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Fas antigen, which belongs to a nerve growth factor/ tumor necrosis factor receptor superfamily, is a membrane protein that induces apoptosis. In humans, distribution of Fas antigen has been reported on cell lines and lymphocytes. Immunohistochemical studies revealed Fas antigen on the keratinocytes of lesional epidermis in lichenoid drug eruption, erythema multiforme, contact dermatitis, bullous pemphigoid, pemphigus vulgaris, and herpes zoster; it is co-expressed with intercellular adhesion molecule-1. Cultured keratinocytes expressing Fas antigen increased from 8.4% to 34.6% after stimulation with interferon gamma for 24 h. Treatment of interferon-gamma – stimulated keratinocytes with anti-Fas for 48 h resulted in DNA fragmentation and death of 32% of cells, suggesting that Fas antigen may mediate apoptosis. The expression of Fas antigen on keratinocytes in lesional skin suggests that death via Fas antigen may play an important role in the pathogenesis of keratinocyte cytotoxicity.

Immunohistochemical studies were performed to establish the distribution of membrane cofactor protein (MCP; CD46), decay-accelerating (DAF; CD55) and homologous restriction factor (HRF20; CD59), in normal skin appendages, and in benign and malignant skin neoplasms. At least two of these regulators were detected on normal eccrine glands, apocrine glands and sebaceous glands. They were also found in cellular naevi (CN), seborrhoeic keratoses (SK), basal cell carcinoma (BCC), Bowen's disease (BD), squamous cell carcinoma (SCC) and Paget's disease (PD). Although there were slight differences in their distribution, these regulators were found in all the cells examined, indicating that they are essential factors in human skin as well as other organs, and in neoplasms, in preventing autologous complement attack.

Thirty-two patients with extramammary Paget's disease during a 15-year period were analyzed.The male to female ratio was 25 to 7, and the average age of the patients was 71.8 years. All the lesions were in the external genitalia or perianal regions. The treatment was composed of a histologically controlled, local wide excision, with regional lymphnode dissection when indicated. The 5-year survival rate was 77.1% and the 10-year rate 48.9%.Bilateral axillary skins in 26 of 32 patients were histologically examined; Paget's cells were also found in bilateral axillae of the 3 patients and in unilateral axilla in another 3 patients. The subclinical, axillary Paget's disease was considered to be a relatively frequent complication.

A case of diffuse neonatal hemangiomatosis is described. At birth, a giant tumor, 10 cm in diameter and 6 cm in height, was present on the left axilla and associated with thrombocytopenia. Numerous cherry-red papules were present on the skin and buccal mucosa. On the second day of life, the giant tumor was excised. Histological examination of the tissue revealed masses of endothelial cells embedded in fibrous tissues. Plain and enhanced computed tomography of the brain revealed a hemorrhage and two hemangiomas. The associations of intravascular papillary endothelial hyperplasia were discussed.

The allotypes of C6, C7, factor B (BF) and factor I (IF) of the human complement system were studied in 11 Japanese patients with pemphigus (5 with pemphigus vulgaris and 6 with pemphigus foliaceus) and 17 with bullous pemphigoid (BP) to investigate the genetic background of these diseases. The allotypes were detected by using isoelectric focusing and immunoblotting. The frequency for IF* A allele in the pemphigus patients was significantly higher (p = 0.009) than that in healthy controls (n = 60). A significant association of IF A allotype with pemphigus was also observed (p = 0.027), with a relative risk of 6.3. There was no association between the C6, C7, BF or IF allotypes and BP. These data suggest that IF A allotype may be an etiological genetic factor in the development of pemphigus.

The dose-response relation (study I) and the effect of the timing of administration (study II) with respect to the antihistaminic activity of a H1-blocking agent, WAL 801 CL (Epinastine), were investigated. In study I, a 10, 20, and 40mg dose of WAL 801 CL or a placebo was administered to 11 healthy male volunteer students (X±SD=23.3±1.3yrs) after breakfast (8:30) by a double-blind fashion using the Latin square design, and the histamine intradermal reaction and psychomotor functions were subsequently examined. In study II, either 20mg of WAL 801 CL or a placebo were administeredto 8 healthy male volunteer students (23.8±1.4yrs) after breakfast (8:00) or after dinner (20:30) in the same way as in Study I, and the histamine intradermal reaction was subsequently examined. WAL 801 CL inhibited the histamine intradermal reaction dose-dependently, and no findings suggesting any effects on the CNS were observed. The inhibitory effect of WAL 801 CL on the histamine intradermal reaction tended to last longer when it was administered in the morning, while the effect tended to be stronger when it was administered in the evening, but the differences were not significant. Thus the results show that WAL 801 CL is a nonsedative H1-blocking agent and that the timing of administration does not critically influence the antihistaminic activity of the drug.

Decay-accelerating factor (DAF) is a 70-kD membrane glycoprotein that regulates autologous complement activation, by preventing assembly of alternative or classical C3/C5 convertases, and has been shown to have a wide tissue distribution. In this study, DAF antigen has been demonstrated at the intercellular spaces of normal human epidermis with monoclonal antibody against DAF using the peroxidase- anti-peroxidase method. The amount of DAF was greater at the granular layer than the basal cell layer as judged by intensity of the staining. Western blot analysis of DAF of the epidermis showed a 55-kD band, whereas that of buffy coat cells was approximately 67 kD. When DAF of the epidermis was treated with ncuraminidase, the molecular weight was reduced to 53 kD, whereas that of buffy coat cells was 56 kD. These results indicated that the content of sialic acid of DAF in the epidermis was different from that of buffy coat cells. In phosphatidylinositol-specific phospholipase C (PIPLC) – treated normal human skin, DAF was not demonstrated in the epidermis, whereas DAF remained unchanged on the elastic fibers. After the treatment of the epidermis by PIPLC, DAF was released into the buffer shown by Western blot analysis. These results suggested that DAF on the epidermis was anchored to keratinocyte via phosphatidylinositol (P1), whereas the anchoring mechanism of DAF on the elastic fibers was not through PI.

Immunoglobulin (Ig) G subclasses in anti-basement membrane zone (BMZ) autoantibodies found in the sera of bullous pemphigoid (BP) and in anti-intercellular substance (ICS) autoantibodies of pemphigus were investigated using immunofluorescent (IF) staining. In BP, IgG4, IgG1, and IgG2 were detected in 13, 5 and 6 of 15 patients, respectively; IgG3 was not detected. In pemphigus, IgG4 was detected in all of 10 patients, IgG1 in 7, IgG2 in one, and IgG3 in one patient, respectively. In both BP and pemphigus, the most prominent subclass in intensity of IF staining was IgG4. Although one BP and one PV patient had only IgG4 autoantibodies, C3 deposition was detected. The quantification of IgG subclasses in the sera of the patients was performed by enzymelinked immunosorbent assays (ELISA). Serum levels of IgG4 in both BP and pemphigus were elevated approximately 3-fold over those in normal controls; those of whole IgG and IgG1–3 were not significantly elevated. Using direct IF staining, the deposition of C3 at the BMZ and at the ICS was demonstrated in 9 of 10 BP and in 3 of 8 pemphigus patients, respectively. The prominent IgG subclasses of anti-BMZ and anti-ICS antibody were IgG4, a non-complement-fixing antibody, suggesting that the deposition of C3 in the lesional skin occurred via the alternative pathway, or that small amounts of IgG1–3 subclass autoantibodies activated the classical pathway.

Between 1976 and 1988, 135 patients with solar keratosis (SK) and 53 patients with squamous cell carcinoma (SCC) on the sun-exposed skin, but without apparent preceding diseases such as burn scars, chronic radiodermatitis, chronic arsenic poisoning, or xeroderma pigmentosum, were encountered. Sixteen of the SCC patients also had SK on other areas of sun-exposed skin. There were 31 SCC patients also showing SK (SK-SCC) and 22 SCC not showing SK (DN-SCC) within the same histologic sections. The mean ages of the patients with SK-SCC and with DN-SCC were similar. Metastases to regional lymph nodes were observed in 5 SK-SCC patients, of whom 3 died of the disease, and in 5 DN-SCC patients, of whom 4 died of the disease. The five-year post-operative survival rates were 70% in SK-SCC and 74% in DN-SCC; the ten-year post-operative survival rates were 70% in SK-SCC and 44% in DN-SCC.

A 77-year-old man was seen with florid, vegetating nodules in the umbilical, axillary and inguinal areas, scaly erythema in the trunk and fragile nails. Histologically, marked to moderate acanthosis and papillomatosis with intraepidermal abscesses composed of acantholytic cells eosinophils and neutrophils were seen in the vegetating lesions which showed intercellular IgG deposit by the direct immunofluorescence technique. There were no circulating pemphigus antibodies. The lesions were successfully treated by topical corticosteroids. However, flaccid bullae with hypopyon showing subcorneal acantholysis and intercellular IgG deposits continued to develop. After 31/2 years, circulating pemphigus antibody of IgG2 subclass was demonstrated.

We have employed a successful therapy for epidermolysis bullosa with high-dose oral tocopherol acetate. Two siblings with dominant dystrophic epidermolysis bullosa of the Cockayne-Touraine type were reported. Both siblings suffered from tense blisters and erosions healing with scars and transient milia on the extremities. Electron microscopic study of the blisters revealed a cleavage beneath the lamina densa in both siblings. High-dose oral tocopherol acetate therapy was administered to them with satisfactory clinical reduction of the blister formation.

A 12-year-old boy presented a slowly growing 3×2.5mm black, flat lesion on the right sole of 8 months' duration. There were junctional nevus cell nests and transepidermal elimination of melanin and dopa-and HMB-45-positive single melanocytes.Differential diagnosis from acral lentiginous melanoma in situ was discussed.

A 53-year-old man with bullous pemphigoid with an extremely low level of C4 level of C4 in the serum is reported

An 89-year-old woman presented a rapidly growing red nodule of 5 years' duration on her left eyelid. Histologically, the entire dermis was occupied by multiple lobules of atypical tumor cell nests surrounded by inflammatory cells and fibrous stroma. The tumor cell nests were connected with the overlying epidermis and extended into the subcutaneous fat and muscles. There were no tendencies towards squamous or glandular differentiation of the tumor cells. Immunohistochemistry showed the tumor cells to be positive for keratin/cytokeratin and epithelial membrane antigen, but negative for neuron specific enolase and vasoactive intestinal polypeptide. S-100 protein-positive Langerhans cells were also found within the tumor nests. There was no apparent evidence of a primary lesion elsewhere.

A 37-year-old male presented with a cauliflower-like tumor in the right buccal mucosa, leukoplakia of the tongue and esophagus, and keratotic papules or plaques on the extremities including bilateral palms and soles, associated with borderline diabetes mellitus and a repeated history of infections. A multi-system keratinizing abnormality was suspected, although no distinct disease category has been found showing similar involvements.

Proliferative activity in Spitz nevus (SN) was determined using proliferating cell nuclear antigen (PCNA) immunostaining and by assessing the mitotic rate. It was compared with that in compound melanocytic nevus (MN) and in malignant melanoma (MM). The PCNA index (number of positive cells/1,000 tumor cells) in SN was 72.8 +/- 45.5% (mean +/- SD), which was statistically significantly higher than that in MN (7.2 +/- 2.7%) and lower than that in MM (248.5 +/- 110%). The PCNA-positive cells in SN and MM were found both in dermal and junctional nests, while those in MN were found almost exclusively in the dermal nests. The mitotic rate in SN was 1.4 +/- 0.96%, while it was nothing in MN and 5.4 +/- 4.2% in MM. There was a statistically significant correlation between the PCNA index and the mitotic rate at r = 0.8946, p < 0.001. The PCNA index, however, appeared to show the proliferative activity of SN more clearly than did the mitotic rate.

285 various pigmented skin lesions from 282 patients were treated over the past 2 years and 10 months using the square and uniform intensity laser equipment. Also, laser effects on 44 skin specimens were studied histologically. The treated clinical lesions included 111 pigmented nevi, 97 nevi spili, 6 Becker's nevi, 10 epidermal nevi, 22 senile freckles, 16 seborrheic keratoses, and 23 other skin lesions. Satisfactory results 6 months or more after the final treatment of 212 of the skin lesions were obtained in 12/96 (12.5%) pigmented nevi; 13/75 (17.3%) nevi spili; 3/5 (60.0%) Becker's nevi; 3/7 (42.9%) epidermal nevi; 9/17 (52.9%) senile freckles; and 9/12 (75.0%) seborrheic keratoses. Judged on the histological examination of pigmented nevi, satisfactory results were obtained in 5 out of 11 superficial compound nevi, 1 out of 32 deep compound nevi, and 2 out of 12 deep intradermal nevi. Assessment methods will be discussed, and ruby laser treatment will be compared to conventional therapy.

Membrane co-factor protein (MCP; CD46) is an integral membrane protein with molecular weight (MW) of the two species of 63 kD and 55 kD, and regulates autologous complement activation, with the activity of factor I cofactor. The quantity of each species is genetically regulated, and two codominantly inherited allelic variants account for the three phenotypic patterns. By immunohistochemical study, MCP was found both in the intercellular spaces of the epidermis and on the endothelial cells in the dermis of normal human skin in vivo. The intensity of the staining pattern was higher in the basal layer than in the granular layer. By Western blot analysis with use of a monoclonal antibody, MCP in the epidermis appeared as several bands ranged from 60-50 kD, with a major band of 56 kD, which was different from those in either polymorphonuclear cells, platelets, and cultured keratinocytes. No other variants were found in the epidermis obtained from skin of 20 normal humans. Complement activation in human skin may be regulated at several steps, including DAF and HRF20, thereby protecting cells from autologous complement attack.

A case of congenital, solitary, cutaneous mesenchymal hamartoma in the palm of the left hand is reported. The mass was composed mainly of an intimate mixture of fibrocollagenous bundles and islands of mature fat cells, distorted blood vessels with smooth muscle in the wall, and eccrine sweat glands. Many mast cells were scattered throughout the fibrocollagenous bundles. The mast cell may be an important cell in this hamartoma.

Identical twin sisters developed generalized erythema and bullae on skin and mucous membranes at 18 and 19 years of age. Atrophic scars and milia were formed later. Indirect immunofluorescence (IF) study of the separated skin by incubation in 1.0M NaCl showed antibasement membrane zone (BMZ) antibodies bound to the dermal side. The HLA-DR typing demonstrated DR2/DW11. Pulse therapy resulted in marked clinical improvement. This is the first report of epidermolysis bullosa acquisita (EBA) in identical twins and suggests the possibility that the disease may have a genetic component.

A 38-year-old Japanese man was seen for severe palmoplantar keratoderma, extending to the dorsal aspects with red rims. He had had spontaneous amputations of the toes and surgical amputation of the right lower leg because of squamous cell carcinoma of the right sole. The clinical symptoms suggested those of mal de Meleda, except for the absence of consanguinity and of granular layers in the epidermis. The keratoderma improved with oral etretinate treatment.

SUMMARY Homologous restriction factor with a molecular weight of 20 kD (HRF20) is a membrane protein that inhibits assembly of the membrane attack complex of homologous complement. Distribution of HRF20 in normal human skin was studied. The plasma membrane of keratinocytes was stained, and the intensity of the staining pattern was higher in the basal cell layer than in the granular layer. Endothelial cells of blood vessels in the dermis were also stained. The molecular weight of HRF20 on erythrocytes and epidermis is 16 kD, determined by Western blot analysis. Those of polymorphonuclear cells and lymphocytes appeared as two bands, a major band of 20 kD and a minor band of 16 kD. Susceptibility of HRF20 to phosphatidylinositol-specific phospholipase C (PIPLC) was examined. After PIPLC treatment of the sections, HRF20 was not detected on the epidermis and was very slightly expressed on the blood vessels. These results indicate that HFR20 attaches to keratinocytes and blood vessels via phosphatidylinositol, regulating the formation of membrane attack complexes of homologous complement on the cell membrane.

The expression of a cell proliferation-associated human nuclear antigen was immunohistochemically studied in human anagen hair and hair follicles using the monoclonal antibody Ki-67. The reaction of Ki-67 in mature anagen hair follicles was observed in the hair matrix cells and outer root sheath (ORS) cells. Nuclear staining was seen in a small number of matrix cells and in some ORS cells; this finding corresponded to the thymidine or bromodeoxyuridine labeling studies previously reported. In addition, there were two different patterns of cytoplasmic staining in the ORS: strong staining of the innermost cells (IMC) and weaker staining of the other ORS cells in the isthmus. Ki-67 reactivity of the IMC layer was observed at each stage of anagen and was regularly seen from the upper bulb to the isthmus. Ki-67 is a commercially available antibody that detects cycling cells. However, the IMCs in anagen hair follicles showed cytoplasmic labeling by Ki-67 from the matrix cells in the upper bulb to the distal portion of the isthmus.

To the Editor.— A 65-year-old Japanese woman was first seen in January 1979 because of a slowly enlarging, extensive, well-demarcated erythematous plaque on the right side of her face (Fig 1, panel A), which had started as a red papule 30 years before. No history of preceding trauma was offered. The general condition of this patient was not impaired. Her family history showed no apparent or chronic infections. Histologic examination of the lesion revealed an epithelioid cell granuloma with periodic acid-Schiff-positive fungal elements in the dermis. Based on the culture findings, a diagnosis of infection with Fusarium species was suggested, but could not be confirmed at the time. The patient was treated with oral griseofulvin and flucytosine with no favorable response. Topical 0.1% to 0.5% amphotericin-B injections were then tried weekly or monthly for 1 year, with partial regression of the plaque. The patient failed to appear for further

SUMMARY Complement components and anaphylatoxins in a Cr inhibitor (CrINH) deficient family were studied. C4a was increased when CrINH was decreased, and C3a was increased in subjects with systemic lupus erythematosus (SLE)-like symptoms and with angioedema attacks. Danazol was effective in controlling the clinical as well as complement abnormalities including low CH50, CrINH and C4, which increased within 10 days after danazol treatment was started. Two-dimensional immunoelectrophoresis of CrINH showed that there was no functionally or electrophoretically abnormal CrINH present before or after danazol treatment. C3a and C4a were considered to play important roles in the pathogenesis of angioedema and associated SLE-like symptoms.

Simultaneous occurrence of bilateral axillary Paget's disease in a 61-year-old male with genital Paget's disease of 2 years' duration was presented. Invasive adenocarcimoma was found in the genital lesion. No regional lymph node metastases ware apparent. The lesions were excised in toto. There has been no recurrence 14 months later. Four previously reported cases of double or triple extramammary Paget's disease, together with two more cases were summarized. Generally, the axillary lesions were clinically insignificant, faintly erythematous patches and could hardly be identified without histological examination.

Echographic differentiation between clinically similar, nodular lesions of the dermis and subcutaneous fat was done in an attempt to open a new field of ultrasonic histopathology. Sector B-mode echography with a 10 MHz transducer was done on 87 patients with nodular lesions in the dermis and subcutaneous fat, and the echograms were compared with microscopic findings. These consisted of nevus pigmentosus in 10, neurofibroma in 10, steatocystoma multiplex in 4, epidermoid cyst in 30, cavernous hemangioma in 4, lipoma in 10, panniculitis in 14 and malignant lymphoma in 5 patients. Neurofibroma and steatocystoma multiplex were as echolucent as lipoma, while nevus pigmentosus and epidermoid cyst were less echolucent. Small internal echoes were observed within the echolucent mass in 15 of 30 lesions of epidermoid cysts. Cavernous hemangioma, panniculitis, and malignant lymphoma were partially echogenic as well as echolucent.

A slowly growing, subcutaneous mass in the left eyebrow region of a 54-year-old Japanese woman showed numerous small epithelial cell nests surrounded by a dense desmoplastic stroma. The epithelial cell nests showed partially keratinizing cystic structures containing a small amount of glycogen. Immunoperoxidase staining for carcinoembryonic antigen was positive only in the lumina or on the ductal lining surface of tumor cells; staining for S-100 protein was positive within almost all of the tumor nests. Birbeck granules indicating Langerhans cells were found within some of the cells.

Superficial lymphadenopathies were examined by sector B-mode echography using a 5 or 10 MHz transducer and compared with microscopic sections. A total of 54 lymph nodes in the inguinal, cervical or axillary regions was studied in 54 patients; the primary skin lesions were benign in 35 and malignant in 19 of these patients. Histologically verified and non-verified, reactive lymphadenopathies showed echolucent nodes with central or medullary echoes; the attenuation of the sensitivity was under 10 decibels (dB). Histologically, the medullary echo corresponded to the medulla of the lymph node and the echolucent zone to the cortex. Tuberculous lymphadenitis, hyalinized, severe fibrosis from foreign body granuloma, and squamous cell carcinoma nests showed irregular, cortical echoes at 0 to 5 dB. Total replacement of the lymph node by the metastases of malignant melanoma or malignant lymphoma showed echolucent nodes without internal echoes, even at 0 dB.

25, 40および60MHzの高周波超音波プローブと周波数可変の発振回路を試作し, 正常および病的皮膚, 可視粘膜の超音波断層像を求めた。ついで, 病変部を切除してふたたび超音波断層像をもとめ, これらを病理組織学的所見と対比検討した。その結果, 角層の厚い手のひら, 足のうらの皮膚での角層・マルピギー層境界, 表皮・真皮間境界, 頭髪ないしうぶ毛の毛包, 毛髪の断面像の描出に成功した。さらに表在性上皮性腫瘍や嚢腫, 炎症性細胞浸潤, 浮腫などの超音波所見と病理組織学的所見との対比を行い, また, 悪性黒色腫の組織学的浸潤度の生体計測への応用を試みた。本装置の開発により無侵襲皮膚病理組織学への第一歩が拓かれたと考えられる。

A Japanese girl, 2 years, 8 months of age, with palmoplantar keratosis and dendritic corneal opacities, showed increased tyrosine levels in the plasma, urine, and cerebrospinal fluid. The mental and physical growth was riot retarded. The hepatorenal functions were within normal limits. Electron microscopically, the epidermal keratinocytes showed increased tonofibrils and no structures suggestive of tyrosine crystals. Cytosol and mitochondrial tyrosine aminotransferase (TAT) activities of the liver were greatly decreased, while p -hydroxyphenyl pyruvate oxidase ( p -HPPO) activity was not decreased. The plasma tyrosine levels were controlled for 3 years with low phenylalanine-tyrosine diet.

In two patients a portwine haemangioma extending from the nose and glabella to the eyelids and a basal cell carcinoma at the medial canthus involving both eyelids were excised and the defect successfully reconstructed by a symmetrical trilobed forehead flap. The indications for our method are discussed.

SUMMARY A 48–year-old Japanese woman with systemic lupus erythematosus-like lesions of the skin and lips was found to have hereditary angio-oedema. Complement studies revealed low CH5O, C19, C4 and C1 inhibitor levels, with normal C3 and C5 levels. Dramatic clinical improvement followed fresh normal human blood transfusion and systemic betamethasone administration, while the deficient complement component levels were unchanged.

An island groin flap was used for satisfactory reconstruction of defects in the anterior thigh, lower abdomen, or perineal regions in 9 patients. This flap has several advantages: simple operation, wide range of coverage, large rotation arc, direct closure of the donor site, and no sacrifice of muscle. Comparison with tensor fascia lata and other musculocutaneous flaps is made.