Cutaneous and Systemic Mastocytosis



Cutaneous and Systemic Mastocytosis


Jeremy C. Wallentine, MD





Key Facts


Terminology



  • Heterogeneous group of clonal neoplastic proliferations of mast cells in ≥ 1 organ system



    • Cutaneous mastocytosis: Confined to skin


    • Systemic mastocytosis: Involvement of at least 1 organ ± skin lesions


Etiology/Pathogenesis



  • Frequently associated with somatic activating point mutations within c-KIT protooncogene


  • About 30% of SM cases associated with TET2 mutations


Clinical Issues



  • 2/3 of cases occur in children


  • Prognosis depends on disease category



    • Pediatric onset CM has favorable outcome


  • Approximately 80% of patients with mastocytosis have evidence of skin involvement


Microscopic Pathology



  • Multifocal compact or diffuse compact mast cell infiltrates


  • Diffuse interstitial infiltration pattern


  • Cytology varies, but abnormal features are almost always detected, including spindling and hypogranularity


  • Frequent bi- or multilobated nuclei usually indicate aggressive disease


Top Differential Diagnoses



  • Reactive mast cell hyperplasia


  • Cutaneous lymphoma


  • Myeloid and lymphoid neoplasms with eosinophilia







This mastocytoma of the skin was present at birth on the right neck of this newborn. Mastocytomas of the skin occur almost exclusively in infants. (Courtesy S. Vanderhooft, MD.)






Mastocytoma of the skin in an infant shows a dense infiltrate of mast cells with epidermal sparing that showed round nuclei with abundant basophilic-staining cytoplasm at high power.


TERMINOLOGY


Abbreviations



  • Cutaneous mastocytosis (CM)


  • Systemic mastocytosis (SM)


Synonyms



  • Mast cell disease


Definitions



  • Heterogeneous group of clonal, neoplastic mast cell proliferations that accumulate in 1 or more organ systems


  • Subtypes based mainly on distribution of disease and clinical manifestations



    • Cutaneous mastocytosis (CM): Mast cell infiltrates confined to skin



      • Urticaria pigmentosa (UP)/maculopapular cutaneous mastocytosis (MPCM)


      • Diffuse cutaneous mastocytosis


      • Mastocytoma of skin


    • Systemic mastocytosis (SM): Involvement of at least 1 extracutaneous organ ± skin lesions



      • Indolent systemic mastocytosis (ISM)


      • Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease (SMAHNMD)


      • Aggressive systemic mastocytosis (ASM)


      • Mast cell leukemia (MCL)


      • Mast cell sarcoma (MCS)


      • Extracutaneous mastocytoma


ETIOLOGY/PATHOGENESIS


Molecular Background



  • Frequently associated with somatic activating point mutations within c-KIT protooncogene



    • Encodes tyrosine kinase receptor for stem cell factor (SCF)


    • Various mutations result in ligand-independent activation of c-KIT tyrosine kinase



      • Constitutively activated c-KIT leads to clonal proliferation of mast cells


    • Most common mutation: D816V in exon 17 encoding tyrosine kinase domain



      • Identified in ≥ 95% of adults with SM when sensitive methods are used


      • Present in 35% of pediatric CM cases


      • Provides relative resistance to prototypical tyrosine kinase inhibitor imatinib


    • Other activating point mutations: D816Y, D816H, D816F, and D816I in exon 17 (rarely seen)



      • Frequency significantly higher in CM than in SM


    • Activating point mutations in exons 8, 9, and 11 (mutually exclusive with codon 816 mutations)



      • 44% of pediatric CM cases


  • Pediatric CM historically regarded as reactive condition with transient dysregulation of local growth factors



    • Increasing evidence supports neoplastic nature associated with activating c-KIT mutations (as in adults)



      • Despite high rate of spontaneous regression (mechanism unknown)


  • Rare familial cases with germline mutations of c-KIT have been reported


  • In patients with SM-AHNMD, additional genetic defects are detected depending on type of AHNMD


  • About 30% of SM cases associated with TET2 mutations



    • TET2 acts as putative tumor suppressor gene


    • 50% of those cases also carry c-KIT D816V mutation


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Very rare




      • Lack exact numbers with regard to frequency


      • Calculated incidence of 5-10 new cases per 1,000,000 population per year in various studies


    • CM



      • UP: Most common CM variant


      • Mastocytoma of skin (10-15% of pediatric CM cases)


      • Diffuse CM (rare)


    • SM



      • ISM: Most common SM variant (46% of SM cases)


      • SM-AHNMD (40% of SM cases)


      • ASM (12% of SM cases)


      • MCL, MCS, and extracutaneous mastocytoma are extremely rare


  • Age



    • Occurs at any age



      • 2/3 occur in children in 1st 2 years of life


    • CM most common in children, less frequent in adults



      • 50% of affected children develop typical skin lesions before 6 months of age


      • May present at birth


    • SM generally diagnosed after 2nd decade of life, rare in pediatric population


  • Gender



    • Slight male predominance in CM


    • M:F = 1:1-1:3 in SM


Site



  • Approximately 80% of patients with mastocytosis have evidence of skin involvement


  • CM: Mast cell infiltrates confined to skin


  • SM: Involvement of at least 1 extracutaneous organ ± skin lesions



    • Bone marrow (BM) almost always involved


    • Skin lesions occur in ≥ 50% of cases, more often in those with indolent disease


    • Spleen, lymph nodes, liver, and gastrointestinal tract mucosa


    • Rarely peripheral blood (PB) shows leukemia


    • Any tissue may be affected


Presentation



  • CM



    • Includes 3 distinct clinicohistopathologic entities


    • Characterized by 2 main groups of symptoms


    • Skin lesions due to mast cell infiltrate and release of mediators (flushing, blistering, pruritus)



      • Lesions can urticate when stroked (“Darier” sign) in 1/2 of cases


    • Systemic symptoms due to release of mast cell mediators (histamine most significant)



      • Headache


      • GI manifestations including acid reflux disease, peptic ulcer disease, and diarrhea


      • Respiratory symptoms including shortness of breath and asthma exacerbations


      • Cardiovascular symptoms including tachycardia, hypotension, syncope, or rarely, even shock


  • UP/MPCM



    • Widespread distribution of tan macules and occasionally nodules or plaques



      • In children, lesions tend to be larger and papular


    • Most lesions show intraepidermal accumulation of melanin pigment


    • Sparing of palms, soles, face, and scalp


    • In children, typically involving head and lateral face


    • Number of lesions varies, but does not predict presence of systemic disease


    • Rare special forms



      • Plaque form: Nonpigmented, plaque-forming lesions in young children


      • Nodular form: Brown nodules


      • Telangiectasia macularis eruptiva perstans (TMEP): Brown macules and erythema with telangiectasias on trunk and extremities


      • Blistering variant (“bullous mastocytosis”): Exaggeration of urticaria due to chymase cleaving dermal-epidermal junction


  • Diffuse CM



    • Diffusely thickened skin with “orange peel” appearance and yellow-red discoloration


    • No discernible individual lesions



    • In more severe variant, blistering may precede mast cell infiltration



      • Differential diagnosis with congenital bullous diseases


    • More likely associated with severe systemic symptoms (higher concentrations of mast cells)



      • GI manifestations (including severe diarrhea), hypotension, or even shock


  • Mastocytoma of skin



    • Single indurated red-brown macule, papule, plaque, or tumor measuring ≤ 4 cm in diameter



      • Multiple mastocytomas in different locations have been reported


    • Almost exclusively in infants


    • Slight predilection for trunk, but also occurs on extremities, head and neck


  • Systemic mastocytosis



    • Includes 6 distinct clinicohistopathologic entities


    • Symptoms grouped into few categories


    • Constitutional symptoms



      • Fatigue, weight loss, fever, diaphoresis


    • Skin manifestations



      • Pruritus, urticaria, dermographism


    • Mediator-related systemic events (due to release of histamine, eicosanoids, proteases, and heparin)



      • Same as CM systemic symptoms


    • Musculoskeletal complaints



      • Bone pain, osteopenia/osteoporosis, fractures, arthralgias, myalgias


    • Symptoms related to organ impairment due to mast cell infiltrates (absent in indolent but present in aggressive variants)



      • Splenomegaly (often minimal)


      • Lymphadenopathy and hepatomegaly (less frequent)


    • Hematological abnormalities



      • Anemia, leukocytosis, eosinophilia (frequent), neutropenia, and thrombocytopenia


      • BM failure only in aggressive or leukemic variants


      • Significant numbers of circulating mast cells are suggestive of MCL


      • 30-40% of SM has associated clonal hematological non-mast cell lineage disease (AHNMD) diagnosed before, simultaneously with, or after SM diagnosis


      • Any defined myeloid or lymphoid malignancy possible, myeloid predominates (chronic myelomonocytic leukemia [CMML] most common)


Laboratory Tests



  • Serum total tryptase



    • Persistently elevated (> 20 ng/mL suggestive of SM, used as minor criterion for diagnosis)



      • Criterion not valid in SM-AHNMD


    • Normal to slightly elevated in patients with CM



      • Usually reserved for adult work-up of CM


  • Histamine



    • May be very elevated in diffuse CM, but are rarely part of routine work-up for CM


Treatment

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Cutaneous and Systemic Mastocytosis

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