Taizan Suchi

An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma associated with haemophagocytic syndrome

Diffuse large B‐cell lymphoma with haemophagocytic syndrome (BCL‐HS) has been reported mainly in Asia and is regarded as a distinct variant of intravascular lymphoma (IVL). However, it is unclear whether all cases of BCL‐HS fall within the framework of IVL and available clinical information is limited. We analysed 25 cases with BCL‐HS, including 11 autopsied cases (median, 66 years; male–female ratio, 1·1:1). The patients presented with fever, anaemia, thrombocytopenia, hepatosplenomegaly, haemophagocytosis, bone marrow invasion, respiratory disturbance and disseminated intravascular coagulopathy, but usually lacked lymphadenopathy, mass formation, neurological abnormalities and skin lesions. The clinical course was aggressive with a median survival of 7 months. The morphological findings were uniform: large lymphoid cells infiltrated vessels and/or sinusoids of the liver, marrow, lung, kidney and other organs. They were positive for CD19, CD20, CD79a and HLA‐DR, but negative for CD10, CD23 and CD30. CD5 was positive in five out of 17 cases. Our critical review indicates that BCL‐HS is the equivalent of the Asian variant of IVL.

Clinicopathologic study of CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract.

The expression of the neural cell adhesion molecule (NCAM) (CD56, NKH-1) is a rare phenomenon in malignant lymphoma. Recently, several authors, including our group, described the clinicopathologic, phenotypic, and genotypic features of NCAM-positive tumors as a unique subgroup within a larger category of hematolymphoid malignancies. Ten cases of CD56+ angiocentric lymphoma occurring in sites other than the upper aerodigestive tract were studied for evaluating their characteristics. The disease occurred in six men and four women varying from 24 to 85 years (mean age, 53 years) who often exhibited a striking predilection for extranodal sites of involvement, such as the skin, gastrointestinal tract, and muscle, usually in the absence of peripheral lymphadenopathy. Although the cytologic appearances and immunophenotypic profile varied from case to case, these tumors often exhibited azurophilic granules, an angiocentric growth pattern, and surface CD3−, T-cell receptor (TCR) antigens−, and CD56+ phenotype without B-cell phenotype, except for a single case of CD3+, TCRα/β+, and CD56+ phenotype. Genotypic investigation exhibited germline configuration of the TCR β and γ chain genes and the immunoglobulin heavy chain gene in all five cases of surface CD3− phenotype examined, whereas the case of CD3+ phenotype showed rearrangement of TCRβ. They seem to constitute a distinct entity of the lineage spectrum spanning from natural killer (NK) cell to NK-like T cell.

Some problems on the histopathological diagnosis of non-Hodgkin's malignant lymphoma -- a proposal of a new type.

A new classification for non‐Hodgkins malignant lymphoma is proposed as the one suited for the Lymphomas in Japan, which is to provide a new subtype “pleomorphic” for those more or less rapid‐growing lymphomas of peripheral T‐cell nature, along with another subtype lymphoblastic, after Nathwani et al. for those of central T‐cell nature. The proposal is based on the result of the investigation by the Study Group for Histopathological Diagnosis on Malignant Lymphoma that (1) the presence of a significant number of T‐cell lymphomas with peculiar “pleomorphism” is responsible for the very low reproducibility rate of histopathological diagnosis on the diffuse, mixed L&H type of Rappaport classification, and (2) the relative incidence of lymphoms of peripheral T‐cell nature including the so‐called adult T‐cell leukemia is much higher in Japan than in the Western countries.

Malignant histiocytosis‐like B‐cell lymphoma, a distinct pathologic variant of intravascular lymphomatosis: a report of five cases and review of the literature

Malignant histiocytosis (MH)‐like B‐cell lymphoma (BCL) is a neoplastic proliferation of large B cells clinically characterized by fever, hepatosplenomegaly, haemophagocytosis and abnormal laboratory data, without lymphadenopathy or skin lesions. Interestingly, most cases have been reported in Asian patients, and it is unclear whether MH‐like BCL is biologically distinct from conventional large B‐cell lymphomas. We report five Japanese patients with MH‐like BCL. Biopsied specimens of bone marrow, liver and/or spleen showed infiltration of neoplastic B cells accompanied by haemophagocytosing histiocytes. Lymphoma cells were positive for CD19, CD20 and HLA‐DR surface antigens, and negative for CD5 and CD10. In four cases elevated serum levels of interleukin (IL)‐6 and the soluble IL‐2 receptor isoform were noted, but not IL‐1β, IL‐2 or tumour necrosis factor‐α. Autopsies of two cases were pathologically diagnosed as intravascular lymphomatosis (IVL). Based on these observations, the current and nine previous cases reported as MH‐like BCL in Japan were re‐evaluated. They appear to form a peculiar variant of IVL, characterized by bone marrow involvement at presentation, haemophagocytic syndrome, and a rapidly aggressive clinical course, but rarely neurological complications or skin lesions. This variant may merit separate consideration because of the problems posed in the initial diagnosis and therapeutic approaches.

Clinicopathologic study of large cell anaplastic lymphoma (ki‐1‐positive large cell lymphoma) among the japanese

The clinical, prognostic, phenotypic, and genotypic findings of 30 patients with large cell anaplastic lymphoma (Ki‐1‐positive large cell lymphoma) were analyzed. There were 13 male and 17 female patients (male‐female ratio, 0.8) whose ages ranged from 3 to 81 years of age (mean, 28 years of age; 67% of the patients younger than 30 years of age). The 5‐year survival rate was 52%; this was better than that of other types of high‐grade peripheral T‐cell lymphoma. Histologic examination showed distinctive morphologic features such as tumor cell pleomorphism, sinus infiltration, fibrosis, partial lymph node involvement, sparing of B‐cell regions, and occasional plasma cell infiltrates. Eighty percent of the cases were of T‐cell phenotype, and others expressed neither B‐cell nor T‐cell markers. The tumors were frequently positive for a histocompatibility antigen (HLA‐DR), CD25 (the interleukin‐2 receptor), and epithelial membrane antigen. Rearrangements of the T‐cell receptor beta gene were observed in nine of 13 cases (69%). These findings indicated that many of the tumors had the phenotype and genotype of activated T‐cells. This study also showed that large cell anaplastic lymphoma has a survival figure intermediate between Hodgkins disease and low‐grade peripheral T‐cell lymphoma.

Clinicopathologic study of PRAD1/cyclin D1 overexpressing lymphoma with special reference to mantle cell lymphoma : A distinct molecular pathologic entity

Mantle cell lymphomas (MCLs) are frequently associated with the overexpression of PRAD1/cyclin D1, activated by 11q13 translocation and its molecular counterpart BCL-1 gene rearrangement. We recently described the correlation of positive nuclear staining using monoclonal antibody against a PRAD1/cyclin D1 product with mRNA overexpression in MCLs. In the present study, we immunohistochemically investigated the PRAD1/cyclin D1 protein in a large series of 334 lymphoproliferative disorders, including 39 cases of MCLs on paraffin sections. Based on the cyclin D1 positivity, CD5 expression, and the morphologic features of the tumor tissue, four groups of MCL-related lesions were identified among the B-cell lymphomas examined: 36 cases with cyclin D1 overexpression, 35 (95%) of which exhibited CD5-positivity and MCL-morphology (Group 1); four cases of lymphomas with MCL morphology and CD5 expression but lacking cyclin D1 overexpression (Group II); four cases of lymphomas without cyclin D1 overexpression and surface CD5 but that fall within the morphologic boundaries of MCLs (Group III); and 11 cases of CD5-positive diffuse large cell lymphomas without cyclin D1 overexpression (Group IV). The Group I cases demonstrated quite homogeneous clinicopathologic features identical to those of MCLs. This group showed a poor prognosis (11% had 5-year survival), which is highly contrasted with that of Group II (100%). Although the four groups of MCL-related lesions sometimes overlapped in their histologic or phenotypic spectrums, each appeared to show distinct clinicopathologic and prognostic profiles. Our study provides a basis for further clarification of the nature of the neoplasms of Groups II, III, and IV. Moreover, this comprehensive study may indicate that the overexpression of PRAD1/cyclin D1 is biologically essential to defining MCLs.

Argyrophil cell carcinoma of the uterine cervix with ectopic production of acth, β-MSH, serotonin, histamine, and amylase

The case of a 38‐year‐old female with primary argyrophil cell carcinoma of the uterine cervix is reported. Two years after operation the patient developed widespread metastases with typical Cushings syndrome. Microscopically, the tumor consisted of solid anaplastic cells, adenocarcinoma, and squamous cells. The plasma levels of ACTH and cortisol were elevated. Many cells of both the primary and metastatic tumors showed argyrophilia. Almost all the cells of the metastases contained numerous round secretory granules measuring about 117μm in diameter. Small rod‐shaped or larger round secretory granules, measuring 250 and 430 μm respectively, were also found in a few of these cells. The tumors in the right lung, pancreas, and kidney contained high levels of ACTH, β‐MSH, serotonin, histamine, and amylase. This is the first report of ectopic production of these five substances from argyrophil cell caricnoma of the uterine cervix.

Clinicopathologic study of nasal T/NK‐cell lymphoma among the Japanese

A high prevalence of nasal lymphoma expressing a T‐ or natural killer (NK)‐cell phenotype (NTCL) with frequent association of Epsteln‐Barr virus (EBV) has been indicated in Asians. To Characterize NTCL among the Japanese, the clinlcopathdogic features of 32 cases were evaluated and the casses worn also analyzed for EBV‐RNA using an ISH method. Morphologically, 31 cases were Identified by atypical pleomorphic lymphoid infiltrates with polymorphous, anglcentric, and necrotic features. Their lymphoma cells ranged in size from small to large and were mixed in varying proportion from case to case. The other one case showed a monomorphic ‘blastic’ appearance. EBV‐encoded small RNA (EBER) was detected in the neoplastic cells of 27 of the 32 cases examined. In the five EBV‐negative cases, one was the ‘blastic’ type. Clonal T‐cell receptor gene rearrangement was detected in none of seven cases examined. The patients had a median follow‐up of 9 months (range, 1 month to 14 years and 11 months). The Kaplan‐Meler estimate of overall survival was 49% at 5 years, correlating with clinical stage. These data support the concept that most cases of NTCL are identified as tumors with T/NK‐cell characteristics and EBV association, distincity different from other peripheral T‐cell lymphomas. Furthermore, the one case of an EBV‐negative ‘blastic’ variant appears not to fit well Into the pleomorphic category but more closely resembles the pathologic features of extranasal angiocentric lymphoma with lymphoblastold appearance. This study also showed no clear difference in clinical aspects other than the original site or in prognosis, between NTCL and extranasal angiocentric lymphomas despite the higher incidence of EBV association and the tendency for that peculiar anatomical site to be restricted to the former group.

Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients.

The expression of cytotoxic granule-associated proteins has been reported in some T-cell or natural killer (NK)-cell lymphomas of mostly extranodal origin, but rarely of nodal origin except for anaplastic large cell lymphoma (ALCL) and Hodgkins disease (HD). This study analyzed 66 nodal lymphomas expressing T-cell intracellular antigen-1 (TIA-1) and/or granzyme B to characterize the clinicopathologic spectrum of these neoplasms. Four main groups could be delineated. The first group consisted of p80/anaplastic lymphoma kinase (ALK)-positive ALCL (n = 35). The patients were 2 to 62 years of age (median age, 16 years), and the lymphomas pursued a relatively indolent clinical course. The tumors were phenotypically of either T- or null-cell type with constant expression of CD30, epithelial membrane antigen (EMA), and p80/ALK, but not CD15 or BCL2. None harbored Epstein-Barr virus (EBV). The second group consisted of peripheral T/NK-cell lymphoma, the nodal high-grade cytotoxic type (n = 13). The patients were 29 to 72 years in age (median age, 55 years), and the tumors pursued an aggressive clinical course. The tumors often showed pleomorphic, anaplastic, or centroblastoid morphology, and were featured by either EBV association or CD56 expression. The third group consisted of peripheral T-cell lymphoma, of the nodal low-grade cytotoxic type (n = 8). The patients, three men and five women, were 31 to 75 years old (median age, 61 years). Notably, six of them exhibited lymphoepithelioid (Lennerts) lymphoma. The fourth group consisted of cytotoxic Hodgkins-like ALCL/HD (n = 10), included seven cases of Hodgkins-like ALCL and three cases of HD, and was characterized by the presence of Reed-Sternberg cells and often the CD15+ phenotype. The patients were all men except for one woman, and they ranged in age from 24 to 84 years (median age, 62 years). The link among these four groups was reinforced by the presence of a highly characteristic large cell with horseshoelike or reniform nuclei-the frequent expression of CD30 and EMA-and the often lack of T-cell receptor-alphabeta. In this series, the expression of p80/ALK and CD56 was also associated with favorable and poor prognoses respectively (p<0.001, log-rank test).

A clinicopathologic study of node‐based, low‐grade, peripheral T‐cell lymphoma. Angioimmunoblastic lymphoma, T‐zone lymphoma, and lymphoepithelioid lymphoma

Postthymic (peripheral) T‐cell malignancy shows marked diversity in histopathologic appearances as well as in clinical and prognostic aspects. Histologic findings and clinical behavior of 110 cases of the three specific types of low‐grade, peripheral T‐cell lymphomas, i.e., lymphoepithelioid (LeL), angioimmunoblastic (AILD), and T‐zone (TzL) lymphomas, were studied. There were 74 men and 36 women (age range, 24 to 90 years; median, 58). Histologic study of LeL, AILD, and TzL showed prominent reactive features which are distinct from those of high‐grade, T‐cell lymphomas (pleomorphic/immunoblastic types). Corresponding to the differences in the histologic pictures of each type, there were differences in the clinical pictures and prognosis. Hypergammaglobulinemia (> 4 g/dl) was more common in AILD than in the others. However, these three types exhibited a widely variegated, sometimes overlapping spectrum of histologic appearances, and it was extremely difficult to distinguish one from the other on several occasions. The same was true of their clinical and laboratory findings, and they had a relatively favorable prognosis as compared with pleomorphic/immunoblastic lymphomas. Although the conventional phenotypic analysis showed the prominent mixture of helper/inducer and cytotoxic/suppressor T‐cells with a varying degree of B‐cells and histiocytes, the double immunohistochemical study revealed that the neoplastic cells consisted predominantly of helper/inducer cells. Furthermore, five cases (5%) showed the morphologic transition among the three types or development into pleomorphic/immunoblastic lymphoma. They seemed to constitute a comprehensive and yet distinct group of T‐cell lymphomas. Based on morphologic findings and clinical data, the authors demonstrated the distinct character of the node‐based, low‐grade, T‐cell lymphomas and also the relationship among the three types in this group. The results of phenotypic and genotypic analyses also support the concept proposed here.