Epidemiology, Prognosis, and RiskFactors in Mastocytosis

Knut Brockow, MD

KEYWORDS

� Mastocytosis � Mast cell activity syndrome� Monoclonal mast cell activation syndrome � Epidemiology � Prognosis � Risk factors

KEY POINTS

� The prevalence of overt mastocytosis has been estimated to be about 10 cases per100,000 inhabitants. That of monoclonal mast cell activation syndrome and of idiopathicmast cell activation syndrome remains unknown.

� Adult patients with mastocytosis predominantly exhibit indolent systemic mastocytosis(ISM) and in children cutaneous mastocytosis (CM) is assumed.

� Regression of mastocytosis in children is common and chronic persistence of skin mas-tocytosis in adults is typical.

� Evolution of ISM into more advanced forms of disease is an exceptional event.

� The life expectancy in patients with CM or ISM is not reduced.

EPIDEMIOLOGY OF MASTOCYTOSIS AND MAST CELL ACTIVATION SYNDROMESPrevalence of Mastocytosis

Mastocytosis is considered to be an orphan disease (affecting <200,000 people in theUnited States). There are no epidemiologic studies to define the precise incidence,point prevalence, or cumulative prevalence of mastocytosis in the general population(Box 1). Because of its rarity many doctors were unfamiliar with this disease and didnot recognize it. Thus, until recently, the number of recognized patients per single cen-ter was not sufficient and not reliable to estimate incidence and prevalence. In 1997, itwas estimated that 1 in 1000 to 8000 new patients seen in dermatology outpatientclinics may have some form of mastocytosis.1 Fortunately, this situation has improvedgreatly during the last two decades and this diagnosis has become more recog-nized.2,3 Another reason for missing data is that firm criteria for the diagnosis of mas-tocytosis have only been defined in 2001 and that the methods and experience todetect mastocytosis have improved, but continue to differ between departments.4

The author has nothing to disclose.Department of Dermatology and Allergy Biederstein, Technische Universitat Munchen, Bieder-steiner Strasse 29, Munich 80802, GermanyE-mail address: knut.brockow@lrz.tum.de

Immunol Allergy Clin N Am 34 (2014) 283–295http://dx.doi.org/10.1016/j.iac.2014.01.003 immunology.theclinics.com0889-8561/14/$ – see front matter � 2014 Elsevier Inc. All rights reserved.

Box 1

Prevalence of mastocytosis

� There is a lack of data to define the exact prevalence

� Prevalence for suspected or confirmed mastocytosis of 13 cases in 100,00 inhabitants is givenin one study

� It remains unclear if and how the inclusion of patients with anaphylaxis, but without skininvolvement, will increase the prevalence

� The prevalence of monoclonal mast cell activation syndrome is unknown

� Only a few patients with idiopathic mast cell activation syndrome have been described

Brockow284

The European Competence Network on Mastocytosis attempts to ensure a goodquality of diagnosis by defining reference and excellence centers for mastocytosis.3,5

In the only available study giving prevalence data in the general population, caseswith confirmed indolent systemic mastocytosis (ISM) or presumed ISM based oneither the presence of maculopapular cutaneous mastocytosis (MPCM) plus tryptaselevels greater than 20 ng/mL or on MPCM together with elevated tryptase levels(>10 ng/mL) or on clinical suspicion together with elevated mediator levels, werecollected.6 The home address was verified and the number of patients was dividedby the number of the total adult population living in this Dutch region. In this study,ISM prevalence in the adult population in the Netherlands has been estimated to be13 cases per 100,000 inhabitants. Of those, 31 patients had MPCM and 10 patientswere seen because of anaphylaxis without skin involvement. When the number of pa-tients in this competence center was analyzed, a steep increase in the number of ISMpatients was noted from 1998 to 2010, which is very likely the result of increased expe-rience and recognition of the disease in this area during these years. At the consensusmeeting of mastocytosis experts in Boston 2010, a general cumulative prevalence ofapproximately 1 in 10,000 persons was also estimated by other centers (LuisEscribano, Patrizia Bonadonna, personal communication, 2012).

Mastocytosis in Different Age and Gender Groups

Mastocytosis can occur in children and adults.7 Although mastocytosis can occur atany age, the onset of mastocytosis is in the first 2 years of life in 50%ormore of cases.8

Congenitalmastocytosis at birth is exceptional.9 In adults,most patients are diagnosedin middle age between 20 and 50 years of age.8 Because of a chronic nature and lowregression rate of adult-age mastocytosis the cumulative prevalence of adult patientsof mastocytosis rises with age. Gender distribution is approximately equal.

Systemic Mastocytosis Without Skin Lesions

It was previously believed that more than 95% of patients with mastocytosis would bedetectable by the presence of typical skin lesions.10 A few years ago, it was discov-ered that approximately 10% of patients with Hymenoptera sting anaphylaxis hadelevated serum tryptase levels greater than 11.4 ng/mL. Of these patients, a substan-tial proportion had ISM without skin lesions (ISM�).11 In one center that recruited pa-tients with classical skin lesions and patients with Hymenoptera sting and idiopathicanaphylaxis for further assessment, the number of patients without skin lesions(ISM�; N 5 46) was nearly as high as that with mastocytosis in the skin (MIS;ISM1; N 5 51) indicating that isolated bone marrow mastocytosis may be an under-estimated subvariant of SM.12

Risk Factors in Mastocytosis 285

Patients with insect-sting anaphylaxis and no MIS had male predominance (78%),less common cutaneous and abdominal symptoms of anaphylaxis, but more oftensyncope, lower baseline tryptase values, less frequently bonemarrowmast cell aggre-gates, and a mast cell–restricted KIT mutation pattern in comparison with ISM1.13

Thus, it has to be assumed that there is an additional specific subpopulation of pa-tients with SM, but without MIS, which may still be underdiagnosed.

Incidence of Monoclonal Mast Cell Activation Syndrome

By consensus classification, mastocytosis is only diagnosed if a set of major and mi-nor criteria is present.3,4 Patients with anaphylaxis and clonal mast cells expressingthe D816V mutation in KIT and expressing the a-chain of the interleukin-2 receptorCD25, but without the full set of criteria needed to diagnose mastocytosis, havebeen described.14,15 The diagnosis for these patients has been named monoclonalmast cell activation syndrome (MMAS).14,16 The prevalence of patients with othersymptoms of MMAS is yet unknown. In patients with anaphylaxis and systemicmast cell activation symptoms but without skin lesions where clonal mast cells couldbe detected, the most patients fulfilled the criteria for SM.17 Because the frequency ofMMAS varies among different study groups between 6% and 27%, it may be assumedthat the distinction between ISM without skin lesions (ISM�) and MMAS also dependson the methods used and the experience of the analyzers.11,17

Incidence of Idiopathic Mast Cell Activation Syndrome

An idiopathic mast cell activation syndrome recently has been defined.16,18 To givethis diagnosis, patients have to exhibit symptoms indicating mast cell mediatorrelease; the involvement of mast cells has to be documented by biochemical measure-ments, preferably by the increase in tryptase during a symptomatic period; symptomsshould respond to therapies with mast cell stabilizing agents or drugs directed againstmast cell mediator production, mediator release, or mediator effects; and other knownmast cell diseases should have been excluded.16 Different physicians in varied disci-plines have seen an increased number of subjects who presented with signs andsymptoms potentially indicating mast cell activation, such as flushing, abdominalpain, diarrhea, and more nonspecific symptoms, but where an extensive medical eval-uation has failed to result in a definitive diagnosis.18 Up to now only one study hasconvincingly presented patients with idiopathic mast cell activation syndrome andstudied the clinical manifestation of the disease in this cohort of 18 patients.19 Aboutthree-quarters of the patients presented with a combination of abdominal pain, der-matographism, and flushing with or without additional symptoms. Of note, only infive of these patients were increased levels of total or mature tryptase measured; inmost patients this increased mediator release was detected by histamine or prosta-glandin D2 measurements, which are more sensitive but less standardized and lessspecific compared with tryptase measurements. Thus, the prevalence of patientswith idiopathic mast cell activation syndrome presenting with otherwise unexplainedclinical symptoms resembling mast cell diseases remains unknown, but seems tobe low.

EPIDEMIOLOGY OF DIFFERENT FORMS OF MASTOCYTOSISPrevalence of Systemic Disease in Patients with Mastocytosis

The prevalence of systemic disease in patients with mastocytosis depends greatly onthe definition of SM, which has been changed in 2001, on the associated developmentof more sensitive methods for detecting mast cells and clonality (eg, use of the

Brockow286

tryptase stain to highlight mast cells), and on the experience of physicians. Theextracutaneous tissue that shows the highest numbers of mast cell in systemicinvolvement and that is still easily available is the bone marrow.20 Whereas in olderstudies mast cell infiltrates were detected in less than half of all patients withMPCM,21 this frequency did increase over the years,22 and with the availability ofnewer methods and criteria, the prevalence of SM in adult patients with MPCM hasrecently been reported to be more than 95% when the most sensitive methods areused by experienced physicians (Box 2).23,24 In children, bone marrow biopsies arerarely performed. In an older study, often more subtle nondiagnostic abnormalitieshave been reported in the bone marrow biopsy specimens of children.25 SM in chil-dren does exist, but overall the diagnosis is seldom made.26,27 Newer studies onthe exact prevalence of SM in children are lacking because of ethical reasons, butavailable evidence indicates that SM in children is rare.

Prevalence of Different Forms of SM

Mastocytosis is subclassified into cutaneous mastocytosis (CM), ISM, aggressive SM(ASM), SM with an associated hematologic non–mast cell disorder (SM-AHNMD),mast cell leukemia (MCL), mast cell sarcoma, and extracutaneous mastocytosis28

with differing typical clinical characteristics (Fig. 1). CM without systemic involvementis assumed but not proven in most children with MIS and seems to be seldom in adultswith mastocytosis.3 In adults and in the small majority of those children with internalinvolvement, ISM is the most common form. The exact frequency of this form dependsstrongly on the specialty of the department seeing the patients. It is prudent to assumethat 90% to 95% of all patients with mastocytosis exhibit ISM. After CM and ISM,SM-AHNMD is the most frequent form of mastocytosis and predominantly seen in he-matology departments. In one large study of the Mayo Clinic analyzing 342 consecu-tive patients, 89% of patients with SM-AHNMD had an associated myeloid neoplasm,such as myeloproliferative neoplasm, chronic myelocytic leukemia, and myelodys-plastic syndrome.29 Diagnoses in the remainder were lymphoma, myeloma, chroniclymphocytic leukemia, or primary amyloidosis. Aggressive SM is rare and often asso-ciated with SM-AHNMD.30 Whereas in specialized hematology departments the fre-quency of ASM, SM-AHNMD, and MCL has been reported to be up to 40%, 12%,and 1% of patients,29 respectively, in our and most other dermatology and allergy de-partments less than 5% of patients fulfill the criteria for these subtypes (Brockow, un-published observation, 2014). Patients with ISM are significantly more likely to haveMIS and less likely to exhibit constitutional symptoms or hepatomegaly comparedwith patients with advanced SM.29 MCL is rare even in hematology departments.29

Of interest, MCL is associated normally with no MIS and it has been speculatedthat in aggressive SM and in SM-AHNMD the frequency of cutaneous signs of

Box 2

Epidemiology of different forms of mastocytosis

� More than 95% of adults but only a minority of children with mastocytosis has systemicinvolvement

� In adults, indolent systemic mastocytosis is predominant, whereas more advanced forms areinfrequent

� Maculopapular cutaneous mastocytosis is the most commonly reported form of mastocytosisin the skin in children and adults

Fig. 1. Typical clinical characteristics of patients with different forms of mastocytosis. ASM,aggressive systemic mastocytosis; CM, cutaneous mastocytosis; ISM, indolent systemic masto-cytosis; ISM�/Ax1, patients with anaphylaxis and isolated bone marrow mastocytosis; MCL,mast cell leukemia; SM-AHNMD, systemic mastocytosis with associated hematologic non–mast cell disease. (Modified from Pardanani A. Systemic mastocytosis in adults: 2013 updateon diagnosis, risk stratification, and management. Am J Hematol 2013 Jul;88:612–24; withpermission.)

Risk Factors in Mastocytosis 287

mastocytosis is only approximately 50%.16 Mast cell sarcoma and extracutaneousmastocytomas are exceedingly rare.4,31

Prevalence of Different Forms of MIS

The characteristics of MIS differ between childhood- and adult-onset mastocytosis.32

In pediatric mastocytosis, different forms of skin involvement exist. In our departmentand some other studies, mostly children with MPCM are seen,8,33 whereas a differentstudy states that mastocytomas would be more prevalent.34 Because children withmastocytomas may be less likely to be presented at specialty departments, it remainsunclear which manifestation may occur more often. Nodular and plaque forms of MISin children are less common.33 The distinction between MPCM and the plaque formmay be difficult, because skin lesions are sometimes only minimally elevated andhave variable sizes. Diffuse CM is the least common form of childhood MIS andmost reference centers only see a few of these patients. In adults, all patients haveMPCM with more or less pigmentation and erythema. The extreme depigmentedtelangiectatic spectrum of this form may also be called telangiectasia macularis erup-tiva perstans, but has to be differentiated from essential telangiectasias.35,36 Becausethere is no clear distinction, the percentage of patients with MPCM called telangiec-tasia macularis eruptiva perstans varies among different physicians in differentstudies.

PROGNOSIS FOR REGRESSION OR PROGRESSION OF DISEASEPrognosis for Resolution of CM in Children

Data on the natural history of childhood-onset mastocytosis comemostly from studieswhere the analysis depended on retrospective chart reviews and reporting on skin ex-aminations.26 Although it often has been stated that resolution of the disease wouldhappen in more than 50% of patients, there are only a small number of studies onwhich this conclusion was based. A recent study attempted to analyze patients witha longer duration of follow-up and re-examined 15 individuals who had been diag-nosed with mastocytosis as children 20 years earlier.26 Complete regression wasseen in 67%, major regression in 20%, and partial regression in 13%. Initial bone

Brockow288

marrow examinations in three patients with SM were associated with later persistentdisease. Thus, mast cell aggregates in the bone marrow biopsies were prognostic forpersistent disease.

Prognosis for Resolution of CM in Adults

For patients with adult-onset mastocytosis, persistence of disease is typical andregression of skin lesions only occurs in a subset of patients. In a study investigatingclinical correlates of MPCM regression in adult patients with SM, 106 patients werefollowed up for a minimum of 10 years.37 Of those, regression was noted in 12 patientswith complete clearance (N 5 5) or a decrease (N 5 7) of skin lesions. An age olderthan 50 years was the only prognostic feature for regression of MPCM. Regressionof MIS was not indicative for the clinical course of disease because two patientswith SM-AHNMD experienced deterioration of their clinical condition, whereas in all10 patients with ISM severity and frequency of symptoms decreased. The regressionof MPCM also did not indicate total clearance from mastocytosis because in all pa-tients in whom bone marrow biopsy results were available at different time points,the later did not differ significantly from the initial findings in patients undergoing theprocedure.

Prognosis for Progression of Disease and Survival

After initial occurrence and deterioration of MIS and clinical symptoms, a stable phaseis seen in most children and adults with mastocytosis.10 The prognosis of patientswith adult ISM has been studied in a long-term follow-up of 145 consecutive adult pa-tients observed for a median of 147 months.24 The results show that the disease wasstable in most patients. There were signs for biologic progression indicating anincreased proliferation of mast cells, such as an increase in serum tryptase greaterthan 200 ng/mL, osteoporosis, or organomegalies in 27% of patients. Only five pa-tients (3%) showed progression from ISM to a more advanced form of SM. One pa-tient developed ASM, three patients SM-AHNMD, and one patient MCL. Thecumulative probability of disease progression in ISM was calculated to be 1.7% in10 years. Multivariate analysis showed that serum b2-microglobulin in combinationwith the presence of KIT-mutation in all hematopoietic lineages was the best combi-nation of independent parameters for predicting disease progression from ISM into amore aggressive form (Box 3). Regarding overall survival, most patients with initialISM had a normal life expectancy and death was directly related to mastocytosis inonly two cases.Thus, evolution of ISM into an aggressive form of the disease has to be considered

to be an exceptional event. The results are in contrast to a retrospective study with 58cases of SM where only 45.5% remained alive after a median follow-up of 7.6 years,38

but in agreement with a later study from the same institution that discriminated be-tween patients with ISM (N5 24) and ASM (N5 16). Eight patients (20%) in this studywith ASM died during the observation period, but none with ISM.39 Apart from the spe-cific subtype of mastocytosis, anemia, increased serum alkaline phosphatase, and thedegree of bone marrow involvement assessed by histopathology had been discussedas predictors for overall survival of mastocytosis in these older studies.39 In the studyby Escribano and coworkers,24 the association between these parameters and overallsurvival in patients with ISM was confirmed. The variables with the highest predictedvalue for a shorter overall survival in the multivariable analysis were age at diagnosisgreater than 60 years, increased serum alkaline phosphatase, and development ofSM-AHNMD. The cumulative probability of death in patients with ISM was 2.2% at5 years and 11% at 25 years.

Box 3

Prognostic factors for mastocytosis

Factors May Indicate

Mast cell aggregates in the initial bonemarrow biopsy

Persistence of pediatric mastocytosis intoadulthood

Advanced age Regression of cutaneous mastocytosis inadults

Presence of KIT mutation in allhematopoietic lineages; elevated b2microglobulin levels

Progression from indolent systemicmastocytosis to more advanced formsof SM

Immature bone marrow mast cell phenotype(CD251/FCεR1low/FSClow/SSClow/CD45low) inabsence of coexisting normal mast cells

Presence of KIT mutation in allhematopoietic lineages

Advanced subtypes of SM, anemia,hypoalbuminemia, serum alkalinephosphatase, blasts in and degree of bonemarrow involvement, advanced age, ageat diagnosis, weight loss, high alleleburden, additional genetic mutations inhematopoietic cells

Decreased survival

Risk Factors in Mastocytosis 289

In a retrospective study on 342 consecutive adult patients seen at the Mayo Clinic,wheremore than half of the patients had advanced forms of SM, life expectancy in ISMwas superior and not significantly different from that of the age and gender-matchedpopulation.40 However, the survival of the smoldering form of ISM, which is character-ized by high mast cell numbers in the tissue, was associated with a shorter survivalcompared with the rest of ISM. The overall median survival in SM-AHNMD was24 months, in patients with ASM 41 months, and in the four patients with MCL only2 months. Multivariable analysis identified advanced age, weight loss, anemia, throm-bocytopenia, hypoalbuminemia, and excess bone marrow blasts as independentprognostic factors for survival.Increased plasma CD25 levels have been reported to be associated with inferior

overall survival in a mixed cohort of patients with advanced and indolent SM, whichwere independent of other risk factors.41 Immunophenotyping may also be of valueas a prognostic marker for disease progression. An immature bone marrow mastcell phenotype (CD251/FCεR1low/FSClow/SSClow/CD45low) in absence of coexistingnormal mast cells correlates with multilineage hematopoietic KIT D816V mutationsmore frequently seen in cases with SM-AHNMD, ASM, and MCL.42 In contrast, inISM bone marrow mast cells display a more mature activated MC phenotype(CD631/CD691/CD2031).In a study measuring KIT D816V–expressed allele burden by quantitative polymer-

ase chain reaction, the allele burden was strongly correlated with disease activity, dis-ease subtype (ISM vs advanced SM), and survival in 63 patients with ISM, 8 patientswith a smoldering type of ISM, 16 patients with AS-AHNMD, and 60 patients with ASMor MCL � AHNMD.30 The prognosis of SM was also related to the pattern of mutatedgenes that were acquired during disease evolution.43 In 39 patients with differentforms of indolent and advanced SM, additional molecular aberrations were found in24 of 27 patients with advanced SM but only in 3 of 12 patients (25%) with ISM.Most frequently affected genes were TET2, SRSF2, ASXL1, CBL, and RUNX1. Mostpatients with advanced SM carried greater than or equal to 3 mutations. The overallsurvival was shorter in patients with additional aberration compared with those withonly KIT D816V mutations.

Brockow290

RISK FACTORS FOR MAJOR COMPLICATIONS OF MASTOCYTOSISRisk Factors for More Severe Clinical Disease

In a prospective study of 48 adults and 19 children with MPCM the extent and densityof cutaneous lesions were compared with symptomatology, tryptase levels, and bonemarrow pathology.32 In children, possibly because of a low number of included pa-tients, symptoms, and available bone marrow pathologies, the extent of cutaneousdisease was not associated with systemic involvement or symptomatology. Therewas a borderline correlation between the extent of cutaneous disease and serum tryp-tase levels (P<.06). Because it is known that patients with diffuse CM involving thewhole body tend to have more severe symptoms and sometimes also positive bonemarrow pathologies,44 it has been discussed that inclusion of a higher number of chil-dren with more severe disease would have been more likely to show a significant as-sociation. This is in agreement with a study of 111 patients with MIS to identifypredictors for severe mast cell activation episodes.45 The results showed that all12 children (11% of total) who suffered symptoms requiring hospitalization alsoexhibited extensive cutaneous disease involving greater than 90% of the body surfacearea. These patients also had higher serum tryptase levels compared with those of therest of the children with skin involvement of less than 90% (45 vs 5 ng/mL). Thus, ahigh extent of cutaneous disease involvement and elevated tryptase levels identifiedpatients at risk for severe and sometimes life-threatening mast cell activation events.Receiver operating characteristic curve analysis showed that serum tryptase levels of7, 16, and 31 ng/mL were the best cut-off values for the risk of daily antimediator ther-apy, hospitalization, and the management in an intensive care unit, respectively. Whenthe data were reanalyzed, it was emphasized that all of the patients who had to betreated in the intensive care unit had extensive blistering, which should be regardedas a predictor for severe complications in children with mastocytosis.46 This is inagreement with rare fatal complications in children with mastocytosis that were re-ported together with severe blistering episodes.47,48

In adults with skin lesions, the extent of lesions correlated to disease duration, pru-ritus, flushing, fatigue, splenomegaly, hepatomegaly, serum tryptase levels, and bonemarrow pathology.32 Thus, an examination of the extent of cutaneous lesions in adultshelps to identify those with more extensive extracutaneous disease.MIS itself may be diagnostic for SM. When new sensitive methods were applied to

analyze the presence of World Health Organization–defined diagnostic criteria forSM in 95 patients with MIS, it was shown that in all 58 bone marrow biopsies inves-tigated an SM could be detected.49 Thus, adult-onset MIS itself was highly predic-tive of systemic involvement in mastocytosis. Baseline serum tryptase and elevatedurinary histamine metabolites have been reported to be surrogate markers forSM.50,51

In a study of 39 adult patients with ISM, the KIT D816V mutation burden as detectedby a sensitive quantitative polymerase chain reaction in peripheral blood cells showsthat mutation levels were associated with baseline serum tryptase levels.52 Baselineserum tryptase levels greater than 20 ng/mL are a minor criterion for SM.4 However,within the group of patients with ISM, the KIT D816V mutation burden in peripheralblood and bone marrow aspirate cells was not correlated with the grade of symptomsof mast cell activation episodes with and without anaphylaxis or with and without oste-oporosis and normal bone mineral density.53

Other predictors for an increased disease severity described in the literature andrelated to baseline serum tryptase levels were soluble CD25, soluble CD117 (KIT),and interleukin-6.54,55

Risk Factors in Mastocytosis 291

Risk Factors for Anaphylaxis in Patients with Mastocytosis

In children with mastocytosis, a significantly increased risk to develop anaphylaxisseems to be restricted to those with extensive skin involvement and high serum tryp-tase levels.45 In adults with mastocytosis, depending on the study population, a cumu-lative prevalence of anaphylaxis has been reported to be between 22% and 49% ofpatients.56–58 Those with systemic disease had an increased risk of anaphylaxiscompared with those with cutaneous disease, especially when atopy was pre-sent.56,58 Anaphylaxis in patients with mastocytosis with but not without skin involve-ment was associated with higher basal serum tryptase levels.56,58

The most frequently reported elicitors of anaphylaxis in patients with mastocytosisare Hymenoptera venoms.56–58 The severity of reactions in patients with mastocytosisseems to be increased compared with those without mastocytosis.59 The level ofbasal serum tryptase is the strongest predictor for a higher severity in insect stinganaphylaxis.60 In contrast to this general principle, a more complex association be-tween serum tryptase levels and the prevalence of insect sting anaphylaxis hasbeen reported with the prevalence initially rising but subsequently falling in relationto increasing serum tryptase levels.61

Whereas there is a strong association between mastocytosis and insect stinganaphylaxis, and whereas not uncommonly patients with idiopathic anaphylaxishave been described in this patient group, the association between mastocytosisand drug or food anaphylaxis does not seem to be strong.62,63 In one study of 137 pa-tients with drug- or food-induced anaphylaxis, only two patients were diagnosed withmastocytosis.62

Risk Factors for Osteoporosis in Patients with Mastocytosis

Vertebral osteoporosis and fractures are frequent in adult patients with SM. In a study of75 patients with SM who underwent skeletal radiographs and bone mineral densityassessment, 37 patients (48%) had bone involvement including osteoporosis (N 5 23;31%)with vertebral fractures in13patients (17%).64 Inone retrospectivestudy in157pa-tients with ISM, 235 lifetime fractures including 140 osteoporotic fractures wererecorded, of which 62% were vertebral.65 Osteoporotic fractures and osteoporosiswere reported to be present in 37% and 28% of patients, respectively. The prevalenceof these manifestations was higher in men than in women. Predictors for osteoporoticmanifestations were older age, male gender, and higher urinary methylhistamine.65

There seems to be no significant correlation between serum tryptase levels and T or Zscores for bone mineral density,66 and in one publication elevated tryptase levelswere associated with an even greater bone density in one cohort of patients.67

REFERENCES

1. Golkar L, Bernhard JD. Mastocytosis. Lancet 1997;349:1379–85.2. Metcalfe DD. Classification and diagnosis of mastocytosis: current status.

J Invest Dermatol 1991;96(Suppl 3):2S–4S.3. Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocy-

tosis: consensus statements on diagnostics, treatment recommendations andresponse criteria. Eur J Clin Invest 2007;37:435–53.

4. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification ofmastocytosis: a consensus proposal. Leuk Res 2001;25:603–25.

5. Valent P, Arock M, Bonadonna P, et al. European Competence Network on Mas-tocytosis (ECNM): 10-year jubilee, update, and future perspectives. Wien KlinWochenschr 2012;124:807–14.

Brockow292

6. van Doormaal JJ, Arends S, Brunekreeft KL, et al. Prevalence of indolent sys-temic mastocytosis in a Dutch region. J Allergy Clin Immunol 2013;131:1429–31.

7. Brockow K, Metcalfe DD. Mastocytosis. Chem Immunol Allergy 2010;95:110–24.8. Kettelhut BV, Metcalfe DD. Pediatric mastocytosis. J Invest Dermatol 1991;96:

15S–8S.9. Kuint J, Bielorai B, Gilat D, et al. C-kit activating mutation in a neonate with in-

utero presentation of systemic mastocytosis associated with myeloproliferativedisorder [letter]. Br J Haematol 1999;106:838–9.

10. Brockow K, Metcalfe D. Mastocytosis. In: Rich R, Fleischer T, Shearer W, et al,editors. Clinical immunology. Vol. 1. 2nd edition. London: Mosby InternationalLtd; 2001. p. 55.1–.9.

11. Bonadonna P, Perbellini O, Passalacqua G, et al. Clonal mast cell disorders inpatients with systemic reactions to Hymenoptera stings and increased serumtryptase levels. J Allergy Clin Immunol 2009;123:680–6.

12. Zanotti R, Bonadonna P, Bonifacio M, et al. Isolated bone marrow mastocytosis:an underestimated subvariant of indolent systemic mastocytosis. Haematolog-ica 2011;96(3):482–4.

13. Alvarez-Twose I, Zanotti R, Gonzalez-de-Olano D, et al. Nonaggressive systemicmastocytosis (SM) without skin lesions associated with insect-induced anaphy-laxis shows unique features versus other indolent SM. J Allergy Clin Immunol.pii: S0091-6749(13)00988-3. http://dx.doi.org/10.1016/j.jaci.2013.06.020. Ac-cessed August 3, 2013. [Epub ahead of print].

14. Sonneck K, Florian S, Mullauer L, et al. Diagnostic and subdiagnostic accumu-lation of mast cells in the bone marrow of patients with anaphylaxis: monoclonalmast cell activation syndrome. Int Arch Allergy Immunol 2007;142:158–64.

15. Akin C, Scott LM, Kocabas CN, et al. Demonstration of an aberrant mast-cellpopulation with clonal markers in a subset of patients with “idiopathic” anaphy-laxis. Blood 2007;110:2331–3.

16. Valent P, Akin C, Arock M, et al. Definitions, criteria and global classification ofmast cell disorders with special reference to mast cell activation syndromes: aconsensus proposal. Int Arch Allergy Immunol 2012;157:215–25.

17. Alvarez-Twose I, Gonzalez de Olano D, Sanchez-Munoz L, et al. Clinical, biolog-ical, and molecular characteristics of clonal mast cell disorders presenting withsystemic mast cell activation symptoms. J Allergy Clin Immunol 2010;125:1269–78.

18. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diag-nostic criteria. J Allergy Clin Immunol 2010;126:1099–104.

19. Hamilton MJ, Hornick JL, Akin C, et al. Mast cell activation syndrome: anewly recognized disorder with systemic clinical manifestations. J Allergy ClinImmunol 2011;128:147–52.

20. Parker RI. Hematologic aspects of mastocytosis: I: bone marrow pathology inadult and pediatric systemic mast cell disease. J Invest Dermatol 1991;96:47S–51S.

21. Czarnetzki BM, Kolde G, Schoemann A, et al. Bone marrow findings in adult pa-tients with urticaria pigmentosa. J Am Acad Dermatol 1988;18:45–51.

22. Topar G, Staudacher C, Geisen F, et al. Urticaria pigmentosa: a clinical, hema-topathologic, and serologic study of 30 adults. Am J Clin Pathol 1998;109:279–85.

23. Brockow K, Ring J. Update on diagnosis and treatment of mastocytosis. CurrAllergy Asthma Rep 2011;11:292–9.

Risk Factors in Mastocytosis 293

24. Escribano L, Alvarez-Twose I, Sanchez-Munoz L, et al. Prognosis in adult indo-lent systemic mastocytosis: a long-term study of the Spanish Network on Mas-tocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514–21.

25. Kettelhut BV, Parker RI, Travis WD, et al. Hematopathology of the bone marrowin pediatric cutaneous mastocytosis. A study of 17 patients. Am J Clin Pathol1989;91:558–62.

26. Uzzaman A, Maric I, Noel P, et al. Pediatric-onset mastocytosis: a long term clin-ical follow-up and correlation with bone marrow histopathology. Pediatr BloodCancer 2009;53:629–34.

27. Carter MC, Uzzaman A, Scott LM, et al. Pediatric mastocytosis: routine anes-thetic management for a complex disease. Anesth Analg 2008;107:422–7.

28. Valent P, Arock M, Akin C, et al. The classification of systemic mastocytosisshould include mast cell leukemia (MCL) and systemic mastocytosis with aclonal hematologic non-mast cell lineage disease (SM-AHNMD). Blood 2010;116:850–1.

29. Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutiveadults: survival studies and prognostic factors. Blood 2009;113:5727–36.

30. Erben P, Schwaab J, Metzgeroth G, et al. The KIT D816V expressed alleleburden for diagnosis and disease monitoring of systemic mastocytosis. AnnHematol 2014;93(1):81–8.

31. Bautista-QuachMA, Booth CL, Kheradpour A, et al. Mast cell sarcoma in an infant:a case report and reviewof the literature. J PediatrHematolOncol 2013;35:315–20.

32. Brockow K, Akin C, Huber M, et al. Assessment of the extent of cutaneousinvolvement in children and adults with mastocytosis: relationship to symptom-atology, tryptase levels, and bone marrow pathology. J Am Acad Dermatol2003;48:508–16.

33. Brockow K. Urticaria pigmentosa. Immunol Allergy Clin North Am 2004;24:287–316, vii.

34. Hannaford R, Rogers M. Presentation of cutaneous mastocytosis in 173 chil-dren. Australas J Dermatol 2001;42:15–21.

35. Weber FP. Telangiectasia macularis eruptiva perstans: probably a telangiectaticvariety of urticaria pigmentosa in an adult. Proc R Soc Med 1930;24:96–7.

36. Moursund MP, Hirschmann VR. Telangiectasia macularis eruptiva perstans: re-view of the literature, report of a case and discussion of the etiology and pathol-ogy of generalized telangiectasia. AMA Arch Derm Syphilol 1951;63:232–49.

37. Brockow K, Scott LM, Worobec AS, et al. Regression of urticaria pigmentosa inadult patients with systemic mastocytosis: correlation with clinical patterns ofdisease. Arch Dermatol 2002;138:785–90.

38. Travis WD, Li CY, Bergstralh EJ, et al. Systemic mast cell disease. Analysis of58 cases and literature review. Medicine (Baltimore) 1988;67:345–68 [Erratumappears in Medicine (Baltimore) 1990;69(1):34].

39. Pardanani A, Baek JY, Li CY, et al. Systemic mast cell disease without associ-ated hematologic disorder: a combined retrospective and prospective study.Mayo Clin Proc 2002;77:1169–75.

40. Lim KH, Pardanani A, Butterfield JH, et al. Cytoreductive therapy in 108 adultswith systemic mastocytosis: outcome analysis and response prediction duringtreatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeox-yadenosine. Am J Hematol 2009;84:790–4.

41. Pardanani A, Finke C, Abdelrahman RA, et al. Increased circulating IL-2Ralpha(CD25) predicts poor outcome in both indolent and aggressive forms of mastocy-tosis: a comprehensive cytokine-phenotype study. Leukemia 2013;27:1430–3.

Brockow294

42. Teodosio C, Garcia-Montero AC, Jara-Acevedo M, et al. An immature immuno-phenotype of bone marrow mast cells predicts for multilineage D816V KIT mu-tation in systemic mastocytosis. Leukemia 2012;26:951–8.

43. Schwaab J, Schnittger S, Sotlar K, et al. Comprehensive mutational profiling inadvanced systemic mastocytosis. Blood 2013;122:2460–6.

44. Waxtein LM, Vega-Memije ME, Cortes-Franco R, et al. Diffuse cutaneous masto-cytosis with bone marrow infiltration in a child: a case report. Pediatr Dermatol2000;17:198–201.

45. Alvarez-Twose I, Vano-Galvan S, Sanchez-Munoz L, et al. Increased serumbaseline tryptase levels and extensive skin involvement are predictors for theseverity of mast cell activation episodes in children with mastocytosis. Allergy2012;67:813–21.

46. Brockow K, Ring J, Alvarez-Twose I, et al. Extensive blistering is a predictor forsevere complications in children with mastocytosis. Allergy 2012;67:1323–4.

47. Murphy M, Walsh D, Drumm B, et al. Bullous mastocytosis: a fatal outcome. Pe-diatr Dermatol 1999;16:452–5.

48. Golitz LE, Weston WL, Lane AT. Bullous mastocytosis: diffuse cutaneous masto-cytosis with extensive blisters mimicking scalded skin syndrome or erythemamultiforme. Pediatr Dermatol 1984;1:288–94.

49. Berezowska S, Flaig MJ, Rueff F, et al. Adult-onset mastocytosis in the skin ishighly suggestive of systemic mastocytosis. Mod Pathol 2014;27(1):19–29.

50. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Im-munol Allergy Clin North Am 2006;26:451–63.

51. van Doormaal JJ, van der Veer E, van Voorst Vader PC, et al. Tryptase and his-tamine metabolites as diagnostic indicators of indolent systemic mastocytosiswithout skin lesions. Allergy 2012;67:683–90.

52. Kristensen T, Broesby-Olsen S, Vestergaard H, et al. Serum tryptase correlateswith the KIT D816V mutation burden in adults with indolent systemic mastocyto-sis. Eur J Haematol 2013;91:106–11.

53. Broesby-Olsen S, Kristensen T, Vestergaard H, et al. KIT D816V mutationburden does not correlate to clinical manifestations of indolent systemic masto-cytosis. J Allergy Clin Immunol 2013;132:723–8.

54. Akin C, Schwartz LB, Kitoh T, et al. Soluble stem cell factor receptor (CD117)and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mas-tocytosis: relationships to disease severity and bone marrow pathology. Blood2000;96:1267–73.

55. BrockowK, AkinC, HuberM, et al. IL-6 levels predict disease variant and extent oforgan involvement in patients with mastocytosis. Clin Immunol 2005;115:216–23.

56. Brockow K, Jofer C, Behrendt H, et al. Anaphylaxis in patients with mastocyto-sis: a study on history, clinical features and risk factors in 120 patients. Allergy2008;63:226–32.

57. Gonzalez de Olano D, de la Hoz Caballer B, Nunez Lopez R, et al. Prevalence ofallergy and anaphylactic symptoms in 210 adult and pediatric patients withmastocytosis in Spain: a study of the Spanish network on mastocytosis(REMA). Clin Exp Allergy 2007;37:1547–55.

58. Gulen T, Hagglund H, Dahlen B, et al. High prevalence of anaphylaxis in pa-tients with systemic mastocytosis: a single-center experience. Clin Exp Allergy2014;44(1):121–9.

59. Ludolph-Hauser D, Rueff F, Fries C, et al. Constitutively raised serum concentra-tions of mast-cell tryptase and severe anaphylactic reactions to Hymenopterastings. Lancet 2001;357:361–2.

Risk Factors in Mastocytosis 295

60. Rueff F, Przybilla B, Bilo MB, et al. Predictors of severe systemic anaphylacticreactions in patients with Hymenoptera venom allergy: importance of baselineserum tryptase. A study of the European Academy of Allergology and ClinicalImmunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Im-munol 2009;124:1047–54.

61. van Anrooij B, van der Veer E, de Monchy JG, et al. Higher mast cell load de-creases the risk of Hymenoptera venom-induced anaphylaxis in patients withmastocytosis. J Allergy Clin Immunol 2013;132:125–30.

62. Bonadonna P, Zanotti R, Pagani M, et al. How much specific is the associationbetween Hymenoptera venom allergy and mastocytosis? Allergy 2009;64:1379–82.

63. Brockow K, Bonadonna P. Drug allergy in mast cell disease. Curr Opin AllergyClin Immunol 2012;12:354–60.

64. Barete S, Assous N, de Gennes C, et al. Systemic mastocytosis and boneinvolvement in a cohort of 75 patients. Ann Rheum Dis 2010;69(10):1838–41.

65. van der Veer E, van der Goot W, de Monchy JG, et al. High prevalence of frac-tures and osteoporosis in patients with indolent systemic mastocytosis. Allergy2012;67:431–8.

66. Rossini M, Zanotti R, Bonadonna P, et al. Bone mineral density, bone turnovermarkers and fractures in patients with indolent systemic mastocytosis. Bone2011;49:880–5.

67. Kushnir-Sukhov NM, Brittain E, Reynolds JC, et al. Elevated tryptase levels areassociated with greater bone density in a cohort of patients with mastocytosis.Int Arch Allergy Immunol 2006;139:265–70.