Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation.

OBJECTIVES: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis. METHODS: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. RESULTS: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. CONCLUSIONS: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

Ineffectiveness of radiotherapy for the treatment of keratoacanthoma centrifugum marginatum: A case report.

Keratoacanthoma centrifugum marginatum (KCM) is a rare variant of keratoacantoma (KA). Although KCM shares histological and clinical features with KA, KCM has no tendency of spontaneous regression, and presents with progressive peripheral expansion with a bank-shaped outer wall and concurrent central healing. As such, early diagnosis and proper treatment of the patient are required. However, because of its rarity, previous reports are insufficient to evaluate which treatment should be selected. Here, we report a case of KCM that responded to radiotherapy, but relapsed 6 months later.

Severe hepatitis arising from ipilimumab administration, following melanoma treatment with nivolumab.

After 4 weeks of the last dose of nivolumab, a 59-year-old man with stage IV melanoma was subject to treatment with ipilimumab. After 5 weeks, the patient developed severe hepatitis, showing markedly elevated levels of both aspartate aminotransferase and alanine aminotransferase (>2000 U/l). Using pulse steroid therapy with 1000 mg/d of methylprednisolone, liver function initially improved, but then deteriorated upon dosage reduction. Subsequently, mycophenolate mofetil (MMF) was administered at a dose of 2 g/d in addition to the corticosteroid, which resulted in aspartate aminotransferase and alanine aminotransferase levels gradually improving to grade 1, and the corticosteroid dose was successfully reduced to 0.5 mg/kg/d of oral prednisolone. Liver function then remained stable when MMF was tapered. In conclusion, the use of MMF improved liver function in this patient with steroid-refractory hepatitis induced by immune checkpoint inhibitor administration.

[Case of metastatic malignant melanoma of the urinary bladder].

A 54-year-old woman underwent resection of malignant melanoma of the left leg and inguinal lymph node metastases and subsequent radiation therapy (60 Gy) following three courses of dacarbazine, nimustine, vincristine and interferon-beta chemotherapy in January 2010. In September 2011, she was referred to our department with the chief complaint of asymptomatic gross hematuria. A non-papillary bladder tumor was detected on cystoscopy and fluorodeoxyglucose (FDG) positron emission fomography-computed tomography revealed increased uptake of FDG only in the area of the bladder tumor. Melanoma cells were also found on urinary cytology. Our diagnosis was metastatic malignant melanoma of the bladder. Complete transurethral resection of the bladder tumor was performed, and pathological examination confirmed metastatic malignant melanoma. Metastatic bladder tumors constitute less than 5% of all bladder tumors. There are metastases in other organs at the time of diagnosis in almost all cases. In Japan, metastatic malignant melanoma of the urinary bladder is rare in clinical practice, there having been about a dozen reported cases. Solitary metastasis as in our case is even rarer.

Availability of sentinel lymph node biopsy for cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma is the second common cutaneous cancer, especially in the elderly. Sentinel lymph node biopsy is generally performed in breast cancers and cutaneous melanomas to detect occult nodal metastases. The benefit of sentinel lymph node biopsy in improving cutaneous squamous cell carcinoma prognosis is doubtful. One hundred and sixty-nine patients who underwent treatment for cutaneous squamous cell carcinoma between 2004 and 2015, and who were followed up for at least 6 months or developed metastases within the follow-up period were included. Forty-nine patients underwent sentinel lymph node biopsy, whereas 120 patients did not, including 13 who exhibited clinical lymph node metastases before treatment. Of these 49 patients, nine (18.4%) presented with sentinel lymph node metastasis, which occurred after treatment in three (6.1%) of them (false-negative). Among the 107 patients who did not undergo lymph node biopsy, 12 (11.2%) developed post-treatment metastases. The metastasis-free and disease-specific survival rates were not significantly different in those who did or did not undergo sentinel lymph node biopsy. Patients with clinical lymph node metastases had a higher risk compared with those without. Patients with T2-T4 tumors had a higher risk compared with those with T1 tumors. When selecting for those with T2 tumors or greater, the same lack of relationship was observed. In conclusion, in this small retrospective cohort, in patients with cutaneous squamous cell carcinoma, there were no significant differences in metastasis-free and disease-specific survival rates between those who did or did not undergo sentinel lymph node biopsy, regardless of T staging.

Pyoderma gangrenosum and underlying diseases in Japanese patients: A regional long-term study.

Pyoderma gangrenosum (PG) is a chronic inflammatory disease of unknown cause that presents as an inflammatory and ulcerative disorder of the skin. PG is often associated with an underlying systemic disease. However, the frequencies of the underlying diseases are unclear in Japanese patients. In this retrospective, observational study, all patients diagnosed with PG who visited dermatology departments of nine regional hospitals in and around Ibaraki Prefecture were collected from 1982 to 2011 or 2014. The diagnoses of PG were based on the characteristic clinical and histological appearances and ruling out of infection. Sixty-two PG patients, including 29 males and 33 females, were identified. The ages of onset were 16-89 years, and the mean age was 50.2 years. Fifty (80%) of the 62 patients presented with an ulcerative PG, and the lower leg was the most common site (74%). Forty-six (74%) PG patients had underlying diseases. The most frequent was ulcerative colitis (32%), followed by myelodysplastic syndrome (11%), rheumatoid arthritis (6%) and aortitis syndrome (5%). For treatment, 54 cases (87%) received systemic corticosteroids and 10 received additional treatment with cyclosporin. There was no significant correlation between underlying diseases and response to the initial treatment. Multivariate analysis revealed that the number of affected sites negatively correlated with successful initial treatment. Fifteen (24%) of the 62 cases relapsed. In conclusion, ulcerative colitis and hematological disorders were frequently associated with PG while approximately a quarter of the cases were idiopathic.

Phosphaturic mesenchymal tumor, mixed connective tissue type, non-phosphaturic variant: report of a case and review of 32 cases from the Japanese published work.

Phosphaturic mesenchymal tumor, mixed connective tissue type (PMTMCT) is a rare neoplasm that can cause tumor-induced osteomalacia due to overproduction of a phosphaturic hormone, fibroblast growth factor 23 (FGF23). We report here a case of subcutaneous PMTMCT, non-phosphaturic variant, in the sole. We also review 32 Japanese cases of PMTMCT reported in detail. They occurred in 16 men and 15 women (one was unknown), with ages ranging 20-73 years (median, 48). Tumors were found in soft tissue, bone and sinuses in 17, 11 and four, respectively. A history of long-standing osteomalacia was noted in all cases except two non-phosphaturic variant cases. Serum FGF23 level was elevated in 11 of 12 cases examined. In terms of follow-up information, metastases were found in four patients, and two patients died of disease. In conclusion, PMTMCT is histologically a benign lesion; however, there may be rare metastatic and malignant cases. Wider recognition of the histological features of this unique neoplasm would aid its distinction from the large number of mesenchymal tumors for which it may be mistaken and should enable correct diagnosis of tumors with osteomalacia.

Verrucous spitz nevus in a Japanese female.

A 23-year-old female presented with a reddish-brown dome-shaped hyperkeratotic nodule of 11 × 10 mm on the left lower leg. Dermoscopic examination demonstrated a prominent whitish scaly area with ring-like appearance, pinkish-white structureless areas, a few milia-like cysts, dotted and glomerular vessels, and light brown globules. The lesion was completely excised under the diagnosis of verruca vulgaris or dermatofibroma. Histopathological examination revealed a well-circumscribed symmetric lesion with hyperkeratosis, acanthosis, and pseudohorn cysts. The lesion was composed of spindle-shaped and epithelioid melanocytes with large cytoplasm arranged in confluent nests surrounded by stromal fibrosis. Mitotic figures and Kamino bodies were absent. Moderate proliferation of capillaries was found in the papillary dermis. Immunohistochemical staining with melan-A or S-100 was positive for tumor cells, but the staining with HMB-45 was negative. Melan-A staining was weaker in the deeply situated cells than in the superficial ones, which is known as stratification. Finally, we made a diagnosis of verrucous Spitz nevus based on these findings. We should have been aware of the entity of verrucous Spitz nevus as a variant of Spitz nevus and its dermoscopic features in order to reach a correct diagnosis before excision.

Two cases of tuberculosis with multiple drug hypersensitivity after drug-induced hypersensitivity syndrome.

Here, we report 2 cases of drug-induced hypersensitivity syndrome (DIHS) caused by salazosulfapyridine and allopurinol during tuberculosis treatment. Both patients also developed multiple drug hypersensitivity (MDH) to several antituberculosis drugs that were used at around the period of DIHS onset, and thus, the treatment could not be successfully completed. Our cases show that MDH can easily occur after development of DIHS. Considering that treatment for tuberculosis requires long-term management with several drugs, it is important to refrain from administering drugs that can cause DIHS during tuberculosis treatment.