Case report
Oxford, UK International IJD Blackwell 1365-4632 45 Publishing, Publishing Journal Ltd, of Ltd. Dermatology 2005
Unusual cutaneous findings of urticaria pigmentosa and telangiectasia macularis eruptiva perstans associated with marked myelofibrosis
Urticariaetpigmentosa Turchin al. and telangiectasia macularis eruptiva perstans
Irina Turchin, BSc, Benjamin Barankin, MD, and Eric Schloss, MD, FRCPC
From the Faculty of Medicine, University of Calgary, Calgary, and the Division of Dermatology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada Correspondence Dr. Benjamin Barankin University Dermatology Center 2-104 Clinical Sciences Building Edmonton, Alberta Canada T6G 2G3 E-mail:
[email protected]
Abstract Mastocytosis is a heterogeneous group of disorders characterized by mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, gastrointestinal tract, and skin. We present a patient with malignant mastocytosis of 11 years’ duration. This case highlights the cutaneous findings of mastocytosis with systemic involvement, yet the patient maintains a relatively normal lifestyle with only minimal discomfort and only borderline normochromic anemia. Thus his course is not truly that of malignant mastocytosis but of indolent systemic mastocytosis with cutaneous findings of telangiectasia macularis eruptiva perstans (TMEP).
This paper was presented at the 62nd Annual American Academy of Dermatology meeting in Washington, DC, February 2004.
Case Report A 66-year-old Caucasian male was referred by his internist for assessment and management of a generalized pruritic eruption consisting of numerous firm, dull-erythematous and pigmented plaques of various sizes with overlying telangiectases (Fig. 1). Past medical history was remarkable for a generalized pruritic papular and pigmented eruption, anorexia, generalized malaise, axillary lymphadenopathy, splenomegaly, and elevated alkaline phosphatase [ALP, 196 units per liter (U/l), normal range 30–120 U/ l] 11 years prior to this presentation. Skin biopsy was consistent with mastocytosis. Peripheral blood smear revealed mild anemia with normal MCV, RDW, and percentage reticulocytes, no significant anisopoikilocytosis, and no leukopenia or thrombocytopenia. Bone marrow aspirate revealed a normal myeloid to erythroid ratio, normal erythropoiesis and granulopoiesis, normal amount of blast cells, adequate amounts of normal appearing megakaryocytes, no foreign cells, and abundant mast cells. Numerous mast cells were ruptured, making an accurate count difficult. Jamshidi biopsy revealed extensive fibrosis with bone marrow replacement of 30–40%, small foci of normal hematopoiesis, diffuse and focal mast cell infiltration. Surface marker studies demonstrated polyclonal B-cell and plasma-cell proliferation with no evidence of lymphoma or © 2006 The International Society of Dermatology
leukemia. The patient was subsequently diagnosed with malignant mastocytosis (despite an absence of circulating mastocytes on the peripheral blood smears) and treated with multiple courses of intralesional triamcinolone, a course of PUVA therapy, a 7-week course of interferon therapy (up to 5 million units subcutaneously per day), and three cycles of cladribine (2-chlorodeoxyadenosine, 2-CdA). These treatments improved the pruritus, but the cutaneous findings remained unchanged. Family history was unremarkable. Review of systems revealed occasional headaches and bone pain. Medications’ list consisted of Talwin® 50 mg tid PRN only. The patient declared an allergy to penicillin, Zantac®, codeine, Ativan®, and NSAIDs. Laboratory investigations revealed mild normochromic anemia (Hgb 12.9 g/dl). Examination of the alkaline phosphatase (ALP), alanine aminotransferase (ALT), gammaglutamyltranspeptidase (GGT), creatinine, electrolytes, and serum electrophoresis did not reveal any abnormalities. Skeletal survey revealed diffuse sclerosis at both humeri and femora with myelofibrosis. Skin biopsy was consistent with urticaria pigmentosa admixed with features of telangiectasia macularis eruptiva perstans. Prominent findings included hyperpigmentation of basal epithelium, increased vascularity with prominent mast cells around small venules, and a moderate number of mast cells in the underlying stroma, with occasional eosinophils (Fig. 2). International Journal of Dermatology 2006, 45, 1215–1217
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Case report Urticaria pigmentosa and telangiectasia macularis eruptiva perstans
Figure 1 Cutaneous findings of mastocytosis [urticaria
pigmentosa (UP) plus telangiectasia macularis eruptiva perstans (TMEP)]
Figure 2 Presence of mast cells, dilated vessels [telangiectasia
macularis eruptiva perstans (TMEP)], and hyperpigmentation of the basal epithelium [urticaria pigmentosa (UP)]. H&E stain × 10
The patient was advised of a diagnosis of systemic mastocytosis. Recommendations were made to proceed with further investigations, i.e. serum tryptase, bone scan, abdominal ultrasound, bone marrow biopsy and aspirate, and to follow up International Journal of Dermatology 2006, 45, 1215–1217
Turchin et al.
with an oncologist. Unfortunately, the patient declined any further investigations and oncology follow up because he was asymptomatic and did not feel much could be done to help him. Mastocytosis is a heterogeneous group of disorders that may be characterized by mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, gastrointestinal tract, and skin.1 The burden of mast cell disease is associated with clinically significant mediators, including histamine, leukotrienes, proteases, and heparin, released from mast cells. Mast cells originate from pluripotent CD 34+ bone-marrow cells and migrate to specific body sites where they mature into fully granulated cells. The regulation of mast cell number and differentiation is under control of many cytokines, i.e. stem cell factor (SCF) and IL-3. The receptor for SCF is c-kit, the transmembrane tyrosine kinase protein. Mutations of c-kit are associated with enhanced receptor function and may contribute to an increase in mast cell number – characteristic of mastocytosis. The pathogenesis of mastocytosis is the result of the increased production of mast cell mediators owing to increased numbers of mast cells.2 Mastocytosis can be categorized into systemic mastocytosis and cutaneous mastocytosis (CM).1 Cutaneous disease can be further subclassified into urticaria pigmentosa (UP), telangiectasia macularis eruptiva perstans (TMEP), mastocytoma, and diffuse cutaneous mastocytosis (DCM).3 Urticaria pigmentosa is the most common form of mastocytosis, characterized by red-brown macules, papules and plaques, as well as pruritus, dermographism and a positive Darier’s sign.3 The lesions of UP tend to be localized to the trunk, although mucous membranes and other body areas can be affected. It is commonly found in children, tends to appear during the first year of life and resolves by adolescence. Telangiectasia macularis eruptiva perstans is a rare form of mastocytosis which occurs mainly in adults. It is characterized by generalized, 2–6 mm, ill-defined, telangiectatic macules on the background of tan or brown macules. Darier’s sign has been reported to be positive by Katsambas et al.2 and negative by Soter.3 Rarely, lesions of TMEP may coexist with UP. In isolated cases, TMEP may have systemic features, i.e. headaches, flushing, vomiting and diarrhea, abdominal cramps, splenomegaly, weight loss, bone pain, new onset fractures, malaise, irritability and nonspecific neuro-psychiatric symptoms.3 Our case highlights such a presentation. A recent diagnostic criteria and classification system by Valent et al.1 does not classify TMEP as a distinct clinical entity of CM but rather as a subvariant of UP. According to this classification system, other UP subvariants are typical UP, plaque-form UP, and nodular UP.1 A diagnosis of mastocytosis is suspected on clinical grounds and established by the histopathologic examination of the involved tissue, such as skin or bone marrow. In 2001, Valent et al.1 proposed mastocytosis diagnostic criteria. According to their proposal, the diagnosis of CM is based on clinical and © 2006 The International Society of Dermatology
Turchin et al.
Urticaria pigmentosa and telangiectasia macularis eruptiva perstans Case report
histological cutaneous findings and the absence of criteria that would allow the diagnosis of systemic mastocytosis. The diagnosis of systemic mastocytosis is based on satisfying one major and one minor criterion or three minor criteria. These diagnostic criteria are reviewed in more detail in Valent et al.1 According to this classification system our patient’s disease would be classified into indolent systemic mastocytosis with cutaneous features and provisionally subclassified into smouldering systemic mastocytosis. Several laboratory investigations and diagnostic imaging studies can be helpful as part of routine evaluation and in establishing the extent of systemic involvement. A complete blood count with differential liver function tests, serum chemistry and tryptase, bone marrow (BM) biopsy and aspirate are recommended for the baseline evaluation of all adult mastocytosis patients.4 In pediatric patients, Escribano et al.4 recommend BM studies only in cases where systemic involvement is highly suspected. Abdominal ultrasound or CT scan, gastrointestinal endoscopy, bone X-rays or scans can be useful adjuncts to an initial evaluation of patients with mastocytosis, particularly if systemic mastocytosis is suspected. Recently, soluble CD 25 and CD 117 (c-kit) plasma measurements have been described. These proteins are associated with the mast cell membrane and in the future, if they become routinely available, their determination may be helpful in suspected cases of systemic mastocytosis.4 There is no curative treatment for mastocytosis. Despite many advances in our understanding of this disease the treatment remains mainly symptomatic and includes avoidance of factors triggering mast cell degranulation and acute-mediator release, antihistamines (e.g. cetirizine, loratadine, ranitidine), ketotifen, doxepin, disodium cromolyn, PUVA, topical and oral corticosteroids, epinephrine preparations, leukotriene antagonists (e.g. montelukast, zafirlukast) some chemotherapeutic agents (interferon-alpha 2b, cladribine) and local radiation therapy.4,5 Imatinib (Gleevec®; Novartis) has shown to be effective against malignant disease driven by c-kit and shows promise in some cases of mastocytosis. It has been shown to induce in vitro apoptosis of mast cells bearing the c-kit mutation, and was effective in 50% (n = 5) of the
© 2006 The International Society of Dermatology
patients in one study. This study suggested that imatinib curbs the growth-promoting role of wild type c-kit or targets an as yet undefined novel oncogenic kinase.6 New imatiniblike compounds are under investigation. In summary, mastocytosis is a rare disease characterized by mast cell hyperplasia in various tissues. A new classification system proposed by Valent et al.1 classifies mastocytosis into cutaneous and systemic disease and proposes criteria for their diagnosis. Our case of a patient diagnosed with malignant mastocytosis 11 years ago highlights a case of cutaneous findings of mastocytosis with systemic involvement, and yet the patient maintains a relatively normal lifestyle with only minimal discomfort and only borderline normochromic anemia, thus not truly a malignant mastocytosis but indolent systemic mastocytosis with cutaneous findings of TMEP. Acknowledgment We would like to thank Dr Robert Turner, Department of Medical Oncology, Alberta Cross Cancer Center, for his expertise and assistance.
References 1 Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leukemia Res 2001; 25: 603 – 625. 2 Katsambas AD, Karpouzis AJ, Koumantali-Mathioudaki E, et al. Mastocytosis with skin manifestations: current status. J Eur Acad Dermatol Venerol 1999; 13: 155 –165. 3 Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am 2000; 14: 537–555. 4 Escribano L, Atkin C, Castells M, et al. Mastocytosis. current concepts in diagnosis and treatment. Ann Hematol 2002; 81: 677 – 690. 5 Marone G, Spadaro G, Granata F, et al. Treatment of mastocytosis: pharmacologic basis and current concepts. Leukemia Res 2001; 25: 583 – 594. 6 Pardanani A, Elliot M, Reeder T, et al. Imatinib for systemic mast-cell disease. Lancet 2003; 362: 535 – 537.
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