Yoshikazu Mizoguchi

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 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).

Comprehensive screening for antigens overexpressed on carcinomas via isolation of human mAbs that may be therapeutic

Although several murine mAbs that have been humanized became useful therapeutic agents against a few malignancies, therapeutic Abs are not yet available for the majority of the human cancers because of our lack of knowledge of which antigens (Ags) can become useful targets. In the present study we established a procedure for comprehensive identification of such Ags through the extensive isolation of human mAbs that may become therapeutic. Using the phage-display Ab library we isolated a large number of human mAbs that bind to the surface of tumor cells. They were individually screened by immunostaining, and clones that preferentially and strongly stained the malignant cells were chosen. The Ags recognized by those clones were isolated by immunoprecipitation and identified by MS. We isolated 2,114 mAbs with unique sequences and identified 21 distinct Ags highly expressed on several carcinomas. Of those 2,114 mAbs 356 bound specifically to one of the 21 Ags. After preparing complete IgG1 Abs the in vitro assay for Ab-dependent cell-mediated cytotoxicity (ADCC) and the in vivo assay in cancer-bearing athymic mice were performed to examine antitumor activity. The mAbs converted to IgG1 revealed effective ADCC as well as antitumor activity in vivo. Because half of the 21 Ags showed distinct tumor-specific expression pattern and the mAbs isolated showed various characteristics with strong affinity to the Ag, it is likely that some of the Ags detected will become useful targets for the corresponding carcinoma therapy and that several mAbs will become therapeutic agents.

Primary primitive neuroectodermal tumor of the kidney

Primitive neuroectodermal tumor (PNET) is a small round cell sarcoma that mainly develops in the central nervous system and soft tissues of childhood; however recently, primary occurrence of this tumor in the kidney has been reported. We experienced one case of PNET primarily arose in the kidney without metastasis. The patient was a 28‐year‐old man whose chief complaint was abdominal pain, especially on exercise. On computed tomography scan and magnetic resonance imaging, a solid lesion was found in the left kidney, and a left nephrectomy was performed based on the diagnosis of a tumor in the left kidney. The tumor was within the parenchyma of lower end of left kidney protruding into the abdominal cavity. Histologically, diffuse proliferation of primitive small round cells with rosette formation was found. Immunohistochemically, MIC2 gene product, neuron‐specific enolase and S‐100 protein were positive. No metastasis to the regional lymph nodes was found. From these observations, the tumor was diagnosed as PNET primarily arising in the left kidney. Although chromosome analysis was not performed, EWS‐FLI1 chimera gene was identified by reverse transcriptase–polymerase chain reaction on the freshly frozen specimen and fluorescence in situ hybridization on paraffin sections.

Immunohistochemical study of hepatic angiomyolipoma

An immunohistochemical study was performed on nine hepatic anglomyolipomas (AML) found in eight patients. Histologically, the tumors were fundamentally composed of the three heterogeneous tissue components of blood vessels, smooth muscle cells (SMC), and fat cells, although the proportions and distributions were quite variable from tumor to tumor and from area to area in the same tumor. Additionally, cellular pleomorphism and atypia with occasional bizarre giant cells were found in the SMC component. This histologic feature might lead to a mistaken diagnosis of malignant neoplasm, and pathologists should therefore be aware of the broad histologic spectrum of hepatic AML. However, the Immunostalning patterns were basically the same in all nine tumors. All tumor components were negative for epithelial membrane antigen (EMA) and for cytokeratin. The spindle‐shaped SMC component of the tumor was occasionally positive for vimentin, desmin and alpha‐smooth muscle actin, whereas epithelioid SMC were negative for all three. Both the epithelioid and spindle‐shaped SMC were occasionally positive for S‐100 and neuron‐specific enolase. All types of SMC in the tumor, whether spindle, epithelioid, intermediate or pleomorphic SMC, were strongly positive for HMB‐45, a melanoma‐specific monoclonal antibody. Fat cells were occasionally positive for S‐100. Endothelial cells were positive for factor Vlll‐associated antigen. Among hepatic tumors HMB‐45 reactivity is, so far as we know, found exclusively in the SMC of AML, and the HMB‐45 reactivity of a hepatic tumor is thus clearly an important piece of information in the diagnosis of AML

Hyalinizing trabecular adenoma of the thyroid: Its unusual cytoplasmic immunopositivity for MIB1

The monoclonal antibody Ki‐67 reacts with a human nuclear cell proliferation‐associated antigen that is expressed in all active parts of the cell cycle and is well established as a marker of cell proliferation. However, the Ki‐67 method requires fresh frozen material. Recently, MIB1 has been reported to give an immunohistochemical staining pattern identical to Ki‐67 on paraffin‐embedded tissue sections, frozen sections and cytological samples? This proliferation‐associated antigen is apparently localized in the nucleus. Recently, we performed immunohistochemical staining using the monoclonal MIB1 antibody upon a variety of tumors and non‐neoplastic conditions of the thyroid. Tumor cells of hyalinizing trabecular adenoma revealed an intense cytoplasmic immunopositivity for MIB1. In contrast, cytoplasmic immunostaining for MIB1 was negative in all other thyroid tumors and non‐neoplastic lesions. Because of this unusual staining pattern, we repeated the staining of all cases and found the results to be reproducible. Therefore, we believe that positive cytoplasmic immunostaining for MIB1 is a characteristic finding of hyalinizing trabecular adenoma and is useful in differentiating it from other thyroid tumors.

Morphological spectrum of cyclin D1-positive mantle cell lymphoma: study of 168 cases.

Immunostaining for cyclin D1 is essential for reliable diagnosis of mantle cell lymphoma (MCL). However, a small number of cyclin D1‐positive lymphomas other than MCL have been encountered. Our goal was to investigate the morphological spectrum of MCL as a disease entity, based on cyclin D1 overexpression. We reviewed 181 biopsy specimens obtained from 168 cases of cyclin D1‐positive MCL. Typical findings were the presence of nodular (53.9% of cases) or diffuse (46.1%) histological patterns, containing mantle zone patterns (16.8%), naked germinal centers (33.5%) and perivascular hyaline deposition (83.2%). Unusual findings of residual germinal centers with a mantle cuff (four cases) and follicular colonization (two cases) were seen. High magnification showed a monotonous proliferation of tumor cells with cytological diversity including small (3.0%), intermediate (43.1%), medium (34.1%), medium– large (13.2%) and large (6.6%) cells. Pleomorphic and blastic / blastoid variants were encountered in 9.6 and 7.2% of cases, respectively. Three cases had foci of cells of considerable size, with a moderately abundant pale cytoplasm resembling marginal zone B cells. Two cases showed an admixture of cells which appeared transformed and mimicked the histology of chronic lymphocytic leukemia / small lymphocytic leukemia. In one, neoplastic mantle zones were surrounded by sheets of mature plasma cells, resembling the plasma cell type of Castleman’s disease. An admixture of areas characteristic of MCL and of other larger cells, indicating histological progression or a composite lymphoma, were observed in seven cases. In high‐grade lesions of five cases, nuclear staining of cyclin D1 was rarely detected. In our experience, cyclin D1 expression was also found in nine lymphomas other than MCL (five plasma cell myelomas, three Hodgkin’s disease and one anaplastic large cell lymphoma). The application of cyclin D1 staining prompted us to recognize the broad morphological spectrum of MCL. MCL can be diagnosed with the application of cyclin D1 immunostaining, if careful attention is given to architectural and cytological features.

Hodgkin's disease expressing follicular dendritic cell marker CD21 without any other B-cell marker: a clinicopathologic study of nine cases.

Reed-Sternberg (RS) and Hodgkins (H) cells are considered to be the neoplastic cells in Hodgkins disease (HD). Although most data suggest their lymphoid origin, the nature of these cells still remains a subject of controversy. Recently, a number of RS cells have been found to express an antigen that is also present on follicular dendritic cells (FDCs), asserting FDCs as the possible progenitor cells of H-RS cells. This prompted us to investigate whether these CD21-positive cases had distinct clinicopathologic characteristics. In a series of 94 examined cases of HD, we identified 9 CD21-positive ones (4 of 37 cases of nodular sclerosis, 1 of 41 mixed cellularity, and 4 of 12 lymphocyte depletion HD) without any other B-cell marker on paraffin sections. The patients varied in age from 16 to 82 years (median, 50 years) and included six men and three women. They had superficial or mesenteric lymphadenopathy without hepatosplenomegaly. Peripheral blood leukocytosis was seen in three patients. The clinical course was indolent, and all patients but one achieved an initial complete response with HD-based treatment regimens, although three of them relapsed. Morphologically, two subgroups could be delineated. Six of the cases were characterized, besides by the classic RS cells, by a varying number of the cells with the distinctive walnutlike or cerebrumlike nuclei and cytologically with cytoplasmic processes. Their fine structural examination also revealed villous processes, but no desmosomes. The other three cases had multinucleated RS cells often with triangular nuclei, but not cytoplasmic processes. The percentage of CD21-positive tumor cells ranged from less than 10% to 60% among the H-RS cells. These RS cells were positive for CD30 (9 of 9), CD15 (7 of 9), CD68 (1 of 8), fascin (8 of 8), S-100 protein (1 of 7), and epithelial membrane antigen (2 of 8) on paraffin sections. Notably, of eight cases examined on frozen sections, two showed immunostaining for DRC1, CD35, R4/23, and Ki-M4p. Only CD35 was also detected in the other two cases. Genotypic investigation showed germline configuration of the T-cell receptor beta and gamma chain genes and the immunoglobulin heavy chain gene in all eight cases examined. In situ hybridization showed Epstein-Barr virus sequences in four cases, three of which were examined by the terminal region analysis and showed the Epstein-Barr virus to be monoclonal. We concluded that in a small proportion (9.6%) of HD, H-RS cells might be derived from FDCs and that they appear to represent a distinct pathologic variant based on morphologic and phenotypic traits within the framework of HD.

Sclerosing mucoepidermoid carcinoma with eosinophilia of the salivary glands

We encountered two cases of low malignant mucoepidermoid carcinoma with scanty cellular atypism which originated in the parotid or submandibular gland and was characterized by marked fibrosis and eosinophilic infiltration within tumor tissue despite the predominance of the squamous component. Here we report these two cases and provide a review of the literature. We believe that clinically these two tumors with stromal fibrosis and eosinophilic infiltration have a low malignant potential, although histological examination revealed a scanty mucus-producing epithelial component. Therefore, we consider this type of tumor as a new subtype of mucoepidermoid carcinoma. A low-malignant mucoepidermoid carcinoma with stromal fibrosis and eosinophilic infiltration, as described in these two cases, may be misdiagnosed as a highly malignant mucoepidermoid carcinoma or squamous cell carcinoma because of its histologically scanty mucus-producing epithelial component. The objective of this study was to clarify their differences and to discuss the rendering of an accurate histological diagnosis, the degree of malignancy in relation to prognosis prediction, and the choice of therapy. In addition, we propose regarding this type of tumor as a new subtype of mucoepidermoid carcinoma.