今日の臨床サポート

転移性肺腫瘍

著者: 礒部 威 島根大学医学部内科学講座呼吸器・臨床腫瘍学

監修: 高橋和久 順天堂大学大学院

著者校正/監修レビュー済:2022/09/28
患者向け説明資料

概要・推奨   

  1. 癌の診断、治療は急速に進歩し、分子標的治療薬や免疫チェックポイント阻害薬の開発、承認が行われている。転移性肺腫瘍についても、的確な診断と適正な治療が求められる。
  1. 転移性肺癌を疑う場合胸部X線写真を、まず最初に行うよう勧められる。しかし、検出率は不十分であるためCT等の評価の追加も検討する(推奨度1)
  1. 胸部CTは、転移性肺癌検出を目的として、あるいは胸部X線写真で異常がある場合に行うよう勧められる(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
礒部 威 : 講演料(アストラゼネカ,ベーリンガーインゲルハイム)[2022年]
監修:高橋和久 : 講演料(アストラゼネカ(株),MSD(株)),研究費・助成金など(小野薬品工業(株),中外製薬(株),ブリストル・マイヤーズスクイブ(株)),奨学(奨励)寄付など(杏林製薬(株),サノフィ(株),大鵬薬品工業(株),中外製薬(株),帝人ファーマ(株),日本イーライリリー(株),日本ベーリンガーインゲルハイム(株))[2022年]

改訂のポイント:
  1. 各種検査、腫瘍マーカーについて追記を行った
  1. 転移性の可能性がある場合の免疫染色について追記を行った

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 肺は、他臓器に原発した腫瘍が転移する頻度が高い。
  1. 原発腫瘍としては、絨毛癌、骨肉腫、精巣腫瘍、悪性黒色腫、腎臓癌が高率であるが、消化器癌、乳癌、胃癌、頭頚部癌でも一定の頻度で肺転移を認める。また、肺に原発した癌が肺内に転移する頻度も高い。
  1. 転移の様式は、①血行性転移、②リンパ行性転移、③経気道性(経気管支性)転移、④臓側胸膜を経由する転移――に大別される。
  1. 血行性転移:頭頚部や腹部の癌では、肺動脈経由の転移が一般的な経路である。
  1. リンパ行性転移:肺門部や縦隔リンパ節に転移を認める。癌性リンパ管症は、肺門部リンパ管が閉塞状態となってリンパ流が逆流し、気管支周囲ないしは胸膜下のリンパ管を逆行して生ずる。
  1. 経気道性(経気管支性)転移は浸潤性粘液腺癌で認められることが多い。
  1. 特殊な転移形式として気管支壁転移(endobronchial metastasis)と呼ばれるものがあり、血痰や気道閉塞を生じるため気道インターベンションを必要とすることが多い。
  1. 臓側胸膜を経由する転移では胸腔を介して播種性に転移し、胸水が貯留し癌性胸膜炎を生じることが多い。
問診・診察のポイント  
  1. 肺に単発または多発する結節性陰影を認めた場合は、患者もしくは家族に悪性疾患の詳細な罹患歴を確認する。

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文献 

L G Quekel, A G Kessels, R Goei, J M van Engelshoven
Miss rate of lung cancer on the chest radiograph in clinical practice.
Chest. 1999 Mar;115(3):720-4.
Abstract/Text STUDY OBJECTIVES: To investigate the miss rate of non-small cell lung cancer (NSCLC) on the chest radiograph. In addition, the characteristics, the delay in diagnosis, and the change in prognosis of the missed lesions were studied.
DESIGN: A retrospective study on patients with histopathologically proven NSCLC during the years 1992 through 1995 in a large community hospital.
SETTING: Department of Radiology, Atrium Medical Center, Heerlen, the Netherlands.
PATIENTS: During the study period, 495 patients presented with NSCLC. Of these patients, the complete set of chest radiographs was available for analysis in 396; there were 300 men and 96 women, with a mean age of 68 years.
MAIN OUTCOME MEASURES: The main outcome measures included the miss rate of NSCLC presenting as nodular lesions. Location, diameter, superposing structures, and delay of missed and detected lesions and the change of prognosis as a consequence of the delay in diagnosis were other measures.
RESULTS: In 49 (19%) of 259 patients with NSCLC presenting as a nodular lesion on the chest radiographs, the lesions were missed. The miss rate was not dependent on location. Superposing structures were more often present in the group of missed lesions than in the group of detected lesions, respectively, 71% and 2%. The median diameter of the missed lesions was 16 mm and of the detected lesions it was 40 mm. The median delay of the missed lesions was 472 days and of the detected lesions it was 29 days. Twenty-two (45%) patients with missed lesions remained in stage T1, 6 (12%) remained in stage T2 and in 21 patients (43%), the tumor stage changed from stage T1 into T2.
CONCLUSION: The miss rate of 19% in our study is low compared with the rate in the literature but it has a definitive impact on prognosis.

PMID 10084482
Abstract/Text BACKGROUND: The incidence and mortality rates of lung cancer have been increasing in many countries. However, the true effectiveness of screening for lung cancer is still controversial. This study aimed to examine the growth pattern of lung cancer and to evaluate the efficacy of screening.
METHODS: The authors linked the records of annual radiologic screening to cancer registry data and conducted a retrospective follow-up study of radiographs in all patients with lung cancer arising in a population undergoing screening.
RESULTS: Among a total of 305,934 participants, screening detected 206 lung cancers, 103 of which were Stage I disease. Seventy-one of the 131 adenocarcinomas were Stage I, and 58% of them showed evidence of cancer for 2 years on a retrospective review of radiographs. Presentation as small faint lesions overlapping the normal chest structures delayed the early detection of adenocarcinoma. The overall sensitivity of screening was 70%, 52% for squamous cell carcinoma and 50% for small cell carcinoma. Rapidly growing Stage II-IV tumors without retrospective evidence of cancer on previous radiographs accounted for most of the cancers detected during the intervals between screening.
CONCLUSIONS: Both the low detectability of Stage I adenocarcinoma and the late recognition of rapidly growing small cell and squamous cell carcinomas reduced the effectiveness of screening. More effective imaging methods and an antismoking campaign are required to reduce lung cancer mortality.

PMID 8402447
Abstract/Text Eighteen radiologists failed to detect 27 potentially resectable bronchogenic carcinomas revealed retrospectively on serial chest radiographs. Most of the cancers were in an upper lobe (n = 22 [81%]), especially the right upper lobe (n = 15 [56%]). More of the cancers were in women (n = 18 [67%]) than in men (n = 9 [33%]). The mean diameter of the missed lesions was 1.6 cm +/- 0.8 (range, 0.6-3.4 cm). Only two lesions (7%) were well defined around their entire extent. A lateral radiograph (available for 23 patients) revealed the missed lesion better than the posteroanterior radiograph in four patients (17%). Six consultant radiologists, who were biased by knowledge that the cases were of missed bronchogenic carcinoma, were individually shown the radiographs in 22 of the cases. Each consultant missed a mean of 26% (5.8 +/- 1.7) of the lesions. At least one of the six consultants missed the lesion in 16 (73%) of the cases. The predominant characteristics of radiographically missed and potentially resectable bronchogenic carcinomas were difficulty in radiographic detection, female gender, and location in an upper lobe, especially on the right side.

PMID 1727272
S Sone, F Li, Z G Yang, S Takashima, Y Maruyama, M Hasegawa, J C Wang, S Kawakami, T Honda
Characteristics of small lung cancers invisible on conventional chest radiography and detected by population based screening using spiral CT.
Br J Radiol. 2000 Feb;73(866):137-45.
Abstract/Text Conventional chest radiography (CXR) is a poor diagnostic tool for detecting lung cancers at a surgically curable stage. To determine the visibility of peripheral small lung cancers on CXR, we retrospectively examined the usefulness of CXR using a consecutive series of 44 cases detected on CT screening and later confirmed by histopathology. All cases had been detected by low dose CT during a population based screening trial for lung cancer. The control group consisted of 48 chest radiographs of normal subjects. Tumour diameters ranged from 6 mm to 45 mm, with 95% (42/44) < or = 20 mm, and 5% (2/44) > 20 mm. CXR failed to detect 77% (34/44) of all cancers, including 79% (33/42) < or = 20 mm and 50% (1/2) > 20 mm. Of the 42 lung cancers < or = 20 mm, 74% (31/42) were located in the well penetrated lung zones and 71% (22/31) of these were missed on CXR. 26% (11/42) were concealed by hilar vessels, mediastinum, heart or diaphragm, and all (11/11) of these were missed on CXR. 93% (39/42) of the lung cancers < or = 20 mm were adenocarcinomas and 79% (31/39) of these were missed on CXR. 7% (3/42) were epidermoid carcinomas or small cell carcinomas and 66% (2/3) of these were missed on CXR. The overall accuracy of interpretation on CXR for lung cancers was 61%, sensitivity was 23% and specificity 96%. Although there was an association between presence of lung cancer and positive reading of CXR (chi 2 test of association, p < 0.05), the percentage of positive readings was only 23%. Thus, CXR was poor at visualizing CT detectable lung cancers of < or = 20 mm diameter, which are usually of very low density, and cannot be relied upon for detection of surgically curable small lung cancer.

PMID 10884725
Z G Yang, S Sone, F Li, S Takashima, Y Maruyama, T Honda, M Hasegawa
Visibility of small peripheral lung cancers on chest radiographs: influence of densitometric parameters, CT values and tumour type.
Br J Radiol. 2001 Jan;74(877):32-41.
Abstract/Text The purpose of this study was to determine the effects of tumour density and tumour type on the visibility of small peripheral lung cancers on chest radiographs. We retrospectively evaluated the visibility of 63 small (< or = 20 mm) peripheral lung cancers on chest radiographs. 48 (76%) were detected in our low dose CT screening for lung cancer and 15 (24%) in routine clinical examination. Analysis was based on tumour optical contrast, gradient at the tumour margin, CT values and tumour type. There were 31 (49%) visible cancers and 32 (51%) invisible cancers on chest radiographs. Visible tumours had an optical density of 0.1-0.3 OD and a gradient of 0.03-0.11 OD mm-1. The mean size of visible tumour (14.3 mm) was larger than that of invisible tumour (11.1 mm; p < 0.001). The mean CT value (-140 HU) of visible tumour was higher than that of invisible tumour (-490 HU; p < 0.001). The detection rates of adenocarcinomas with lepidic growth (0% for type A, 29% for type B and 68% for type C) were less than those with hilic growth (100% for types D-F). All squamous and small cell carcinomas with hilic growth were visible on chest radiographs, but the numbers of each were small. In summary, tumour type influenced the contrast, gradient, CT values and margin of the tumour. Small adenocarcinomas with a lepidic tumour growth were less well seen on chest radiographs compared with small lung cancers with hilic tumour growth.

PMID 11227774
L G Quekel, A G Kessels, R Goei, J M van Engelshoven
Detection of lung cancer on the chest radiograph: a study on observer performance.
Eur J Radiol. 2001 Aug;39(2):111-6.
Abstract/Text STUDY OBJECTIVES: to study the validity and observers consistency in the detection of lung cancer on the chest radiograph.
MATERIALS AND METHODS: the chest radiographs of 100 clinical cases were interpreted by 14 observers. The radiographs were obtained from 30 patients with initially missed but histopathologically proven non-small cell lung cancer (NSCLC), 35 patients with other cardiopulmonary diseases and 35 patients with no abnormalities. The observers consisted of ten experienced radiologists, two-experienced chest physicians and two residents in radiology. All observers were unaware of the study design. The validity and observer consistency was determined for each observer.
RESULTS: the mean sensitivity and specificity of the ten radiologists were 0.36 and 0.90. For the two chest physicians, the mean sensitivity and specificity were 0.29 and 0.96. For the two residents in radiology, mean sensitivity and specificity were 0.25 and 0.94. The mean interobserver kappa and mean intraobserver kappa for the radiologists were 0.38 and 0.54. For the two chest physicians, the mean interobserver kappa was 0.43, while the intraobserver kappa was 0.59. For the two residents in radiology, mean interobserver kappa was 0.35 and the intraobserver kappa was 0.42. There was no significant relation between the consistency parameters and validity parameters. The interobserver and intraobserver kappa values showed good correlation.
CONCLUSION: the validity of the chest radiograph and observers consistency in the detection of nodular lung cancer varies widely. The level of experience is likely to influence the diagnostic performance.

PMID 11522420
M Peuchot, H I Libshitz
Pulmonary metastatic disease: radiologic-surgical correlation.
Radiology. 1987 Sep;164(3):719-22. doi: 10.1148/radiology.164.3.3615867.
Abstract/Text Radiologic-surgical correlative studies were performed for new pulmonary parenchymal nodules in 100 lungs of 84 patients with previously treated extrathoracic malignancies. Ten patients with radiographically typical bronchogenic carcinomas were excluded from analysis. Of 237 nodules resected, 173 (73%) were identified with computed tomography (CT) and 64 (27%) were not. Two hundred seven (87%) were of metastatic origin, 21 (9%) were benign, and nine (4%) were bronchogenic carcinomas. Of those nodules seen with CT and not with radiography of the chest, 84% were of metastatic origin. Between patients with carcinoma and those with sarcoma or melanoma, there was little difference in the percentage of nodules found with CT. More resected nodules were metastases in the sarcoma-melanoma group (93%) than in the carcinoma group (77%). New bronchogenic carcinomas and benign lesions were more common in the carcinoma group. Chest radiography disclosed all nodules resected in 44% of cases, whereas CT disclosed 78%. Of 65 nodules detected as solitary nodules with chest radiography, only 35 (54%) proved to be truly solitary, whereas 35 of 44 (80%) detected with CT were truly solitary.

PMID 3615867
N Altorki, M Kent, M Pasmantier
Detection of early-stage lung cancer: computed tomographic scan or chest radiograph?
J Thorac Cardiovasc Surg. 2001 Jun;121(6):1053-7. doi: 10.1067/mtc.2001.112827.
Abstract/Text OBJECTIVE: Computed tomography has recently been proposed as a useful method for the early detection of lung cancer. In this study we compared the stage distribution of lung cancers detected by a computed tomographic scan with that of lung cancers detected by a routine chest x-ray film.
METHODS: Two groups of patients with biopsy-proven non-small cell lung cancer were reviewed. In the first group of 32 patients, the tumors were detected by a computed tomographic scan. In a second group (n = 101), the lung cancers were detected on routine chest x-ray films. Patients with pulmonary symptoms or a history of cancer were excluded.
RESULTS: There was no difference in age, sex, or cell-type distribution between the 2 groups. A significantly greater number of patients undergoing a computed tomographic scan had stage IA disease compared with those having an x-ray film. Of the 32 patients in the group having a scan, 10 had tumors 1 cm or less in size versus 6 of 101 in the group having a chest radiograph. Additionally, there was a significant reduction in advanced stage disease in the group having a scan.
CONCLUSIONS: In this retrospective study, a higher incidence of stage IA lung cancers and significantly fewer cases of more advanced disease were observed in patients screened with computed tomography than in those having a chest radiograph. These data suggest that computed tomographic screening may be of value in improving the survival of patients with non-small cell lung cancer.

PMID 11385370
S Diederich, M Semik, M G Lentschig, F Winter, H H Scheld, N Roos, G Bongartz
Helical CT of pulmonary nodules in patients with extrathoracic malignancy: CT-surgical correlation.
AJR Am J Roentgenol. 1999 Feb;172(2):353-60. doi: 10.2214/ajr.172.2.9930781.
Abstract/Text OBJECTIVE: Our aim was to assess the sensitivity of helical CT for revealing pulmonary nodules. Thoracotomy with palpation of the deflated lung, resection, and histologic examination of palpable nodules was used as the gold standard.
SUBJECTS AND METHODS: Thirteen patients underwent helical CT (slice thickness, 5 mm; reconstruction intervals, 3 mm and 5 mm; interpreted by two independent observers). Subsequently, patients underwent unilateral (n = 6) or bilateral (n = 7) surgical exploration, and CT-surgical correlation of 20 lungs was performed.
RESULTS: Ninety nodules were resected (61 were smaller than 6 mm; 13 were 6-10 mm; 11 were larger than 10 mm; in five nodules, the size was not recorded at surgery). Sixty-nine nodules were located in the pulmonary parenchyma and 21 in the visceral pleura. Of the 90 lesions, 43 (48%) were found on histology to represent metastases. For lesions detected by at least one observer, the sensitivity of helical CT was 69% for intrapulmonary nodules smaller than 6 mm, 95% for intrapulmonary nodules larger than or equal to 6 mm, and 100% for histologically proven intrapulmonary metastases larger than or equal to 6 mm. For lesions smaller than or equal to 10 mm, sensitivity was better using a reconstruction interval of 3 mm rather than of 5 mm.
CONCLUSION: In this study, the sensitivity of helical CT exceeded the sensitivity of conventional CT in previous reports. However, because of limitations in the detection of intrapulmonary nodules smaller than 6 mm and of pleural lesions, complete surgical exploration should remain the procedure of choice in patients undergoing pulmonary metastasectomy. Preoperative helical CT should be used to guide the surgeon to lesions that are difficult to palpate.

PMID 9930781
R Kakinuma, H Ohmatsu, M Kaneko, K Eguchi, T Naruke, K Nagai, Y Nishiwaki, A Suzuki, N Moriyama
Detection failures in spiral CT screening for lung cancer: analysis of CT findings.
Radiology. 1999 Jul;212(1):61-6.
Abstract/Text PURPOSE: To clarify the computed tomographic (CT) findings and the progression of minute lung cancers that were missed at initial spiral CT screening but were later detected.
MATERIALS AND METHODS: The findings from seven patients with lung cancer that was missed at the initial spiral CT screening were reviewed. Retrospective CT findings, time to detection, cell type, and pathologic stage were evaluated.
RESULTS: Minute lung cancers missed at early spiral CT included a nodule among the shadows of old tuberculosis (n = 2), a faint nodule with high attenuation in the center of the nodule (n = 1), an increase in attenuation just adjacent to an axial peripheral pulmonary vessel (n = 1) and adjacent to a craniocaudal peripheral pulmonary vessel (n = 1), and a minute faint nodule (n = 2). The time to detection ranged from 6 to 18 months. At pathologic examination, six cancers were stage I, and one was stage II.
CONCLUSION: Minute nodules of lung cancer that are near the threshold of detectability may be missed at spiral CT screening. It is important to examine noncalcified nodules with thin-section CT even when lesions from prior disease, such as those from old tuberculosis, exist and to evaluate the shadows of pulmonary vessels carefully. A follow-up examination is highly recommended.

PMID 10405721
J W Gurney
Missed lung cancer at CT: imaging findings in nine patients.
Radiology. 1996 Apr;199(1):117-22.
Abstract/Text PURPOSE: To assess the imaging findings and course of lung cancers missed on computed tomographic (CT) scans.
MATERIALS AND METHODS: A retrospective review of CT scans was performed on nine patients who underwent CT examination for various clinical indications and in whom a lung cancer had been missed. Subspecialty chest radiologists determined whether retrospectively identified lesions were missed due to observer error or technical failure.
RESULTS: Five missed tumors were peripheral and four were central in location. All peripheral tumors were less than 3 mm in diameter. The interval from initial examination to detection of peripheral tumors ranged from 8 to 95 months. This interval for central tumors was shorter (3-14 months). Estimated doubling times ranged from 24 to 285 days.
CONCLUSION: Small lung cancers that are near the threshold for detectability may be missed at CT. Such failure of detection is attributable primarily to the poor conspicuity of lesions. Retrospective identification at CT raises medicolegal issues.

PMID 8633132
C S White, B M Romney, A C Mason, J H Austin, B H Miller, Z Protopapas
Primary carcinoma of the lung overlooked at CT: analysis of findings in 14 patients.
Radiology. 1996 Apr;199(1):109-15.
Abstract/Text PURPOSE: To describe the appearances of overlooked lung cancer at computed tomographic (CT) examination and to analyze the reasons for failure to diagnose these lesions.
MATERIALS AND METHODS: Fourteen patients with 15 overlooked lung cancers were identified by radiologists at three institutions. Location, shape, and cell type of each cancer were reviewed, and other relevant findings of CT examinations were assessed.
RESULTS: The missed tumors manifested as endobronchial lesion (n = 10), solitary parenchymal nodule (n = 2), area of focal peripheral air-space disease (n = 2), or pleural-based thickening (n = 1). Eleven (73%) of the 15 lesions were located in a lower lobe. In six (43%) of 14 patients, major distracting findings were present elsewhere in the thorax.
CONCLUSION: Endobronchial location and lower lobe predominance were the most common characteristics of overlooked lung cancer at CT. The presence of unrelated major abnormalities at CT may also have contributed to failure to diagnose the tumor.

PMID 8633131
M Remy-Jardin, J Remy, F Giraud, C H Marquette
Pulmonary nodules: detection with thick-section spiral CT versus conventional CT.
Radiology. 1993 May;187(2):513-20.
Abstract/Text Spiral volumetric computed tomography (CT) with single breath-hold technique was compared with conventional sequential CT in 39 patients. The spiral CT protocol consisted of a 10 mm/sec table feed during a 24-second breath hold at 145 mA, with reconstruction of images at 10-mm intervals; one (n = 21) or two (n = 18) sequences were necessary to screen the complete lung. Conventional CT was performed with a 1-second scan time, 145 mA, and contiguous 10-mm-thick sections. In the 39 patients studied with each technique, no lung nodule was detected in three, two had a single nodule, and 29 had multiple nodules. Two patients with normal findings at chest radiography and three with a solitary pulmonary nodule at conventional CT had multiple nodules at spiral CT. Mean number of nodules per patient was significantly higher with spiral versus conventional CT (18 +/- 4.5 vs 12.6 +/- 3.2 [mean +/- standard error of the mean], P = .01) as were the number of nodules less than 5 mm in diameter per patient (12.7 +/- 3.7 vs 8.4 +/- 2.3, P < .05) and 5-10 mm in diameter (2.9 +/- 0.9 vs 2.4 +/- 0.8, P < .05). Respiratory motion artifacts were never observed with spiral CT although they were present on four conventional CT scans.

PMID 8475300
B MacDougall, B Weinerman
The value of sputum cytology.
J Gen Intern Med. 1992 Jan-Feb;7(1):11-3.
Abstract/Text OBJECTIVE: To assess the value of cytologic examination of expectorated sputum in the diagnosis and management of patients with suspected lung cancer.
DESIGN: Retrospective chart review.
SETTING: Inpatient wards, tertiary care university hospital.
MEASUREMENTS AND MAIN RESULTS: The charts of 357 patients were reviewed. Two hundred eighty-eight of the 357 patients had had initial sputum cytologic examination prior to other diagnostic procedures, of which 41 (15%) had positive cytologic results. Thirty-six of the 41 were confirmed histologically or shown to have metastatic spread by noninvasive tests. Of the 222 patients with negative or unsatisfactory sputum tests, 97 went on to bronchoscopy and 35 had needle-aspiration biopsies. In the population of patients whose chest x-rays were highly suggestive of primary or metastatic lung cancer, the positive rate for cytologic examination was 38/94 (40%). There was no false-positive test in this study. Of the 50 patients with positive cytologic results, five (10%) had diseases that were of a different cell type; two of these five (40%) had diseases that involved small-cell cancer. There was an unsatisfactory delay in obtaining these samples for analysis.
CONCLUSIONS: Sputum cytology was found to be too insensitive and insufficiently accurate to be included in the routine workup of a patient suspected of having lung cancer. The results of the test did not influence further diagnostic procedures. This test should, therefore, be reserved for patients considered on initial assessment to be too sick for further investigations and treatment.

PMID 1548535
A Gledhill, C Bates, D Henderson, P DaCosta, G Thomas
Sputum cytology: a limited role.
J Clin Pathol. 1997 Jul;50(7):566-8.
Abstract/Text AIMS: To determine the cost and sensitivity of sputum cytology in routine use and to determine when sputum cytology is most appropriate.
METHODS: A retrospective study, based on all sputum cytology requests received in five histopathology/cytopathology laboratories in Yorkshire from 1 January to 31 December 1993. Cytology findings were correlated with histological diagnosis or clinical outcome, and related to the speciality of the referring clinician.
RESULTS: Laboratory practice and performance was similar in all five centres. The average laboratory cost of sputum cytology was 26.93. The mean absolute sensitivity was 36% and the specificity was 99.6%. The majority of specimens was submitted by general physicians or geriatricians. The largest proportion of positive specimens were submitted by chest physicians.
CONCLUSIONS: Often sputum cytology is used inappropriately as a screening investigation on, or soon after, admission. In addition, it is used inappropriately before bronchoscopy. Sputum cytology should be limited to individuals in whom a histological diagnosis is desired, but in whom bronchoscopy is inappropriate or unsuccessful.

PMID 9306936
A Sing, N Freudenberg, C Kortsik, H Wertzel, B Klosa, J Hasse
Comparison of the sensitivity of sputum and brush cytology in the diagnosis of lung carcinomas.
Acta Cytol. 1997 Mar-Apr;41(2):399-408.
Abstract/Text OBJECTIVE: To describe the role of sputum and brush cytology in the diagnosis of lung carcinoma and to elucidate the influence of tumor location, histologic tumor type and stage on the sensitivity of both methods.
STUDY DESIGN: Retrospective and performed on 415 lung cancer patients. Two hundred of them were investigated only by sputum collection, 119 only by brushing and 96 by both methods.
RESULTS: The overall sensitivity of the sputum technique was 0.403 and that of the brush method 0.500, while a combination of both showed a sensitivity of 0.640. The diagnostic yield depended on tumor location, histologic tumor type and stage. Sputum specimens were most valuable in the detection of early and peripheral carcinomas, whereas brushing was superior in finding more advanced and centrally located malignancies. Regarding tumor type, squamous cell carcinomas were diagnosed to the greatest extent by both methods.
CONCLUSION: A complementary role of both cytologic techniques can be postulated by our data as well as by a literature review.

PMID 9100773
J J Bechtel, T L Petty, G Saccomanno
Five year survival and later outcome of patients with X-ray occult lung cancer detected by sputum cytology.
Lung Cancer. 2000 Oct;30(1):1-7.
Abstract/Text BACKGROUND: A cohort of 51 consecutive patients with roentgenographically occult lung cancer, identified by sputum cytology and confirmed by bronchoscopy was reported previously.
METHODS: All patients have now been followed beyond 5 years and the causes of death ascertained.
RESULTS: The actual 5-year survival of 27 patients who were resected for cure was 74% including death for all causes. The 5-year survival of all patients who received either surgery or radiation in an attempt to cure was 54.3%. Twelve secondary cancers were found by sputum cytology; eight of these patients have died.
CONCLUSIONS: Sputum cytology can be useful in the identification of early stage lung cancer in patients at high-risk where the chances of cure are favorable.

PMID 11008005
J K Frost, W C Ball, M L Levin, M S Tockman, R R Baker, D Carter, J C Eggleston, Y S Erozan, P K Gupta, N F Khouri
Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study.
Am Rev Respir Dis. 1984 Oct;130(4):549-54.
Abstract/Text The Johns Hopkins Lung Project was designed to determine whether the addition of cytologic screening to the radiographic screening of high-risk volunteers could enhance the early detection of asymptomatic lung cancer and whether early therapeutic intervention in detected cases could significantly reduce the mortality from this disease. Male volunteers, 45 yr of age and older, who smoked at least 1 pack of cigarettes per day were recruited from the Baltimore metropolitan area. All of the 10,387 acceptable high-risk volunteers received annual chest radiographic screening. By random assignment, one half received cytologic examination of induced sputum in addition to the roentgenogram. This report describes the results of the initial screening. Compared with usual methods of clinical diagnosis, screening by both roentgenography and cytology identified a greater proportion of the lung cancer cases at an earlier stage. Screening by sputum cytology was found to improve the detection only of squamous cell carcinoma. In the dual-screen group, sputum cytology accounted for 28% of the detected cases, and resulted in 39% additional detection of lung cancer over that achieved by roentgenography. There was no corresponding decrease in prevalence. Lung cancers detected by cytology alone were found at very early stages. Although there has been an increase in average survival, much of this increase, if not all, may have resulted from lead-time and sampling bias.

PMID 6091505
M R Melamed, B J Flehinger, M B Zaman, R T Heelan, W A Perchick, N Martini
Screening for early lung cancer. Results of the Memorial Sloan-Kettering study in New York.
Chest. 1984 Jul;86(1):44-53.
Abstract/Text The Memorial Sloan-Kettering lung cancer screening program was begun in 1974 to evaluate sputum cytology as a supplement to the annual chest x-ray examination for early detection and diagnosis. The 10,040 adult, male cigarette smokers who enrolled were randomly assigned to receive annual chest x-ray examinations only or a dual screen with annual chest x-ray examination and four monthly sputum cytology evaluation. Over 40 percent of the 288 who developed lung cancer were diagnosed in stage I, and their survival was 76 percent at five years; overall survival was 35 percent. Nearly one third of the lung cancers detected on first examination on the dual screen, and 14 percent of those on subsequent examinations were found by cytologic examination. The same number of cancers developed in the x-ray screen only group, and were diagnosed at a later date. Despite the delay, survival and mortality were the same, suggesting that the squamous carcinomas detected by cytologic examination alone are very slow growing and tend to remain localized until detectable by x-ray examination.

PMID 6734291
V Paul Doria-Rose, Pamela M Marcus, Eva Szabo, Melvyn S Tockman, Myron R Melamed, Philip C Prorok
Randomized controlled trials of the efficacy of lung cancer screening by sputum cytology revisited: a combined mortality analysis from the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study.
Cancer. 2009 Nov 1;115(21):5007-17. doi: 10.1002/cncr.24545.
Abstract/Text BACKGROUND: : Two randomized controlled trials of lung cancer screening initiated in the 1970s, the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study, compared 1 arm that received annual chest X-ray and 4-monthly sputum cytology (dual-screen) to a second arm that received annual chest X-ray only. Previous publications from these trials reported similar lung cancer mortality between the 2 groups. However, these findings were based on incomplete follow-up, and each trial on its own was underpowered to detect a modest mortality benefit.
METHODS: : The authors estimated the efficacy of lung cancer screening with sputum cytology in an intention-to-screen analysis of lung cancer mortality, using combined data from these trials (n = 20,426).
RESULTS: : Over (1/2) of squamous cell lung cancers diagnosed in the dual-screen group were identified by cytology; these cancers tended to be more localized than squamous cancers diagnosed in the X-ray only arm. After 9 years of follow-up, lung cancer mortality was slightly lower in the dual-screen than in the X-ray only arm (rate ratio [RR], 0.88; 95% confidence interval [CI], 0.74-1.05). Reductions were seen for squamous cell cancer deaths (RR, 0.79; 95% CI, 0.54-1.14) and in the heaviest smokers (RR, 0.81; 95% CI, 0.67-1.00). There were also fewer deaths from large cell carcinoma in the dual-screen group, although the reason for this is unclear.
CONCLUSIONS: : These data are suggestive of a modest benefit of sputum cytology screening, although we cannot rule out chance as an explanation for these findings. Cancer 2009. (c) 2009 American Cancer Society.

PMID 19637354
Rebecca M Lindell, Thomas E Hartman, Stephen J Swensen, James R Jett, David E Midthun, Mark A Nathan, Val J Lowe
Lung cancer screening experience: a retrospective review of PET in 22 non-small cell lung carcinomas detected on screening chest CT in a high-risk population.
AJR Am J Roentgenol. 2005 Jul;185(1):126-31. doi: 10.2214/ajr.185.1.01850126.
Abstract/Text OBJECTIVE: The objective of our study was to retrospectively review the PET results of non-small cell lung carcinomas detected on screening chest CT in a high-risk population.
CONCLUSION: PET findings were negative in 32% of the cases of non-small cell carcinomas that were detected on screening CT in a high-risk patient population. These tumors were small, low-grade, or both. The most common histology was bronchioloalveolar cell carcinoma. The role of PET in evaluating screening-detected indeterminate nodules in a high-risk population may be more limited than in a general population.

PMID 15972412
Daniel L Fortes, Mark S Allen, Val J Lowe, Keh-Hsien Robert Shen, Dennis A Wigle, Stephen D Cassivi, Francis C Nichols, Claude Deschamps
The sensitivity of 18F-fluorodeoxyglucose positron emission tomography in the evaluation of metastatic pulmonary nodules.
Eur J Cardiothorac Surg. 2008 Dec;34(6):1223-7. doi: 10.1016/j.ejcts.2008.09.007. Epub 2008 Oct 9.
Abstract/Text OBJECTIVE: Pulmonary metastasectomy is beneficial in select patients. The sensitivity of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) for pulmonary metastasis is unknown. The aims of the study were to determine the accuracy of FDG-PET in detecting pulmonary metastasis and identify factors affecting sensitivity.
METHODS: All patients undergoing metastasectomy from September 2002 through December 2006 who had both chest computed tomography (CT) and FDG-PET scans or a fused CT/FDG-PET within 6 weeks prior to surgery were reviewed. Univariate and multivariate analysis were performed to determine predictors of positivity.
RESULTS: There were 83 patients (41 men, 42 women) who had 104 resections. Median age was 61 years (range, 32-87). In total 154 nodules were resected; 1 nodule in 47 patients and multiple in 36. Histopathology was adenocarcinoma in 94 nodules, sarcoma in 18, squamous cell carcinoma in 15, renal cell carcinoma in 7 and other in 20. At least one nodule was FDG-PET positive in 68 patients (81.9%). True positive FDG-PET was found in 104 nodules (67.5%) while 50 were false negative (32.5%). Multivariate analysis revealed tumor diameter and grade correlated with increased sensitivity of FDG-PET.
CONCLUSION: FDG-PET is positive in only 67.5% of metastatic pulmonary nodules. Nodule size and grade affect the sensitivity of FDG-PET for metastatic pulmonary nodules. FDG-PET is not a sensitive test in the evaluation of patients considered for pulmonary metastasectomy. Moreover, a negative FDG-PET should not be used to rule out metastatic disease.

PMID 18848459
Paul Cronin, Ben A Dwamena, Aine Marie Kelly, Steven J Bernstein, Ruth C Carlos
Solitary pulmonary nodules and masses: a meta-analysis of the diagnostic utility of alternative imaging tests.
Eur Radiol. 2008 Sep;18(9):1840-56. doi: 10.1007/s00330-008-0970-5. Epub 2008 Jul 8.
Abstract/Text The purpose was to assess the clinical utility of diagnostic tests for identifying malignancy within a solitary pulmonary nodule (SPN), and to create a nomogram or "look-up" table using clinical data and non-invasive radiology (positive) test results to estimate post-test probability of malignancy. Studies that examined computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT) for the evaluation of SPN. Two reviewers independently abstracted data and assessed study quality. Study-specific and overall positive likelihood ratios (LRs) for each diagnostic test confirming a diagnosis of malignancy and negative LR for each diagnostic test excluding a diagnosis of malignancy within an SPN were calculated. Forty-four of 242 articles were included. Positive LRs for diagnostic tests were: CT 3.91 (95% confidence interval 2.42, 5.40), MRI 4.57 (3.03, 6.1), PET 5.44 (3.56, 7.32) and SPECT 5.16 (4.03, 6.30). Negative LRs were: CT 0.10 (0.03, 0.16), MRI 0.08 (0.03, 0.12), PET 0.06 (0.02, 0.09) and SPECT 0.06 (0.04, 0.08). Differences in performance for all tests were negligible; therefore, the clinician may confidently use any of the four tests presented in further evaluating an SPN. Given the low cost and prevalence of the technology, SPECT appears to be the leading choice for additional testing in SPN evaluation.

PMID 18607593
Paul Cronin, Ben A Dwamena, Aine Marie Kelly, Ruth C Carlos
Solitary pulmonary nodules: meta-analytic comparison of cross-sectional imaging modalities for diagnosis of malignancy.
Radiology. 2008 Mar;246(3):772-82. doi: 10.1148/radiol.2463062148. Epub 2008 Jan 30.
Abstract/Text PURPOSE: To perform a meta-analysis to estimate the diagnostic accuracy of dynamic contrast material-enhanced computed tomography (CT) and magnetic resonance (MR) imaging, fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and technetium 99m ((99m)Tc) depreotide single photon emission computed tomography (SPECT) for evaluation of solitary pulmonary nodules (SPNs).
MATERIALS AND METHODS: Data sources were studies published in PubMed between January 1990 and December 2005. The selected investigations were comparative and noncomparative diagnostic cohort studies to examine the operating characteristics of the four imaging modalities for evaluation of SPNs, involving at least 10 enrolled participants with histologic confirmation and having sufficient data to calculate contingency tables. A random coefficient binary regression model with disease probability conditioned on test results was used to summarize test performance and construct summary receiver operating characteristic (ROC) curves. Sensitivities, specificities, predictive values, diagnostic odds ratios, and areas under the ROC curve were calculated.
RESULTS: Forty-four studies--10 dynamic CT, six dynamic MR, 22 FDG PET, and seven (99m)Tc-depreotide SPECT--met the inclusion criteria. (One study was included in both the FDG PET and SPECT groups.) Sensitivities, specificities, positive predictive values, negative predictive values, diagnostic odds ratios, and areas under the ROC curve were, respectively, 0.93 (95% confidence interval [CI]: 0.88, 0.97), 0.76 (95% CI: 0.68, 0.97), 0.80 (95% CI: 0.74, 0.86), 0.95 (95% CI: 0.93, 0.98), 39.91 (95% CI: 1.21, 81.04), and 0.93 (95% CI: 0.81, 0.97) for dynamic CT; 0.94 (95% CI: 0.91, 0.97), 0.79 (95% CI: 0.73, 0.86), 0.86 (95% CI: 0.83, 0.89), 0.93 (95% CI: 0.90, 0.96), 60.59 (95% CI: 5.56, 115.62), and 0.94 (95% CI: 0.83, 0.98) for dynamic MR; 0.95 (95% CI: 0.93, 0.98), 0.82 (95% CI: 0.77, 0.88), 0.91 (95% CI: 0.88, 0.93), 0.90 (95% CI: 0.85, 0.94), 97.31 (95% CI: 6.26, 188.37), and 0.94 (95% CI: 0.83, 0.98) for FDG PET; and 0.95 (95% CI: 0.93, 0.97), 0.82 (95% CI: 0.78, 0.85), 0.90 (95% CI: 0.83, 0.97), 0.91 (95% CI: 0.84, 0.98), 84.50 (95% CI: 34.28, 134.73), and 0.94 (95% CI: 0.83, 0.98) for (99m)Tc-depreotide SPECT.
CONCLUSION: Dynamic CT and MR, FDG PET, and (99m)Tc-depreotide SPECT are noninvasive and accurate in distinguishing malignant from benign SPNs; differences among these tests are nonsignificant.

(c) RSNA, 2008.
PMID 18235105
Frank C Detterbeck, Andrew G Nicholson, Wilbur A Franklin, Edith M Marom, William D Travis, Nicolas Girard, Douglas A Arenberg, Vanessa Bolejack, Jessica S Donington, Peter J Mazzone, Lynn T Tanoue, Valerie W Rusch, John Crowley, Hisao Asamura, Ramón Rami-Porta, IASLC Staging and Prognostic Factors Committee, Advisory Boards, Multiple Pulmonary Sites Workgroup, Participating Institutions
The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification.
J Thorac Oncol. 2016 May;11(5):639-650. doi: 10.1016/j.jtho.2016.01.024. Epub 2016 Mar 3.
Abstract/Text INTRODUCTION: Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify; a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue.
METHODS: A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review.
RESULTS: Details of the evidence base are summarized in other articles. Four patterns of disease are recognized; the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor-T3 for a same-lobe, T4 for a same-side (different lobe), and M1a for an other-side location-with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic-type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same-side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement.
CONCLUSION: We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
PMID 26940528
Kenichi Suda, Isao Murakami, Kazuko Sakai, Hiroshi Mizuuchi, Shigeki Shimizu, Katsuaki Sato, Kenji Tomizawa, Shuta Tomida, Yasushi Yatabe, Kazuto Nishio, Tetsuya Mitsudomi
Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer.
Sci Rep. 2015 Sep 24;5:14447. doi: 10.1038/srep14447. Epub 2015 Sep 24.
Abstract/Text Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.

PMID 26400668

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