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Cutaneous T-cell lymphoma (CTCL) is a disease entity characterized by a primary sporadic T-cell proliferation in the skin. Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes adult T-cell leukemia/lymphoma. Recently, several authors have detected the HTLV-1 genome in genomic DNA from patients with CTCL and proposed a causal relation of HTLV-1 to CTCL. However, it remains controversial because these studies contain some problems in materials used to detect HTLV-1. We investigated both fresh and cultured T lymphocytes (128 specimens) derived from 50 Japanese patients with CTCL, where HTLV-1 is endemic, by using polymerase chain reaction with four sets of primers including gag,pol,env, and pX regions of HTLV-1 to elucidate the relationship between HTLV-1 and CTCL in Japan. However, none of the 128 DNA specimens revealed positive for HTLV-1 in contrast to the previous studies. We conclude that CTCL, which does not include HTLV-1, is present although the pathogenesis of CTCL may be different by areas or races. © 1997 by The American Society of Hematology.

BACKGROUND Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of the mature helper T-lymphocyte. Human T-lymphotropic virus type 1 (HTLV-1) has been shown to be the cause of this neoplasm. Recently, however, the HTLV-1 genome has been found in some patients with cutaneous T-cell lymphoma (CTCL), which suggests a causal relation of HTLV-1 to CTCL. Thus, the relation between the HTLV-1 genome and CTCL, as well as the difference between ATLL and CTCL, have come into question. METHODS The authors examined two patients with CTCL whose serum anti-HTLV-1 antibodies were constantly positive. The Southern blot technique, inverse polymerase chain reaction (IPCR), and polymerase chain reaction (PCR) with four sets of primers for gag, pol, env, and pX regions of HTLV-1 were used to clarify the distinctions between ATLL and CTCL. RESULTS Clinically, one patient presented with multiple subcutaneous nodules with involvements of the internal organ, and the other patient was typical for mycosis fungoides. No integration of HTLV-1 DNA was detected by IPCR or the Southern blot technique in either patient. PCRs with the four sets of primers were all found to be positive for HTLV-1 except one. CONCLUSIONS The authors conclude that ATLL should be differentiated from CTCL in view of the responsibility of HTLV-1 for promoting or maintaining CTCL. Cancer 1997; 79:269-74. © 1997 American Cancer Society.

The coexistence of two cutaneous non-Hodgkin's lymphomas of different lineage is rare. We report a patient with an indolent erythrodermic cutaneous T-cell lymphoma followed by an aggressive B-cell lymphoma. To our best knowledge, this is the first report describing Epstein-Barr virus-associated B-cell lymphoma in a patient with cutaneous T-cell lymphoma. We suggest that the long-standing cutaneous T-cell lymphoma, as well as the long-term chemotherapy, suppressed host immunity and caused reactivation of latent Epstein-Barr virus.

HMB-45 is a monoclonal antibody specific for melanoma cells and premature developing melanocytes. We examined the expression and specific subcellular binding sites of HMB-45 in various types of melanocytes including epidermal melanocytes from fetuses and infants with or without tyrosinase-negative oculocutaneous albinism (type IA), melanin-producing and non-producing melanoma cell lines (G361 and MeWo), and in vivo melanoma cells (melanotic and amelanotic malignant melanoma). Subcellular HMB-45 binding was examined by using post-embedding immunogold electron microscopy with rapid freezing and freeze substitution fixation methods without the use of chemical fixatives to preserve the intracytoplasmic delicate antigen property of HMB-45. HMB-45 antigen was detected not only in in vivo melanoma cells and normal fetal melanocytes, but also in melanocytes in the other conditions. Post-embedding immunogold electron microscopy revealed that HMB-45 antigen was exclusively localized to stages I and II melanosomes in the cytoplasm of neoplastic melanocytes, but was detected mainly on stages II and III melanosomes in the melanocytes from fetuses and infants. In tyrosinase-negative oculocutaneous albinism, only stages I and II melanosomes were detected in the cytoplasm, but both stages of melanosomes were HMB-45 positive. We conclude that HMB-45 appears mainly on the immature melanosomes during melanogenesis in both neoplastic and non-neoplastic melanocytes regardless of their tyrosinase activity, but the intracytoplasmic localization of HMB-45 antigen is different by each condition of melanocytes.

We report a case who was clinically and histopathologically diagnosed as herpetiform pemphigus (HP) and associated with autoimmune hemolytic anemia (AIHA). However, immunofluorescence studies demonstrated concurrent anti-cell-surface and anti-basement-membrane-zone antibodies in the patient's serum. Immunochemical studies showed that the patient's serum reacted with both the pemphigus foliaceus antigen and the two bullous pemphigoid antigens. Subsequently, the patient developed AIHA. Both anemia and skin lesions were successfully treated with oral prednisolone. We believe that this is the first case with HP in association with AIHA. The presence of autoantibodies against multiple antigens suggests an abnormal immunologic tolerance in the antibody production system in this patient.

We analyzed the location of binding sites for pemphigus vulgaris (PV) antigen and pemphigus foliaceus (PF) antigen in the human epidermis using serum samples obtained from three patients with PV and three patients with PF. Confocal laser scanning microscopy, immunofluorescent examination of ultrathin cryosections, and immunoperoxidase electron microscopy demonstrated discontinuous dots along the epidermal cell surfaces. Immunogold electron microscopy of ultrathin cryosections showed specific binding of PV and PF autoantibodies only to desmosomes. Post-embedding immunogold electron microscopy using cryofixation and cryosubstitution enabled the whole depth of the epidermis to be examined and the binding of PV and PF autoantibodies to be quantitated by counting gold particles. Both PV and PF autoantibodies bound to all desmosomes in the epidermis, but not to the surface of the non-desmosomal keratinocytes. The majority of auto-antibody binding occurred in the extracellular domain (PV, 62%; PF, 69%). The statistical analysis of two-way analysis of variance regarding the number of gold particles labeling a single desmosome confirmed a significant interaction between subtypes of pemphigus (PV and PF) and the different epidermal cell layers (p < 0.044). The results indicate that the number of gold particles bound to individual desmosomes with PV sera was significantly higher in the lower epidermis than in the upper epidermis, and that of PF sera showed reciprocal pattern. This inversely graded binding pattern suggests heterogeneity of the composition of the desmosomes, which may explain the differences in level of acantholysis between PV and PF.

Background: Parakeratosis variegata is a rare skin disease first described in 1890. Even today, the disease entity remains confusing because various names indicating similar skin conditions have been used. Several cases of parakeratosis variegata have been reported to develop into cutaneous T-cell lymphoma, but there have been no reports describing the occurrence of lymphoma after a long-term follow-up period nor have T-cell receptor gene rearrangements been monitored in this disease. Objective: Our purpose was to determine whether parakeratosis variegata (long-standing premycotic condition) can develop into cutaneous T-cell lymphoma. Methods: We analyzed skin specimens from a patient with a 33-year history of parakeratosis variegata by Southern blotting using a T-cell receptor gene probe. Results: We could detect apparent rearranged bands of T-cell receptor gene in the skin specimens taken in 1993 in contrast to the DNA analysis in 1988 which featured no such rearranged band. Conclusion: This case represents a critical stage of parakeratosis variegata converting to lymphoma. Our results indicate that parakeratosis variegata generated monoclonality of T cells in its chronic course.

Background: Parapsoriasis en plaques (large-plaque type) is a premalignant condition capable of developing into cutaneous T-cell lymphoma (CTCL). However, it is not known whether the early stage of CTCL can be distinguished from parapsoriasis en plaques. Objective: Our purpose was to determine whether parapsoriasis en plaques can develop into CTCL. Methods: The clinical appearance, histopathologic features, immunophenotype, DNA rearrangements, and clinical course were analyzed in 20 cases. Results: T-cell receptor β-chain gene rearrangement was detected in four of the 20 cases. No clinical, histopathologic, or immunohistochemical differences were found between patients with and without gene rearrangement. Conclusion: The early stage of CTCL cannot be differentiated from parapsoriasis en plaques by clinical features, histopathologic characteristics, or immunophenotype. Patients with parapsoriasis en plaques exhibit heterogeneous findings, which may include monoclonal proliferation. Patients with long-standing parapsoriasis-like lesions resistant to conventional treatment require careful monitoring for the possible development of cutaneous lymphoma.

We have examined the character and carcinogenic properties of the normal-appearing epidermis overlying basal cell carcinomas by immunohistochemical methods, employing a series of monoclonal antibodies. The labelling index was significantly increased in the atrophic epidermis overlying basal cell carcinomas (solid type, n = 20), compared with the epidermis overlying or adjacent to squamous cell carcinoma (n = 20), keratoacanthoma (n = 10), dermatofibroma (n = 10), neurofibroma (n = 10), soft fibroma (n = 10), pyogenic granuloma (n = 10) and cutaneous leiomyoma (n = 5). Cells which expressed epidermal growth factor (EGF) receptor were detected in all layers of the epidermis over the basal cell carcinomas, but not the other tumours. Basement membrane-related antigens, including bullous pemphigoid antigen and GB3 antigen, were decreased in the epidermis. AE1, the monoclonal antibody against basal cell keratin, reacted with the uppermost layers of the normal-appearing epidermis overlying the basal cell carcinomas. ICAM-1 expression was very weak in the overlying epidermis. The dermis subjacent to the proliferating epidermis showed staining for transforming growth factor-alpha (TGF-alpha), strong positive PECAM-1 staining of endothelium, and numerous HLA-DR-positive cells. From these results, we suggest that the proliferative activity in the epidermis overlying basal cell carcinomas is not a state induced by the dermal infiltrate, but represents carcinogenic activity of the epidermis.

We describe two cases of malignant schwannoma in the skin that did not originate from a nerve trunk and was not associated with neurofibromatosis. Light microscopy showed that both tumors were composed predominantly of atypical spindle-shaped cells. Immunohistochemical analysis was performed with various monoclonal antibodies against mesenchymal determinants. In both patients, tumor cells were positive for S-100 alpha and S-100 beta, neuron-specific enolase, vimentin, neurofilament protein, and myelin basic protein, and negative for HMB-45, glial fibrillary acidic protein, epithelial membrane antigen, and desmin. Electron microscopy revealed that the tumor cells possessed indented nuclei with an electron-lucent cytoplasm. Immunoelectron microscopy showed diffuse fine granular staining for S-100 alpha, not detectable in normal Schwann cells, in the cytoplasm of the tumor cells.

A patient with collagenofibrotic glomerulopathy associated with hepatic persinusoidal fibrosis is described. Renal biopsy revealed that the glomerular tufts contained homogeneous material that was proved by electron microscopy to be collagen fibers. The material was reactive to anti-type III collagen monoclonal antibody. Liver biopsy also showed an increase of type III collagen fibers in the perisinusoidal area. Since the serum procollagen III peptide level was elevated in this patient, fibrosis may have been simultaneously activated in kidney and liver by some unknown condition.

We examined the localization of DNA replicating cells and ras oncogene product p21 positive cells in proliferating skin diseases, such as psoriasis vulgaris, lichen planus, verruca vulgaris, verruca plana juvenilis and seborrheic keratosis. ras p21-positive cells were found rather in the differentiated layers than in the proliferating layers of the epidermis. We indicate that the expression of ras p21 can be associated with the differentiation of epidermal keratinocytes not only in tumor tissues but also in inflammatory skin diseases.

Juvenile chronic myelogenous leukaemia (JCML) is a rare haematological malignancy of myelomonocytic lineage that affects patients less than 4 years of age and is known as an entity different from adult-type chronic myelogenous leukaemia. In JCML, skin manifestations are relatively common but most of them have been reported as a non-specific eruption, which histologically may show changes resembling neurofibromatosis or xanthogranuloma. We present a 2-year-old boy with JCML who developed a recurrent annular erythema in which leukaemic infiltrates were confirmed histologically, even though his bone marrow examination suggested that be remained in haematological remission.

The diagnosis of tyrosinase-negative oculocutaneous albinism (OCA) was made in a 19-week-old fetus by skin biopsy. Because the parents had an 11-year-old son with tyrosinase-negative OCA, they requested that the fetus be aborted at the 20th week of gestation. A histological analysis of the eyes was performed. Throughout the retina, the ganglion cell layer was separated from the inner neuroblastic layer by the inner plexiform layer. However, the number of ganglion cells was decreased and the nerve fiber layer was immature. Bipolar and horizontal cells had begun to segregate into the inner nuclear layer. Rods and cones were identifiable in the posterior, but not peripheral, retina. Cones were more numerous in the center of the retina, and no rod-free area was identifiable. In addition, the ciliary body (epithelial folds, blood vessels in the mesodermal connective tissue core, and ciliary muscle) was less developed than in a normal fetus. Melanosomes in the retinal pigment epithelium only contained filaments without melanization and were therefore classified as stage I or II melanosomes. However, the ciliary epithelium also contained some stage III melanosomes with melanin adherent to the filaments.

An electron microscopic DOPA reaction test of fetal skin was used for the prenatal diagnosis of tyrosinase-negative oculocutaneous albinism (OCA). The subject was a 34-year-old Japanese woman in her second pregnancy. Her first child, born in 1982, had been previously examined and confirmed to have tyrosinase-negative OCA. The parents requested a prenatal diagnosis and we sampled skin from the upper trunk of the fetus. On conventional electron microscopy, the development of melanosomes in interfollicular melanocytes had progressed no further than stage II. Fetal skin samples incubated with L-DOPA solution indicated a lack of tyrosinase activity and showed that the melanosomes had not progressed beyond stage II. In skin samples from the trunks of three Japanese fetuses aborted for other reasons at 19-20 weeks of gestation, most premature melanosomes were further melanized to stage IV after incubation with L-DOPA solution. A prenatal diagnosis of tyrosinase-negative OCA was made. The parents requested a termination and skin biopsies of the abortus confirmed the diagnosis. This study shows that tyrosinase is normally present in melanocytes of the fetal epidermis at 20 weeks' gestation, and that the electron microscopic DOPA reaction test of a fetal skin biopsy specimen is safe and practical, and provides reliable information for making a prenatal diagnosis of tyrosinase-negative OCA in the second trimester.

We describe an 82-year-old man with CD8 + lymphoepithelioid lymphoma localized to the skin. The skin lesion had been present for 18 years. Histologically there was a dense infiltrate that consisted of atypical lymphoid cells and large epithelioid cells, thereby resembling the so-called Lennert's lymphoma. Local radiotherapy proved effective in reducing the size of the tumor. To the best of our knowledge, this is the first report of primary lymphoepithelioid lymphoma of the skin.

Bullous pemphigoid (BP) is a blistering skin disease in which autoantibodies develop to hemidesmosomal components of the epidermal basement membrane zone, including two major antigenic proteins of the 230-kD antigen (BPAG1) and the 180-kD antigen (BPAG2). The present study demonstrated the precise ultrastructural localization of the epitopes for autoantibodies against BPAG1 and BPAG2 in normal skin. Autoantibodies against either BPAG1 or BPAG2 were affinity-purified using nitrocellulose membrane, which was blotted with SDS-PAGE-fractionated antigens from human epidermal extract as the immunoabsorbent. Postembedding, immunogold electron microscopy was performed after skin was processed by rapid freezing and freeze substitution fixation without chemical fixatives. Purified autoantibodies against BPAG1 bound only to the intracellular domain of the hemidesmosome, and 80% of the gold labeling was within 40-140 nm from the plasma membrane (mean distance 91 nm inside). In contrast, the autoantibodies against BPAG2 bound along the plasma membrane of the hemidesmosome, and 80% of the gold labeling was within 10 nm outside to 50 nm inside the cells (mean distance 12 nm inside). These results suggest that the autoantibodies against BPAG1 and BPAG2 react with the epitopes localizing in distinct regions of the hemidesmosome complex, and may play different roles in the blister formation in patients with BP.

Summary Two cases are reported of cutaneous anaplastic large-cell lymphoma with the suppressor/cytotoxic (CD8) phenotype. In both cases there was a solitary skin tumour in which there was a dense infiltrate with large irregularly shaped cells which on immunophenotyping expressed CD8. DNA hybridization analysis showed rearrangements of the T-cell-receptor gene in both cases.

summary The localization of DNA replicating cells, epidermal growth factor (EGF) receptor-expressing cells and ras oncogene product p21 (p-21ras) positive cells were examined in various skin tumours to elucidate the role of EGF receptor and p21ras in the epidermis. Normal skin, keratoacanthoma (KA), solar keratosis (SK), Bowen's disease (BD), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and extramammary Paget's disease (PD) were studied. EGF receptors were seen in proliferating layers, where DNA replicating cells localize, but p21ras was found in the more differentiated layers. We conclude that EGF receptor expression is closely associated with cellular proliferation, but p21ras may play a role in the differentiation of cells in various skin tumours.

SUMMARY Ten patients with B cell lymphoma of the skin have been treated in a 5 year period at the Keio University Hospital, Tokyo. Most present with an asymptomatic solitary nodule or multiple tumours of the skin but limitation to the skin is rare. Histopathology showed medium to large lymphoid cells in the dermis and subcutis. Radiotherapy was given for cutaneous lesions in conjunction with chemotherapy if there were metastases.

Background: The cell production vs the cell loss rate is one of the most important parameters in evaluating growth and biological behavior of neoplasms. Individual cell disintegration in tissues, apoptosis , is a constant finding in various tumors and has been shown, by using several techniques, as a recognizable cell death that is different from necrosis. Design: We studied the apoptosis-proliferation ratio in various lymphoproliferative disorders in the skin, including mycosis fungoides (MF), cutaneous T-cell lymphoma showing solid tumor mass (CTCL), B-cell lymphoma of the skin (BCL), lymphomatoid papulosis (LyP), and cutaneous pseudolymphoma by using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL), a newly developed method to detect internucleosomal breaks characteristic of apoptotic cells. Setting: University referral center. Patients: Fifty patients with cutaneous lymphoproliferative diseases. Main Outcome Measures: Proliferation indexes and apoptosis index calculated by using immunohistochemical techniques. Results: The proliferation indexes in pseudolymphoma, which were calculated by using immunohistochemical analyses with anti-proliferating cell nuclear antigen and anti-M1B-1 monoclonal antibodies, were significantly lower than the indexes of MF, CTCL, BCL, and LyP, whereas, the apoptosis index in Lyp was significantly higher than in any other lymphoproliferative diseases studied. The apoptosis-proliferation ratio in the tumor stage of MF, CTCL, and BCL was almost constant, but the ratios in LyP and the plaque stage of MF were significantly higher than in the other diseases studied. Conclusions: The clinical behavior of each lymphoproliferative disease in the skin seemed to be reflected in the apoptosis and proliferation indexes. We conclude that these indexes may become useful factors in the determination of the diagnosis and the prognosis for patients with lymphoproliferative diseases. Arch Dermatol. 1997;133:829-833

Figure 1. A 44-year-old man was found to have an umbilical tumor. Examination revealed the lesion to be firm and subcutaneous, approximately 5 cm in diameter, with erythema around the navel. The cervical and inguinal lymph nodes were enlarged. Computed tomography revealed an umbilical mass measuring 4.5 cm by 3.5 cm (Panel A, arrow) and multiple enlarged lymph nodes in the pelvis. A skin-biopsy specimen showed massive infiltration of the dermis by medium-sized, atypical lymphoid cells, which infiltrated between the bundles of collagen (Panel B; hematoxylin and eosin, ×200). Cells similar to those of the Sister Joseph's node were also . . .