面部Merkel細(xì)胞癌臨床病理觀察

閆青葉 高麗 李印

·臨床論著·

面部Merkel細(xì)胞癌臨床病理觀察

閆青葉*高麗 李印△

（南陽(yáng)市中心醫(yī)院病理科，河南 南陽(yáng) 473000）

探討面部Merkel細(xì)胞癌（Merkel cell carcinoma，MCC）臨床病理特征。觀察2例面部Merkel細(xì)胞癌患者的臨床病理特點(diǎn)和免疫組化結(jié)果，分析其臨床特點(diǎn)并復(fù)習(xí)文獻(xiàn)。2例老年女性患者無(wú)意中發(fā)現(xiàn)面部質(zhì)硬腫塊，逐漸增大，腫物最大徑分別為2.5 cm和1.5 cm，例1皮表呈紅色，例2皮膚色澤正常。鏡下腫瘤細(xì)胞位于皮下及真皮內(nèi)，浸潤(rùn)性生長(zhǎng)；細(xì)胞藍(lán)染、圓形、大小均勻一致、松散、胞質(zhì)較少，核仁不易見(jiàn)，細(xì)胞核空泡狀，核分裂多見(jiàn)；免疫組化：2例瘤細(xì)胞CK20、Syn、AE1/AE3陽(yáng)性。治療及隨訪：例1行單純腫物切除，術(shù)后10個(gè)月出現(xiàn)局部復(fù)發(fā)并廣泛轉(zhuǎn)移，2 m后死亡。例2確診后行腫物擴(kuò)大切除，隨訪8 m無(wú)局部復(fù)發(fā)及轉(zhuǎn)移。Merkel細(xì)胞癌是罕見(jiàn)皮膚神經(jīng)內(nèi)分泌腫瘤，惡性程度高，預(yù)后差。

面部；Merkel細(xì)胞癌；臨床病理

Merkel細(xì)胞癌（Merkel cell carcinoma，MCC）是一種皮膚原發(fā)性神經(jīng)內(nèi)分泌癌，惡性程度高，預(yù)后差，臨床較為罕見(jiàn)，易誤診。

隨著對(duì)MCC研究深入，目前認(rèn)為MCC致病因素主要包括Merkel細(xì)胞多瘤病毒（Merkel cell polyoma virus，MCPyV）和紫外線輻射誘導(dǎo)基因損傷[1]。臨床上對(duì)該腫瘤的診斷主要依靠組織病理和免疫組化相結(jié)合。本文通過(guò)分析面部MCC的臨床病理特點(diǎn)并復(fù)習(xí)相關(guān)文獻(xiàn)，以提高對(duì)該病的認(rèn)識(shí)。

1 資料與方法

1.1 臨床資料

病案1 患者女，87歲。2月前患者無(wú)意中發(fā)現(xiàn)右側(cè)面部腫物，約黃豆大小，無(wú)疼痛，無(wú)破潰，未做治療，腫塊逐漸增大至約蠶豆大小?！?型糖尿病”病史7年，應(yīng)用“諾和靈30R早16 U 晚12 U”降糖。入院測(cè)空腹血糖13.97 mmol·L-1，糖化血紅蛋白9.50%。體檢：右側(cè)面部見(jiàn)隆起腫塊，皮表紫紅色，無(wú)破潰，觸之質(zhì)硬，大小約2.5×1.5 cm，活動(dòng)度差，無(wú)壓痛，無(wú)紅腫。全身未觸及腫大淋巴結(jié)。腫物行手術(shù)切除，術(shù)中所見(jiàn)：腫物位于皮下及真皮內(nèi)，灰紅灰白，無(wú)包膜，與周圍組織界不清。術(shù)后病理結(jié)果示：右側(cè)面部Merkel細(xì)胞癌。

病案2 患者女，68歲。1月前患者無(wú)意中發(fā)現(xiàn)右側(cè)鼻根部腫物，約綠豆大小，無(wú)紅腫、疼痛，無(wú)破潰，未做治療，腫塊逐漸增大至約黃豆大小，質(zhì)硬。體檢：右側(cè)鼻根部見(jiàn)一隆起型腫塊，皮表色澤正常，無(wú)破潰，觸之質(zhì)硬，直徑約0.7 cm，活動(dòng)度可，無(wú)壓痛，無(wú)紅腫。全身未觸及腫大淋巴結(jié)。腫物行手術(shù)切除，術(shù)中所見(jiàn)：腫物位于皮下及真皮內(nèi)灰紅灰白，無(wú)包膜，與周圍組織界不清。術(shù)后1周病理結(jié)果示：右側(cè)鼻根部Merkel細(xì)胞癌。再次行腫物邊界擴(kuò)大切除術(shù)，術(shù)后病理顯示切緣未見(jiàn)癌生長(zhǎng)。

1.2 方法

切除標(biāo)本經(jīng)10％中性福爾馬林溶液固定、常規(guī)制片、光鏡觀察；免疫組化學(xué)采用EnVision二步法，所選抗體AE1/AE3、CK20、CD56、Syn、TTF-1、LCA、CD20、CD45RO、MPO、HMB-45、Melan-A、S100、CD99、Ki-67（均購(gòu)自鄭州賽諾特生物技術(shù)有限公司）。

2 結(jié)果

2.1 巨檢

例1 灰紅灰白不規(guī)則組織三塊，總大小約2.5×1.5×1 cm，無(wú)包膜，切面灰白，質(zhì)硬。例2灰紅灰白不規(guī)則腫物1枚，大小約0.7×0.7×0.6 cm，無(wú)包膜，切面灰白，質(zhì)硬。

2.2 鏡檢及免疫組化

2例腫瘤細(xì)胞均位于皮下及真皮內(nèi)，組織學(xué)特征基本相似。例1腫瘤細(xì)胞呈彌漫、巢團(tuán)狀、浸潤(rùn)脂肪組織，與周邊組織分界不清（圖1A）。例2腫瘤細(xì)胞呈彌漫、巢團(tuán)狀、條索狀浸潤(rùn)皮下膠原纖維組織，與周邊組織分界不清（圖1B）。2例細(xì)胞均藍(lán)染、圓形、大小均勻一致、松散、胞質(zhì)較少，核仁不易見(jiàn)，細(xì)胞核空泡狀（圖1C，1D），核分裂多見(jiàn)（圖1C）。CK20均(+)（圖1E，1F），Syn均(+)（圖1G），AE1/AE3均(+)。

2.3 治療及隨訪

例1患者確診后拒絕腫物邊緣擴(kuò)大切除及放化療，術(shù)后10 m出現(xiàn)局部復(fù)發(fā)，并廣泛轉(zhuǎn)移，2 m后死亡。例2患者確診后行腫物邊緣擴(kuò)大切除，隨訪8 m未出現(xiàn)局部復(fù)發(fā)及轉(zhuǎn)移。

圖1 病理結(jié)果

注：A例1腫瘤細(xì)胞位于皮下及真皮內(nèi)，細(xì)胞圓形、藍(lán)染、大小均勻一致、松散、胞質(zhì)較少、呈巢狀分布（x10)；圖B例2腫瘤細(xì)胞位于皮下及真皮內(nèi)，呈條索狀，浸潤(rùn)性生長(zhǎng)（x10）；圖C例1細(xì)胞核空泡樣，核仁不易見(jiàn)，核分裂（紅色箭頭）較多（x40）；圖D例1 CK20核周見(jiàn)環(huán)狀、逗點(diǎn)狀（+） （EnVision二步法 x20）；圖E例2 CK20核周見(jiàn)環(huán)狀、逗點(diǎn)狀（+）（EnVision二步法 x20）；圖F例1 Syn細(xì)胞質(zhì)染色呈彌漫強(qiáng)陽(yáng)性（+）（EnVision二步法 x20）；圖G Syn例2細(xì)胞質(zhì)染色呈彌漫強(qiáng)陽(yáng)性（+）（EnVision二步法 x20）

3 討論

3.1 臨床特點(diǎn)

MCC自1972年由Toker首次報(bào)道，它的起源細(xì)胞至今仍有爭(zhēng)議。目前認(rèn)為MCPyV陽(yáng)性的腫瘤細(xì)胞起源于包括前B/前B淋巴細(xì)胞，成纖維細(xì)胞，真皮間充質(zhì)干細(xì)胞和上皮細(xì)胞[2,3,4]。MCC通常發(fā)生在老年白種人頭部/頸部受陽(yáng)光照射的皮膚上，也常涉及到軀干和四肢，粘膜很少受到影響。

臨床上，MCC表現(xiàn)為快速生長(zhǎng)，無(wú)痛，紅斑/紫色結(jié)節(jié)或斑塊。MCC發(fā)病率低，經(jīng)檢索中國(guó)知網(wǎng)、萬(wàn)方數(shù)據(jù)庫(kù)、維普期刊（主題詞為Merkel 細(xì)胞癌），截止2021年3月26日國(guó)內(nèi)共報(bào)道201例，加上本組2例共計(jì)203例。發(fā)病年齡11歲-109歲，平均發(fā)病年齡64歲，中位發(fā)病年齡68歲，女多于男（1.3：1）。發(fā)生于面部的有85例，占42.5%，發(fā)病年齡23歲-109歲，平均發(fā)病年齡70歲，中位發(fā)病年齡72-73歲，女性多于男性（2.3：1）。腫物一般呈淡粉、暗紅、紫紅色結(jié)節(jié)與文獻(xiàn)[5]報(bào)道基本一致。

國(guó)內(nèi)發(fā)生于面部的患者共85例，除去無(wú)可用資料的21例，腫物最小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，本組中1例有糖尿病史，共9例。

3.2 MCC的病因及發(fā)病機(jī)制

MCC發(fā)展的危險(xiǎn)因素包括紫外線照射、年齡的增長(zhǎng)和免疫抑制；而致病因素中則大部分由MCPyV引起，并且經(jīng)ATOH1誘導(dǎo)[6]，少數(shù)由紫外線誘導(dǎo)基因損傷引起。TP53和RB1基因的突變常常促進(jìn)腫瘤發(fā)生，研究發(fā)現(xiàn)MCPyV陽(yáng)性腫瘤可能是真正的神經(jīng)內(nèi)分泌癌，具有皮膚來(lái)源；MCPyV陰性腫瘤則來(lái)自角蛋白細(xì)胞或表皮干細(xì)胞，可能是具有神經(jīng)內(nèi)分泌分化的鱗狀細(xì)胞癌，由紫外線誘導(dǎo)基因損傷引起[7]。

3.3 病理特點(diǎn)

3.3.1 大體所見(jiàn)

MCC巨檢無(wú)特異性，與大多數(shù)惡性腫瘤一樣，無(wú)包膜，切面灰紅、灰白，實(shí)性，多質(zhì)硬，界限不清，呈浸潤(rùn)性生長(zhǎng)。

3.3.2 組織學(xué)特點(diǎn)

MCC的特征是位于真皮和/或皮下組織的藍(lán)染、圓形細(xì)胞腫瘤，呈片狀和巢狀，一些病例可見(jiàn)假菊形團(tuán)結(jié)構(gòu)，一般不累及表皮。腫瘤細(xì)胞核漿比較高，核染色質(zhì)呈“鹽和胡椒”狀，核仁模糊。可見(jiàn)大量的核分裂象，散在的凋亡細(xì)胞，偶見(jiàn)細(xì)胞區(qū)域性壞死。

3.3.3 免疫組化

MCC臨床特征及大體檢查無(wú)特異性，診斷主要靠組織病理和免疫組化。組織病理鏡下腫瘤細(xì)胞分化低，需要與多種低分化腫瘤相鑒別，如惡性小細(xì)胞黑色素瘤、淋巴瘤、PNET、低分化鱗癌、肺小細(xì)胞癌皮膚轉(zhuǎn)移等。MCC具有上皮和神經(jīng)內(nèi)分泌雙向分化特征。CK20分子量為46 kDa，是MCC的可靠免疫標(biāo)記物。突觸素[8]（Synaptophysin，Syn）是一種位于突觸前囊泡內(nèi)的糖蛋白，是神經(jīng)內(nèi)分泌腫瘤的特異性標(biāo)記物。本例中CK20、Syn、CD56、AE1/AE3、LCA、CD20、CD45RO、TTF-1、MPO、HMB-45、Melan-A、S100、CD99進(jìn)行聯(lián)合檢測(cè)，結(jié)果CK20在腫瘤細(xì)胞中顯示特征性的核周環(huán)狀、逗點(diǎn)狀陽(yáng)性，Syn彌漫強(qiáng)陽(yáng)性，AE1/AE2核周逗點(diǎn)狀弱陽(yáng)性，Ki-67增殖指數(shù)約80%，其余均陰性，可以惡性小細(xì)胞黑色素瘤、淋巴瘤、PNET、低分化鱗癌、肺小細(xì)胞癌，診斷MCC。

3.4 治療

MCC治療主要依靠多學(xué)科綜合治療，對(duì)MCC治療方案的選擇依賴于全面的報(bào)告和準(zhǔn)確臨床分期。目前手術(shù)是治療的重要組成部分，局部病變主要靠廣泛切除和局部淋巴結(jié)清掃，輔以放射治療，以減少頻繁的局部復(fù)發(fā)。

廣泛局部切除是MCC治療的標(biāo)準(zhǔn)，但最佳切緣寬度仍有爭(zhēng)議，NCCN指南推薦切緣至腫瘤2-2.5 cm ，而新近一項(xiàng)多中心回顧性研究顯示[9]切緣(0.5- 1 cm)與切緣(> 1 cm)均與預(yù)后無(wú)關(guān)，而手術(shù)深部切緣殘留腫瘤與預(yù)后獨(dú)立相關(guān)。手術(shù)后輔助放療效果明顯，文獻(xiàn)報(bào)道[10]完整切除腫物加放射治療可以改善局部區(qū)域的無(wú)病生存。本組中腫物擴(kuò)大切除患者預(yù)后較好，與文獻(xiàn)一致?，F(xiàn)在細(xì)胞毒性化療已被ICI取代。特別是PD-1/PD-L1通路的抑制劑已被證明能釋放抗腫瘤作用。臨床試驗(yàn)證明對(duì)難治性晚期患者有效（客觀緩解率為32%）[11]，且MCPyV陽(yáng)性和MCPyV陰性的病例對(duì)這些制劑同樣敏感。

3.5 預(yù)后

MCC預(yù)后差，預(yù)后不良因素有男性、腫物大于2 cm、遠(yuǎn)處轉(zhuǎn)移、核分裂。Harms等[12]報(bào)道，單純皮膚表面局部腫瘤的5年生存率為50.6% ，有淋巴結(jié)轉(zhuǎn)移的為35.4%，有遠(yuǎn)處轉(zhuǎn)移的為13.5%，30%的患者在就診時(shí)已發(fā)生轉(zhuǎn)移。并且與其他解剖區(qū)域的MCC相比，位于頭頸部的MCC預(yù)后更差?？赡苁且?yàn)槊娌磕[瘤的手術(shù)切除難度大，醫(yī)生既要達(dá)到所需的切除幅度，還要考慮令人滿意的功能和美容效果。另外頭頸部區(qū)域內(nèi)極其復(fù)雜的淋巴循環(huán)系統(tǒng)，使淋巴結(jié)清掃極具挑戰(zhàn)性。也有研究表明腫瘤在面部位置是一個(gè)很好的預(yù)后因素，因?yàn)槊娌康牟∽?，可能比在其他地方更早被發(fā)現(xiàn)[13]。

總之，Merkel細(xì)胞癌惡性程度高、預(yù)后差。及早診斷和治療有利于改善預(yù)后。

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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.

作者簡(jiǎn)介：閆青葉，女，醫(yī)師，主要從事軟組織病理，Email：yanqingye2805@163.com；

李印，男，副主任醫(yī)師，主要從事腫瘤病理學(xué)工作，Email：wxfwxf123456qq@163.com。

10.1056/NEJMoa2117995.

（2021-10-27）