Bone marrow neoplastic

Bone marrow - neoplastic myeloid

Mast cell neoplasms

Systemic mastocytosis



Last author update: 7 August 2023
Last staff update: 22 September 2023

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PubMed Search: Systemic mastocytosis

See Also: Cutaneous mastocytosis

Mark Girton, M.D.
Nadine Aguilera, M.D.
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Cite this page: Girton M, Aguilera N. Systemic mastocytosis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowsystemicmastocytosis.html. Accessed September 30th, 2023.
Definition / general
  • Mastocytoses are a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells in 1 or more organ systems
  • Mast cells are cytologically and immunophenotypically abnormal in neoplastic mast cell proliferations
Essential features
  • Systemic mastocytosis is a neoplastic condition in which histomorphologically atypical mast cells involve tissue sites including bone marrow, skin and other tissues
  • Occurs primarily in adults and is strongly associated with c-KIT mutations with the majority being KIT D816V
  • Also associated with myeloid neoplasms
  • Major or minor criteria are required for diagnosis and include identification of atypical spindled mast cell clusters, aberrant expression of CD25, CD2 or CD30, the presence of a KIT mutation or elevated serum tryptase
  • Categories of disease are based upon sites of involvement, related symptoms and laboratory findings
Terminology
  • According to the 2017 WHO classification, mastocytosis is classified into the following categories
    • Cutaneous mastocytosis
      • Urticaria pigmentosa / maculopapular cutaneous mastocytosis
      • Diffuse cutaneous mastocytosis
      • Mastocytoma of skin
    • Systemic mastocytosis
      • Indolent systemic mastocytosis
      • Bone marrow mastocytosis
      • Smoldering systemic mastocytosis
      • Systemic mastocytosis with an associated hematological neoplasm
      • Aggressive systemic mastocytosis
      • Mast cell leukemia
    • Diagnosis of these entities requires correlation with burden of disease (B findings) and cytoreduction requiring (C findings), which indicate organ involvement with and without organ dysfunction, respectively (see Clinical features)
ICD coding
  • ICD-10:
    • D47.02 - systemic mastocytosis
    • C96.21 - aggressive systemic mastocytosis
    • C94.3 - mast cell leukemia
  • ICD-11:
    • 2A21.00 - mast cell leukemia
    • 2A21.0Y - other specified systemic mastocytosis
    • 2A21.0Z - systemic mastocytosis, unspecified
Epidemiology
  • Prevalence estimate of 10 - 13 per 100,000 (Transl Res 2016;174:86, Cancers (Basel) 2021;13:6380)
  • Indolent / smoldering types present at median age of ~50 years; more aggressive types present at older age with a median of ~70 years
  • Pediatric systemic mastocytosis is extremely rare
    • Mastocytoses in pediatric patients are predominantly cutaneous limited (not systemic) with a bimodal incidence of birth to 2 years and over 15 years
    • ~50% of cases are self limited, resolving after onset of puberty
  • M ≈ F; most studies show no significant difference or only slight differences in incidence among men and women (Transl Res 2016;174:86)
  • Familial disease is rare, accounting for ~1 - 2% of all cases (Br J Haematol 2021;193:845)
  • Bone marrow or bone involvement is present in up to 90% of systemic mastocytosis cases
Sites
Pathophysiology
  • Clonal expansion of cells with mast cell differentiation having c-KIT mutation
  • Mast cell proliferation and degranulation results in destructive lesions
Etiology
  • Generally thought to differentiate from a CD34+, CD117 / KIT+, CD13+ hematopoietic progenitor cells or a mast cell committed precursor
  • Proto-oncogene c-KIT (Leukemia 2015;29:1223)
    • Chromosome 4
    • Codes for tyrosine protein kinase KIT, CD117 or mast / stem cell growth factor receptor (SCFR)
    • KIT is dimerized by stem cell growth factor, ultimately inducing cell survival, proliferation and differentiation
    • In mastocytosis, c-KIT mutation leads to stem cell growth factor independent activation of KIT
    • The most common c-KIT mutation is KIT D816V, while cutaneous mastocytosis has more frequent non-D816V codon 816 mutations
    • Mast cell release of mediators including histamine may contribute to increased osteoblast activity, activation of osteoclasts and formation of sclerotic lesions
Clinical features
  • Course is variable from benign and self limited to aggressive with a variety of symptoms which differ based on disease subtype (Am J Hematol 2021;96:508)
  • Most commonly affected sites are skin (urticaria pigmentosa) and bone marrow
  • 4 categories of systemic mastocytosis presenting symptoms
    • Constitutional: weight loss, fever and diaphoresis, fatigue
    • Skin manifestations: urticaria and pruritus, flushing, dermatographism
    • Mediator related systemic events: abdominal pain, headache, hypotension, syncope
    • Musculoskeletal symptoms: osteoporosis, osteopenia, bone pain and fracture, arthralgia and myalgia
  • Other presentation findings may include organ impairment associated with infiltration, especially in aggressive systemic mastocytosis and mast cell leukemia
  • Symptoms related to mast cell degranulation with associated increased serum tryptase may be diagnosed as mast cell activation syndrome
    • Mast cell activation syndrome is not considered a subtype of systemic mastocytosis and may be diagnosed in the absence of mastocytosis if criteria are not fulfilled
    • In the absence of all required diagnostic criteria, a clonal mast cell population with KIT D816V mutation or aberrant surface CD25 warrants a diagnosis of monoclonal mast cell activation syndrome
  • Patients with mediator related symptoms and systemic mastocytosis are designated as having primary (clonal) mast cell activation syndrome, which has diagnostic and therapeutic implications
  • Systemic mastocytosis with an associated hematological neoplasm (AHN): associated and often clonally related secondary myeloid neoplasm, most commonly chronic myelomonocytic leukemia
  • C (cytoreduction requiring) findings:
    • Neoplastic mast cell infiltration impacting bone marrow function is defined as ≤ 1 cytopenia, absolute neutrophil count < 1.0 x 109/L, hemoglobin < 10 g/dL or platelet count < 1.0 x 109/L
    • Abnormal liver function with ascites and elevated liver enzymes with or without hepatomegaly, cirrhosis, portal hypertension
    • Large osteolytic lesions (≥ 20 mm) with or without bone pain, pathologic fractures (excepting osteoporosis related fractures)
    • Palpable splenomegaly with hypersplenism with or without weight loss, hypalbuminemia
    • Gastrointestinal mast cell infiltrates causing malabsorption with or without weight loss
  • B (burden of disease) findings:
    • > 30% of mast cells on bone marrow biopsy and serum total tryptase > 200 ng/mL or KIT D816V mutation with VAF ≥ 10% in bone marrow cells or peripheral blood leukocytes (Leukemia 2022;36:1703)
      • International Consensus Classification (ICC): high mast cell burden, > 30% of bone marrow cellularity by mast cell aggregates (assessed on bone marrow biopsy) and serum tryptase > 200 ng/mL)
    • Dysplastic changes or myeloproliferation in nonmast cell lineages, without meeting criteria for associated hematological neoplasm, with normal or only slightly abnormal blood counts
      • ICC: cytopenia (not meeting criteria for C findings) or cytosis excluding reactive causes and other myeloid neoplasm criteria are not met
    • Hepatomegaly without liver dysfunction, palpable splenomegaly without hypersplenism or lymphadenopathy
    • Additional provisional B finding proposed for the upcoming WHO fifth edition update
      • KIT D816V mutation with variant allele fraction ≥ 10% in bone marrow cells or peripheral blood leukocytes (Leukemia 2022;36:1703)
Diagnosis
  • 2017 WHO classification diagnostic criteria for systemic mastocytosis; must demonstrate major criterion and at least 1 minor criterion or ≥ 3 minor criteria
  • ICC diagnostic criteria are very similar to the WHO 5th edition criteria; variation from WHO 5th edition are noted
    • Major criterion
      • Multifocal dense mast cell infiltrates detected in sections of bone marrow or extracutaneous organs; infiltrate is defined as ≥ 15 mast cells in aggregate (ICC specifies that the mast cells must express tryptase or CD117)
    • Minor criteria
      • > 25% of mast cells in bone marrow biopsy are spindled, have abnormal morphology of bone marrow aspirate / tissue infiltrate mast cells are immature or atypical
      • Detection of KIT mutation in blood, bone marrow or other nonskin tissue (activating point mutation at codon 816 or any KIT mutation conferring ligand independent activation (Leukemia 2022;36:1703)
      • Expression of one or more of the following antigens in the mast cell population in addition to normal mast cell markers (by flow cytometry or IHC): CD25, CD2, CD30 (Leukemia 2022;36:1703)
      • Persistent serum total tryptase > 20 ng/mL (except in context of associated myeloid neoplasm)
  • Diagnostic criteria for variants of systemic mastocytosis (in addition to general criteria above)
    • Indolent systemic mastocytosis
      • No C findings indicative of organ involvement
      • No evidence of associated hematological neoplasm
      • Low mast cell burden
      • Skin lesions are almost always present
    • Bone marrow mastocytosis
      • Similar criteria as indolent variant with bone marrow involvement
      • No skin lesions
      • Proposed fifth edition WHO criteria refinement includes tryptase < 125 ng/mL (Leukemia 2022;36:1703)
    • Smoldering systemic mastocytosis
      • ≥ 2 B findings in absence of C findings
      • No evidence of associated hematological neoplasm
      • High mast cell burden
      • Does not meet mast cell leukemia criteria
    • Systemic mastocytosis with an associated hematological neoplasm
      • Associated hematological neoplasm including myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, lymphoma or other WHO classified distinct hematological neoplasm
    • Aggressive systemic mastocytosis
      • ≥ 1 C finding
      • Does not meet mast cell leukemia criteria
      • Skin lesions are usually absent
    • Mast cell leukemia
      • Diffuse infiltration of bone marrow by dense aggregates of atypical, immature mast cells
      • ≥ 20% mast cells in bone marrow aspirate
      • Classic: ≥ 10% white blood cell count is mast cells in peripheral blood
      • Aleukemic: < 10% peripheral blood mast cells (more common than classic)
        • Skin lesions are usually absent
  • Additional morphologic pattern proposed for the upcoming WHO fifth edition update:
    • Well differentiated systemic mastocytosis (Leukemia 2022;36:1703)
      • May occur in any subtype with mast cells lacking atypical histomorphologic characteristics, may not have expression of CD25, CD2 or CD30, predominantly lacking KIT D816V mutation (J Allergy Clin Immunol 2016;137:168)
      • High percentage of bone marrow mast cells
      • Predominantly in women, childhood onset and familial aggregation
Laboratory
  • Complete blood count (CBC) may demonstrate anemia, thrombocytopenia, thrombocytosis, leukocytosis or eosinophilia
  • Serum tryptase > 20 ng/mL (fluoro immunoenzymatic assay [Pharmacia, Uppsala, Sweden]) is a minor diagnostic criterion (Arch Pathol Lab Med 2007;131:784)
  • Elevated histamine metabolites in 24 hour urine sample may be present in patients with cutaneous lesions
Radiology description
  • Skeletal involvement reported in 70 - 90% of patients (Annu Rev Med 2004;55:419)
  • Osteoporosis reported in up to 40% of patients; dual energy Xray absorptiometry (DEXA) of hip and spine should be performed (Cancers (Basel) 2021;13:6380)
  • Most common skeletal findings:
    • Multiple focal sclerotic axial and appendicular bone lesions
    • Diffuse, circumscribed, sclerotic foci with alternating zones having normal or reduced density in axial skeleton, ribs, humerus, femur
Prognostic factors
  • Prognosis is linked to disease subclassification (Am J Hematol 2021;96:508)
    • Favorable prognosis
      • Indolent / smoldering systemic mastocytosis
        • 3% progression to more aggressive forms in study with median follow up of > 10 years; life expectancy is approximately normal
    • Poor prognosis
      • Aggressive systemic mastocytosis
        • Overall median survival of ~40 months
      • Systemic mastocytosis with an associated hematological neoplasm
        • Overall median survival of ~24 months (longer in patients with myeloproliferative neoplasms, shorter in those with chronic myelomonocytic leukemia, myelodysplastic syndrome or acute leukemia)
      • Mast cell leukemia
        • ~2 year overall median survival
  • Prognosis is linked to independent risk factors
    • Age: > 60 years
    • Platelet count: < 150 x 109/L
    • Serum alkaline phosphatase above reference interval
    • Presence of adverse mutation in ASXL1, RUNX1, SRSF2 or NRAS
    • Increased plasma IL2Rɑ / CD25 confers worse prognosis in indolent SM
Case reports
  • 33 year old man with abdominal pain and blood per rectum (Ann Gastroenterol 2019;32:208)
  • 50 year old man with foamy mastocytosis who presented with flushing, fever, intestinal disorder, skin lesions and splenomegaly (Blood 2018;131:586)
  • 62 year old man with systemic mastocytosis and essential thrombocythemia who presented with thrombocytosis and hepatosplenomegaly with cutaneous papules (Medicina (Kaunas) 2019;55:528)
  • 83 year old man with systemic mastocytosis and multiple myeloma who presented with hematuria and bone pain (Blood 2018;132:1545)
Treatment
  • Indolent disease may not require treatment or treatment may be aimed at symptomatic management, including antihistamines, leukotrienes, mast cell stabilizers, proton pump inhibitors, calcium vitamin D, bisphosphonates; epinephrine may be needed for patients having risk of anaphylaxis (Am J Hematol 2021;96:508)
  • Avoidance of exposures that aggravate mast cell degranulation including temperature extremes, mechanical irritation, medications and alcohol
  • Aggressive disease requiring cytoreductive therapy may be treated with the following agents
    • Interferon alpha is often paired with prednisone; may have severe side effects including myelosuppression
    • 2-chlorodeoxyadenosine issued as a second line therapy for interferon alpha refractory disease; may have severe side effects including myelosuppression, lymphopenia and risk of opportunistic infection
    • Cladribine purine analog with mechanism independent of tyrosine kinase inhibition
    • Tyrosine kinase inhibitors
      • Avapritinib targets PDFRɑ and KIT (Int J Mol Sci 2021;22:2983)
      • Midostaurin targets FLT3, KIT D816V mutation (Blood 2020;135:1365)
      • Imatinib targets BCR::ABL, wild type KIT
      • Nilotinib targets BCR::ABL, wild type KIT
      • Dasatinib dual SRC / ABL inhibitor
    • Chemotherapy regimens employed in acute myeloid leukemia
    • Allogeneic stem cell transplantation in rare cases
Microscopic (histologic) description
  • Neoplastic mast cells may be spindled to round / oval (similar to normal mast cells) with variable cytoplasmic granularity
  • Spindled mast cell aggregates may invoke a streaming-like appearance
  • Bone marrow aspirate sampling of mast cells may be limited due to associated reticulin or collagen fibrosis
  • Characteristically, mast cells have a light blue-gray cytoplasm; granules may be inconspicuous on H&E sections but are more prominent with regional distribution on Wright-Giemsa stained bone marrow aspirate and peripheral blood smears
  • Basophilic to amphipathic cytoplasmic granules may obscure mast cell nuclei on Wright-Giemsa stain
  • On H&E sections, round mast cells with central nuclei may give a fried egg-like appearance at low power, raising a differential that includes hairy cell leukemia (Arch Pathol Lab Med 2007;131:784)
  • Mast cell nuclei may have 1 to a few prominent nucleoli and relatively smooth nuclear chromatin
  • Mast cell aggregates may be intermixed with lymphohistiocytic proliferations, often with interspersed eosinophils and plasma cells
  • Atypical mast cell features include spindle morphology, hypogranulation and atypical nuclear borders
  • Bone may demonstrate osteosclerosis, increased trabeculation volume, increased cortical thickness and narrowing of marrow spaces
Microscopic (histologic) images

Contributed by Mark Girton, M.D. and AFIP
Marrow mast cell cluster

Marrow mast cell cluster

Intermixed with lymphoid aggregate

Intermixed with lymphoid aggregate

Aspirate with mast cells Aspirate with mast cells Aspirate with mast cells

Aspirate with mast cells

Mast cell cluster

Mast cell cluster


Hypercellular bone marrow biopsy

Hypercellular bone marrow biopsy

Bone marrow biopsy with marrow replacement

Bone marrow biopsy with marrow replacement

Cytologic spectrum

Cytologic spectrum

CD117 positive mast cells

CD117 positive mast cells

CD25 positive mast cells

CD25 positive mast cells


CD2 positive mast cells

CD2 positive mast cells

CD30 positive mast cells

CD30 positive mast cells

CD117 positive mast cells

CD117 positive mast cells

Mast cell tryptase positive

Mast cell tryptase positive

CD25 positive mast cells

CD25 positive mast cells


Perifollicular distribution

Perifollicular distribution

Characteristic sclerosis

Characteristic sclerosis

Mast cell infiltrate

Mast cell infiltrate

Delicate collagen fibrils and eosinophils

Delicate collagen fibrils and eosinophils

Mast cell staining

Mast cell staining


Interfollicular pattern

Interfollicular pattern

Diffuse involvement

Diffuse involvement

Ovoid nuclei with eosinophilic cytoplasm

Ovoid nuclei with eosinophilic cytoplasm

Spindle shaped mast cells

Spindle shaped mast cells

Spindly configuration

Spindly configuration

Peripheral smear images

Contributed by Mark Girton, M.D.
Peripheral blood mast cell Peripheral blood mast cell Peripheral blood mast cell

Peripheral blood mast cell

Positive stains
Negative stains
Flow cytometry description
  • Neoplastic mast cell populations may be difficult to sample because of associated reticulin or collagen fibrosis; therefore, the population of interest may be underrepresented in flow cytometry assays
  • Antibodies against CD45, CD13, CD33, CD117, CD25 and CD2 are typically positive in neoplastic mast cells, while CD34 is generally expected to be negative, except in mast cell precursors
  • Nonneoplastic mast cells lack expression of CD25 and CD2
  • CD38 expression may be seen in normal mast cell precursors
Molecular / cytogenetics description
Sample pathology report
  • Blood, peripheral smear:
    • Unremarkable peripheral blood smear (see comment)
    • Comment: Microscopic examination of the peripheral blood smear demonstrates a normal red blood cell count with erythrocytes, which are morphologically unremarkable. The white blood cell count is normal and leukocytes are morphologically unremarkable. Platelets are normal in number and morphology.

  • Bone marrow, left, aspirate smear:
    • Trilineage hematopoiesis with occasional mast cells present (see comment)
    • Comment: Microscopic examination of the bone marrow aspirate demonstrates a spicular and cellular specimen which is adequate for evaluation. There is trilineage hematopoiesis. Erythroid precursors demonstrate normoblastic maturation. Myeloid precursors demonstrate the full spectrum of maturation. The myeloid to erythroid (M:E) ratio is normal at 2.3:1. Megakaryocytes are present and appear normal in number and morphology. There are occasional mast cells present, some of which demonstrate a spindled morphology. There is no increase in blasts. An iron stain demonstrates the presence of storage iron and no significant increase in ring sideroblasts.

  • Bone marrow, left, core biopsy:
    • Limited subcortical specimen showing trilineage hematopoiesis with involvement by systemic mastocytosis (see comment)
    • Comment: Microscopic examination of the core biopsy demonstrates a subcortical bone marrow specimen limited sampling, which precludes evaluation of the cellularity. There is trilineage hematopoiesis and small, ill defined lymphoid aggregates. Immunohistochemical staining for CD117 and mast cell tryptase demonstrate clusters of spindle shaped mast cells. Staining for CD25 is positive and staining for CD2 is negative. The lymphoid aggregates are composed of a mixture of B cells and T cells as demonstrated by CD20 and CD3 positivity, respectively. The myeloid to erythroid ratio appears normal. Megakaryocytes are present and appear normal in number and morphology. A PAS stain highlights the myeloid elements and megakaryocytes. An iron stain shows the presence of storage iron. A reticulin stain is not evaluable due to the limited specimen size.

  • Bone marrow, left, clot section:
    • Normocellular bone marrow with trilineage hematopoiesis and involvement by systemic mastocytosis (see comment)
    • Comment: Microscopic examination of the clot preparation demonstrates a cellular specimen that is adequate for evaluation. The clot section appears normocellular. There is trilineage hematopoiesis. The myeloid to erythroid ratio appears normal. Megakaryocytes are present and appear normal in number with unremarkable morphology. There are multiple lymphoid aggregates present with mast cell clusters having focal areas of scattered eosinophils. Immunohistochemical staining for CD117 and mast cell tryptase demonstrate clusters of spindle shaped mast cells. Staining for CD25 is positive and staining for CD2 is negative. The lymphoid aggregates are a mixture of B cells and T cells as demonstrated by CD20 and CD3 positivity, respectively. There is no increase in blasts. An iron stain shows the presence of storage iron and no ring sideroblasts.
    • In summary, the patient's specimen demonstrates an overall normocellular bone marrow with trilineage hematopoiesis and involvement by systemic mastocytosis. Correlation with molecular and genetic studies is recommended.
Differential diagnosis
Board review style question #1
Regarding systemic mastocytosis, which of the following is the most commonly associated hematological neoplasm (AHN)?

  1. Acute myeloid leukemia (AML)
  2. Chronic myelomonocytic leukemia (CMML)
  3. Chronic myelocytic leukemia (CML)
  4. Plasma cell myeloma
  5. Polycythemia vera (PV)
Board review style answer #1
B. Chronic myelomonocytic leukemia (CMML). Associated hematological neoplasms are reported to include CMML, non-Hodgkin lymphoma, refractory anemia with ring sideroblasts and thrombocytosis, essential thrombocythemia, multiple myeloma, monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, myelofibrosis and acute myeloid leukemia. CMML is the most commonly reported associated hematological neoplasm (Am J Hematol 2016;91:692).

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Reference: Systemic mastocytosis
Board review style question #2
Which of the following features fulfills a fifth edition WHO classification minor diagnostic criterion for systemic mastocytosis?

  1. Identification of a BRAF V600E mutation in blood, bone marrow aspirate or nonskin tissue
  2. Mast cell expression of CD25, with or without CD2, in combination with normal mast cell markers
  3. Mast cells expressing CD117 or tryptase by immunohistochemical staining
  4. Multiple dense mast cell groups as defined by ≥ 15 mast cells per aggregate in bone marrow or other extracutaneous organ
Board review style answer #2
B. Mast cell expression of CD25, with or without CD2, in combination with normal mast cell markers. The fifth edition WHO’s diagnostic criteria for systemic mastocytosis must demonstrate major criterion and at least 1 minor criterion or ≥ 3 minor criteria. Major criterion includes: multifocal dense mast cell infiltrates detected in sections of bone marrow or extracutaneous organs (infiltrate is defined as ≥ 15 mast cells in aggregate). International Consensus Classification (ICC) specifies that the mast cells must express tryptase or CD117. Minor criteria include: > 25% of mast cells in bone marrow biopsy are spindled, have abnormal morphology of bone marrow aspirate / tissue infiltrate mast cells are immature or atypical; detection of KIT mutation in blood, bone marrow or other nonskin tissue (activating point mutation at codon 816); expression of one or more of the following antigens in the mast cell population in addition to normal mast cell markers (by flow cytometry or IHC): CD25, CD2, CD30; and persistent serum total tryptase > 20 ng/mL (except in context of associated myeloid neoplasm; may be adjusted in this context according to ICC). Additional provisional minor criteria proposed for the fifth edition WHO include CD30 expression and any KIT mutation conferring ligand independent activation (Leukemia 2022;36:1703).

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Reference: Systemic mastocytosis
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