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Polish Journal of Pathology
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vol. 62

Systemic mastocytosis (SM) and associated malignant bone marrow histiocytosis – a hitherto undescribed form of SM-AHNMD

Zbigniew Rudzki
Karl Sotlar
Andrzej Kudela
Jolanta Starzak-Gwóźdź
Hans-Peter Horny

Pol J Pathol 2011; 2: 101-104
Online publish date: 2011/08/18
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Systemic mastocytosis (SM) is a rare haematopoietic malignancy, typically presenting with bone marrow involvement and characterised by frequent activating mutations in the catalytic domain of the tyrosine kinase receptor C-KIT, usually D816V [1, 2]. A unique feature of SM is its frequent association with other haematopoietic non-mast cell lineage neoplastic disease (SM-AHNMD), found in approximately 30% of SM cases [3]. The AHNMD components described so far belong to a wide spectrum of haematopoietic neoplasia, including lymphomas, chronic myeloproliferative neoplasms, myelodysplastic syndromes and acute myeloid leukaemias; however, to the best of our knowledge, association of SM with histiocytic neoplasia has not been described. In contrast to acute leukaemias with monocytic/monoblastic differentiation, the neoplasms with features of mature histiocytes are probably even less frequent than SM, accounting for much less than 0.5% of all haematopoietic malignancies [4]. Referred to as “histiocytoses” or “histiocytic sarcomas”, they typically present as solid-organ tumours, but may also be primarily based in bone marrow [5]. We describe a first case of SM-AHNMD in which the non-mast cell component was a histiocytic sarcoma with features of reticulum/interdigitating cell origin.

An elderly female presented with several months history of fatigue, fever, weight loss and night sweats. There was no organomegaly, but chest X-ray revealed numerous, small, osteolytic and osteosclerotic lesions of T12, L1 and bilateral ribs. The patient was anaemic (haemoglobin 114 g/l, erythrocytes 2.9 × 109/l) and thrombocytopenic (platelets 90 × 109/l). White blood cell count (4 × 109/l) included 16% bands, 32% segmented neutrophils, 12% eosinophils, 36% lymphocytes and 4% monocytes. LDH was normal (236 U/l). Serum mast cell tryptase was not measured at that time. The past medical history did not include any medical conditions or therapies known to increase the risk of haematopoietic neoplasia.

Trephine bone marrow biopsy revealed highly cellular fibrotic marrow. Haematoxylin/eosin and Giemsa stains, CD34 and CD117 failed to show excess of blasts. Three major haematopoietic lineages were not dysplastic, occupying 25-30% of intertrabecular spaces. Remaining areas contained patchy infiltrates, composed of two different types of atypical cells, forming distinct and non-overlapping clusters (Fig. 1 A-C). The first population comprised smaller, round, oval, and rarely spindle-shaped cells usually without obvious cytoplasmic granules, characterised by expression of mast cell markers, including CD25, in keeping with their neoplastic nature (Fig. 1 D-E). The second atypical population consisted of markedly larger cells with occasional phagocytosis. These cells were negative for mast cell markers, expressing instead histiocytic antigens along with focal S100, CD10 and faint CD1a in single cells, indicating an aberrant immunoprofile, consistent with histiocytosis/histiocytic sarcoma, likely with interdigitating reticulum cell differentiation (Fig. 1 F). Complete immunoprofiles of both atypical populations are summarised in Table I.

In order to detect the D816V mutation of C-KIT, tryptase-positive mast cells were microdissected by laser pressure catapulting, pooled and used for nested PCR followed by melting point analysis with the LightCyclerTM sequence detection system (ROCHE Molecular Systems, Mannheim, Germany) using the DNA Master Hybridization Probes kit, as described by the manufacturer. This methodology is described in detail elsewhere [6, 7]. Mast cells were found positive for the mutation. The mutation was not investigated in the histiocytic component or three-lineage haematopoiesis.

After a period of good symptomatic response to interferon alpha lasting for 10 months, the patient reported relapse of progressive fatigue, dyspnoea and bone pains. She declined further investigations and treatment and died shortly thereafter of cardiac arrest. No autopsy was performed.

This case, like many other cases of SM-AHNMD, presented not only a diagnostic challenge, but also a clinical dilemma, as selecting the optimal cytoreductive therapy for SM-AHNMD is frequently hampered by different biology of both neoplastic components. Contemporary indications to treat both SM and AHNMD independently are based on limited empiric experience [8]. Of note, due to the extreme rarity of histiocytic sarcoma, there is no universally adopted or even widely recommended therapy for this malignancy. In the present case the patient’s age and cardiovascular comorbidities discouraged any aggressive approach. Monotherapy with interferon alpha proved to be a reasonable palliative regimen, resulting in 10-month remission.

To summarise, we presented a case of systemic mast cell disease associated with a histiocytic neoplasm, representing a new subtype of SM-AHNMD. This report makes the list of non-mast cells tumours comprising SM-AHNMD complete in regard to all the major WHO categories of haematopoietic malignancies.


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2. Furitsu T, Tsujimura T, Tono T, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest 1993; 92: 1736-1744.  

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8. Valent P, Akin C, Sperr WR, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res 2003; 27: 635-641.

Address for correspondence

Dr. Zbigniew Rudzki

Consultant Histopathologist

Department of Histopathology

Birmingham Heartlands Hospital

Bordesley Green East, Bordesley

Birmingham, B9 5SS, United Kingdom

tel. +44 121 424 0703

fax +44 121 424 0196

e-mail: zbigniew.rudzki@heartofengland.nhs.uk
Copyright: © 2011 Polish Association of Pathologists and the Polish Branch of the International Academy of Pathology This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
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