Highly variable clinical feature and course of aggressive digital papillary adenocarcinoma.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare cutaneous tumor with sweat gland differentiation. Due to the high risk of local recurrence and delayed metastasis, the wide local resection of the primary lesion and long-term follow up are recommended for ADPA. Here, we report two cases of ADPA. Case 1 had a blue-gray nodule on the tip of the right middle finger. Case 2 had had a papule on the dorsal side of the left ring finger for 13 years. In both cases, papillary proliferations of the tumor cells showed multilobular adenomatous structures with back-to-back patterns characteristic of ADPA. We amputated the finger at the proximal interphalangeal joint and performed a wide resection of the primary tumor in Case 1 and 2, respectively. Sentinel lymph node biopsy in the axilla was performed, and no sentinel lymph node metastasis was found in either case. Among the previously reported ADPA cases, clinically, most lesions were skin-colored or tan-brown to gray. The blue-gray color in Case 1 is thought to be extraordinary for ADPA. In Case 2, the patient had had the small lesion for more than 13 years and the tumor size had been stable during that long period. The present two cases suggest that ADPA shows a prominent variety of both clinical features and disease courses, and that we cannot exclude the possibility of ADPA even in cases of blue-gray nodules or small, stable, non-progressive papules.

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

BACKGROUND: For longitudinal melanonychia, clinical and dermoscopic criteria for differentiating malignant melanoma in situ from benign nevus/lentigo/functional melanonychia have not been fully established. OBJECTIVE: To propose a clinical classification of longitudinal melanonychia that is useful in judging the need for follow-up. METHODS: A total of 137 patients with longitudinal melanonychia referred to our outpatient clinic in the most recent eight years were included. The mean and median lengths of follow-up for patients were 5.0 and 5.5 years, respectively. We classified the 137 lesions into three types by clinical and dermoscopic features of the nail and periungual skin, including Hutchinson sign, variation of color, and borders in the pigmentation band. We observed type I and II lesions with dermoscopy every six months and three months, respectively. RESULTS: After follow-up, all 72 lesions classified as type I were thought to be benign nevus/lentigo/functional melanonychia. Five of the 52 lesions classified as type II showed enlargement during follow-up, and biopsy was performed. Of these five lesions, three were diagnosed as nevus/lentigo, and the other two were diagnosed as malignant melanoma in situ. All 13 lesions classified as type III were diagnosed as malignant melanoma in situ. CONCLUSION: We can expect a type I lesion to be a benign nevus/lentigo/functional melanonychia and a type III lesion to be a malignant melanoma in situ; however, type II lesions fall in a gray zone. We believe this classification is useful in deciding treatment and follow-up.

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

BACKGROUND: 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. METHODS: We analyzed the clinicopathologic relationship among tumor thickness, mitotic index, tumor infiltrating lymphocytes (TIL), tumor size, regional lymph node metastasis and prognosis in 66 Japanese patients with thin melanomas. Immunohistochemical evaluations for TIL were also performed. RESULTS: Thirty-one of the 66 melanomas were Clark level I without lymph node metastasis (0/31, 0%). In tumors of Clark level II or higher (35/66), there were five (14%) regional lymph node metastasis. Melanomas with two or more mitoses in 1 mm(2) per high-power fields showed higher frequencies of lymph node metastasis (2/3, 67%), compared to those with fewer than two mitoses (3/32, 9%). Tumors with intensive TIL that partially or completely surrounded the tumor revealed higher frequencies of lymph node metastasis (5/28, 18%), compared to those with none or slight TIL (0/7, 0%). The main components of TIL were CD8-positive T lymphocytes. No metastasized tumors were under 2.0 cm(2) . CONCLUSIONS: The presence of mitotic activity, large tumor size and an intense lymphocytic infiltrate should prompt sentinel lymph node biopsy in thin melanomas.

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.

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 ((99m)Tc)-tin colloid, (99m)Tc-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. (99m)Tc-tin colloid, (99m)Tc-phytate, PBV and indocyanine green are useful tracers for SN mapping.

Therapy-related myelodysplastic syndrome developed by dacarbazine, nimustine hydrochloride and vincristine sulfate (DAV) therapy for patient with malignant melanoma.

Therapy-related myelodysplastic syndrome (t-MDS) is mostly attributed to chemotherapeutic agents of alkylating agents. Few studies have evaluated the late effects of chemotherapy for malignant melanoma (MM). To evaluate whether dacarbazine, nimustine hydrochloride and vincristine sulfate (DAV) therapy for MM related to t-MDS or not, a retrospective analysis was performed. We conducted a retrospective case-control study in a cohort of the 217 patients diagnosed with MM from 1989-2007 in Aichi Medical University Department of Dermatology and Nagoya University Graduate School of Medicine Department of Dermatology. One hundred and fifty-five of the 217 patients with MM were prospectively followed after DAV therapy or with or without local injection of ß-interferon, of whom two patients developed t-MDS. Cytogenetic abnormalities were found in two of the 35 patients by chromosome banding method - leukemia (G-Banding). The karyotypes were found in the chromosome of -5, deletion (5), addition (7) and 7q-. In conclusion, DAV therapy should be used carefully for older patients with MM after satisfactory operation.

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.

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 case of peripheral neuropathy and skin ulcer in a patient with rheumatoid arthritis after a single infusion of tocilizumab.

We report a case of peripheral neuropathy and skin ulcer in a patient with rheumatoid arthritis (RA) who received tocilizumab. A 65-year-old woman with a 20-year history of RA participated in a tocilizumab clinical trial. She received a single dose of 8 mg/kg tocilizumab intravenously. The following day the patient started to experience numbness and purpura in all four extremities. The purpura of her left lower limb became necrotic, and a skin ulcer appeared 3 weeks later. Steroid-pulse treatment was initiated 12 weeks after tocilizumab administration, with the result that the numbness improved, and the skin ulcers showed complete epithelialization.

A pilot study of human interferon beta 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.

Establishment of tyrosinase sequence database in normally pigmented Indians and Japanese for rapid determination of novel mutations.

BACKGROUND: Many mutations of the tyrosinase gene have been reported in oculocutaneous albinism type I (OCA1) patient. In the future, a greater number of novel mutations will be found as the search for pathological mutations in the tyrosinase genes of OCA patients from various ethnic origins. For rapid determination in future whether an observed mutation is a polymorphism or a novel pathological one, sequence databases of the gene of various ethnic people are needed. OBJECTIVE: We established a sequence database of the tyrosinase gene of Japanese as well as Indian people. METHOD: We collected DNA from 109 Japanese and 103 Indians with normal pigmentation and analyzed their tyrosinase gene using a direct sequencing method. RESULT: The database shows an apparent difference between the two ethnic groups in polymorphisms of the tyrosinase gene namely, Q402 allele, Y192 allele and IV2+24 insT were found in the Indian population, but not in the Japanese. On the other hand, some Japanese had IV2-21 insT but none of the Indians did. The database supports the notion that the tyrosinase gene evolved and extended separately in the two ethnic groups. And the developing database confirmed that the reported mutations causing Indian and Japanese OCA were not among the polymorphisms in the database, which conversely gives genetical proof of the "genuine" pathological mutations. CONCLUSION: Eventually, the sequence database we established will contribute to demonstrating novel mutations of albinism in Indians and Japanese.

A case of hypersensitivity syndrome induced by methimazole for Graves' disease.

Drug-induced hypersensitivity syndrome is one of the most severe forms of drug eruption and is characterized by high fever and multiorgan involvement. Reactivation of human herpesvirus-6 (HHV-6) or cytomegalovirus (CMV) has been suggested to be involved in this syndrome, although the exact role of these viruses remains elusive. We report the case of a 50-year-old Japanese male with Graves' disease who developed hypersensitivity syndrome caused by the antithyroid drug methimazole (MMI). After treatment with MMI 30 mg three times daily for 1(1/2) months, the patient developed generalized exfoliative erythematous eruption and high fever. Cessation of treatment with the drug improved his condition. Readministration of MMI worsened his clinical features. Treatment with high-dose methylprednisolone for 6 days and subsequent administration of prednisolone 20 mg twice daily improved his clinical manifestations. Elevated titers of anti-HHV-6 immunoglobulin G (IgG) and anti-CMV IgG antibodies were observed, and these gradually decreased during the clinical course, indicating reactivation of HHV-6 and CMV. Drug-induced lymphocyte stimulation test for MMI was negative. This is the first reported case of MMI-induced hypersensitivity syndrome associated with the reactivation of HHV-6 and CMV.