Masahiro Amano

CD56: a useful marker for diagnosing Merkel cell carcinoma

BACKGROUND Merkel cell carcinoma (MCC) of the skin is an aggressive but rare malignant neuroendocrine tumor. For its pathological diagnosis, we use a panel of immunohistochemical markers, such as cytokeratin 20 (CK 20), epithelial membrane antigen (EMA), chromogranin A, neuron specific enolase (NSE), synaptophysin, and Leu7 (CD57) to demonstrate its epithelial and neuroendocrine features. CD56, or neural cell adhesion molecule (NCAM), has been demonstrated recently as the tumor marker of the pulmonary neuroendocrine cell system. Its expression in MCC, however, has still rarely been investigated. Furthermore, in such very few previous studies on NCAM expression in MCC, all the tumor cells were not necessarily demonstrated to express NCAM. OBJECTIVES To study the immunoreactivity of CD56 in MCC, especially using a monoclonal antibody of a clone 1B6, different from those adopted in the previous reports. METHODS We reexamined CD56 expression immunohistochemically in five MCC cases, along with the conventional panel of markers described above, using paraffin-embedded tissue sections. RESULTS CD56 revealed the most diffuse and intense positive staining, which was noted along the cell borders, in all specimens compared with other neuroendocrine tumor markers. CONCLUSIONS The results of our study indicate that CD56, especially a new monoclonal antibody (clone 1B6), is a useful immunohistochemical marker for MCC.

New entity, definition and diagnostic criteria of cutaneous adult T-cell leukemia/lymphoma : Human T-lymphotropic virus type 1 proviral DNA load can distinguish between cutaneous and smoldering types

Adult T‐cell leukemia/lymphoma (ATLL) has been divided into four subtypes up to now: (i) acute; (ii) lymphoma; (iii) chronic; and (iv) smoldering. Skin lesion(s) may be present and the cases showing less than 5% abnormal T‐lymphocytes in peripheral blood without involvement of other organs, have been classified as smoldering ATLL. However, this type of ATLL with skin manifestations had a worse prognosis than that without skin lesions. This study aimed to define and distinguish cutaneous ATLL lacking nodal lymphoma and leukemic change from smoldering ATLL. We propose an entity of cutaneous ATLL, which has less than 5% abnormal T lymphocyte in peripheral blood, a normal lymphocyte count (i.e. <4 × 109/L), no hypercalcemia and lactate dehydrogenase values of up to 1.5 times the normal upper limit. At least one of the histologically proven skin lesions should be present accompanying monoclonal integration of human T‐cell lymphotropic virus type 1 (HTLV‐1) proviral DNA in the skin lesion. Blood samples were collected from 41 HTLV‐1‐infected patients, 21 asymptomatic carriers, 16 patients with cutaneous ATLL and four patients with smoldering ATLL. HTLV‐1 proviral loads, soluble interleukin‐2 receptors and other parameters were examined in each case. HTLV‐1 proviral DNA loads in smoldering ATLL group are significantly higher than those in asymptomatic carrier and cutaneous ATLL group. Cutaneous ATLL may be a distinct entity that should be separated from smoldering ATLL clinically and virologically.

Phase II study of i.v. interferon-gamma in Japanese patients with mycosis fungoides

A multisite, open‐label, non‐randomized, single‐arm phase II study was conducted to evaluate the efficacy and safety profiles of interferon‐γ in Japanese patients diagnosed with stage IA–IIIA mycosis fungoides (MF). Interferon‐γ was administrated i.v. to 15 patients at a dose of 2 million Japan reference units once daily over 5 days a week for the first 4 weeks, followed by subsequent intermittent injection. The primary efficacy end‐point was the overall skin response during the study as assessed according to the evaluation criteria for chemotherapeutics for malignant skin carcinomas. Of the 15 patients, 11 (73.3%) achieved the objective response. Of the other four patients, three remained on treatment during study with stable disease and one showed disease progression. The median duration of stable disease was not reached but was 170 days or more (range, 29 to ≥253 days). As assessed according to the modified severity weighted assessment tool, nine patients (60.0%) achieved the objective response. The most common drug‐related adverse event (AE) was influenza‐like illness occurring in all patients enrolled, which did not lead to discontinuation of the study. Two serious AE were reported in two patients: aggravation of MF and aggravation of cataract, neither of which was considered directly related to the study drug. The patient with aggravation of MF died 50 days after the initiation of the study treatment. Another patient was withdrawn from the study due to drug‐related cough, which disappeared after discontinuation of the drug. Overall, interferon‐γ was effective and well‐tolerated in Japanese patients with MF.

Epstein–Barr virus-associated primary central nervous system lymphoma in a patient with adult T-cell leukemia / lymphoma

We present a case of Epstein–Barr virus (EBV)‐associated primary central nervous system lymphoma (PCNSL) arising from a patient with cutaneous‐type adult T‐cell leukemia/lymphoma (ATLL). Extranodal sites affected by ATLL include the skin, lung, liver, gastrointestinal tract and central nervous system (CNS). CNS involvement usually occurs as an acute and lymphoma‐type ATLL. PCNSL is a rare type of tumor and the vast majority of PCNSL are of B‐cell lineage. Individuals with acquired, iatrogenic or congenital immunodeficiency are at increased risk of PCNSL, which is commonly associated with EBV. In our patient, the expression of latent infection membrane protein 1 (LMP1), EBV nuclear antigen 2 (EBNA2), and EBV‐encoded small RNA (EBER) in tumor cells confirmed a type III latency of EBV infection. Human T‐cell lymphotropic virus type I (HTLV‐I) can induce immunodeficiency before the overt development of ATLL. The HTLV‐I infection led to suppression of the immune system and the development of EBV‐associated PCNSL. This is the first reported case of the clinicopathological features of EBV‐associated PCNSL arising from a patient with ATLL.

Dermatan 4-O-sulfotransferase 1-deficient Ehlers-Danlos syndrome complicated by a large subcutaneous hematoma on the back.

Dear Editor A 13-year-old Japanese boy was admitted to our hospital for the treatment of a massive subcutaneous hematoma on the back. He was born to healthy parents, who were second cousins once removed. At birth, he was diagnosed with arthrogryposis. He had bilateral cryptorchidism, corrected surgically at the age of 1 year. Bilateral hydronephrosis was detected in infancy. At the age of 12 years, he developed perforation of colon diverticula. He had had multiple episodes of large subcutaneous hematomas. The hematoma, which had enlarged rapidly after being hit by a chair, was painful and 23 cm 9 28 cm in size (Fig. 1a, b). He had a round face with hypertelorism, short palpebral fissures, strabismus, a short nose with a hypoplastic columella, low-set and rotated ears, and microretrognathia (Fig. 1c). His skin was hyperextensible (Fig. 1d), redundant (Fig. 1a,b) and fragile (tearing after minor traumas) with atrophic scars on bilateral elbows (Fig. 1a), knees and buttocks. He had cylindrical and slender fingers with clinodactyly (Fig. 1e), and fine acrogeria-like palmar creases (Fig. 1f,g). He had hypermobility especially in small joints (Beighton score, 4), talipes valgus and planus (Fig. 1h,i), and rigidity of bilateral shoulders. Hematoxylin–eosin-stained light microscopy of the skin specimen from the upper arm showed that fine collagen fibers were predominant in the reticular to papillary dermis and normally thick collagen bundles were markedly reduced (Fig. 1j). Electron microscopy showed that the collagen fibrils were dispersed in the reticular dermis, whereas each collagen fibril was smooth and round, not varying in size and shape (Fig. 1l), as compared with a skin specimen from an age-matched control (Fig. 1k). He was suspected to have dermatan 4-O-sulfotransferase 1 (D4ST1)-deficient Ehlers–Danlos syndrome (DDEDS). Direct sequencing of the gene, carbohydrate sulfotransferase 14 (CHST14) encoding D4ST1, detected a homozygous missense mutation (c.842C>T; p.Pro281Leu), commonly identified in Japanese patients (Fig. 1m). Dermatan 4-O-sulfotransferase 1-deficient EDS is a recently delineated form of EDS, clinically characterized by progressive multisystem fragility-related manifestations (skin (e) (g)

Prognostic index for chronic- and smoldering-type adult T-cell leukemia-lymphoma

Adult T-cell leukemia-lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering ATL. We conducted a nationwide retrospective survey on ATL patients, and 248 fully eligible individuals were used in this analysis. In the univariate analysis, sex, performance status, log10 (soluble interleukin-2 receptor [sIL-2R]), neutrophils count, and lymphadenopathy showed values of P < .05 in training samples. A multivariate analysis was performed on these factors, and only log10 (sIL-2R) was identified as an independent prognostic factor in training samples. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: indolent ATL-PI (iATL-PI) = 1.51 × log10 (sIL-2R [U/mL]). The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6 years, 5.5 years, and not reached for patients in the high-, intermediate-, and low-risk groups, respectively (P < .0001). To make the scoring system clinically practicable, we simplified iATL-PI according to trichotomizing sIL-2R at 1000 and 6000 U/mL, using a quartile point. Patients with more than 6000 U/mL sIL-2R were categorized into the high-risk group, less than and equal to 1000 U/mL into the low-risk group, and the others into the intermediate-risk group, and MSTs were 1.6 years, not reached, and 5.5 years, respectively (P < .0001). iATL-PI has potential as a novel tool for a risk-adapted therapeutic approach.

Meeting report on the possible proposal of an extranodal primary cutaneous variant in the lymphoma type of adult T-cell leukemia-lymphoma

Based on the advances in research on the clinicopathophysiology of adult T‐cell leukemia‐lymphoma (ATL), Japanese researchers collected and evaluated cases of smoldering ATL exhibiting primary cutaneous manifestation but showing poor prognosis. Macroscopic findings of skin eruptions were categorized into the patch, plaque, multipapular, nodulotumoral, erythrodermic and purpuric types, as previously reported. Pathological findings were divided into low or high grade based on epidermotropism, tumor cell size and perivascular infiltration. Eight eligible cases were evaluated among 14 collected cases. Macroscopic findings were nodulotumoral in six cases, a subcutaneous tumor in one case and plaque in one case, and the number and size were heterogeneous in each case. Pathological findings of all eight cases were T‐cell lymphoma, high‐grade type (pleomorphic, medium or large size), with prominent perivascular infiltration and scant epidermotropism. To diagnose such cases as the “lymphoma type of ATL, extranodal primary cutaneous variant”, it is essential to examine each case carefully, including cutaneous lesions at onset, lymph nodes and other organ involvement using computed tomography (CT) and/or positron emission tomography/CT, as well as the percentage of abnormal lymphocytes in peripheral blood. Based on the results of an ongoing nationwide survey on ATL, ATL with cutaneous lesions will be analyzed to investigate the incidence and prognosis of the so‐called “lymphoma type of ATL, extranodal primary cutaneous variant”.

A Case of Nivolumab-Induced Severe Mononeuropathy Multiplex and Rhabdomyolysis

We report an 81-year-old man with multiple liver metastases after tumorectomy for primary mediastinal malignant melanoma, who experienced limb weakness and sensory disturbance after nivolumab monotherapy. He was diagnosed with nivolumab-induced mononeuropathy multiplex and rhabdomyolysis based on serologic examination, muscle biopsy, magnetic resonance imaging of the limbs, and a nerve conduction study. A course of intravenous methylprednisolone (mPSL) was initiated at 1 g/day for 3 days. After that, oral prednisolone (PSL) was started at 1 mg/kg/day and gradually tapered. Limb muscle strength improved, but when PSL was reduced to 0.3 mg/kg/day, the weakness recurred, and a nerve conduction study showed exacerbation of mononeuropathy multiplex. The patient was again administered intravenous mPSL (0.5 g/day for 3 days) followed by oral PSL at 0.5 mg/kg/day, and his neurological symptoms improved. Nivolumab, an immune checkpoint inhibitor, is used for the treatment of advanced melanoma and other cancers and causes various immune-related adverse events (irAEs). However, neurological irAEs related to nivolumab are rare. Furthermore, there are no reports of simultaneous nerve and muscle impairment. Unexpected irAEs affecting various organs should be recognized and treated appropriately.

Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010-2011: A nationwide survey

Adult T‐cell leukemia–lymphoma (ATL) is a mature T‐cell malignancy associated with human T‐cell leukemia virus type 1 (HTLV‐1) infection. Japan is the most endemic country for HTLV‐1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV‐1 carriers spread from endemic areas to non‐endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital‐based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60–75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu–Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one‐third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV‐1 carrier status are needed.

Nail apparatus melanoma in a Japanese population: a comparative study of surgical procedures and prognoses in a large series of 151 cases

BackgroundNail apparatus melanoma (NAM) is a rare subtype of malignant melanoma with a prevalence that varies among populations. Conservative surgical approaches for thin to intermediate NAMs have recently been reported, however, their adoption is controversial, and resulting long-term prognoses are unknown.ObjectivesThe purpose of this study was to determine the prognosis of NAM in a sample Asian population, and to investigate whether there is a difference in the local control and overall survival (OS) rates according to the extent of resection of the primary tumour.Materials & methodsWe performed a retrospective study of NAM patients treated at five medical institutions in Japan between 2000 and 2013. Outcomes according to surgery (amputation vs. resection) and tumour thickness were compared.ResultsWe identified 151 cases of NAM in 83 men and 68 women; the thumb (n = 50; 33.1%) and hallux (n = 55; 36.4%) were the most common sites. No local recurrence was detected following any of the surgical procedures; Kaplan-Meier survival analysis revealed that the surgical procedure type was not significantly associated with disease-free survival (p = 0.786) or OS (p = 0.997). Five-year OS rates according to tumour thickness were 100% for in situ, 94.4% for ≤1-mm, 91.7% for 1.01-2.0-mm, 72.7% for 2.01-4.0-mm, and 47.6% for ≥4.01-mm tumours.ConclusionSurgical procedure type does not influence survival as long as total primary tumour resection is accomplished. The prognosis of NAMis comparable to that of other types of melanoma.