Japanese Dermatological Association Guidelines: Outlines of Guidelines for Cutaneous Squamous Cell Carcinoma 2020.

In consideration of the development of treatment options for squamous cell carcinoma (SCC), the Japanese Skin Cancer Society issued the first guidelines of SCC in 2007 and revised them in 2015. Here, we report the English version of the 2020 edition of the Japanese SCC guidelines. The first half of this article is an overview of SCC including actinic keratosis and Bowen's disease, and the second half discusses three clinical questions: (i) treatment of actinic keratosis; (ii) determination of the resection margin of the primary lesion; and (iii) treatment of radically incurable cases, as contemporary problems encountered in treating SCC. In these evaluations, all processes were implemented according to the Grading of Recommendations, Assessment, Development, Evaluation system. Also, items of recommendation concerning each clinical question were determined by a multidisciplinary expert panel consisting of dermatologists, plastic/reconstructive surgeons, radiologists, and oncologists through a comprehensive literature search and systematic reviews.

Exploration of a standard treatment for Buruli ulcer through a comprehensive analysis of all cases diagnosed in Japan.

Buruli ulcer (BU) is a refractory skin ulcer caused by Mycobacterium ulcerans or M. ulcerans ssp. shinshuense, a subspecies thought to have originated in Japan or elsewhere in Asia. Although BU occurs most frequently in tropical and subtropical areas such as Africa and Australia, the occurrence in Japan has gradually increased in recent years. The World Health Organization recommends multidrug therapy consisting of a combination of oral rifampicin (RFP) and i.m. streptomycin (SM) for the treatment of BU. However, surgical interventions are often required when chemotherapy alone is ineffective. As a first step in developing a standardized regimen for BU treatment in Japan, we analyzed detailed records of treatments and prognoses in 40 of the 44 BU cases that have been diagnosed in Japan. We found that a combination of RFP (450 mg/day), levofloxacin (LVFX; 500 mg/day) and clarithromycin (CAM; at a dose of 800 mg/day instead of 400 mg/day) was superior to other chemotherapies performed in Japan. This simple treatment with oral medication increases the probability of patient adherence, and may often eliminate the need for surgery.

Chemoradiation using low-dose cisplatin and 5-fluorouracil in locally advanced squamous cell carcinoma of the skin: a report of two cases.

Recently, low-dose 5-fluorouracil/cisplatin induction concurrent with radiation (chemoradiation) has been reported to be effective for locally advanced squamous cell carcinoma of the otorhinolaryngologic and gynecologic regions. However, to date, this therapeutic option has not been evaluated for squamous cell carcinoma of the skin. We evaluated chemoradiation therapy using cisplatin and 5-fluorouracil in two patients with locally advanced squamous cell carcinoma of the skin. Administration of cisplatin and 5-fluorouracil was conducted concurrently with conventionally fractionated radiation therapy. Cisplatin (patient 1: 4 mg/m(2)/d on days 1 to 5; patient 2: 15 mg/m(2)/d on days 1 to 5) and 5-fluorouracil (patient 1: 400 mg/m(2)/d for 7 days; patient 2: 850 mg/m(2)/d for 5 days) were administered intravenously for 1 hour and for 24 hours, respectively. Patient 1 underwent two courses of chemotherapy with a 3-week interval, and patient 2 underwent a single course of chemotherapy. The primary tumor of both patients showed complete regression, leaving ulceration. In patient 1, the ulceration completely resolved after 3 months. Patient 2 underwent surgical resection and full-thickness skin grafting. A histopathologic examination confirmed complete tumor regression. Neither patient suffered any serious side effects during this treatment. We conclude that chemoradiation using cisplatin and 5-fluorouracil was effective in these two patients with locally advanced squamous cell carcinoma of the skin. Several randomized studies have shown concurrent chemoradiation to be superior to radiation alone. This regimen is an option in managing patients who have unresectable primary tumors or who require preservation of local function.

Collagen-poly glycolic acid hybrid matrix with basic fibroblast growth factor accelerated angiogenesis and granulation tissue formation in diabetic mice.

Because poor skin wound healing associated with diabetes is thought to be partly a result from impaired angiogenesis, treatments that improve angiogenesis could have important clinical applications. We herein report the effects of novel developed material, collagen-poly glycolic acid fiber hybrid matrix, being used together with basic fibroblast growth factor to promote wound healing of full-thickness skin defects on the back of type 2 diabetic Lepr(db) mice. Our data indicates that this therapeutic approach markedly promotes angiogenesis and granulation tissue formation in comparison with other conditions 14 days after wounding.

Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.

Aberrant methylation of promoter CpG islands (CGI) is involved in silencing of tumor suppressor genes and is also a potential cancer biomarker. Here, to identify CGIs aberrantly methylated in human melanomas, we did a genome-wide search using methylation-sensitive representational difference analysis. CGIs in putative promoter regions of 34 genes (ABHD9, BARHL1, CLIC5, CNNM1, COL2A1, CPT1C, DDIT4L, DERL3, DHRS3, DPYS, EFEMP2, FAM62C, FAM78A, FLJ33790, GBX2, GPR10, GPRASP1, HOXA9, HOXD11, HOXD12, HOXD13, p14ARF, PAX6, PRDX2, PTPRG, RASD1, RAX, REC8L1, SLC27A3, TGFB2, TLX2, TMEM22, TMEM30B, and UNC5C) were found to be methylated in at least 1 of 13 melanoma cell lines but not in two cultured normal melanocytes. Among these genes, Peroxiredoxin 2 (PRDX2) was expressed in normal melanocytes, and its expression was lost in melanomas with methylation. The loss of expression was restored by treatment of melanomas with a demethylating agent 5-aza-2'-deoxycytidine. In surgical melanoma specimens, methylation of PRDX2 was detected in 3 of 36 (8%). Furthermore, immunohistochemical analysis of PRDX2 showed that disappearance of immunoreactivity tends to associate with its methylation. PRDX2 was recently reported to be a negative regulator of platelet-derived growth factor signaling, and its silencing was suggested to be involved in melanomas. On the other hand, 12 CGIs were methylated in >or=9 of the 13 melanoma cell lines and are considered as candidate melanoma biomarkers.

Silencing of the thrombomodulin gene in human malignant melanoma.

The loss of thrombomodulin (TM) expression is associated with tumour growth, infiltration and lymph node metastasis in human tumours. In melanoma cell lines, TM is reported to mediate cell adhesion, and its introduction into TM-negative melanoma cell lines suppresses their growth. In this study, we analysed TM expression in surgical melanoma specimens and the role of its promoter methylation in the loss of its expression. In 15 (75%) of the 20 specimens (five from a primary site and 15 from metastatic sites), melanoma cells lacked TM immunoreactivity. Methylation of the TM promoter region was detected in 10 (67%) of the 15 TM-negative specimens by methylation-specific polymerase chain reaction, whereas methylation was detected in two (40%) of the five TM-positive specimens. In cell lines, complete methylation of the TM promoter CpG island was detected in six (46%) of 13 melanoma cell lines, whereas no methylation was detected in two cultured normal melanocytes. There was a good correlation between the methylated status of the CpG island and the loss of TM messenger RNA (mRNA) expression. Treatment of melanoma cell lines with a demethylating agent, 5-aza-2'-deoxycytidine, induced demethylation of the promoter CpG island and the restoration of mRNA and protein expression. These findings suggest that most human melanomas lack TM expression, and that methylation of the promoter CpG island is one of the mechanisms responsible.

Promoter methylation profiling of 30 genes in human malignant melanoma.

Aberrant methylation and demethylation of promoter CpG islands lead to silencing of tumor-suppressor genes and abnormal expression of normally methylated genes, respectively. Here, we analyzed human melanomas for their methylation and demethylation profiles. Methylation status of core regions in promoter CpG islands was examined for 20 (candidate) tumor-suppressor genes, 4 genes that are not considered as tumor-suppressors, but are frequently silenced in human cancers, and 6 normally methylated melanoma antigen genes (MAGEs). Analysis of 13 melanoma cell lines and 2 cultured normal human epidermal melanocytes (HEMs) showed that 9 tumor-suppressor genes and all 4 non-tumor-suppressor genes were methylated in at least 1 cell line, but never in HEMs, and that all 6 MAGE genes were demethylated in 3 to 13 cell lines. Interestingly, we detected no methylation of MGMT, PTEN, MTAP and p27, which were previously reported as silenced in melanomas. Furthermore, 3 genes that were frequently methylated in the cell lines and 6 MAGE genes were analyzed in 25 surgical melanoma samples. RARB, RASSF1A and 3-OST-2 were methylated in 5 (20%), 9 (36%) and 14 (56%) samples, respectively. MAGE-A1, A2, A3, B2, C1 and C2 were demethylated in 9 (36%), 22 (88%), 20 (80%), 7 (28%), 21 (84%) and 16 (64%) samples, respectively. At least 1 gene was methylated in 18 (72%) samples and at least 1 was demethylated in 24 (96%) samples. No correlation between frequent methylation and frequent demethylation was observed. These profiles showed that both aberrant methylation and demethylation occur widely in human melanomas.

Distal phalangeal metastasis of extramammary Paget's disease.

A rare case of phalangeal metastasis of extramammary Paget's disease in a 68-year-old man is described. The patient developed an erythematous, slightly elevated area in the pubic region. A biopsy specimen demonstrated numerous, large, rounded cells with ample pale-staining cytoplasm proliferating in the epidermis. With a diagnosis of extramammary Paget's disease, he underwent wide local excision and inguinal node dissection. Eleven months postoperatively, the patient developed a tender, red, swollen right ring finger. Bone X-ray showed that the distal phalanx of the ring finger had completely dissolved. Histopathological examination demonstrated proliferation of tumor cells in the adipose tissue. They had poorer and darker cytoplasm than the Paget's cells in the epidermis of the pubic region. Immunohistochemically, these cells showed the same staining pattern as did the Paget's cells at the primary site. Accordingly, the patient was diagnosed with distal phalangeal metastasis of extramammary Paget's disease. Two weeks after the appearance of the distal phalangeal metastasis, the patient died of cancerous pleurisy. It has been reported that patients with phalangeal metastasis have a very poor prognosis.

Drug eruption due to peplomycin: an unusual form of Stevens-Johnson syndrome with pustules.

A rare case of Stevens-Johnson syndrome (SJS) due to peplomycin in a 48-year-old man is described. The patient had squamous cell carcinoma on the scalp and underwent preoperative neoadjuvant chemotherapy with peplomycin. On the fifth day of the chemotherapy, he developed a fever and multiple dusky violaceous erythematous areas and pustules on his trunk, thighs, and palms. Erosive erythema and erosions also developed on his soles, scrotum, and oral mucosa. A biopsy specimen taken from the eruption on the thigh revealed marked liquefaction degeneration of the basal layer of the epidermis. Laboratory examinations demonstrated aggravation of liver function. Additionally, the patient developed conjunctivitis and corneal erosions. Although he had some subcorneal pustules, we diagnosed the case as an unusual form of SJS because of severe mucous membrane involvement. Oral prednisolone was administered, and the symptoms subsided. Then the patient underwent wide local excision. One month after surgery, we performed patch tests and a lymphocyte stimulation test with negative results. Then we re-administered peplomycin starting with 1/20 of a daily dose and gradually increasing the dose each day. After administration of the regular daily dose, the patient had a relapse of fever, eruptions, stomatitis, corneal erosions, and liver dysfunction. Therefore, a definite diagnosis of drug eruption due to peplomycin was made.

Mucinous nodules on the skin overlying a rheumatoid arthritic joint.

A rare case of mucinous nodules on the skin overlying rheumatoid synovitis in a 79-year-old man is described. The patient had a five year history of RA. The patient had complained of arthralgia in the left elbow joint, and X-ray demonstrated narrowing of thejoint space along with bone destruction. He underwent an intraarticular injection of dexamethazone and lidocaine. Three weeks later, he noticed two dome-shaped nodules about 5 mm in size developing on the elbow. Histopathological examination demonstrated poorly defined mucinous nodules in the upper dermis. The mucinous material positively stained with alcian blue and colloid iron, and was metachromatic with toluidine blue. These positive stainings disappeared after hyaluronidase digestion. Five to six weeks after being resected, both nodules recurred. Lesional injections of triamcinolone were effective. The intraarticular injections preceding the appearance of the nodules might have created channels from the joint space to the skin. Leakage of activated synovial cells, which produced hyaluronic acid, through the channels might have caused the mucinous stroma of the nodules.