UPMC Dermatopathology "Case of the Month" Presentations
UPP - Department of Dermatology, Dermatopathology Unit
Case Authors: Justin J. Vujevich MD, Marion M. Vujevich MD and Drazen Jukic MD PhD
APRIL 2004 CASE OF THE MONTH
DISCUSSION & DIAGNOSIS
DIAGNOSIS
Final Diagnosis: Mast Cell Infiltrate, of Concern for Mastocytosis
DISCUSSION
Mast cells are derived from pluripotent CD34+ precursors in the bone marrow and circulate in the peripheral blood as agranular, monocytic-appearing cells (2). Circulating masts cells express CD34, the receptor for mast cell growth factor (CD117, KIT) and low-affinity immunolglobulin G (IgG) receptors (FcyRII).
KIT is the product of the proto-oncogene, c-kit, which belongs to the type III receptor tyrosine kinase subfamily (3). KIT is expressed on mast cells, and has been described in patients with mastocytosis (3). Activation of KIT induces cellular growth and prevents apoptosis. The ligand for KIT is stem cell factor (SCF), an important growth factor for mast cells. SCF is produced by bone marrow cells, fibroblasts, keratinocytes, endothelial cells, and reproductive Sertoli and granulose cells.
Mastocytosis is a general term implying a local and systemic accumulation of mast cells. Although the pathogenesis is uncertain, it appears that over-expression of SCF and/or an activation of KIT leads to increased mast cell growth and development in the skin.
Clinically, four types of mastocytosis exist. Most patients are diagnosed with Type I mastocytosis. These patients have characteristic reddish-brown skin macules and papules, 1cm or less in diameter, on the trunk and proximal extremities. There may be associated mast-related symptoms, such as flushing, dermatographism, syncope, nausea, vomiting, or diarrhea. Extracutaneous disease may be seen in the bone marrow, liver, spleen, lymph nodes and gastrointestinal tract. Patients with Type II mastocytosis are typically adults with or without skin lesions, but with systemic involvement, including associated myeloproliferative or myelodysplastic disorders. In type III mastocytosis, or lymphadenopathic mastocytosis with eosinophilia, patients have an absence of cutaneous lesions and have associated lymphadenopathy, hepatosplenomegaly, gastrointestinal symptoms, and peripheral eosinophilia. Type IV mastocytosis patients rarely have skin lesions, but have multi-organ involvement, with mast cell leukemia in peripheral blood and bone marrow.
Clinicians may test for evidence of mast cell hyperplasia on physical exam by firmly rubbing an erythematous lesion to produce an urticarial wheal at the lesion site. This is called “Darrier’s sign,” and is caused by the release of vasoactive mediators, such as histamine, leading to clinical manifestations of urticaria, wheal, and flare with pruritis. Our patient had a positive “Darrier’s sign” with stroking on physical exam.
Histologically, mast cells are found concentrated in small numbers (up to ten mast cells per 40X field(1)) perivascularly in normal dermis skin. They are oval or spindle-shaped cells with a centrally located round nucleus, giving a “fried egg” appearance. Mast cells contain numerous cytoplasmic granules which contain preformed mediators (histamine, heparin, tryptase, chymase, chemotactic factors) that are released at time of stimulation. These granules do not routinely stain with H&E. As a consequence, mast cells may be indistinguishable from other perivascular infiltrate cells.
Staining with methylene blue (Giemsa
stain) and toluidine blue reveal purple-red cytoplasmic granules, and staining
with alcian blue reveals blue cytoplasmic granules.
In skin biopsies of mastocytosis, lesional skin reveals an increased number
of perivascular mast cells in the upper dermis, with scattered eosinophils.
This type of infiltrate was seen in our patient’s biopsy. Immunohistochemistry
staining specific for a granule-associated serine proteinase, tryptase, and
to c-kit, a type III receptor tyrosine kinase on mast cell membranes, may be
utilized to determine the infiltrate of cells. Both of these stains were positive
in our patient’s biopsy.
Biopsies of non-lesional skin from patients with mastocytosis have normal concentrations
of mast cells. In this case, a biopsy of the bone marrow or gastrointestional
tract may be indicated in a patient of whom mastocytosis is suspected, but the
skin biopsy reveals normal tissue.
In the absence of an obvious inflammatory dermatitis or proliferative process, mastocytosis may be included under the “normal skin” differential diagnosis. This differential includes ichtyosis, fungal infection, porokeratosis, hypopigmentation, hyperpigmentation, macular amyloidosis, onchocerciasis, argyria, urticaria, anetoderma, cutis laxa, mucinosis, atrophoderma, and liproatrophy.
The cells within the perivascular and interstitial infiltrate may resemble histiocytes, Langerhans cells, or B cells. Immunohistochemistry stains may be needed to distinguish these cells from a mast cell infiltrate. Our patient’s immunohistochemistry staining was negative for CD68, CD1a, and CD30.
REFERENCES
(1) Sweet WL, Smoller BR. Perivascular mast cells in urticaria pigmentosa. J Cutan Pathol 1996;23:247.
(2) Kirshenbaum AS, Kessler SW, Goff JP, et al. Demonstration of the origin of human mast cells from CD34 bone marrow progenitor cells. J Immunol 1991;46,1410-15.
(3) Nagata H, Worobec AS, Oh Ck et al. Identification of a point mutation in the catalytic domain of the proto-oncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci USA 1995;92,10560-4.
(4) Kasper CS, Freeman
RG, Tharp MD. Diagnosis of mastocytosis subsets using a morphometric point counting
technique. Arch Dermatol 1987;123,1017.
