論文

Title:Case of squamous cell carcinoma showing delayed metastasis and histologically exhibiting alterations of the surrounding immune cell populations along with the tumor invasion: Expression of monocyte chemotactic protein-1 in deeply invaded tumor cells and interleukin-6 in surrounding histiocytes

Cutaneous angiosarcoma (CAS) is a malignant sarcoma with poor prognosis. Programmed cell death-1 (PD-1)/programmed cell death-1 ligand-1 (PD-L1) expression reflects antitumor immunity, and is associated with patient prognosis in various cancers. The purpose of this study is to investigate the relationship between PD-1/PD-L1 expression and CAS prognosis. CAS cases (n = 106) were immunohistochemically studied for PD-L1 and PD-1 expression, and the correlation with patient prognosis was analyzed. PD-L1 expression was assessed by flow cytometry on three CAS cell lines with or without IFNgamma stimulation. A total of 30.2% of patients' samples were positive for PD-L1, and 17.9% showed a high infiltration of PD-1-positive cells. Univariate analysis showed a significant relationship between a high infiltration of PD-1-positive cells with tumor site PD-L1 expression and favorable survival in stage 1 patients (p = 0.014, log-rank test). Multivariable Cox-proportional hazard regression analysis also showed that patients with a high infiltration of PD-1-positive cells with tumor site PD-L1 expression were more likely to have favorable survival, after adjustment with possible confounders (hazard ratio (HR) = 0.38, p = 0.021, 95% confidence interval (CI) 0.16-0.86). Immunofluorescence staining of CAS samples revealed that PD-L1-positive cells were adjacent to PD-1-positive cells and/or tumor stroma with high IFNgamma expression. In vitro stimulation with IFNgamma increased PD-L1 expression in two out of three established CAS cell lines. Our results suggest that PD-1/PD-L1 expression is related to CAS progression, and the treatment with anti-PD-1 antibodies could be a new therapeutic option for CAS.

<症例のポイント>尋常性天疱瘡の小児発症例はまれであり、今回われわれは4歳で発症した尋常性天疱瘡の1例を報告した。高用量ステロイド内服で速やかに症状は改善し、10ヵ月で寛解に至った。年齢を問わず難治性口腔内びらんの鑑別として、尋常性天疱瘡をあげるべきである。(著者抄録)

<症例のポイント>放射線照射部位に一致して再燃した落葉状天疱瘡の1例を報告した。放射線照射後、皮疹の再燃に伴って血中抗デスモグレイン(Dsg)1抗体ELISA値が上昇、局所外用治療により低下した。皮疹が照射部に限局した理由として、放射線照射により表皮細胞間結合の構造が変化する可能性や、正常免疫応答が阻害され無疹部より抗原抗体反応が生じやすくなっている可能性を考えた。局所外用治療で皮疹軽快、抗Dsg1抗体ELISA値が低下した経過から、局所の免疫制御機構が自己抗体産生に関連している可能性が示唆された。自己免疫性水疱症を基礎疾患にもつ患者に放射線療法を施行する場合、症状を再燃させる可能性を留意すべきである。(著者抄録)

<症例のポイント>間擦部に皮疹を有する増殖性天疱瘡を報告した。初診時および治癒過程の皮膚症状と病理組織像を比較検討し、増殖性は表皮肥厚と真皮浮腫という2つの要素によるものと考えた。増殖性局面の形成に好酸球が重要な役割を果たしている可能性があると思われた。(著者抄録)

BACKGROUND: An anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell-derived or immune cell-derived markers and clinical predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice. METHODS: We retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks. RESULTS: As for pretreatment prognostic factors, ECOG performance status (PS) >/=1, maximum tumor diameters of >/=30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio [HR] 0.29 [P<0.001], HR 0.40 [p=0.003], HR 0.29 [P<0.001], HR 0.42 [P=0.004], respectively) on univariate analysis. Among these factors, PS and LDH were identified as independent variables by multivariate analysis. As for early markers examined during therapy, patients with absolute lymphocyte count (ALC) >/= 1000/mul (Week3: HR 0.40 [P=0.004], Week6: HR 0.33 [P=0.001]) and absolute neutrophil count (ANC) <4000/mul (Week3: HR 0.46 [P=0.014], Week6: HR 0.51 [P=0.046]) had significantly better OS. CONCLUSION: ALC>/=1000/mul and ANC<4000/mul during treatment appear to be early markers associated with OS. Nivolumab might have minimal efficacy in patients with a massive tumor burden.

59歳女。原発性免疫不全症候群(選択的IgA2欠損症)患者であり、14年前より口唇左上部の皮下硬結が出現し、粉瘤の診断で経過観察されていたが、4年前に全摘生検を行い、腺癌と診断された。追加切除目的で受診し、上口唇左上部にやや弾性硬で多毛を伴う淡紅色の皮下硬結(9.5×8.5mm大)を認めた。病理組織学的所見では角質嚢腫が少ないものの異型性の乏しい腫瘍細胞が管腔構造を形成しながら間質に浸潤性に増殖しており、免疫染色にてCK7陽性、CK20陰性であった。微小嚢胞性付属器癌と診断して腫瘍切除、皮弁形成術と瘢痕拘縮形成術を行い、術後4年経過現在、再発・転移を認めていない。