrast to adults, where peripheral T-cell lymphoma (PTCL) is the most frequent T-cell neoplasia, PTCL in children is exceptional and remains a challenging diagnosis even for experienced haematopathologists. Other rare T-cell lymphomas occasionally seen in children are panniculitis like T-cell lymphomas, NK/T-cell lymphomas and hepatosplenic gamma delta-lymphomas. Of note angioimmunoblastic T-cell lymphoma is never seen in children. Mimickers of T-cell lymphomas like viral or immunological disorders in children are more frequent than manifest T-cell lymphomas and knowledge of these reactive conditions and their differential diagnosis is essential. The recognition of typical histopathological and clinical features along with knowledgeable use and interpretation of immunohistochemical and molecular markers are mandatory for a reliable diagnosis of childhood T-cell lymphomas.     

Histopathology and immunohistochemistry of peripheral T cell lymphomas: a proposal for their classification.

Based on the results of histological and immunohistochemical observations of a large number of peripheral T cell lymphomas from China, England, Germany and Japan, histological and cytological morphology were correlated with immunophenotype, aetiological association with HTLV-1, and clinical behaviour to produce a working classification of the T cell lymphomas. This classification, based mainly on cytological criteria, divides the peripheral T cell lymphomas into tumours of low grade and high grade malignancy. Adult T cell lymphoma/leukaemia (ATLL) is caused by HTLV-1 and belongs chiefly to the high grade category. Some tumours are characterised by an admixture of other cells (epithelioid cells, follicular dendritic cells, etc) and structures (high endothelial venules, follicles), which may indicate the secretion of lymphokines by the tumour cells. Clear cells seem to be specific for T cell lymphomas and may occur in various types of peripheral T cell lymphoma.     

Post-transplant T-cell lymphoproliferative disorder/T-cell lymphoma: a report of three cases of T-anaplastic large-cell lymphoma with cutaneous presentation and a review of the literature

AIMS: To report the clinical, pathological and immunohistochemical features of three cases of post-transplant T-cell lymphoproliferative disorder (T-PTLD) T-cell lymphoma with primary cutaneous presentation. METHODS AND RESULTS: Three cases of primary cutaneous post-transplantation anaplastic large-cell lymphomas occurred in renal transplant recipients and were shown to display a T-cell immunophenotype; all were ALK 1 protein and EMA negative and two were Epstein-Barr virus positive using in-situ hybridization. Two displayed a CD4+ phenotype, two were focally CD56+ and all three were negative for the cytolytic enzyme granzyme B. In two cases monoclonality was established by T-cell receptor gene rearrangement study. All presented with nodular cutaneous involvement and all were ultimately fatal. CONCLUSION: T-PTLDs are uncommon histological subtypes both in a general context and associated with cutaneous presentation. Our findings suggest clinicopathological and immunophenotypic similarities to primary cutaneous anaplastic large-cell lymphoma but with a progressive clinical behaviour similar to previously reported T-PTLD and to systemic nodal ALK- anaplastic large-cell lymphoma.     

Benign and malignant lymphoid lesions of the stomach. A histological reappraisal in the light of the Kiel classification for non-Hodgkin''s lymphomas

Twenty-two cases of lymphoid tumours of the stomach were reviewed by application of the Kiel classification for non-Hodgkin's malignant lymphomas. Four cases of pseudolymphomas were found, one of which had been previously misdiagnosed as malignant lymphoma. The remaining cases were all malignant tumours with B-cell lymphoma features. These were divided into seven low grade lymphomas (three immunocytomas and four centroblastic/centrocytic) and II high grade lymphomas (six centroblastic and five immunoblastic lymphomas). No cases of Hodgkin's disease or lymphoblastic lymphoma were observed. The Kiel nomenclature was not only easy to apply, but also helped to differentiate pseudolymphoma from malignant lymphoma. Both the pseudolymphomas and the malignant lymphomas were consistently associated with follicular gastritis. This lesion, while intrinsically non specific, was sometimes accompanied by suggestions of transition between itself and the lymphoma, a fact which at least raises the possibility of a transformation of the former into the latter.     

A reassessment of primary thyroid lymphoma: high-grade MALT-type lymphoma as a distinct subtype of diffuse large B-cell lymphoma

AIMS: Primary lymphoma of the thyroid gland (PTL) is a relatively rare disease. During an 18-year period, 53 cases of primary non-Hodgkin's lymphoma involving this extranodal site were seen at our institutions. The aims of this study were to evaluate the spectrum of PTLs using current lymphoma classification concepts and immunocytochemical markers, determine whether features of MALT-type lymphoma were evident in PTL, and if there was any clinical significance of such a finding. METHODS AND RESULTS: The cases were retrospectively studied clinically, histologically and immunohistochemically. The tumours were classified according to the Revised European-American Lymphoma Classification of lymphoid malignancies (REAL classification). Thirty-eight patients were females, 15 were males and mean age at diagnosis was 66.3 years (range 38-90). Three cases were low-grade marginal zone lymphomas (low-grade MALT-type lymphomas). There were 45 diffuse large B-cell lymphomas (DLBCL) of which there were 27 DLBCL-NOS and 18 high-grade MALT-type lymphomas. Within the diffuse large B-cell lymphoma (DLBCL) category, cases were subdivided into those without (DLBCL-NOS) and those with features of 'high-grade' MALT-type lymphoma based on presence of a low-grade component or large cell lymphoepithelial lesions (HG MALT-type lymphoma). In addition there were three follicle centre lymphomas, one anaplastic large cell lymphoma and one peripheral T-cell lymphoma. Twenty cases were stage IE, 18 stage IIE, and four stage IV. All patients with low-grade MALT-type lymphoma are alive without disease. The 5-year survivals for DLBCL-NOS and HG MALT-type lymphoma were 75% and 25%, respectively. Univariate analysis (log rank) among the DLBCLs showed stage (P < 0.001) and subtype (P = 0.005) were associated with survival. Stage was associated with type of DLBCL, 65% of DLBCL-NOS being stage IE compared to 20% of HG MALT-type lymphomas. CONCLUSIONS: We conclude that primary thyroid lymphomas occur most commonly in elderly women and are frequently present in clinical stage IE and IIE. Low-grade MALT-type lymphomas are relatively uncommon but appear to have a favourable prognosis. DLBCL is the most common lymphoma and features of MALT can be seen in over one-third of cases. As a group, HG MALT-type lymphomas had a worse outcome than DLBCL-NOS, primarily due to higher clinical stage at diagnosis. These two subtypes of DLBCL appear to be distinct clinical and histological entities.     

Peripheral T/NK-cell lymphoma: a report of the IXth Workshop of the European Association for Haematopathology

AIMS: In April 1998, The European Association for Haematopathology organized the IXth workshop on peripheral T-cell and NK-cell lymphomas and leukaemias. The workshop focused on unusual subtypes of these rare malignancies, allowing evaluation of the recently published WHO classification of neoplastic diseases of the lymphoid tissues. METHODS AND RESULTS: One-hundred and three cases were centrally immunophenotyped and hybridized for EBER1/2 of Epstein--Barr virus. All cases were reviewed by a panel of experienced haematopathologists and classified according to the new WHO classification for lymphoid neoplasms. Three cases were considered as precursor T-cell and 95 cases as peripheral T/NK-cell lymphoma/leukaemia. Although the cases represented a selected series of unusual cases, the following conclusions could be made: (i) Most lymphomas except the hepatosplenic gamma/delta T-cell lymphomas showed a rather broad morphological spectrum, with differences both between and within individual tumours. (ii) This heterogeneity was also reflected by the immunophenotype, for instance a variable expression of CD30 was found in many enteropathy type T-cell lymphomas. (iii) Exceptions in phenotype were regularly found in almost all categories, indicating that phenotype should not be the final determining factor in classification. (iv) The great majority of T-cell lymphomas expressed the alpha/beta T-cell receptor, with the exception of all but one hepatosplenic T-cell lymphomas and a few other extranodal peripheral T cell lymphomas. (v) Malignancies of precursor cells, blastic NK-cell lymphoma/leukaemia, adult T-cell lymphoma/leukaemia and most AIL-type T-cell lymphomas did not express cytotoxic molecules such as TIA1 and granzyme-B. In contrast, all five aggressive NK/T-cell lymphomas/leukaemias, a single case of large granular lymphocyte leukaemia and 40 of 47 primary extranodal lymphoma/leukaemias expressed these molecules. In hepatosplenic gamma/delta T-cell lymphoma, five of six cases showed expression of TIA1 but not of granzyme-B. (vi) Seven tumours developed after organ-transplant, four cases being EBV-positive. No distinct phenotype could be attributed to these cases. CONCLUSIONS: Most peripheral T/NK cell lymphomas could be categorized as distinct entities as described in the recently proposed WHO classification for lymphoid neoplasms.     

Primary malignant lymphoma of the colon and rectum. A histopathological and immunohistochemical analysis of 45 cases with clinicopathological correlations

Primary colorectal lymphoma accounts for only about 0.2% of large intestinal malignancies. Management difficulties are compounded by a lack of consistent pathological reporting and by the use of numerous different classifications. Forty-five cases of primary colorectal lymphoma are included in this study. The presenting features are indistinguishable from those of colorectal cancer. Seven patients had a history of chronic ulcerative colitis but no other predisposing factors were identified. Immunohistochemical studies showed that all tumours were of B-cell phenotype. Most tumours were difficult to characterize using standard pathological classifications such as Kiel, except for the 11 cases of malignant (multiple) lymphomatous polyposis, which were morphologically diffuse centrocytic lymphomas. Twenty-nine lymphomas showed the morphological and immunohistochemical features associated with tumours arising in mucosa-associated lymphoid tissue. These tumours showed variable but often marked polymorphism and we have used the term polymorphic B-cell lymphoma to describe them. Consistency was achieved between three observers as to whether these tumours were low or high grade, and grade was found to be prognostically important. A modified Dukes staging system was adopted and there was a trend for early stage to give prognostic advantage. This study supports the view that surgery should be the primary treatment for localized lymphoma of the gastrointestinal tract with radiotherapy and/or chemotherapy for advanced cases and for malignant lymphomatous polyposis.     

Emmprin, a cell surface inducer of matrix metalloproteinases (MMPs), is expressed in T-cell lymphomas

Degradation of the extracellular matrix by matrix metalloproteinases (MMPs) is a crucial step in tumour invasion and metastasis. In human carcinomas, tumour cell-fibroblast interactions (TFIs) have been demonstrated to play a role in the up-regulation of MMP levels in tumours, and emmprin is a surface molecule on tumour cells that stimulates nearby fibroblasts to produce MMP-1, 2, and 3. T-cell lymphomas frequently show extranodal organ involvement and skin invasion, but a role for TFIs in their invasion has not been examined in detail. This study investigated TFIs in T-cell lymphomas with special reference to emmprin expression and MMP production. Immunohistochemically, only germinal centre cells and some histiocytes expressed emmprin in non-neoplastic lymph nodes (ten cases), while all T-cell lymphomas [14 cases of adult T-cell leukaemia/lymphoma (ATLL), six cases of lymphoblastic lymphoma, seven cases of anaplastic large cell lymphoma, and nine cases of angio-immunoblastic T-cell lymphoma] expressed emmprin strongly and diffusely. FACS analysis of peripheral blood from normal individuals revealed that small fractions of B-cells, T-cells, and monocytes expressed emmprin, whereas emmprin-expressing T-cells were much increased in number, and expressed this protein to a higher level, in ATLL patients. In vitro co-cultures of emmprin-positive HTLV-1-transformed lymphocytes (MT-2) and emmprin-negative human fibroblasts enhanced the production of pro-MMP-2 (gelatinase A) and active MMP-2, compared with cultures of either cell type alone. This stimulation was inhibited by an activity-blocking peptide against emmprin. Moreover, in histopathological sections from patients with ATL skin involvement, MMP-2 was demonstrated in fibroblasts around infiltrating ATL cells, but not in fibroblasts in non-diseased areas. In conclusion, emmprin is overexpressed by T-lymphoma cells, when compared with normal counterparts, and facilitates MMP-2 production via interactions with fibroblasts, which could play a role in stromal invasion by lymphoma cells.     

Classification of cell lineage and anatomical site, and prognosis of extranodal T-cell lymphoma – natural killer cell, cytotoxic T lymphocyte, and non-NK/CTL types

Due to their minority among the non-Hodgkin lymphomas, classification of extranodal T-cell lymphomas, including those of the natural killer (NK) cell type, has long been controversial and unclear, and the clinical outcome is not well clarified. Recently, new well-defined disease entities have been described based on tumor cell biology combined with anatomical site, clinical features, Epstein-Barr virus (EBV) status, and cell lineage as determined by immunophenotype and genotype. Cytological features are usually not specific, and there are no morphologic correlates with the classification of extranodal T/NK-cell lymphomas. From a human T-cell lymphotropic virus type 1 (HTLV-1) endemic area in Japan, we report here the analysis of 144 cases of extranodal T-cell lymphoma, from which fresh tissues were available. As the clinicopathological features were known, we simply reclassified the cases according to cell lineage and anatomical site. The extranodal T-cell lymphomas were classified into three types on the basis of cell lineage: (1) natural killer cell (NK) type [sCD3-, CD56+, T-cell receptor gene (TCR) germline], (2) cytotoxic T lymphocyte (CTL) type [sCD3+, TIA-1+, TCR rearranged, CD8+/-, CD4-/+], and (3) non-NK/CTL type [sCD3+, TIA-1-, TCR rearranged, CD4+/-, CD8-/+]. In addition to cell lineage, the anatomical site and clinical features were added for subclassification. NK type tumors (35 cases) included the lymphoblastic type, nasal/nasal-type NK lymphoma, and NK leukemia. The CTL type (46 cases) included anaplastic large cell lymphoma (ALCL), cutaneous type, intestinal, gamma delta T-cell type, and an unspecified type. The non-NK/CTL type (63 cases) included adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and an unspecified type. With the exception of ATLL and MF, most extranodal T-cell lymphomas had a cytotoxic phenotype of NK type or CTL type and were often associated with EBV infection. MF and the unspecified type within the non-NK/CTL tumors, with the exception of ATLL, had a favorable prognosis. However, NK and CTL types, with the exception of ALCL, were associated with a poor prognosis. Our results indicate that anatomical site and cell lineage are useful predictors of clinical outcomes of extranodal T-cell lymphomas.