Case Series of Morbihan Disease (Extreme Eyelid Oedema Associated with Rosacea): Diagnostic and Therapeutic Approaches

Morbihan disease (MD) is a rare form of rosacea that presents with chronic erythema and solid oedema on the upper half of the face. A diagnosis of MD can be made only after eliminating diseases that are similar in terms of clinical and histopathological presentation. The cause of MD remains unclear and no standardised treatment is yet available. MD often tends to be recalcitrant to therapies commonly used to treat rosacea, including systemic corticosteroids, antibiotics, isotretinoin, and topical regimens. Thus, surgical interventions have been attempted but most cases have exhibited unsatisfactory responses. We treated six patients with extreme eyelid lymphoedema without any other cutaneous manifestation. Surgical eyelid reduction was performed in all patients, because ptosis and narrowing of the visual field were the major complaints. Histopathological tests revealed various extents of perivascular and perifollicular inflammation, and dermal oedema. After surgery, patients with severe inflammatory cell infiltration (including mast cells) exhibited a tendency toward recurrence. Other patients with severe dermal oedema exhibited better responses to surgical reduction, and thus no recurrence. We propose that MD should be included in the differential diagnosis of persistent, chronic eyelid oedema even if eyelid oedema is the only manifestation; the histological features may aid in the selection of appropriate therapeutic strategies. We suggest that eyelid reduction surgery can be a useful treatment option for MD patients when there is no massive mast cell infiltration.     

Efficacy of long‐term intralesional triamcinolone in Morbihan's disease and its possible association with mast cell infiltration

Morbihan's disease is characterized by chronic persistent facial edema of the upper half of the face, absence of typical diagnostic findings, and refractoriness to treatment. A 44‐year‐old man was diagnosed with Morbihan's disease based on clinical signs and histopathology, which showed dermal edema in upper dermis, discrete lymphocytic infiltrate without granulomatous reaction, and mast cell infiltration. After long‐term therapy with intralesional triamcinolone a remarkable objective and subjective clinical response was observed. Reported cases of Morbihan's disease are reviewed, with respect to their treatment and histopathological findings. Mast cell infiltration has been observed on histopathology in most patients who responded to intralesional triamcinolone, suggesting a possible marker of response. The long‐lasting response seen in our case indicates the efficacy of intralesional triamcinolone in this rare condition.     

What dermatologists need to know about mast cell disease: a dermatopathologist's view.

Mast cell disease involves a group of conditions characterized by the infiltration of mast cells in the tissues and organs. Mast cell disease predominantly affects the skin, presenting in the form of urticaria pigmentosa. This concise review article defines mast cell disease. This paper presents a dermatopathologist's perspective on the diagnosis, management, and treatment of mast cell disease.     

The cosmetic treatment of urticaria pigmentosa with Nd:YAG laser at 532 nanometers

Background Urticaria pigmentosa is a cutaneous disorder involving infiltration of the skin with mast cells. Histologically the papillary dermis has an increased number of mast cells with an increase in basal layer pigmentation. In addition to possible systemic symptoms, patients with urticaria pigmentosa can suffer emotionally from the cosmetic nature of this skin disease. Objective The purpose was to investigate the use of a diode‐pumped Nd:YAG laser at 532 nm for the treatment of the cosmetic comorbidity of urticaria pigmentosa lesions. Methods A 19‐year‐old white male with urticaria pigmentosa had multiple lesions on the dorsum of the hands and forearms. A test site on the right inner arm was treated with a DioLite? 532 nanometer laser. Because of satisfaction with the treatment of the test site lesions, multiple lesions on the dorsal hands and forearms were also treated with the DioLite? 532 nanometer laser. Results There was a dramatic clinical reduction in the amount of lesions on the dorsum of the hands and forearms. The test site lesions on the right inner arm had not recurred. Conclusion The diode‐pumped Nd:YAG laser at 532 nanometers should be considered part of a dermatologist's armamentarium for the treatment of a patient's cosmetic concerns with lesions of cutaneous mastocytosis.     

A Case of Cutaneous Mastocytosis in a Child with Prominent Langerhans Cell Infiltration

Abstract: We recently encountered a 2‐year‐old boy with slightly infiltrative brown papules on the face, trunk, and extremities. Stroking of one of the papules produced an urticarial wheal (positive Darier’s sign). Histopathologic tests revealed a dense infiltration of mast cells containing numerous granules and showing metachromasia under Toluidine blue staining. Immunohistochemical tests revealed that these cells were positive for CD68 and for c‐kit. In addition, dermal dendritic cells that were positive for S100 and CD1a immunostaining were intermingled with the mast cells. We confirmed through electron microscopy that the dermal dendritic cells that were observed adjacent to the infiltration of mast cells had Birbeck granules in their cytoplasm, namely Langerhans cells. However, because of the greater numbers of mast cells than Langerhans cells, and because of the absence of both monomorphic LC proliferation and systemic symptoms of Langerhans cell histiocytosis, the present case favors a diagnosis of cutaneous mastocytosis in a child with Langerhans cell infiltration.     

Treatment of urticaria pigmentosa using interferon alpha

Long-term treatment with interferon alpha (IFN-α) has recently been shown to reduce the bone marrow infiltrate and cutaneous lesions in systemic mast cell disease. We therefore administered this cytokine to six patients with urticaria pigmentosa for up to 12 months, using subcutaneous injections of 5×10⁶U, initially five times, and subsequently three times a week. The generally well-tolerated therapy resulted in marked improvement of the cutaneous symptoms, especially in three of the patients who suffered from very severe pruritus. Two of the patients with bone marrow infiltration showed normal findings after treatment. However, in none of the patients was there any change in the skin lesions, or decrease in the degree of cutaneous mast cell infiltration, as evidenced by light and electron microscopic examination. These findings indicate that IFN-α is highly effective in the control of symptoms, but otherwise does not influence the cutaneous lesions of urticaria pigmentosa.     

Increased plasma histamine level in eosinophilic fasciitis

In a patient with eosinophilic fasciitis, a biopsy specimen obtained within 4 weeks of the onset of symptoms showed infiltration of the subcutis and fascia with mast cells, and there was up to a 19-fold increase in plasma histamine levels. The patient improved and experienced softening of the skin when treated with systemic corticosteroids and a histamine2-receptor antagonist, and her plasma histamine level returned to normal. Tissue mast cell infiltration and excessive plasma histamine levels were not present in two otherwise similar patients with eosinophilic fasciitis who were studied 7 months after disease onset. It is possible that mast cells play a pathogenic role in some patients with eosinophilic fasciitis.     

Mastocytosis.

Mastocytosis represents a heterogeneous group of clinical disorders resulting from the infiltration of mast cells in the skin and other organs. Although mastocytosis was first described over 130 years ago, the pathophysiologic mechanisms responsible for this disease have been identified only recently. This article discusses the salient clinical features of the disease, the mechanisms responsible for its development, and provides treatment approaches that have proven useful for managing patients with this disorder.     

Atypical maculopapular cutaneous mastocytosis showing a nevus spilus‐like lesion

A 13‐year‐old Korean girl presented with a 7‐year history of a pruritic, light‐brown patch containing multiple 0.2‐ to 0.5‐cm brownish‐to‐reddish maculopapules on the left anterior chest. When her skin was rubbed, the lesion became itchy and red. Histopathologic evaluation demonstrated marked dense dermal infiltration of mast cells. We report a rare case of atypical maculopapular cutaneous mastocytosis with clinical features similar to those of nevus spilus.     

Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates

Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cell-nerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases.     

Establishing an allergic eczema model employing recombinant house dust mite allergens Der p 1 and Der p 2 in BALB/c mice

The major house dust mite allergens Der p 1 and Der p 2 are prevalent inducers of eczema. Der p 1 is a cysteine protease disrupting epithelial barriers, whereas Der p 2 functionally mimics the LPS‐binding compound MD‐2 within the TLR4 complex. In this work, we tested the percutaneous sensitizing capacity of recombinant (r) Der p 1 and Der p 2 in BALB/c mice. Mice were sensitized by percutaneous application of low (10 μg/application) and high dose (100 μg) rDer p 1 or rDer p 2, or with rDer p 1 followed by rDer p 2. Allergen‐specific and total IgE antibodies were determined by ELISA. Eczema of BALB/c was classified by the itching score and corresponded to erosions. Infiltrating immune cells were identified by haematoxylin/eosin and Giemsa staining for eosinophils or mast cells, CD3 staining for T lymphocytes. Percutaneous treatments with rDer p 1, but not rDer p 2‐induced specific IgG1. However, cotreatment with rDer p 1 led to increase in anti‐Der p 2 IgG titres. Both allergens elicited skin erosions because of scratching, thickening of the epidermis, and eosinophil and T‐cell infiltration. Our data indicate that recombinant mite allergens in the absence of adjuvant are sufficient for inducing eczema in BALB/c mice. As the enzymatic activity of an allergen might be an important cofactor for specific sensitization via the skin, Der p 1 may act as adjuvant for other allergens too. The presented mouse model is suitable for investigating the mechanisms of allergic eczema.     

Case of aquagenic urticaria: Case report and the results of histopathological examination

Aquagenic urticaria (AU) is a rare skin condition in which dermal contact with water serves as a trigger of urticaria and pruritus. To make a diagnosis, a water challenge test is useful. We herein report a 16‐year‐old Japanese boy diagnosed with AU by water provocation test. The induced skin lesion histologically showed prominent degranulation of mast cells and lymphocytic infiltration throughout the dermis. This is the second report documenting the histopathological features of AU.     

Abundant eosinophil infiltration in a neurofibroma

We report a case of sporadic cutaneous neurofibroma showing diffuse eosinophil infiltration in a 72-year-old woman. The neurofibroma had been on the skin of the left anterior shoulder for approximately 10 years. The presence of mast cells is well known in neurofibroma. However, infiltration of neurofibromas by eosinophils has not yet been documented. We propose that eosinophil infiltration is mediated by the effects of mast cells. We suggest that this is indirect evidence that mast cells in some neurofibromas are not quiescent but active. We also reintroduce the notion that acid-fast stains are a useful method to discriminate between mast cell granules and eosinophil granules.     

Human mast cells express androgen receptors but treatment with testosterone exerts no influence on IgE‐independent mast cell degranulation elicited by neuromuscular blocking agents

Please cite this paper as: Human mast cells express androgen receptors but treatment with testosterone exerts no influence on IgE‐independent mast cell degranulation elicited by neuromuscular blocking agents. Experimental Dermatology 2010; 19: 302–304. Abstract: Women predominate in the anaphylactic reactions to neuromuscular blocking agents (NMBA). The expression of oestrogen receptors has been demonstrated in mast cells and oestrogen treatment can enhance mast cell degranulation, but the influence of androgens remains largely unclear. Our immunocytochemical study showed the expression of androgen receptor (AR) in mast cells isolated from human foreskin as well as in two human mast cell lines, HMC‐1 and LAD2. The amount of AR was most abundant in human skin mast cells as determined by real‐time polymerase chain reaction analysis. Treatment of the HMC‐1 mast cells with testosterone or 17β‐oestradiol, alone or in combination with different NMBA, did not affect mast cell degranulation as measured by the release of β‐hexosaminidase. Our study shows for the first time the expression of AR in human skin mast cells. Further studies using primary human mast cell cultures are needed to understand whether and how sex hormones can influence mast cell activation.     

Urticaria pigmentosa

A 2-year- old child with multiple brownish papules over trunk and limbs for one year having history of occasional blister formation is described. Histopathology revealed perivascular mast cell infiltration. Symptomatic treatment with topical corticosteroids and oral antihistaminics was effective.     

Malignant Schwannoma Arising in Patients with Von Recklinghausen's Disease: Report of Two Cases and the Comparison of Mast Cells between Benign and Malignant Portions

We described two cases of malignant schwannoma arising in patients with von Recklinghausen's disease and examined the mast cells infiltrated into histologic sections. One of the two cases histologically revealed apparent mast cell infiltration in some areas of malignant schwannoma as well as in the benign neurofibroma. The malignant lesion demonstrated significantly increased percentages of degranulated mast cells over the benign lesion using FITC-avidin staining. In an electron microscopic study, mast cells in the malignant lesion displayed empty granules, piecemeal degranulation, and canaliculi structures suggesting activation. These findings were not observed in the benign lesion. The other patient histologically showed no mast cells in the malignant lesion, although the benign neurofibroma in the patient disclosed numerous mast cells. The first patient had neither recurrence nor distant metastasis. On the other hand, the second patient without mast cells in the histology had multiple distant metastases. These findings raise questions about the role of mast cells in malignant schwannoma.     

Serum levels of soluble stem cell factor and soluble KIT are elevated in patients with atopic dermatitis and correlate with the disease severity

BACKGROUND: Mast cell infiltration in skin lesions of atopic dermatitis (AD) is considered to play an important role in the pathogenesis of the disease. The most common factor that stimulates mast cell growth, migration and differentiation is stem cell factor (SCF), and the interaction of SCF and its receptor, KIT (tyrosine kinase transmembrane receptor), appears to be the key event in the recruitment and proliferation of mast cells. OBJECTIVES: To determine whether any altered metabolism of SCF and/or KIT is present in patients with AD. METHODS: We measured serum levels of soluble SCF (sSCF) and soluble KIT (sKIT) using enzyme-linked immunosorbent assay in 54 patients with AD, five patients with erythrodermic psoriasis vulgaris and 64 healthy individuals. RESULTS: Serum levels of both peptides in AD patients were significantly higher than those in healthy individuals, whereas patients with psoriasis vulgaris did not show any difference from healthy controls. Both sSCF and sKIT levels were positively correlated with the disease severity in AD patients, and decreased after effective treatment with topical corticosteroids. Conclusion Serum levels of sSCF and sKIT may be useful indicators for evaluation of the activity and severity of AD.     

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.     

Skin disruption is associated with indomethacin‐induced small intestinal injury in mice

One mechanism by which non‐steroidal anti‐inflammatory drugs (NSAIDs) cause intestinal injury is by inducing matrix metalloproteinases (MMPs) that degrade and remodel the extracellular matrix. In addition to the intestinal mucosa, MMPs are expressed in the skin and can be activated by mast cell‐secreted tryptase. We therefore investigated whether intestinal injury resulting from treatment with the NSAID indomethacin induced MMPs in the skin of mice and caused an associated disruption of skin function. Hairless mice and mast cell‐deficient mice were administered indomethacin, after which damage to the jejuna and skin was assessed with immunohistochemistry and Western blotting. The plasma concentration of inflammatory mediators was assessed to evaluate potential pathways for signalling skin disruption in response to intestinal injury. In hairless mice with intestinal injury, transepidermal water loss (TEWL) was higher and skin hydration was lower than in control mice. The expression levels of mast cells, tryptase, MMP‐1 and MMP‐9 were also increased, with concurrent degradation of types I and IV collagen. In contrast, no changes in skin TEWL or skin hydration were observed in mast cell‐deficient mice with indomethacin‐induced intestinal injury. In all mice evaluated, the plasma concentrations of IgE, IgA, histamine and TNF‐α were increased in response to indomethacin treatment. Skin disruption was strongly associated with indomethacin‐induced small intestinal injury, and the activation of mast cells and induction of tryptase, MMP‐1 and MMP‐9 are critical to this association.     

Immunohistochemical clues to the diagnosis of Mondor’s disease of the penis

Mondor’s disease of the penis is usually a benign, self‐limiting process of acute onset. To date, there have been few studies about its diagnosis and treatment. It is difficult to differentiate MD of the penis from sclerosing lymphangitis of the penis, because the symptoms, epidemiology and aetiology are similar, and because veins are histologically very similar to lymphatics. We report a case of MD in which immunochemical markers such as CD31 and D240 allowed us to specifically discriminate between the small vein and lymphatic vessels. This is important not only for the recognition of MD at any site, but for many other diseases in which veins or lymphatic vessels are affected.