Dai Ogata

Clinical characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients

BACKGROUND The importance of the genetic background of melanoma cells to the individual susceptibility to treatment has become apparent. In Caucasians, BRAF mutations are frequently detected in lesions on the skin of younger patients compared to NRAS and KIT mutations. However, clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations have not been fully evaluated in East Asians. OBJECTIVE To clarify clinical and pathological characteristics associated with BRAF, NRAS and KIT mutations in Japanese melanoma patients. METHODS Clinical data were retrospectively collected from 11 hospitals in Japan. BRAF, NRAS and KIT mutations were evaluated with polymerase chain reaction and Sanger sequencing. The relationships between these gene mutations and pathological and clinical findings were analyzed. RESULTS The number of cases examined was 171 (primary: 135, metastases: 11, paired: 25), and all were Japanese patients. The detection rates of BRAF, NRAS and KIT mutations were 30.4%, 12.3% and 12.9%, respectively. Compared with the wild type, the presence of BRAF mutations was significantly associated with younger age (median, 50.0 years vs. 70.0 years, p<0.001). BRAF mutation was frequently detected in the lesions of the scalp (80%; 4/5), trunk (72.0%; 18/25), extremities (56.7%; 17/30) and neck (44.4%; 4/9), and the least prevalent were the face (22.2%; 2/9), nail (12.5%; 3/24), palm or sole (8.9%; 4/45) and mucosa (0%). NRAS mutations were prevalent in the face (33.3%) and palm or sole (20.0%), and the median age of these patients was 70.5 years. A KIT mutation was observed in the nail apparatus (25%), palm or sole (15.6%) and mucosa (18.2%). The median age of the patients with a KIT mutation was 63.0 years. Heterogeneity of mutations between primary and metastatic lesions was detected in six of 25 cases (24%). Solar elastosis was identified in 12 of 71 cases (15.3%), among which four cases harbored BRAF(V600E) (2 cases), BRAF(V600K), NRAS(Q61K) or NRAS(Q61L), respectively. CONCLUSION Some clinical characteristics associated with BRAF, NRAS and KIT mutations were observed in Japanese patients, and we observed both similarities to and differences from those of Caucasians. Our findings could provide useful information in efforts to clarify the tumor genesis of malignant melanomas.

Usefulness of sentinel lymph node biopsy for prognostic prediction in extramammary Paget's disease.

BackgroundComplete excision of the primary lesion has long been considered the standard treatment for extramammary Paget’s disease (EMPD). However, the presence of lymph node metastases has been reported as an important prognostic factor.ObjectivesWe evaluated the association between lymph node metastasis and prognosis for EMPD using sentinel lymph node (SLN) biopsy.Materials and methodsThis retrospective study included 59 patients with histopathologicallyconfirmed primary EMPD. A total of 45 patients with microinvasion to the papillary dermis and deep invasion into the reticular dermis or subcutaneous tissue were included in the analysis. The survival curves of the SLN-negative group and the SLN-positive group were compared and we examined the risk factors for SLN positivity.ResultsA total of 139 SLNs were excised from one (28 patients) or both inguinal regions (31 patients). The average number of detected SLNs was 2.4. The incidence of SLN metastases was 16.9%. SLN positivity rates according to level of invasion were 0% for intraepithelial lesions, 4.1% for microinvasion, and 42.8% for dermal invasion. The five-year survival rates were 100% in the SLN-negative and 24% in the SLN-positive groups (p = 0.0001).ConclusionReticular dermis or subcutaneous tissue invasion was a significant independent risk factor for SLN positivity according to multivariate analysis. The result of SLN biopsy affected prognosis. It is extremely important to accurately ascertain the presence, i.e. the number, or absence of regional lymph node metastases in patients with EMPD. We conclude that SLN biopsy may be appropriate for cases where invasion is suspected.

Dermoscopic features of ocular and extraocular sebaceous carcinomas

Sebaceous carcinomas are rare but potentially fatal malignant adenocarcinomas with varying degrees of sebaceous differentiation. Several dermoscopic findings of extraocular sebaceous carcinomas have been reported; however, there are no previous reports of ocular sebaceous carcinomas detected using dermoscopy. We present a case of ocular sebaceous carcinomas showing specific findings from dermoscopy, and describe the common dermoscopic characteristics. In our cases and a review of cases in the literature, we noted that polymorphous vessels and yellowish areas were observed in all eight cases. Thus, we consider that dermoscopic findings of polymorphous vessels with yellow backgrounds suggest sebaceous carcinoma.

Successful treatment of bilateral multiple lymph node metastases in extramammary Paget's disease with surgery and sequential chemotherapy of S‐1 and docetaxel

Dear Editor, Patients with bilateral lymph node metastases of extramammary Paget’s disease (EMPD) have a very poor prognosis, and the management of enlarged regional lymph nodes is controversial. We successfully treated a 77-year-old man with bilateral multiple lymph node metastases of EMPD with surgery and sequential chemotherapy of S-1, containing a 5-fluorouracil derivative (Taiho Pharmaceutical, Tokyo, Japan) and docetaxel (TXT). He had a medical history of autoimmune hepatitis and received a patch graft surgery to bilateral inguinal hernia 3 months before. He had noticed a gradually enlarging erythema around the base of the penis for 1 year. Physical examination revealed erythema with irregularly shaped erosion, 5.0 cm 9 3.5 cm in diameter, on the base of the penis (Fig. 1a). The serum carcinoembryonic antigen (CEA) level was 140.1 ng/mL (normal range, <4). Computed tomography (CT) disclosed neither lymphadenopathy nor signs of distant metastasis. We performed local excision with a wide margin and sentinel lymph node biopsy. Histology revealed Paget cells in the epidermis and dermis, with lymphatic invasion (Fig. 1b). The sentinel lymph nodes were metastasis-positive (right, 2/2; left, 3/3). Accordingly, following the initial surgery, we performed bilateral inguinal lymph node dissection. As a result, tumor cells were found to involve 28 of 31 (right, 12/12; left, 16/19) dissected lymph nodes. Post-surgery, CT revealed left external iliac lymph node swelling (Fig. 1c), and elevated serum CEA levels (161.6 ng/mL) were observed. Because the patient preferred aggressive treatment, we attempted chemotherapy with S-1 and TXT, referring to the report by Matsushita et al. We started delivery of S-1 (100 mg/m per day for 14 days consecutively, first cycle) and TXT (60 mg/m per day on day 1) at 2-week intervals in an outpatient clinic. The patient developed grade 4 neutrophil count decrease, grade 3 white blood cell decrease and grade 2 anorexia (Common Terminology Criteria for Adverse Events version 4.0). We immediately administrated granulocyte colony-stimulating factor and he passed without any side-effect afterwards. We consequently decreased the S-1 and TXT doses to 60 and 40 mg/m, respectively, after the second cycle. As a result, he could complete the therapy without any major adverse event after the second cycle. After the third cycle, the swollen external iliac lymph nodes were reduced from 12 to 6 mm upon CT (Fig. 1d), and the serum CEA level was decreased to 40.6 ng/mL. One year post-surgery, he remains alive and disease-free. In this case, there was no sign of lymph node and distant metastasis in imaging findings at initial therapy. We performed inguinal dissection in hope of the possibility of complete resection with a plan that we perform sequential chemotherapy, if metastasis has occurred. In addition, the efficacy of taxanes and oral S-1 has been reported in recent years. This case demonstrates the excellent effect of surgery and sequential S-1/TXT chemotherapy in a patient with multiple lymph node metastases of EMPD. This regimen has the advantage that it can be carried out in an outpatient clinic, and improvement of the prognosis of advanced EMPD patients can be expected. (a)

Characteristic dermoscopic features of verruciform xanthoma: Report of three cases

1 Kossard S, Epstein EH Jr, Cerio R, Yu LL, Weedon D.Basal cell carcinoma. In: World Health Organization Classification of Tumours, Pathology & Genetics of Skin Tumours. LeBoit PE, Burg G, Weedon D, Sarasin A, eds. Lyon: IARC Press, 13–19, 2006. 2 Giacomel J, Lallas A, Argenziano G et al. Dermoscopy of basosquamous cell carcinoma. Br J Dermatol 2013; 169: 358–364. 3 Swanson PE, Fitzpatrick MM, Ritter JH et al. Immunohistologic differential diagnosis of basal cell carcinoma, squamous cell carcinoma, and trichoepithelioma in small cutaneous biopsy specimens. J Cutan Pathol 1998; 25: 153–159. 4 Jones MS, Helm KF, Maloney ME. The immunohistochemical characteristics of the basosquamous cell carcinoma. Dermatol Surg 1997; 23: 181–184. 5 Beer TW, Shepherd P, Theaker JM. Ber EP4 and epithelial membrane antigen aid distinction of basal cell, squamous cell and basosquamous carcinomas of the skin. Histopathology 2000; 37: 218–223. (a)

Randomized phase III trial of adjuvant therapy with locoregional interferon beta versus surgery alone in stage II/III cutaneous melanoma: Japan Clinical Oncology Group Study (JCOG1309, J-FERON)

Randomized phase III trial (JCOG1309) has been started to confirm the superiority of adjuvant therapy with locoregional interferon beta over surgery alone in overall survival for patients with stage II/III cutaneous melanoma.

Nail apparatus melanoma in a Japanese population: a comparative study of surgical procedures and prognoses in a large series of 151 cases

BackgroundNail apparatus melanoma (NAM) is a rare subtype of malignant melanoma with a prevalence that varies among populations. Conservative surgical approaches for thin to intermediate NAMs have recently been reported, however, their adoption is controversial, and resulting long-term prognoses are unknown.ObjectivesThe purpose of this study was to determine the prognosis of NAM in a sample Asian population, and to investigate whether there is a difference in the local control and overall survival (OS) rates according to the extent of resection of the primary tumour.Materials & methodsWe performed a retrospective study of NAM patients treated at five medical institutions in Japan between 2000 and 2013. Outcomes according to surgery (amputation vs. resection) and tumour thickness were compared.ResultsWe identified 151 cases of NAM in 83 men and 68 women; the thumb (n = 50; 33.1%) and hallux (n = 55; 36.4%) were the most common sites. No local recurrence was detected following any of the surgical procedures; Kaplan-Meier survival analysis revealed that the surgical procedure type was not significantly associated with disease-free survival (p = 0.786) or OS (p = 0.997). Five-year OS rates according to tumour thickness were 100% for in situ, 94.4% for ≤1-mm, 91.7% for 1.01-2.0-mm, 72.7% for 2.01-4.0-mm, and 47.6% for ≥4.01-mm tumours.ConclusionSurgical procedure type does not influence survival as long as total primary tumour resection is accomplished. The prognosis of NAMis comparable to that of other types of melanoma.

An enlarged intramuscular venous malformation in the femoral region successfully treated with complete resection

Highlights • We successfully resected a large intramuscular venous malformation relapsed after surgery.• Resection of venous malformations may improve appearance and physical function.• However, partial resection may cause excess blood loss or postoperative recurrence.

A case of human papillomavirus-associated squamous cell carcinoma with bone invasion and verruca vulgaris of the fingernails

Squamous cell carcinoma (SCC) usually develops from previous lesions, such as those resulting from actinic keratosis, Bowen disease, burns, and chronic radiation dermatitis. In addition, published reports show an association between SCC and high-risk human papillomavirus (HPV). Bone invasion by digital SCC is rare and its association with high-risk HPV is unclear. We herein report a case of HPV-associated SCC with bone invasion and verruca vulgaris of the fingernails. High-risk HPV type 16 and low-risk [...]

Pilot study on the correlation between dermoscopic patterns and fluorescence in situ hybridization findings using whole-slide digital imaging for acral volar melanocytic lesions

Dermoscopic evaluation of acral volar skin is helpful in differentiating malignant melanomas (MM) from benign melanocytic nevi. However, histological diagnosis remains difficult because sufficient evidence of histopathological changes to establish a diagnosis of MM are not easily obtained. The aim of the present study was to evaluate the effective use of fluorescence in situ hybridization (FISH) in the diagnosis of acral volar melanocytic lesions, and to determine whether acral volar melanocytic lesions show characteristic molecular biological features of malignant melanoma via FISH. We classified acral volar melanocytic lesions showing junctional findings into three groups: (A) parallel ridge pattern (PRP) on dermoscopic examination with melanoma in situ; (B) PRP with insufficient melanocyte proliferation and atypia to diagnose malignant melanoma using hematoxylin–eosin staining; and (C) junctional nevi. We performed FISH analysis using the same tissue section that was used for hematoxylin–eosin staining. FISH positivity was seen in 80% (4/5) of the group A sections, and in 80% (4/5) of the group B sections. One case in group C was only 0.3% over the established criteria line (63.3% > 63% in RREB1). Our results suggest that FISH using whole‐slide digital imaging may be useful in the diagnosis of early in situ MM when a typical PRP is observed in an acral volar skin lesion with non‐diagnostic histopathology.