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以眼科首诊的朗格汉斯细胞组织细胞增生症一例

A case of Langerhans cell histiocytosis first diagnosed in ophthalmology

来源期刊： 眼科学报 | 2023年9月 第38卷 第9期： 652-660 发布时间： 收稿时间：2024/1/17 15:19:47 阅读量：2241
作者：
尹雪,
杨晖,
傅征,
张琳,
关键词：
肿物朗格汉斯细胞组织细胞增生症病理活组织检查病例报告
tumor Langerhans cell histiocytosis (LCH) pathological biopsy case report
DOI：
10.12419/2301280001
患者，男性，1岁9个月。以“发现右眼上、下眼睑肿物25 d”首诊于眼科，要求切除，但经影像学及病理学检查，诊断为多发性朗格汉斯细胞组织细胞增生症，且全身骨骼多处出现溶骨性改变，不符合切除指征。给予多次全身化学治疗后眼部肿物明显变小。该例诊治提醒眼科医生，眼部肿物可由全身系统性疾病引起，不可盲目切除，必要时做进一步检查。术中切除物均建议行病理活组织检查，以免延误治疗。
patient, male, 1year and 9months old, was first diagnosed as “eye tumor” in the ophthalmology department and requested for excision. But it was diagnosed as multiple Langerhans cell histiocytosis (LCH) through imaging and pathological examination ultimately.Bone lytic changes appeared in many parts of the whole body, which did not meet the indication of excision.The tumor was smaller after systemic chemotherapy. The diagnosis and treatment of this case suggests ophthalmologists that eye tumors can be caused by caused by systemic diseases, systemic diseases. During operation, it is recommended to perform pathological biopsy to avoid treatment delay.
朗格汉斯细胞组织细胞增生症(Langerhans cell histiocytosis,LCH)是一种罕见的以CD1a/CD207阳性的未成熟树突状细胞增殖为特征的炎性髓系肿瘤，病变主要表现为不规则骨源性软组织肿块[1]。LCH多见于儿童，可累及眼眶和眼周皮肤，形成眼部肿物，容易误诊，为提高眼科医生对该病的认识水平，改善患者预后，现将病例报告如下。

1 病例资料

患儿，男性，1岁9个月。主诉“发现右眼上、下睑缘肿物25 d”。家属25 d前发现患儿右眼上、下睑有肿物隆起，且有变大的趋势，于2021年7月27日就诊于我院眼科门诊，要求手术切除。既往史和家族史无特殊。门诊专科检查：患儿右眼上、下睑颞侧各见一圆形隆起肿物，下睑肿物呈紫红色，边界请，直径约2 cm，破溃处已结痂，上睑肿物呈圆形隆起，位于皮下，直径约1.5 cm，质地中等，无压痛，活动度差，边界不清(图1)。角结膜情况可，红光反射可见。眼球运动不配合，遮挡单眼可追物。
图 1 患儿初诊时眼部情况，右眼上、下睑见肿物隆起
Figure 1 At first visit,mass swelling was found in the upper and lower eyelid of the right eye
门诊行局部B超检查(图2)：右额部至右眼角外侧至面颊部皮下软组织层多个混合性回声区：软组织蜂窝织炎伴脓腔形成伴上颌窦炎伴上颌骨破坏？遂行头颅CT检查(图3)：怀疑朗格汉斯细胞组织细胞增生症，建议进一步检查。遂立即收入院，完善全身检查：神志清楚，精神反应可，全身皮肤、黏膜无黄染，无瘀点、瘀斑，头颅无畸形，肝脾触诊未见阳性体征。右侧颞部及头顶部颅骨可触及缺损，大小分别为3 cm×5 cm、1.5 cm×3 cm，前囟近闭。眼部检查同门诊。颈软、无抵抗，心肺腹及神经系统查体未见明显异常。B超检查：双肾、肾上腺区、肝脏、胰腺、脾脏、睾丸及附睾未见明显异常。脊柱全长DR(图4)：T5、6椎体、左侧髂骨翼及右侧坐骨、股骨粗隆间多发骨质破坏，L5椎体可疑骨质破坏。胸部CT平扫+三维重建(图5)：胸腺形态异常伴密度稍增高，多发颈、胸椎椎体及附件、多发肋骨、左侧锁骨及肩胛骨骨质破坏。四肢全长DR(图6)：双侧肱骨上段、右侧股骨上段及右侧坐骨多发骨质破坏，结合病史考虑朗格汉斯细胞组织细胞增生症。骨穿后骨髓涂片：增生活跃骨髓象，未见明显异常细胞。
图2 眼部B超
Figure 2 Ocular B-ultrasound
(A)右额部至右眼角外侧至面颊部皮下软组织层探及多个混合性回声区，相互融合；(B)最大位于面颊部范围约5.75×3.3 cm，界不清，上颌骨骨面粗糙不均；(C)上颌窦结构不清晰，CDFI其内无回声区未探及明显血流信号。
(A)The subcutaneous soft tissue layer from the right forehead to the outer corner of the right eye to the cheek and multiple mixed echo zones were fused with each other. (B)The maximum range was 5.75×3.3 cm in the cheek, the boundary was unclear. (C)The maxillary bone surface was rough and uneven, the maxillary sinus structure was unclear, and the CDFI blood flow signals were not obvious.
图3 头颅CT平扫+三维重建
Figure 3 Head CT plain scan + 3D reconstruction
(AB) 右眼眶外侧壁骨皮质不完整，骨质破坏区可见软组织密度影填充，其内可见低密度囊变坏死区。双侧眼球对称，密度均匀，位置形态未见异常。球后间隙清晰，视神经眶内段形态 和密度未见明显异常。（CDE）右眼眶外侧壁、左侧眼眶、上颌骨、下颌骨及右额骨见片状不规则溶骨性骨质破坏。（FGH）双侧顶骨、枕骨右侧、右侧颞骨乳突部、右侧寰椎后弓、颅底骨多发溶骨性破坏，呈地图样改变。黄色箭头所指为眼眶肿物，橙色箭头所指为溶骨性改变。
(AB) The external wall of the right orbit showed irregular lytic bone destruction. Incomplete bone cortex, soft tissue density shadow filling in the bone destruction area, and low density cystic necrosis area within it. Bilateral eyeballs were symmetrical, the density was uniform, and the position and morphology were normal. The retrobulbar space was clear, and the shape and density of the medial orbital segment of the optic nerve were normal. (CDE) The external wall of the right orbit, left orbital, maxilla, mandible and right frontal bone showed irregular lytic bone destruction. (FGH) Multiple osteolytic destruction existed in bilateral parietal bone, right occipital bone, right temporal bone mastoid bone, right posterior atlas arch, skull base bone, like a map. The yellow arrows indicate orbital masses and the orange arrows indicate osteolytic changes.
图4 脊柱全长DR影像
Figure 4 Full length DR Image of the spine
T5、6椎体、左侧髂骨翼及右侧坐骨、股骨粗隆间多发骨质破坏，L5椎体可疑骨质破坏(橙色箭头)。
Multiple bone destruction in T5, 6 vertebrae, left iliac wing, right ischium, femur intertrochanter, suspected bone destruction in L5 vertebrae (orange arrow).
图5 胸部CT三维重建影像
Figure 5 Chest CT 3D reconstruction
胸部CT三维重建影像： (A为正面观)胸4、6、8、12椎体、右侧第6前肋骨、左侧锁骨、左侧第1前肋、左侧肩胛骨多发骨质破坏，胸6椎体明显变扁伴周围软组织密度影； (B为背面观)颈7右侧附件及棘突、胸9右侧附件多发骨质破坏(橙色箭头)。
(A)Multiple bone destruction of thoracic vertebrae 4, 6, 8, 12, left clavicle, left 1st anterior rib, right 6th anterior rib, left scapula, marked squishing of thoracic 6 vertebrae with surrounding soft tissue density shadow. (B) Multiple bone destruction of cervical 7, right adnexa and spinous process, thoracic 9, right adnexa (orange arrow).
图6 四肢全长DR影像
Figure 6 Full length DR Images of limbs
四肢全长DR影像：(A)双侧肱骨上段；(B)右侧股骨上段及右侧坐骨多发骨质破坏(橙色箭头)。
Multiple bone destruction in the(A)upper humerus; (B)right upper femur and right ischium on both side (orange arrow).
行诊断性病灶切除并行病理学活组织检查(右顶部部分病灶，图7)，免疫组化结果显示：CD163(组织细胞+ )，CD1a(朗格汉斯细胞++)，CD34(血管+)，CD68(组织细胞+)，CK(-)，Langerin(朗格汉斯细胞+)，LCA(炎细胞+)，S-100(朗格汉斯细胞+ )，Vimentin(+)，SMA(血管+ )，CD56(-)，Ki67(约18%)。诊断：朗格汉斯细胞组织细胞增生症。
图7 右顶部病灶病理检查
Figure 7 Pathological examination of lesions
大体所见，灰黄灰褐色组织4块，总大小3.5 cm ×2.3 cm ×1.2 cm, 切面灰黄灰红色，实性，质中。光镜所见，组织中弥漫片状分布的单核样细胞、泡沫样细胞及多核巨细胞，部分区域出血变性坏死，单核样细胞多呈类圆形，部分可见核钩，核分裂象少量，间质血管增生扩张充血伴淋巴细胞、浆细胞浸润，并见散在嗜酸性粒细胞浸润，周边可见增生变性的纤维组织。
In large body, there are 4 pieces of grayish-yellow grayish-brown tissue, the total size is 3.5 cm × 2.3 cm × 1.2 cm, the section is grayish-yellow grayish-red, solid and medium in quality. As seen by light microscopy, the tissue was diffuse with mononuclear cells, foam-like cells and multinucleated giant cells; some areas were hemorrhagic degeneration and necrosis; mononuclear cells were mostly circular; nuclear hooks were seen in some areas, with a small amount of nuclear division phase; interstromal vascular hyperplasia and dilatation and congestion accompanied by lymphocyte and plasma cell infiltration; scattered eosinophils were seen, and proliferative and degenerative fibrous tissues were seen around.
诊断明确后转入内科，开始予CHFU-LCH-2012方案化学治疗初始治疗[每周1次长春地辛3 mg/(m2·d)+泼尼松40 mg/(m2·d)，第5、6周逐渐减停]，同时予口服钙剂及奥美拉唑护胃治疗，骨科予支具保护治疗，患儿右眼睑肿物较前有消退(图8)。化疗2周后查体：右上、下眼睑可见肿物，大小约1.0 cm×0.5 cm× 0.5  cm，皮肤呈暗紫色，质软，未见渗血；头部切口愈合良好，无渗血、渗液。心、肺未见明显异常，腹软，肝、脾肋下未扪及。
图8 患儿化疗后眼部肿物逐渐缩小
Figure 8 The eye mass of the patientshrinked gradually after chemotherapy
(A)化疗3 d；(B)化疗1周；(C)化疗2周。
(A)chemotherapy for 3 days; (B)chemotherapy for 1 week; (C)chemotherapy for 2 weeks.
此后一年患儿定期复查并根据复查结果调整化疗方案，共化疗23次。一年后复查。患儿右眼睑肿物的范围、隆起度均较前明显消退(图9)。头颅CT平扫+三维重建(图10)：颅骨多发骨质破坏区，范围较前不同程度缩小；右眶周围软组织稍肿胀。脊柱+四肢全长DR(图11)：T6椎体形态较前改善，左侧肱骨上段及右侧股骨上段骨质破坏范围较前缩小，所见脊柱其他诸骨目前未见明显骨质破坏。骨盆DR(图12)：右侧坐骨、左侧髂骨及右股骨小粗隆处骨质破坏，部分范围较前缩小。继续密切随访。
图9 患儿化疗23个疗程后，肿物明显缩小
Figure 9 After 23 courses of chemotherapy, the tumor was significantly reduced
图10 头颅CT平扫+三维重建
Figure 10 Head CT plain scan + 3D reconstruction
颅骨多发溶骨性骨质破坏区范围较前缩小。右眼眶外侧壁、右额骨片状不规则溶骨性骨质破坏区范围较前缩小，部分仍见软组织影填充，局部骨质形态较前规整。右眶周围软组织稍肿胀。黄色箭头所指为眼眶肿物。
The area of multiple lytic bone destruction in skull was reduced. The area of irregular lytic bone destruction in the lateral wall of the right orbit and the right frontal bone was smaller than before, some soft tissue shadow filling was still seen, and local bone shape was more regular than before. Slight swelling of the right periorbital soft tissue. The yellow arrows indicate orbital masses.
图11 脊柱+四肢全长DR
Figure 11 Full length of spine + limbs DR
脊柱各段生理弯曲存在；T6椎体明显变扁，形态较前改善(橙色箭头)。其他椎体及附件形态尚可，未见骨质破坏。左侧肱骨上段及右侧股骨上段骨质密度减低区范围较前缩小，周围见硬化边。余四肢长骨未见明显骨质破坏征象，诸关节在位，周围软组织无明显异常。
Physiological curvature of the spine exists; The T6 vertebrae are clearly flattened and their shape is improved (orange arrow). Other vertebral bodies and appendices were in good shape, and no bone destruction was observed. The bone density reduction area of the left upper humerus and the right upper femur was smaller than before, and there were sclerotic edges around them. No obvious signs of bone destruction were found in the long bones of the remaining limbs, the joints were in place, and the surrounding soft tissues were normal.
图12 骨盆DR
Figure 12 Pelvis DR
右侧坐骨、左侧髂骨及右股骨小粗隆处见多发透亮影(橙色箭头)，部分较前范围缩小，双侧髋关节间隙未见狭窄、增宽。双侧股骨头等大，髋关节软组织未见明显异常密度影。
Multiple bright shadows (orange arrows) were seen on the right ischiatic bone, left iliac bone and right femur lesser trochanter, some of which were smaller than the previous range. There was no narrowing or widening of the bilateral hip space. The femoral head was equal in size on both sides, and the soft tissue of hip joint had no obvious abnormal density shadow.

2 讨论

LCH可累计全身各个器官，因而临床表现多种多样[2]。LCH以儿童多发，其中 1~4岁为发病高峰年龄。LCH发病年龄越小、病变范围越大、累及器官越多，预后越差，因此应长期随访。
LCH的诊断主要依据临床表现、影像学和病理学检查，其中影像学检查尤为重要，但最终诊断仍需病理组织学证实，典型的病理组织表现为特征性朗格汉斯细胞组织细胞增生。本例患儿的全身骨骼多处出现溶骨性改变，符合朗格汉斯细胞组织细胞增生症的表现，后经病理组织学检测确诊。
眼眶也为LCH的好发部位，以侵蚀眶骨为主，可累及额骨，形成眶颅沟通，也可累及颞叶前极、颞上窝、翼腭窝及颞肌，引起额部或颧面部肿块和眼球突出[3]。眼眶LCH的临床表现多样化，易漏诊、误诊。其鉴别诊断主要依据临床表现和影像学检查，需与眼眶皮样囊肿、转移性神经母细胞瘤以及儿童横纹肌肉瘤、粒细胞肉瘤等骨源性肿瘤进行鉴别[4]：1)眼眶皮样囊肿，儿童多发，多见于眶外上方，CT影像可见骨压陷性缺失，病变内密度不均，囊内多呈低密度；2)转移性神经母细胞瘤，通常为双侧眼眶周软组织肿胀，影像学检查可见腹部原发性肿瘤，可伴有骨质破坏，常有腹痛病史以及伴发热、消瘦等全身症状[5]；3)横纹肌肉瘤，儿童常见的眼眶恶性肿瘤，进展非常迅速，眶上部较为常见，多发生于肌锥外间隙，病变处形成明显的软组织肿块，早期即可导致眼眶骨质破坏；4)粒细胞肉瘤，急性非淋巴细胞性白血病髓外浸润引起的眼部肿瘤，因异常白细胞在骨膜下所形成的一种局限性浸润，一般双眼发病，表现为眶周肿块，可有骨质破坏，可通过外周血或骨髓穿刺辅助诊断[6]。
根据器官受累的数量，可将LCH分为单器官系统受累(single system LCH,SS-LCH)和多器官受累(multisystem LCH,MS-LCH)[7]。目前的治疗原则总体为: SS-LCH有一定的自限性，可根据病变大小和部位选择手术切除；MS-LCH 一般采用系统化疗，目前仍以疗程为12 个月的泼尼松联合长春碱类治疗为标准的一线化疗方案，对于一线化疗效果欠佳的难治性 LCH，可进行二线治疗，现尚无标准方案[8]。同时造血干细胞移植可作为一种有效的挽救治疗方案[9]。此外，针对促分裂素原活化蛋白激酶(mitogen-activated protein kinases, MAPK)信号通路突变的个体化靶向治疗对高危LCH患者(累及多个危险器官、对一线治疗无效的患者)具有重要意义[10]，丝氨酸/苏氨酸蛋白激酶(B-Raf serine/threonine kinase,BRAF)抑制剂(威罗菲尼、达拉菲尼)和丝裂原细胞外信号调节激酶抑制剂(曲美替尼)已用于难治性复发性LCH患者的临床治疗。所有的LCH患者均长期密切随访，但LCH患者个体差异很大，目前尚无完整的随访方案[11]。本病例患儿病变累及骨、皮肤等多个器官，需进行系统化疗。
本病例以眼部肿物首诊于眼科，家属起初也仅要求切除肿物、保持面部美观，后经进一步详细检查确诊为LCH，且为MS-LCH，经化疗后肿物明显减小。接诊此例患者，有下列几点与眼科医生分享：1)接诊眼部肿物尤其是眶周肿物要谨慎，不可盲目切除，必要时做进一步检查(如B超、CT、MRI检查)，避免漏诊、误诊；2)占位性病变的诊断不可仅依靠影像学检查，病理活组织检查是金标准。对于本例患儿，可能有初级眼科医生误诊为睑板腺囊肿而直接手术切除，因此建议切除的离体组织都建议病理活组织检查；3)多种全身性疾病均可以引起眼部局部表现，眼科医生必须有相关概念，最大限度减少误诊、漏诊，以免延误治疗。

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1、福建省卫生健康科技计划项目青年科研课题 (2021QNB024)；厦门市医疗卫生指导 项目(3502Z20209224, 3502Z20214ZD1240),
This work was supported by the Fujian Province Health Science and Technology Project(2021QNB024); Xiamen medical and health guidance project(3502Z20209224, 3502Z20214ZD1240)()
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