1、孤立性肺结节 solitary pulmonary nodule -两个国际指南解读,山东大学附属千佛山医院呼吸科 张劭夫,MacMahon H, MB, BCh, BAO. Austin JH, MD Gamsu G, MD Guidelines for Management of Small Pulmonary Nodules Detected on CT Scans: A Statement from the Fleischner Society1Radiology 2005; 237:395400,NaidichDP, Bankier AA, MacMahon H Recommenda
2、tions for the Management of Subsolid Pulmonary Nodules Detected at CT: A Statement from the Fleischner Society , Radiology, 2013, 266: 304-317,根据：两个国际指南解读,Felix Fleischner MD,1893年出生于维也纳 1919毕业于维也纳大学医学院 19191932年，在 wilhelminen Hospital工作 1932年起，任维也纳儿童医院放射科主任 1938年赴美，在Massachusetts General Hospital 做
3、2年实习医生，及2年开业医生 1942年 Boston Beth Israel Hospital 全职放射科医生 1945年 Boston Beth Israel Hospital 放射科主任，直至1960年退休 1950年被Harvard Medical School教授 发表论文251篇 退休后作为顾问会诊医生服务于Boston多家医院，并担任国际级讲师,1969年11月由8位医生成立一个以X-线为主要研究工具诊断胸部疾病的学会组织， Dr Fleischner 应邀参加，但他在学会成立前3个月游泳时死于心脏病，为了纪念他，学会被命名为Fleischner Society Fleischn
4、er Society目的：更好诊断胸部疾病，发展放射病学技术 Fleischner Society目标：面向有志于研究胸部疾病的医生和科学家的国际非盈利性组织 Fleischner Society规则：仅有65名会员，会员必须接受严格的肺病学、生理学、病理学、麻醉学和外科学训练 主要成就：发表论文数百篇，其中有些指导性文件成为行业指南。,肺科临床实践中肺结节阴影是一个常见问题，出现频率由: 原来的胸片发现的0.2%到现在肺癌低剂量CT筛查研究中的约4060%。,Lung nodules are a common problem in pulmonary practice. Estimates
5、of their frequency range from 0.2% in older studies with chest radiographs to approximately 4060% in lung cancer screening trials using low-dose computed tomography (CT) (17).,Ost D，GouldMK.Decision Making in Patients with Pulmonary NodulesAm J Respir Crit Care 2012，Med Vol 185, (4), 363372,肺结节定义：,孤
6、立性肺结节(solitary pulmonary nodule)经典定义：单发、球形、边界清楚、直径等于3cm的高密度阴影，周围完全由充气的肺组织包绕不伴有肺不张、肺门肿大和胸腔积液的亚厘米级结节(subcentimeter nodules) ：直径8mm 结节。形态可呈球形或非球形。两种形态均可见于恶性结节。肺内小结节（Small Pulmonary Nodules，SPN）: 10 mm 肿块(masses)：3cm 直径的病灶被称为肿块而不再称为结节。在明确诊断前原则上应认为恶性。,1 Ost D, Fein AM, Feinsilver SH. Clinical practice: t
7、he solitary pulmonary nodule. N Engl J Med 2003;348:25352542. 2 Gould MK, Fletcher J, Iannettoni MD, Lynch WR, Midthun DE, Naidich DP, Ost DE. Evaluation of patients with pulmonary nodules: when is it lung cancer? ACCP evidence-based clinical practiceguidelines (2nd edition). Chest 2007;132:108S130S
8、.3 Xu DM, van der Zaag-Loonen HJ, Oudkerk M, Wang Y. Smooth or attached solid indeterminate nodules detected at baseline CT screening in the nelsonstudy: cancer risk during 1 year of follow-up. Radiology 2009;250:264272.4 Ost D, Fein A. Evaluation and management of the solitary pulmonary nodule. Am
9、J Respir Crit Care Med 2000;162:782787.,在肺癌筛查的临床研究中，基线筛查时发现小结节病变占8%51%，而且结节通常为多发性96%的非钙化结节10 mm，72%的结节5 mm。对于那些10 mm 的微小结节，由于很难确定其性质，故统称为“肺内小结节”（Small Pulmonary Nodules，SPN）。,根据肺内小结节的密度，可将其分成3类：,根据结节的磨玻璃阴影所占比例分为3类： 1、纯磨玻璃结节（a pure ground-glass appearance pGGN）2、部分磨玻璃结节或混合性非实性结节（ mixed ground-glass o
10、r part-solid appearancealso called semisolid mGGN)3、实性结节（a pure solid appearance SSN)以上特征有助于对结节的性质进行判断,术 语,实性结节 (solidary nodule),非实性结节 (subsolid nodule),纯磨玻璃 密度结节 （pure ground-glass nodule pGGN）,部分实性结节 （part-solid GGN）,孤立性肺结节（SN）,+,(A) Ground-glass opacity. (B) Mixed ground glassand solid nodule, a
11、lso called a semisolid nodule.(C) Solid lung nodule.,非实性结节：磨玻璃密度结节（ground-glass nodule, GGN）,毛玻璃成分为均匀的磨砂状阴影，有时可见小空泡征通常这样的毛玻璃样结节进展很慢，或数年无变化，或仅表现为逐渐密实。这种影像特征在病理上往往对应为原位腺癌或不典型腺样增生。,毛玻璃成分为均匀的磨砂状阴影，有时可见小空泡征，通常这样的毛玻璃 样结节进展很慢，或数年无变化，或仅表现为逐渐密实。这种影像特征在病理 上往往对应为原位腺癌或不典型腺样增生。,55 岁女性，体检发现右上肺阴影2 年。无吸烟史。CT 影像学所见：
12、右肺上叶尖段、后段毛玻璃样结节影，密度浅淡为纯毛玻璃样，边界欠清晰。尖段病灶直径约6 mm, 未见分叶毛刺，有小空泡征（图1），后段病灶4 mm 有分叶（图2）。随访2 年，未见体积增大但密度略有增浓，右上叶尖段病灶周围疑有增粗的血管，右上叶后段病灶有血管进入。遂剖胸手术。术后病理：右肺上叶尖段见肺泡上皮异型增生，伴肺泡间隙增宽，肺泡纤维组织增生伴玻璃样变，考虑肺泡上皮不典型腺瘤样增生（直径 6 mm）。右肺上叶后段肺泡上皮异型增生，部分腺体符合原位腺癌（直径 4 mm）,非实性结节：部分实性结节（part-solid GGN）,部分毛玻璃样结节可伴有空泡征、支气管造影征或微结节，其中实性成分
13、往往为浸润性腺癌。5 mm 的实性成分以微浸润腺癌多见，或为预后良好的伏壁生长型。,部分毛玻璃样结节可伴有空泡征、支气管造影征或微结节，其中实性成分 往往为浸润性腺癌。5 mm 的实性成分以微浸润腺癌多见，或为预后良好的 伏壁生长型。,55 岁男性，体检发现右肺阴影9 个月。 吸烟600 年支。CT 影像学所见：右下 肺见一小结节12 mm11 mm，部分毛 玻璃样影，中心为小片实性密度，可见一血管进入肿瘤。随访中见结节分叶明显，中心实性成分有增大趋势（图3）。遂电视辅助胸腔镜手术（VATS）探查，术中冰冻切片为腺癌。手术病理：右肺下叶前基底段浸润性腺癌，12 mm10 mm 6 mm，以伏壁
14、生长型为主，伴有乳头状腺癌成分。,实性结节 solid nodule,实性结节，致密均匀的小结节，如伴有分叶、刷状毛刺、胸膜牵扯征，则恶性可能性极大。由于病灶小，很难穿刺明确病理，且正电子发射体层摄影（PET）对于8 mm 的病灶，诊断的假阴性率明显增高，因此随访中观察有无进展并结合影像学特征是临床上决定是否开胸探查的主要依据。值得注意的是，恶性实性结节的病理类型多为浸润性腺癌，以腺泡状、乳头状和实性亚型为主。在小结节病灶中即使是实性结节也极少见到鳞癌，有作者分析了107 个小结节病灶，无一例为鳞癌。,56 岁女性，体检发现右下肺结节影5 个月。 无吸烟史。胸部CT 影像学所见（2011 年9
15、 月）：右肺下叶结节状影，直径约10 mm， 边界清楚与胸膜紧邻，内部密度均匀为实 性结节。5 个月后随访CT 薄层重建可见轻 度分叶征象。遂剖胸探查。病理：右肺下叶浸润性腺癌，乳头状腺癌为 主，中分化，肿瘤大小8 mm7 mm7 mm。,实性结节：致密均匀的小结节，如伴有分叶、刷状毛刺、胸膜牵扯征，则恶性可能性极大。由于病灶小，很难穿刺明确病理，且正电子发射体层摄影（PET）对于8 mm 的病灶，诊断的假阴性率明显增高，因此随访中观察有无进展并结合影像学特征是临床上决定是否开胸探查的主要依据。值得注意的是，恶性实性结节的病理类型多为浸润性腺癌，以腺泡状、乳头状和实性亚型为主。在小结节病灶中即
16、使是实性结节也极少见到鳞癌，我们分析了107 个小结节病灶，无一例为鳞癌。,有些良性实性结节，仅靠影像学特点很难判断其性质，在随访中也可见病灶明显增大，最终探查结果为错构瘤，这提示我们即使良性病变也有增大的趋势。举例：男性54 岁，体检发现右下肺结节影2 月。吸烟400 年支。胸部CT 影像学所见：右下肺结节，边界锐利有分叶。随访中结节影明显增大， 2010 年12 月剖胸探查行右下肺楔形切除。手术病理：错构瘤，直径8 mm。,右下肺实性结节，边缘锐利且有分叶， 随访过程中明显增大，手术病理：错构瘤。 提示：良性病变也可表现增大趋势,MacMahon H, MB, BCh, BAO. Aust
17、in JH, MD Gamsu G, MD Guidelines for Management of Small Pulmonary Nodules Detected on CT Scans: A Statement from the Fleischner Society1Radiology 2005; 237:395400,在此之前， Ost等在NEJM发表的综述和实2003年由美国胸科医师协会颁布的实性肺结节管理指南是临床肺结节诊疗的主要的指导性文件,Guidelines for the management of the solitary pulmonary nodule were pu
18、blished in 2003 by the American College of Chest Physicians and A review in by Ost and colleagues in the New England Journal of Medicine,两者均推荐分别于发现结节后的3、6、12、（18）和24个月进行CT随访。其目的在于对这些未能确定性质的小结节中的某些将会证明是恶性的，以及尽可能早期干预而增加治愈机会。这不可避免的产生假阳性所带来的诸如患者焦虑、手术潜在的并发症甚至因手术死亡、增加患者经济负担、浪费医疗资源、使患者丧失对放射医师的信任和增加辐射负担等一系列
19、问题。,大量研究证实：不吸烟患者肺内5mm小结节为恶性的比率不足1%（即2年的时间病灶增大或转移） 然而，目前的实际情况是对这部分偶然发现结节病灶的患者常常在两年内会多次进行CT随访，动态观察。 因此，考虑到辐射问题，尤其是年轻患者，我们必须考虑建立新的适当的随访策略。（The radiation issue is particularly important in younger patients and must be taken into account in determining appropriate follow-up strategies）,肺结节的CT表现：结节大小,Mayo
20、 Clinic CT Screening Trial： 在无癌症病史的患者5mm的极小肺结节恶性比例低于1%,Midthun等发现：不同大小结节的恶性可能性比率为： 3 mm ： 0.2% 47 mm ： 0.9%, 820 mm ： 18%20 mm ： 50%,Midthun DE, Swensen SJ, Jett JR, Hartman TE. Evaluation of nodules detected by screening for lung cancer with low dose spiral computed tomography. Lung Cancer 2003;41(
21、suppl 2):S40.,肺结节大小与性质的关系,7个CT肺癌筛查研究表明，不同大小的肺结节的恶性率为： 5 mm结节：01% 5- 10mm： 628% 1120-mm ： 3364% 20 mm ： 6482%,In seven studies of nodules detected in lung cancer screening trials, the prevalence of malignancy： 01% in patients with nodules less than 5 mm in diameter, 628% for 5- to 10-mm nodules, 3364
22、% for 11- to 20-mm nodules, 6482% for nodules measuring greater than 20 mm,Wahidi MM, Govert JA, Goudar RK, Gould MK, McCrory DC. Evidence for the treatment of patients with pulmonary nodules: when is it lung cancer? ACCP evidence-based clinical practice guidelines (2ndedition). Chest 2007;132:94S10
23、7S.,Henschke 等人对19932003年总共2897例(5)非钙化肺结节患者进行回顾性分析，分别分为直径5mm组和59mm组分析。以3、6、12个月的间隔时间进行CT扫描。与更积极的短期随诊相比，378例5mm结节患者的初始于第12个月的随诊，无一例导致诊断延误,They performed a retrospective review of a total of 2897 baseline screening studie performed between1993 and 2002）On the basis of the results of these follow-up st
24、udies and biopsies, the authors determined that when the largest noncalcified nodule was smaller than 5 mm in diameter (378 patients), a follow-up study in 12 months would have resulted in no case of delayed diagnosis, compared with more aggressive short term follow-up.,直径59mm的结节在48个月的随诊检查中6%患者观察到结节
25、增大，且其均为恶性病灶。因此，建议对于在基线筛查时直径小于5mm的肺结节患者应在12个月后进行年度随诊检查，无须进行间隔扫描。,However, when the largest nodule was 59 mm in diameter, approximately 6% of cases (all of which were malignant) showed interval nodule growth detectable on 48-month follow- up scans.（Therefore, they recommended that patients with nodule
26、s no larger than 5 mm in diameter on a baseline screening CT scan should be referred for repeat annual screening in 12 months time, with no interval scans）,肺结节的CT表现：结节增长（倍增时间）,Hasegawa M, Sone S, Takashima S, et al. Growth rate of small lung cancers detected on mass CT screening. Br J Radiol 2000;73
27、: 12521259.,Hasegawa et al 在一个为期3年的肿块筛查 研究中的不同结节平均倍增时间 （Mean volume doubling times）1 pGGN 813 days 2 mGGN 457 days 3 sN： 149 days,非吸烟者的肿瘤倍增时间 较之吸烟者为长 （the mean volume doubling timefor cancerous nodules in nonsmokerswas significantly longer than that forcancerous nodules in smokers.）,以上资料进一步支持对于小的非实性
28、或部分实性结节应当延长随访时间须注意的是：一个倍增时间60天的5mm结节12个月后的直径为20.3mm,而一个倍增时间240天的同样大小的结节12个月后则仅为直径7.1mm,（These data further support the use of extended follow-up intervals for small nonsolid or partly solid nodules, even in high-risk patients.）（Note that a 5-mm nodule with a doubling time of 60 days will reach a dia
29、meter of 20.3 mm in 12 months, whereas a similar nodule with a doubling time of 240 days would reach a diameter of only 7.1 mm in the same period.）,肺结节的CT表现：危险因素,吸烟： The relative risk for developing lung carcinoma in male smokers was about 10 times that in nonsmokers in the eight prospective studies
30、 reviewed for the 1982 report of the Surgeon General on “The Health Consequences of Smoking” (25). For heavy smokers, the risk was 1535 times greater (25,26).Despite initial evidence suggesting an increased risk of lung cancer in women compared with that in men with an equal smoking history, this ha
31、s not been confirmed in more recent studies (2730),1982年“吸烟对健康影响研究”表明：男性吸烟者肺癌的发病率是不吸烟者的10倍。大量吸烟者可达1535倍尽管早期研究曾发现同样吸烟史情况下，女性肺癌发病率高于男性，但近年来的研究并未证实这一结果,A history of lung cancer in first-degree relatives is also a notable risk factor, and strong evidence for a specific lung cancer susceptibility gene ha
32、s been discovered recently (31,32). Other established risk factors include exposure to asbestos, uranium, and radon (3335). However, cigarette smoke remains the overwhelmingly dominant culprit.,一级亲属的癌症家族史是一个重要的危险因子，已经发现一个特异性肺癌敏感基因。其他危险因素有：接触石棉、铀、氡然而，吸烟具危险因素之首。,patients clinical risk factors,当前得出的初步结
33、论（certain tentative conclusionscan be drawn at the present）,1Approximately half of all smokers over 50 years of age have at least one lung nodule at the time of an initial screening examination. In addition, approximately 10% of screening subjects develop a new nodule during a 1-year period (36).） 2
34、. The probability that a given nodule is malignant increases according to its size (4,5). Even in smokers, the percentage of all nodules smaller than 4mmthat will eventually turn into lethal cancers is very low (1%), whereas for those in the 8-mm range the percentage is approximately 10%20% (4,7,8,3
35、7). 3. Cigarette smokers are at greater risk for lethal cancers, and malignant nodules in smokers grow faster, on average, than do those in nonsmokers (19,25,26). Also, the cancer risk for smokers increases in proportion to the degree and duration of exposure to cigarette smoke (38).,1. 约一半50岁以上的吸烟者
36、在最初CT筛查检查时肺部至少发现一个肺结节。约10%的患者一年内又会发生新的结节。2 结节恶性的概率与其大小相关。即使是吸烟者所有结节最终变成致命癌症的机会也很低（1%），而对于8mm结节的患者，其概率约为1020%。3 吸烟是致命性肺癌的主要危险，吸烟者的恶性结节生长较之不吸烟者增快。吸烟的程度和时间长短与患肺癌的危险成比例。,MacMahon H, MB, BCh, BAO. Austin JH, MD Gamsu G, MD Guidelines for Management of Small PulmonaryNodulesDetected on CT Scans: A Stateme
37、nt from the Fleischner Society1Radiology 2005; 237:395400,4. Certain features of nodules correlate with likelihood of malignancy, cell type, and growth rate. For instance, small purely ground-glass opacity (nonsolid) nodules that have malignant histopathologic features tend to grow very slowly, with
38、 a mean volume doubling time on the order of 2 years (19). Solid cancers, on the other hand, tend to grow more rapidly, with a mean volume doubling time on the order of 6 months. The growth rate of partly solid nodules tends to fall between these extremes, and this particular morphologic pattern is
39、highly predictive of adenocarcinoma (3941).5. Increasing patient age generally correlates with increasing likelihood of malignancy. Lung cancer is uncommon in patients younger than 40 years and is rare in those younger than 35 years (42). At the other end of the age scale, although the likelihood of
40、 cancer increases, surgical intervention carries greater risks. Also, the likelihood of a small nodule evolving into a cancer that will cause premature death becomes a lesser concern as comorbidity increases in a person and predicted survival decreases with advancing years.,4 结节的一些特征与结节的性质、细胞类型和生长速度
41、相关。 譬如，即便是具有恶性特征的小的pGGN其生长也很缓慢，平均倍增时间约为2年。而实性结节生长较快，平均倍增时间6个月。部分GGN作为一种特殊的形态类型是肺腺癌的一个标志，生长速度介于两者之间。5 随年龄增加结节的恶性可能性增加。40岁以下肺癌少见，35岁以下罕见。年龄大者，虽然肺癌可能性增加，但外科治疗的风险亦增加。随着年龄增加，患者并发症增加以及预计生存率降低，会减少对小结节发展为将导致患者过早死亡的肺癌的关注。,MacMahon H, MB, BCh, BAO. Austin JH, MD Gamsu G, MD Guidelines for Management of Small
42、PulmonaryNodulesDetected on CT Scans: A Statement from the Fleischner Society1Radiology 2005; 237:395400,管理策略：Management approach,Henschke et al (5) described earlier, the authors found no cancers in patients in whom the largest noncalcified nodule was less than 5 mm in diameter on the initial scan
43、(zero of 378 patients). Thus there was no advantage in performing short-interval follow- up for nodules smaller than 5 mm in their study, even in high-risk patients.we recommend altering the existing recommendations, which indicate that every indeterminate nodule, regardless of size and morphology,
44、should be subjected to a minimum of four or fivefollow-up CT examinations before being designated benign and the patient being reassured,Henschke等人较早认为：在最初扫描时，最大非钙化肺结节直径5mm的患者，肺癌的比率为0（0/378）。因此，对5mm的肺结节患者，即便具有高危因素，短期内随访亦不能获益。因此，我们推荐修订现存的指南推荐意见，即对每一个不确定的肺结节，不论其大小和形态如何，均应在确定其性质之前接受最少45次的CT随访扫面。,现存指南：-
45、Ost D, Fein AM, Feinsilver SH. The solitary pulmonary nodule. N Engl J Med 2003; 348:25352542. Tan BB, Flaherty KR, Kazerooni EA, Iannettoni MD; American College of Chest Physicians. The solitary pulmonary nodule. Chest 2003;123(suppl 1):89S96S.,一如前述，约10%的50岁以上的随访患者在一年的时间内会产生一个新结节。假设人口统计学特征类似，则在当前指南
46、所推荐的2年最低随访期内，在最初CT检测到的肺结节患者中，约有20%至少会产生一个新的结节。这将会又开始另外一轮的CT随访研究，在这新的一轮CT随访扫描过程期间势必又产生相同比例的新的结节。因此，严格的按照现有的ACCP的肺结节管理指南操作将会导致多轮2年以上的随访研究，使较大比例的患者接受胸部CT检查。,As summarized above, In addition, approximately 10% of screening subjects develop a new nodule over a 1-year period, Assuming similar demographics
47、, approximately 20% of patients who have a nodule detected on CT scans can be expected to have at least one new nodule detected during the currently recommended 2-year minimum follow-up period, which will in turn mandate another series of follow-up CT studies with similar opportunities for new nodul
48、es to be detected during the additional follow-up period. Therefore, strict application of the existing recommendations would result in multiple follow- up studies over 2 or more years for a large proportion of all patients who undergo thoracic CT.,MacMahon H, MB, BCh, BAO. Austin JH, MD Gamsu G, MD
49、 Guidelines for Management of Small Pulmonary NodulesDetected on CT Scans: A Statement from the Fleischner Society1Radiology 2005; 237:395400,对于大于8 mm的结节，可考虑给予增强CT扫描、PET-CT、经皮肺活检和胸腔镜活检等进一步检查由于进一步检查方法很大程度上取决于操作者的技能、可用的设备，并且这些方法常常对于亚厘米级的结节不适用，故而本指南对此不作详细推荐。,In the case of nodules larger than 8mm, addi
50、tional options such as contrast materialenhanced CT, positron emission tomography (PET), percutaneous needle biopsy, and thoracoscopic resection can be considered (4346). Because these approaches depend greatly on available expertise and equipment and have limited applicability to nodules in the subcentimeter range, we have chosen not to offer detailed recommendations in this regard,
