面部Merkel细胞癌临床病理观察

闫青叶 高丽 李印

·临床论著·

面部Merkel细胞癌临床病理观察

闫青叶*高丽 李印△

（南阳市中心医院病理科，河南 南阳 473000）

探讨面部Merkel细胞癌（Merkel cell carcinoma，MCC）临床病理特征。观察2例面部Merkel细胞癌患者的临床病理特点和免疫组化结果，分析其临床特点并复习文献。2例老年女性患者无意中发现面部质硬肿块，逐渐增大，肿物最大径分别为2.5 cm和1.5 cm，例1皮表呈红色，例2皮肤色泽正常。镜下肿瘤细胞位于皮下及真皮内，浸润性生长；细胞蓝染、圆形、大小均匀一致、松散、胞质较少，核仁不易见，细胞核空泡状，核分裂多见；免疫组化：2例瘤细胞CK20、Syn、AE1/AE3阳性。治疗及随访：例1行单纯肿物切除，术后10个月出现局部复发并广泛转移，2 m后死亡。例2确诊后行肿物扩大切除，随访8 m无局部复发及转移。Merkel细胞癌是罕见皮肤神经内分泌肿瘤，恶性程度高，预后差。

面部；Merkel细胞癌；临床病理

Merkel细胞癌（Merkel cell carcinoma，MCC）是一种皮肤原发性神经内分泌癌，恶性程度高，预后差，临床较为罕见，易误诊。

随着对MCC研究深入，目前认为MCC致病因素主要包括Merkel细胞多瘤病毒（Merkel cell polyoma virus，MCPyV）和紫外线辐射诱导基因损伤[1]。临床上对该肿瘤的诊断主要依靠组织病理和免疫组化相结合。本文通过分析面部MCC的临床病理特点并复习相关文献，以提高对该病的认识。

1 资料与方法

1.1 临床资料

病案1 患者女，87岁。2月前患者无意中发现右侧面部肿物，约黄豆大小，无疼痛，无破溃，未做治疗，肿块逐渐增大至约蚕豆大小。“2型糖尿病”病史7年，应用“诺和灵30R早16 U 晚12 U”降糖。入院测空腹血糖13.97 mmol·L-1，糖化血红蛋白9.50%。体检：右侧面部见隆起肿块，皮表紫红色，无破溃，触之质硬，大小约2.5×1.5 cm，活动度差，无压痛，无红肿。全身未触及肿大淋巴结。肿物行手术切除，术中所见：肿物位于皮下及真皮内，灰红灰白，无包膜，与周围组织界不清。术后病理结果示：右侧面部Merkel细胞癌。

病案2 患者女，68岁。1月前患者无意中发现右侧鼻根部肿物，约绿豆大小，无红肿、疼痛，无破溃，未做治疗，肿块逐渐增大至约黄豆大小，质硬。体检：右侧鼻根部见一隆起型肿块，皮表色泽正常，无破溃，触之质硬，直径约0.7 cm，活动度可，无压痛，无红肿。全身未触及肿大淋巴结。肿物行手术切除，术中所见：肿物位于皮下及真皮内灰红灰白，无包膜，与周围组织界不清。术后1周病理结果示：右侧鼻根部Merkel细胞癌。再次行肿物边界扩大切除术，术后病理显示切缘未见癌生长。

1.2 方法

切除标本经10％中性福尔马林溶液固定、常规制片、光镜观察；免疫组化学采用EnVision二步法，所选抗体AE1/AE3、CK20、CD56、Syn、TTF-1、LCA、CD20、CD45RO、MPO、HMB-45、Melan-A、S100、CD99、Ki-67（均购自郑州赛诺特生物技术有限公司）。

2 结果

2.1 巨检

例1 灰红灰白不规则组织三块，总大小约2.5×1.5×1 cm，无包膜，切面灰白，质硬。例2灰红灰白不规则肿物1枚，大小约0.7×0.7×0.6 cm，无包膜，切面灰白，质硬。

2.2 镜检及免疫组化

2例肿瘤细胞均位于皮下及真皮内，组织学特征基本相似。例1肿瘤细胞呈弥漫、巢团状、浸润脂肪组织，与周边组织分界不清（图1A）。例2肿瘤细胞呈弥漫、巢团状、条索状浸润皮下胶原纤维组织，与周边组织分界不清（图1B）。2例细胞均蓝染、圆形、大小均匀一致、松散、胞质较少，核仁不易见，细胞核空泡状（图1C，1D），核分裂多见（图1C）。CK20均(+)（图1E，1F），Syn均(+)（图1G），AE1/AE3均(+)。

2.3 治疗及随访

例1患者确诊后拒绝肿物边缘扩大切除及放化疗，术后10 m出现局部复发，并广泛转移，2 m后死亡。例2患者确诊后行肿物边缘扩大切除，随访8 m未出现局部复发及转移。

图1 病理结果

注：A例1肿瘤细胞位于皮下及真皮内，细胞圆形、蓝染、大小均匀一致、松散、胞质较少、呈巢状分布（x10)；图B例2肿瘤细胞位于皮下及真皮内，呈条索状，浸润性生长（x10）；图C例1细胞核空泡样，核仁不易见，核分裂（红色箭头）较多（x40）；图D例1 CK20核周见环状、逗点状（+） （EnVision二步法 x20）；图E例2 CK20核周见环状、逗点状（+）（EnVision二步法 x20）；图F例1 Syn细胞质染色呈弥漫强阳性（+）（EnVision二步法 x20）；图G Syn例2细胞质染色呈弥漫强阳性（+）（EnVision二步法 x20）

3 讨论

3.1 临床特点

MCC自1972年由Toker首次报道，它的起源细胞至今仍有争议。目前认为MCPyV阳性的肿瘤细胞起源于包括前B/前B淋巴细胞，成纤维细胞，真皮间充质干细胞和上皮细胞[2,3,4]。MCC通常发生在老年白种人头部/颈部受阳光照射的皮肤上，也常涉及到躯干和四肢，粘膜很少受到影响。

临床上，MCC表现为快速生长，无痛，红斑/紫色结节或斑块。MCC发病率低，经检索中国知网、万方数据库、维普期刊（主题词为Merkel 细胞癌），截止2021年3月26日国内共报道201例，加上本组2例共计203例。发病年龄11岁-109岁，平均发病年龄64岁，中位发病年龄68岁，女多于男（1.3：1）。发生于面部的有85例，占42.5%，发病年龄23岁-109岁，平均发病年龄70岁，中位发病年龄72-73岁，女性多于男性（2.3：1）。肿物一般呈淡粉、暗红、紫红色结节与文献[5]报道基本一致。

国内发生于面部的患者共85例，除去无可用资料的21例，肿物最小0.2 cm，最大9 cm，平均值2.1 cm，中位值1.7 cm。8例患者有糖尿病史，本组中1例有糖尿病史，共9例。

3.2 MCC的病因及发病机制

MCC发展的危险因素包括紫外线照射、年龄的增长和免疫抑制；而致病因素中则大部分由MCPyV引起，并且经ATOH1诱导[6]，少数由紫外线诱导基因损伤引起。TP53和RB1基因的突变常常促进肿瘤发生，研究发现MCPyV阳性肿瘤可能是真正的神经内分泌癌，具有皮肤来源；MCPyV阴性肿瘤则来自角蛋白细胞或表皮干细胞，可能是具有神经内分泌分化的鳞状细胞癌，由紫外线诱导基因损伤引起[7]。

3.3 病理特点

3.3.1 大体所见

MCC巨检无特异性，与大多数恶性肿瘤一样，无包膜，切面灰红、灰白，实性，多质硬，界限不清，呈浸润性生长。

3.3.2 组织学特点

MCC的特征是位于真皮和/或皮下组织的蓝染、圆形细胞肿瘤，呈片状和巢状，一些病例可见假菊形团结构，一般不累及表皮。肿瘤细胞核浆比较高，核染色质呈“盐和胡椒”状，核仁模糊。可见大量的核分裂象，散在的凋亡细胞，偶见细胞区域性坏死。

3.3.3 免疫组化

MCC临床特征及大体检查无特异性，诊断主要靠组织病理和免疫组化。组织病理镜下肿瘤细胞分化低，需要与多种低分化肿瘤相鉴别，如恶性小细胞黑色素瘤、淋巴瘤、PNET、低分化鳞癌、肺小细胞癌皮肤转移等。MCC具有上皮和神经内分泌双向分化特征。CK20分子量为46 kDa，是MCC的可靠免疫标记物。突触素[8]（Synaptophysin，Syn）是一种位于突触前囊泡内的糖蛋白，是神经内分泌肿瘤的特异性标记物。本例中CK20、Syn、CD56、AE1/AE3、LCA、CD20、CD45RO、TTF-1、MPO、HMB-45、Melan-A、S100、CD99进行联合检测，结果CK20在肿瘤细胞中显示特征性的核周环状、逗点状阳性，Syn弥漫强阳性，AE1/AE2核周逗点状弱阳性，Ki-67增殖指数约80%，其余均阴性，可以恶性小细胞黑色素瘤、淋巴瘤、PNET、低分化鳞癌、肺小细胞癌，诊断MCC。

3.4 治疗

MCC治疗主要依靠多学科综合治疗，对MCC治疗方案的选择依赖于全面的报告和准确临床分期。目前手术是治疗的重要组成部分，局部病变主要靠广泛切除和局部淋巴结清扫，辅以放射治疗，以减少频繁的局部复发。

广泛局部切除是MCC治疗的标准，但最佳切缘宽度仍有争议，NCCN指南推荐切缘至肿瘤2-2.5 cm ，而新近一项多中心回顾性研究显示[9]切缘(0.5- 1 cm)与切缘(> 1 cm)均与预后无关，而手术深部切缘残留肿瘤与预后独立相关。手术后辅助放疗效果明显，文献报道[10]完整切除肿物加放射治疗可以改善局部区域的无病生存。本组中肿物扩大切除患者预后较好，与文献一致。现在细胞毒性化疗已被ICI取代。特别是PD-1/PD-L1通路的抑制剂已被证明能释放抗肿瘤作用。临床试验证明对难治性晚期患者有效（客观缓解率为32%）[11]，且MCPyV阳性和MCPyV阴性的病例对这些制剂同样敏感。

3.5 预后

MCC预后差，预后不良因素有男性、肿物大于2 cm、远处转移、核分裂。Harms等[12]报道，单纯皮肤表面局部肿瘤的5年生存率为50.6% ，有淋巴结转移的为35.4%，有远处转移的为13.5%，30%的患者在就诊时已发生转移。并且与其他解剖区域的MCC相比，位于头颈部的MCC预后更差。可能是因为面部肿瘤的手术切除难度大，医生既要达到所需的切除幅度，还要考虑令人满意的功能和美容效果。另外头颈部区域内极其复杂的淋巴循环系统，使淋巴结清扫极具挑战性。也有研究表明肿瘤在面部位置是一个很好的预后因素，因为面部的病变，可能比在其他地方更早被发现[13]。

总之，Merkel细胞癌恶性程度高、预后差。及早诊断和治疗有利于改善预后。

1 Walsh NM, Cerroni L. Merkel cell carcinoma: A review[J]. J Cutan Pathol, 2021, 48(3): 411-421.

2 Harms PW, Harms KL, Moore PS, et al. The biology and treatment of Merkel cell carcinoma: current understanding and research priorities[J]. Nat Rev Clin Oncol, 2018, 15(12): 763-776.

3 Pietropaolo V, Prezioso C, Moens U. Merkel cell polyomavirus and Merkel cell carcinoma[J]. Cancers (Basel), 2020, 12(7): 1774.

4 Kervarrec T, Samimi M, Guyétant S, et al. Histogenesis of Merkel cell carcinoma: a comprehensive review[J]. Front Oncol, 2019, 9: 451.

5 Tello TL, Coggshall K, Yom SS, Yu SS. Merkel cell carcinoma: an update and review: current and future therapy[J]. J Am Acad Dermatol, 2018,78(3): 445-454.

6 Harms PW, Harms KL, Moore PS, et al. The biology and treatment of Merkel cell carcinoma: current understanding and research priorities[J]. Nat Rev Clin Oncol, 2018, 15(12): 763-776.

7 Knepper T, Montesion M, Russell JS, et al. The genomic landscape of Merkel cell carcinoma and clinicogenomic biomarkers of response to immune checkpoint inhibitor therapy[J]. Clin Cancer Res, 2019, 25(19): 5961-5971.

8 赵声春, 贾其磊, 章培, 等．免疫组化在肺小活检中对肺癌组织学分型的鉴别诊断意义[J]. 现代肿瘤医学, 2018, 26(12): 45-48．

9 Jaouen F, Kervarrec T, Caille A, et al. Narrow resection margins are not associated with mortality or recurrence in patients with Merkel cell carcinoma: A retrospective study[J]. J Am Acad Dermatol, 2021, 84(4): 921-929.

10 Mohammed UA, Mai M, Khaled F. Favorable response to treatment with avelumab in an HIV-positive patient with advanced Merkel cell carcinoma previously refractory to chemotherapy [J]. Case Rep Oncol, 2018, 11(2): 467-475.

11 王红群, 石怀银, 李杰. Merkel细胞癌3例临床病理观察[J]. 诊断病理学杂志, 2019, 12(2): 178-183.

12 Harms KL，Healy MA，Nghiem P，et al. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system[J]. Ann Surg Oncol, 2016, 23(11): 3564-3571.

13 李珍, 杨淑霞. 改良Mohs显微描记手术治疗Merkel细胞癌二例[J]. 中华皮肤科杂志, 2020, 53(5): 45-47.

Clinicopathological observation of facial Merkel cell carcinoma

Yan Qing-ye, Gao Li, Li Yin△

(Department of Pathology, Nanyang Central Hospital, Nanyang 473000, Henan, China)

To study the clinicopathological features of Merkel cell carcinoma of the face.The clinicopathological features and immunohistochemical results of 2 patients with facial Merkel cell carcinoma were observed. The clinical features were analyzed and the literature was reviewed.Both female cases accidentally found hard facial mass, which gradually grew with the maximum diameter 2.5 cm and 1.5 cm, respectively. The skin surface of case 1 was red, and normal in case 2. Microscopically, the tumor cells were located in the subcutaneous and dermis and grew infiltratively. The cells were blue stain, round, uniform in size, loose, less cytoplasm, nucleoli were not easy to see, the nuclei were vacuolar and mitosis was common. Immunohistochemistry showed positive CK20, SYN and AE1/AE3 in 2 tumor cells. Treatment and follow-up: Case 1 received simple resection of the tumor, and local recurrence and extensive metastasis occurred 10 months after surgery, and he died 2 months later. Case 2 underwent extensive resection of the tumor after diagnosis, and no local recurrence or metastasis was found in the 8-month follow-up.Merkel cell carcinoma is a rare cutaneous neuroendocrine tumor with high malignancy and poor prognosis.

Face; Merkel cell carcinoma; Clinical pathology

·PROGRESS·

Effectiveness of BNT162b2 Vaccine against Critical Covid-19 in Adolescents

Samantha M Olson, et al.

Background: The increasing incidence of pediatric hospitalizations associated with coronavirus disease 2019 (Covid-19) caused by the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United States has offered an opportunity to assess the real-world effectiveness of the BNT162b2 messenger RNA vaccine in adolescents between 12 and 18 years of age.

Methods: We used a case-control, test-negative design to assess vaccine effectiveness against Covid-19 resulting in hospitalization, admission to an intensive care unit (ICU), the use of life-supporting interventions (mechanical ventilation, vasopressors, and extracorporeal membrane oxygenation), or death. Between July 1 and October 25, 2021, we screened admission logs for eligible case patients with laboratory-confirmed Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2) in case patients as compared with two hospital-based control groups: patients who had Covid-19-like symptoms but negative results on testing for SARS-CoV-2 (test-negative) and patients who did not have Covid-19-like symptoms (syndrome-negative).

A total of 445 case patients and 777 controls were enrolled. Overall, 17 case patients (4%) and 282 controls (36%) had been fully vaccinated. Of the case patients, 180 (40%) were admitted to the ICU, and 127 (29%) required life support; only 2 patients in the ICU had been fully vaccinated. The overall effectiveness of the BNT162b2 vaccine against hospitalization for Covid-19 was 94% (95% confidence interval [CI], 90 to 96); the effectiveness was 95% (95% CI, 91 to 97) among test-negative controls and 94% (95% CI, 89 to 96) among syndrome-negative controls. The effectiveness was 98% against ICU admission and 98% against Covid-19 resulting in the receipt of life support. All 7 deaths occurred in patients who were unvaccinated.

Conclusions: Among hospitalized adolescent patients, two doses of the BNT162b2 vaccine were highly effective against Covid-19-related hospitalization and ICU admission or the receipt of life support. (Funded by the Centers for Disease Control and Prevention.).

N Engl J Med. 2022 Jan 12.

作者简介：闫青叶，女，医师，主要从事软组织病理，Email：yanqingye2805@163.com；

李印，男，副主任医师，主要从事肿瘤病理学工作，Email：wxfwxf123456qq@163.com。

10.1056/NEJMoa2117995.

（2021-10-27）