The main findings of this study can be summarised as follows:
- Among the four defined subtypes of SM, indolent SM was the most frequent (n = 35), with SM-AHNMD (n = 20) next in line, and therefore much more common than aggressive SM (n = 7) or the very rare true mast cell leukaemia (n = 2).
- Clinically, mastocytosis was never included in the differential diagnosis. Therefore, SM-AHNMD proved to be primarily a histological diagnosis that apparently depends on the experience of the haematopathologist, particularly his or her familiarity with mast cell proliferative disorders.
- The frequency distribution of the AHNMD shows a pronounced predominance of myelogenous neoplasms (18 of 20), in particular AML (n = 4) and MDS/MPS (n = 7).
- Sixteen of the 20 cases with SM-AHNMD showed a point mutation of the C-KIT protooncogene, mostly of the common type D816V (14 of 16).
- Mast cells of both the compact infiltrates and the diffuse (loosely scattered) compartments exhibited an abnormal immunophenotype, with coexpression of tryptase and CD25, which is never encountered in normal/reactive mast cells. These findings are of particular importance for the discrimination of mastocytosis from mast cell hyperplasia and for the diagnosis of indolent SM in patients with cutaneous mastocytosis lacking compact mast cell infiltrates within the bone marrow.
Very little is known about the frequency distribution of mastocytosis within the spectrum of suspected haematological disorders, and about the subtypes of the associated haematological malignancies in SM-AHNMD. We found that mastocytosis is a very rare disorder, amounting to only 0.3% of diagnoses established on bone marrow biopsies (nearly 19 500) evaluated in a reference centre for haematopathology (institute of pathology, University of Lübeck, Lübeck, Germany) within a period of about three years. Among the myelogenous tumours (approximately 4100), mastocytosis made up about 1.5% of all cases and thus belonged to the group of rare neoplasms. SM-AHNMD is a novel entity defined in the recent WHO classification of malignant tumours of the haemopoietic tissues and comprises all cases of SM with an associated non-mast cell lineage clonal haematological disease. 1
As expected, myelogenous malignancies made up most of the AHNMDs (18 of 20), with a predominance of MDS/MPS (n
7) and AML (n
4), the former including a spectrum of myelogenous tumours, in particular CMML, which were defined in the recent WHO classification of malignant haemopoietic tumours. 1
Our findings on the frequency distribution of AHNMDs are comparable to published data, which also reported a preponderance of myelogenous malignancies compared with overt lymphoproliferative disorders. 8,
The total number of published cases of SM-AML amounts to nearly 30 and covers the whole spectrum of subtypes according to the FAB classification, with a peak for AML types M2 and M5. 8,
Moreover, most subtypes of chronic myeloproliferative disorders have been described as AHNMDs, including essential thrombocythaemia. 10
However, to the best of our knowledge, an association of SM with Philadelphia chromosome positive chronic myeloid leukaemia has not been reported. 9
According to all published data, the most frequent myelogenous neoplasm associated with SM is CMML, which is included in the group of MDS/MPS. 7,
According to our experience, the incidence of a diagnosis of SM-AHNMD should increase if appropriate immunostaining using antibodies against the diagnostically relevant mast cell related markers, such as tryptase (enabling the detection of even very small compact mast cell infiltrates) and CD25 (defining an abnormal immunophenotype of mast cells seen only in neoplastic states), were applied routinely in all bone marrow trephines containing infiltrates of MDS, AML, and CMML (MDS/MPS). Although tryptase cannot be regarded as a specific marker for mast cells (atypical basophils in chronic myeloid leukaemia and myeloblasts in AML have also been shown to express this protease) and CD25 (anti-interleukin 2 receptor) is not a specific marker for a particular haemopoietic cell (although it is expressed on basophils and a subset of T cells), it should be emphasised that cells coexpressing tryptase and CD25 in the setting of a haematological disease are probably abnormal mast cells and therefore can be regarded as a diagnostic clue for mastocytosis because basophils usually do not contain amounts of tryptase detectable by immunohistochemistry. 12,
Diffuse dense blast cell infiltrates might obscure or even distort pre-existing compact mast cell infiltrates, a phenomenon we recently found in a patient with AMLM2 and t(8;21), in whom compact mast cell infiltrates were found only in the second bone marrow biopsy removed after induction chemotherapy with pronounced aplasia of blast cells and haemopoiesis. This case is described in detail in a recent publication. 14
Regarding the low incidence of lymphoproliferative disorders within the spectrum of AHNMDs, we could add two patients with unusual types of plasma cell dyscrasia to the current literature. 15
One patient had a plasma cell myeloma of IgM/κ subtype and the other a plasma cell myeloma of IgG/λ subtype, with associated secondary generalised amyloidosis. We are aware of only one other published case of SM plasma cell myeloma. 16
With regard to the pathogenesis of mastocytosis, the detection of activating point mutations of C-KIT in a large proportion of patients with mastocytosis strongly indicates that most (all?) cases of mastocytosis, in particular the systemic or leukaemic variants, are clonal haematological neoplasms, obviously of bone marrow origin. According to our own largely unpublished observations, C-KIT mutations can be detected in about 80% of all patients with SM, especially when more sensitive molecular methods such as peptide nucleic acid mediated PCR clamping or nested PCR on pooled microdissected single mast cells are performed on routinely processed bone marrow biopsies. 6,
We found point mutations of C-KIT in 16 of 20 of the bone marrow specimens containing tissue infiltrates of SM-AHNMD. Most (14 of 16) of these point mutations belonged to the so called common type, D816V, a finding that agrees with recently published data. 17
The uncommon point mutation D816Y was detected twice. However, the point mutation recently described by Pullarkat et al
in three of five (Asp816His) SM-AHNMDs was not found in our patients. 18
It also seems that the variability of C-KIT mutations in bone marrow infiltrates of mastocytosis is very much lower than in cutaneous mastocytosis. 6
“Cells coexpressing tryptase and CD25 in the setting of a haematological disease are probably abnormal mast cells and therefore can be regarded as a diagnostic clue for mastocytosis”
In a small proportion of the AHNMDs, other clonal markers were detected—for example, the 8;21 translocation in one of our patients with SM-AMLM2 and monoclonal gammopathies or paraproteinaemias (IgM/κ and IgG/λ, respectively) in the two patients with SM plasma cell myeloma. 14,
One of these patients presented clinically with a secondary intestinal amyloidosis, and the bone marrow biopsy was then performed to assess or exclude plasma cell myeloma. 15
The detection of SM was unexpected in this patient. Such findings clearly raise the question of a possible pathophysiological relation between SM and the AHNMD. The most likely answer is that both haematological diseases evolve from an early uncommitted haemopoietic progenitor cell as a primary monoclonal disease, with further evolution into phenotypically different subclones. 8
This hypothesis is the most likely in the most common forms of SM-AHNMD, namely those with associated myelogenous neoplasms. However, there is the possibility of the coincidental development of two distinct clonal haematological tumours. 8
This concept would fit for the rare occurrence of SM associated with lymphoproliferative disorders/plasma cell dyscrasias. Interestingly, monoclonal gammopathy of unclear significance is much more common in patients with mastocytosis than overt B cell neoplasms/plasma cell myelomas and, moreover, point mutations of C-KIT have been detected in circulating B cells. 19,
Finally, is there any clinical relevance for the coincidental histomorphological detection of SM in the bone marrow of patients within the setting of another haematological malignancy? The clinical relevance of such histological, mostly unexpected, findings is largely unknown. It must be stated that as far as we know at this time, the “SM” in SM-AHNMD should be treated like pure SM and the “AHNMD” should usually be treated in the same manner as pure AHNMD. 21
However, the resistance of neoplastic mast cells to cytoreductive drugs has to be borne in mind. In this regard, it is also noteworthy that imatinib is unlikely to be an effective agent in such patients because the D816V mutation of C-KIT converts KIT to an imatinib resistant kinase receptor. 20
This fact is underlined by our findings in a patient with AML type M2 with t(8;21) in whom treatment resulted in long standing complete haematological and cytogenetic remission of the AML but the disclosure and persistence of SM. 14
In addition, a patient with AML associated with mast cell leukaemia was reported to achieve complete molecular remission of the AML soon after induction chemotherapy, whereas the mastocytosis persisted after standard chemotherapy and allogeneic stem cell transplantation. 22
Take home messages
- Systemic mastocytosis (SM) with an associated clonal haematological non-mast cell lineage disease SM-AHNMD can be diagnosed histologically in bone marrow trephines only after immunostaining with antibodies against tryptase, KIT, and CD25
- Most AHNMDs are of myeloid origin and C-KIT point mutations were present in 18 of the 20 cases
- The prognostic relevance of detecting SM associated with another haematological neoplasm remains unclear, but mast cell resistance to most cytoreductive agents is of major importance for treatment planning
To summarise, SM-AHNMD is a primarily morphological diagnosis based on a thorough investigation of bone marrow trephine specimens including tryptase and CD25 immunohistochemistry. The most frequent AHNMDs are myelogenous neoplasms belonging to the group of myelodysplastic/myeloproliferative syndromes (CMML) and acute myeloid leukaemias.