Indolent systemic mastocytosis associated with atypical small lymphocytic lymphoma: a rare form of concomitant lymphoproliferative disease

Patients with systemic mastocytosis (SM) may acquire an associated hematologic non-mast cell (MC)-lineage disease (AHNMD). In most cases, a myeloid neoplasm is diagnosed, whereas the occurrence of a lymphoproliferative disease is an extremely rare event. We report on a patient with indolent SM associated with small lymphocytic lymphoma (SLL). The patient presented with lymphadenopathy, maculopapular exanthema, and elevated serum tryptase. The bone marrow biopsy showed focal MC aggregates together with SLL. As assessed by immunostaining, neoplastic MC were found to exhibit CD117 and CD25 but did not display CD5 or CD20, whereas SLL cells were found to coexpress CD5 and CD20 but did not express MC antigens. The KIT mutation D816V was detected in sorted CD34(+) cells and unfractionated marrow cells but not in CD5(+) SLL cells, confirming the coexistence of 2 distinct neoplasms.     

No relationship between histamine release measured as metabolite excretion in the urine, and serum levels of mast cell specific tryptase in mastocytosis

To test the hypothesis that histamine release in mastocytosis patients generally occurs without activation of the mast cells, histamine turnover, measured as histamine metabolite excretion in the urine, was compared with the serum level of mast cell specific tryptase, which is released only during active discharge of mast cell granular contents. Twenty mastocytosis patients with a wide range of histamine turnover rates were investigated. Slightly increased levels of tryptase were found in seven patients with no obvious relationship to histamine metabolite excretion. In contrast, there seemed to be a connection between the tryptase level and the severity of symptoms. These results strengthen the view that histamine in mastocytosis is predominantly released from the mast cells without any accompanying active release process. This does not exclude the possibility that, in some mastocytosis patients, a limited number of mast cells, or a subpopulation, may be actively secreting histamine together with tryptase.     

Analysis of the wheal-and-flare reactions that follow the intradermal injection of histamine and morphine in adults with recurrent, unexplained anaphylaxis and systemic mastocytosis

It has been suggested that patients with recurrent, unexplained anaphylaxis may be more responsive, and patients with systemic mastocytosis, less responsive, to mast cell-derived mediators, including histamine, compared to normal subjects. This would help explain why patients with recurrent, unexplained anaphylaxis have an anaphylactic response and, conversely, why patients with systemic mastocytosis can tolerate high levels of plasma histamine. To test this hypothesis, intradermal titrations (0.02 ml of solution from 1 ng/ml to 2 micrograms/ml) of histamine and morphine sulfate (MS) (10 ng/ml to 10 micrograms/ml) were administered to normal volunteers (N = 15), patients with recurrent, unexplained anaphylaxis (N = 10), and patients with systemic mastocytosis (N = 18). Antihistamines were stopped at least 72 hours before the study. Resultant areas of wheal and flare were determined with a computerized morphometric system. Comparison of any two given means at each dose of histamine or morphine with the two-sample Student's t test with Bonferroni inequality demonstrated no significant differences (p greater than 0.05) among the three groups. The median amount of MS or histamine required to produce a half-maximal response was compared for equality. None of the differences observed reached statistical significance, in agreement with the similarity of the dose-response curves. An analysis of the correlation between response to MS and to histamine in individual subjects revealed the responses to be significantly correlated in all cases, with the exception of wheal in patients with recurrent, unexplained anaphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Levels of mast-cell growth factors in plasma and in suction skin blister fluid in adults with mastocytosis: correlation with dermal mast-cell numbers and mast-cell tryptase.

BACKGROUND: Mast-cell accumulation has been observed in the skin and other organs of patients with systemic indolent mastocytosis (SM). The basis for this pathologic increase is not fully understood. OBJECTIVE: We sought to determine levels of mast-cell growth factors in the skin and plasma of patients with SM, patients with atopic dermatitis (AD), and healthy individuals and to correlate these levels to dermal mast-cell numbers and levels of mast-cell tryptase. METHODS: Skin suction blister fluid and plasma levels of stem-cell factor, IL-3, IL-4, IL-6, vascular endothelial growth factor, and total mast-cell tryptase were analyzed by means of ELISA. The number of mast cells was determined in a biopsy section taken from adjacent skin. RESULTS: Mast-cell numbers in the dermis were higher in patients with SM compared with numbers in patients with AD (P <.001) or in healthy control subjects (P <.0001) and correlated with tryptase levels in both skin blister fluid (P <.0001) and plasma (P <.0001). Stem-cell factor and vascular endothelial growth factor levels in the skin blister fluid and plasma of patients with SM were not significantly different from those in patients with AD or healthy control subjects. IL-3 and IL-4 levels were below the limit of detection. IL-6 levels were significantly increased in the plasma of patients with SM compared with in plasma of patients with AD (P <.002) and healthy control subjects (P <.0001) and correlated with plasma tryptase levels (P <.05) and dermal mast-cell numbers (P <.02). CONCLUSION: Because elevated levels of IL-6 could contribute to the fever, fatigue, and osteoporosis observed in patients with SM and because IL-6 is antiapoptotic for mast cells, IL-6 could potentiate the biologic consequences of this disease.     

Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis

The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, for example, in SRSF2, ASXL1, or RUNX1. Complex molecular profiles are frequently associated with the presence of an associated hematologic neoplasm (AHN) and an unfavorable clinical outcome. However, little is known about the incidence and prognostic impact of cytogenetic aberrations. We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n = 102, 94%) with indolent (ISM, n = 26) and advanced SM (n = 83) with (n = 73, 88%) or without AHN. An aberrant karyotype was identified in SM‐AHN (16/73, 22%) patients only. In patients with an aberrant karyotype, additional somatic mutations were identified in 12/16 (75%) patients. Seven of 10 (70%) patients with a poor‐risk karyotype, for example, monosomy 7 or complex karyotype, and 1/6 (17%) patients with a good‐risk karyotype progressed to secondary acute myeloid leukemia (n = 7) or mast cell leukemia (n = 1) within a median of 40 months (range 2‐190, P = .04). In advanced SM, the median overall survival (OS) of poor‐risk karyotype patients was significantly shorter than in good‐risk/normal karyotype patients (4 vs 39 months; hazard ratio 11.7, 95% CI 5.0‐27.3; P < .0001). Additionally, the shortened OS in patients with poor‐risk karyotype was independent from the mutation status. In summary, a poor‐risk karyotype is an independent prognostic variable in advanced SM. Cytogenetic and molecular analyses should be routinely performed in all patients with advanced SM ± AHN because these investigations greatly support prognostication and treatment decisions.     

Failure of sulfites to produce clinical responses in patients with systemic mastocytosis or recurrent anaphylaxis: Results of a single-blind study

Although sulfite sensitivity can precipitate asthma in a subpopulation of subjects with asthma, its role in precipitating anaphylaxis or as a nonspecific mast cell degranulator in systemic mastocytosis has not been examined. To evaluate critically the importance of sulfites in these diseases, eight patients with systemic mastocytosis and 25 patients with unexplained, recurrent anaphylaxis were challenged in a single-blind fashion; sodium bisulfite in capsules was administered in increasing doses of 1, 5, 10, 25, 50, 100, and 200 mg every 30 minutes. On separate occasions a liquid suspension of 200 mg of sodium bisulfite was administered to one patient with systemic mastocytosis and nine patients with anaphylaxis. Vital signs, pulmonary function tests, plasma histamine levels, and clinical reactions were monitored. There were no observable responses in either the mastocytosis group or in 23 of 25 patients in the anaphylaxis group. Two patients in the anaphylaxis group with initial positive challenges had similar symptoms on subsequent placebo challenge. One subject with asthma and with a history suggestive of sulfite sensitivity responded to oral challenge with 5 mg of sodium bisulfite and 100 micrograms of sodium bisulfite intradermally with a dramatic reduction in FEV, requiring treatment with bronchodilators. A comparison of baseline plasma histamine levels with those obtained after the sulfite challenge procedure in each category demonstrated a significant rise (p less than 0.05) in the systemic mastocytosis group. The overall level of significance determined by applying paired sample t tests to the histamine data from all subjects was p less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lymphadenopathy,elevated serum IgE levels,autoimmunity, and mast cell accumulation in flaky skin mutant mice

The autosomal recessive mutation “flaky skin” ( fsn ) causes pleiotropic abnormalities in the immune and hematopoietic systems accompanied by pathologic changes in the skin. Homozygotes ( fsn/fsn ) showed increased size and histological alterations in the spleen and lymph nodes. Abnormalities in lymphoid architecture of the spleen in fsn/fsn mice were accompanied by marked increases in total numbers of B cells, macrophages, and immature erythroid cells. Splenic B cells displayed elevated MHC class II expression. Serum IgE levels were greater than 100 μg/ml by 10 weeks of age, representing > 7000-fold increase compared with normal littermates. This increased IgE level was associated with elevated IL-4 production by spleen cells and with increased amounts of serum IL-4. Serum IgM, IgG1, and IgG2b levels were also increased in fsn/fsn mice while IgG3 was decreased. Autoimmunity in fsn/fsn mice was evidenced by glomerulonephritis accompanied by immune complex deposition in the kidneys, increased serum blood urea nitrogen levels, and the presence of circulating anti-double-stranded DNA autoantibodies. Pathological changes in the skin of fsn/fsn mice were characterized by epidermal hyperplasia and mixed dermal inflammation. Increased numbers of mast cells were also observed in the dermis of the truncal skin as well as in the epithelial stomach. These marked immunological abnormalities suggest that the fsn locus encodes a major immunoregulatory molecule important in multiple immune and hematopoietic functions.     

Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease

BACKGROUND: The serum tryptase level is used as a diagnostic marker in mastocytosis and is considered to reflect the burden of (neoplastic) mast cells (MC). METHODS: In the present study, serum tryptase levels were measured in patients with mastocytosis by fluoroenzyme immunoassay and compared with the extent of infiltration of the bone marrow (BM) by neoplastic MC, determined by tryptase immunohistochemistry. Sixteen patients with cutaneous mastocytosis (CM) and 43 patients with systemic mastocytosis (SM) were examined. RESULTS: In most patients with CM (defined by the absence of dense compact MC infiltrates in tryptase-stained BM sections), normal or near-normal serum tryptase levels (median 10 ng/ml, range 2-23 ng/ml) were measured. By contrast, in the vast majority of patients with SM, elevated serum tryptase levels (median 67 ng/ml) were found. In addition, there was a significant correlation between the grade of infiltration of the BM by neoplastic MC and tryptase levels in patients with SM (r = 0.8). Moreover, enzyme levels differed significantly among the groups of patients with different types of SM. The highest levels (>900 ng/ml) were detected in the patient with MC leukemia, 2 patients with slowly progressing SM and high MC burden (smoldering SM) and 1 patient with indolent SM. In contrast, in all 3 patients with isolated BM mastocytosis (no skin lesions and no signs of multiorgan involvement), serum tryptase levels were <20 ng/ml. CONCLUSIONS: In summary, our data suggest that the measurement of serum tryptase is a reliable noninvasive diagnostic approach to estimate the burden of MC in patients with mastocytosis and to distinguish between categories of disease.