Yonago Acta medica 2014;57:99–101

Original Article

The Expression of Melanoma Inhibitory Activity on Mast Cells in Child Patientswith Cutaneous Mastocytosis
Yuko Ehara, Yuichi Yoshida, Makoto Tahira and Osamu Yamamoto
Division of Dermatology, Department of Medicine of Sensory and Motor Organs, School of Medicine, Tottori University Faculty ofMedicine, Yonago 683-8504, JapanABSTRACT

report an expression of MIA on mast cells in patientswith cutaneous mastocytosis and discuss its clinical significance.

Background

Cutaneous mastocytosis is a disordercharacterized by the proliferation of mast cells in theskin. Melanoma inhibitory activity (MIA) is a serum
marker for malignant melanoma. However, it has notbeen known on MIA expression of cutaneous mastocytosis.
Methods We investigated the expression of MIA in
4 child patients with cutaneous mastocytosis immunohistochemically and serum MIA level in 1 patient by
enzyme-linked immunosorbent assay.
Results
Histopathological examination revealed diffuse mast cell infiltration in the dermis. MIA was positive for infiltrating mast cells in all patients. Serum levelof MIA was elevated in 1 patient.
Conclusion Although it was difficult to assess thesignificance of elevated serum levels of MIA in childpatients, MIA was expressed on infiltrating mast cells inour study. Based on our findings, mast cell-derived MIA
might be related to the formation of pigmented regionsin cutaneous mastocytosis.

MATERIALS AND METHODS
Four patients with cutaneous mastocytosis were studied.
Immunohistochemistry of formalin-fixed and paraffinembedded sections was performed by using the standard
automated avidin-biotin complex method. The sections
were incubated with anti-MIA antibody (5 µg/mL, R&DSystems, Minneapolis, MN) for 30 min at room temperature. They were then incubated for 30 min with a universal secondary antibody with a RED Map kit (Ventana
Medical Systems, Tucson, AZ). Toluidine-blue staining
was also performed. Serum MIA level was assayed byusing an MIA enzyme-linked immunosorbent assay kit(Roche, Mannheim, Germany).
RESULTS
Patient reports

Patient 1: A 1-year-old boy presented with multiple
brown macules on the trunk (Fig. 1a). His mother had
noticed pigmented macules 8 months before presentation. Since the number of the region had increased, hewas referred to our department. On physical examination, Darier’s sign was positive on the macule. Family
histories were unremarkable. Based on clinical andhistopathological examinations, a diagnosis of urticaria
pigmentosa was made.

Key words

immunohistochemistry; mast cells; mastocytosis; melanocyte; melanoma inhibitory activity
Mastocytosis is a disorder characterized by the proliferation and accumulation of mast cells in the skin and/or other organs (systemic mastocytosis). It is known
that about 80% of patients are cutaneous mastocytosis.1
Cutaneous mastocytosis is classified into urticaria pigmentosa, solitary mastocytoma and diffuse cutaneousmastocytosis. Melanoma inhibitory activity (MIA) is an
11-kD protein that is used as a serum marker for malignant melanoma.2 Recently, we have shown that MIA isexpressed on mast cells of neurofibroma in patients withneurofibromatosis type 1 (NF1).3 However, it has notbeen clear on MIA expression of cutaneous mastocytosis. Therefore, we investigated the expression of MIA
in 4 patients with cutaneous mastocytosis. We herein

Patient 2: A 2-year-old boy presented with a 20-month
history of multiple brown macules on the abdomen andlower extremities. Darier’s sign was positive on the macule. Based on clinical and histopathological examinations, a diagnosis of urticaria pigmentosa was made.
Patient 3: An 8-month-old boy presented with a brown
nodule, 14 × 7 mm in size on the right side of abdomen(Fig. 1b). Based on clinical and histopathological examinations, a diagnosis of solitary mastocytoma was made.

Corresponding author: Yuko Ehara, MD
yukoehara@med.tottori-u.ac.jp
Received 2014 May 16
Accepted 2014 June 3
Abbreviations: MIA, melanoma inhibitory activity; NF1, neurofibromatosis type 1

Patient 4: A 1-year and 9-month-old boy presented witha 14-month history of multiple brown macules on the ex99

Y. Ehara et al.

acbFig. 1. Clinical features in Patients 1, 3 and 4.
a: Multiple reddish-brown macules on the back in Patient 1.
b: A brown nodule on the right side of abdomen in Patient 3.
c: Multiple brown macules on the extremities in Patient 4.

tremities (Fig. 1c). Based on clinical and histopathological examinations, a diagnosis of urticaria pigmentosawas made. There was no evidence of systemic involvement in all patients.
Histopathology

Histopathological examination revealed a diffuse mastcell infiltration in the dermis in all patients (Fig. 2a: Patient 1). Toluidine-blue staining showed metachromaric
granules in the infiltrating cells (Fig. 2b: Patient 4). Immunohistochemically, most of infiltrating mast cells
were strongly positive for MIA (Fig. 2c: Patient 1).
Serum level of MIA

Serum level of MIA was 21.5 ng/mL in Patient 4 (normal,
healthy adult < 8.8 ng/mL).4abcFig. 2. Histopathological examination.
a: Diffuse mast cell infiltration in the dermis in Patient 1 (hematoxylin and eosin). Bar = 500 µm.
b: Infiltrating cells are positive for toluidine-blue staining in Patient 4. Bar = 250 µm.
c: Most of mast cells are positive for melanoma inhibitory activity in Patient 1. Bar = 500 µm.

100MIA in mastocytosis

expression and promoter activity.10 Recently, it has beenreported that the risk for malignant melanoma among
patients with systemic mastocytosis appeared higher
than in the general population.11 Mast cells would interact with melanocytes through the release of cytokines.
But the direct connection with the MIA is unidentified
at present. Further studies will be necessary to elucidate
the effect of MIA with melanocytes from cutaneousmastocytosis.

Table 1. Cutaneous mastocytosis in this report
Pa-			tient Age
SexDiagnosis

MIA
staining

Serum MIA
(ng/mL)

12
34UP
UP
CM
UP++++ND
NDND
21.5

1 yr
2 yr
8 mo
1 yr 9 mo

Male
MaleMaleMaleCM, cutaneous mastocytoma; MIA, melanoma inhibitory activity;
ND, not done; UP, urticaria pigmentosa.

The authors declare no conflict of interest.

The results of these patients are shown in Table 1.

References
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DISCUSSION
Mastocytosis is a rare disease characterized by the proliferation of mast cells in tissues. In children, mast cell
hyperplasia is restricted to the skin in most patients incontrast to adult patients with systemic involvement.5 It
is known that childhood-onset mastocytosis often goes
into remission. Since we have previously found that
MIA is expressed on mast cells of neurofibroma in patients with NF1,3 we were interested in MIA expression
in mastocytosis. As expected, MIA was also expressedon mast cells in child patients with cutaneous mastocytosis. It has been reported that blood serotonin levels arerelated to clinical symptoms.6 In addition, it is known
that elevation of basal tryptase levels are risk factors foranaphylaxis.7 Since MIA might be a potential biomarker
in cutaneous mastocytosis, we investigated serum levelsof MIA in 1 patient. Serum level of MIA was actuallyelevated in those patients. However, it has been reported
that serum levels of MIA in children were usually elevated compared with those in adults because MIA isalso expressed in chondrocytes.4 Therefore, it was difficult to assess the significance of elevated serum levels ofMIA in child patients with cutaneous mastocytosis. The
mutations of c-kit has been identified in adult-, but not
in childhood-onset mastocytosis.8 Since MIA was also
expressed on mast cells in normal skin (not shown) as
well as neurofibromas in NF1, the expression may not bespecific for mast cells in child-onset cutaneous mastocytosis. Although the mechanisms of MIA expression on
mast cells are unknown, it has been reported that MIA
shares structural homologies with some integrins andhas a function for an inhibition of apoptosis in melanocytic cells.9 In addition, the transcription factor, SOX10
has been highly relevanted for melanoma development
and survival, and that SOX10 inhibition reduced MIA101