Delineation of patterns of bone marrow mast cell infiltration in systemic mastocytosis: value of CD25, correlation with subvariants of the disease, and separation from mast cell hyperplasia

In most cases, the diagnosis of systemic mastocytosis (SM) is based on histomorphologic evaluation of the bone marrow. We analyzed mast cell (MC) infiltration patterns in 57 cases of SM and 31 cases of mast cell hyperplasia (MCH). Tryptase immunohistochemical analysis was used for MC detection and CD25 to distinguish neoplastic from normal MCs. The following infiltration patterns were found: I, diffuse interstitial; II, focal, dense; III, focal, dense with an additional diffuse component, located preferentially around focal infiltrates; IV, focal, dense with an additional diffuse component evenly distributed throughout; and V, diffuse, dense. In 29 cases of MCH, MCs formed the type I pattern. The majority of SM cases exhibited patterns II to V; type IV was the most frequent (n = 36). Type V was seen in 3 cases of MC leukemia and 1 case of smoldering SM. In 1 case of SM, type I infiltration was found; the SM diagnosis was based on 3 minor SM criteria. Our data show that the infiltration pattern in SM correlates with the disease subtype and should be recognized as an important aspect in the histomorphologic evaluation of the bone marrow.     

SYSTEMIC MASTOCYTOSIS WITHOUT CUTANEOUS INVOLVEMENT

An autopsy case of systemic mastocytosis without cutaneous involvement in a 76-year-old woman was described. The patient presented with general malaise, chest and epigastric discomfort, flushing of the face and progressive hepatosplenomegaly, and she terminated in hemorrhagic complications of DIC within 2 months. There was neither rash nor urticaria pigmentosa recognizable in the entire course. The diagnosis was made by the histologic identification of abnormal aggregates of mast cells in a bone marrow aspirate. These mast cell granules were chloroacetate esterase-positive, peroxidase-negative, and electronmicroscopically they were composed of fine granular materials containing variable numbers of lamellar structures. At autopsy, diffuse infiltration of the mast cells was found in the liver, spleen, bone marrow, lymph nodes, lungs, kidneys, stomach, and adrenal glands.     

The faces of mast cell disease: bone marrow infiltrates in 3 patients with systemic mastocytosis

The clinical spectrum of mast cell disease ranges from relatively innocuous and histologically subtle urticarial skin lesions to an aggressive and fatal leukemic form of mast cell proliferation. Not surprisingly, mast cell infiltrates may show significant microscopic heterogeneity, particularly in the bone marrow, the most common site of involvement in systemic mastocytosis (SM). Herein, 3 cases are presented to illustrate the clinical and morphologic heterogeneity of mast cell disease: the first patient, with long standing urticaria pigmentosa, developed anemia and thrombocytopenia; the second patient presented with a pathologic fracture; and the third patient was suspected to have refractory anemia. Upon bone marrow examination, all 3 patients showed mast cell infiltration with distinct morphologic features and all met the WHO criteria for aggressive systemic mastocytosis. Histochemical methods continue to play a role in the identification of mast cells, with some limitations depending on the degree of differentiation of the mast cells and tissue processing methods. Immunohistochemistry has contributed to the identification of mast cells. Coexpression of CD117 and CD25, as well as expression of the more specific immunohistochemical marker tryptase, is seen in systemic SM. The latter may also be employed as a serum marker in the diagnosis and follow-up of patients with SM. The mast cells, in the majority adults with SM, have somatic point mutations of KIT.     

Systemic mastocytosis without cutaneous involvement

An autopsy case of systemic mastocytosis without cutaneous involvement in a 76-year-old woman was described. The patient presented with general malaise, chest and epigastric discomfort, flushing of the face and progressive hepatosplenomegaly, and she terminated in hemorrhagic complications of DIC within 2 months. There was neither rash nor urticaria pigmentosa recognizable in the entire course. The diagnosis was made by the histologic identification of abnormal aggregates of mast cells in a bone marrow aspirate. These mast cell granules were chloroacetate esterase-positive, peroxidase-negative, and electronmicroscopically they were composed of fine granular materials containing variable numbers of lamellar structures. At autopsy, diffuse infiltration of the mast cells was found in the liver, spleen, bone marrow, lymph nodes, lungs, kidneys, stomach, and adrenal glands.     

Systemic mastocytosis associated with generalized osteopenia: Histopathological characterization of the skeletal lesion using undecalcified bone from two patients

Although mast cell proliferation in the bone marrow frequently occurs in systemic mastocytosis and is often associated with radiographically detectable bone lesions, the pathologic correlates of the skeletal abnormalities are poorly characterized. We therefore examined three nondecalcified transiliac crest biopsy specimens from two patients with systemic mastocytosis and diffuse osteopenia with vertebral crush fractures. Marrow involvement included unusual mast cell aggregates, as revealed by metachromatic staining, that mimicked granulomas. Histomorphometric analysis of trabecular bone revealed accelerated bone remodeling or “turnover” characterized by osteoidosis, peritrabecular fibrosis, increased numbers of osteoblasts and osteoclasts, and an increase in osteoclastic resorbing surfaces.Our observations and review of the literature suggest that with the recent development of techniques for assessing undecalcified bone biopsy specimens, mastocytosis will probably be shown to be a more common etiology in “osteoporosis” than previously recognized. Metachromatic staining of the biopsy specimen should be a routine procedure in the investigation of any patient who undergoes diagnostic bone biopsy.     

Systemic mastocytosis presenting with a prominent B lymphocyte proliferation in the bone marrow and extensive fibrosis of the spleen

Systemic mastocytosis is a disease characterized by multifocal mast cell proliferation in the bone marrow or other extracutaneous organs. Because of loosely scattered and hypo-/agranular mast cells, the diagnosis is sometimes very difficult. In the bone marrow, mast cell infiltration may be associated with prominent lymphoid infiltration leading to a misdiagnosis of a low grade non-Hodgkin lymphoma. A 49-year-old woman presented with right arm and leg pain, psychiatric symptoms, and diarrhea for four years. Physical examination and laboratory investigation revealed hepatosplenomegaly, anemia, mild thrombocytosis, mild leucocytosis and lymphocytosis. In the bone marrow biopsy, there was a prominent B lymphocyte proliferation reminiscent of a low grade non-Hodgkin lymphoma/leukemia and there were some spindle cells aggregates in paratrabecular location. The consecutive bone marrow biopsies were similar to the first. The subsequent splenectomy specimen exhibited striking fibrosis. In the lymph node sections, there was marginal zone hyperplasia. Multifocal accumulations of mast cells were strongly positive with mast cell tryptase and CD117 on immunohistochemical staining, though no metachromasia was identified in Giemsa and Toluidine Blue stained aspirates and tissue sections, probably due to hypo-/agranulation of mast cells. The case was presented to emphasize the importance of the antibody to mast cell tryptase in the diagnosis of mastocytosis and to discuss problems of differential diagnosis of systemic mastocytosis.     

Skeletal mastocytosis.

AIMS--To characterise the condition of skeletal mastocytosis, an uncommon cause of apparently "idiopathic" osteoporosis. METHODS--Transiliac crest biopsy specimens submitted over a period of five years were examined for nodular accumulation of mast cells. The cases were reviewed histologically and clinical follow up was obtained from hospital notes. RESULTS--Six cases of mastocytosis occurring in bone biopsy specimens submitted to our department were identified. Four patients presented initially with vertebral collapse and the other two were known to have extraskeletal mast cell disease at presentation. On clinical review of the four patients with vertebral collapse, one was found to have urticaria pigmentosa. This patient died from his mastocytosis, whereas the three patients without evidence of extraskeletal disease remain alive and well. Histological examination showed that patients with the poorer clinical outcome had severe peritrabecular fibrosis as well as mast cell nodules; those with prolonged disease-free survival had nodules without peritrabecular fibrosis. CONCLUSION--There is a form of mastocytosis which presents clinically as "idiopathic" osteoporosis. Clinically it does not have the same prognostic implications as skeletal disease in "malignant mastocytosis", running a much more benign course.     

Hematopathology of the bone marrow in pediatric cutaneous mastocytosis. A study of 17 patients

Sixteen bone marrow aspirates and 15 trephine core biopsies from 17 children with cutaneous mastocytosis, of which 15 exhibited urticaria pigmentosa and 2 exhibited diffuse cutaneous mastocytosis, were evaluated for the presence of bone marrow-associated pathologic conditions. Eight bone marrow aspirates from 8 children and 23 trephine core bone marrow biopsies from 16 children who had had evaluation for hematologic abnormalities not associated with cutaneous mastocytosis served as a control population. Eosinophilia was a prominent finding in bone marrows of 9 of 17 patients who had cutaneous mastocytosis. Increased mast cell numbers in bone marrow aspirates were observed in 5 children with cutaneous mastocytosis (5 of 16) and in 2 of the control children (2 of 8). Examination of the trephine core bone marrow biopsies obtained from patients with cutaneous mastocytosis demonstrated focal perivascular and paratrabecular aggregates consisting of mast cells, eosinophils, and early myeloid cells in 10 of 15 individuals. Similar lesions were observed in trephine core bone marrow biopsies of 3 of 16 control patients. The focal mast cell lesions characteristic of adult systemic mastocytosis were not observed. The authors conclude that cutaneous mastocytosis in the pediatric age group is rarely associated with definitive bone marrow findings suggestive of systemic mast cell disease and that this observation is consistent with previous reports that cutaneous mastocytosis in the majority of pediatric cases resolves by adulthood.     

Diagnostic value of tryptase in anaphylaxis and mastocytosis

Serum (or plasma) levels of total and mature tryptase measurements are recommended in the diagnostic evaluation of systemic anaphylaxis and systemic mastocytosis, but their interpretation must be considered in the context of a complete workup of each patient. Total tryptase levels generally reflect the increased burden of mast cells in patients with all forms of systemic mastocytosis (indolent systemic mastocytosis, smoldering systemic mastocytosis, systemic mastocytosis associated with a hematologic clonal non-mast cell disorder, aggressive systemic mastocytosis, and mast cell leukemia) and the decreased burden of mast cells associated with cytoreductive therapies in these disorders. Causes of an elevated total tryptase level other than systemic mastocytosis must be considered, however, and include systemic anaphylaxis, acute myelocytic leukemia, various myelodysplastic syndromes, hypereosinophilic syndrome associated with the FLP1L1-PDGFRA mutation, end-stage renal failure, and treatment of onchocerciasis. Mature (beta) tryptase levels generally reflect the magnitude of mast cell activation and are elevated during most cases of systemic anaphylaxis, particularly with parenteral exposure to the inciting agent.     

Mastocytosis and related disorders

Mastocytosis represents a heterogeneous group of disorders characterized by an abnormal accumulation of mast cells in one or more organ systems. Mastocytosis is further divided into different subtypes according to the sites of involvement, laboratory findings, and degree of organ impairment. Cutaneous mastocytosis is diagnosed in the presence of skin involvement and absence of extracutaneous disease, and is most commonly seen in the pediatric population. Systemic mastocytosis, the disease form most commonly seen in adults, is characterized by the presence of multifocal, compact (dense) mast cell aggregates in the bone marrow or other extracutaneous organs. The mast cells may display atypical, often spindle-shape morphology and/or aberrant CD2 and/or CD25 expression. Elevation of serum tryptase and/or presence of KIT D816V mutation are other common findings. Systemic mastocytosis is further divided into different subtypes based on a combination of clinical features and laboratory findings. Recent studies have indicated that CD30 is frequently expressed in aggressive systemic mastocytosis and mast cell leukemia but infrequently in indolent systemic mastocytosis, and may be a useful marker for distinguishing these subtypes of systemic mastocytosis from one another. A group of related myeloid disorders, collectively termed myelomastocytic overlap syndromes, may pose diagnostic difficulty because of their significant clinical and pathologic overlap with systemic mastocytosis, and these will also be discussed in this review.     

An immunohistochemical study of the bone marrow lesions of systemic mastocytosis: expression of stem cell factor by lesional mast cells

The bone marrow biopsy in mastocytosis often reveals characteristic mast cell collections associated with lymphoid cell aggregates. There is limited information on the composition of these aggregates and whether they contain cytokines important to mast cell growth and development. We thus performed an immunohistochemical characterization of bone marrow lesions in 7 patients with systemic indolent mastocytosis. In nodular lesions, the collections of mast cells were surrounded by lymphoid aggregates; these aggregates consisted of a mixture of B and T cells. Immunohistochemical staining for stem cell factor (SCF) revealed the presence of this cytokine in the lesional mast cells with a granular staining pattern. These results show that the characteristic nodular lesions observed in bone marrow biopsy specimens of patients with mastocytosis bearfeatures of benign lymphoid aggregates and that SCF is present in these lesions, creating a potential autocrine or paracrine growth and differentiation loop for mast cells and lymphoid progenitors.     

Lymph node findings in generalized mastocytosis

Lymph nodes from 21 cases of generalized mastocytosis were studied histologically to confirm or exclude mast cell infiltration, and to investigate their micro-architecture. Mast cell infiltrates were detected in 17 (80%) of the lymph nodes and were found mainly in the medullary cords and sinuses. Diffuse infiltration was seen in 14 cases and focal infiltration in three cases. The following pathological findings were frequently observed: germinal centre hyperplasia (n = 14), which is probably a nonspecific finding; and hyperplasia of small blood vessels, which sometimes resembled high endothelial venules (14), eosinophilia (8), plasmacytosis (7) and collagen fibrosis (6), all of which may well be related to the effects of mediators released by mast cells. Infiltrates of acute or chronic myeloid leukaemia were seen in six lymph nodes. Division of the cases into two prognostically different groups, i.e. systemic mastocytosis, in which the skin lesions of urticaria pigmentosa are present and the prognosis is favourable, and malignant mastocytosis, in which there is no cutaneous involvement and the prognosis is poor, revealed that all six lymph nodes exhibiting leukaemic infiltrates came from the malignant mastocytosis group; eosinophilia, plasmacytosis and fibrosis were seen significantly more often in malignant than in systemic mastocytosis, but blood vessel hyperplasia and germinal centre hyperplasia were encountered with the same high frequency in both groups; and mast cell atypia tended to be more pronounced in malignant mastocytosis; this diagnosis could therefore easily be missed without naphthol AS-D chloroacetate esterase staining.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute myeloid leukemia (AML-M2) with mast cell hyperplasia of bone marrow: a report of three cases

Bone marrow mastocytosis, though infrequently documented in Indian patients, may be observed in association with many non mast cell hematological neoplasms, including acute myeloblastic leukemia (AML) and myelodysplastic syndromes (MDS). We report three cases of acute myeloid leukemia with excess of mast cells in the bone marrow (BM) samples. Mast cell hyperplasia may remain under diagnosed due to shortcoming of morphological identification and diagnostic workup.     

Gastrointestinal manifestations of systemic mastocytosis

Systemic mastocytosis (SM) is an uncommon neoplastic proliferation of mast cells involving single or multiple organs. The skin is most commonly involved, presenting as urticaria pigmentosa, followed by bone marrow involvement, which is the commonest extracutaneous. The gastrointestinal tract is reported to be involved in about 70–80% of cases of systemic mastocytosis. The pattern and extent of mucosal involvement and the histological appearance are now becoming clear as there is heightened awareness by clinicians of the possibility of the gastrointestinal tract being affected by the disease and increased endoscopic procedures. The symptoms appear non-specific with abdominal pain as the leading complaint followed by nausea, vomiting and diarrhoea. Cases of systemic mastocytosis are being diagnosed by mucosal biopsies with gastrointestinal involvement as the presenting pathology. A case of systemic mastocytosis is described diagnosed on gastrointestinal symptoms and endoscopic mucosal biopsies.     

Mastocytosis, classification, biological diagnosis and therapy

In mast cell (MC) disorders (mastocytosis), clinical symptoms are caused by the release of chemical mediators from MCs, the pathologic infiltration of neoplastic MCs in tissues, or both. Cutaneous mastocytosis is a benign disease in which MC infiltration is confined to the skin. In pediatric cases cutaneous mastocytosis might regress spontaneously. Systemic mastocytosis (SM) is more frequently diagnosed in adults and is a persistent (clonal) disease of bone marrow-derived myelomastocytic progenitors. The somatic c-kit mutation D816V is found in the majority of such patients. The natural clinical course in SM is variable. Whereas most patients remain at the indolent stage for many years, some have aggressive SM (ASM) at diagnosis. Other patients have an associated clonal hematologic none MC lineage disease (AHNMD). MC leukemia (MCL) is a rare disease variant characterized by circulating MCs and fatal disease progression. Two important diagnostic clues in SM are an increased serum tryptase level and the presence of abnormal mast cells in the bone marrow. The current review provides an overview of mastocytosis and its subvariants, the new classification of these diseases, a practical guide for the biological diagnosis and advances and future directions in therapy of these pathologies.     

Mast cell leukemia with rapidly progressing portal hypertension

Reported herein is an autopsy case of mast cell leukemia, a rare form of systemic mastocytosis, complicated with portal hypertension. A 52-year-old woman presented with urticaria-like skin symptoms, anemia, and thrombocytopenia. Atypical mast cells (CD2+, CD25+, CD117+) with toluidine blue metachromasia were found in the peripheral blood and on bone marrow aspiration smears. Chemotherapy with cytosine arabinoside and idarubicin was ineffective and the patient died of multi-organ failure with rapidly progressing hepatosplenomegaly and large-volume ascites 3 months after admission. At autopsy the bone marrow, spleen, liver, and lymph nodes were extensively infiltrated by atypical tumor cells with occasional bi- or multi-lobated nuclei. They were positive for mast cell tryptase and possessed an activating mutation of the c-kit gene (D816V). Ascites (2200 mL) and non-ruptured esophageal varices with submucosal hemorrhage indicated the presence of severe portal hypertension. Although there was no evidence of liver cirrhosis, the hepatic sinusoids were clogged with tumor cells, with a tendency to be more severe in the perivenular areas, and the lumens of central veins were obliterated by tumor cell infiltration. The present case demonstrates that non-cirrhotic portal hypertension due to blocking of sinusoidal and venous flow could be a serious complication in mast cell leukemia.     

Mast cell infiltrates of the skin and the mastocytosis syndrome

Mast cell diseases are reviewed from both their cutaneous and their systemic aspects. Emphasis is placed upon the various histologic types of mast cell infiltrates, including the spectrum of mast cell hyperplasias, mastocytomas, diffuse mastocytosis in the skin, and malignant mast cell disease. Correlation of the different types of mast cell lesions with systemic involvement is made and the varieties of systemic lesions are reviewed.     

Analysis of the lineage relationship between mast cells and basophils using the c-kit D816V mutation as a biologic signature

BACKGROUND: Mast cells and basophils share similar morphologic and functional properties; however, it is not known whether they are derived from a bilineage (basophil/mast cell)-restricted progenitor. OBJECTIVE: To assess whether basophils and mast cells are derived from common committed progenitors using the c-kit D816V mutation as a biologic signature. METHODS: The D816V c-kit mutation found in mast cells of patients with systemic mastocytosis is used as a trackable genetic marker to assess the lineage relationship between mast cells and basophils. Blood and bone marrow aspirates were collected from 33 consecutive patients with mastocytosis with different disease severity. Peripheral blood basophils, monocytes and neutrophils were sorted by immunomagnetic beads. Presence of the D816V c-kit mutation was analyzed by restriction fragment length polymorphism in the genomic DNA and mRNA from sorted cells in all patients and in the genomic DNA of individual basophils of 1 patient. RESULTS: The c-kit D816V mutation was detectable in basophils of 5 patients (15%). All 5 patients had the c-kit mutation also detectable in monocytes and thus had multilineage involvement. Single cell analysis of the genomic DNA in 1 patient showed a similar degree of clonal expansion in basophils, monocytes, and neutrophils. Mutated c-kit was expressed at the mRNA level in all 5 patients. There was no difference in surface Kit expression levels in basophils. CONCLUSION: Basophils carrying the D816V c-kit mutation in mastocytosis were detected only in the context of a multilineage involvement. These results argue against the presence of a bilineage-restricted committed progenitor for mast cells and basophils.