Akihiro Sakakibara

The Majority of Generalized Pustular Psoriasis without Psoriasis Vulgaris Is Caused by Deficiency of Interleukin-36 Receptor Antagonist

Generalized pustular psoriasis (GPP) is a rare inflammatory skin disease that can be life-threatening. Recently, it has been reported that familial GPP is caused by homozygous or compound heterozygous mutations of IL36RN. However, the majority of GPP cases are sporadic and it is controversial whether IL36RN mutations are a causative/predisposing factor for sporadic GPP. We searched for IL36RN mutations in two groups of GPP patients in the Japanese population in this study: GPP without psoriasis vulgaris (PV), and GPP with PV. Eleven cases of GPP without PV (GPP alone) and 20 cases of GPP accompanied by PV (GPP with PV) were analyzed. Surprisingly, 9 out of 11 cases of GPP alone had homozygous or compound heterozygous mutations in IL36RN. In contrast, only 2 of 20 cases of GPP with PV had compound heterozygous mutations in IL36RN. The two cases of GPP with PV who had compound heterozygous mutations in IL36RN are siblings, and both cases had PV-susceptible HLA-A*0206. We determined that GPP alone is a distinct subtype of GPP and is etiologically distinguished from GPP with PV, and that the majority of GPP alone is caused by deficiency of the interleukin-36 receptor antagonist due to IL36RN mutations.

Human papillomaviruses of the mucosal type are present in some cases of extragenital Bowen's disease

Background  Bowens disease in the genital area is generally considered to be caused by mucosal high‐risk human papillomaviruses (HPVs). However, the detection rate and spectrum of HPVs in extragenital Bowens disease are various and it is not clear to what extent HPV is involved in its pathogenesis.

Applicability of radiocolloids, blue dyes and fluorescent indocyanine green to sentinel node biopsy in melanoma

Patients with primary cutaneous melanoma underwent sentinel node (SN) mapping and biopsy at 25 facilities in Japan by the combination of radiocolloid with gamma probe and dye. Technetium‐99m (99mTc)‐tin colloid, 99mTc‐phytate, 2% patent blue violet (PBV) and 0.4% indigo carmine were used as tracers. In some hospitals, 0.5% fluorescent indocyanine green, which allows visualization of the SN with an infrared camera, was concomitantly used and examined. A total of 673 patients were enrolled, and 562 cases were eligible. The detection rates of SN were 95.5% (147/154) with the combination of tin colloid and PBV, 98.9% (368/372) with the combination of phytate and PBV, and 97.2% (35/36) with the combination of tin colloid or phytate and indigo carmine. SN was not detected in 12 cases by the combination method, and the primary tumor was in the head and neck in six of those 12 cases. In eight of 526 cases (1.5%), SN was detected by PBV but not by radiocolloid. There were 13 cases (2.5%) in which SN was detected by radiocolloid but not by PBV. In 18 of 36 cases (50%), SN was detected by radiocolloid but not by indigo carmine. Concomitantly used fluorescent indocyanine green detected SN in all of 67 cases. Interference with transcutaneous oximetry by PVB was observed in some cases, although it caused no clinical trouble. Allergic reactions were not reported with any of the tracers. 99mTc‐tin colloid, 99mTc‐phytate, PBV and indocyanine green are useful tracers for SN mapping.

Dermoscopic evaluation of vascular structures of various skin tumors in Japanese patients.

Dermoscopic analysis of skin tumor has been mainly focused on pigmented structures. Recently, several different morphological types of vessels were found to be well associated with pigmented or non‐pigmented skin tumors in white subjects. Therefore, the recognition of such vascular structures has been applied for diagnostic purposes. As little statistical information on the various pigmented skin tumor vessels of Japanese patients has been reported, we therefore tried to evaluate the association between various vascular structures and 741 tumor lesions of Japanese patients. Vascular structures were dermoscopically recognized in 41 of 102 cases of melanoma, 104 of 119 basal cell carcinoma (BCC), 86 of 257 seborrheic keratosis (SK), 35 of 210 dermal and compound nevus (DN/CN), six of 12 squamous cell carcinoma (SCC) and 16 of 41 Bowen disease (BD). The structures of arborizing and glomerular vessels statistically revealed diagnostic specificity for BCC and BD, respectively, and hairpin vessels were helpful for differentiating SK from other pigmented tumors, as already reported in white patients. The most common vascular pattern observed in melanoma was the linear–irregular structure, but this pattern in Japanese patients had less diagnostic value than in white patients, because its sensitivity was not significantly higher than in SCC. The most remarkable differences between our study and previous reports with white patients were low frequency and sensitivity of dotted, comma and polymorphous vessels in lesions of melanoma, BCC and DN/CN; these vessels had less diagnostic value for Japanese patients. Finally, the frequency of vascular structures observed in melanoma rose along with the increase of the Breslow’s tumor thickness, and 88% of melanomas with vascular vessels revealed tumor thicknesses of more than 2 mm.

A Pilot Study of Human Interferon β Gene Therapy for Patients with Advanced Melanoma by in vivo Transduction Using Cationic Liposomes

BACKGROUND Cationic liposomes containing the human interferon beta (HuIFNbeta) gene (IAB-1) was used for the clinical trial for glioma patients. HuIFNbeta gene therapy showed much higher anti-tumor activity compared with the administration of HuIFNbeta protein for melanoma. These results suggest that HuIFNbeta gene therapy is an attractive strategy for the treatment of melanoma. METHODS Stage IV or III melanoma patients with cutaneous or subcutaneous metastatic lesions were enrolled in this pilot study. IAB-1 was dissolved by sterile PBS at a concentration of 30 microg DNA/ml and was injected into cutaneous or subcutaneous metastatic nodules three times a week for 2 weeks and the effect on the injected and non-injected metastatic lesions was evaluated. RESULTS Clinical responses were as follows (five patients): mixed response (MR) and no change in each one patient, and progressive disease in three patients. In the MR patient, the IAB-1 injected lesion disappeared clinically and histopathologically and one-half of IAB-1 non-injected skin metastases were transiently inflamed and mostly regressed. In the responded non-injected lesions of this patient, histopathologically, infiltration of CD4 positive T cells was observed around the melanoma cells in the dermis, which expressed the HLA-Class II antigen. Adverse events due to this gene therapy were not recognized in any of the patients. CONCLUSIONS The efficacy of this gene therapy was generally insufficient; however, some immunological responses were recognized in one patient. No adverse events were observed. HuIFNbeta gene therapy could be an attractive strategy for treatment of a variety of malignancies, including melanoma, though some modifications should be required.

Interval sentinel lymph nodes in patients with cutaneous melanoma: A single-institution study in Japan

Interval sentinel lymph nodes (ISLN) are defined as the lymph nodes located between the primary melanoma and anatomically well‐defined lymph nodal basins. It was reported that the ISLN appeared to be at the same metastatic risk as sentinel lymph nodes (SLN) in the traditional nodal basins. This study aimed to examine the incidence and metastatic risk of the ISLN in melanoma patients. Between June of 1999 and December of 2008, 117 patients enrolled at Nagoya University Hospital underwent SLN biopsy for primary cutaneous melanoma with a Breslow thickness of at least 1.0 mm. Triple techniques with lymphoscintigraphy, blue dye injection and gamma probe were used for the biopsy except for 13 cases that underwent lymphoscintigraphy, ultrasonography and blue dye injection, but without gamma probe. Patients who had melanoma of the head and neck were excluded from this analysis. The SLN were identified in 253 nodal basins from 117 patients, and ISLN were found in six patients (5%). We recognized 41 (17%) SLN metastases in 246 conventional nodal basins and one (14%) in seven ISLN. Although ISLN were identified infrequently, the incidence of metastasis into the ISLN was similar to that into SLN in conventional nodal basins. It is therefore recommended that preoperative lymphoscintigraphy and intraoperative recognition of ISLN should be performed.

Proposed classification of longitudinal melanonychia based on clinical and dermoscopic criteria.

For longitudinal melanonychia, clinical and dermoscopic criteria for differentiating malignant melanoma in situ from benign nevus/lentigo/functional melanonychia have not been fully established.

Postoperative DAV-IFN-β therapy does not improve survival rates of stage II and stage III melanoma patients significantly.

Background  DAV‐interferon (IFN)‐β therapy is a combination chemotherapy of dacarbazine (DTIC), nimustine (ACNU) and vincristine (VCR) with local subcutaneous injection of IFN‐β that is widely employed as postoperative adjuvant chemotherapy to treat malignant melanoma in Japan. However, the efficacy of DAV‐IFN‐β therapy has not been confirmed by randomized controlled trials and the benefit of DAV‐IFN‐β therapy has not been established yet. This study evaluated the contribution of DAV‐IFN‐β therapy to improve survival of postoperative patients with cutaneous melanoma.

Clinicopathologic analysis of 66 Japanese thin melanomas with metastasis of sentinel or regional lymph node.

Assessment of sentinel lymph node status is commonly performed in the treatment of cutaneous melanoma. However, there are no definite guidelines for thin melanomas with Breslow tumor thickness <1.0 mm, in part because thin melanomas are relatively infrequently positive for lymph node metastasis.

Lentigo maligna : a unique case with pronounced nesting of atypical melanocytes seen at histologic examination

• A 64-year-old woman presented with a 3-year history of a solitary tan-to-brown macule arising on her cheek. On initial examination, a half-moon-shaped, black-brown macule that measured 10 X 6 mm with a light-brown macule was observed. The lesion was well demarcated, with a partially serrated margin (Fig. 1). These clinical findings were suggestive of lentigo maligna. The brownish-black macule (darker portion) was tolally excised. Its histologic examination disclosed a conspicuous nest formation in the epidermis, numerous melanophages, and solar elastosis in the upper dermis. Most of the nests showed a variety in size and shape, and were mainly located at the dermoepidertnal junction (Fig. 2). Some of the nests were well demarcated and round in shape, just like those in junctional nevus or of superficial spreading melanoma in situ (Fig. 3). The nests consisted of pleomorphic melanocytes with irregularly shaped nuclei containing a large amount of melanin (Fig. 4). Although the atypical melanocytes extended downward to the hair follicle, invasion of the dermis could not be detected. These clinical and histologic findings led us to the diagnosis of melanoma in .silu, specifically lenligo maligna. Superficial spreading melanoma in situ was also listed as a differential diagnosis in histopathology. Junctional nevus was excluded by the proliferation of atypical melanocytes. The remaining light-brown macule (lighter portion) was then removed surgically, along with a 5-mm border. Histologically, this portion was quite different from the darker portion. It showed epidermal atrophy, increased large basal melanocytes with cellular atypia, and marked solar elastosis in the upper dermis, which was the typical histologic features of lentigo maligna described previously (Fig. 5). No nesting was found in this portion. The definite diagnosis of lentigo maligna was made. No recurrence or distant metastasis has occurred 6 months after the surgical excision.