More than twenty genotypes of human papillomaviruses (HPVs) are associated with mucosal lesions and more than thirty genotypes with cutaneous lesions. We established a method using consensus polymerase chain reaction (PCR) with restriction endonuclease analysis of PCR products, which can detect and distinguish mucosal high risk HPV types 16, 18, 31, 33, 52b and 58 (J. Gen. Virol. 72, 1039, 1991). By using this method, we analyzed 39 cases of cervical carcinomas and 27 cases of cervical intraepithelial neoplasias (CIN). It was found that the HPV16 was most prevalent in malignant (19 cases) and premalignant (19 cases) cervical lesions, but other types including HPV18, 31, 33, 52b and 58 were also detected especially in cervical carcinomas. We also established a highly sensitive method for specific detection of HPV types 16, 18, and 33 (Jpn. J. Cancer Res., 81, 1, 1990) . The method detected HPV16 DNA in only 5 out 92 cases of cytologically or histologically normal cervices (Jpn. J. Cancer Res., 82, 532, 1991) . HPV16 was also predominantly detected in penile (68 out of 111 cases) and tongue (8 out of 24 cases) squamous cell carcinomas.
HPV16 E6E7 region produces at least three different species of E6E7 mRNAs (unspliced E6-E7, spliced E6* I and E6* II) in the HPV16-containing carcinoma cells. We synthesized each of the E6E7 cDNAs and studied on their biological activities. The E6*I cDNA showed highest activities of ras-collaborative transformation of primary rat fibroblasts and induction of cellular DNA synthesis. We analyzed HPV16 E6E7 mRNAs in three cervical carcinomas and six CINs which contained HPV16 DNA by PCR with reverse transcription (RT-PCR) . The major transcript from HPV16 E6E7 region was E6* I except for one CIN tissue where only the full-length E6-E7 mRNA was detected.
Different from E7 genes of mucosal high-risk HPVs, E7 genes of HPV5 and HPV8, which are associated with epidermodysplasia verruciformis (EV) were inactive for transforming ability in cell lines. We cloned HPV5 and 8 E7s separately into the expression vector pcD2Y or pGEM3Zf and examined their biological and biochemical activities. Although HPV5 and 8 E7s failed to immortalize primary baby rat kidney cells, they collaborated with activated ras gene to transform primary rat embryo fibroblasts (Jpn. J. Cancer Res., 82, 1340, 1991) and baby rat kidney cells. In vitro binding experiment of retinoblastoma tumor suppressor protein (RB) detected the complex formation of HPV5 and 8 E7s with RB but with reduced affinities compared to HPV16 E7.

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The reconstrucion of the surgical defect is essential for the treatment of skin cancer. As for the procedures, there are various techniques such as split thickness skin graft, full thickness skin graft, skin flaps and musculocutanneous flaps. Advantages and disadvantages of each procedures are reviewed briefly. In my opinion, the decision which technique to choose depends on the type of the cancer, the depth of tumor invasion, the location of the tumor, the age and the complication of the patient, the expected prognosis, the curability, and the surgeons' skill. Some of the clinical cases are presented, and the process of decision making is discussed for each cases. Presented cases are basal cell epithelioma on the nose, malignat melanoma of the sole, squamous cell carcinoma of the foot, basal cell epithelioma invading the orbita, ulcerating basal cell epithelioma on the upper lip, chondrosarcoma on the nose, genital Paget's disease and invasive aquamous cell carcinoma of the lower abdomen.

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Skin cancer is the most common malignant neoplasm in the United States and Europe. However, these tumors are less common in Japan. Radiotherapy is an excellent modality for the treatment of selected basal cell and squamous cell carcinomas. Many patients in a foreign country prefer radiotherapy because of no pain with treatment, no hospitalization and good cosmetic result. On the other hand, skin cancer arising from scars is contraindicated for radiotherapy. A survey of the literature showed that the 5-year recurrence rates were 3 to 10% dependent on the tumor size. In addition, recurrenes following radiotherapy are satisfactorily managed by radical surgical treatment. Total skin electron irradiation for both mycosis fungoides and subcutaneous T cell lymphoma, at least in early stages, leads to a complete remission of long duration. However, the techniques of total skin electron irradiation are very difficult because of difficulty of homogeneous dose distribution for a large field. Malignant melanoma is one of the radioresistant tumors. The in vitro survival curve of malignant melanoma cell is characterized by a wide shoulder, indicating a large ability to repair sublethal radiation damage. The literatures showed that fraction size rather than total dose was of importance for the radiation response of malignant melanoma. Some authors have recently reported the excellent result of treatment for patients with advanced or recurrent carcinoma using ¹⁹²Ir wire. We described the role of radiotherapy for malignant neoplasm of skin in detail.

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The clinical effects of hyperthermia with combinations of other therapeutic modalities on cutaneous melanomas, sarcomas and lymphomas were reported. The local hyperthermia was found to cause rapid involution of the inoperable malignant lesions but the recurrence was also rapid if the therapy was ceased. Therefore, it was concluded that hyperthermia alone is not able to cure the malignant lesions but needs other modalities to be combined. Hyperthermia has been utilized to augment the curative effects of chemo-and radiation therapies so far, but in the dematological fields, it was suggested from our basic and clinical investigations that hyperthermia should be effective if it is combined with BRM (Biological Response Modifiers) therapy using interferons or interleukins.

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Biological response modifier (BRM) is a generic term of the biological products that exerts their cytotxic effects on cancer cells. The progress in culture techniques and molecular biology have made it possible to use clinically a variety of natural and recombinant BRMs for the treatment of malignant tumors since the early 1980's. The large numbers of clinical trials have been conducted in phase I and phase II trials for various kinds of malignant tumors, including malignant melanoma and mycosis fungoides (MF) . In these recent trials in Japan, the marked anti-tumor efficacy of interferon (IFNs) and tumor necrosis factor (TNF) has been experienced.
It is rather difficult to summarize various clinical trials. In this manuscript, a couple of our cases treated successfully with TNF for Merkel cell carcinoma and with IFN-γ for MF would be presented, in addition to the significant anti-tumor effects of BRMs recently reported in the manuscripts. Our data from clinical researches conducted with IFN-β is also shown. Finally, the clinical significance of BRM will be discussed briefly as the future cancer therapy.

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We reported on one case of Bowen's disease believed to have arisen from porokeratosis. It is known that malignant tumors develop from the porokeratosis eruption, so the course of the disease has to be monitored over a period of time. Further, acutive histological examination should be carried out with this disease when the following are recognized in the area of the eruption, erythema, roughening of the surface, warts, erosion, ulcers, or the adherence of a crust.

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We reported three patients with primary malignant melanomas on the scalp and eyebrow area which developed regional metastases. Histologic examination of three primary lesions revealed lentigo maligna melanoma (LMM) . In the past, we treated 13 patients with LMM on the cheek and lip by local wide excision without lymphadenectomy. However, no patient had local recurrences or metastases. Taken together, these results suggest that the rate of metastasis of LMM of the terminal hair area is higher than that of the cheek and lip.
Regional metastatic lesions in one patient with LMM of the scalp were treated by local injection of interferon beta (Feron), resulted complete response. She is alive for 20 months after the operation of primary lesion.

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The patient was a 39-year-old male. Family history revealed that his sister and her second son were diagnosed as having jaw cysts. The patient himself underwent cystectomy twice, in December of 1971 and in February of 1986, under the diagnosis of the bilateral jaw cysts of the mandible and maxilla. In May of 1991, a fistula communicating between the left maxillary sinus and oral cavity emerged and within several months the patient lost 10 kg. of body weight. In 1988, he noticed a black spot at the right root of the nose, which enlarged gradually with manifesting bleeding and crust formation. He was referred to us on August 19. An 8×6mm-sized, black nodule was recognized and up to 3mm. diameter similar nodules were also scattered on the other parts of the face. Almost all nodules consisted of multiple, miliary-sized fused nodules. Up to 2mm diameter infundibuliform pits were seen on the palm and planter areas. Under the diagnosis of BCNS, brain X-ray CT was performed. In addition to the calcification of falx cerebri and tentorium cerebelli, a water-dense tumor with bone destruction was disclosed at the left maxillary sinus. The histopathology of the biopsy specimen from the left maxillary sinus was compatible with well-differenti-ated squamous cell carcinoma. On September 28, the partial resection of the light maxillary sinus and resection of the facial neoplasms was performed simultaneously. Six out of nine facial nodules were histologically diagnosed as basal cell epithelioma (solid type) .
This case is considered as a typical case of BCNS. It is important to recognize that squamous cell carcinoma can arise from the jaw cysts of BCNS, because it might affect the prognosis of the patients. Only three similar cases have been reported in the world.

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Clinical and histopathological examinations were carried out on 133 basal cell epitheliomas (BCEs) from 23 patients with xeroderma pigmentosum (XP) . A total of 69 BCEs occurred in 10 patients with XP-A (age at first excision: 6-22y, average: 11.5y) ; 34 in 8 XP-variant (22-47y, 30.8y) ; 16 in 1 XP-E; 9 in 2 XP-F; 4 in 1 XP-D; and 1 in 1 XP-C. Of the 133 BCEs, 131 (99%) developed on sun-exposed areas. Clinically, most cases presented as a small, black, glossy nodule. Histopathologically, the solid type of BCE was most common (94%) . The age of onset of skin cancer is characteristically earlier in patients with XP. Although the mean age at first excision was 24 years among the 23 XP patients in this study, it differed considerably from one XP group to another. Ninety seven percent of the BCEs developed on the face in the patients with XP. This high incidence in comparison with 70% in patients without XP suggests that sunlight plays a significant role in the development of skin cancers in XP.

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Malignant skin tumors are generally found on the face and should be treated with surgical excision routinely. The importance of surgical excision is beyond question and immediate reconstruction of facial full-thickness tissue defects is a commonly accepted surgical principle used to preserve function and minimize cosmetic deformity.
In facial reconstruction, the excellent functional and esthetic results according to regional esthetic unit are familiar to most plastic surgeons. Recently, subunit principle has generally been employed and now further advanced miniunit principle has come to be advocated and applied.
Tequniques and three case reports describe its application to facial full-thickness tissue defects after skin cancer surgery.
Case 1: A 67-year-old man presented with a basal cell carcinoma measuring 32 × 21mm of the right cheek. There were no clinically positive lymphnodes. Excision of the tumor produced a defect of three-fourth of the right suborbital cheek zone. After arranging the defect fit the natural suborbital cheek subunit, recostruction was performed with an anteriorly based cervicofacial flap in exact size of missing subunit and secondary donor site defect was covered with an anteriorly based neck flap. Additional skin graft was performed to the retroauricular region hidden behind the ear.
After operation the patient received chemotherapy with 90mg dose of pepleomycin. No evidence of recurrence has been noted for 2 years postoperatively and the patient now has almost normal symmetric appearance and function with concealed edge scars of the flap.
Case 2: A 71-year-old man presented with a squamous cell carcinoma measuring 22 × 18mm of the right mandible. There were no clinically positive lymphnodes. Excision of the tumor produced a defect of three-fourth of the right buccomandibular cheek zone. After arranging the defect fit the natural buccomandibular cheek subunit, reconstruction was performed with a posteriorly based neck flap in exact size of missing subunit and secondary donor site defect was almost sutured primarily with an additional skin graft using formerly excized normal skin.
After operation the patient received chemotherapy with 60mg dose of pepleomycin. No evidence of recurrence has been noted for 12 months postoperatively and the final result left the patient with adequate facial contour, normal appearing skin cover and concealed grafted skin.
Case 3: A 49-year-old man presented with a dermatofibrosarcoma protuberans measuring 12mm in diameter of the right upper lip.
Excision of the tumor produced a full thickness defect of three-fourth of the lateral subunit of the upper lip. The remaining tissues of the lateral subunit were excised. An exact pattern of the opposite normal lateral subunit is outlined and an Abbe flap was taken from the midline of the lower lip and transferred in two stages. No evidence of recurrence has been noted for 10 months postoperatively.
Like tissue was replaced in kind, border scars are positioned esthetically, and the orbicularis sphincter is reconstituted with an intact symmetrical comissure, muscular modiolus, and upper and lower lip symmetry. In this series of patients, we have presented a method of facial reconstruction emphasizing the judicious choice and modificatin of recipient and donor tissue to provide for the exact replacement of facial full-thickness tissue defects as subunits, thereby reproducing the expected contours and landmarks that create the final excellent esthetic result.

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We report 20 cases of dermatofibrosarcoma protuberans treated with operations. Follow up terms are from 2 years minimum to 15 years maximum and 3.8 years average. In 1 case, local recurrence was experienced. At surgical excision, all the tumors are excised beyond the depth of fascia. Surgical margins are decided according to tumor's original size.

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A strategy in the treatment of melanoma consists of wide excision of the primary tumor and regional lymph node dissection. In this report, we described a case that required in-continuity lymph node dessection. A 57-year old man who had skin lesions of malignant melanoma on the dorsum of his left foot and leg, respectively. It was thought that the primary tumor on the left foot metastasized intransitly to the skin of the leg through the lymph vessels around the great saphenous vein. The skin along the great saphenous vein was removed, added to the conventional surgical treatment. In-continuity lymph node dissection seems to be useful to prevent the intransit metastasis, although such approach isimpractical.

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SCC on a toe web is very rare. A 68-year-old woman had SCC on the rt. III toe web. After excising the lesion, we covered the defect with the first web space flap as an island flap. This flap is based on the superficial first metatarsal artery, an extension of the dorsalis pedis artery and usually used in closing various small defects located on web space of the hand as a free flap.

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Seventy-nine patients with cutaneous malignant melanoma treated at Kanazawa University Hospital between 1975 and 1990 were reviewed to evaluate prognostic factors. Stage at diagnosis, Clark's level, and thickness of the primary lesion were identified as significant prognostic variables. An analysis of the survival of 57 patients with stage II and stage III disease did not reveal a benefit for elective lymph node dissection and postsurgical adjuvant chemotherapy. However, although stasitically not significant, a group of patients receiving presurgical combination chemotherapy with DTIC, ACNU, and vincristine (DAV) tended to have better prognosis than those underwent surgery without chemotherapy. The prognosis of 5 cases who received presurgical fast neutron beam irradiation was also reported.

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Forty five cases of cutaneous malignant melanomas in Department of Dermatology, Niigata University School of Medicine were statistically studied. These cases were 16 males and 29 females. The peak for age distribution was seen between 60 and 69 years old. The average age of the cases at first visit was 57.9 years. Acral lentiginous melanoma accounted for 51.1%, nodular melanoma 15.6%, superficical spreading melanoma 17.8%, lentigo maligna melanoma 4.4% of the total cases. Ten cases (22.2%), 6 cases (13.3%), 23 cases (51.1%) and 6 cases (13.3%) were in stage I, II, III and IV, respectively. The histological micrometastasis of lesionallymphnodes was recognized in 6 cases (23.1%) of the 26 cases that had received prophylacted lyrphnode dissection. The tumor thickness and level of all the 6 cases were over 1.5 mm and level III, respectively. Seven cases of the 26 cases that had received a curative surgical treatment died. The tumor thickness and level of all the 7 cases were over 3.0mm and level III, respectively. The five years survival rate of the stage I cases was 89%. Those of stage II, III and IV were 67%, 39% and 0%, respectively. It is cofirmed that the tumor thickness and level of the primary lesions correlates well with their prognosis.

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A 79-year-old Japanese female with skin metastasis of Maibomian gland adenocarcinoma is described.
She noticed her cutaneous lesion on her left cheek about three months before visiting our dermatological outpatient clinic. The primary tumor of her left upper eyelid was resected in January of 1984. In 1987, it recurred and metastasized to her cervical lymph node as well as to her left cheek.
Histologically, the tumor cells of the primary lesion of the upper eyelid were composed of three types: undifferentiated or germinative, foamy, and clear cells.
In the central part of the tumor lobes, there were a lot of foamy and clear cells of various shapes and sizes surrounded by germinative cells. The histological findings of the lymph node and of the metastatic skin lesions resemble those of the primary tumor closely.
In addition, the elimination phenomenon was found in the skin metastatic lesions.
The histochemical stain with Sudan III was positive for cytoplasm of the foamy cells in the metastatic skin lesions.
Ultrastructurally, tumor cells posess irregular nuclei, and many lipid droplets. Well -developed organella, especially many mitochondria are seen. Few, poorly-developed desmosomes are seen on plasma membrane.

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A 68-year-old Japanese man with various clinical features of metastatic skin cancer is described. He had suffered from ethmoid adenocarcinoma with cervical lymphnode metastasis. About 2 years later, multiple nodules developed on the neck, while at the same time maculopapules appeared on the anterior chest forming lace-like pattern. Biopsy specimen taken from the nodule revealed the diffusely scattered numerous tumor cells in the dermis. Histologic finding from the chest lesion showed the accumulation of tumor cells within the dermal vessels. No inflammatory change was observed in both specimens. Both anti-factor VIII and UEA-I immunohistological staining showed intense positive reaction on the vesseles. Although the specificity to blood vessel of anti-factor VIII and UEA-I antibody is not perfect, it seems to be blood vessels, because of the intensity and equality of their positive reaction.

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Three cases of metastatic skin cancer referred to our clinic were reported.
Case 1: A 64-year-old female had a livid induration on her right forearm originated from adenocarcinoma of the breast.
[Pathological findings] Solid proliferation of the tumor cells with duct-formation in the dermis.
Case 2: A 58-year-old female had nodules on her lower abdomen, gluteal cleft and anterior part of both thighs originated from carcinoma of uterine cervix.
[Pathological findings] Solid proliferation of large tumor cells in the dermis, and a few keratinizing cells on the peripheral site of the tumor mass were observed.
Case 3: A 76-year-old male had tumor on his frontal region of the scalp, probably originated from prostatic carcinoma or lung carcinoma.
[Pathological findings] There were tumor cells with ductal structure in the dermis. Partially, epidermal invasion was observed. PAP (Prostatic Acid Phosphatase) stain and PSA (Prostatic Specific Antigen) stain were negative. Intraductal micro villi were observed electron-microscopically.

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We reported a case of malignant trichilemmoma occurred on the left cheek of 87 years old female. Histology of biopsied and simply resected specimens showed several lobules consisting of clear cells and basaloid cells. No horn pearls were seen. During 9 months after the operation, no local recurrence or distant metasasis has not been seen.

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A 4-year-old boy visited our division in October, 1991, with a nodule. His mother noticed a rice-sized nodule on his left elbow 2 years ago. The papule had gradually grown to be a pea-sized nodule. He had been treated with cryotherapy for 2 months by a doctor before he visited our division. The nodule was a 10×12×4mm sized, dome-shaped, hard, skin-colored tumor with crust on the top of it. We clinically diagnosed it as dermatofibroma or follicular tumor and excised it totally. The histological diagnosis was dermatofibrosarcoma protuberans. The tumor was composed of spindle-shaped cells with large, slightly atypical and spindle-shaped nuclei. The tumor cells were arranged in a storif orm pattern. They invaded the epidermis and caused ulceration in the center portion. He was re-operated upon and has been disease-free for 8 months.

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A 72-year-old man came to us for the granulomatous lesion on the right groin and scrotum of about 6 month's duration Histologically, Paget's cells were found in hair follicles and eccrine ducts, as well as within the epidermis.
Although the tumor was resected along with skin of normal appearance within 3 cm around it, Paget's cells infiltrated to the edge of the operated tissue in the direction of the right groin.

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A 44-year-old male had been suffered from psoriasis for 12 years. He had been treated with tar and topical steroid. In addition, he received PUVA and UVB therapy for 12 years since 1979. The total irradiated amount of UVA and UVB was 831 joules/cm² and 102 joules/cm², respectively. He had also taken etretinate in 1984 and methotrexate in 1987. When he was admitted to our hospital for the exacerbation of psoriasis, a lot of pigmented frecles were found. Forty-eight pigmented lesions could be classified into 5 different types; type A to E. Type A is lentigo simplex which shows an increased production of melanin. Type B is a lentigo simplex with atypical melanocytic hyperplasia. Type C shows a lentigo simplex with atypical melanocytic hyperplasia and remarkable pigment blockade. Type D is a junction nevus with nests of atypical melanocytes. Type E is a lentigo maligna with the nests of atypical spindle- shaped melanocytes that extents along epidermal-dermal junction. Type E pigmented lesions are distributed in intermittently sun-exposed skin. In this case, there were 2 nevus cell nevus, 12 type A, 20 type B, 5 type C, 5 type D, and 4 type E in 48 pigmented lesions. There was no correlation between the size and the type of pigmented lesions.

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A statistical study of 179 patients with malignant tumors diagnosed at Department of Dermatology, Tokyo Medical and Dental University from 1987 to 1992 is reported. Malignant tumors include basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Paget's disease, Bowen's disease, and solar keratosis.
1) The incidence was 0.549% of the total patients in this period, and the patients with malignant tumors have increased gradually.
2) The tumors of basal cell carcinoma, squamous cell carcinoma, and solar keratosis were mostly located on the face and neck, and the tumors of malignant melanoma and Bowen's diasease were mostly on the lower extrimities.
3) One hundred and seventy three patinets were treated surgically.
4) The tumors derived from xeroderma pigmentosum were 31 cases. Three patients with malignant melanoma and 2 patients with extramammary Paget's disease were died.

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A phase II clinical study of a human leukocyte interferon-α preparation (FPI-31) was performed in the patients with malignant tumors of skin.
In 20 patients with mycosis fungoides (MF), FPI-31 injected intramuscularly, 13 patients responded.
FPI-31 was also injected into the tumor tissue, and the following result was obtained.
All 3 patients with MF responded; in 2 patients with metastatic malignant melanoma, responder was one; in 7 patients with Bowen's disease, responder was 6; all 2 patients with solar keratosis responded.
The main adverse reactions were fever, anorexia and increased serum GPT. However, they were mild and transient.
These results suggested usefulness of FPI-31 in the treatment of patients with malignant tumors of skin, particularly MF.

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