A Comprehensive Study of the Immunophenotype and its Clinicopathologic Significance in Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell tumor caused by human T-lymphotropic virus type 1 (HTLV-1). The typical ATLL immunophenotypes are described in the 2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (positive: CD2, CD3, CD5, CD4, and CD25; negative: CD7, CD8, and cytotoxic markers; and partially positive: CD30, CCR4, and FOXP3). However, limited studies are available on the expression of these markers, and their mutual relationship remains unknown. Furthermore, the expression status of novel markers associated with T-cell lymphomas, including Th1 markers (T-bet and CXCR3), Th2 markers (GATA3 and CCR4), T follicular helper markers (BCL6, PD1, and ICOS), and T-cell receptor (TCR) markers, and their clinicopathologic significance is unclear. In this study, we performed >20 immunohistochemical stains in 117 ATLL cases to determine the comprehensive immunophenotypic profile of ATLL, which were compared on the basis of clinicopathologic factors, including morphologic variants (pleomorphic vs anaplastic), biopsy locations, treatments, Shimoyama classification-based clinical subtype, and overall survival. CD3+/CD4+/CD25+/CCR4+ was considered a typical immunophenotype of ATLL, but approximately 20% of cases did not conform to this pattern. Simultaneously, the following new findings were obtained: (1) most cases were negative for TCR-ß and TCR-δ (104 cases, 88.9%), indicating the usefulness of negative conversion of TCR expression to provide differentiation from other T-cell tumors; (2) the positivity of CD30 and CD15 and the negativity of FOXP3 and CD3 were significantly associated with anaplastic morphology; and (3) atypical cases, such as T follicular helper marker-positive (12 cases, 10.3%) and cytotoxic molecule-positive cases (3 cases, 2.6%), were identified. No single markers could predict the overall survival among patients with acute/lymphoma subtypes of ATLL. The results of this study illustrate the diversity of ATLL phenotypes. In T-cell tumors occurring in HTLV-1 carriers, the possibility of ATLL should not be eliminated even when the tumor exhibits an atypical phenotype, and the confirmation of HTLV-1 in the tissue is recommended.

High Prevalence of Distinct Human Herpesvirus 8 Contributes to the High Incidence of Non-acquired Immune Deficiency Syndrome-Associated Kaposi's Sarcoma in Isolated Japanese Islands.

Background: Non-acquired immune deficiency syndrome (AIDS) Kaposi's sarcoma (KS) is extremely rare in Japan but highly endemic in Okinawa, especially in Miyako Islands. We aimed to elucidate the exact incidence and cause of this high prevalence. Methods: Non-AIDS KS cases in Okinawa Prefecture over the past 31 years were reviewed, and human herpesvirus 8 (HHV8) seroprevalence in Miyako Islands was determined. We examined whole-genome sequences of 3 HHV8 strains and performed whole-exome sequencing of 4 male patients from Miyako Islands. Results: Approximately half of the non-AIDS KS cases in Okinawa Prefecture were from Miyako Islands. The age-adjusted incidence rate was 0.87/105 per year for Miyako Islands and 0.056/105 per year for the rest of Okinawa. Human herpesvirus 8 seroprevalence was 15.4% in Miyako Islands. The 3 HHV8 genomes isolated from Miyako islanders formed a phylogenetically branch distinct from those of previously sequenced HHV8 strains and shared specific mutations in 9 proteins. These mutations were verified in Okinawan patients other than those from Miyako Islands. Whole-exome sequencing of the 4 male Miyako Islanders did not reveal shared pathogenic mutations. Conclusions: Miyako Islands are an endemic area of non-AIDS KS. The high rate of a distinct HHV8 may contribute to the high incidence of KS in the region.

Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency.

We herein describe a case of a 17-year-old boy with intractable common warts, short stature, microcephaly and slowly-progressing pancytopenia. Simultaneous quantification of T-cell receptor recombination excision circles (TREC) and immunoglobulin κ-deleting recombination excision circles (KREC) suggested very poor generation of both T-cells and B-cells. By whole exome sequencing, novel compound heterozygous mutations were identified in the patient's DNA ligase IV (LIG4) gene. The diagnosis of LIG4 syndrome was confirmed by delayed DNA double-strand break repair kinetics in γ-irradiated fibroblasts from the patient and their restoration by an introduction of wild-type LIG4. Although the patient received allogeneic hematopoietic stem cell transplantation from his haploidentical mother, he unfortunately expired due to an insufficiently reconstructed immune system. An earlier definitive diagnosis using TREC/KREC quantification and whole exome sequencing would thereby allow earlier intervention, which would be essential for improving long-term survival in similar cases with slowly-progressing LIG4 syndrome masked in adolescents.

Neonatal pemphigus vulgaris.

A male newborn with skin erosions was born to a 32-year-old woman who was under treatment for pemphigus vulgaris that had been diagnosed 16 months earlier. Antibodies to desmoglein (Dsg)1 and Dsg3 were analyzed by enzyme-linked immunosorbent assay. Index values of antibodies to Dsg1 and Dsg3 were 49 (normal index values, <14) and 121 (normal index values, <7), respectively. Those findings concluded a diagnosis of neonatal pemphigus vulgaris. No new vesicles or bullae appeared in the newborn after the birth. Non-corticosteroid ointments produced prompt epithelialization on the erosive lesions. All the eruptions disappeared in 3 weeks. The level of serum anti-Dsg3 autoantibodies when measured at the 76th day was negative (<5).

Case of linear immunoglobulin A bullous dermatosis associated with acquired hemophilia.

Linear immunoglobulin (Ig)A bullous dermatosis is a rare autoimmune subepidermal bullous dermatosis caused by circulating IgA autoantibodies directed against the antigens at the basement membrane zone. Most linear IgA bullous dermatosis cases are idiopathic, but some are associated with the use of certain drugs, infections, lymphoproliferative disorders, internal malignancies, autoimmune disorders, collagen diseases or, very rarely, other skin diseases, including autoimmune bullous diseases. Acquired hemophilia is also rare; it is a coagulation disease caused by anti-factor VIII IgG antibodies. Acquired hemophilia has been reported to be associated with malignant tumors, pregnancy or postpartum, drug reactions, collagen diseases such as rheumatoid arthritis, autoimmune disorders, and skin diseases such as psoriasis and pemphigus. We report a case of hemophilia acquired during the course of linear IgA bullous dermatosis and review reported cases of autoimmune bullous dermatoses associated with acquired hemophilia.

Case of pemphigus foliaceus that shifted into pemphigus vulgaris after adrenal tumor resection.

A 79-year-old Japanese woman visited our hospital on 6 May 2003, who had suffered from erythema and crusted vesicles located on the head, face and trunk. The eruptions first appeared in February 2003. Histopathological findings included blister formation spreading from just below the horny layers to the upper squamous layers, where acantholytic cells were observed. Direct immunofluorescence disclosed immunoglobulin G depositions in the epidermal intercellular spaces. Enzyme-linked immunosorbent assay showed an elevated titer of anti-desmoglein (Dsg)1 autoantibodies (154 index value), but almost normal levels of anti-Dsg3 autoantibodies (8 index value in serum). The diagnosis at first was made as pemphigus foliaceus (PF). Topical use of corticosteroids alone could control the eruptions well. Systemic examinations on admission revealed a right adrenal tumor that had caused Cushing's syndrome. Its resection was performed on 24 July 2003. Histopathological diagnosis of the removed tumor was a functional adrenal adenoma. The symptoms had worsened after the resection. Topical use of corticosteroids alone could no longer control the symptoms. Additional p.o. medications of minocycline hydrochloride and nicotinic acid amides improved the symptoms to some extent. However, oral cavity erosions appeared in December 2004, and the titer of anti-Dsg3 autoantibodies in serum elevated, suggesting a transition from PF to pemphigus vulgaris (PV). p.o. administration of corticosteroids started, which improved the symptoms significantly. To date, there have been no reports of pemphigus complicated with an adrenal tumor that caused Cushing's syndrome in Japan. The present case is particularly interesting in that the symptoms became worse after the tumor resection and that the first diagnosis of PF shifted into PV after the operation.

Systemic lupus erythematosus complicated with protein-losing enteropathy: a case report and review of the published works.

A 45-year-old man was referred to our hospital with a history of multiple erythematous skin lesions of several months' duration. Blood examination revealed extreme hypoproteinemia and hypoalbuminemia, as well as the presence of antinuclear antibodies. A skin biopsy specimen showed liquefaction degeneration at the dermoepidermal junction and dense lymphocyte and neutrophil infiltration around the vessels and appendages in the upper and middle dermis. Chest X-ray and computed tomography showed a pleural effusion and thoracic paracentesis revealed a mononuclear cell-dominant cell infiltration, suggestive of serositis. Technetium-99m ((99m)Tc)-labeled human serum albumin scintigraphy and α(1)-antitrypsin clearance revealed protein leakage along the digestive tracts from the stomach to the jejunum. From the above findings, the patient was diagnosed with systemic lupus erythematosus (SLE) complicated by protein-losing enteropathy (PLE). Treatment with oral prednisolone significantly improved his clinical symptoms and hypoalbuminemia. This case highlighted the utility of (99m)Tc-labeled human serum albumin scintigraphy and α(1)-antitrypsin clearance in the diagnosis of PLE. We also present a published work review on PLE associated with connective tissue disease revealing a relatively higher prevalence in patients of Asian ethnicity, including Japanese.

Necrotizing fasciitis caused by Streptococcus pneumoniae.

A 69-year-old woman presented with shivering and pain in the lower extremities on 5 April 2006; she was referred to the dermatology division of our hospital on the following day with difficulty in walking. She had been suffering from non-viral, non-alcoholic liver cirrhosis, and was being treated by the Division of Internal Medicine. Physical examination showed edema in the lower extremities and light purpuras on the groin and legs. Low blood pressure had been observed since admission. Necrotizing fasciitis (NF) was suspected on the basis of the skin symptoms, systemic conditions, and magnetic resonance imaging. During surgical debridement under general anesthesia, cardiopulmonary arrest occurred, and the patient died 12 h after admission. NF, in its early stages, exhibits few skin changes. In order to differentiate it from other skin infections, it is necessary to take into account blood pressure, abnormal systemic conditions, and severe pain out of proportion to its minor skin changes. In the present case, Streptococcus pneumoniae was detected by blood culture. Soft tissue infectious diseases caused by S. pneumoniae, especially NF, are very rare. We have reviewed reported cases of NF caused by S. pneumoniae.