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张品良 三甲
张品良 副主任医师
山东省肿瘤医院 呼吸内科

小细胞肺癌的诊断、筛查与临床表现

Discussion 讨论

This discussion is being updated to correspond with the newly updated algorithm. Last updated 02/24/17 此讨论更新到与最新的工作步骤相一致。最后更新2017年2月24日

Overview 概述

Neuroendocrine tumors account for approximately 20% of lung cancers; most (approximately 14%) are small cell lung cancer (SCLC). 1,2 In 2017, an estimated 31,000 new cases of SCLC will occur in the United States. 3 Nearly all cases of SCLC are attributable to cigarette smoking. 4 Although the incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1.2 Management of SCLC and other lung neuroendocrine tumors (LNTs) is described in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines(R)) for SCLC and for LNTs, which include the algorithms and this supporting Discussion text (see the NCCN Guidelines(R) for SCLC and Lung Neuroendocrine Tumors in the NCCN Guidelines for Neuroendocrine Tumors, available at NCCN.org). The Summary of the Guidelines Updates section in the algorithm describes the most recent revisions, which have been incorporated into this revised Discussion (see the NCCN Guidelines for SCLC). For the 2017 update for SCLC, nivolumab and nivolumab with ipilimumab were added as new options for second-line and beyond (ie, subsequent) systemic therapy; 5 new imaging guidelines for response assessment after systemic therapy were also added in addition to other changes as outlined in the summary updates. The NCCN Guidelines for SCLC were originally published 20 years ago and have been subsequently updated at least once every year (see NCCN.org). 6 山东省肿瘤医院呼吸内科张品良
神经内分泌肿瘤约占肺癌的20%;大多数(约14%)是小细胞肺癌(SCLC)。1,2 估计2017年美国将有31000例新发SCLC病例。3几乎所有的SCLC病例都是由吸烟引起的。4虽然小细胞肺癌的发病率一直呈下降趋势,但是在女性中的发病率升高,男女发病率之比现在是1:1。2小细胞肺癌与其他肺神经内分泌肿瘤(LNTs)的管理在小细胞肺癌和LNTs的NCCN肿瘤学临床实践指南(NCCN指南®)中描述,包括工作步骤和此支持讨论内容(见神经内分泌肿瘤NCCN指南中的SCLC和肺神经内分泌肿瘤NCCN指南®,可在NCCN.org获得)。在工作步骤中总结的指南更新部分介绍了最近的修订,已纳入到本修订的讨论中(见小细胞肺癌NCCN指南)。小细胞肺癌2017版更新,增加了尼鲁单抗和尼鲁单抗联合伊匹单抗作为一个新的二线及二线以上(即后续)全身治疗选择;5 在更新摘要中,除了概述其他的变化外,还增加了全身治疗后疗效评估新的影像指南。小细胞肺癌的NCCN指南最初发表于20年前,随后至少每年更新一次(见NCCN.org)。6

SCLC is characterized by a rapid doubling time, high growth fraction, and early development of widespread metastases. Most patients with SCLC present with hematogenous metastases; approximately one third present with limited disease confined to the chest. SCLC is highly sensitive to initial chemotherapy and radiotherapy; however, most patients eventually die of recurrent disease. 7 In patients with limited-stage SCLC, the goal of treatment is cure using chemotherapy plus thoracic radiotherapy. 8,9 In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. 10 Note that the definitions for limited-stage and extensive-stage SCLC incorporate TNM staging (see the NCCN Guidelines for SCLC and Staging in this Discussion). Surgery is only appropriate for a few patients (2%–5%) with surgically resectable stage I SCLC. 11 Clinical trials generally represent state-of-the-art treatment for patients with SCLC. Despite recent advances, the standard therapy for SCLC as outlined by these NCCN Guidelines still needs to be improved. Thus, participation in clinical trials should be strongly encouraged.
小细胞肺癌的特点是倍增时间短、增殖比率高以及广泛转移发生早。大多数小细胞肺癌患者有血行转移;约三分之一的局限期疾病局限于胸部。小细胞肺癌对初始化疗和放疗高度敏感;然而,大多数患者最终死于复发性疾病。7局限期小细胞肺癌患者,治疗的目标是采用化疗+胸部放疗治愈。8,9 广泛期疾病患者,单纯化疗可减轻大多数患者的症状、延长生存;然而,长期生存罕见。10要注意的是,局限期和广泛期小细胞肺癌的定义结合TNM分期(见小细胞肺癌NCCN指南和本讨论中的分期)。手术只适合少数手术可切除的I期小细胞肺癌患者(2%–5%)。11临床试验通常为小细胞肺癌患者提供最先进的治疗。虽然最近有进步,但是这些NCCN指南所概括的小细胞肺癌的标准治疗仍有待改进。因此,应强烈鼓励参与临床试验。

Smoking cessation should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas (see the NCCN Guidelines for Smoking Cessation, available at NCCN.org). 12 Former smokers should be strongly encouraged to remain abstinent. Patients with SCLC who continue to smoke have increased toxicity during treatment and shorter survival. 13 Programs using behavioral counseling combined with FDA–approved medications that promote smoking cessation can be very useful.
应强烈提倡小细胞肺癌和其他高级别神经内分泌癌患者戒烟(见戒烟NCCN指南,可在NCCN.org获得)。12应该强烈鼓励既往吸烟者保持戒烟。在治疗期间继续吸烟的小细胞肺癌患者毒性增加且生存期更短。13使用行为咨询计划并结合FDA批准的促进戒烟的药物可能是非常有用的。

Diagnosis 诊断

Screening 筛查

Ideally, a screening test should detect disease at an early stage when it is still curable. Currently, no effective screening test is available to detect early-stage SCLC; the disease is typically diagnosed when patients present with symptoms indicative of advanced-stage disease. 14 The National Lung Screening Trial (NLST) reported that screening with annual, low-dose, spiral CT scans decreased lung cancer–specific mortality in asymptomatic high-risk individuals (see the NCCN Guidelines for Lung Cancer Screening, available at NCCN.org). 15 Although low-dose CT screening can detect early-stage non-small cell lung cancer (NSCLC), it does not seem to be useful for detecting early-stage SCLC.14-16 Low-dose CT screening is probably not useful because of the aggressiveness of SCLC, which results in the development of symptomatic disease between annual scans, thereby limiting the potential effect on mortality. 14
理想情况下,筛查应检出早期仍可治愈的疾病。目前,没有有效的筛选检查可以检出早期小细胞肺癌;通常是当患者出现晚期疾病症状时才确诊。14国家肺癌筛查试验(NLST)报道,每年1次低剂量螺旋CT扫描筛查,在无症状高危个体中肺癌特异性死亡率下降(见NCCN肺癌筛查指南,可在NCCN.org获得)。15虽然低剂量CT筛检可以发现早期非小细胞肺癌(NSCLC),但似乎对检出早期小细胞肺癌没有用。14-16低剂量CT筛查可能没有用是因为小细胞肺癌的侵袭性,导致在每年1次的检查之间发展为有症状的疾病,因此限制了对死亡率的潜在影响。14

Manifestations 表现

SCLC typically presents as a large hilar mass and bulky mediastinal lymphadenopathy that cause cough and dyspnea. 17 Frequently, patients present with symptoms of widespread metastatic disease, such as weight loss, debility, bone pain, and neurologic compromise. It is uncommon for patients to present with a solitary peripheral nodule without central adenopathy. In this situation, fine-needle aspiration (FNA) may not adequately differentiate small cell carcinoma (which is a high-grade neuroendocrine carcinoma) from low-grade (typical carcinoid), intermediate-grade (atypical carcinoid), or large-cell neuroendocrine carcinoma (LCNEC) (which is also a high-grade neuroendocrine carcinoma) (see Lung Neuroendocrine Tumors in the NCCN Guidelines for Neuroendocrine Tumors available at NCCN.org). 18,19
小细胞肺癌的典型表现为肺门大肿块和纵隔巨大淋巴结,引起咳嗽和呼吸困难。17患者常常出现广泛的转移性疾病症状,如体重减轻、乏力、骨痛和神经损害。无中央淋巴结的孤立性周围型结节患者罕见。在这种情况下,细针穿刺抽吸(FNA)或许不能充分区分小细胞癌(这是一种高级别的神经内分泌癌)、低级别(典型类癌)、中等级别(不典型类癌)或大细胞神经内分泌癌(LCNEC)(这也是一种高级别神经内分泌癌)(见神经内分泌肿瘤NCC指南中的肺神经内分泌肿瘤,可在NCCN.org获得)。18,19

Many neurologic and endocrine paraneoplastic syndromes are associated with SCLC. 20-22 Neurologic syndromes include Lambert-Eaton myasthenic syndrome, encephalomyelitis, and sensory neuropathy. Patients with the Lambert-Eaton syndrome present with proximal leg weakness that is caused by antibodies directed against the voltage-gated calcium channels. 23,24 Paraneoplastic encephalomyelitis and sensory neuropathy are caused by the production of an antibody (anti-Hu) that cross-reacts with both small cell carcinoma antigens and human neuronal RNA-binding proteins resulting in multiple neurologic deficits. 25
许多神经系统和内分泌副肿瘤综合征与小细胞肺癌有关。20-22神经系统症状包括兰伯特-伊顿肌无力综合征、脑脊髓炎以及感觉神经病变。有兰伯特-伊顿综合征(类重症肌无力综合征)的患者表现为近端下肢无力,是由抗电压门控钙通道抗体引起的。23,24副肿瘤性脑脊髓炎和感觉神经病变是由一种抗体(抗-Hu)引起的,该抗体既能与小细胞癌抗原结合,又能与人神经元RNA结合蛋白相互作用导致多神经损伤。25

SCLC cells sometimes produce polypeptide hormones, including vasopressin (antidiuretic hormone [ADH]) and adrenocorticotropic hormone (ACTH), which cause hyponatremia of malignancy (ie, syndrome of inappropriate ADH secretion [SIADH]) and Cushing syndrome, respectively. 26,27 In patients with SCLC, SIADH occurs more frequently than Cushing syndrome. Cancer treatment and/or supportive care may also cause hyponatremia (eg, cisplatin, opiates). 28 Treatment for SIADH includes fluid restriction (which is difficult for patients because of increased thirst), demeclocycline, or vasopressin receptor inhibitors (ie, conivaptan, tolvaptan) (see Principles of Supportive Care in the NCCN Guidelines for SCLC).28-30 ADH levels and hyponatremia usually improve after successful treatment for SCLC.
小细胞肺癌细胞有时会产生多肽激素,包括加压素(抗利尿激素[ADH])和促肾上腺皮质激素(ACTH),分别引起恶性低钠血症(即抗利尿激素分泌异常综合征[SIADH])和库欣综合征。26,27在小细胞肺癌患者中,抗利尿激素分泌异常综合征(SIADH)比库欣综合征更常见。癌症治疗和/或支持治疗也可能导致低钠血症(如顺铂、阿片类)。28抗利尿激素分泌异常综合征(SIADH)的治疗包括限制液体(因为口渴,这对患者是困难的)、地美环素或加压素受体抑制剂(即考尼伐坦、托伐普坦)(见小细胞肺癌NCCN指南中支持治疗的原则)。28-30 在小细胞肺癌治疗成功后,ADH(抗利尿激素)水平与低钠血症通常改善。

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张品良
张品良 副主任医师
山东省肿瘤医院 呼吸内科
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