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The European Competence Network on Mastocytosis (ECNM) is a Europe-wide, multinational cooperative approach attempting to improve recognition, diagnosis, and therapy of mastocytosis. The network is composed of local centers, physicians, and scientists who have dedicated their work to patients with mastocytosis. However, because of the rarity and complexity of the disease, each single component in the network alone would fail to meet important demands and to reach solid conclusions in this field of applied medicine. The ECNM represents an attempt to overcome this restriction as a cooperative multicenter platform that should serve as an important basis for the development of new therapeutic strategies and diagnostic concepts, and for the standardization of techniques used to determine diagnostic and prognostic parameters. Moreover, using future central databases and registries, a suitable infrastructure for the development of co-operative multicenter clinical trials will be established. In addition, the ECNM is dedicated to provide the best available information about the disease to patients and physicians.

Background: Mastocytosis is comprised of a group of heterogeneous diseases involving various organs. Urticaria pigmentosa is the most common manifestation of cutaneous mastocytosis; others include mastocytoma, diffuse mastocytosis, and telangiectasia macularis eruptiva perstans. Methods: We describe a case of indolent mastocytosis presenting as scarring alopecia. The scalp biopsy revealed a perifollicular and dermal inflammatory infiltrate composed predominantly of mast cells, which was confirmed by tryptase and Giemsa stains. Results: The preponderance of mast cells in the biopsy prompted testing for urine N-methylhistamine levels, which were elevated and confirmed the diagnosis of mastocytosis. This is the first report of mastocytosis presenting as scarring alopecia. Conclusions: This case suggests that the diagnosis of mastocytosis should be entertained in patients presenting with scarring alopecia accompanied by an intense mast cell infiltrate on scalp biopsy and also supports the notion that mast cells may be involved in the pathogenesis of alopecia.

Background An increase in colony-forming progenitor cells (CFU) is typically seen in myeloproliferative disorders (MPD). Systemic mastocytosis (SM) is a haemopoietic neoplasm involving myeloid progenitors similar to MPD. In the present study, we measured the levels of peripheral blood (pb) and bone marrow (bm) CFU in patients with different categories of SM, and compared them with those obtained in MPD patients and healthy controls. Materials and methods Numbers of CFU (CFU-GM, BFU-E, CFU-GEMM) were measured in a colony assay in 25 patients with SM [indolent SM (ISM), n = 15; smouldering SM (SSM), n = 3; SM with an associated haematologic clonal non-mast cell lineage disease (SM-AHNMD), n = 5; aggressive SM (ASM), n = 1; mast cell leukaemia (MCL), n = 1] and 37 with MPD [chronic myeloid leukaemia (CML), n = 10; polycythemia vera (PV), n = 8; essential thrombocytosis (ET), n = 9; idiopathic myelofibrosis (IMF), n = 10]. Results In the patients with MPD, elevated numbers of pb CFU were detected in all groups when compared with healthy controls (P

Resume La mastocytose systemique est une pathologie rare, parfois agressive, au diagnostic difficile. Nous rapportons l’observation d’une malade de 72 ans chez qui le diagnostic de mastocytose maligne a necessite la realisation de deux myelogrammes et trois biopsies osteomedullaires associees a des colorations specifiques. Malgre un traitement par interferon, un sarcome mastocytaire du sternum apparait un an apres le debut des symptomes suivi un an plus tard d’une leucemie aigue myeloblastique aboutissant rapidement au deces.

Objective To study clinicopathologic correlations and identify prognostically important variables in patients with systemic mast cell disease (SMCD) who have no associated hematologic disorders. Patients and Methods We identified 40 adult patients with SMCD without associated hematologic disorders. Clinical, laboratory, and bone marrow (BM) histologic findings at the time of referral were evaluated (November 1980-February 2001) for possible correlations with a history of aggressive systemic mastocytosis (retrospectively analyzed) as well as survival (prospectively analyzed). Results The median follow-up time from diagnosis was 108 months and from BM examination was 24 months. A history of aggressive systemic mastocytosis correlated significantly with increased BM mast cell (MC) content, unfavorable MC infiltration pattern, BM eosinophilia, and elevated serum alkaline phosphatase (SAP) level, but not with BM angiogenesis, reticulin fibrosis, or levels of MC mediators. Of these factors, increased BM MC content and elevated SAP level were also associated with shortened survival from time of referral. Conclusions This study suggests that the BM MC burden, BM eosinophilia, and SAP level are prognostically important in SMCD without associated hematologic disorders. In contrast, BM angiogenesis, reticulin fibrosis, and levels of MC mediators showed no prognostic relevance.

Systemic mast cell disease (SMCD) cannot be distinguished from reactive mastocytosis (RM) by quantitation of mast cells in aspirate smears, and few studies have analyzed systematically the morphologic features of mast cells in SMCD vs RM. In addition, although SMCD is associated with myeloproliferative disorders/myelodysplastic syndromes (MPD/MDS), it is not known whether subtle signs of dysplasia or MPD can be found in SMCD, suggesting most cases are part of a dysplastic or myeloproliferative process. We compared 18 bone marrow specimens with SMCD with 10 bone marrow specimens from patients with RM. Mast cells in SMCD were more likely to show cytoplasmic hypogranularity, uneven granule distribution, and fusiform morphologic features. Eight cases of SMCD (44%) demonstrated MPD/MDS, and 9 cases (50%) showed subtle evidence of dyspoiesis, with megaloblastic change, nuclear budding of erythroid precursors, and/or atypical megakaryocytes. Mast cells in SMCD appear morphologically different from those in reactive proliferations. Dyspoietic features were present in most cases of SMCD, suggesting that SMCD is part of a spectrum of chronic myeloproliferative/ myelodysplastic disorders.

Mastocytosis is a heterogeneous group of disorders characterised by an abnormal growth and accumulation of mast cells in skin, bone marrow, gastrointestinal tract, liver, spleen, and lymph nodes. Symptoms occur due to the release of histamine, prostaglandin D2, heparin and other mediators derived from mast cells. The clinical feature covers a broad spectrum from single mastocytoma to malignant mastocytosis and mast cell leukaemia. We report on two cases with adult benign systemic mastocytosis to show the variety of symptoms. Diagnostics oriented according to symptoms and options on therapy are presented as well as differential diagnosis and associated haematological disorders. The importance of advice and regular follow-ups of patients with systemic mastocytosis is emphasised.

One of the major advances in the histological diagnosis of bone marrow (BM) involvement in mastocytosis has been the specific immunohistochemical detection of tryptase on most cells (MC), which has shown to be of great diagnostic value, especially in cases of malignant mastocytosis. On the other hand, recent studies have clearly shown that bone marrow mast cells can be specifically identified and accurately enumerated using multiparametric flow cytometry, which allow a systematic analysis of the immunophenotypic characteristics of bone marrow mast cells. Once this flow cytometric approach was applied for the analysis of BMMC from mastocytosis patients clear immunophenotypical differences were found between BMMC from normal individuals and adults with mastocytosis. The most characteristic immunophenotypic feature, both in malignant and adult indolent systemic mast cell disease, being the coexpression of CD2 and CD25 antigens, never present in normal bone marrow mast cells and, which constitute an aberrant hallmark of bone marrow mast cells in adult mastocytosis. Furthermore, bone mast cells from mastocytosis display a higher reactivity for CD35, CD63, and CD69 activation-associated antigens. Based on these results it could be concluded that the use of multiparametric flow cytometric immunophenotyping of BMMC in adult patients suffering from cutaneous mastocytosis can be of great utility for the diagnosis of BM involvement; additionally, this might also help to establish the real incidence of BM involvement in cutaneous mastocytosis.

BACKGROUND The Asp816Val mutation in the catalytic domain of the c-kit receptor has been identified in patients with systemic mastocytosis. METHODS To determine whether this mutation is associated with identifiable clinical patterns of disease and prognosis, a total of 65 patients with mastocytosis were screened for the presence of the Asp816Val mutation in peripheral blood mononuclear cells (PBMCs). RESULTS By analysis of HinfI digestion products, the authors found that the overall prevalence of this mutation in the current patient series was 25%. The presence of the Asp816Val mutation in PBMCs was observed in 15 adults (of 16 Asp816Val mutation positive patients) and 1 infant, but not in any children with mastocytosis. Patients whose PBMCs were positive for this mutation (category II and a subset of category Ib mastocytosis patients) manifested a more severe disease pattern, with clinical features ranging in severity from early to advanced myelodysplastic or myeloproliferative syndromes. These patients more commonly had osteosclerotic bone involvement (a clinical feature primarily observed in mastocytosis patients with an associated hematologic disorder) as well as immunoglobulin dysregulation and peripheral blood abnormalities. Furthermore, pedigree analysis of three families provided evidence that the mutation was somatic. CONCLUSIONS Twenty-five percent of all patients with mastocytosis had the Asp816Val mutation in PBMCs; 56% of these patients had evidence of a myelodysplastic or myeloproliferative syndrome, and 44% had been clinically placed in the indolent mastocytosis category, suggesting that the current classification scheme used to assign prognosis may be inadequate. Therefore, determination of the presence or absence of this mutation in PBMCs of mastocytosis patients offers a useful adjunct in determining the extent of workup and assigning prognosis in this complex and heterogeneous disease. Cancer 1998;83:2120-2129. © 1998 American Cancer Society.

The term "mastocytosis" is used to describe a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MCs). Cutaneous and systemic variants exist. Systemic mastocytosis may show an indolent or malignant clinical course. In malignant mastocytosis (MM), the diagnosis often is missed because the MCs are morphologically abnormal and lack metachromatic granules or the underlying histologic picture is complex. The cytoplasmic serine protease tryptase is produced by MCs and is thought to be expressed at all stages of MC maturation. To assess the diagnostic value of tryptase staining in mastocytosis, tissue sections from 93 patients with mastocytosis, including MM (n = 37), systemic indolent mastocytosis (n = 47), urticaria pigmentosa (n = 5), MC leukemia (n = 2), and solitary skin mastocytoma (n = 2) were stained with the antitryptase antibody G3. The results were compared with those of Giemsa and chloroacetate esterase (CAE) staining. Using antitryptase antibody G3, MC infiltrates were identified in all patients examined, including those with MM (37 of 37), and virtually all the neoplastic MCs (95%) appeared to react with G3. In MM, significantly fewer MCs were positive in Giemsa (54.5%; p0.05) and CAE (78.8%; p0.05). Moreover, G3 produced clear diagnostic staining in all cases of MM, but the proportion of cases with clear diagnostic results (10% of neoplastic cells positive) was considerably lower with Giemsa (48.6%; p0.05) and CAE (75.7%; p0.05) staining. By contrast, tryptase, Giemsa, and CAE produced diagnostic staining of MCs in virtually all cases of systemic indolent mastocytosis, urticaria pigmentosa, and solitary skin mastocytoma. In systemic mastocytosis, survival was significantly reduced in cases with Giemsa-/tryptase+ or CAE-/tryptase+ tumor cells compared to those cases with Giemsa+ or CAE+ MC infiltrates (p0.001).

Objective. To report the bone marrow MRI findings of patients with mastocytosis and correlate them with clinical, pathologic, and radiographic features. Design and patients. Eighteen patients with mastocytosis had T1-weighted spin echo and short tau inversion recovery MRI of the pelvis at 0.5 T. In each patient the MR pattern of marrow disease was classified according to intensity and uniformity and was correlated with the clinical category of mastocytosis, bone marrow biopsy results, and radiographic findings. Results. Two patients had normal MRI scans and normal bone marrow biopsies. One patient had a normal MRI scan and a marrow biopsy consistent with mastocytosis. Fifteen patients had abnormal MRI scans and abnormal marrow biopsies. There were several different MR patterns of marrow involvement; none was specifically associated with any given clinical category of mastocytosis. Fifteen of the 18 patients had radiographs of the pelvis; of those, 13 with abnormal MRI scans and abnormal marrow biopsies had the following radiographic findings: normal (nine); sclerosis (three); diffuse osteopenia (one). Conclusion. While radiographs are very insensitive for the detection of marrow abnormalities in mastocytosis, MRI is very sensitive and may display several different patterns of marrow involvement.

Mastocytosis is a heterogeneous group of disorders characterized by mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, gastrointestinal tract, and skin. We present a patient with malignant mastocytosis of 11 years’ duration. This case highlights the cutaneous findings of mastocytosis with systemic involvement, yet the patient maintains a relatively normal lifestyle with only minimal discomfort and only borderline normochromic anemia. Thus his course is not truly that of malignant mastocytosis but of indolent systemic mastocytosis with cutaneous findings of telangiectasia macularis eruptiva perstans (TMEP).

Mastocytosis is a spectrum of disorders characterized by an aberrant proliferation of tissue mast cells. Although this disease process often affects the skin, it may involve multiple organs. The clinical disorder varies according to patient age, the clinical manifestations demonstrated, and the extent of the mast cell proliferative process. A myriad of clinical symptoms occur, and these may be localized to the organ system involved or may be systemic, depending on whether there is local or generalized mast cell mediator release. Diagnosis includes the demonstration of increased tissue mast cells in involved organs as well as increased levels of biochemical mediators. Patients with cutaneous involvement only have the best prognosis. Treatment is directed toward stabilizing mast cell mediator release and blocking the effects of those mediators generated.

Systemic mastocytosis is a rare and occasionally aggressive condition that raises major diagnostic challenges. We report a case in a 72-year-old patient in whom the diagnosis of malignant mastocytosis required two bone marrow smears and three bone marrow biopsies examined using specific staining techniques. Despite interferon therapy, a mast-cell sarcoma of the sternum developed 1 year after symptom onset, followed 1 year later by acute myeloblastic leukemia, which was rapidly fatal.

OBJECTIVE. Systemic mastocytosis is a hematologic neoplasm characterized by abnormal accumulation and growth of mast cells in one or more organ systems. We analyzed five patients with systemic mastocytosis referred for FDG positron emission tomography who had biopsy-proven mast cell infiltrates in various organs.CONCLUSION. Our findings indicate that FDG positron emission tomography is not useful for staging and follow-up of aggressive systemic mastocytosis.

Studies on the proliferative compartment of human tissue mast cells (MCs) and their tumours (mastocytosis) have not been performed. We have used the monoclonal antibody PC10 to study MCs in reactive or hyperplastic states (chronic non-specific lymphadenitis, n = 10; benign and malignant solid tumours, n = 5) and in the various subtypes of mastocytosis (urticaria pigmentosa, n = 22; solitary mastocytoma of the skin, n = 7; systemic mastocytosis; n = 8; malignant mastocytosis, n = 4). The identification of PC10-positive MC nuclei was achieved by double staining. We found no PC10-positive MCs in reactive or hyperplastic states, or in 14 of 22 cases of urticaria pigmentosa. PC10-positive MCs could be identified in all other mastocytosis but mostly in very low numbers. The mean percentages of PC10-positive MCs amounted to 0.5 in eight positive cases of urticaria pigmentosa, 1.2 in mastocytoma, 0.7 in systemic mastocytosis, and 4.0 in malignant mastocytosis. The difference between the latter form of mastocytosis and each of the other subtypes proved to be significant (P < 0.05). The very small proliferative compartment in the cutaneous and systemic variants of mastocytosis is in accord with their favourable prognosis. Most of the patients with systemic mastocytosis in the present study are all alive and well up to 12 years after diagnosis. In contrast, most of the patients with malignant mastocytosis died within 1 year of diagnosis.

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)

Summary Blood findings in 61 cases of generalized mastocytosis (GM) were evaluated. The cases were divided into two major variants: Systemic mastocytosis (SM; n= 34) with urticaria pigmentosa-like skin lesions, and malignant mastocytosis (MM; n = 27), without skin involvement. The following results were obtained: 1 Significant differences between MM and SM were found in the main haematological parameters (erythrocyte, platelet and leucocyte counts and haemoglobin level): normal values were found in 16 of the SM cases, but never in MM. 2 The main pathological findings were: in SM, anaemia (9/34) and leucocytosis (5/34); and in MM, leucocytosis (19/ 27), monocytosis (14/271, eosinophilia (12/27), bicytopenia (12/27, mostly anaemia with thrombocytopenia), basophilia (10/27) and isolated anaemia (7/27). 3 The major finding was a significant difference between MM and SM in the incidence of myeloproliferative disorders (MPD), myelodysplasia and mast cell leukaemia (MCL): these disorders occurred in 23 (92%) MM patients, but only in two (6%) SM patients (P < 0.001). The four instances of MCI, and two of myelodysplasia all occurred with MM. Of the 19 cases of MPD, six (SM, 1; MM. 5) were acute variants (acute myeloid and myelomonocytic leukaemias) and 13 (SM. 1; MM, 12) were chronic variants. No case of malignant lymphoma was noted. 4 The blood picture in 10 of the 13 chronic MPD cases represented an atypical chronic myeloid leukaemia for which the preliminary descriptive term‘mastocytosis-associated MPD’is proposed. 5 A survey of 103 published cases (SM, 77; MM. 26) yielded similar findings, including a high incidence of MPD and MCL in MM. These findings add further weight to the argument for recognizing SM and MM as two separate entities.

We describe a patient with fever and multiple osteolytic bone lesions accompanied by hypercalcemia, a duodenal ulcer, anemia, and thrombocytopenia. Bone marrow showed a dense infiltration by abnormal cells characterized by small basophil granula, erythrophagocytosis and nuclear atypia. These cells were positive for toluidine blue and partly for myeloperoxidase and chloroacetate esterase, expressed myeloid differentiation markers, and exhibited multiple numerical and structural chromosome aberrations. Molecular genetic analysis showed no breakpoint cluster region rearrangement. Electron microscopy demonstrated granula both of basophil and mast cell type. Concluding, in this patient an acute hematopoietic malignancy with many features of malignant mastocytosis but also with signs of a basophil differentiation. This is further support for a hematopoietic stem cell origin of human mast cells.

A 10-year–old German shepherd dog was presented with right fore limb oedema, ascites and hepatomegaly. A clinical diagnosis of ehrlichiosis and liver failure was made. Response to therapy was unfavorable and with the owner's consent, euthanasia was performed. Necropsy findings revealed a markedly enlarged liver whose surface had numerous cream colored nodular masses. On histopathology, the liver tissue was destroyed by the infiltrating neoplastic mast cells and eosinophils. Based on the gross and microscopic findings, the condition was diagnosed as metastatic mastocytoma that resulted in liver failure. Occurrence of systemic mastocytosis without overt cutaneous lesions is rare. This article documents a case of liver failure due to malignant mastocytosis of which there are scant reports. The Kenya Veterinarian Vol. 30 (1) 2006: pp. 19-22

Mastocytosis is a rare disease characterized by accumulation of mast cells in tissues. To investigate whether an altered regulation of mast cell apoptosis might be involved in the pathogenesis of mastocytosis, expression of the apoptosis-preventing molecules bcl-2 and bcl-xL was studied by immunohistochemistry in skin and bone marrow lesions of mastocytosis patients. In addition, reverse transcription-polymerase chain reaction was used to investigate levels of bcl-2 and bcl-xL mRNA in cutaneous mastocytosis lesions. Since activating mutations of c-kit are known to be associated with some forms of mastocytosis, human mast cell cultures were also stimulated via c-kit and the expression of bcl-2 and bcl-xL was assessed by immunoblotting. In patients with mastocytosis, the expression of bcl-2 protein but not bcl-xL in cutaneous mast cells was significantly enhanced, compared to healthy controls. Evaluating different subgroups of adult and pediatric mastocytosis patients, all groups were found to express significantly increased levels of bcl-2 protein, and none of the patient groups was found to overexpress bcl-xL, with the exception of solitary mastocytomas that showed a tendency for up-regulated bcl-xL protein. Furthermore, the expression of bcl-2 mRNA was significantly enhanced in cutaneous lesions of adult and pediatric patients, while bcl-xL mRNA levels were only slightly increased in pediatric, but not in adult patients with mastocytosis. In contrast to the skin lesions, bone marrow infiltrates of patients with systemic mastocytosis showed only low or absent immunoreactivity for bcl-2, but marked expression of bcl-xL. In vitro, stimulation of two different mast cell culture systems by activation of c-kit resulted in up-regulation of bcl-2 and also in an increase of bcl-xL, although less pronounced. Thus, overexpression of bcl-2 and bcl-xL leading to prolonged survival of mast cells may contribute to the pathogenesis of mastocytosis. Our findings may help to develop new strategies for the treatment of this disease.

Recently, aberrant coexpression of CD2 and CD25 has been reported to reliably distinguish neoplastic mast cells from normal or so-called reactive mast cells. Such expression is included in the consensus diagnostic criteria for systemic mast cell disease (SMCD). In our study of patients with SMCD, we found CD2 expression to be more prevalent on mast cells from patients without an associated haematological disorder (P = 0.04). Furthermore, no correlation was found between mast cell CD2 expression and other clinicopathological features in these patients.

RESULTS: The 349 cases of MM were evenly distributed between age groups 65. A majority of MM occurred in Caucasians (86.8%) and in the bone marrow (73.4%). 55.6% of patients 65 were male. 55.6% of MM had lymph node invasion. 28.6% of patients >65 had a history of a prior malignancy compared to only 4.8% of patients 50. Multivariate analysis identified age 50-65 (OR 4.9) and age >65 (OR 17.3) as associated with increased mortality.

The term 'mastocytosis' denotes a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MC) in one or more organ systems. Over the last 20 years, there has been an evolution in accepted classification systems for this disease. In light of such developments and novel useful markers, it seems appropriate now to re-evaluate and update the classification of mastocytosis. Here, we propose criteria to delineate categories of mastocytosis together with an updated consensus classification system. In this proposal, the diagnosis cutaneous mastocytosis (CM) is based on typical clinical and histological skin lesions and absence of definitive signs (criteria) of systemic involvement. Most patients with CM are children and present with maculopapular cutaneous mastocytosis (=urticaria pigmentosa, UP). Other less frequent forms of CM are diffuse cutaneous mastocytosis (DCM) and mastocytoma of skin. Systemic mastocytosis (SM) is commonly seen in adults and defined by multifocal histological lesions in the bone marrow (affected almost invariably) or other extracutaneous organs (major criteria) together with cytological and biochemical signs (minor criteria) of systemic disease (SM-criteria). SM is further divided into the following categories: indolent systemic mastocytosis (ISM), SM with an associated clonal hematologic non-mast cell lineage disease (AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL). Patients with ISM usually have maculopapular skin lesions and a good prognosis. In the group with associated hematologic disease, the AHNMD should be classified according to FAB/WHO criteria. ASM is characterized by impaired organ-function due to infiltration of the bone marrow, liver, spleen, GI-tract, or skeletal system, by pathologic MC. MCL is a 'high-grade' leukemic disease defined by increased numbers of MC in bone marrow smears (>or=20%) and peripheral blood, absence of skin lesions, multiorgan failure, and a short survival. In typical cases, circulating MC amount to >or=10% of leukocytes (classical form of MCL). Mast cell sarcoma is a unifocal tumor that consists of atypical MC and shows a destructive growth without (primary) systemic involvement. This high-grade malignant MC disease has to be distinguished from a localized benign mastocytoma in either extracutaneous organs (=extracutaneous mastocytoma) or skin. Depending on the clinical course of mastocytosis and development of an AHNMD, patients can shift from one category of MC disease into another. In all categories, mediator-related symptoms may occur and may represent a serious clinical problem. All categories of mastocytosis should be distinctively separated from reactive MC hyperplasia, MC activation syndromes, and a more or less pronounced increase in MC in myelogenous malignancies other than mastocytosis. Criteria proposed in this article should be helpful in this regard.

Mastocytosis is a disease characterized by an abnormal increase in mast cells. Manifestations of the disease are provoked in large part by the resultant increase in mast cell-derived mediators, which have a variety of local and systemic effects. Mastocytosis is variable in respect to the organ systems involved, clinical manifestations, and association with hematologic diseases. This has suggested the need for an improved classification scheme to allow assessment of prognosis and therapy. The heterogeneity of the disease patterns in mastocytosis strongly suggests that more than one biologic lesion may occur in the developmental sequence that leads to placement of mature mast cells in tissues.

Four patients with systemic mastocytosis, two men and two women, are presented. Three of them (patients 1, 2, and 4) developed portal hypertension and ascites without histological evidence of cirrhosis in liver biopsy. The remaining patient (patient 3) had severe bone lesions with multiple vertebral fractures. None of the patients had skin or lymph node involvement. Two patients (patients 1 and 2) died 12 and 9 months after diagnosis with acute nonlymphocytic leukemia and overt mastocytic leukemia, respectively, while the other two (patients 3 and 4) are alive 58 and 14 months after diagnosis. Treatment with hydroxyurea or cytosine arabinoside had not any beneficial effect in two patients, while a substantial amelioration of back pain had been obtained by local irradiation and recombinant human interferon-alpha-2b administration in one patient (patient 3). All patients had laboratory findings compatible with autoimmune cholangitis. We concluded that systemic mastocytosis is a rare cause of noncirrhotic portal hypertension often simulating autoimmune cholangitis and leading to the erroneous diagnosis of liver cirrhosis. Diagnosis is based on the presence of mast cells in Giemsa-stained liver histological sections, and it may be confirmed by immunohistochemical detection of tryptase in the cytoplasm of these abnormally proliferating cells. Am J Gastroenterol

Systemic mastocytosis is uncommon. Symptoms result from local infiltration and degranulation of mast cells. Reports in the literature describe successful use of interferon alpha and radiotherapy to produce reduction in symptoms and bulk of disease. We report a patient who responded to radiotherapy but not interferon alpha.

Systemic mastocytosis is a rare disease characterized by mast cell infiltration of organs. Bony pain is present in up to 28% of cases and is frequently chronic and difficult to palliate. Historical attempts at pain control have exclusively involved medical therapy. We report three cases of refractory bone pain in two patients with advanced systemic mast cell disease and associated bony involvement, which were treated with radiotherapy. This report represents some of the first uses of radiotherapy in this disease. Two patients with a primary diagnosis of systemic mastocytosis and bony pain unresponsive to medical therapy were referred for palliative radiotherapy. In the first case, referral was made because of a painful thoracolumbar spine and left shoulder, and in the second, for bilateral lower extremity pain. Patients were irradiated on megavoltage equipment to 30 Gy in 200 and 300 cGy daily fractions. For the first patient, treatment reduced pain scores from 8/10 (severe) to 3-4/10 (moderate) by 1 month posttreatment, with subsequent varying pain until his death 4 months after his second treatment. The second patient achieved pain relief from 10/10 pretreatment to 1-2/10 while on treatment. This proved durable for 9 months until her death due to disease progression. The first patient had a slight exacerbation of his thrombocytopenia during his initial treatment, but otherwise neither patient experienced any acute complications from the radiation treatments. When patients with advanced systemic mastocytosis require large narcotic doses for incomplete bone pain control associated with demonstrable bony involvement, the relatively slight risks of palliative radiation to bone may be favorably weighed against the likelihood of pain relief.

IN systemic mastocytosis, an abnormal proliferation of mast cells infiltrates the skin, bone marrow, spleen, liver, and lymph nodes.1 2 3 The release of mast-cell mediators such as histamine causes systemic attacks, with flushing, itching, headache, gastrointestinal symptoms, and even vascular collapse with syncope.1 Although the life expectancy of most patients is good, some have a malignant form of the disease, aggressive systemic mast-cell disease, in which there is marked infiltration of organs by mast cells and a rapidly progressive downhill course.1 The presence of leukemic circulating mast cells indicates a particularly grave prognosis.1 , 4 , 5 So far, there is no effective treatment for . . .

Summary Lymphoproliferative and myeloproliferative malignancies have been noted in patients with systemic mastocytosis' and urticaria pigmentosa.^ However, to our knowledge an association between mastocytosis and malignant melanoma has not been reported previously.

A case of malignant mastocytosis with peripheral blood involvement is presented. The course of the patient's illness was complicated by recurrent hypotensive episodes, presumed to have been caused by mast cell degranulation. Treatment with hydroxyurea was associated with persistent hypotension which resulted in death. It has been proposed that the diagnosis of mast cell leukemia be given to patients presenting with greater than 10% atypical mast cells in the blood. However, review of 16 published cases of malignant mastocytosis with circulating mast cells reveals that the clinical manifestations, complications, and survival do not vary significantly with the percentage of peripheral blood mast cells. Patients with malignant mastocytosis with significant involvement by atypical mast cells in the bone marrow and peripheral blood should be considered as having an aggressive disease, regardless of the percentage of circulating mast cells.

We report the clinical and pathologic findings in one case of mast cell leukemia observed in a series of 60 patients with systemic mast cell disease. The leukemic variant of systemic mast cell disease is rapidly fatal (mean duration of survival, less than 6 months) in contrast to most nonleukemic cases, which follow an indolent clinical course. On the basis of our case and eight previously reported cases, mast cell leukemia is characterized by a substantial increase in atypical mast cells in the peripheral blood, diffuse infiltration with atypical mast cells in the bone marrow, a strong association with peptic ulcer disease, prominent constitutional symptoms, and hepatosplenomegaly. These cases should be distinguished from malignant mastocytosis without a substantial number of circulating atypical mast cells and also cases of acute nonlymphocytic leukemia that arise in the background of systemic mast cell disease.

Based on study of 58 histologically proved cases of SMCD, we believe that the prognosis of most SMCD patients can be anticipated at the time of initial diagnosis by using 5 independent significant predictors developed in a multivariate model. Our study confirms the significance of several previously reported poor prognostic factors: absence of skin involvement and the presence of hepatosplenomegaly, cytologic atypia, and a hypercellular bone marrow. However, in contrast to previous reports we did not find a uniform correlation between the presence or absence of skin involvement and prognosis. The observation that anemia was strongly related to so many prognostic variables may be due to the number of patients in our study with associated hematologic disorders. Alternatively, this evidence of ineffective erythropoiesis may support the concept that SMCD is a myeloid stem cell disorder and frequently affects other hematopoietic cell lines. The observation that death occurs within the first 3 years in most fatal cases of SMCD suggests that these patients should be followed carefully for this interval after initial diagnosis, especially if poor prognostic features are present. Currently there is no curative therapy for SMCD.

Systemic mast cells disease (SMCD) is an uncommon disorder that constitutes approximately 10% of all mastocytoses. Diagnosis requires a substantial degree of clinical suspicion, which may not be present if characteristic skin lesions of urticaria pigmentosa are not observed. Lack of well-defined histopathologic features for the disease have delayed or prevented the diagnosis of SMCD. An initial diagnosis of "myeloproliferative disorder," chronic granulocytic leukemia, or myelofibrosis is frequently made. Study of the clinical and pathologic features of 26 cases of SMCD indicated that affected patients are generally middle aged and may have had urticaria pigmentosa for many years. Gastrointestinal symptoms are common, and splenomegaly and hepatomegaly along with radiographic evidence of generalized bone disease are usually noted. Hematologic factors are highly variable. Characteristic histopathologic features of SMCD are described for bone marrow, lymph nodes, liver, and spleen. The authors consider tissue fixation and staining methods to help identify mast cell lesions.

Summary Mast cells (MC) are regular constituents of soft tissue and occur with varying frequency in nearly every organ. They derive from monocytic cells occuring in the adhering mononuclear fraction of the peripheral blood. Their subsequent evolution into mature MCs is primed by a MC generating lymphokine released by sensitized T-cells on restimulation by the antigen. MC granules contain preformed heparin histamine and eosinophil chemotactic factors. Other factors such as leukotriene B 4 can be produced by MCs following stimulation. This is the case during the initial phase of nonspecific inflammations, when MCs are stimulated by complement activation. In the immediate type hypersensitivity reaction giving rise to IgE, MC degranulation occurs independent from complement. In IgG and IgM mediated reactions, however, MC involvement is effected by complement consumption and C5 a generation. In delayed type hypersensitivity MCs increase locally. Their functional significance remains obscure. MC neoplasias are rare and generally confined to the dermis. Cutaneous mastocytoses are called benign mastocytoma when localized and urticaria pigmentosa when disseminated. Generalized mastocytosis involves extracutaneous tissue irrespective of skin involvement. Those associated with urticaria pigmentosa-like skin lesions, present at the onset of the disease, have a significantly higher survival rate than those lacking a primary skin involvement. The term urticaria pigmentosa should be reserved for cases of cutaneous mastocytosis without extracutaneous involvement. Cases of mastocytoses lacking primary skin lesions assume a malignant course and are additionally aggravated by high incidence of myeloproliferative disorders and MC leukemia. MC sarcoma is an extremely rare neoplasia of MCs which may also terminate as a MC leukemia.

Using a pH-adjusted toluidine blue stain (pH range, 2.5–6.5), we sequentially examined the staining pattenrs of mast cells in tissue sections taken from patients with localized or reactive mast cell lesions and benign or malignant mastocytosis syndromes. Reactive or benign lesions stained well over the entire rang eof pHs and were separated from malignant mast cell proliferations which stained poorly and with greatest intensity in the less acidic range (pH greater than 3.5). Patients with disseminated mast cell lesions but without tumor masses or leukemia had a staining pattern between that of benign and malignant lesions. Basophils stained intensely at pH 2.5, and metachromasia rapidly diminished at higher pH. The use of the pH dependent toluidine blue stain may be an adjunct in recognizing patients with mast cell lesions, predicting their prognosis, and distinguishing basophils from mast cells.

Proliferation of tissue mast cells in more than one organ is a rare disease, called generalized mastocytosis. Findings obtained in 35 cases were compared with 125 case reports in order to elucidate the course of the disease and its clinical picture. The results indicated that generalized mastocytosis has to be divided into two variants, designated systemic mastocytosis and malignant mastocytosis. Systemic mastocytosis is characterized by urticaria pigmentosa-like skin eruptions, with simultaneous infiltration of at least one visceral organ (usually bone marrow). Other frequently involved organs are spleen, liver, and lymph nodes. The age curve is biphasic, with one peak in early childhood and another in the 6th decade. The prognosis of systemic mastocytosis is generally favorable (actuarial survival 0.88 one year after diagnosis). In contrast to systemic mastocytosis, malignant mastocytosis does not show urticaria pigmentosa-like skin lesions. In this variant of generalized mastocytosis, frequently involved organs are bone marrow, spleen, liver, and lymph nodes. Common symptoms are anemia and eosinophilia. The age curve shows a peak in later life (6th and 7th decades). Malignant mastocytosis is never seen in children. The clinical course is usually rapid, and prognosis correspondingly poor (actuarial survival 0.23 one year after diagnosis).

A case of "tissue mast cell leukemia" in a 34-year old white woman is reported. The possible association with urticaria pigmentosa and myeloid leukemia is considered.

The neoplastic proliferation of tissue mast cells constitutes a group of rare diseases that have localized and systemic variants. The cytologic ( n = 7) and histologic ( n = 38) findings in bone marrow from a total of 45 patients with systemic mastocytosis were evaluated. Three distinct histologic patterns of marrow involvement were distinguished. In 21 cases a patchy or focal infiltration pattern was encountered. Mast cell aggregates were located predominantly in peritrabecular and perivascular areas. The adjacent trabeculae were thickened. A dense network of reticulin fibers and foci of lymphocytes accompanied the mast cell infiltrates. Increased numbers of eosinophils frequently demarcated the mast cell infiltrates from the surrounding tissue. In the noninfiltrated marrow areas hematopoiesis and the distribution of fat cells appeared to be normal. This histologic pattern, designated type 1, was observed exclusively in patients showing primary involvement of the skin, indistinguishable from urticaria pigmentosa. In 14 additional cases peritrabecular and perivascular sheets of mast cells, with concomitant fibrosis and osteosclerosis, were also present. Unlike the findings in type 1, however, the noninfiltrated marrow areas showed marked reductions in fat cell content and markedly increased granulocy-topoiesis or increased numbers of blast cells (infiltration pattern type 2). On the basis of the hematologic and clinical findings, chronic myeloid leukemia was diagnosed in six of these cases, myelomonocytic leukemia in three cases, and acute myeloid leukemia in two cases. The bone marrow of three patients was diffusely infiltrated by atypical mast cells, leading to marked hypoplasia of fat cells and blood cell precursors. These histologic features were identified as infiltration pattern type 3. The diagnosis of mast cell leukemia was confirmed in all three cases by the presence of numerous mast cells in the blood. The prognosis for patients with the type 1 marrow infiltration pattern and primary skin involvement was favorable (actuarial survival rate five years after diagnosis, 0.75). This variant was called benign systemic mastocytosis. Primary skin involvement did not occur in the patients with type 2 or 3 infiltration patterns. The prognosis for these patients was poor (actuarial survival five years after diagnosis, 0.17 for type 2 and 0.00 for type 3). These two forms were accordingly designated malignant systemic mastocytosis.

Mastocytosis represents a spectrum of clinical disorders that results from an aberrant proliferation of tissue mast cells. This disease process may be confined to the skin (cutaneous mastocytosis) or may involve multiple organs (systemic mastocytosis). Parameters that are useful in differentiating cutaneous from systemic disorders include patient age, symptom complex, and clinical signs. A wide range of clinical symptoms may be encountered in patients with mastocytosis which result from the release of pharmacologically potent mast cell mediators. Distinct cutaneous patterns resulting from skin mast cell infiltrates can be helpful in identifying patients with systemic involvement. The diagnosis of mastocytosis is confirmed by demonstrating increased tissue mast cells in involved organs. The overall prognosis for patients with proliferative mast cell disease is relatively good, although a small percentage are at risk for developing a fatal neoplastic disorder (malignant mastocytosis). Treatment of mastocytosis is directed at both inhibiting mast cell degranulation and blocking the potential systemic effects of released secretory products. Future therapeutic advances depend upon an improved understanding of the basic mechanisms involved in mast cell mediator release and the forces that govern mast cell growth and development.

Malignant systemic mastocytosis is a rare disorder, a subgroup of the mast cell neoplasms. Its clinical and histological diagnosis is often difficult, especially in patients without cutaneous involvement. We report an unsuspected case who underwent laparotomy complicated by life-threatening hypotension consistent with vasoactive mediator release from mast cells. The subsequent use of two chemotherapy regimens is detailed and both induced transient reduction in disease bulk.

Excerpt Urticaria pigmentosa was first described in 1869 by Nettleship (1) and named by Sangster (2) in 1878. In this disease, mast cell infiltration is confined entirely to the skin. By 1923, 306 ...