何國(guó)華 任小平 楊媛 賀瑩 趙志娟 兀威
【摘要】 現(xiàn)階段肺癌依舊是全球發(fā)病率和死亡率排名第一的惡性腫瘤。早期診斷及治療是提高肺癌患者生存率和預(yù)后的關(guān)鍵,全面地認(rèn)識(shí)和掌握肺癌各種形式的臨床表現(xiàn)是早期診斷的重要環(huán)節(jié),尤其是以肺外癥狀首發(fā)的病例。本文深入分析了與肺癌相關(guān)的多種非轉(zhuǎn)移性肺外表現(xiàn),分別對(duì)表現(xiàn)于內(nèi)分泌系統(tǒng)、神經(jīng)系統(tǒng)、皮膚、免疫系統(tǒng)、眼部等的臨床特征以及治療進(jìn)展等做一綜述,從而減少臨床漏診、誤診率,提高臨床表現(xiàn)不典型肺癌的早期診斷率。
【關(guān)鍵詞】 肺癌 早期診斷 非轉(zhuǎn)移性肺外表現(xiàn)
[Abstract] Lung cancer is still the leading malignancy incidence rate and mortality rate in the world. Early diagnosis and treatment is the key to improve the survival rate and prognosis of lung cancer patients. A comprehensive understanding and mastery of various forms of clinical manifestations of lung cancer is an important link in early diagnosis, especially the cases with extrapulmonary symptoms. This paper deeply analyzes a variety of non metastatic extrapulmonary manifestations related to lung cancer, and summarizes the clinical characteristics and treatment progress of endocrine system, nervous system, skin, immune system and eyes, so as to reduce the rate of clinical missed diagnosis and misdiagnosis and improve the early diagnosis rate of atypical lung cancer.
[Key words] Lung cancer Early diagnosis Non-metastatic extrapulmonary manifestations
First-author’s address: Xi’an Medical College, Xi’an 710068, China
doi:10.3969/j.issn.1674-4985.2022.03.042
肺癌的非轉(zhuǎn)移性肺外表現(xiàn)是指由原發(fā)性肺癌引起的非轉(zhuǎn)移性的呼吸道以外的臨床表現(xiàn),不包括肺癌遠(yuǎn)處轉(zhuǎn)移所引起的臨床表現(xiàn),又稱為腫瘤的副癌綜合征或腫瘤副癥[1]。研究表明,20%的肺癌被誤診是因?yàn)榕c腫瘤遠(yuǎn)處轉(zhuǎn)移無(wú)關(guān)、缺乏特異性的癥狀與體征[2]。肺外表現(xiàn)對(duì)于肺癌早期診斷、指導(dǎo)治療、隨診以及監(jiān)測(cè)病情有著重要意義。
1 內(nèi)分泌系統(tǒng)
肺癌細(xì)胞具有變異性,這也是非轉(zhuǎn)移性肺外表現(xiàn)常表現(xiàn)于內(nèi)分泌系統(tǒng)的原因之一。肺癌細(xì)胞可分泌20多種生物活性物質(zhì)和內(nèi)分泌激素,進(jìn)而引起異位綜合征,主要包括高鈣血癥、抗利尿激素分泌不當(dāng)綜合征、庫(kù)欣綜合征、低血糖、肢端肥大癥、類癌綜合征、男性乳房發(fā)育癥等。有部分肺癌患者在臨床和影像學(xué)檢查未發(fā)現(xiàn)異常時(shí),首先表現(xiàn)出內(nèi)分泌功能的紊亂,因此臨床醫(yī)師應(yīng)重視鑒別診斷,提高臨床表現(xiàn)不典型肺癌的早期診斷率。
1.1 高鈣血癥 內(nèi)分泌綜合征中的抗利尿激素分泌不當(dāng)綜合征(syndrome of inappropriate antidiuretic hormone secretion,SIADH)和惡性體液高鈣血癥(hierarchical holographic modeling,HHM)是肺癌中最常見(jiàn)的副腫瘤綜合征[3]。惡性腫瘤所致高鈣血癥中,肺癌所占比例最高[4]。最常見(jiàn)的與高鈣血癥相關(guān)的癌癥類型是鱗狀細(xì)胞癌,其發(fā)病率高達(dá)23%[5-6]。據(jù)文獻(xiàn)[7]報(bào)道,HHM的大多數(shù)病例是由于局部骨溶解或甲狀旁腺激素相關(guān)肽的分泌,而不到1%的病例是由于甲狀旁腺激素的異位分泌。當(dāng)HHM與甲狀旁腺激素相關(guān)肽的產(chǎn)生有關(guān)時(shí),其臨床特征表現(xiàn)為惡心、嘔吐、腹痛和便秘,這樣的胃腸道癥狀最常見(jiàn)。除此之外,還有循環(huán)影響(口渴、多尿、脫水和腎衰竭)以及其他的一些神經(jīng)精神癥狀,例如疲勞、嗜睡、情緒變化和認(rèn)知功能障礙等[8-9]。
惡性腫瘤高鈣血癥預(yù)后極差,目前尚無(wú)明確的治療指南[10]。對(duì)于大多數(shù)副腫瘤內(nèi)分泌綜合征,治療潛在的惡性腫瘤是有效的治療策略[11]。當(dāng)肺癌患者出現(xiàn)急性高鈣血癥時(shí),臨床上通常需要進(jìn)行靜脈輸液和頻繁監(jiān)測(cè)鈣水平,借助雙膦酸鹽或降鈣素的短期應(yīng)用可對(duì)骨吸收進(jìn)行有效抑制。另外,采用地諾單抗進(jìn)行治療也是一種可預(yù)防骨轉(zhuǎn)移患者骨相關(guān)事件的方法[12]。
1.2 抗利尿激素分泌異常綜合征 抗利尿激素分泌異常綜合征是指由于多種因素所致的抗利尿激素分泌異常增多,從而導(dǎo)致的液體潴留、排鈉增多以及稀釋性的低鈉血癥等有關(guān)臨床表現(xiàn)的一組綜合征。研究表明,10%~45%的小細(xì)胞肺癌(非小細(xì)胞肺癌為1%)可產(chǎn)生異位抗利尿激素[13]。頭痛和疲勞等非特異性癥狀可能是副腫瘤性SIADH的最初表現(xiàn)。SIADH的癥狀取決于低鈉血癥的嚴(yán)重程度,慢性、輕度至中度低鈉血癥可能不會(huì)產(chǎn)生任何明顯的神經(jīng)癥狀,但急性(<48 h)、嚴(yán)重(血清鈉<120 mgN/L)低鈉血癥會(huì)導(dǎo)致腦水腫、精神狀態(tài)改變或癲癇發(fā)作,甚至死亡。副腫瘤性SIADH的治療方法與非癌癥患者的治療方法基本相同,其復(fù)發(fā)可能與腫瘤復(fù)發(fā)或進(jìn)展有關(guān)[14-15]。
1.3 異位庫(kù)欣綜合征 1928年,Brown首次在類癌腫瘤中描述異位庫(kù)欣綜合征(endogenous Cushing’s syndrome,ECS),該綜合征雖為第二常見(jiàn)的副腫瘤綜合征,多發(fā)生于小細(xì)胞肺癌或不太常見(jiàn)的支氣管類癌中[15],但由于報(bào)道的論文有限,僅見(jiàn)于所有小細(xì)胞肺癌(small cell lung cancer,SCLC)的1%~5%[16]。由小細(xì)胞肺癌引起的異位庫(kù)欣綜合征多見(jiàn)于男性患者,表現(xiàn)為明顯的色素沉著、高血壓、水腫、嚴(yán)重低鉀血癥伴肌無(wú)力以及高血糖的癥狀。
在上述提及的病例中,有多達(dá)50%的肺癌患者會(huì)被檢測(cè)到促腎上腺皮質(zhì)激素水平的升高[5,7,15],異位促腎上腺皮質(zhì)激素產(chǎn)生腫瘤的最常見(jiàn)位置仍然是肺[17]。找到并去除促腎上腺皮質(zhì)激素產(chǎn)生源,可有效治愈或減少癥狀,并降低血清皮質(zhì)醇水平。在大多數(shù)情況下,對(duì)潛在癌癥的治療也將改善ECS,理想的治療是切除腫瘤[18]。
1.4 肢端肥大癥 異位肢端肥大癥通常由異位生長(zhǎng)激素釋放激素(growth hormone-releasing hormone,GHRH)引起,或腫瘤異位生長(zhǎng)激素分泌引起,分泌異位GHRH或生長(zhǎng)激素的最常見(jiàn)腫瘤是支氣管類癌和胰島細(xì)胞瘤[19],與肢端肥大癥相關(guān)的其他類型肺癌也有報(bào)道,包括小細(xì)胞肺癌、細(xì)支氣管肺泡癌和表皮樣癌[20]。多數(shù)患者是因GHRH相關(guān)并發(fā)癥就診時(shí)得以診斷[21]。腫瘤的完全手術(shù)切除是異位肢端肥大癥的最佳治療方法。
2 神經(jīng)系統(tǒng)
2.1 副腫瘤性神經(jīng)綜合征 副腫瘤性神經(jīng)綜合征(para neoplastic syndromes,PNS)是由癌癥的遠(yuǎn)程效應(yīng)引起的神經(jīng)障礙,其本質(zhì)上是具有自身免疫性的。與大多數(shù)副腫瘤綜合征不同的是,它們與局部腫瘤或轉(zhuǎn)移效應(yīng)無(wú)關(guān)[22-23]。腫瘤抗體似乎是發(fā)病機(jī)制的核心,但腫瘤抗體的缺乏并不能排除PNS的診斷。
診斷副腫瘤性神經(jīng)疾病的最好方法是識(shí)別與各種癌癥特異性相關(guān)的抗腫瘤蛋白抗體。浦肯野細(xì)胞抗體17型(PCA-1,即抗Yo)和抗神經(jīng)元核抗體1型(ANNA-1,即抗Hu)是研究人群中最常見(jiàn)的腫瘤抗體,γ-氨基丁酸B-R抗體在50%~60%的病例中與惡性腫瘤有關(guān),通常是小細(xì)胞肺癌。與五氯苯甲醚-1(PCA-1)抗體相關(guān)的最常見(jiàn)臨床綜合征是副腫瘤性小腦變性(paraneoplastic cerebellar degeneration,PCD)[24]。邊緣性和間腦性副腫瘤性腦炎是典型的與Ma2 IgG相關(guān)的臨床表型[25-26]。
由于免疫反應(yīng)有助于限制癌癥的生長(zhǎng)和轉(zhuǎn)移,所以對(duì)潛在腫瘤的早期發(fā)現(xiàn)、管理以及免疫抑制治療是PNS長(zhǎng)期預(yù)后的重要因素[27-28]。如果在診斷PNS時(shí)未檢測(cè)到腫瘤,則應(yīng)對(duì)具有腫瘤抗體的PNS進(jìn)行癌癥監(jiān)測(cè),以免漏診。除此之外,該腫瘤的免疫聯(lián)合治療應(yīng)盡快開(kāi)始,以減少不可逆的神經(jīng)元丟失,避免嚴(yán)重的神經(jīng)功能障礙[29]。
2.2 肌無(wú)力綜合征 肌無(wú)力綜合征(lambert-eaton myasthenic syndrome,LEMS)是一種神經(jīng)肌肉接頭的自身免疫性疾病,其特征是肌肉無(wú)力和自主神經(jīng)功能障礙。在神經(jīng)受到刺激后,肌電圖上表現(xiàn)為復(fù)合肌肉動(dòng)作電位較低,低頻刺激(3 Hz)時(shí)動(dòng)作電位減少10%以上,高頻刺激(20 Hz以上)后增加100%以上[30-31]。文獻(xiàn)[31]有60%的LEMS患者與副腫瘤相關(guān),小細(xì)胞肺癌最為常見(jiàn),主要在其診斷后兩年內(nèi)發(fā)現(xiàn)。在極少數(shù)情況下,副腫瘤性LEMS患者會(huì)發(fā)生小腦變性,但也有部分副腫瘤性小腦變性患者卻沒(méi)有肌無(wú)力的臨床常有體征或癥狀[32-33]。
LEMS易被誤診為皮肌炎、重癥肌無(wú)力等,因此對(duì)原因不明的腦、脊髓、周圍神經(jīng)病變者,尤其是伴低熱或咳嗽等癥狀者,應(yīng)考慮到原發(fā)性肺癌的可能,并及時(shí)反復(fù)進(jìn)行相關(guān)的檢查。
3 皮膚系統(tǒng)
皮膚表現(xiàn)可能是內(nèi)部惡性腫瘤的第一個(gè)跡象[34]。在40歲以上的男性中,肺癌是最常見(jiàn)的轉(zhuǎn)移到皮膚的內(nèi)部惡性腫瘤,而在40歲以上的女性中,肺癌是第三常見(jiàn)的,僅次于乳腺癌和結(jié)腸癌。皮膚轉(zhuǎn)移可能表現(xiàn)為丘疹、斑塊、結(jié)節(jié)或潰瘍,這通常預(yù)示著預(yù)后不良。
3.1 黑棘皮病 黑棘皮病(acanthosis nigricans,AN)的特征性表現(xiàn)是皮膚增厚和色素沉著過(guò)度,主要發(fā)生在頸部至腋窩,是與肺癌相關(guān)的罕見(jiàn)副腫瘤綜合征之一[35]。大多數(shù)情況下,AN是由肥胖、代謝綜合征、糖尿病患者的代謝紊亂或藥物等因素所導(dǎo)致。與AN相關(guān)的最常見(jiàn)的組織學(xué)癌癥類型是腺癌,通常涉及胃腸系統(tǒng)(胃腺癌),但有研究發(fā)現(xiàn),在鱗狀細(xì)胞肺癌中也觀察到了AN[36]。臨床醫(yī)生應(yīng)考慮任何不明原因皮膚病變其潛在惡性腫瘤的可能性,并開(kāi)展適當(dāng)?shù)臋z查。
3.2 肥大性肺性骨關(guān)節(jié)病 肥大性肺性骨關(guān)節(jié)病(hypertrophic pulmonary osteoarthropathy,HPOA)也稱為Marie-Bamberger綜合征,是一種罕見(jiàn)的副腫瘤綜合征,其典型特征是杵狀指、長(zhǎng)管狀骨骨膜病及關(guān)節(jié)痛三聯(lián)征[2,37]。在HPOA病例中,80%是由副腫瘤綜合征引起的,更常見(jiàn)的是非小細(xì)胞肺癌,較少見(jiàn)的是小細(xì)胞肺癌,可通過(guò)全身骨顯像的特征影像進(jìn)行確診[38-39]。因此遇到突發(fā)性關(guān)節(jié)炎時(shí),尤其是吸煙患者,醫(yī)生應(yīng)保持高度警惕。此肺外表現(xiàn)通過(guò)切除腫瘤可能會(huì)改善或緩解,除此之外,非甾體抗炎藥的治療可以緩解癥狀。
4 眼部的肺外表現(xiàn)
與癌癥相關(guān)的視網(wǎng)膜病變(cancer-associated retinopathy,CAR)比較罕見(jiàn),通常與小細(xì)胞肺癌有關(guān),是一種表現(xiàn)為不對(duì)稱的嚴(yán)重視力喪失的雙側(cè)性疾病[40]。在常見(jiàn)的臨床表現(xiàn)中,CAR影響視錐細(xì)胞和視桿細(xì)胞,可導(dǎo)致視錐功能障礙。皮質(zhì)類固醇可能對(duì)控制CAR有效。
彌漫性葡萄膜黑色素細(xì)胞增生(diffuse uveal melanocytic proliferation,DUMP)是一種非常罕見(jiàn)的副腫瘤綜合征,其特征為葡萄膜黑色素細(xì)胞良性增生,典型表現(xiàn)為雙側(cè)視力下降。DUMP與眼外系統(tǒng)惡性腫瘤相關(guān),最常見(jiàn)的是男性肺癌和女性泌尿婦科癌癥(卵巢癌)。DUMP患者在幾個(gè)月內(nèi)經(jīng)歷緩慢、無(wú)痛、雙側(cè)(大多數(shù)情況下不對(duì)稱)的進(jìn)行性視力喪失過(guò)程。全身皮質(zhì)類固醇和眼眶放療對(duì)DUMP是無(wú)效的,潛在腫瘤的切除或可使DUMP消除[41]。
5 其他肺外表現(xiàn)
血液系統(tǒng)可表現(xiàn)為貧血、粒細(xì)胞增多癥、紅細(xì)胞增多癥等,通常在癌癥診斷后被發(fā)現(xiàn),其預(yù)后較差,沒(méi)有特定的治療方法,肺癌的成功治療可改善血液系統(tǒng)疾病。
副腫瘤性腎小球疾?。╬araneoplastic glomerular disease,PGD)于1966年首次報(bào)道,發(fā)病率約為10.9%[42]。膜性腎?。╩embranous nephropathy,MN)可能與肺、前列腺和胃腸道實(shí)體瘤的惡性腫瘤有關(guān)[43]。眾所周知,在對(duì)惡性腫瘤進(jìn)行有效治療后,大多數(shù)腎臟損害可以減輕,其特點(diǎn)是尿蛋白減少和腎功能改善[44]。對(duì)于伴有腎功能不全的癌癥患者,定期隨訪非常關(guān)鍵,尤其是中老年患者,更應(yīng)重視腫瘤相關(guān)性腎損害的治療和預(yù)后。
6 小結(jié)
肺癌的肺外表現(xiàn)較復(fù)雜且診斷困難,常缺乏典型的呼吸道癥狀和體征。全面地認(rèn)識(shí)和掌握肺癌各種形式的臨床表現(xiàn)是早期診斷的重要環(huán)節(jié),尤其是以肺外癥狀首發(fā)的病例。近年來(lái),在研究與肺癌相關(guān)的副腫瘤綜合征方面已取得了顯著性進(jìn)展。當(dāng)出現(xiàn)文中所涉及的肺外表現(xiàn)時(shí)應(yīng)警惕原發(fā)性肺癌的可能,并及時(shí)做好肺部的相關(guān)檢查以進(jìn)一步明確診斷并及時(shí)治療。
參考文獻(xiàn)
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(收稿日期:2021-11-30) (本文編輯:姬思雨)
中國(guó)醫(yī)學(xué)創(chuàng)新2022年3期