Shigeto Matsushita

SUCCESSFUL TREATMENT OF SCLERODERMA WITH PUVA THERAPY

PUVA therapy was carried out on four patients with scleroderma; three of them had cutaneous manifestations of progressive systemic sclerosis and one other exhibited generalized morphea. PUVA therapy was given with daily doses of 0.25 J/cm2 or 0.4 J/cm2 for 3–8 weeks, resulting in total doses between 3.5 J/cm2 and 9.6 J/cm2. All four patients responded well to this treatment; improvements of hand closure, skin sclerosis index, and flexion of fingers or knee joints were obtained. Thus, PUVA appeared to be beneficial for treating scleroderma.

Spontaneous regression of recurrent and metastatic Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a malignant neuroendocrine tumor with a high rate of recurrence and metastasis. Despite its high degree of malignancy, spontaneous regression has been documented. We report an 87‐year‐old woman who presented with recurrent MCC on her left cheek and regional lymph node metastasis. Although she received no treatment due to her poor condition, the recurrent metastatic lesion regressed spontaneously within 2 months.

Successful treatment of metastatic extramammary Paget’s disease with S-1 and docetaxel combination chemotherapy

Dear Editor, Metastatic extramammary Paget’s disease (EMPD), which is highly intractable to surgery and chemotherapy, has been treated by combination chemotherapy with 5-fluorouracil (5-FU), epirubicin (EPI), cisplatin (CDDP), vincristine (VCR) and mitomycin C (MMC) (FECOM), and with 5-FU plus CDDP. However, outcomes remain unsatisfactory. We successfully treated a 69-year-old man with FECOM-resistant metastatic EMPD with a combination of S-1, a drug containing a 5-FU derivative (Taiho Pharmaceutical, Tokyo, Japan) and docetaxel (TXT). He had noticed a gradually-enlarging reddish tumor on his genitalia 6 months earlier. Skin biopsy performed elsewhere returned a histological diagnosis of EMPD and he was referred to us in September 2007. Physical examination revealed faint erythema with an irregularly shaped reddish tumor, approximately 2.5 cm in diameter, on his scrotum (Fig. 1a). Serum carcinoembryonic antigen (CEA) was 2.1 ng ⁄mL (normal range, <4 ng ⁄mL). Computed tomography (CT), ultrasonography and positron emission tomography disclosed neither lymphadenopathy nor signs of distant metastasis. We performed local excision with a wide margin and sentinel lymph node biopsy. Histology revealed Paget cell nests in the epidermis, dermal invasion by the tumor (Fig. 1b), and involvement of sentinel lymph nodes of the left inguinal area by Paget cells (Fig. 1c). We dissected the left inguinal and iliac lymph nodes. Tumor cells involved five of 11 dissected lymph nodes. After five cycles of FECOM delivered between January and August 2008, new mass lesions arose in the left lateral wall of the bladder, in both lungs as lymphangitis carcinomatosa (Fig. 2a) and at multiple bone sites. His serum CEA was 159.5 ng ⁄mL. The tumors were immunohistochemically positive for cytokeratin (CK)19, known to be expressed in EMPD. HisserumsolubleCK19 fragment (CYFRA211) level was 69.8 ng ⁄mL (normal range, <2.8 ng ⁄mL). Whole-body examination disclosed neither CEA nor CYFRA21-1 indicativeof theoriginaldisease,andconsequently we diagnosed the new lesions as metastases from EMPD. As treatment with TXT and the combination of paclitaxel and trastuzumab met with limited success in EMPD patients, and because combination chemotherapy with S-1 and TXT was highly effective in patients with advanced gastric adenocarcinoma, we tried the latter treatment. On March 2009, we started the delivery of S-1 (80 mg ⁄m per day for 14 consecutive days, first cycle) and TXT (40 mg ⁄m per day on day 1), at 2-week intervals. Because he developed grade 3 diarrhea (National Cancer Institute Common Terminology Criteria, ver. 3.0), we decreased the S-1 dose to 60 mg ⁄m per day after the second cycle. Dyspnea and pleural effusion disappeared after two cycles. After the third cycle, he was discharged and chemotherapy was continued at our outpatient clinic. CT revealed the complete disappearance of the bladder and lung metastases after the completion of five cycles (Fig. 2b); his multiple bone metastases persisted but did not enlarge. His serum CEA and CYFRA 21-1 dropped to 8.4 and 4.0 ng ⁄mL, respectively. According to the Response Evaluation Criteria in Solid Tumors he achieved a partial response. On August 2010, he underwent the 15th chemotherapy cycle; currently, his bone metastases have not enlarged andnonewmetastatic lesionshaveappeared. Wada et al. who used xenografts of a gastric cancer cell line demonstrated that the synergistic antitumorand growth-inhibitory effects of TXT and S-1 were significant and more potent than of TXT and

Hedgehog Pathway Inhibitors Promote Adaptive Immune Responses in Basal Cell Carcinoma

Purpose: Basal cell carcinomas (BCCs) are tumors ignored by immune surveillance. Activated Hedgehog (Hh) signaling within primary cilia is a key driver in the pathogenesis of BCCs. We examined immune alterations during treatment with systemic Hh inhibitors. Experimental Design: We investigated biopsies from patients with BCC before (23 patients) and after 4 weeks of treatment (5 patients) with Hh signaling inhibitor. Ber-Ep4, BCL-2, Ki-67, CD4, CD8, MHC class I, HLA-DR-class II, and SOX9 were analyzed by immunohistochemistry. Primary cilia were analyzed by double immunofluorescence of acetylated tubulin and SOX9. Differential gene expression for 84 cytokines and chemokines was analyzed in 3 patients. Results: After 4 weeks of treatment, we found reduction of Ki-67, SOX9, Ber-EP4, and BCL-2 expression in tumors associated with morphologic signs of squamous differentiation. In addition, the number of cilia-positive BCC cells was significantly decreased. An upregulation of MHC I expression on the cell membranes of residual tumor cells and an influx of CD4+, HLA-DR-class II+, and CD8+ cells with invasion into the tumor cell nests were found. Finally, qPCR arrays showed the differential expression of genes involved in modulating immune responses. Conclusions: We show that Hh pathway inhibitor–induced tumor regression is accompanied by a dynamic change of the microenvironment with a disruption of immune privilege involving an influx of cytotoxic T cells, activation of the adaptive immune functions, and a profound alteration of the local chemokine/cytokine network. Clin Cancer Res; 21(6); 1289–97. ©2015 AACR.

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.

Submental perforator flap: location and number of submental perforating vessels.

The sites and numbers of submental perforator vessels were examined using a Doppler probe in 21 volunteers. The subcutaneous vascular network from each perforator was studied in three cases of dissection of upper-neck lymph nodes among the volunteers. A perforator from the submental vessels was noted in all 21 volunteers: a single perforator in 13 cases, and double perforators in eight. The main perforator, which had some subdermal branches, was located 31.8 (8.3) mm in front of the facial artery that was palpated at the mandible. Five patients who presented with skin defects on the cheek and the chin had the submental perforator flap reconstructed, excluding the platysma muscle. All flaps covered the wounds. The submental perforator flap was useful for reconstructing skin defects on the cheek and the chin, because the site of the submental perforator was stable and raising the flap was easy, and the colour and texture matches were acceptable.

The role of sentinel lymph node biopsy in the management of invasive extramammary Paget's disease: Multi-center, retrospective study of 151 patients

BACKGROUND Although extramammary Pagets disease (EMPD) mostly presents as intraepithelial carcinoma, we sometimes encounter patients with invasive EMPD (iEMPD) who have lymph node metastasis and may develop distant metastasis. Although sentinel lymph node biopsy (SLNB) is widely accepted for various cancers, there is no large study that has assessed its role in iEMPD. OBJECTIVE The main objective of this study is to assess the role of SLNB in patients with iEMPD. MATERIALS AND METHODS We retrospectively collected data on 151 iEMPD patients treated from 1998 to 2012 in 11 institutes in Japan. All 151 patients received curative surgery for their primary tumor and none of them had distant metastasis. SLNB was performed on the 107 patients without lymphadenopathy to determine their LN status. The 44 other patients with lymphadenopathy underwent one of the following procedures to determine their LN status: SLNB in 22 cases, immediate LN dissection in 21, and LN biopsy in 1. RESULTS Compared to those without lymphadenopathy, patients with lymphadenopathy had advanced primary tumors (nodule in the primary tumor, thicker tumor, deeper invasion level, and lymphovascular invasion). The rate of LN metastasis in patients with lymphadenopathy was 80%, compared to 15% in patients without lymphadenopathy who underwent SLNB. Compared to those with negative SLN, patients with positive SLN had advanced primary tumors (nodule in the primary tumor, deeper invasion level, and lymphovascular invasion). Multivariate analysis revealed that dermal invasion (odds ratio 5.8, p=0.04) and lymphovascular invasion (odds ratio 18.0, p=0.0023) were independent factors associated with SLN positivity. Notably, there was no difference in survival between patients with or without SLN metastasis (p=0.71). On the other hand, patients with lymphadenopathy showed worse survival than those with positive SLN (p=0.045). CONCLUSION Clinical lymphadenopathy was strongly correlated with pathological LN metastasis and also associated with worse survival than absence of lymphadenopathy. The rate of occult LN metastasis detected by SLNB was 15%. Survival was not affected by SLN status even when an advanced primary tumor was present in patients with positive SLN. Our results raise the possibility that SLNB and subsequent LN dissection improved the survival of patients with early stage lymphatic spread. Our study indicates that SLNB should be considered for iEMPD if lymphadenopathy is not apparent.

Giant malignant peripheral nerve sheath tumor of the scalp

Herein, we describe a rare case of giant malignant peripheral nerve sheath tumor of the head in a 38‐year‐old Japanese man. The tumor measured 210 mm at its largest diameter and was ulcerated, hemorrhagic, multilocular and non‐mobile. It should be noted that the patient stubbornly refused to see a doctor for a long time, resulting in the extreme growth of the tumor. We suspect a psychological basis for this behavior. Dermatohistopathological findings of the biopsy indicated ancient schwannoma and total excision was therefore performed. However, after 4 months, the patient developed multiple metastases and died. Post‐mortem skin biopsy revealed features of malignant peripheral nerve sheath tumor. We performed immunohistochemical studies on the primary and recurrent lesions and concluded that there was a difference in the expression of Ki67 and p16. We propose that the expressions of Ki67 and p16 should be checked for all lesions of peripheral nerve sheath tumor for distinguishing benign from malignant forms.

Encapsulated fat necrosis in a patient with Ehlers-Danlos syndrome

Mobile encapsulated lipoma, first described by Sahl in 1978 (1), is characterized by its great mobility within subcutaneous adipose tissue and presentation with or without tenderness when the nodules are manipulated. This lipomas histopathology is very characteristic; i.e., it consists of mature viable or degenerative lipocytes encapsulated by fibrous tissue. We report a case of this so‐called mobile encapsulated lipoma involving a patient with Ehlers‐Danlos syndrome. This case is the first report of mobile encapsulated lipoma in a patient with a disease of this type. We discuss its pathogenesis and the nomenclature for these lesions.

Usefulness of docetaxel as first-line chemotherapy for metastatic extramammary Paget's disease

In invasive extramammary Pagets disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S‐1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first‐line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1‐year overall survival rate determined by the Kaplan–Meier method was 75.0%. All adverse effects were manageable and no treatment‐related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first‐line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results.