Crystal-Storing Histiocytosis: Report of a Rare Case Presenting With Pathological Fracture of Femur. Is There More to the Entity?

Crystal-storing histiocytosis (CSH) is a rare histiocytic lesion, most often described in association with lymphoid malignancies, especially plasma cell myeloma or lymphomas associated with monoclonal gammopathy. A few cases have also been described in patients without an underlying lymphoid/plasmacytic neoplasm. The histiocytes are characterized by intralysosomal accumulation of crystals composed of whole or part of the immunoglobulin molecule. The pathobiology is largely unclear. It is a rare phenomenon and the available literature is restricted to case reports and a few case series. We present a case of a 70-year-old gentleman who presented with pathological fracture of left neck of femur secondary to CSH, a presentation so far unreported in the literature. Because of associated clinical features, a plasma cell dyscrasia was suspected and the workup, including bone marrow biopsy, yielded a diagnosis of plasma cell myeloma. Histological examination of the excised femoral head showed near complete replacement of the marrow spaces with sheets of histocytes rich in intracytoplasmic crystals and only occasional plasma cells. The peculiar presentation with pathological fracture of femur in the index case and predominant tumefactive lesions in the cases in the literature might suggest a possible neoplastic origin of this lesion.

Crystal storing histiocytosis of the skin associated with multiple myeloma.

BACKGROUND: Crystal storing histiocytosis (CSH) imitating rhabdomyoma is a very rare disease entity involving different tissues. The skin is involved in extremely rare cases. OBJECTIVES: To describe the clinical and histopathological characteristics in a patient with unusually extensive skin involvement. OBSERVATIONS: A 62-year-old woman presented with a large red infiltrated verrucosus lesion on the anterior aspect of the chest and on the neck. The skin biopsy revealed histiocytes throughout the whole dermis containing thin crystalloid structures in the cytoplasm. Upon histopathological examination, crystal-storing histiocytosis was diagnosed and consequently a hematological examination revealed multiple myeloma IgG Kappa. Skin involvement by CSH proceeded the diagnosis of multiple myeloma by 4 years. CONCLUSIONS: Phagocytosis of crystals of immunoglobulins by histiocytes (crystals storing histiocytosis) is a rare symptom associated most often with lymphoproliferative disease. The clinical picture is not characteristic, in the histopathologic picture it is striking similarity to rhabdomyoma. The skin involvement by crystal storing histiocytosis can be the first symptom of malignant lymphoma that can proceed the hematological malignancy by years.

Plasma vascular endothelial growth factor (VEGF) measured in seventy dogs with spontaneously occurring tumours.

BACKGROUND: Vascular endothelial growth factor (VEGF) acts specifically on endothelial cells mediating tumour neovascularisation and initiating tumour growth and metastasis. In humans, high VEGF levels are correlated with poorer prognosis but in dogs minimal information on plasma VEGF is available. Therefore, we analysed plasma VEGF in a variety of spontaneous canine tumours. MATERIALS AND METHODS: Plasma from seventy dogs with various spontaneous tumours was taken prior to radiation therapy. A human VEGF ELISA was used for analysis. RESULTS: Mean plasma VEGF was 7.2+/-7.8 pg/ml. Mean plasma VEGF level varied among different tumour types with the highest level in oral melanomas (12.4 pg/ml). In patients with sarcomas of soft tissue or bone origin, plasma VEGF levels increased significantly with decreasing haemoglobin concentration (p =0.013). CONCLUSION: Canine plasma VEGF levels depend on tumour histology, with higher levels found in more aggressive tumours. The negative correlation between plasma VEGF and haemoglobin (hb) is most probably due to tissue hypoxia seen in anaemic animals.

Flow cytometric evaluation of hemophagocytic disorders in canine.

BACKGROUND: Hemophagocytic macrophages in canine bone marrow are observed in malignant histiocytosis as well as benign hemophagocytic histiocytosis. Cytomorphologic evaluation alone may be inadequate to consistently differentiate between benign and malignant forms of hemophagocytic disorders. OBJECTIVE: The purpose of this study was to evaluate the ability of flow cytometry and immunophenotyping to differentiate between benign and malignant types of hemophagocytic disorders in dogs. METHODS: Blood smears and bone marrow differential cell counts were evaluated for 10 dogs with hemophagocytic disorders. Bone marrow samples were labeled with monoclonal antibodies to CD18, MCH class-II, Thy-1, CD14, CD3, and CD21. Using flow cytometry, forward-angle versus side-angle light scatter plots were analyzed and immunophenotypes were determined. RESULTS: Scatter plots from 3 dogs with a necropsy diagnosis of malignant histiocytosis revealed 2 atypical cell clusters. One cluster contained cells of similar size or larger than immature myeloid cells and metamyelocytes. Cells in the other cluster were highly granular, with granularity similar to or greater than that of metamyelocytes. In bone marrow from dogs with malignant histiocytosis that was labeled with anti-CD14 antibody, macrophages represented 29-48% of nucleated cells. Seven dogs had a clinical or histopathologic diagnosis of benign hemophagocytic syndrome. Three of the dogs had normal cell distribution in scatter plots. Two dogs had 2 abnormal cell clusters: 1 within the immature myeloid and metamyelocyte gates and the other with granularity similar to or greater than that of metamyelocytes. The remaining 2 dogs had an atypical cell population, mostly within the immature myeloid gate. For dogs with benign hemophagocytic syndromes, 6-17% of cells in the bone marrow were CD14 positive. CONCLUSIONS: The cellular distribution in scatter plots and the total number of macrophages in bone marrow may be useful in differentiating malignant histiocytosis from benign hemophagocytic syndromes in dogs.

Evidence for a hybrid macrophage phenotype in erythrophagocytic histiocytosis.

PURPOSE: The phenotype of the proliferating cells in two patients with erythrophagocytic histiocytosis is described. These 6- and 18-month-old female patients presented with fever, anemia, hepatosplenomegaly, and lymphadenopathy. MATERIALS AND METHODS: Clinical histories were reviewed, and pathological specimens of both patients were studied by histology, and electron microscopy/immunohistochemistry using antibodies against macrophage and Langerhans cell (LC) antigens. RESULTS: Histology revealed prominent erythrophagocytosis of proliferating histiocytes. By immunohistochemistry, conventional macrophage (HAM-56, alpha 1-antitrypsin, alpha 1-antichymotrypsin, lisozyme, CD68, and alpha-subunit of S-100 protein) and LC (CD1a and S-100 protein) markers were positive, as well as double labeling for CD1a and alpha 1-antichymotrypsin, in a majority of proliferating cells. Ultrastructural examination revealed Birbeck granules and prominent phagolysosomes frequently in the same cell. CONCLUSIONS: The hybrid ultrastructural and immunohistochemical phenotype between phagocytic macrophage and LC of proliferating histiocytes supports the common origin of these different histiocyte subtypes. This unusual phenotype might be the expression of the proliferating (hybrid) precursor or be the effect of unknown stimuli. Additional cases of childhood erythrophagocytic histiocytosis should be studied with immunophenotyping and ultrastructure to determine whether the hybrid phenotype represents a specific entity or an epiphenomenon.

An unusual histiocytic disorder responding to cyclosporine therapy: a case report.

PURPOSE: To describe the clinical and pathologic presentation and course of a 7-week-old girl with anemia, thrombocytopenia, and organomegaly who was found to have a histiocytic disorder distinct from previously reported cases. METHODS: Bone marrow specimens were studied with conventional methods. A liver biopsy specimen was evaluated by routine and immunohistochemical methods and electron microscopy. RESULTS: The patient was found to have a unique histiocytic disorder in which lesional cells displayed an atypical phenotype. Cyclosporine therapy was associated with a prompt, complete, and apparently permanent resolution of disease. CONCLUSION: This case appears to represent an atypical histiocytic disorder with unique clinical and pathologic features. The disorder resolved after the initiation of cyclosporine therapy.

Histiocytic sarcoma of the spleen associated with hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia as a possibly unique clinical entity--report of three cases.

We report three patients with histiocytic sarcoma of the spleen associated with severe hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia. After the clinical diagnosis of splenic tumor of unknown origin was made, all three patients underwent splenectomy. The histiocytic origin of the tumor was confirmed histopathologically and immunohistochemically using a panel of antibodies. In contrast to malignant histiocytosis (MH), which typically reveals severe generalized clinical manifestations and a rapidly fatal course caused by the disseminated proliferation of neoplastic histiocytes, these patients were asymptomatic or showed only mild clinical symptoms for a long period of time until the recurrence was detected by which time the tumor cells had already spread to other organs. All three cases were characteristically associated with hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia, which returned to normal after splenectomy. Splenic histiocytic sarcoma with the features described here may represent a unique clinical entity, distinct from MH.

A case of pleomorphic T-cell lymphoma with a high content of reactive histiocytes presented with hypereosinophilia.

A case of peripheral T-cell lymphoma classified, according to the updated Kiel classification, as a large pleomorphic T-cell lymphoma with a high content of reactive histiocytes and blood hypereosinophilia is reported. Light microscopic examination revealed a diffuse effacement of the lymph node structure by large pleomorphic lymphoma cells mixed with eosinophils and many histiocytes, some of them presenting discrete features of hemophagocytosis. The neoplastic cells were CD3, CD5, CD8 and HLA-DR positive but failed to show CD30 antigen. DNA molecular analysis displayed simultaneous rearrangements of the genes coding for the delta chain of the T-cell receptor and for the Ig heavy chain. Increased serum levels of angiotensin converting enzyme and ferritin were found and probably induced by the reactive histiocytes. Immunoassays (ELISA) with antibodies directed against some cytokines and against the Tac peptide (sIL-2R) were performed. They demonstrated high serum levels of sIL-2R and a slight increase in GM-CSF, but neither IL-5 nor IL-3. The association of blood hypereosinophilia and histiocytic hyperplasia with a peripheral T-cell lymphoma is discussed.

[The morphofunctional characteristics of the mononuclear phagocytes in the concentrated venous blood leukocytes of patients with histiocytosis]. / Morfofunktsional'naia kharakteristika mononuklearnykh fagotsitov leikokontsentrata venoznoi krovi bol'nykh gistiotsitozami.

Morphological and cytochemical examinations of mononuclear phagocytes (MP) from venous blood leukoconcentrate were carried out in 25 patients with chronic monocytic leukemia, 7 patients with malignant histiocytosis, 3 patients with Langerhans' cell histiocytosis and 26 patients with reactive proliferations of the cells belonging to MP system associated with autoaggressive, infectious diseases or tumors. Morphofunctional features of MP from the patients with tumor and reactive histiocytosis may serve additional criteria in differential diagnosis of the diseases in which pathological process runs with participation of MP system cells.

[Diagnostic value of serum iron metabolism parameters in patients with malignant and reactive histiocytosis]. / Diagnosticheskoe znachenie syvorotochnykh pokazatelei obmena zheleza u bol'nykh zlokachestvennym i reaktivnymi gistiotsitozami.

Difficulties in the morphological diagnosis of the diseases due to proliferation of mononuclear phagocyte system (MPS) cells have stimulated the search for additional differential-diagnostic criteria. The investigations were conducted in 10 malignant histiocytosis, 16 histiocytosis-X, and 34 reactive histiocytosis patients. The assay of serum ferritin was shown to have high informative value for clinical practice. The presence of extremely high hyperferritinemia in patients with morphologically verified histiocytic proliferations has evidenced a malignant character of the process.

Phenytoin-induced hemocytophagic histiocytosis indistinguishable from malignant histiocytosis.

We have reported a case of phenytoin-induced hemocytophagic histiocytosis indistinguishable on clinical and histopathologic grounds from malignant histiocytosis. We emphasize the need to investigate for microbiologic causes and drug ingestion, even if the diagnosis of malignant histiocytosis is plausible. We think that reactive and malignant histiocytosis are not really two distinct entities with different etiologies, but a continuum of host responses to several insults with different degrees of aggressiveness depending on the host immune status.

Spontaneous NBT reduction by monocytes as a marker of disease activity in children with histiocytosis.

In an attempt to define a biological marker of monocyte hyperactivation in the course of infantile histiocytosis, the spontaneous nitroblue tetrazolium (NBT) reduction assay was applied to monocytes from 13 children with Langerhans cell histiocytosis (LCH), familial haemophagocytic lymphohistiocytosis (FHL), juvenile xanthogranuloma or malignant histiocytosis. Significant increase in NBT reduction was observed in the patients with both active LCH and FHL in comparison with control subjects, who were either healthy or affected by different conditions. A close relationship between spontaneous reduction rate and clinical condition of the patients was evident in patients tested at diagnosis, during remission and during the course of disease reactivation. Interleukin-1 (IL-1) production by monocytes was also evaluated: the patients with LCH and FHL displayed a significant increase in in vitro IL-1 production by lipopolysaccharide-stimulated monocytes. In our experience the spontaneous NBT reduction assay was a sensitive, quite specific, low-cost and reproducible test for the evaluation of children with histiocytosis. Useful information may be obtained at diagnosis but also during the clinical course of disease by using this marker of monocyte spontaneous activation.