Follicular extension of atypical keratinocytes predicts the resistance of actinic keratosis to topical imiquimod treatment: A single-center retrospective analysis.

Topical imiquimod therapy has been widely used for actinic keratosis (AK). However, some cases are refractory to treatment. Therefore, an indicator that can predict its efficacy is desired. Herein, we retrospectively analyzed 52 AK lesions treated with imiquimod to investigate the characteristics of refractory lesions. Imiquimod was applied in a cycle of three times weekly for 4 weeks, followed by a 4-week break. This treatment cycle was repeated up to three times and treatment responses were evaluated. As a result, a complete response (CR) was observed in 78.8% (41/52) of lesions. Next, treatment response of lesions was correlated with clinicopathological characteristics including clinical morphology and thickness, pathological morphology and thickness, and presence of follicular extension (FE). Of these, lesions with FE were significantly less responsive to imiquimod treatment; while 92.6% of AK lesions without FE achieved a CR, only 64.0% of AK lesions with FE achieved a CR (p = 0.029). Logistic regression analysis revealed that FE was the sole significant predictor of its efficacy (p = 0.019). These results suggest that preliminary histological evaluation of FE may be useful to predict the efficacy of imiquimod for AK.

Thymoma-associated multi-organ autoimmunity: A case of graft-versus-host disease-like erythroderma complicated by Good syndrome successfully treated by thymectomy.

Thymoma-associated multi-organ autoimmunity disease (TAMA) is a rare paraneoplastic disorder, clinicopathologically similar to graft-versus-host disease (GVHD). Many reported cases follow a difficult course; half of them die from serious infectious diseases subsequent to immunosuppression induced by chemotherapy for unresectable thymoma, or intensive therapies including systemic steroids for complicating autoimmune diseases and GVHD-like symptoms. We report a patient whose skin symptoms were improved subsequently to total thymectomy. The patient also presented with hypogammaglobulinemia, which led to the diagnosis of complicated Good syndrome. Taking account of her immunodeficient condition, antibiotics and i.v. immunoglobulin were administrated promptly on onset of bacterial pneumonia, which was successfully treated. According to a review of the published work, treatments with systemic steroids for skin symptoms have limited effects and may contribute to serious infection. Our case indicates that successful treatment of thymoma itself may lead to the amelioration of the disease. The management priority should be given to the treatment of thymoma and the control of subsequent immune abnormality other than GVHD-like erythroderma.

Novel and recurrent ATP2A2 mutations in Japanese patients with Darier's disease.

Darier's disease (DD, keratosis follicularis: OMIM#124200) is an autosomal dominant skin disorder characterized by multiple dark brown keratotic plaques and warty papules covered by thick crusts. Most cases of DD are caused by mutations in ATP2A2, which is expressed in both the skin and the brain. ATP2A2 encodes the cardiac muscle SERCA2a protein and the ubiquitously expressed SERCA2b. SERCA2 plays an important role as a calcium pump. It is thought that a mutation in ATP2A2 causes dyskeratosis and abnormality of cell-cell adhesion. Here, we report five DD patients from five independent families who presented or were referred to the Nagoya University Hospital in the past five years. We detected five mutations in ATP2A2, including a previously unreported mutation. We observed no apparent genotype/phenotype correlation between types and sites of the ATP2A2 mutations and DD phenotypes in the present series of DD patients. Genetic diagnosis from ATP2A2 mutation search is useful for the definite diagnosis of DD, although it is difficult to predict the severity and prognosis of skin symptoms from the results of the ATP2A2 mutation analysis in DD patients.

Acral melanoma with hyperkeratosis mimicking a pigmented wart.

Acral lentiginous melanoma (ALM) of the sole sometimes has a hyperkeratotic appearance and mimics a pigmented wart. We report a case of an 81-year-old woman with an ALM on the left sole with hyperkeratosis. Due to its presentation it was difficult to make a correct diagnosis at the beginning. Finally we noticed several small, pigmented macules around the wart-like lesion with the parallel ridge pattern on dermoscopy, strongly suggesting acral melanoma. When a hyperkeratotic pigmented lesion on the sole is encountered, one should rule out melanoma by careful examination of the periphery of the lesion. Dermoscopy is a helpful adjunct for the diagnosis of an unusual case like this.

Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma.

Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics. Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on the palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin-binding protein p34, located at a previously linked locus at 15q22. α- and γ-adaptin-binding protein p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicating a role in membrane trafficking. Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation.

Dermoscopic features of eccrine porocarcinoma arising from hidroacanthoma simplex.

Eccrine porocarcinoma is a rare cutaneous neoplasm that mainly affects elderly people and grows slowly over a long period of time but often experiences an accelerated growth phase. Eccrine porocarcinoma may arise de novo or evolve from a pre-existing benign eccrine poroma. We reported a 86-year-old Japanese woman presenting with two reddish-colored pendulated lesions on a keratotic light brown plaque on the right thigh. Dermoscopic examination of the light-brown plaque demonstrated many whitish globular structures in a light-brown background. At the two reddish-colored pendulated lesions, polymorphous and prominent vessel proliferation was observed together with irregularly shaped whitish negative network. Immunohistochemical study demonstrated a positive CEA staining at ductal structures and atypical clear cells of reddish nodules. A diagnosis of eccrine porocarcinoma arising in a pigmented hidroacanthoma simplex was eventually established, and the dermoscopic features of eccrine porocarcinoma from hidroacanthoma simplex was described for the first time.

Dermoscopy of Pigmented Bowen's Disease Mimicking Early Superficial Spreading Melanoma.

A 89-year-old Japanese woman presented at our clinic because of a several months' history of an asymptomatic gradually enlarging pigmented skin lesion on the dorsum of the left foot. Physical examination revealed a single hyperpigmented oval macule of 5 mm with a rough surface. The color of the lesion was dark brown to light brown. Dermoscopic examination demonstrated atypical pigment network with small dotted vessels. Irregular streaks were also partially noted at the periphery. We suspected superficial spreading melanoma and performed an excision. The histologic features were consistent with a diagnosis of pigmented Bowen's disease. We could not completely account for dermoscopic aspects from the pathological findings of hematoxylin and eosin-stained specimens; therefore, specimens were stained with Fontana-Masson stain. It clearly demonstrated the distribution of melanin in the epidermis. We concluded that atypical network was due to an uneven melanin deposition in the variably thickened epidermal rete ridges.

[A case of dermal cutaneous alternariosis].

Alternaria is a saprophytic fungus that naturally subsists on decaying plant materials, but may be an opportunistic pathogen in immunocompromised hosts. We describe a case of dermal cutaneous alternariosis in a 70-year-old patient, who was on systemic steroid administration for autoimmune hemolytic anemia. The patient also had chronic heart failure, liver dysfunction, and diabetes mellitus. Infection was confirmed by histological examination, and multiple positive culture results. Treatment with oral terbinafine and itraconazole was ineffective. We review the literature of dermal cutaneous alternariosis reported in Japan; including our case, 15 cases have been reported. Recognition of Alternaria as a potential opportunistic pathogen is important for the differential diagnosis of dermatologic lesion, such as granulomatous lesion or ulcer, in immunocompromised hosts.

Beta-mannosidosis with angiokeratoma corporis diffusum.

Beta-mannosidosis is a lysosomal disorder which is caused by a deficiency of beta-mannosidase. This disorder was first described in goats. Twelve human cases have already been reported. We present the first case in Japan in whom the diagnosis was reached from angiokeratoma corporis diffusum. Futhermore, mental retardation, hearing loss, and renal failure were also detected. Pseudoxanthoma elasticum was also present, but whether it is a complication of beta-mannosidosis or not remains unknown. The activity level of beta-mannosidase in the patient's plasma was only 2% of the normal range, while that in the patient's mother was 40%. We suggest that beta-mannosidosis should be one of the differential diagnoses when lysosomal enzyme disorders are suspected in cases of angiokeratoma corporis diffusum.

[Aseptic meningitis as a complication caused by an allergic reaction after microvascular decompression: two case reports].

We report here two cases of patients complicated with aseptic meningitis after microvascular decompression (MVD). The first case, a 56-year-old female complained of headache with high fever 18 days after the MVD for right trigeminal neuralgia. The amount of cells in cerebrospinal fluid (CSF) had so much increased that bacterial meningitis was suspected. However, there was no improvement after antibiotics therapy, so immune globulin was injected and the meningitis gradually improved. Eosinophilia remained in peripheral blood and the symptoms improved rapidly after the steroid therapy. Because of this, we suspected that meningitis was caused by an abnormal allergic reaction. The second case, a 30-year-old male complained of headache with mild fever 15 days after MVD for left hemifacial spasm. The amount of cells in CSF increased, so bacterial meningitis was suspected. Eosinophilia remained in peripheral blood and the steroid therapy proved very effective for the meningitis. Because of this, we suspected that meningitis was caused by an abnormal allergic reaction. We suspected that the two patients suffered from aseptic meningitis caused by allergic reaction, and the antigen for this abnormal allergic reaction was the foreign materials used for MVD. The materials were Dacron for prostesis, Goatex or Lyodula for dural plasty, fibrin glue for preventing CSF leakage. We ascertained that the abnormal allergic reaction was caused by human fibrinogen in the second case. It is important to be aware of such allergic reaction to fibrin glue in the post-operative stage after MVD.

Advanced glycation end product-modified beta2-microglobulin is a component of amyloid fibrils of primary localized cutaneous nodular amyloidosis.

Primary localized cutaneous nodular amyloidosis is a rare form of cutaneous amyloidosis. Amyloid fibrils in primary localized cutaneous nodular amyloidosis have been reported to be originated from immunoglobulin light chains. Immunohistochemical studies on the lesional skins of four patients with primary localized cutaneous nodular amyloidosis demonstrated that amyloid deposits of all cases showed a positive reaction with the antibodies for beta2-microglobulin and advanced glycation end products as well as immunoglobulin light chain (kappa or lambda). No beta2-microglobulin and advanced glycation end product immunoreactivity was found in the amyloid deposits of other primary localized cutaneous amyloidosis (lichen amyloidosis and macular amyloidosis). Double immunofluorescence study of the lesional skin of primary localized cutaneous nodular amyloidosis showed that anti-kappa light chain, anti-beta2-microglobulin and anti-advanced glycation end product antibodies mostly reacted with the same area of amyloid deposit. Amyloid proteins were sequentially extracted with distilled water from one case of primary localized cutaneous nodular amyloidosis and recovered in the five water-soluble fractions (fractions I-V). Immunoblot assay of amyloid fibril proteins demonstrated that immunoreactive polypeptides with anti-kappa light chain antibody (29 kDa) and with anti-beta2-microglobulin antibody (12 kDa) were detected in fractions I-V, whereas immunoreactive polypeptide with anti-advanced glycation end product antibody (12 kDa) was detected exclusively in fractions III-V but not in fractions I and II. Two-dimensional polyacrylamide gel electrophoresis revealed that 12 kDa polypeptide in fractions I and II was electrophoretically identical with authentic beta2-microglobulin and that beta2-microglobulin in fractions III-V was advanced glycation end product-modified beta2-microglobulin with more acidic pI value. These results indicate that beta2-microglobulin is another major component of amyloid fibrils in primary localized cutaneous nodular amyloidosis and that beta2-microglobulin in primary localized cutaneous nodular amyloidosis is partly subjected to the modification of advanced glycation end product.