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Disease Summaries

Mastocytosis - Where are we now?

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Posted: July 2011

Odette McNeill, MD, FRACP
University of Western Sydney
Department of Allergy and Immunology, Campbelltown Hospital
Sydney, Australia
Constance H. Katelaris, MD, FRACP PhD
Professor, Immunology and Allergy
University of Western Sydney
Campbelltown Hospital
Sydney, Australia
 

 

Abstract

Over the last few years, there has been a proliferation of literature in accredited medical journals enhancing our understanding and knowledge of mastocytosis. This article will review the definition and diagnosis of mastocytosis, and provide a literature review on the varied clinical manifestations and current management options for mastocytosis.

Key words : mastocytosis, tryptase, anaphylaxis, mast cell

Introduction

Mast cells (MCs) play a central role in anaphylaxis and allergic disease. They are implicated in various autoimmune diseases, inflammatory conditions and certain malignancies [1]. Mastocytosis refers to a heterogeneous group of disorders characterised by the presence of excessive MCs in one or more tissues. It is a rare disorder, and the exact incidence is unknown. There are diverse clinical manifestations of this disease, so it is important to recognise these to be able to provide optimum management for patients with mastocytosis. This article will review the definition and diagnosis of mastocytosis, and provide a literature review on the varied clinical manifestations and current management options for mastocytosis.

Criteria/Definition

Diseases of MC disorders can be classified according to their clinical presentation, pathologic findings and prognosis [2].

The current WHO classification of mastocytosis is outlined in Table 1 [3]. It is imperative to recognise the different variants of mastocytosis as therapeutic options and prognosis are very dependent on the classification. The definitive WHO diagnosis of systemic mastocytosis requires the presence of one major and one minor criteria; OR three minor criteria. (Table 2, [4])

Clinical Features

Mastocytosis affects males and females in equal ratios. Children are more likely to have a benign course, with the majority having cutaneous manifestations only. Adults appear to have a more persistent course of the disease. Table 3 summarises the clinical findings of patients documented in 3 recent major papers [5,6,7].

Brockow et al [5] found that the triggers for anaphylaxis in patients with mastocytosis (Hymenoptera stings, foods and medication) appear to be very similar in individuals without mastocytosis. However, the association between Hymenoptera venom allergy and mastocytosis seems to be more specific compared to food or drug-induced systemic reactions [8]. Potier et al [9] suggested screening patients with Hymenoptera and Diptera anaphylaxis for mastocytosis with basal serum tryptase and skin biopsy. In his study, 23 of 140 patients with Hymenoptera and Diptera anaphylaxis had an elevated basal tryptase. The diagnosis of mastocytosis was made in 17 patients (5 CM and 12 SM). These patients also had more frequent flushing and less urticaria during an episode of anaphylaxis [9]. Alcohol, exercise and aspirin are potential triggers, and are also important co-factors in anaphylaxis [5].

Patients with extensive systemic disease, elevated baseline serum tryptase and elevated IgE have an increased risk for developing severe anaphylaxis [5,6]. Allergic disease in patients with mastocytosis occurs with a similar frequency as in the general population [6]. Co-existing atopy appears not to influence masctocytosis-related symptoms [6]. Interestingly, the presence of atopy did not appear to be a major risk factor for anaphylaxis, in contrast to patients without mastocytosis [5]. According to Gonzalez et al [6], the pattern of aeroallergen sensitisation in atopic patients with mastocytosis did not differ from that found in patients without mastocytosis.

Osteoporosis due to mastocytosis is becoming increasingly acknowledged [10]. The presence of osteoporosis especially in young males should alert the treating physician to the possibility of a diagnosis of mastocytosis. In a Spanish review of 145 adult patients with ISM [11], osteoporosis occurred in 18% of patients. Other skeletal findings include patchy or diffuse bone sclerosis and osteolysis.

Skin findings in Cutaneous Mastocytosis

1) Urticaria pigmentosa (UP) - this is the most common form of skin manifestation in children and adults. It appears as yellow to reddish-brown macules and can be slightly raised papules (see Picture 1a-c). It usually occurs on the upper and lower extremities, but the chest and abdominal wall can be affected as well. It is rare on the palms, soles, face, scalp and other sun-exposed areas. Darier's sign can be elicited (which is defined as the development of erythema and urticaria within 5 minutes after persistent scratching or rubbing of affected skin).

2) Telangiectasia macularis eruptive perstans - this is rare and is characterised by tan to brown macules with presence of telangiestasia.

3) Mastocytomas of the skin - this is less common than UP and is usually present in children. There is a typical history of flushing when the lesion is rubbed or disturbed. These lesions may spontaneously involute.

Pathogenesis

MC growth, differentiation and survival are dependent on stem cell factor (SCF) which acts primarily via the receptor tyrosine kinase c-kit (CD 117) on the surface of MCs. This stimulates various signal transduction pathways which ultimately leads to increased number of MCs (see Diagram 1) [2]. KIT encodes for the protein c-kit. Therefore, activating mutations of KIT results in "overactive" KIT in mastocytosis. Various mutations have now been described; the commonest being D816V (in codon 816 with valine being substituted for aspartate).

Other described mutations include TET2 mutation (associated with D816V mutation and monocytosis) [12], FIP1L1-PDGFRA (associated with eosinophilia) and JAK2V617F (restricted to SM-AHNMD) [7]

Diagnosis

It is recommended that all adults presenting with mastocytosis undergo bone marrow examination as the incidence of systemic disease is high [7]. The reverse is true for infants and children unless SM is suspected or there is presence of peripheral blood abnormalities, splenomegaly, hepatomegaly or lymphadenopathy [13].

Bone marrow trephine evaluation should include staining for tryptase, c-kit/CD117 and CD25 [14]. Bone marrow aspirate should be sent for flow cytometry for immunophenotyping [14,15]. Neoplastic MCs appear to aberrantly express CD25 and CD2.

The presence of D816V KIT mutation should be determined. This provides additional information, therapeutic options and prognosis as outlined below.

Baseline serum tryptase levels should be obtained. A level of >20ng/ml on at least 2 occasions is suggestive of systemic mastocytosis [14]. Serial tryptase levels are also helpful in disease burden monitoring especially in post cytoreduction therapy [14].

Comprehensive allergic workup (including skin prick testing, total and specific IgE) should be performed on all patients [6].

All patients with systemic mastocytosis should undergo a bone mineral density scan. Osteoporosis by WHO definition warrants treatment with bisphosphonates [14].

Management

In a recent international consensus on the treatment recommendation in mastocytosis [14], H1 and H2 histamine receptor antagonists are the first line therapeutic option. This has been shown to be useful in decreasing mediator-related symptoms [14,16]. Additionally, H2 histamine receptor antagonists are useful in gastric hypersecretion and duodenal ulcer disease associated with mastocytosis [14,16]. Other options include the use of short term glucocorticoids, oral cromolyn sodium and proton pump inhibitors depending on the severity of their clinical symptoms.

There are no controlled studies on leukotriene receptor antagonists (LTRA) and mastosytosis. However, patients with recalcitrant mediator symptoms not controlled on a combination of H1 and H2 antihistamine has been shown to respond to LTRA [14,16,17].

High dose aspirin may be used to control severe flushing in patients known to be tolerant to aspirin or non-steroidal anti-inflammatory drugs [14,16]. If their aspirin tolerability is unknown, their initial dose should be taken in a supervised setting.

Education regarding avoidance of triggers is important in all cases of systemic mastocytosis. Patients at risk should also carry adrenaline auto-injectors and be trained to use them under prescribed situations [5,14]. Valent et al [14] recommended a stepwise approach in the treatment of these patients depending on their clinical symptoms (Table 4).

For patients with mastocytosis who have anaphylaxis to Hymenoptera, immunotherapy is recommended [14] and has been shown to be effective [18]. Premedication with anti-histamine is recommended [5], and therapy may need to be life-long.

In patients with recalcitrant cutaneous involvement despite H1 and H2 therapy, topical corticosteroids and PUVA may be considered as this is effective in some patients [16]. A validated method for monitoring cutaneous disease using SCORMA index has been used [19]. This index is scored on the size of cutaneous involvement, intensity and the patient's subjective symptoms. This is relevant in children where regular venesection for serum tryptase levels may be more difficult. Localised mastocytoma causing troublesome symptoms may be surgically resected [20].

General anaesthesia poses special risks for the patient with mastocytosis. Many agents used are direct MC releasers increasing the risk of anaphylaxis perioperatively. Patients are often premedicated with H1 and H2 blockers, and glucocorticoids. H1 and H2 blockers have been reported to reduce unprovoked attacks [16]. However, there is no systematic data to support this [13,21]. In a series of 29 general anaesthetics performed in 22 paediatric patients, deviation from routine anaesthesia techniques was not necessarily warranted [22].

Preliminary data on the use is anti-IgE (omalizumab) on patients with recurrent anaphylaxis appears promising. Recently, Omalizumab has been shown to significantly reduce the attacks of unprovoked anaphylaxis in mastocytosis in a case report of 2 patients [23]. Additionally, Siebenbar et al reported major improvement of severe intractable pruritus and urticaria in a patient with cutaneous mastocytosis after commencement of omalizumab [24]. Omalizumab has been shown to reduce the level of circulating IgE and downregulate MC FcεRI expression and function [25]; therefore potentially increasing the threshold for MC degranulation [23].

Appropriate selection of patients for aggressive therapy is crucial [14]. The presence of B and C findings should be noted. B findings refer to organ enlargement in the absence of organ dysfunction. Patients with B findings are not treated but are reviewed regularly for C findings. C-findings signify the presence of organ impairment secondary to excessive MC infiltration; and aggressive cytoreductive therapy is warranted [14,26]. Currently, no standard therapy for patients with aggressive disease has been outlined [3]. Cytoreductive agents that have been used include cytosine arabinoside, danorubicin, doxorubicin and vincristine. Cladribine or Interferon-alpha (IFN-α) are reserved for patients with slowly progressing ASM or SSM with high MC burden [3,27]. These agents are not without major side effects.

Patients without c-kit D816V mutation appear to respond very well to imatinib [28]. Imatinib (Gleevec) acts on wild type KIT but not on the mutated 816 codon [3]. Studies are ongoing with other novel KIT inhibitors including dasatinib and midostaurin [27].

Splenectomy has been performed in patients with ASM or SM-AHNMD [29]. There is limited experience with bone marrow transplantation in aggressive mastocytosis; the current data on the efficacy of this therapy is mixed [30].

Prognosis

Recent studies in the literature have now provided us with better understanding of prognosis in patients with mastocytosis. In a large cohort of 342 patients, Lim et al [7] concluded that patients with ISM have a good prognosis with life expectancy not significantly dissimilar from their age and sex matched counterparts. In addition, leukaemic conversion is rare (3-6%) in ISM [7,11]. This result was duplicated in a recent Spanish study of 145 patients [11]. In patients with ISM, serum β2-microglobulin together with the presence of D816V mutation were indentified as markers for disease progression [11]. The poorest prognosis occurred in patients with MCL with a median survival of 2 months. The median survival of SM-AHNMD and ASM was 2 and 3.5 years respectively. Poor prognostic factors include advanced age, weight loss, hypoalbuminaemia, thrombocytopaenia and excess bone marrow blasts [7].

Summary

In summary, this review highlights the heteregenous clinical manifestations of mastocytosis. As it is a rare disease, the Allergist is likely to be involved in the care of such patients. It is imperative to diagnosis and classify patients accurately so that a realistic prognosis can be given and optimal management and follow up can be implemented.

References

1. Takemoto, C. Mast Cells-Friend or Foe? J Pediatr Hematol Oncol 2010 Jul;32(5):342-344

2. Metcalfe D. Mast cells and mastocytosis. Blood 2008;112(4):946-956

3. Swerdlow SH, Campo E, Harris NL, et al. Mastocytosis (Mast cell disease). In: World Health Organization (WHO) Classification of Tumours. Vol 2. Lyon, France: IARC Press; 2008:54-63

4. Valent, P, Horny, HP, Li, CY, et al. Mastocytosis. In: World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues, Lyon IARC Press 2001:291

5. Brockow K, Jofer C, Behrendt, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 2008;63:226-232

6. Gonzalez de Olano D, de la Hoz Caballer B, Nunez Lopez R, et al. Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis (REMA). Clinical and Experimental Allergy 2007;37:1547-1555

7. Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood, 2009;113(23), 5727-36

8. Bonadonna P, Zanotti R, Pagani M, et al. How much specific is the association between hymenoptera venom allergy and mastocytosis? Allergy 2009;64:1379-1382

9. Potier A, Lavigne C, Chappard D et al. Cutaneous manifestations in hymenoptera and diptera anaphylaxis: relationship with basal serum tryptase. Clin and Exp Allergy 2009;39:717-725

10. Mathew R. Dhillon V. Shepherd P. Systemic mastocytosis presenting as osteoporosis--a case report. Clinical Rheumatology 2009;28(7):865-6

11. Escribano L, Alvarez-Twose I, Sanchez-Munoz L, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124(3):514-21

12. Tefferi A, Levine RL, Kim KH et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1-L1-PDGFRA correlates. Leukemia 2009;23:900-904

13. Heide R, Beishuizen A, de Groot H, et al. Mastocytosis in children: A protocol for management. Pediatric Dermatology 2008;25(4):493-500

14. Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J of Clin Invest 2007;37:435-453

15. van Daele PL, Beukenkamp BS, Geertsma-Kleinekoort WM, et al. Immunophenotyping of mast cells: a sensitive and specific diagnostic tool for systemic mastocytosis. Netherlands Journal of Medicine 2009;67(4):142-6

16. Escribano C, Akin M, Castells et al. Mastocytosis: current concepts in diagnosis and treatment. Ann Hematol 2002;81:677-690

17. Tolar J, Tope WD, Neglia JP. Leukotriene-Receptor inhibition for the treatment of systemic mastocytosis. NEJM 2004;350(7):735-6

18. Gonzalez de Olano, Alvarez-Twose I, Esteban-Lopez M et al. Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis. J Allergy Clin Immunol 2008;121:519-26

19. Heide R, van Doorn K, Mulder PG et al. Serum tryptase and SCORMA (SCORing MAstocytosis) Index as disease severity parameters in childhood and adult cutaneous mastocytosis. Clin and Exp Derm 2008;34:462-468.

20. Zhu L, Lang JH, Wang WY. Images for diagnosis. A vulva mastocytoma having grown for eighteen years. Chinese Medical Journal 2010;123(3):382-4

21. Dewachter P, Mouton-Faivre C, Cazalaa JB, et al. Mastocytosis and anaesthesia. Annales Francaises d Anesthesie et de Reanimation 2009; 28(1):61-73

22. Carter M, Uzzaman A, Scott L et al. Pediatric Mastocytosis: routine anesthetic management for a complex issue. Anesth Analg 2008;107:422-427

23. Carter MC, Robyn JA, Bressler PB et al. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol 2007;119:1550-1551

24. Siebenhaar F, Ku¨hn W, Zuberbier T et al. Successful treatment of cutaneous mastocytosis and Me´nie` re disease with anti-IgE therapy. J Allergy Clin Immunol 2007;120(1):213-5

25. Beck LA, Marcotte GV, MacGlashan D et al. Omalizumab-induced reductions in mast cell Fcepsilon RI expresiion and function. J Allergy Clin Immunol 2004;114:527-30

26. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25(7):603-25.

27. Pardanani A, Tefferi A. Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature. Current Opinion in Hematology 2010;17:125-132

28. Pardanani A, Elliott, Reeder T et al. Imatinib for systemic mast-cell disease. Lancet 2003;362:535-37

29. Friedman B, Garling G, Norton J et al. Splenectomy in the management of systemic mast cell disease. Surgery 1990;107:94-100.

30. Przepiorka D, Giralt S, Khouri I et al. Allogenic marrow transplantation for myeloproliferative disorders other than chronic myelogenous leukaemia : a review of forty cases. Am J Hematol. 1998;57:24-28

Tables and Images

Table 1. WHO classification of mastocytosis variants

Variant term Subvariant
Cutaneous mastocytosis (CM) Urticaria pigmentosa (UP)
Maculopapular CM (MPCM)
Diffuse CM (DCM)
Mastocytoma of the skin
Indolent systemic mastocytosis (ISM) Smoldering SM (SSM)
Isolated bone marrow mastocytosis (BMM)
Systemic mastocytosis with an associated clonal haematological non-mast cell linieage disease (SM-AHNMD/SM-AHD) SM-Acute myeloid leukaemia
SM-Myelodysplastic syndromes
SM-Chronic myelomonocytic leukaemia
SM-Non Hodgkins Lymphoma
SM-Myeloproliferative disease
SM-Hypereosinophilic syndrome
Aggressive systemic mastocytosis (ASM)  
Mast cell leukaemia (MCL) Aleukaemic MCL
Mast cell sarcoma  
Extracutaneous mastocytosis  

 

Table 2 WHO criteria for systemic mastocytosis

Major criterion
The presence of multifocal dense aggregates of >15 mast cells as detected with tryptase or other special stains in bone marrow or other extracutaneous organs

Minor criteria

1 Atypical morphology or spindle shapes in >25 percent of the mast cells in bone marrow sections, bone marrow aspirate, or other extracutaneous tissues

2 Mutational analysis of KIT showing a codon 816 mutation (eg, Asp816Val) in bone marrow, blood, or extracutaneous organs

3 Bone marrow or other extracutaneous mast cells expressing the surface markers CD2, CD25, or both

4 Baseline serum tryptase levels >20 ng/mL. (This criterion does not apply to patients with AHNMD)

 

Table 3. Clinical manifestations of mastocytosis

Clinical manifestations Brockow et al, 2007 [5] Gonzalez et al, 2007 [6] Lim et al, 2009 [7]
Numbers studied 120 patients
46 children
74 adults
210 patients
47 children
163 adults
342 adult patients
Sex, female (%) Children
41
Adult
65
Children
36
Adult
54
45
Classification, (n)
 CM
 ISM
  SSM
  BMM
 ASM
 SM-AHD
 Mastocytoma
 MCL
Children
48
0

0
0
Adult
13
59

1
1
Children
40:8
0

0
0
0
7
Adult
8
140

3
3
3
1


46
23
14
12
40

1
Cutaneous symptoms, %
 Flushing, %
 Pruritus, %
  Children
70:74
37:50
Adult
74
50
53*
Urticaria pigmentosa, %     41
Gastrointestinal‡, %   Children
30
Adult
46
65
Sweating, %   Children
13
Adult
13
 
Neuropsychiatric,%   Children
0
Adult
23
 
Constitutional symptoms◊, %     42
Musculoskeletal¶, %     31
Anaphylaxis, % Children
9
Adult
49
Children
6.4
Adult
22
17
Atopy, %

 Asthma
 Rhinitis
 Conjunctivitis
 Atopic dermatitis
 Urticaria
Children
11
Adult
28
Children
47
10.6
14.8
19.1
6.3
21.2
Adult
57
7.3
31.2
24.5
2.4
25.7
 
Hepatomegaly, %     27
Splenomegaly, %     37
Hepatosplenomegaly, %     21
Lymphadenopathy, %     21
Leukaemic transformation (AML or MCL), %     6
Baseline tryptase (ng/ml), Children
6(1-46)
Adult
25.5
(3-200)
Children
6(3-115)
Adult
26.7(4-550)
63.3 (3.7-2000)
Ig E (kU/L) NR# Children
27(3-700)
Adult
20(6-1200)
 

‡ Includes nausea/vomiting, dyspepsia, dysphagia, diarrhoea, constipation, abdominal cramps, gastrointestinal tract bleeding malabsortion, and steatorrhoea
* Includes pruritus, flushing, urticaria, and angioedema
◊ Includes weight loss, fever, chills, and night sweats
¶ Includes bone pain, arthralgias and myalgias
# NR, Not relevant

 

Table 4 Stepwise therapeutic options in systemic mastocytosis.[14]

Clinical symptoms and mediator effects Step Therapeutic options*
Recurrent hypotension and tachycardia 1
2
3
H1 and H2 histamine receptor antagonists
Glucocorticoids
Aspirin in select cases (if tolerated)
Recurrent shock 1
2
3
H1 and H2 histamine receptor antagonists
Glucocorticoids
Monoclonal anti-IgE
With co-existing allergy (specific IgE demonstrable) 1
2
3
H1 and H2 histamine receptor antagonists
Specific venom immunotherapy
Short-term oral glucocorticoids
Peptic ulcer disease + bleeding (ASM/MCL) 1
2
3
H2 histamine receptor antagonists
Proton pump inhibitors + H2 blockers
Fibrinogen, coagulation factors or platelets
Diarrhoea, abdominal pain, nausea, vomiting 1
2
3
4
H1 and H2 histamine receptor antagonists
Oral cromolyn
Leukotriene antagonists
Short-term glucocorticoids
Skeletal pain without osteopenia/osteoporosis 1
2
Analgesics, NSAIDs# (if tolerated), opiates in severe cases
Radiation
Severe osteopenia/ osteoporosis 1
2
3
Oral bisphosphonates
Intravenous bisphosphonates
Interferon-alpha
Headaches 1
2
H1 and H2 histamine receptor antagonists
Oral cromolyn

*All patients at risk are advised to carry adrenaline auto-injecters
#NSAIDs, non-steroidals anti-inflammatory drugs

 

Diagram 1

Diagram 1 [2]. Signal transduction events initiated by Kit and Fc_RI leading to specific mast cell responses, and the integration of these pathways for the synergistic enhancement of mast cell mediator release. Used with permission of American Society of Hematology, from Mast cells and mastocytosis, Metcalfe D. Blood 2008;112(4); permission conveyed through Copyright Clearance Center, Inc.

 

Picture 1

1a  
Picture 1a. Characteristic skin lesions on the arm
seen in urticaria pigmentosa
 
1a 1a
Picture 1b. Histopathology of urticaria pigmentosa
highlighting the abundance of mast cells
Picture 1c. Characteristic skin lesions
seen on the back in urticaria pigmentosa