Cell cycle checkpoints are a regulatory mechanism that prevents transition of cells into subsequent phases until all processes in the previous phase are completed, ensuring genomic integrity. Arrest in G1 is considered to prevent aberrant replication of damaged DNA and arrest in G2 allows cells to avoid segregation of defective chromosomes. Therefore, defective cell cycle checkpoints lead to gene mutations and chromosome damage which contribute to tumorigenesis. However, recent observations indicate that loss of checkpoint function in cancer cells is associated with their sensitivity to antineoplastic treatments such as chemotherapy and radiation. By treatment with those genotoxic agents, cancer cells having impairment of checkpoint functions initially arrest in the G2 phase of the cell cycle but are unable to maintain cell-cycle arrest. Those cells eventually die as they enter mitosis. This process is referred to as ‘mitotic catastrophe’. In this review, we propose the critical relationship between checkpoint functions and sensitivity of cancer cells to anti-tumor therapies. [Skin Cancer (Japan) 2004; 19: 281-286]

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Recent molecular analyses showed marked differences in the genetic make-up of melanomas that depend on the anatomical location and sun-exposure pattern. In particular, acral melanomas showed characteristic chromosomal aberrations and much lower frequency of BRAF mutation when compared to superficial spreading melanomas that mostly arise in intermittent sun-exposed body areas. These results validate the clinicopathological classification of cutaneous melanoma types originally proposed by Clark et al., and further indicate that potential therapeutic targets might vary among melanoma types. Similar analyses examining common melanocytic nevi and Spitz nevi showed virtually no chromosomal aberrations in these benign melanocytic tumors. This is contrasted by frequent and multiple copy number changes in most melanomas, and strongly suggests potential usefulness of genomic profiling by means of comparative genomic hybridization (CGH) or multiplex ligation- dependent probe amplification (MLPA) as adjunctive diagnostic methods in the future. Finally, RT-PCR assays detecting transcripts of melanocyte differentiation antigens such as tyrosinase and MART-1 were introduced in the diagnosis of sentinel lymph nodes, which may provide relevant information for patients' outcome. [Skin Cancer (Japan) 2004; 19: 287-292]

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We examined cubital and popliteal lymph nodes using the combined system with the lymph scintigraphy and computed tomography. The dynamic scintigraphy was useful when we were concerned about cubital and popliteal lymph nodes. We observed cases which had sentinel lymph nodes on cubital and/or popliteal regions using dynamic scintigraphy. The fusion of static scintigraphy and computed tomography (CT/SPECT: single photon emission computed tomography) was useful in recognizing the anatomical location of sentinel lymph nodes before biopsy. We observed the sentinel lymph node which was the deep cubital lymph node in the forearm region using the CT/SPECT combined system. [Skin Cancer (Japan) 2004; 19: 293-297]

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Hyperthermia is a promising approach for cancer therapy. The inevitable technical problem with hyperthermia is the difficulty in heating only the tumor region and avoiding damage to healthy tissue. Magnetite nanoparticles have been applied in an attempt to overcome these disadvantages. Magnetite nanoparticles generate heat in an alternating magnetic field. We have developed antibody-conjugated magnetoliposomes and magnetite cationic liposomes. We previously reported that our hyperthermia system induces antitumor immunity. In the present study, we show that HSP70 expression following hyperthermia induces antitumor immunity. Based on this mechanism, our hyperthermia system is regarded as an in situ vaccination. The combined therapy of hyperthermia with immunotherapy, such as cytokines (IL-2 or GM-CSF), recombinant HSP70, hsp70 genes, and dendritic cells, resulted in strong antitumor activity in mice. These results suggest that hyperthermia-induced antitumor immunity has important implications in the development of novel therapies, and the combination with immunotherapy is a promising approach. [Skin Cancer (Japan) 2004; 19: 298-305]

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The rationale for immunotherapy of melanoma is based on the knowledge of recent advances in molecular tumor immunology. Based on this information, clinical trials of peptide vaccine therapy and immunogene therapy have been conducted in patients with advanced melanoma.
This review summarizes the clinical trials and discusses their limits and problems. Clinical trials revealed that specific cytotoxic T cells were induced in the patients and toxicity was minimum; however, clinical response was limited. I have attempted to identify possible reasons for the limited clinical efficacy of these vaccines and suggest a way to improve the clinical outcome of peptide-based vaccination and immunogene therapy for melanoma.
Further improvement of immunotherapy is expected for patients with melanoma. [Skin Cancer (Japan) 2004; 19: 306-312]

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EORTC classification is used usually among dermatopathologists, and hematopathologists to adapt a new WHO classification to cutaneous lymphoma. There are some differences between both classifications, especially the concept of follicular and B large cell lymphoma, T/NK cell lymphoma, blastic NK cell lymphoma and ATLL. These problems were discussed from the standpoint of the hematopathologist and modified new WHO classification was proposed for practical use. [Skin Cancer (Japan) 2004; 19: 313-321]

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A 58-year-old female came to our hospital with a tumor on her scalp with 30 years' history. The tumor gradually enlarged and had secreted mucous discharge for several years. Histologically, it showed poroma cells with proliferating small basophilic cells, scattered sweat ducts, and atypical clear cell proliferation. Immunohistologically, endothelial cells of eccrine ducts and atypical cells showed positive stain in PAS, CAM5.2, EMA, and negative in CEA. This suggested a malignant change of eccrine poroma to eccrine porocarcinoma. [Skin Cancer (Japan) 2004; 19: 322-325]

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57 cases of cutaneous malignant melanoma observed at the Department of Dermatology, Tokyo Medical University during the course of 16 years (1986-2002) were statistically analyzed. The gender distribution was 26 males and 31 females. On average, 12% of the head and face, 12% of the trunk, 21% of the arm and 51% of the legs were involved. There were 23 cases (40%) of nodular melanoma, 7 cases (12%) of superficial spreading melanoma, 18 cases (32%) of acral lentiginous melanoma and 5 cases (9%) of lentigo maligna melanoma. 7 cases (12%) were in stage I, 20 cases (35%) in stage II, 8 cases (14%) in stage III and 3 cases (5%) in stage IV. The ten-year survival ratio was examined. [Skin Cancer (Japan) 2004; 19: 326-330]

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To improve the response to chemotherapy for advanced skin cancers and soft tissue sarcomas, effective drugs should be selected for each patient. From 2002, we tried to select the anticancer drugs based on the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) ; it is one of the useful clinical chemosensitivity tests for some malignant tumors. This test has been applied to 7 cases of skin cancer and 2 cases of soft tissue sarcoma. It is inconclusive whether the results of this assay will correlate with the clinical effects of the drugs; however, this test may serve as a guide to select the specific regimens of chemotherapy for skin cancers and soft tissue sarcomas, thus avoiding the side effects of the ineffective anticancer drugs. [Skin Cancer (Japan) 2004; 19: 331-335]

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We reported a case of radiation-induced squamous cell carcinoma on the bilateral middle finger of an 87-year-old physician.
He had exposed his hands to radiation without defense when he took an X-ray photograph. Squamous papules and ulcers occurred on both of his hands 10-years ago. The ulcer on the right middle finger enlarged rapidly after a one-month duration. A biopsy specimen showing squamous cell carcinoma derived from chronic radiation dermatitis, and disarticulation at the PIP joint of the right middle finger was performed. Six month later, hyperkeratotic tumor newly occurred on the opposite middle finger, and were operated on in the same way. The remaining lesions of chronic radiation dermatitis were treated by topical bleomycin hydrochloride. Since medical workers carelessly exposed their skin to radiation several decades ago, attention to late occurrence of radiation-induced skin cancer is needed. [Skin Cancer (Japan) 2004; 19: 336-339]

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A 56-year-old Japanese female came to our hospital because of a rapidly growing tumor with pedunculated appearance. From the histopathological and immunohistochemical findings, we diagnosed the patient's condition as DFSP. A pedunculated appearance is relatively rare for DFSP. There have been only six reports, all of which have been from Japan. The reason for the appearance of this tumor is unknown. However, we speculated that the location of the tumor or a racial difference may affect its pedunculated appearance. [Skin Cancer (Japan) 2004; 19: 340-343]

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The patient was a 56-year-old man with malignant melanoma of his right thumb and multiple liver metastasis. No metastatic lesion was found in other organs. The primary lesion was surgically resected and the liver metastasis was treated with hepatic arterial infusion of CDDP (2 course) . Because no response was observed, dacarbazine and nimustine were added in the third course of hepatic arterial infusion. By the 6th course of the combination chemotherapy, the metastatic lesions were reduced up to 94% in size. During 18 months under the follow-up period, the response was maintained, and he could keep his job and continue with his daily life. This protocol was good for the improvement of the quality of life of the patient with multiple liver metastasis of melanoma. [Skin Cancer (Japan) 2004: 19: 344-348]

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Hyperthermic isolated limb perfusion (HILP) with 450mg of carboplatin (CDBCA) and 9 million units of natural interferon (n-IFN)-β, were administered and left inguinal lymph node dissection was performed on a patient with metastatic malignant melanoma of her right leg.
The patient was a 59-year-old woman, who was referred to our department in June 2000. Examination showed a large macular lentiginous melanoma, on the nail bed of her right 1st toe. The tumor was excised surgically on 12 July. Sentinel node biopsy showed no metastasis. Accordingly, the patient was diagnosed as being at stage II (pT₃, N₀, M₀). Three cycles of systemic chemo-immunotherapy (DAC-Tam plus n-IFN-β) were given until October 2000. Subcutaneous injection of n-IFN-β was performed every two weeks.
The patient maintained complete remission (CR) for about 11 months until June 2001. She noticed tumors in her right inguinal region. Biopsy revealed right lymph node metastasis of neoplastic cells. HILP with CDBCA and n-IFN-β, and left inguinal lymph node dissection was performed on 15 August 2001. There were no major changes in the systemic circulation and no severe toxicity by HILP with CDBCA and n-IFN-β. The patient has since maintained CR for about twenty months from August 2001. [Skin Cancer (Japan) 2004; 19: 349-354]

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We here report a case of an 82-year-old man who had been treated with cyclosporine A for psoriasis, with primary cutaneous anaplastic large cell lymphoma (ALCL) showing high levels of sIL-2R. He noticed rapidly developing subcutaneous tumors on the inguinal lesion and the buttocks during 1 month. Serum levels of sIL-2R remarkably increased although no metastatic lesions were detected. Histological examination revealed a dermal tumor composed mainly of large atypical lymphocytes. Immunohistochemical staining showed that tumor cells were positive with CD30 and EMA, and were negative with CD15, anaplastic lymphoma kinase and EBV-associated antibodies. He was treated with both roentgen ray therapy and a local injection of IFN-γ. Respiratory failure due to pleural metastasis was the leading cause of death 8 months after the initial onset. Levels of sIL-2R may be a prognostic marker of primary cutaneous ALCL because serum levels of sIL-2R correlated with the disease activity in this case. [Skin Cancer (Japan) 2004; 19: 355-358]

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To identify the risk factors for lymph node metastasis of squamous cell carcinoma of the skin (SCC), retrospective analysis of 118 SCC cases was performed. Variables included patient age, sex, location, lesion size, tumor thickness, level of invasion, and histological growth pattern. A multiple logistic regression model was applied to identify important risk factors for lymph node metastasis. The significantly important risk factors were location and growth pattern. In the former, SCC on the hands and feet had higher risk for metastasis than head and neck with an odds ratio of 8.3 (p=0.027) . In the latter, SCC with infiltrative growth pattern (INFγ) had an odds ratio of 5.9 compared with expansive growth pattern (p=0.032) . In SCC, which has the risk factors identified in this study for lymph node metastasis, sentinel node biopsy should be taken into consideration. [Skin Cancer (Japan) 2004; 19: 359-363]

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We report a case of a 65-year-old female with anti-phospholipid syndrome who first visited our clinic on August 2001. She had been suffering from a yellow-white, non-melanotic elevating skin lesion, with ulceration on the right lumbar, since 1990. Ulceration gradually had been epithelialized by ointment. However the tumor lesion had developed into a larger and higher, hen-egg-sized mass, and formed ulceration. The patient subsequently experienced pain. The first diagnosis following a biopsy was kerathoacanthoma. We performed an operation to remove the tumor completely and applied skin grafting under local anesthesia. Histopathological final diagnosis was seborrheic keratosis. We assumed that the reasons for the big growth and ulceration were closely related with administration of oral steroids for anti-phospholipid syndrome. In this report, we described a rare case of big seborrheic keratosis with ulceration on the right lumbar, showing non-melanotic colors. [Skin Cancer (Japan) 2004; 19: 364-366]

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The potential for certain cutaneous B-cell pseudolymphomas (CBPL) to progress to cutaneous B-cell lymphoma (CBCL) has been reported.
We report a case of CBPL. A 44-year-old female presented with a 6-year history of ill-defined redbrown plaque with numerous small nodules on her left cheek. Although the lesion had been treated with surgical extirpation, a number of intralesional steroid injections, topical steroids and oral antibiotics for 6 years at previous hospitals, it had recurred frequently. The biopsy revealed a dense lymphocytic infiltrate admixed with eosinophils and focal reactive lymphoid follicles. Immunophenotypic studies did not show the presence of phenotypic aberrance, coexpression of markers, monotypic immnoglobulin (Ig) light chain and lack of cell surface Ig expression in CD20-positive cells. Furthermore, gene rearrangement of the JH gene was negative via PCR. This case did not fulfill the criteria of CBCL, but the high frequency of local recurrence at short interval should be considered worrisome for potential progression to lymphoma. Local radiation therapy was effective for the treatment of this case. [Skin Cancer (Japan) 2004; 19: 367-371]

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