以发热、关节炎、皮肤色素沉着为主要表现的血管免疫母细胞性T细胞淋巴瘤1例

Abstract

Angioimmunoblastic T-cell lymphoma is a rare T-cell lymphoma. The clinical manifestations are not specific. In addition to the common clinical manifestations of lymphomas such as fever, weight loss, night sweats and lymphadenopathy, it may also have skin rashes, arthritis, multiple serous effusions, eosinophilia and other systemic inflammatory or immune symptoms. The lymphoma cells of angioimmunoblastic T-cell lymphoma originates from follicular helper T cells, and the follicular structure of lymph nodes disappears. In the tumor microenvironment, in addition to tumor cells, there are a large number of over-activated immune cells, such as abnormally activated B cells, which produce a series of systemic inflammation or immune-related symptoms. This disease is rare and difficult to diagnose. This article reports a 36-year-old female. She got fever, joint swelling and pain, skin pigmentation, accompanied by hepatomegaly, splenomegaly, lymphadenopathy, anemia and other multiple-systems manifestations. The clinical manifestations of this patient were similar to autoimmune diseases such as adult onset Still's disease, rheumatoid arthritis, and systemic sclerosis, which made the diagnosis difficult. At the beginning of the disease course, the patient got arthritis and fever. And her white blood cells were significantly increased. Adult onset Still's disease should be considered, but her multiple-systems manifestations could not be explained by adult onset Still's disease. And her arthritis of hands should be distinguished with rheumatoid arthritis. However, the patient's joint swelling could get better within 3-7 days, and there was no synovitis and bone erosion on joint imaging examination. The rheumatoid factor and anti-CCP antibody were negative. The diagnostic evidence for rheumatoid arthritis was insufficient. The patient's skin pigmentation and punctate depigmentation were similar to those of systemic sclerosis. But the patient had no Raynaud's phenomenon, and her sclerosis-related antibody was negative. The diagnostic evidence for systemic sclerosis was also insufficient. After 3 years, she was finally diagnosed with angioimmunoblastic T-cell lymphoma by lymph node biopsy aspiration. This case suggests that the clinical manifestations of angioimmunoblastic T-cell lymphoma are diverse, and some symptoms similar to immune diseases may appear. When the patient's clinical symptoms are atypical and immune diseases cannot explain the patient's condition, and further evidence should be sought to confirm the diagnosis.

1. 病例资料

患者, 女，36岁，主因“间断关节肿痛、发热3年余，皮肤色素沉着1年半”于2019年8月入北京大学人民医院风湿免疫科住院治疗。3年多前患者无明显诱因出现反复双膝关节肿痛，肿胀3~7 d可自行缓解，伴发热，体温最高39.5 ℃，发热与关节肿痛无平行关系，未见皮疹，白细胞21.40×10⁹/L，血红蛋白及血小板未见异常，C-反应蛋白21 mg/L，铁蛋白210.5 μg/L(ng/mL)，X线片提示双膝关节未见异常，予泼尼松片40 mg每日1次口服，上述症状缓解，白细胞降至正常，激素逐渐减量至停药(共服用4个月)，后未再发热。2年多前出现全身多关节疼痛，呈游走性，伴间断关节肿胀，乏力明显，化验提示中度贫血，抗人球蛋白试验++，骨髓穿刺涂片提示骨髓增生Ⅲ级，无血液系统恶性疾病证据。予对症治疗，症状时轻时重。2年前起停经。1年半前开始逐渐出现关节活动受限，双手握拳不实，双腕屈曲受限，伴颈部皮肤色素沉着，且逐渐延及躯干和四肢，伴局部斑点状色素脱失，腋部、阴部毛发脱落，无雷诺(Raynaud)现象，食欲减退，消瘦，体质量下降约18 kg, 上述症状进行性加重，且入院前2~3个月再次出现间断低热，体温最高38 ℃，无反复口腔溃疡、脱发、光过敏、口干、眼干等。查体:体温37.3 ℃，体型消瘦，除额面部外全身色素沉着，伴斑点状色素脱失，双前臂皮肤弹性减退。双侧腋窝及腹股沟可触及数枚肿大淋巴结，大者约2 cm×3 cm，活动可，无压痛。心肺查体(-)，腹软，全腹无明显压痛、反跳痛及肌紧张，肝肋下5 cm，脾肋下2横指。双膝关节肿胀、压痛，双膝浮髌试验(+)，左腕活动受限，左手2~4指可疑天鹅颈样畸形(图 1)。

图 1.

患者的临床表现

Clinical manifestations

A, suspected swan neck-like deformation of the patient's 2 to 4 fingers on both hands; B, pigmentation of the back skin with punctate depigmentation; C, swelling of the knee joint and pigmentation of the surrounding skin.

入院后完善各项辅助检查。血常规:白细胞4.20×10⁹ /L，中性粒细胞3.30×10⁹ /L，淋巴细胞0.50×10⁹ /L，血红蛋白72 g/L，血小板115×10⁹ /L。C-反应蛋白22.55 mg/L，红细胞沉降率115 mm/h，降钙素原正常。尿、便常规和肝、肾功能正常。D-Dimer 1 156 μg/L(ng/mL)。IgA 5.73 g/L，IgG 22.2 g/L，IgM 1.310 g/L，IgE＞2500 IU/mL，补体C3 0.960 g/L，补体C4 0.239 g/L，类风湿因子阴性。抗人球蛋白试验+, 肿瘤标记物、病原学、自身抗体谱、血/尿M蛋白均阴性。

手关节彩超:部分指间关节骨赘; 多屈指肌腱腱周积液，未见滑膜炎及骨侵蚀。腹部增强CT提示肝、脾大; 纵隔、双侧锁骨上窝、双侧腋窝、腹腔、腹膜后及双侧腹股沟多发肿大淋巴结。PET-CT提示，全身多发脱氧葡萄糖(flurodeoxyglucose, FDG)代谢增高灶，累及骨及多淋巴结区，肝脾大伴FDG代谢增高。肌电图:神经源性损害(四肢运动、感觉纤维均受累，下肢最为显著)。

甲状腺功能检查:FT3 2.73 pmol/L，FT4 10.71 pmol/L，TSH 3.548 mIU/L(μIU/mL)，其余均在正常范围内。性腺功能:卵泡刺激素0.86 IU/L，黄体生成素＜0.20 IU/L，雌二醇35.47 ng/L(pg/mL)，孕酮0.83 μg/L(ng/mL)，泌乳素15.53 μg/L(ng/mL)，睾酮＜0.10 nmol/L。垂体磁共振未见异常。

皮肤活检:上皮角不规则下延，真皮乳头层及浅层见色素沉积。

腋窝淋巴结活检病理提示(图 2):淋巴结正常结构不清楚，可见弥漫增生的淋巴样细胞，细胞中等大小，部分细胞中等偏大，部分细胞胞浆透明，小血管增生，免疫组化染色发现CD20(－)，PAX5(－)，CD3(+)，CD5(+)，CD23、CD21(FDC+)，CD10(灶+)，CD43(+)，CD8(bf +)，CD4(+)，CD56(－)，CD30(－)，Bcl-6(－)，CD2(+)，CD7(+)，CXCL13(+)，TIA1(+)，GramB(+)，CD138(灶+)，Ki67(70%+)，EBER(－)。病理考虑血管免疫母细胞性T细胞淋巴瘤。

图 2.

腋窝淋巴结活检病理切片(HE染色)

Pathology of axillary lymph node biopsy (HE staining)

A, ×100; B, ×400.

经多学科团队讨论，考虑患者血管免疫母细胞性T细胞淋巴瘤诊断，患者转至血液科继续行化疗治疗。

2. 讨论

血管免疫母细胞性T细胞淋巴瘤是一种罕见的T细胞淋巴瘤，临床表现不特异，除发热、体质量下降、盗汗、淋巴结肿大等淋巴瘤共同临床表现外，也可有皮疹、关节炎、多浆膜腔积液、嗜酸性粒细胞增多等全身炎症/免疫性疾病表现^[1-3]。本例患者表现为间断发热、多关节炎、皮肤色素沉着伴斑点状色素脱失，肝、脾、淋巴结肿大，贫血等多系统受累。

本例患者临床表现与多种自身免疫病，如与成人Still病、类风湿关节炎、系统性硬化病等表现相似，给诊断带来困难。

在病程初期，患者最先以关节炎、高热起病，白细胞明显升高，抗生素治疗无效，激素治疗有效，应考虑成人Still病可能，但患者无皮疹，且关节痛和发热关系不平行，患者后续出现皮肤色素沉着、色素脱失，以及其他多系统受累表现，用成人Still病不能解释患者病情全貌。

从关节炎角度来看，患者多关节肿痛，双手2~4指可疑天鹅颈样变形，应与类风湿关节炎相鉴别，但患者关节肿胀3~7 d即可好转，X线片未见骨质破坏，关节超声未见滑膜炎及骨侵蚀，类风湿因子及抗CCP抗体阴性，考虑类风湿关节炎诊断证据不足。

患者皮肤弹性减退、色素沉着伴点状色素脱失，与硬皮病皮肤表现类似，但患者无雷诺现象，硬皮病抗体谱阴性，皮肤活检未见典型硬皮病表现，肺CT未见明显异常，考虑系统性硬化病诊断证据不足。

除自身免疫病外，患者有肝、脾肿大，内分泌异常，皮肤病变，需考虑POEMS(polyneuropathy organomegaly endocrinopathy momoclonal protein skin changes)综合征，患者虽然无神经系统自觉症状，但肌电图提示神经源性损害，似乎印证了POEMS综合征的初步诊断，但后续化验结果提示，患者无血、尿M蛋白，以及VEGF升高等表现，POEMS综合征诊断证据不足。

淋巴结活检最终明确了血管免疫母细胞性T细胞淋巴瘤的诊断，而患者内分泌异常方面主要表现为低促性腺激素性性腺功能减退及低T3综合征，考虑可能与疾病消耗状态相关。

血管免疫母细胞性T细胞淋巴瘤起源于滤泡辅助性T细胞，淋巴结的滤泡结构消失，其肿瘤微环境中除肿瘤细胞外，存在着大量过度活化的免疫细胞，如异常活化的B细胞，产生一系列全身炎症或免疫相关症状，故而除淋巴瘤常见发热、乏力、盗汗、体质量下降等症状外，该病全身免疫系统表现尤为突出^[4-6]。本例患者表现为关节炎、皮肤表现及血清免疫球蛋白升高、Coombs试验阳性等。该病的症状有时与自身免疫病难以鉴别，淋巴结活检是确诊的关键。

Funding Statement

北京大学人民医院研究与发展基金(RDX 2019-02)

Supported by Peking University People's Hospital Research and Development Funds(RDX 2019-02)