Content » Vol 94, Issue 5

Short communication

Increased Risk of Malignant Melanoma in Patients with Systemic Mastocytosis?

Hans Hägglund1,6, Birgitta Sander2,6, Theo Gülen3,6, Bernt Lindelöf 4 and Gunnar Nilsson5,6*

Departments of 1Hematology and 3Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, 2Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, 4Dermatology Unit, Department of Medicine, Karolinska Institutet, 5Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, SE-171 76 Stockholm, and 6Mastocytosis Center Karolinska, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden. E-mail:

Accepted Oct 24, 2013; Epub ahead of print Jan 28, 2014

Mastocytosis, a group of rare disorders that occur in both children and adults, is characterised by abnormal growth and pathological accumulation of mast cells in one or more organs, most commonly the skin (1). Urticaria pigmentosa (UP) is the most common cutaneous variant. In cases of extracutaneous involvement, systemic mastocytosis (SM) can be diagnosed on the basis of the criteria formulated by the WHO. The course of SM in most patients (90%) is indolent, with more aggressive presentation in only a few.

The incidence of cutaneous melanoma is increasing and although this malignancy and mastocytosis originate from 2 different types of cells (melanocytes from the neural crest and mast cells from haematopoetic stem cells, respectively) they share certain similarities, including expression of the transcription factors MITF and STAT3, and dependence of the growth factor receptor KIT and its ligand stem cell factor for their growth and development (2, 3). We have found 5 published case reports that suggest a relationship between these 2 pathologies. In the first, published in 1979, a patient with nodular mastocytosis developed both melanocytoma and mastocytoma (4). In the second, UP and SM preceded a metastatic melanoma (5) and the third involved combined mastocytoma-junctional naevus (6). In the fourth case, malignant melanoma was diagnosed prior to SM (7). And finally, a patient with telangiectasia macularis eruptive perstans (TEMP), a rare form of cutaneous mastocytosis, was found to have a malignant melanoma (8).

Here, we describe our 4 additional cases and discuss possible associations between these 2 diseases.


Eighty-one patients with confirmed SM, diagnosed and treated at the Mastocytosis Centre at Karolinska University Hospital and Karolinska Institutet from 2007–2011, 4 were also diagnosed with malignant melanoma.


Among our 81 Swedish patients diagnosed with mastocytosis between 2007 and 2011, 4 (5%) were also diagnosed with malignant melanoma (Table I). Three of these patients (nos 2–4) suffered from both UP and SM and none of these were treated with PUVA. Of those with UP, 2 had indolent SM and cutaneous melanoma and are still alive, while one was diagnosed with a melanoma metastasis that proved fatal. Patient no. 1 did not have UP, but an aggressive form of SM with an associated clonal haematologic non-mast cell lineage disorder instead and died later of leukaemia (9). In this patient a KIT D816V mutation was detected in the bone marrow mast cells, but not in the melanoma. Both in the case of our patients and those reported previously, the time point at which the first symptoms of mastocytosis and melanoma appeared is usually not known, making it impossible to determine which of these developed first.

Table I. Characteristics of 4 patients with systemic mastocytosis (SM) and malignant melanoma (MM)

Pat. no./Sex


Age at SM diagnosis (years)

Age at which symptoms began (years)

CD2+/ CD25+a

Serum tryptaseb (ng/ml)

CM/UP present

MM type, Localisation, Clark level, thickness


Age at diagnosis of MM









Skin, NOS, II, 0.4 mm, not ulcerated



Died from SM



















Skin nodular, III, 1.4 mm, not ulcerated











Lymph metastasis, no primary MM identified



Died from melanoma

aAll patients showed spindle-shaped morphology and KIT D816V mutations of mast cells.

bNormal range 11.4 ng/ml.

cMajor WHO criteria fulfilled.

CM: cutaneous mastocytosis; ISM: indolent systemic mastocytosis; SM-AHNMD/eo/MCL/HCL: SM-associated clonal haematological non-mast cell lineage disorder/eosinophilia/mast cell leukaemia/hairy cell leukaemia: nk.: not known; UP: urticaria pigmentosa; NOS: not otherwised specfied


Although based on a small number of SM patients, we found that the risk for melanoma among patients with SM appeared higher than in the general population (5% vs 1.2–1.6 % (Cancer incidence in Sweden 2011, Swedish Board of Health and Walfare). This poses the question whether there are any plausible biological explanations for an enhanced incidence of melanoma among patients diagnosed with SM. Both mast cells and melanocytes are dependent on the binding of stem cell factor (SCF) to the KIT receptor. Loss of KIT function results in piebaldism, a disorder of pigmentation characterised by loss of melanocytes which leads to patches of white skin and hair (10). In the case of SM a KIT D816V mutation is present in almost all cases (1, 11), whereas in melanoma KIT mutations or other gene modifications are less common (< 40%). Moreover, even when a KIT mutation is present in a patient with melanoma, this mutation is different from that associated with SM (D816V) (2).

On the other hand, melanocytes are highly responsive to proliferative cytokines and it can be speculated that cytokines produced by the large numbers of pathological mast cells observed in mastocytosis contribute to increased risk for melanoma. A plausible hypothesis is that upregulated expression and secretion of the growth factor SCF and other cytokines by mast cells recruit and stimulate the proliferation of melanocytes, which could promote tumourigenesis (12–14) (Fig. 1).

Fig. 1. Melanocytes (top) and mast cells (bottom) can interact and promote the cell growth and other cellular functions through the release of cytokines, e.g., interleukin (IL)-6, IL-8, basic fibroblast growth factor (bFGF), nerve growth factor (NGF) and stem cell factor (SCF). Hepatocyte growth factor (HGF) is bound to the extracellular matrix (ECM) from which it can be released by heparin released from degranulated mast cells. Both mast cells and melanocytes express the SCF receptor KIT. Mast cells in systemic mastocytosis patients exhibit a D816V KIT mutation, which leads to a ligand-independent activation of the receptor. Mutations or amplifications of KIT are less frequent in melanoma.


In addition, cutaneous mastocytosis is often treated with PUVA. Since PUVA is known to be a risk-factor for melanoma, such treatment should be used with more caution (15). None of our patients described in this report received PUVA treatment.

We conclude that patients with cutaneous and/or SM should be monitored carefully for possible lesions that precede melanoma such as dysplastic naevi.


This study was financed by grants from the Swedish Cancer Society; and through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institutet.

The authors declare no conflict of interest.


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