We report the efficacy of combination chemotherapy of low-dose cisplatin and fluorouracil (low-dose CF: cisplatin: 5-10mg/body, day1-5 (or 1-7), fluorouracil: 800-1000mg/body, dayl-5 or 1-7) for extramammary Paget's disease. Low-dose CF was given to seven patients with metastatic lesions. There were 5 males and 2 females with an age range of 54-91; the median was 74 years. Toxicities including renal impairment and neutropenia were mild and reversible. Partial response was seen in 3 cases (duration: 4, 5, 6 months) . Bone pain by metastasis and edema of the skin were also improved in some patients. We concluded that this protocol may be considered in the patients with advanced extramammary Paget's disease. We also review recent evaluation of therapeutic regimens for extramammary Paget's disease and sweat gland carcinoma. [Skin Cancer (Japan) 2003; 18: 93-98]

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The sunlight can induce a variety of acute and chronic skin reactions, including sunburn, suntanning, immunosuppression, photoaging, pre-malignant conditions, and cancer development. These changes occur as a sequence of events, but not independently. Any photobiologic reaction must be preceded by a photochemical reaction, which initiates after a certain chromophore absorbs light energy. It is well known that nuclear DNA is an important chromophore for ultraviolet carcinogenesis, and that UVB radiation induces DNA damage such as pyrimidine dimer formation. Recently we have demonstrated, using model mice of xeroderma pigmentosum, that DNA damage is an initial event to develop sunburn, immunosuppression, photoaging, and then to malignant changes. It is important to protect acute sunburn reaction for the inhibition of skin cancers. [Skin Cancer (Japan) 2003; 18: 101-105]

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Actinic keratosis (AK) is known as a premalignant skin cancer, which is caused by an excessive exposure to the sun. The clinical feature is not a single one, but definitely characteristic of keratinization with somewhat color change.There are five major appearances, namely erythematous, pigmented, keratopapular, verrucous and cutaneous horn. The final histopathological diagnosis of AKs are grouped as three types: hypertrophic, atrophic and bowenoid. Acantholytic feature is often encountered, and that is a significant sign of a tendency toward a development of invasive carcinoma (squamous cell carcinoma, SCC) . There are also several special histologic types of AKs. Treatment for the care of AKs has been done in different ways, and as most of them are destructive, so no excised specimens can be obtained. I recommend the best way against AKs is a non-destructive surgical maneuver, which makes the specimen histopathological discussion. Shave excision is a satisfactory way, because it is simple without any special instruments and a possible biopsy. AK is a fearless tumor of carcinoma in situ, but an exact precursor of SCC. [Skin Cancer (Japan) 2003; 18: 106-114]

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As skin cancers occur on sun-exposed skin, lip cancers develop on sun-damaged the lower lip, namely on chronic actinic cheilitis. The prognosis of lip cancer is worse than skin cancer, and more sophisticated ways of reconstruction may be required. Diagnosis and treatment of chronic actinic cheilitis is needed before it may progress into invasive squamous cell carcinoma.
On the basis of 24 cases we treated, clinical features, histopathology, and mode of therapy of treating chronic actinic cheilitis were discussed. When examining the lip, care should be made to check erosion, crusts, loss of plasticity, indistinct vermilion border and focal areas of whitish thickening. [Skin Cancer (Japan) 2003; 18: 118-123]

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A lentigo maligna can be defined as an early stage of lentigo maligna melanoma or a lentigo maligna melanoma in situ. It doesn't occur frequently in comparison with the other subtypes of malignant melanomas. Dermoscopy is very useful in early and correct diagnosis of malignant melanoma, allowing us to evaluate the structure of the surface profiles of pigmented skin lesions in detail. As for treatment, early diagnosis is the best treatment of malignant melanoma because an advanced malignant melanoma is usually incurable. [Skin Cancer (Japan) 2003; 18: 126-130]

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Porokeratosis is a keratotic dermatosis which shows keratotic plaques or papular lesions, those are histologically characterized by cornoid lamella formation. It may how autosomal dominant inheritance. Disseminated superficial actinic porokeratosis (DSAP) is a type of porokeratosis which is provoked by chronic sun light exposure. Porokeratosis is a cancer prone disease which causes mainly squamous cell carcinoma and less commonly basal cell carcinoma or Bowen's disease. It has been shown that DSAP developed cutaneous carcinomas in 3.3%; on the other hand, disseminated superficial porokeratosis in 25.0%, localized type in 22.8%, and linear type in 15.9%.
When the lesions of porokeratosis show inflammatory changes, rapid growth or ulcer formation, histopathological examinations should be done to detect early malignant changes. Recently a disease-associated gene was detected to localize on 12q23. 2-24.1; however, precise functions of the gene are not clear. [Skin Cancer (Japan) 2003; 18: 132-135]

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Keratinocytes in the epidermis are exposed to sun light, inducing DNA damage such as cyclobutane pyrimidine dimmers and (6-4)photoproducts. In patients with xeroderma pigmentosum, the nucleotide excision repair, which plays a role in DV induced DNA damage, is disrupted. Thus, we speculate the mechanism of UV carcinogenesis observing the skin cancer in XP patients and non-XP patients.
Gene alterations of RAS and p53 mutations in skin cancers from XP patients are summarized from our data and others. We concluded that the sun exposure causes the mutations in the oncogene and tumor suppressor genes, and another important aspect is where these mutations occur. In case sites of RAS mutations are not colon 12, 13, 61, which causes the activation of oncogene, the transforming activity is very low, though the mutations are detected elsewhere.
Gene alterations detected are predominantly transition type at the dipyrimidine sites both in melanoma and non-melanoma skin cancers observed in XP patients. Gene alterations of non-melanoma skin cancer in sun exposed areas in non-XP patients are also predominated by the transition type mutations at the dipyrimidine sites. [Skin Cancer (Japan) 2003; 18: 137-146]

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Photochemotherapy utilizing 8-methoxypsoralen and ultraviolet A (PUVA) is a highly effective and widely used treatment for psoriasis and other dermatoses. Several studies in the United States and Europe have demonstrated that long-term oral PUVA therapy is associated with an increased occurrence of skin cancer.
Although the carcinogenic potency of PUVA in Japanese patients may be lower than that in Western populations, skin cancer can develop associated with carcinogenic risk factors. The carcinogenecity of concomitant use of oral cyclosporin A and photochemotherapy is the focus of interest.
In order to find out PUVA-induced malignant and pre-malignant skin conditions, an adequate knowledge of such lesions and risk factors is needed. PUVA lentigines and PUVA keratoses are observed in long-term PUVA therapy, but the carcino-genic potential of these lesions is still unclear. [Skin Cancer (Japan) 2003; 18: 148-155]

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A series of our studies demonstrated that wrinkling on the human face is initiated at the eye corner which is the most frequently sun-exposed area. The depth of the wrinkling was found to be paralleled by the diminished elastic property in the same area, indicating that a significant decrease in the skin elasticity is mainly responsible for the formation of wrinkling. In our studies using rat hind limb skins for elucidating the causative factors of the reduced elasticity, we found that wrinkle formation in the skin following long-term UVB irradiation was accompanied by decreases in skin elasticity and the concomitant curling of elastic fibers in the dermis which suggested that the tortuosity of dermal elastic fibers is an important determinant in reducing the skin elasticity. Since the damage in three dimensional elastic fiber structures seems to be attributable to the partial digestion by elastases, the degradative enzymes for elastic fibers, whose activities in the dermis were enhanced by repeated UVB irradiations, we determined whether the inhibition of elastase activity in vivo would prevent the damage of dermal elastic fibers and might eradicate wrinkle formation associated with the loss of skin elasticity. Because the major elastase in the skin under non-inflammatory onditions is skin fibroblast elastase, we used a specific inhibitor of that enzyme to assess its biological role in wrinkle formation. The hind limb skins of Sprague-Dawley rats or hairless mice were irradiated with UVB at a suberythemal dose 3 times a week for 6 weeks. During that period, 0.1-10.0 mM N-phenetylphosphonyl-leucyl-tryptophane (NPLT), an inhibitor of skin fibroblast elastase, was applied topically 5 times a week. NPLT application at concentrations of 0.1-1.0 mM eradicated wrinkle formation in a dose-dependent manner, with a peak for inhibition at 1.0mM. This inhibition was accompanied by a continued low tortuosity of dermal elastic fibers and a maintenance of skin elasticity. These findings suggest that skin fibroblast elastase plays an essential role in the degeneration and /or tortuosity of elastic fibers induced by cumulative UVB irradiation and that its inhibition would provide a desirable model for preventing sun-induced wrinkling. [Skin Cancer (Japan) 2003; 18: 157-164]

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We experienced a case of apocrine adenocarcinoma of the left axilla. The patient was an 83-year-old man, who had a reddish indurated plaque, 26×26×6mm in size and partly ulcerated, on his left axilla. Biopsy of the lesion showed the features of adenocarcinoma. Because no other neoplasm was found in other organs of the body, we considered the adenocarcinoma as a primary lesion. The patient underwent local resection of the lesion along with lymphnode biopsy under local anesthesia, as he had suffered from cerebral infarction one month before the surgery. Histopathologic examination of the excised lesion revealed features of moderately differentiated adenocarcinoma showing decapitation secretions in glandular structures. The stroma showed marked fibrosis. The diagnosis of apocrine adenocarcinoma was established. The biopsied lymph node revealed metastasis to the node. After the surgery, adjuvant radiotherapy was given to the left axilla. The patient is currently well 24 months after the radiotherapy. [Skin Cancer (Japan) 2003; 18: 165-168]

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We report a case of a 38-year-old female patient with metastatic carcinoma of unknown origin. She had a one-year history of subcutaneous tumor in the left axillae, and visited Kitakyushu Municipal Medical Center Hospital. She underwent a resection of the tumor. Histopathalogically, a section showed an infiltration of round to polygonal tumor cells with eosinophilic granules in the abundant cytoplasm. The tumor cells did not demonstrate nests or glandular structure. Immunohistochemically, the tumor cells were positive for EMA, CAM5.2, S-100 protein, GCDFP-15, and negative for CEA and ER. We could not detect any primary tumors, and have therefore diagnosed this tumor as metatstatic carcinoma of unknown origin. [Skin Cancer (Japan) 2003; 18: 169-173]

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Verrucous carcinoma (VC) is a clinicopathologic variant of well-differentiated squamous cell carcinoma with an indolent clinical course. We presented a 76-year old patient with VC that developed a rapid local recurrence and an osteodestructive change. The patient had a cauliflower-like, large tumour on the sacral region. Histologically, hyperkeratotic and papillomatous proliferation of tumour cells with little nuclear atypia was observed. A wide excision was performed, but local recurrence with osteolysis of the 5th sacrum and coccyx occurred two months later. The patient received an operation to remove the tumour including the bone and adjuvant chemotherapy (C'A'; carboplatin, doxorubicin). Recurrence has not been observed for 25 months. Histological examination of the recurrent tumour showed minimal invasion of the tumour cells into the bone, whereas the invasions of osteocrusts and the formation of lymphoid follicles were marked. This potent immune reaction might cause osteolysis and also suppress the ability of the tumour cells to metastasize. In addition, immunohistochemical examination revealed positive proliferating cell nuclear antigen expression at the basement of the tumour nests and negative p53 protein expression. Several apoptotic tumour cells were detected by the TUNEL method. These results seem to represent a nature of VC that aggressively invades surrounding tissues but rarely metastasizes. [Skin Cancer (Japan) 2003; 18: 174-178]

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We reported a 59-year-old male with recurrent Paget's disease in the anal region associated with metastasis to the groin and iliac lymphnodes. After surgical excision, he had received radiation therapy and low dose FP chemotherapy. After he had received three courses of low dose FP chemotherapy, CT examination revealed para-aortic lymph node swelling. We thought they possibly were metastasized lymph nodes.
Immunohistological study showed androgen receptors and erbB2 oncogene on metastatic tumor cells of the iliac lymphnodes. Anti-androgen therapy is effective against extramammary Paget's disease. We conducted anti-androgen therapy on this case. It was reported that erbB2 oncogene was related with a bad prognosis. So at first we speculated a poor prognosis of this case. For the following 1 year after this therapy, no recurrence of tumor or visceral metastasis was found. We thought the tumor was in a dormant state, though the value of serum CEA gradually increased.
This case had p53 variated oncogene, although this oncogene was unusually manifested on cells of extramammary Paget's disease. We initially considered this case as Extramammary Paget's disease. More immunohistochemical examination revealed cytokeratin 7 and 20 antigen on the metastatic tumor's cells. This finding suggested that it was the pagetoid phenomenon arising from the adenocarcinoma in the anal region.
Further observation and accumulation of the cases treated with anti-androgen therapy were warranted. [Skin Cancer (Japan) 2003; 18: 179-183]

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We report a case of Merkel cell carcinoma with proven brain metastasis. The patient was a 73-year-old man who presented with a one-month history of a rapidly enlarging scalp mass. The mass was widely resected in December 1998, and histological examination revealed Merkel cell carcinoma. In July 1999, a computed tornography (CT) scan of the head demonstrated brain metastasis. Radiotherapy to the brain was instituted. In addition, a CT scan of the abdomen showed lymphnode matastasis in July 2000. He was started on chemotherapy, which consisted of a regimen of cyclophosphamide, adriamycin, and vincristine. He responded well to radiation and chemotherapy and is alive and neurologically intact three years after brain metastasis. To our knowledge, all previous patients except one with metastatic Merkel cell carcinoma to the brain died within 1 year of the metastasis. We review the treatment options in patients with brain metastasis. [Skin Cancer (Japan) 2003; 18: 184-188]

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We reported a case of Muir-Torre Syndrome. A 67-year-old man revisited our clinic complaining of two small nodules on his nose. Histological examination revealed sebaceomas. He had two keratoacanthomas at his first visit 18 years ago. Altogether, he had 4 keratoacanthomas, 2 squamous cell carcinomas, 4 sebaceous tumors, 2 benign skin tumors and two colorectal carcinomas during his entire course. The histology of the squamous cell carcinomas was deep invasive and prominent keratosis and its prognosis was good. This case suggested that multiple keratoacanthomas was the possibility of the initial sign of Muir-Torre syndrome. We discussed on the prognosis of squamous cell carcinoma of MuirTorre Syndrome. [Skin Cancer (Japan) 2003; 18: 189-192]

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A 75-year-old female was referred to our clinic in 1996, because of erythematous pruritic papules and plaques distributed on her feet. The diagnosis of chronic type adult T-cell leukemia (ATL) was made by serological and histological examinations. She was treated with oral glucocorticoids and an anticancer agent, etoposide. In July 2001, her skin lesions and physical signs became worse. Serological examination revealed an elevation of serum calcium and alkaline phosphatase levels. Since hypercalcemia is one of the severe complications of acute crisis in ATL, combination chemotherapy with VCAP-AMP-VECP was employed. Although her physical signs improved after starting this chemotherapy began, it was difficult to control her skin eruptions. In October, sobuzoxane was finally prescribed for her intractable eruptions. Two week after starting sobuzoxane treatment, the skin eruptions disappeared dramatically. Complete remission of ATL is maintained with sobuzoxane alone. Sobuzoxane appears to be one of the most effective agents especially for ATL skin lesions. [Skin Cancer (Japan) 2003; 18: 193-197]

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A 75-year-old man underwent surgical resection of apocrine adenocarcinoma of the right inguinal area in February, 2000. Five months after the operation, he developed fever of unknown origin and was admitted to the hospital. The administration of corticoids ameliorated the fever temporally but he died due to fungal infection in April, 2001. Autopsy revealed non-Hodgkin's lymphoma of the mesentery and no recurrence of apocrine adenocarcinoma. The literature concerning the double cancer were also presented. [Skin Cancer (Japan) 2003; 18: 198-202]

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We report two cases of stage IV malignant melanoma with long survival. The first case was a 43-year-old man with a black tumor on his back. In September, 1992 he received wide resection and 10 courses of DAV-feron chemotherapy after the operation. In October, 1997 metastases of the right axillary and right supraclavicular lymph nodes and skin metastasis on the nape were found. He received resection of these lesions followed by 2 courses of DAC-Tam chemotherapy. He has been tumor-free for more than 57 months thereafter.
The second case was a 42-year-old man with a black tumor on his left thumb. In October, 1994 amputation of the left thumb and right axillary lymph node dissection were performed. He received 14 courses of DAV-feron chemotherapy after the operation. In April, 2000 left subclavicular lymph node metastasis was found. He received resection of metastasis and 2 courses of DAC-Tam chemotherapy. He has been tumor-free for more than 23 months thereafter. These two cases of stage IV malignant melanoma were successfully threated by DAC-Tam chemotherapy combined with surgical resection of metastasic lesions. [Skin Cancer (Japan) 2003; 18: 203-207]

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An 83-year-old man noted rapidly progressing nodes with recurrent bleeding on the scalp for 2 months. He had no history of head injury, although he had renal failure, hypertension and gallstones. The patient first visited the department of surgery in a neighboring hospital, and a biopsy of the node disclosed the findings of angiosarcoma. The patient was referred to our department for the treatment with IL-2 and electron beam. Examination on admission revealed palm-sized, welldemarcated darkly-reddish plaque on the left parietal and occipital scalp. Several thumb-head sized dome-shaped nodes were coalesced on the center of the plaque. Local injection of IL-2 was started and then electron beam therapy (totally 50 Gy) was added. Pulmonary metastases were found on 75th day of hospitalization, and the patient died of respiratory failure one month later. Post-mortem examination revealed multiple metastases of the both lungs, the liver, the diaphragm and the cervical lymph nodes. Tumor cells were also found in the pleural fluid.
We clinically and pathologically compared the same site on admission and on post-mortem examination. Plaque lesions on admission underwent nodular lesions on autopsy. Histologically, the density of tumor cells was increased whereas the formation of vascular lumina was obscure in the specimens of the autopsy. The densities of p53 and MIB-1 positive cells were greater in the specimens of the autopsy than those on admission. [Skin Cancer (Japan) 2003; 18: 208-213]

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In 2002, the International Union Against Cancer (UICC) proposed a new TNM classification for malignant melanoma, adopting the revised staging systemrecently proposed by the American Joint Committee on Cancer (AJCC) . In this classification, tumor thickness is used in the evaluation of primary lesion and Clark's level is applied only to T1 sub-classification. In addition, ulcers in primary lesions, number of regional lymph node metastases, differentiation of macroscopic metastasis from microscopic metastasis to the lymph node, and serum LDH are taken into account in the staging and sub-staging. To evaluate the significance of this new classification for Japanese patients, 342 melanoma patients (214 from the National Cancer Center Hospital and 128 from Shinshu University Hospital) were analyzed by the previous UICC-TNM classification (1997) and this new UICC-TNM classificationo 5-year survival rates by the previous UICC classification were 97.5% at stagel, 86.2% at stage2, 53.2% at stage3, and 13.4% at stage4, and those by the new UICC classification were 95.3% at stagel, 72.8% at stage2, 46.0% at stage3, and 13.4% at stage4. As a result, the 5-year survival rate at each stage of the new UICC classification was a little lower than that of the previous UICC-TNM classification. The new UICC-TNM classification seems to be a better indicator of prognosis for each stage, if the sub-stage categories are taken into account. Further study of a larger nurnber of Japanese patients is required to obtain decisive results. [Skin Cancer (Japan) 2003; 18: 214-220]

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