1. Difficult Cases: Mast Cell Disorders
NAIA Speaker: Joyce E. Yu, MD, FAAAAI
Columbia University Medical Center
Morgan Stanley Children’s Hospital, New York, NY
Mentor: Cem Akin, MD, PhD, FAAAAI
Harvard Medical School
Brigham and Women’s Hospital, Boston, MA

2. Case #1
A 55 year old female referred for evaluation of a mast cell disorder
Episodic flushing, abdominal pain, profuse diarrhea, hypotension
6 episodes of presyncope or syncope in 2.5 years
No itching, hives, angioedema
No association with foods, exercise or new medications
Prior colonoscopy/EGD and endocrine workup at outside hospital negative (carcinoid, pheochromocytoma)

3. Case #1
PMH: Allergic rhinitis (pollen, dust mites, cat), asthma, splenectomy (after trauma), cholecystectomy
Meds: Calcium and vitamin D
Allergies: NKMA, no food, insect sting or latex allergy
FH: Allergic rhinitis in brother and sister, venom allergy in sister
SH: Teacher, no tobacco or alcohol
ROS: Negative for fever, night sweats, weight loss, lymphadenopathy, jaundice

4. Physical Exam Gen: NAD, obese HEENT: mild turbinate edema CV: normal
Lung: normal
Abd: no organomegaly
Lymph: no LAD
Skin: no rashes

5. Q1. Urticaria pigmentosa (UP) is the most common physical exam finding in mastocytosis. Which of the following is a typical feature of UP?
Commonly involves face and hands
Commonly involves trunk and proximal parts of extremities
Associated with itching at baseline
Characterized by urticarial wheals lasting for <2 hours

6. Q1. Urticaria pigmentosa (UP) is the most common physical exam finding in mastocytosis. Which of the following is a typical feature of UP?
Commonly involves face and hands
Commonly involves trunk and proximal parts of extremities
Associated with itching at baseline
Characterized by urticarial wheals lasting for <2 hours

7. Urticaria pigmentosa
UP is seen in 80% of patients with systemic mastocytosis
It is a fixed hyperpigmented rash that can appear as macules, papules, or small nodules that can be reddish-brown or brown in color
Spares sun-exposed areas
Lesions may urticate with friction, heat, alcohol, stress (Darier’s sign)
Lesions may also form blisters when rubbed or stroked

8. Laboratory evaluation of our patient
Normal: CBC with differential, electrolytes, liver function, 24 hour 5-HIAA, serum VIP, calcitonin
Food allergy skin and blood tests: negative
Inhalant allergy testing: Positive for dust mites
Colonoscopy and EGD: Normal (no mast cell stains were performed at outside hospital)
Tryptase: 8 ng/ml (baseline), 14 ng/ml 3 hours after an attack

9. Q2. Which of the following statements is correct about tryptase levels in this patient (8 ng/ml at baseline, 14 ng/ml after an event)?
The increase after the event is suggestive of mast cell degranulation
The increase is within laboratory variability range and does not confirm mast cell activation
Plasma histamine is a more sensitive marker of mast cell activation, and therefore the results are meaningless
Neither value is greater than 20 ng/ml and therefore the results rule out mastocytosis

10. Q2. Which of the following statements is correct about tryptase levels in this patient (8 ng/ml at baseline, 14 ng/ml after an event)?
The increase after the event is suggestive of mast cell degranulation
The increase is within laboratory variability range and does not confirm mast cell activation
Plasma histamine is a more sensitive marker of mast cell activation, and therefore the results are meaningless
Neither value is greater than 20 ng/ml and therefore the results rule out mastocytosis

11. Tryptase is the best validated marker of mast cell burden and activation
Primarily produced by mast cells
Smaller quantities by basophils and myeloid progenitor cells
Baseline levels correlate with mast cell burden
Mast cells spontaneously release alpha and beta protryptases which contribute to baseline levels
Median level is 5 ng/ml
Normal level can be up to 11.4 ng/ml
Baseline levels >20 ng/ml is a minor diagnostic criterion for mastocytosis
Increased transiently in systemic anaphylaxis
Due to release of mature (mostly beta) tryptase stored in granules
Half life of about 1 hr
Needs to be checked within 3-4 hours after the event
Meaningful increase: Baseline + 2 ng/ml + 20% of baseline

12. Case #1
Due to unexplained symptoms and elevated tryptase levels after an event the patient was recommended to have a bone marrow biopsy and aspiration
Bone marrow biopsy (initial report):
Normocellular marrow
Scant mast cells with occasional spindle shaped forms
Negative for mastocytosis

13. Case #1
Despite the initial pathology report, due to persistent clinical suspicion, CD25 staining was requested
Positive on scattered mast cells
C-kit mutational analysis in bone marrow aspirate came back positive for D816V mutation

14. Q3. What is the most appropriate diagnosis for this patient?
Indolent systemic mastocytosis
Aggressive systemic mastocytosis
Monoclonal mast cell activation syndrome (MMAS)
Idiopathic anaphylaxis

15. Q3. What is the most appropriate diagnosis for this patient?
Indolent systemic mastocytosis
Aggressive systemic mastocytosis
Monoclonal mast cell activation syndrome (MMAS)
Idiopathic anaphylaxis

16. Disorders associated with mast cell activation
Primary (clonal mast cells)
Systemic mastocytosis
Monoclonal mast cell activation syndrome
Secondary
IgE mediated
Non-IgE mediated: autoimmune disorders, reactions to vancomycin, physical urticaria
Idiopathic
Includes idiopathic anaphylaxis, urticaria/angioedema and mast cell activation syndrome

17. Diagnostic Criteria for Systemic Mastocytosis
Systemic mastocytosis: 1 major + 1 minor or 3 minor MMAS: 1-2 minor clonality criteria*
Major
Multifocal clusters of mast cells (>15 MC per cluster) in bone marrow or GI tract
Minor
Spindle shaped mast cells in >25% of the infiltrate
Baseline tryptase >20 ng/ml
Codon 816 c-kit mutation*
Aberrant CD25/CD2 expression on mast cells*

18. Comparing Bone Marrow Lesions in Mastocytosis and MMAS*
* Tryptase-positive mast cells (Brown)
Systemic Mastocytosis:
Several clusters of mast cells
Spindle-shaped mast cells
Monoclonal Mast Cell Activation Syndrome:
Very few clusters of mast cells
Spindle-shaped mast cells

19. Classification of Mastocytosis
Cutaneous mastocytosis (mainly diagnosed in children)
Involves only skin (no bone marrow or GI involvement)
UP (most common)
Diffuse cutaneous mastocytosis
Solitary mastocytoma
Systemic mastocytosis (bone marrow aspirate and biopsy are required to assess bone marrow involvement)
Indolent
SM-AHNMD (associated hematologic clonal non-mast cell disease: commonly myeloproliferative or myelodysplastic disorders)
Aggressive systemic mastocytosis
C Findings = Liver, (ascites), GI (malabsorption), bone marrow dysfunction (cytopenias (Hgb <10, ANC <1000, or platelets < 100K), weight loss, splenomegaly
Mast cell leukemia
>10% MC in peripheral blood
>20% in bone marrow smears

20. Case #1
Patient was placed on high dose H1 antihistamine, H2 antihistamine, oral cromolyn, montelukast, and prescribed self- injectable epinephrine
No further syncopal episodes but continued to have flushing, abdominal pain and diarrhea requiring several ER visits
Declined long term prednisone. No significant reponse to ketotifen or plaquenil

21. Q4. What is the most appropriate next management step?
Cytoreductive therapy with imatinib
Interferon alpha
Allergen immunotherapy to dust mites
Omalizumab

22. Q4. What is the most appropriate next management step?
Cytoreductive therapy with imatinib
Interferon alpha
Allergen immunotherapy to dust mites
Omalizumab

23. Carter et al. JACI 2007:119:1550
The authors of the article referenced above demonstrate that omalizumab therapy reduced the frequency of anaphylactic episodes in 2 patients with systemic mastocytosis.
The mechanism of how omalizumab decreases the anaphylaxis remains unclear.

24. Treatment of indolent systemic mastocytosis and MMAS includes:
H1 and H2 antihistamines: Age appropriate doses may be used once or twice daily. E.g. loratidine, cetirizine, fexofenadine, desloratadine, diphenhydramine, hydroxyzine, raniditine, famotidine
Self injectable epinephrine
Oral cromolyn: Adult dose 200 mg PO QID
Anti-leukotrienes: Age appropriate dose of montelukast, zileuton, zafirlukast
Steroids: E.g. adult dose prednisone 5-10 mg daily maintenance
ASA (if urinary 11-b-PGF2a is elevated and if patient’s tolerance is known): Adult dose 81 mg QD-325 mg BID
Consider omalizumab: 300mg q4 weeks
Mast cell cytoreductive therapy may be considered in recurrent life threatening mast cell activation symptoms: E.g. cladribine, IFN-α

25. Case #2
56 year old female referred for routine management of systemic mastocytosis
Skin lesions of UP at 54
Urticate with heat and friction
PMH: Ulcerative colitis
ROS: Episodic abdominal pain and diarrhea, otherwise asymptomatic

26. Case #2 Lab evaluation: Tryptase 52 ng/ml CBC with diff, LFTs nl
Colonoscopy with biopsy
Transverse colon: 60 MC/HPF with clustering and CD25 expression, c/w involvement with SM
Rectum: Chronic active colitis, normal mast cells
Bone marrow biopsy
Moderately hypercellular but no overt dysplasia or hematologic disorder
15% marrow space occupied by MC infiltrates
D816V c-kit mutation positive

27. Case #2, follow up
Patient remained largely asymptomatic except some intermittent fatigue
Serial labs over time:
Tryptase: 52, 80, 88, 144 ng/ml
Hgb: 13, 12.8, 11, 9.6 g/dl
Imaging
Mild splenomegaly and mesenteric lymphadenopathy

28. Q5. What is the most appropriate category of this patient’s mastocytosis?
Indolent systemic mastocytosis (ISM)
Aggressive systemic mastocytosis (ASM)
SM-AHNMD (SM with associated clonal hematologic non-mast cell lineage disease)
MCL

29. Q5. What is the most appropriate category of this patient’s mastocytosis?
Indolent systemic mastocytosis (ISM)
Aggressive systemic mastocytosis (ASM)
SM-AHNMD (SM with associated clonal hematologic non-mast cell lineage disease)
MCL

30. Systemic mastocytosis: Natural course
Progression from ISM to ASM is rare but can occur in ~3% of the cases
Prognosis and survival rates with vary with the type of SM
ISM patients have a better life expectancy than ASM patients
Risk factors for progression
Older age at diagnosis
Absence of skin lesions
Presence of c-kit D816V mutation in multiple hematopoietic lineages
Hepatosplenomegaly
Higher tryptase levels (>100 ng/ml)

31. Q6. What is the most appropriate next management step?
Increase H1 antihistamines
Omalizumab
Mast cell cytoreductive therapy with cladribine
Imatinib

32. Q6. What is the most appropriate next management step?
Increase H1 antihistamines
Omalizumab
Mast cell cytoreductive therapy with cladribine
Imatinib

33. Imatinib resistance in D816V+ mastocytosis
Akin et al. J Allergy Clin Immunol Jul;114(1):13-9
A - C-kit is a tyrosine kinase (TK) receptor
B - In wild type Kit, ATP binds to the kinase domain of the receptor after dimerization by stem cell factor
C - Imatinib (tyrosine kinase inhibitor) binds the enzymatic pocket to block ATP binding and thus receptor activation
D - C-kit mutation D816V (90% of SM cases) confers resistance to imatinib by altering the binding site. Therefore, most SM patients are not candidates for imatinib

34. Cytoreductive therapy in mastocytosis
Imatinib effective in:
Rare D816V negative cases
Chronic eosinophilic leukemia associated with mastocytosis, FIP1L1/PDGFRA positive
Cladribine
Nucleoside analog that intercalates into DNA to trigger apoptosis
May be used in imatinib resistant cases
Bone marrow suppression and immunosuppression are common side effects
IFN-α
May be useful in slowly progressing aggressive mastocytosis
Side effects such as flu-like symptoms limit patient compliance
Investigational tyrosine kinase inhibitor therapy
Stem cell transplantation

35. Case #2, follow up Started on Cladribine Serial labs:
Tryptase 144, 108, 81 ng/ml (in 3 months)
HGB: 9.6, 11.3, 12 g/dl
Skin lesions largely resolved
Remains asymptomatic
Future options may include investigational tyrosine kinase inhibitor

36. Mastocytosis: Special considerations
Hymenoptera anaphylaxis is high (approx. 10% incidence)
Hypotension without urticaria/angioedema after insect sting suggests underlying mastocytosis
Requires life long venom immunotherapy
Osteoporosis in approximately 30% of patients
Screening bone densitometry
Follow up with at least yearly tryptase and CBC with diff
Trigger avoidance (variable): Heat, alcohol, stress, exercise, drugs (incl. opioids, NSAIDs, muscle relaxants, vancomycin)

37. Mast Cell Disorder Diagnosis Algorithm- When to consider a BM biopsy
Thorough history and exam including food, medications, insect stings, latex, radiographic contrast media, exercise and skin evaluation
No UP or IgE mediated trigger identified
Hypotensive episode without urticaria/angioedema following insect sting
Urticaria pigmentosa (new onset or existing) in an adult patient
Tryptase level
BM biopsy
BM biopsy
>20ng/mL
<20ng/mL
BM biopsy
Hypotensive syncope or presyncope without urticaria or angioedema
YES NO
Consider measuring mast cell mediators for mast cell activation syndrome
-24 h urine N-methylhistamine
11-b-PGF2a
BM biopsy
*BM biopsy should consist of staining for tryptase,
CD117 ,CD25 and c-kit D816V mutation