Histiocyte proliferating diseases that we often experience in the dermatologic clinics include histiocytosis-X particularly Letterer-Siwe disease, non-X histiocytosis such as xanthogranuloma, multicentric reticulohistiocytosis, xanthoma disseminatum, and verruciform xanthoma, and fibro-histiocytic tumors represented by dermatofibroma, dermatofibrosarcoma protuberans, and malignant fibrous histiocytoma, as well as malignant histiocytosis. The other diseases, for example, congenital self-healing reticulohistiocytosis and generalized eruptive histiocytoma may be observed in very rare instance. We investigated cell types by using immunohistochemical markers for the prolifearting histiocytic cells on the paraffin sections from 40 cases. A clear result was obtained that S-100 positive cells belonging to T-zone histiocyte lineage are proliferating in histiocytosis-X, while lysozyme positive mononuclear phagocytes are the major cell type in malignant histiocytosis. Although in the rests of the diseases cells are positively reacted for α₁-antichymotrypsin, α₁-antitrypsin and vimentin, differentiation of the diseases by such immunomarkers was not enabled. There was a tendency that non-X histiocytosis represented by xanthogranuloma showed stronger reactivity for α₁-antichymotrypsin and α₁-antitrypsin, whereas the cells in fibro-histiocytic tumors are rather strongly positive for vimentin. Further studies are required for the proliferating cells positive for α₁-antichymotrypsin, α₁-antitrypsin and vimentin.

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Twenty one patients were diagnosed as “malignant histiocytosis (MH)” according to clinical mainifestations, for example severe inflamatory reactions, progressive pancytopenia, huge hepatosplanomegaly, and the presence of hemohagocytic cells in bone marrow. In comparison with large anaplastic cell lymphoma, the clinical features of “MH” patients were characterized by the systemic symptoms and rapid clinical course. Cells with histiocytic appearance in these patients were classified in to 3 subgroups on the basis of the morphologic atypism; blastic, intermediate, or mature type. Histiocytic cells from 17 out of 21 patients belonged to the blastic or intermediate type, suggesting the neoplastic nature. Hemophagocytic cells without remarkable atypism, which were observed in bone marrow of the most patients, showed the mature type appearance, and were recognized as activated histiocytes. In 6 “MH” patients with neoplastic cells, 3 patients were recognized as histiocytic disorder, 2 as T-cell one, and one as B-cell one according to the immunophenotype and immunogenotype.
Interestingly, one of the T-cell type showed phenotype of CD2+CD3-CD4-CD8-EAG+with large granular lymphocyte (LGL) appearance, and another CD2+CD3+CD4-CD8-EAG+LGL also increased in the terminal phase of a “MH” patient with B-cell neoplasm. In addition, either neoplastic or benign LGL disorders revealed “MH” like systemic symptoms in occasion. Thus, LGL/Tγ cells as well as the hemophagocytic cells are thought to play a main role for the hematopathologic and clinical manifestation of “MH” in reticuloendotherial system, especially in spleen, and hyper-production of cytokines by thesee cells may closely related the systemic and unreguratable symptoms, tentatively named “cytokine-crisis”

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Malignant histiocytosis (MH, histiocytic medullary reticulosis, HMR) in children demonstrates following characteristics; (1) Clinical symptoms are mostly due to hypercytokinemia elicited by proliferating T cells and activated monocytes/macrophages, (2) The bone marrow smear is helpful in the diagnosis revealing proliferation of monoblastoid (or immunoblastoid) cells and monocytes/macrophages including hemophagocytes, (3) No cohesive lesions in the involved lymph nodes or spleen, (4) As therapeutic modality anti-neoplastic agents are indispensable, (5) Patients who become refractory to such treatment suffer multiple organ failure and take fatal outcomes, (6) Viral infection may play some roles in the pathogenesis. Our clinical studies on 20 patients indicated that MH (HMR) consists mostly of aberrant T cell proliferative disorders and hyperferritinemia, high serum phenylalanine-tyrosine ratio and hypercytokinemia (elevated levels of serum interferon-gamma, cytotoxic factor and soluble interleukin-2 receptor) are useful indicators reflecting disease activity.

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Recent advances in immunology and molecular biology revealed that majority of cases previously defined as true histiocytic neoplasias proved to be T-and B-cell lymphomas. We presented here several examples: Tr-lymphoma, malignant hisiocytosis-like B-cell lymphoma malignant histiocytosis presenting as lethal midline granuloma (MH-LMG). The MH-LMG is considered now to be a proliferation of natural killer cells by several investigators.
We reviewed 1, 766 cases with malignant lymphoma and related diseases diagnosed at 17 hospitals situated in Osaka and Hyogo prefectures. On purely morphological grounds, thirty-five cases were selected as candidates of true histiocytic tumor, of these enzyme and immunohistochemical procedures were made on 23 cases. The results showed that 12 cases (52%) were of B-cell type, three cases (13%) T cell type, six cases (26%) true histiocytic type and two cases null cell type. Therefore frequency of cases with true histiocytic neoplasias among cases with malignant lymphoma and related conditions in Japan may be 0.5%.

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An autopsy case of Hermansky-Pudlak syndrome (HPS) was reported. In Japan, up till now, more than 30 patients with this disease have been described in the literature, in which the autopsy studies ware rare.
A 39 year-old male was admitted of the hospital, because of cough and dyspnea on exertion. The family history revealed consaguineous marriage of his parents. He was albino and had often experienced the prolongation of epistaxis since his high school days. On admission, chest X-rays revealed bilateral pneumothorax and diffuse reticulonodular shadows. At sewing operation for pneumothorax, lung biopsy was performed, demonstrating pulmonary fibrosis and deposits of brownish granular materials in alveolar epithelia and macrophages. Lumi-aggregometer represented a decrease of secondary platelet aggregation and an absence of ATP release. From these results, the diagnosis of HPS associated with pulmonary fibrosis was settled. In spite of steroid therapy, he was died of pleural hemorrhage 9 days after operation. Autopsy revealed accumulation of brownish granular materials in the epithelial cells of renal tubules, alveolar macrophages, and in the cells of reticuloendothelial tissues, particularly in the bone marrow, spleen, and liver. The granular deposits were confirmed histochemically to be a ceroid pigment and ultrastructurally to consist of membrane-bound, osmophilic amorphous inclusions.
From the clinical manifestaions and pathological findings, this case was considered to be a hereditary generalized ceroid storage disease associated with pulmonary fibrosis and these lesions were suggested to result from a lysosomal dysfunction of macrophages in tissues.

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Four cases of familial hemophagocytic lymphohistiocytosis(FHL) occurring in a Japanese family are reported. They presented with typical fever, hepatosplenomegaly, and convulsions in the first year of their lives. These children were products of unconsanguineous marriage, and all children in that family were affected by FHL. Family history was otherwise unremarkable. Pertinent laboratory findings included pancytopenia, liver dysfunction and hypofibrinogenemia in all four cases. Hypertriglyceridemia was recorded in the fourth child. Clinical course was fulminant in all four cases. They died between 30 and 78 days after the onset of the disease. Autopsy revealed maked hepatosplenomegaly, marked atrophy of systemic lymphoid organs, and varaible degrees of lymphohistiocytic infiltration in many internal viscera. The infiltralion was noted in almost every organ, but was most prominent in spleen, bone marrow, and central nervous system. Many of these histiocytes showed variable degrees of hemophagocytosis. Immunohistochemical studies of proliferating histiocytes have shown following results: Leu M1(+), Leu 4(-), Leu 8(-), HLA-DR(+), Leu-M5(+), S-100 protein (-), α-1-antichymo-trypsin (+), lysozyme (+), and epithelial membrane antigen (EMA) (-). These data indicate that proliferating histiocytes are carrying markers similar to those of sinus histiocytes in reactive lymph nodes, and that they do not carry markers of T-zone histiocytes. Lack of cellular atypia as well as negative staining patterns for EMA suggest benign nature of these histiocytes. However, a possibility of malignancy cannot be ruled out with certainty, as these histiocytes infiltrated and destroyed the parenchyma of brain in all four cases.

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Follicular dendritic cell (FDC) is an unique cell type locating in normal or reactive lymph follicle and forming a reticular framework by their dendritic cytoplasmic processes. FDC has a special ability to capture and retain antigens in the form of immune complexes on their surface and it is believed that it may play important roles in immune response. Recent papers have indicated that FDCs are also present in the neoplastic follicles of follicular lymphomas. Their features, however, are still unclear. In the present study, the immunohistochemical and electron microscopic examinations of FDCs in the neoplastic follicles of 11 cases of follicular lymphoma were performed to elucidate their functional significance in this kind of neoplasia. These results were also compared with FDCs in the reactive (non-neoplastic) follicles and the stromal cells in diffuse follicular center cell lymphomas including the cases which were diagnosed as follicular lymphoma previously or pseudo-nodular lymphoblastic lymphoma.
The findings obtained from this study are summarised as following: 1) FDCs in follicular lymphoma revealed almost the same ultrastructual features and antigenic phenotypes as those in reactive follicle, 2) some of them appeared to have the immune complex trapping ability, 3) DRC-1+stromal cells were present focally or vestigially in diffuse lymphoma but no distinct immune complex trapping ability was defined on these cells, even in the case developing from follicular lymphoma, and 4) no DRC-1+ cells were detected in the pseudonodular lymphoblastic lymphoma. These findings suggested that the presence of FDC or related cells might be related to B-cell growth and functional FDC might be changing the form and functional properties during the progression from follicular lymphoma to diffuse lymphoma.

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