BASICS
Mastocytosis is a heterogeneous group of disorders due to the abnormal clonal proliferation and accumulation of atypical mast cells in one or more organs of the body.
DESCRIPTION
- Two clinical diagnostic categories: cutaneous mastocytosis (CM) or systemic mastocytosis (SM)
- SM constitutes 10 " 15% of all the cases.
- Clinical symptoms may include a combination of constitutional symptoms, skin findings, symptoms due to mediator release, and those due to organ infiltration.
- Most patients have only skin involvement with characteristic of tan to red-brown macules; firm, fixed papules; or plaques called urticaria pigmentosa (UP).
- Symptoms of mastocytosis may occur with physical or pharmacologic stimulation, causing mast cell (MC) degranulation and release of chemical mediators, such as histamine, leukotrienes, and prostaglandins.
- Adult mastocytosis is a disorder related to clonal proliferation of mast cells secondary to a gain-of-function point mutation in the proto-oncogene c-kit (D816V in >95% of cases).
- Childhood mastocytosis is only associated with c-kit, D816V in 40% of cases; majority of cases are limited to the skin and spontaneously resolve.
EPIDEMIOLOGY
- Incidence and prevalence are unknown due to many indolent cases and because no registries exist for reporting these disorders.
- Bimodal peak incidence during infancy and early childhood, and then in middle age (30 to 49 years)
- ~2/3 of reported CM cases are found in children, most during 1st year of life.
- Overall: male=female; slight female predominance in adults.
Genetics
Gain-of-function point mutations in c-kit, in particular D816V
- C-kit is a proto-oncogene that encodes receptor tyrosine kinase (KIT or CD-117) located on many hematopoietic stem cells, including mast cells.
- Autophosphorylation of tyrosine residues in the presence of gain-of-function c-kit mutations leads to unregulated proliferation of mast cells.
- C-kit mutations (mostly D816V) are detectable in >90% of adult SM, whereas they are detectable in the skin of 86% of childhood cutaneous lesions.
- Mutations in other genes may also be pathogenic in some cases. TET2 and NRAS have been suggested, but their role in pathogenesis and prognosis has yet to be determined.
- There is no known genetic transmission.
RISK FACTORS
Age (bimodal); c-kit-activating mutations
DIAGNOSIS
- Diagnosis is by identification of malignant mast cells by their morphology, immunophenotype, and/or molecular signature. WHO defined these criteria in 2008.
- To diagnose SM: 1 major and 1 minor criterion or 3 minor criteria should be present
- Major criterion
- Multifocal dense infiltrates of mast cells (>15 mast cells in aggregated) detected in bone marrow and/or other extracutaneous organs.
- Minor criteria
- 25% MC in infiltrates are spindle-shaped or have atypical morphology.
- Detection of point mutation at CD816 of KIT
- MC expression of CD2 and/or CD25
- Serum tryptase ≥20 ng/mL (if no AHNMD)
- (MC; AHNMD- associated clonal hematologic non-MC lineage disease)
- WHO classification of mastocytosis
- "B " findings
- BM biopsy showing >30% infiltration by MC
- Signs of dysplasia or myeloproliferation in non-MC lineage(s)
- Hepatomegaly without impairment of:
- Liver function and/or palpable splenomegaly
- Without hypersplenism and/or lymphadenopathy on palpation or imaging
- "C " findings
- BM dysfunction manifested by one or more cytopenia(s)
- Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension
- Skeletal involvement with large osteolytic lesions and/or pathological fractures
- Palpable splenomegaly with hypersplenism
- Malabsorption with weight loss due to gastrointestinal mast cell infiltrates
- Classification of mastocytosis (WHO 2008)
- CM
- UP (sometimes called maculopapular cutaneous mastocytosis [MPCM]),
- Solitary or multiple mastocytomas or nodular cutaneous mastocytosis
- SM
- Indolent systemic mastocytosis (ISM). No "C " findings. No AHNMD. Usually with skin lesions
- Aggressive: one or more "C " findings. No MCL. Usually without skin lesions
- Mast cell leukemia (MCL): BM biopsy with diffuse MC infiltration, aspirate with >20% MC.
- Mast cell sarcoma: Unifocal MC tumor. No SM. Destructive growth pattern. High-grade cytology
- Extracutaneous mastocytoma: Unifocal MC tumor. No SM. Nondestructive growth pattern. Low-grade cytology
- Clinical features
- Evaluation for mast cell disorder recommended for patient with symptoms attributable to SM activation (i.e., flushing, urticaria, diarrhea, wheezing, fatigue, or musculoskeletal pain) affecting at least two organ systems
- Anaphylactic reactions have been reported in all clinical variants; more frequently seen in systemic/advanced disease and adult population
- Diagnostic tests and interpretation: Mechanical stimulation, such as scratching or rubbing over papule/macule, will elicit an urticarial response (Darier sign). In a clinically typical presentation, in the absence of nonlesional dermographism, this may be sufficient to eliminate need for biopsy in making the diagnosis.
- 3-mm punch biopsy of any form of CM, fixed with formalin and stained with Giemsa, toluidine blue, or Leder stains
- Immunohistochemical staining for tryptase or KIT (CD117) can also be performed.
HISTORY
- Constitutional: fatigue, weight loss, fever, diaphoresis
- Dermatologic: pruritus, flushing, edema, and development of UP; history of lesions spontaneously urticating or blistering, particularly in infancy and childhood
- Neurologic: light-headedness, headache, syncope, or near-syncope
- Cardiovascular: palpitations, episodic vascular collapse, hypotension
- GI: nausea, vomiting, abdominal pain, diarrhea, weight loss, peptic ulcer disease
- Musculoskeletal: myalgias, poorly localized bone pain, skeletal deformities, pathologic fractures or compression radiculopathies, osteopenia, or osteoporosis
PHYSICAL EXAM
- Complete dermatologic exam looking for characteristic lesions of UP (tan-yellow to brown to reddish brown macules or papules located on extremities, trunk, and abdomen and usually sparing sun-exposed areas, including palms, soles, and scalp) or solitary or multiple tan-to-brown plaques suggestive of mastocytomas, or mat-like telangiectasia on the trunk suggestive of TMEP
- Darier sign is pathognomonic for presence of mast cell infiltration in any of the above lesions.
- Palpate for hepatomegaly, splenomegaly, or lymphadenopathy.
DIAGNOSTIC TESTS & INTERPRETATION
If suspecting SM:
- CBC with differential; liver function tests; serum tryptase (>20 ng/mL significant in the absence of leukemia or myeloproliferative disorder). It is elevated in nearly 75% of adults with SM. In children, elevated tryptase levels correlate with symptoms of mast cell degranulation but not as strongly with SM or prognosis.
- Optional: Urine histamine metabolite (24-hour urine for 1-methyl-4-imidazole acetic acid) levels are more sensitive than histamine levels and correlate with bone marrow involvement. Elevated plasma histamine levels, although demonstrated in most children with mastocytosis, does not always correlate with bone marrow involvement.
- Screening bone densitometry may be indicated if bone involvement is suspected. Skeletal survey and bone scans/x-ray may be indicated if specific complaints are present. Pathologic fractures along with high serum tryptase level is considered a marker of advanced disease.
Initial Tests (lab, imaging)
Follow-Up Tests & Special Considerations
Bone marrow (BM) biopsy is one of the starting points in diagnosis of SM, as it is almost always involved in adults.
- Indicated in adults with tryptase >20 ng/mL and the following:
- UP even in the absence of signs or symptoms of systemic disease, or
- Unexplained flushing, anaphylaxis, GI abnormalities (diarrhea, malabsorption, peptic ulcer disease), peripheral blood abnormalities, organomegaly, pathologic bone fractures, or any other concerns for SM
- Multifocal infiltrates of >15 mast cells diagnostic of SM (WHO major criterion)
- BM mast cell infiltration with spindled mast cells exhibiting CD25/CD2 positivity, D816V c-kit mutation, and cytoplasmic overexpression of tryptase (CD117) is prognostic of ISM.
- BM mast cell with a more immature phenotype (clonal involvement of all myeloid lineages with D816V c-kit mutation; decreased expression of CD117; positivity for CD25 and CD123 is prognostic of more aggressive forms of SM.
- It may also provide information about an AHNMD.
- BM biopsy typically is not recommended for pediatric mastocytosis unless patient has unexplained findings suggestive of extracutaneous involvement, such as cytopenias, other hematologic abnormalities, or symptoms from target organ mast cell infiltration (i.e., unexplained hepatosplenomegaly or peptic ulcers).
TREATMENT
Management goals are for symptom trigger avoidance and/or symptom-directed therapy.
- Avoid environmental triggers of mast cell degranulation (hymenoptera venom, extreme heat or temperature change, vigorous exercise, and trauma to the lesions).
- Avoid drugs or chemicals that degranulate mast cells: opioid analgesics, aspirin or other NSAIDs, polymyxin, vancomycin, iodinated contrast dyes, anesthesia (i.e., succinylcholine, atracurium, enflurane, isoflurane, and d-tubocurarine), although risk with low mast cell load, such as solitary mastocytoma, may be very low. Local lidocaine, propofol, fentanyl, and vecuronium bromide are safe.
- Premedication may be necessary before a necessary exposure or use of drug (i.e., prednisone and H1 and H2 antihistamines before anesthetic exposure).
- Most patients can tolerate acetaminophen, local anesthetics, and benzodiazepines.
- Consider an epinephrine kit for patients with severe mast cell degranulation.
MEDICATION
First Line
Noncytoreductive therapies
- Oral nonsedating H1 antihistamines used for preventing or treating flushing and pruritus
- Child
- Cetirizine: 6 to 12 months: 2.5 mg/day; 1 to 2 years: start at 2.5 mg/day, may increase to BID if needed; 2 to 5 years: start at 2.5 mg/day, and may increase to 2.5 mg BID or 5 mg/day; >6 years " see adult dosing.
- Hydroxyzine: 2 mg/kg/day divided q6 " 8h
- Fexofenadine: 2 to 11 years: 30 mg BID; >12 years " see adult dosing.
- Adult: cetirizine: 10 mg daily; hydroxyzine: 25 mg PO q6h or fexofenadine: 180 mg daily
- Doxepin may also be useful when all other antihistamines are ineffective. Doxepin has been shown to have greater H1 antagonizing effects than H1 blockers.
- Be careful with doxepin and H1 blockers together, due to risk for QT prolongation.
- Oral H2 antihistamines may be helpful for abdominal pain, heartburn, cramping, and diarrhea and may enhance H1 antihistamine effects for histamine-mediated systemic symptoms.
- Child
- Ranitidine: 1 month to 16 years: 4 to 8 mg/kg/day divided BID, maximum 300 mg/day; >16 years " see adult dosing.
- Famotidine: 0.5 to 1 mg/kg/day at bedtime or BID, maximum 40 mg/day
- Adult: ranitidine: 150 mg PO BID; famotidine: 20 mg PO up to BID, or cimetidine: 400 mg PO BID (or up to 800 mg BID; short-term if clinically indicated)
- Both H1 and H2 blockers should be used chronically to treat recurrent symptoms of histamine release or pruritus.
- Cromolyn sodium effective for GI symptoms (malabsorption, nausea, abdominal pain, and diarrhea) and pruritus
- Start at 200 mg PO QID, increase by 100 mg per week until reach of desired maximum dose to avoid side effects (abdominal cramping, pain, diarrhea).
- Child (2 to 12 years): 60 to 100 mg PO QID
- May take several weeks before benefits noted
- Corticosteroids
- Anecdotal/few case reports; potent topical corticosteroids under occlusion for up to 2 months for localized skin lesions
- Intralesional corticosteroid for solitary mastocytoma or temporary use of systemic corticosteroids for severe skin disease, recurrent hypotensive episodes, diarrhea with malabsorption, and ascites
- Oral PUVA photochemotherapy and narrowband UVB phototherapy for pruritus and urticaria (short-term benefit, high relapse rate)
- Omalizumab (anti-IgE) for select patients with otherwise uncontrolled idiopathic anaphylaxis or with anaphylaxis during initiation of specific immunotherapy (case report)
- Calcium and vitamin D for prevention of bone disease; use of bisphosphonates is controversial.
- Non-NSAID analgesia for bone pain
Second Line
Chemotherapy or cytoreductive/cytostatic agents are typically reserved for most severe or aggressive forms of systemic mastocytosis (ASM, MCL) when benefits outweigh the risks. In most cases, responses are limited, incomplete, and short-lived.
- Not recommended in children due to adverse side effects
- Interferon-α (IFN-α) is often used as first-line therapy for symptomatic or aggressive SM; shown to improve multisystem symptoms, including skeletal, with partial remission rates of about 20%; and an overall response rate of 60%.
- 1 to 3 MU SC 3 times per week with gradual escalation to 3 to 5 MU 3 to 5 times per week, if tolerated (1)[A]
- Prednisolone or prednisone (1 mg/kg/day) at start of treatment, tapered over 2 to 3 months, shown to help improve tolerability and response (1)[A].
- Cladribine, first-line therapy in cases requiring rapid mast cell debulking or patients refractory or intolerant to IFN-α. Responses noted in all forms of SM except SM-AHNMD, however, with variable duration, potential toxicities include myelosuppression and lymphopenia with increased opportunistic infection risk (1)[A].
- Imatinib, dasatinib, and midostaurin, all inhibitors of tyrosine kinase, have shown disappointing results in clinical trials in SM with c-kit mutations, although imatinib is FDA-approved for treatment of adult SM without the KIT D816V mutation or unknown c-kit mutation status. It is most effective in patients who carry the F1P1L1-PDGFRα oncogene (seen in lymphadenopathic systemic mastocytosis with eosinophilia subvariant of ASM) (1,2)[A],(3)[C].
- Masitinib mesylate, inhibitor of KIT and PDGFRAα mutations, may provide symptomatic improvement in SM and CM with handicap but does not effectively reduce mast cell burden (1)[A].
- Thalidomide has anecdotally been shown to produce partial remissions in some cases of ASM.
- The role of stem cell transplantation is yet to be established.
- Midostaurin is a new investigational agent that has showed promise.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Depends on type of SM, coexisting disorders, severity of mediator-related symptoms, and therapy
- Most children with ISM will continue to have ISM throughout their lifetime.
- Long-term follow-up for children with UP is indicated.
- Recommend at least an annual follow-up with serum tryptase, CBC, and complete metabolic panel monitoring, especially if symptomatic or more lesions are developing.
- Patients with more severe mediator-related symptoms or high disease burden require more frequent follow-up with appropriate laboratory monitoring and diagnostic imaging.
PROGNOSIS
- Excellent prognosis for CM, especially in pediatric patients " most are self-limiting, some persistent and can progress to well-differentiated or indolent adult SM
- Good prognosis for adults with ISM
- <3% of indolent mastocytosis cases progress to more aggressive form of disease (MCL, mast cell sarcoma, ASM). These can have a poor prognosis.
REFERENCES
11 Akin C, Valent P. Diagnostic criteria and classification of mastocytosis in 2014. Immunol Allergy Clin North Am. 2014;34(2):207 " 218.22 Pardanani A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol. 2015;90(3):250 " 262.33 Ustun C, Reiter A, Scott BL, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014;32(29):3264 " 3274.
CODES
ICD10
- Q82.2 Mastocytosis
- D47.0 Histiocytic and mast cell tumors of uncertain behavior
- C96.2 Malignant mast cell tumor
ICD9
- 757.33 Congenital pigmentary anomalies of skin
- 202.60 Malignant mast cell tumors, unspecified site, extranodal and solid organ sites
SNOMED
- cutaneous mastocytosis (disorder)
- Systemic mast cell disease (disorder)
- urticaria pigmentosa (disorder)
- Indolent systemic mastocytosis
- Urticaria pigmentosa, multiple nodules AND/OR plaques
CLINICAL PEARLS
- Symptoms of mast cell activation can overshadow the cutaneous findings, which can be subtle and easily overlooked. The brownish papules and macules should be carefully sought in cases of unexplained recurrent anaphylaxis, flushing, hypotension, and peptic ulcer disease. When hypotension or anaphylaxis-like presentation of SM occurs, it is not accompanied by urticaria.
- Patients with SM should consider wearing medical alert jewelry to ensure appropriate emergency treatment and anesthesia precaution.