Cutaneous mastocytosis: demographic aspects and clinical features of 55 patients

BACKGROUND: Mastocytosis is a rare, heterogeneous group of disorder with abnormal increase of mast cells in one or more organ systems. OBJECTIVE: To evaluate the demographic and clinical features of cutaneous mastocytosis (CM). METHODS: Records of 55 patients with cutaneous mastocytosis were retrospectively analysed. RESULTS: Of the 22 females and 33 males, 80% had urticaria pigmentosa/maculopapular CM and 20% had mastocytoma. Of all cases, 81.8% had first lesions in childhood. The most common presentation was involvement of trunk together with extremities. Thirteen (23.6%) patients had history of bulla; Darier's sign was positive in 34 of 38 patients. Itching was the most common complaint, provocated by hot weather/bath. CONCLUSION: Clinical presentations of urticaria pigmentosa/maculopapular CM and mastocytoma are similar regarding gender, age of onset, age of diagnosis, and presence of Darier's sign and history of bulla. In contrast to mastocytoma, urticaria pigmentosa/maculopapular CM lesions were frequently located on trunk together with extremities.     

Cutaneous mastocytosis: A dermatological perspective

Mastocytosis is a rare disease characterised by expansion and collection of clonal mast cells in various organs including the skin, bone marrow, spleen, lymph nodes and gastrointestinal tract. The prevalence of mastocytosis has been estimated to be one in 10 000, while the estimated incidence is one per 100 000 people per year. Cutaneous mastocytosis is classified into (i) maculopapular cutaneous mastocytosis, also known as urticaria pigmentosa; (ii) diffuse cutaneous mastocytosis; and (iii) mastocytoma of the skin. In adults, cutaneous lesions are usually associated with indolent systemic mastocytosis and have a chronic evolution. Paediatric patients, on the contrary, have often cutaneous manifestations without systemic involvement and usually experience a spontaneous regression. Diagnosis of cutaneous mastocytosis may be challenging due to the rarity of the disease and the overlap of cutaneous manifestations. This short review describes pathogenesis and clinical aspects of cutaneous mastocytosis with a focus on diagnosis and currently available therapies.     

Telangiectasia macularis eruptiva perstans,a form of cutaneous mastocytosis,associated with malignant melanoma

A 62‐year‐old obese woman presented with a malignant melanoma (Stage la). In addition, she had disseminated telangiectatic macules on both thighs. Intensive rubbing of lesions resulted in wheals. Biopsy revealed increased numbers of mast cells. We diagnosed telangiectasia macularis eruptiva perstans, a rare clinical form of adult maculopapular cutaneous mastocytosis, a group which also includes urticaria pigmentosa. No evidence was found for systemic involvement. Possible associations with malignant tumors and the possible role of c‐kit mutations both in development of melanoma and mastocytosis are discussed.     

Cutaneous mastocytosis in children: a clinical analysis of 71 cases

OBJECTIVE: To characterize the clinical features, response to therapy, evolution and prognosis of cutaneous mastocytosis in children. BACKGROUND: Mastocytosis in children, instead of being induced by a potentially oncogenic c-kit mutation, is probably a clonal disease with benign prognosis. METHODS: The clinicopathological features, evolution and response to treatment were analysed in 71 children with mastocytosis. RESULTS: There were 53 (75%) cases of urticaria pigmentosa, 12 (17%) cases of mastocytoma, and six (8%) cases of diffuse cutaneous mastocytosis. In 92% of cases disease onset was in the first year of life. There was a male predominance 1.8 : 1. Treatment did not modify the disease evolution. Eighty per cent of patients improved or had spontaneous resolution of the disease. CONCLUSION: The most frequent clinical form of mastocytosis was urticaria pigmentosa followed by mastocytoma and diffuse cutaneous mastocytosis. Darier's sign was present in 94% of cases. A negative Darier's sign does not rule out mastocytosis. In contrast to adults, mastocytosis in children usually has a benign course making sophisticated or invasive diagnostic tests unnecessary. A classification of paediatric cutaneous mastocytosis is proposed.     

皮肤肥大细胞增生症15例临床病理分析

目的:探讨皮肤肥大细胞增生症(CM)的临床病理和免疫表型特征.方法:对15例CM进行临床病理观察和免疫表型检测(SP法染色).结果:15例患者年龄为2个月～27岁,其中10例患者年龄<6个月,男:女为1:1.1.荨麻疹样色素沉着/斑丘疹皮肤肥大细胞增生症13例,肥大细胞瘤2例.甲苯胺蓝染色显示15例肥大细胞胞质内均出现多少不等的紫红色异染颗粒.免疫组化染色显示10/12例患者肥大细胞表达类胰蛋白酶(tryptase),8/12例患者肥大细胞表达CD117,所有患者肥大细胞均不表达CD1a和S-100蛋白.结论:CM好发于儿童,大多数患儿在6个月内发病,其诊断通过询问病史及体格检查可以确定,皮损组织病理检查可确定真皮内肥大细胞数量增多,但类胰蛋白酶或CD117阴性不能排除该病的诊断.儿童CM预后较好,大多数患儿皮损在青春前期或青春期改善或消退.     

Cutaneous mastocytosis with atypical mast cells and giant cytoplasmic granules

A 12-year-old male presented with an 8-year history of five firm cream colored papules on the right vertex of the scalp. A biopsy showed a dense infiltrate of monomorphous mast cells involving the dermis and extending into the subcutis. A relatively well-circumscribed cluster of larger cells showed pleomorphic nuclei with bilobed and multilobed morphology. Both mast cell populations had an eosinophilic cytoplasm filled with granules ranging in size from small to giant forms. By immunohistochemistry, the cells expressed CD117, tryptase and CD68, and were negative for AE1/AE3, CD1a, CD2 and CD25. S-100 staining revealed only faint cytoplasmic positivity and myeloperoxidase had an inhomogeneous patchy pattern, with an overall staining of less than 5% of the cells. A diagnosis of cutaneous mastocytosis was made and after 6 months follow-up, no progression observed. Clinical correlation and awareness of these unusual morphologic features as being part of the spectrum of cutaneous mastocytosis are important to avoid an erroneous diagnosis of malignancy. Although pleomorphic, multilobed nuclear morphology and giant cytoplasmic granules have not been associated with an aggressive behavior or systemic mastocytosis, close clinical observation is warranted in this context.     

Systemic mastocytosis--case report and literature review

A 74-year-old Chinese male has had diffuse asymptomatic thickening, wrinkling, and mild hyperpigmentation of the skin with prominent skin markings and a leathery appearance over the neck, abdomen, flanks, and flexural area for forty years. Darter's sign was positive. Skin biopsy showed a dense band-like infiltration of mast cells into the upper dermis. Mast cell infiltration into the bone marrow and liver was also proved histologically. Electron microscopic studies of the skin and liver specimens were performed. Related aspects of diffuse and systemic mastocytosis are discussed. To our knowledge, this is the first reported Chinese case of diffuse and systemic mastocytosis in English literature. A review of the literature on systemic mastocytosis is also included.     

Diffuse cutaneous mastocytosis: pseudoxanthomatous variant

Diffuse cutaneous mastocytosis is one of the extremely rare benign forms of mastocytosis that have varied clinical presentations. The pseudoxanthomatous variant is an extremely rare multinodular nonpigmented entity. Only two cases have been reported so far in the literature. We report a 21 year old female patient who had diffusely infiltrated skin with multiple papulo-nodular lesions resembling xanthomas and the classical histopathological features of mastocytosis.     

Management of a neonate with diffuse cutaneous mastocytosis: Case report and literature review

Mastocytosis is an accumulation of clonal mast cells within tissues, commonly caused by mutations in the KIT proto‐oncogene. This report describes the management of a neonate with diffuse cutaneous mastocytosis (DCM) caused by a rare activating KIT mutation, specifically internal tandem duplication of the Ala502Tyr503 pair on exon 9, and reviews current data regarding work‐up of DCM in pediatric patients.     

曲尼司特治疗泛发性肥大细胞增生病1例

报告曲尼司特治愈泛发性肥大细胞增生病1例,患儿男,6岁,面部,躯干,四肢广泛分布许多绿豆至黄豆大的斑丘疹和丘疹,部分为小结节或增生性瘢痕样皮损,明显高出皮面,呈圆形,椭圆形或不规则形,大多呈棕红色或棕褐色,组织病理检查示表皮角化过度伴角化不全,真皮浅,中层及附属器周围见致密的肥大细胞和少许嗜酸性粒细胞浸润,诊断为泛发性肥大细胞增生病,单用曲尼司特口服至第110天时,除留有少许点状色素沉着外,面部,躯干,四肢的皮损全部清退,服药期间未见不良反应,停药后随访6个月无复发。     

Familial urticaria pigmentosa associated with thrombocytosis as the initial symptom of systemic mastocytosis and Down''s syndrome

Most cases of urticaria pigmentosa are confined to the skin, but visceral involvement and/or haematological abnormalities have been observed. It is still a matter of debate whether all forms of mastocytosis are true neoplasias or reactive hyperplasias. Familial inheritance of urticaria pigmentosa is rare. We report on a fraternal set with urticaria pigmentosa as part of a systemic mastocytosis. The first patient additionally revealed persistent thrombocytosis and splenomegaly. His brother developed urticaria pigmentosa, intermittent diarrhoea, hepatomegaly and asthma bronchiale associated with trisomy 21 (Down's syndrome). The association of mastocytosis with thrombocytosis has seldom been described. In our patient it preceded the development of systemic mastocytosis. The association with Down's syndrome has not been reported until now.     

Genotype and phenotype analysis of patients with pediatric cutaneous mastocytosis,especially wild-type KIT patients

Pediatric cutaneous mastocytosis (CM) is mainly attributed to gain-of-function mutations in KIT in mast cells. On the other hand, growing evidence suggests that CM patients exist without KIT mutations. To date, the association between the KIT mutation status and clinical phenotype has not been elucidated in pediatric CM, especially in patients with wild-type KIT. Nevertheless, genetic analysis has yet to be performed with whole KIT sequence of mast cells in Japanese patients with pediatric CM. In the present study, 11 Japanese patients with pediatric CM were analyzed to determine whether they had KIT mutations in their skin, and their clinical phenotypes were observed. The approximate frequency of patients with KIT mutation and that of wild-type KIT was almost consistent with the European analysis. The distribution of overall macules was similar between the patients with and without KIT mutations.     

The efficacy of omalizumab in Cutaneous Mastocytosis: A case series

Background: Mastocytosis describes a heterogeneous group of disorders arising from a clonal proliferation of mast cells. Given the lack of curative treatments for the cutaneous form, there is a significant need for superior therapies. Omalizumab is a recombinant DNA‐derived humanized IgG monoclonal antibody that selectively binds to human immunoglobulin E (IgE). It represents a potential treatment for the management of cutaneous mastocytosis, which currently has no standard treatment. Methods: Two patients were treated with subcutaneous omalizumab 300 mg every 4 weeks. Discussion: Patient 1 experienced 50% reduction in cutaneous infiltration and moderate improvement in pruritus. Patient 2 underwent 90% complete clearance of cutaneous lesions and reported full resolution of pruritus. The median duration of treatment was 24 weeks and time to response was 8 weeks. No significant changes in tryptase levels were observed. Both patients experienced injection site reactions. Conclusion: We provide evidence from two cases supporting the efficacy of IgE‐mediated therapy in the treatment of cutaneous mastocytosis. Even at a higher‐than‐standard dose (300 mg vs. 150 mg), the drug was well‐tolerated. As we await the results of pivotal clinical trials, omalizumab appears to be a promising treatment option in patients with cutaneous mastocytosis unresponsive to traditional therapies.     

Effects of topical treatment with the raft modulator miltefosine and clobetasol in cutaneous mastocytosis: a randomized, double-blind, placebo-controlled trial

Background  Mastocytosis is characterized by the accumulation and activation of mast cells in different organs, most commonly the skin. Miltefosine, a raft modulator, has recently been shown to inhibit the activation of mast cells and to reduce mast cell-driven skin inflammatory responses.
Objectives  To study the safety and efficacy of topical miltefosine treatment of skin lesions in patients with mastocytosis.
Methods  Thirty-nine adult patients with mastocytosis with skin involvement were treated in a double-blind, placebo-controlled, parallel trial with topical miltefosine and clobetasol for 2 weeks. Treatment areas were analysed for changes in skin lesions and symptoms following mechanical irritation using novel volumetric imaging techniques and quantitative histomorphometry.
Results  Miltefosine and clobetasol failed to reduce significantly weals and flare-type skin responses following mechanical provocation. Miltefosine showed a trend towards reducing the volume of weals. Clobetasol significantly decreased the volume of weals and the number of mast cells in the upper dermis. Treatment with miltefosine, but not with clobetasol, was often associated with eczematous skin irritation, which may, at least in part, be related to the formulation of miltefosine containing the potentially irritating alkanol propanediol as the vehicle.
Conclusions  Raft modulators such as miltefosine are promising candidates for novel therapeutic strategies in patients with cutaneous mastocytosis. Future studies should be performed with improved formulations using nonirritant vehicles.     

A new variant of mastocytosis: report of three cases clinicopathologically mimicking histiocytic and vasculitic disorders

Cutaneous mastocytosis (CM) or urticaria pigmentosa is characterized by abnormal proliferation and accumulation of mast cells. Clinically, CM usually presents as symmetrically distributed red-brown macules or papules that develop weals, erythema and often pruritus on stroking (Darier's sign). The histological hallmark of the disease is an increase in oval to spindle-shaped mast cells in the dermis located around blood vessels and skin appendages. We describe three patients with a new clinicopathological type of CM, which clinically mimics a histiocytic disorder and histologically mimics leucocytoclastic vasculitis (LV). Three infants (two boys and one girl) developed generalized reddish-yellow-brown macules of 3-10 cm with occasional scaling and crusting on the trunk and extremities without further symptoms or organ involvement except variable itching. Histology revealed diffuse and dense dermal infiltrates of eosinophils, neutrophils and nuclear debris with perivascular accentuation, imitating LV. This infiltrate masked large epithelioid cells, positive for macrophage markers, which by special histochemical stains for metachromatic granules turned out to be mast cells. This is the first report of this new variant of CM, which may cause considerable diagnostic difficulties both clinically and histopathologically.     

Pleomorphic mastocytoma associated with loss of chromosome 5, PDGFRA,and HRAS mutations: A case of cutaneous mastocytosis with severe atypia and indolent behavior

A 21‐year‐old female presented with a 5‐year history of an erythematous papule on her right breast. The biopsy showed a dense, dermal nodular infiltrate, extending focally into the subcutaneous tissue. The infiltrate was composed predominantly of pleomorphic cells with bi‐lobed, multi‐lobed, horseshoe, or ring‐shaped nuclei. There was a smaller subset of monomorphous cells characterized by a round, reniform, or elongated single‐lobed nucleus. Accompanying cells included few foamy histiocytes, lymphocytes, and numerous scattered eosinophils. No necrosis, vascular invasion, or ulceration was present. The pleomorphic and monomorphic granular cells were positive for Giemsa stain as well as for tryptase, CD117, CD68, CD2, and CD30 immunohistochemistry and negative for S100, CD1a, myeloperoxidase, lysozyme, and CD56. Clinical examination was negative for any additional similar lesions and serum tryptase was within normal limits. The bone marrow was not biopsied. In addition, fluorescent in situ hybridization revealed multiple clones with loss of number 5 chromosome and PDGFRA and HRAS mutations. The lesion did not recur or progress after a 6‐year clinical follow‐up. To our full knowledge, we report the first case of pleomorphic mastocytoma with loss of chromosome 5 and PDGFRA and HRAS mutations.     

Confusion in determination of two types of cutaneous adverse reactions to drugs,maculopapular eruption and erythema multiforme,among the experts: A proposal of standardized terminology

The clinical classification of cutaneous adverse reactions by drugs should be clearly distinguished to avoid conceptual confusion and inconsistency. Although dermatologists appear to have established a roughly common consensus for cutaneous adverse reactions, some types are more rigorously defined than other, possibly misleading classifications. To assess the consensus on the clinical classifications, we investigated the concordance rate of diagnosis by Japanese experts through a snap visual inspection of various clinical pictures exhibiting erythema multiforme and maculopapular eruption types of cutaneous adverse reactions. The experts were shown images on a screen and were then asked to decide whether to classify cases as maculopapular eruption or erythema multiforme type, and the concordance rates were calculated. Overall, the mean concordance rate was 71.6% (standard deviation, 17.3%), and only 33.8% of cases had a 90% or more concordance rate. Our study shows that the determinations of erythema multiforme and maculopapular eruption types by the existing classification criteria were confusing even among experts, which prompted us to standardize the terminology. We propose clinically defining erythema multiforme type as generalized macules mainly of 1 cm or more with a tendency of elevation and coalescence, and maculopapular eruption type as generalized erythema other than erythema multiforme type. Currently, the clinical definitions of cutaneous adverse reactions are poorly described, which may be problematic upon analyzing large volumes of data. Our proposal for a new terminology will enhance the accuracy and consistency of information for the correct analysis of cutaneous adverse reactions.     

Nodular and bullous cutaneous mastocytosis of the xanthelasmoid type: case report

Severe generalized nodular and bullous mastocytosis of the xanthelasmoid type is described in a 7-month-old boy. Reddish to yellowish-brown xanthelasmoid papules and nodules first developed in the inguinal region a few weeks after birth and then progressively spread to cover nearly the entire body surface. There was severe pruritus and recurrent episodes of blistering. The diagnosis of cutaneous mastocytosis of the xanthelasmoid type with subepidermal bullae was confirmed by skin biopsies showing solid and deeply penetrating infiltrates of metachromatic mast cells under light and electron microscopy. Systemic involvement of other organs, however, was excluded by bone scintigraphy, abdominal ultrasound, bone marrow aspiration and echocardiography. The extensive skin involvement was reflected in highly elevated urinary levels of histamine (263.4 microg L(-1)) and its metabolite N-methylimidazole acetic acid (20.8 mg L(-1)). The patient was systematically well and received only symptomatic treatment. Over a period of 1 year, the condition gradually improved, and the skin lesions began to flatten and regress.