Final Diagnosis - Systemic Mastocytosis with Associated Clonal Hematological Non-mast-cell Lineage Disease.
FINAL DIAGNOSIS
Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease.
Definition
Mastocytosis is a myeloproliferative neoplasm attributed to a clonal, proliferation of mast cells that accumulate in one or more organ systems. It is characterized by the presence of multiple foci of compact clusters or cohesive aggregates, and or infiltrates of abnormal mast cells. Its subtypes are recognized mainly by the distribution of the disease and their clinical manifestations. In cutaneous mastocytosis (CM), the mast cell infiltration remains confined to the skin, and they can spontaneously regress. Systemic mastocytosis (SM) is characterized by involvement of at least one extracutaneous organ with or without evidence of skin lesions, and associated multiorgan failure and poor survival.
Diagnosis[1]
The prerequisites for the diagnosis of SM can be made when the major criterion and at least one minor criterion are present, or when more than three minor criteria are present.
Major criterion
- Multifocal dense infiltrates of mast cells (greater-than or equal to 15 mast cells in aggregates) detected in sections of bone marrow and/or other extracutaneous organ(s).
Minor criteria
- In biopsy sections of bone marrow or other extracutaneous organs,
>25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology or,
>25% of all mast cells in bone marrow aspirate smears are immature or atypical. - Detection of an activating point mutation at codon 816 of KIT in bone marrow, blood or another extracutaneous organ
- Mast cells in bone marrow, blood or other extracutaneous organs express CD25, with or without CD2, in addition to normal mast cell markers
- Serum total tryptase is persistently exceeding 20 ng/mL, unless there is an associated myeloid neoplasm, in which case this parameter is not valid.
Systemic mastocytosis is further characterized into 5 variants including indolent systemic mastocytosis, smouldering systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, aggressive systemic mastocytosis and mast cell leukanemia (Table 1 and Table 2) [1].
Table 1: Diagnostic criteria for the variants of systemic mastocytosis
Table 2: B ('burden of disease') and C ('cytoreduction-requiring') findings in systemic mastocytosis, which indicate organ involvement without and with organ dysfunction, respectively
In systemic mastocytosis with an associated hematological neoplasm (AHN) up to 40% of the cases are diagnosed before, simultaneously with, or after the diagnosis of hematological neoplasm that meets the criteria for a distinct entity in the WHO classification[2]. In theory, any defined myeloid or lymphoid disease may occur as the AHN, such as a myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, multiple myeloma, and lymphomas. Myeloid neoplasms predominate with chronic myelomonocytic leukemia (CMML) being the most common[3]. The majority of AHN cases have an activating KIT D816V mutation, which is generally identified in both compartments of the lesion. In patients with AHN, clinical symptoms and disease course relate both to the associated hematological disorder and to the SM.
Epidemiology and clinical presentation
Generally diagnosed in the second decade of life, SM has a slight female predominance. Clinical presentations are grouped into 4 categories:
- Constitutional symptoms (fatigue, weight loss, fever, diaphoresis),
- Skin manifestations (pruritus, urticaria, dermatographism, flushing),
- Mediator-related systemic events (abdominal pain, gastrointestinal distress, syncope, headache, hypotension, tachycardia, respiratory symptoms) and
- Musculoskeletal symptoms (bone pain, osteopenia/osteoporosis, fractures, arthralgias, myalgias)[1].
These symptoms can range from mild in some patients, due to the limited extent of the disease, to severe, life-threatening mediator-release events, due to mast cells visceral organ infiltration.
Site of involvement
The bone marrow is generally involved in SM, thus the bone marrow biopsy is strongly recommended for morphologic and molecular examination for exclusion or confirmation. The mast cell leukemia is rare, but it is defined by the peripheral blood involvement with an increased number of mast cells. In addition to the lymphoid organs, other organ systems such as the liver and the gastrointestinal tract mucosa can be involved.
Treatment and prognosis
All patients with SM received therapy for SM, including antihistamine or corticosteroid therapy for mediator-release symptoms, interferon alpha, anti-CD25, cladribine, imatinib and/or dasatinib[4]. They also received other therapies aimed at the AHN component. Wang et al showed that the prognosis of patients with AHN was significantly worse than of patients with pure SM, and the cause of death was exclusively attributed to the underlying hematological malignancies[4]; therefore, recognizing the AHN is critical when diagnosing systemic mastocytosis.
Case review 1
The hematologic malignancy that preceded the diagnosis of AHN in our patient is a myeloid neoplasm with t (8; 13) (p11.1; q12) and trisomy 21. This translocation is usually associated with the ZNF198-FGFR1 gene rearrangement, which would support classification of this neoplasm as a myeloid neoplasm with FGFR1 abnormality. Flow cytometric studies performed on the bone marrow at the outside hospital were reported to demonstrate no monotypic B-cell population, phenotypically abnormal T-cell population or increase in blasts. The in house review of the bone marrow approximated 100% cellularity with myeloid-predominant trilineage hematopoiesis, eosinophilia, basophilia and occasional atypical megakaryocytes, in addition to 4% blasts based on the manual differential count. Although mast cells were somewhat increased, there was no definite morphologic or immunophenotypic findings diagnostic of involvement by a mast cell neoplasm. Myeloid/lymphoid neoplasms with FGFR1 rearrangement
Hematological neoplasms with FGFR1 rearrangement are a diverse group of neoplasms that can present as a myeloproliferative neoplasm, acute myeloid leukemia, T- or B-lymphoblastic leukemia/lymphoma or mixed-phenotype acute leukemia[5]. The 2016 WHO recommends cases with additional mutations such as KIT D816V- positive systemic mastocytosis, be classified as systemic mastocytosis with an associated hematological neoplasm.
Sites of involvement
The lymphoid tissues such as the bone marrow, the peripheral blood, lymph nodes and the spleen are primarily involved, in addition to the liver.
Clinical features
Patients are generally young with a slight male predominance. The clinical presentation is dependent on the myeloid or lymphoid neoplasm expressed, but overall, about 90% of patients have peripheral blood or bone marrow eosinophilia[5]. The eosinophils belong to the neoplastic clone, as do the lymphoblasts and myeloblasts in cases in transformation[5].
Genetics
A diverse array of translocations with an 8p 11 breakpoint can trigger this syndrome. Additional cytogenetic aberrancies can occur, most notably trisomy 21. In general, all FGFR1 rearrangements encode an aberrant tyrosine kinase[5].
Prognosis and predictive factors
Myeloid neoplasms with FGFR1 abnormalities have a poor prognosis because there is no established tyrosine kinase inhibitor therapy. Hematopoietic stem cell transplantation is recommended for the management of these patients[5].
Case review 2
The patient was started on induction chemotherapy as one would do would normally for acute leukemia because of the apparent rapid progression of his disease in addition to worsening pain, fever, and splenomegaly with multiple infarctions. He was induced with the combination of idarubicin and cytarabine. To this regimen, he had a rapid response with a decrease of his white blood cell counts into a normal range, recovery of his platelets and hemoglobin, and improvement of his performance status.
The day 18 bone marrow biopsy and aspirate showed a hypercellular marrow with numerous atypical mast cells. Both flow cytometric and immunohistochemical studies demonstrate aberrant expression of CD25 by the mast cells. Although the molecular studies did not detect any mutations in the targeted regions, our patient met the major and two minor criterias for the diagnosis of systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease (AHN). The major criterion is the presence of multifocal, dense infiltrates of mast cells (greater than or equal to15 mast cells in aggregates) detected in sections of bone marrow biopsy; the minor criterias are: 1) in biopsy sections of bone marrow, >25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology or, of all mast cells in bone marrow aspirate smears, >25% are immature or atypical; 3) mast cells in bone marrow express CD2 and/or CD25 in addition to normal mast cell markers (Figures 5 and 6).
Patient continues to have persistent disease on thyrosine kinase inhibitors (was switched from imatinib to gleevec). He had a splenectomy and full ablative haploidentical peripheral blood stem cell transplant that was conditioned with fludarabine, busulfan, and Cytoxan.
The patient had progression of disease and expired 2 years after his initial diagnosis.
REFERENCES
- Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edition. Lyon, France: IARC press 2016; pp: 61-67.
- Pardanani A, Lim KH, Lasho TL, et al., "Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies". Blood 2009; 114: 3769-72.
- Iliakis T, Rougkala N, Diamantopoulos PT., et al., "An Adult Patient with Systemic Mastocytosis and B-Acute Lymphoblastic Leukemia," Case Reports in Medicine, vol. 2014, Article ID 526129, 5 pages, 2014.
- Wang SA, Hutchinson L, Tang G, et al., "Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components." Am J Hematol. 2013 Mar;88(3):219-24.
- Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edition. Lyon, France: IARC press 2016; pp: 70-77.
Contributed by Stell Patadji, MD, Rebecca Leeman-Neill, MD/PhD, Miroslav Djokic, MD