Lung Cancers Manifesting as Part-Solid Nodules in the National Lung Screening Trial

Cardiopulmonary Imaging Original Research Yip et al. Lung Cancers Manifesting as Part-Solid Nodules Cardiopulmonary Imaging Original Research Rowena Yip 1 Claudia I. Henschke 1 Dong Ming Xu 1 Kunwei Li 1,2 Artit Jirapatnakul 1 David F. Yankelevitz 1 Yip R, Henschke CI, Xu DM, Li K, Jirapatnakul A, Yankelevitz DF Keywords: CT screening, growth rates, subsolid nodules, survival, volume doubling times DOI:10.2214/AJR.16.16930 Received June 27, 2016; accepted after revision October 25, 2016. The statements contained herein are solely those of the authors and do not represent or imply concurrence of or endorsement by National Cancer Institute or National Institutes of Health. This study was supported in part by the Flight Attendants Medical Research Institute. C. I. Henschke is a named inventor on patents and patent applications relating to the evaluation of pulmonary nodules on CT scans of the chest that are owned by Cornell Research Foundation (CRF). As of April 2009, she has divested herself of all royalties and other interests arising from these. D. F. Yankelevitz is a named inventor on a number of patents and patent applications relating to the evaluation of diseases of the chest including the measurement of nodules. Some of these, which are owned by CRF, are nonexclusively licensed to GE Healthcare. As an inventor of these patents, D. F. Yankelevitz is entitled to a share of any compensation that CRF may receive from its commercialization of these patents. He is also an equity owner in Accumetra and serves on the advisory board of GRAIL. 1 Department of Radiology, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Pl, New York, NY 10029. Address correspondence to R. Yip (rowena.yip@ mountsinai.org). 2 Department of Radiology, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. AJR 2017; 208:1011 1021 0361 803X/17/2085 1011 American Roentgen Ray Society Lung Cancers Manifesting as Part-Solid Nodules in the National Lung Screening Trial OBJECTIVE. The objective of our study was to determine how often death occurred from lung cancers that manifested as part-solid nodules in the National Lung Screening Trial (NLST). MATERIALS AND METHODS. NLST radiologists classified nodules as solid, groundglass, or mixed. All lung cancers classified as mixed nodules by NLST radiologists were reviewed by four experienced radiologists and reclassified as solid, nonsolid, or part-solid nodules. When possible, volume doubling times (VDTs) were calculated separately for the entire nodule and for the solid component of the nodule. RESULTS. Of 88 screening-diagnosed lung cancer cases identified by the NLST radiologists as mixed nodules, study radiologists confirmed that 19 were part-solid nodules. All the part-solid nodules were present at baseline (time 0), and none of the patients with a part-solid nodule had lymph node enlargement at CT before diagnosis or metastases at resection. Multilobar stage IV (T4N0M1) bronchioloalveolar carcinoma was diagnosed in one patient 25.0 months after study randomization, and the patient died 67.9 months after randomization. All 18 patients with a solitary or dominant part-solid nodule underwent surgery, and none died of lung cancer. From randomization, the average time to diagnosis was 18.6 months and the average time of follow-up was 79.2 months. On the last CT examination performed before diagnosis, the average size of the solid component of the part-solid nodules was 9.2 mm (SD, 4.9); the solid component was larger than 10 mm in five patients. The median VDT based on the entire nodule was 476 days, and the median VDT based on the solid component alone was 240 days. CONCLUSION. None of the patients with lung cancer manifesting as a solitary or dominant part-solid nodule had lymph node enlargement or metastases at pathology, and none died of lung cancer within the follow-up time of the NLST. C T screening for lung cancer has increased awareness about the different types of nodules identified on CT scans. In 2002, the Early Lung Cancer Action Project (ELCAP) investigators introduced the term subsolid nodules and identified two distinct subtypes: nonsolid nodules and part-solid nodules [1]. Sone et al. [2] subsequently used these terms to describe the results of a lung mass screening program in Nagano, Japan [2]. By that time, it was recognized that lung cancers manifesting as subsolid nodules on thin-section CT scans were typically Noguchi types A C adenocarcinomas [1 5]. Since then, considerable evidence, which is summarized by Yip et al. [6], has accumulated about the indolent course of lung cancers manifesting as nonsolid nodules, including their slow growth rates and virtually 100% cure rates when re- sected early. Consensus, however, about the behavior of part-solid nodules has not been reached perhaps in part because of the need for a consistent definition to differentiate partsolid nodules from solid nodules [7]. The outcomes of patients with nonsolid nodules have been summarized by use of the International Early Lung Cancer Action Program (I-ELCAP) [8] and the National Lung Screening Trial (NLST) databases [9]. The outcomes of patients presenting with partsolid nodules have been summarized by use of the I-ELCAP database [7]. The comprehensive multidisciplinary analyses by Travis et al. [10] led to a revised pathology classification [11] and recommendations that CT images be reviewed when making the pathologic diagnosis. It was also realized that the focus of analysis both radiologically and pathologically should be on the solid component AJR:208, May 2017 1011

Yip et al. within the part-solid nodule instead of on the overall size of the entire nodule [10 12]. To further understand CT findings and outcomes of lung cancers manifesting as part-solid nodules, we again turned to the NLST because this prospectively collected CT screening database followed all enrolled participants to the close of the trial regardless of diagnostic workup and treatment [13, 14]. Our goal was to ascertain whether patients with lung cancer manifesting as partsolid nodules died and, if so, whether the cause of death (COD) was lung cancer. Materials and Methods The NLST enrollment started in 2002 and ended in 2004 [13, 14]. At enrollment, participants were randomly assigned to either CT screening or chest radiographic screening. If assigned to CT screening, the trial provided three rounds of screening: a baseline CT examination (time 0), which is referred to as the T0 examination; a 1-year follow-up CT examination, which is referred to as the T1 examination; and a 2-year follow-up CT examination, which is referred to as the T2 examination. CT screening ended in 2006, and all participants were followed to the end of the study in December 2008. The NLST thus provided up to 4 years of followup after the last CT screening examination (i.e., T2 examination). All cases of lung cancer were classified in the NLST database as being diagnosed after positive findings at screening, negative findings at screening, or a missed screening examination or in the period of follow-up after CT screening. In the NLST, lung cancer stage at the time of diagnosis was assigned according to the 6th edition of the AJCC Cancer Staging Manual of the American Joint Committee on Cancer (AJCC) [15]. COD due to lung cancer, the primary endpoint of the study, was determined by the Endpoint Verification Team using the NLST endpoint verification process after the close of the study [16]. Our study focused on CT screen-detected cases of lung cancer because the CT scans of this group were available for review. The CT scans of patients with cancers not detected at CT screening were not available because the cancer that was ultimately diagnosed might not have been present on the last screening CT examination and CT scans obtained after the completion of the three rounds of screening were not provided as part of the NLST database. The timing of the rounds of screening CT examinations, diagnoses, and follow-ups are given relative to the time each participant was randomly assigned to undergo CT screening because this is how they were reported. The first baseline imaging examination at time 0 (T0) was typically performed shortly after randomization, and the two annual repeat CT screening examinations occurred at approximately 12-month intervals after T0 so that the T1 examination was approximately 365 days (12 months) after T0, and the T2 examination was approximately 730 days (24 months) after T0. Nodule Consistency The NLST radiologists described nodule consistency as ground-glass, mixed, or solid [13, 14]. Mixed nodules were defined as having both ground-glass and solid components. Because the lobe in which the lung cancer was diagnosed was documented in the NLST database by the particular cancerous nodule, we searched the NLST database to identify all participants assigned to CT screening whose condition was diagnosed as lung cancer and who had at least one mixed nodule identified in the same lobe where the cancer was located. All images of these patients with a mixed nodule were downloaded from the Cancer Imaging Archive using the NLST Query Tool [17]. All figures shown in this article are CT images of mixed nodules in the NLST database. Radiologist Review of Lung Cancers Manifesting as Mixed Nodules in the National Lung Screening Trial All CT images of screen-detected cases of lung cancer in patients with a mixed nodule in the same lobe as the one where cancer was diagnosed were reviewed independently by four experienced radiologists (13, 17, > 25, and > 25 years of experience) at Icahn School of Medicine at Mount Sinai. The radiologists assessed nodule location, consistency, and growth. Nodule consistency was determined by each radiologist using the following criteria [18]: A nodule was classified as a nonsolid nodule if the underlying parenchyma was visible except for branching blood vessels within the nodule. The term nonsolid is equivalent to pure ground-glass. If the nodule had nonsolid components and solid components within it that obscured the underlying lung parenchyma, it was classified Fig. 1 61-year-old woman (case 3 in Table 1) with diagnosis of adenocarcinoma, stage IIIB, manifesting as mixed nodule in left upper lobe (LUL) 137 days (4.6 months) after randomization. CT scan obtained at baseline (time 0 [T0] = 58 days after randomization) shows that LUL part-solid nodule (arrow) measures 18 12 mm and that solid component measures 8 6 mm. No follow-up CT images are available. Slice thickness was 2.5 mm. Fig. 2 62-year-old woman (case S13 in Table 3) with diagnosis of non small cell carcinoma, stage IIIB, manifesting as mixed nodule in left lower lobe (LLL) 15 days after randomization. CT scan obtained at baseline (time 0 [T0] = 0 days after randomization) shows LLL nodule (23 15 mm) (arrow); this nodule was reclassified as solid with nonsolid rim at follow-up CT (not shown) and is peripheral to another LLL solid nodule (9 8 mm), which is adjacent to cystic airspace. Enlarged mediastinal lymph nodes are identified. Slice thickness was 2.5 mm. 1012 AJR:208, May 2017

Lung Cancers Manifesting as Part-Solid Nodules Fig. 3 67-year-old woman (case S8 in Table 3) with diagnosis of squamous cell carcinoma, stage IIIA, manifesting as solid mass in right upper lobe (RUL) 37 days after randomization. CT scan obtained at baseline (time 0 [T0] = 13 days after randomization) shows mass (57 53 mm) (arrow) with central cavitation and nonsolid rim peripheral to mass. Enlarged mediastinal lymph nodes are identified. Slice thickness was 3.2 mm. as a part-solid nodule (Fig. 1). If the lung parenchyma within the entire nodule was obscured, it was classified as a solid nodule (Fig. 2). The solid nodule classification was retained even if there was a thin nonsolid rim surrounding the nodule because this nonsolid rim may be caused by partial volume averaging at the periphery of a nodule (especially with thicker CT sections) or by a minimal lepidic component or edema, which can occur in cell types of carcinoma other than adenocarcinoma (Fig. 3). If the solid component of a part-solid nodule was more than 80% of the entire nodule diameter, it was also classified as a solid nodule because this strategy maintains the spirit of the part-solid definition. Also, when a nodule showed internal necrosis or cavitation (Fig. 3), was adjacent to a cystic airspace (Fig. 4), or grew around a cystic airspace, it was classified as a solid nodule. After independent review by each radiologist, the cases were then reviewed jointly by all four radiologists. Because thick-section CT slices were acquired in the NLST, the differentiation of part-solid nodules from other nodule types was problematic in some cases (Fig. 5). When all four radiologists did not agree about the consistency of the nodule being reclassified as either solid or nonsolid instead of part-solid, the nodule continued to be classified as a part-solid nodule for the purposes of this study. All visualized mediastinal lymph nodes were measured. If the short axis of a lymph node was larger than 10 mm, it was classified as being enlarged. For comparison purposes, all cases with lung cancer as the COD that were classified as mixed according to the NLST radiologists, which were reclassified by the reviewing radiologists, are also summarized. Volume Doubling Times Volume doubling times (VDTs) were calculated manually on the basis of the change in the overall size of the nodule and were calculated separately for the change in the size of the solid component using CT scans from two examinations. The two CT examinations with the longest time interval between them (ideally CT scans obtained at T0 and T2, if available) were chosen for calculating VDTs because the accuracy of the VDT increases with Fig. 5 66-year-old man (case 4 in Table 1) with diagnosis of squamous cell carcinoma, stage IA, manifesting as a mixed nodule in left upper lobe (LUL) 70 days (2.3 months) after randomization. CT scan obtained at baseline (time 0 [T0] = 21 days after randomization) shows small 7 7 mm nodule (arrow). Because consensus among four reviewing radiologists about nodule consistency was not reached, it was classified as part-solid nodule. Slice thickness was 2 mm. Fig. 4 60-year-old woman (case S3 in Table 3) with diagnosis of non small cell carcinoma, stage IV, manifesting as solid mass in right upper lobe (RUL) 19 days after randomization. CT scan obtained at baseline (time 0 [T0] = 0 days after randomization) shows large solid mass (66 20 mm) (arrow) surrounds large cyst. Mass extends to right hilum on other images (not shown). Enlarged mediastinal lymph nodes are also present. Slice thickness was 2.5 mm. increasing time between the scans [19]. Measurements were made on the CT images obtained with the thinnest section available using standard lung window settings (width, 1500 HU; level, 650 HU). For each case, two radiologists measured the maximum length of the entire nodule (L e ), perpendicular width of the entire nodule (W e ), maximum length of the solid component of the nodule (L s ), and perpendicular width of the solid component (W s ) on the CT image containing the largest crosssectional area of the nodule. If there were multiple solid components, then the radiologists were directed to choose the largest one. Two radiologists performed the measurements on the CT scans for each AJR:208, May 2017 1013

Yip et al. of the available CT screening studies (T0, T1, and T2). The equation for calculating VDT is as follows: VDT (d) = [ ] number of days between ln 2 2 CT examinations (LW LWt 2 ) [ { (LW LWt 1 ) }] ln where L is the length, W is the maximum perpendicular width, and LW is the estimate of the height of the volume based on the geometric mean of the length and width [20]; t 2 is the time of the second CT examination, and t 1 is the time of the first CT examination. The VDT was calculated separately for the entire nodule and for the solid component alone. For purposes of determining the median VDT, cases with no change in the measurements were considered to have the maximum measured VDT among cases that had shown a change. All statistical analyses were performed using statistics software (SAS, version 9.4, SAS Institute). Frequencies and descriptive statistics of lung cancers manifesting as part-solid nodules such as the average diameter of the entire nodule, average diameter of the solid component, and time intervals between randomization and diagnosis were obtained. Average diameter is defined as the average of the nodule length and width. The Kruskal- Wallis test was used to compare differences between two or more groups of continuous variables. Results Of the 26,722 participants who were randomly assigned to the CT screening arm of the NLST, 985 (3.7%) were found to have at least one mixed nodule identified on a screening CT study. Of these 985 participants, 108 had at least one mixed nodule documented in the same lobe where lung cancer was ultimately diagnosed. Of these 108 participants, we focused on the 88 patients with screen-detected cases of cancer; the remaining 20 patients had cancer that was not detected at screening. After review of the CT images of the 88 patients by the four radiologists, 19 were found to have the lung cancer manifesting as a partsolid nodule. The remaining 69 patients had lung cancer manifesting as either a solid nodule (n = 67) or a nonsolid nodule (n = 2). The diagnosis, cell type, time from randomization to lung cancer diagnosis, and time from randomization to last follow-up or death for the 19 cases of lung cancer manifesting as a part-solid nodule are given in Tables 1 and 2. Table 1 shows the 18 patients with a solitary or dominant part-solid nodule who did not die of lung cancer, and Table 2 TABLE 1: Screen-Detected Cases of Lung Cancer Manifesting as a Part-Solid Nodule in Patients Who Did Not Die of Lung Cancer According to the National Lung Screening Trial (NLST) Endpoint Process [16] Case No. Lung Cancer Diagnosis Lobe Cell Type Stage No. of Days (mo) After Randomization Last Follow-Up CT Measurements a of Part-Solid Mass or Nodule in Cancerous Lobe (CT Measurements a of Solid Component of Nodule), mm Lung Cancer Diagnosis Last CT Scan (T1/T2) First CT Scan (T0) Part-Solid Nodule VDT (d) Solid Component of Part-Solid Nodule Treatment 1 LUL BAC IB 2489 (83.0) 1066 (35.5) T2, 45 35 (27 15) 36 33 (21 10) 1147 493 L, C 2 RUL AC IB 2455 (81.8) 765 (25.5) T2, 47 40 (27 14) 45 33 (13 12) 1411 376 L, C 3 LUL AC IA b 2258 (75.3) 137 (4.6) 18 12 (8 6) L 4 LUL SCC IA 2641 (88.0) 70 (2.3) 7 7 (4 4) L 5 RML AC IA 2252 (75.1) 505 (16.8) T1, 13 10 (8 6) 10 8 (5 4) 403 223 L 6 LUL AC IA 2268 (75.6) 446 (14.9) T1, 19 14 (9 8) 19 13 (9 8) No change No change L, C 7 RML Mixed BAC IA 2292 (76.4) 681 (22.7) 12 11 (6 6) L 8 RLL BAC IB 2732 (91.1) 509 (17.0) Resected; T1, 23 15 (11 8) 18 9 (8 5) 250 240 L 9 RUL Mucinous AC IA 2275 (75.8) 926 (30.9) T1, 20 14 (11 6) 11 10 (4 4) 166 109 W 10 RUL AC IA 2493 (83.1) 1176 (39.2) T2, 11 11 (4 3) 10 6 (3 2) 453 458 L 11 RLL AC IA 1282 (42.7) 578 (19.3) T1, 20 17 (8 7) 19 12 (5 4) 377 146 Multiple W, R 12 RLL Acinar AC IA 2716 (90.5) 805 (26.8) T2, 17 14 (12 10) 13 9 (5 4) 476 189 L 13 LUL AC IA 2660 (88.7) 452 (15.1) T1, 15 10 (7 6) 11 8 (5 5) 261 268 L 14 RUL BAC IA 2426 (80.9) 485 (16.2) T1, 19 13 (13 11) 15 12 (7 6) 532 137 L 15 LUL BAC IA 2256 (75.2) 791 (26.4) T1, 17 10 (16 8) 11 10 (5 3) 678 138 S 16 LUL BAC IA 2275 (75.8) 44 (1.5) 26 22 (5 5) L 17 RUL AC IA 2355 (78.5) 132 (4.4) 17 6 (13 3) L 18 LUL BAC IA 2627 (87.6) 484 (16.1) T1, No change 6 6 (4 4) No change No change L, C Note The data presented here are the findings noted by the four reviewing radiologists. They reviewed the cancerous lobe on the screening CT examinations and reviewed the medical records for the lung cancer diagnosis and timing of the diagnosis. None of these patients had mediastinal lymph node enlargement, which was defined as mediastinal lymph nodes greater than 10 mm in the short axis. T2 = second annual CT examination, T1 = first annual CT examination, T0 = baseline CT examination (typically occurred shortly after NLST randomization), VDT = volume doubling time, LUL = left upper lobe, BAC = bronchioloalveolar carcinoma, L = lobectomy, C = chemotherapy, RUL = right upper lobe, AC = adenocarcinoma, SCC = squamous cell carcinoma, RML = right middle lobe, RLL = right lower lobe, W = wedge resection, R = radiation, S = segmentectomy. a Length width. b Listed as stage IIIB in the NLST database. 1014 AJR:208, May 2017

Lung Cancers Manifesting as Part-Solid Nodules TABLE 2: Screen-Detected Case of Lung Cancer a Manifesting as a Part-Solid Nodule in a Patient With Lung Cancer as the Cause of Death According to the National Lung Screening Trial (NLST) Endpoint Process [16] Case No. Lung Cancer Diagnosis Lobe Cell Type Stage Death shows the single patient with multifocal lung cancer who died of lung cancer. Among the 67 patients with lung cancer manifesting as a solid nodule, 14 died of lung cancer, and these cases are summarized in Table 3. The two cases of lung cancer that were reclassified as manifesting as a nonsolid nodule have already been reported [9]. The average length and width of each nodule as measured by the radiologists, the presence of mediastinal lymph node enlargement, and VDT (when available) are also given in Tables 1 3. Screen-Detected Cases Manifesting as a Part-Solid Nodule The cancer was present on the CT images at T0 for all 19 patients with a part-solid nodule. Of these 19 patients, 18 had a solitary or dominant part-solid nodule. A single patient (Table 2 and Fig. 6) already had multilobar part-solid nodules and solid nodules at T0 but continued to undergo screening for the subsequent two annual rounds of screening (T1 and T2) before stage IV (T4N0M1) multilobar bronchioloalveolar carcinoma was diagnosed 25.0 months after randomization. This patient died 67.9 months after randomization. The 18 patients with a solitary or dominant part-solid nodule are listed in Table 1. All but one of these nodules were diagnosed as adenocarcinoma or bronchioloalveolar carcinoma. The single exception was case 4 (Fig. 5), which was diagnosed as squamous cell carcinoma. The reviewing radiologists could not reach a consensus about the consistency of this small 7 7 mm nodule (Fig. 5); therefore, case 4 was classified as a part-solid nodule, as discussed in the Materials and Methods section. The discrepancy in the classification of this nodule resulted from the use of No. of Days (mo) After Randomization CT Measurements b of Largest Part-Solid Nodule c (Solid Component of Largest Nodule), mm Lung Cancer Diagnosis Last CT Scan (T1/T2) First CT Scan (T0) thick-section CT images; three of the four reviewing radiologists thought that case 4 was a solid nodule with spiculations rather than a part-solid nodule, but thin-section CT images were not available to reach a consensus. Another case (case 3 in Table 1 [Fig. 1]) was classified as stage IIIB according to the NLST staging criteria. However, no enlarged lymph nodes were identified on the CT scans by either the NLST radiologist or the four reviewing radiologists and no lymph node metastases were found at surgery. The most likely explanation for the stage IIIB classification is that an additional adenocarcinoma not identified on the CT images was found in the resected specimen, which led to the T4N0M0 (stage IIIB) classification by the NLST staging criteria. Also pointing toward this possibility was that lobectomy was performed 4.6 months after randomization, no chemotherapy was given, and the person did not die of lung cancer during the long follow-up of 2258 days (75.3 months). Cases of multiple adenocarcinomas without mediastinal lymph node metastases would be classified as stage IA according to the I-ELCAP criteria [21, 22]. Because this classification has now gained widespread acceptance [23 25], this case was considered to be stage IA in our analysis. Considering all 18 cases with lung cancer manifesting as a solitary or dominant partsolid nodule, none had mediastinal lymph node enlargement on any of the CT scans before diagnosis. The average diameter of the entire part-solid nodule at T0 was 14.8 mm (SD, 9.0) and included two nodules (cases 1 and 2 [Fig. 7]) that were larger than 30 mm in diameter. The average diameter of the solid component of the 18 part-solid nodules at T0 was 6.3 mm (SD, 3.3). Largest Part-Solid Nodule VDT (d) Solid Component of Largest Part-Solid Nodule Treatment 19 All lobes BAC IV 2037 (67.9) 751 (25.0) T2, 35 26 (30 12) 22 17 (17 11) 382 519 Wedge biopsy Note The data presented here are the findings noted by the four reviewing radiologists. They reviewed the cancerous lobes on the screening CT examinations and reviewed the medical records for the lung cancer diagnosis and timing of the diagnosis. Lymph node enlargement, which was defined as mediastinal lymph nodes greater than 10 mm in the short axis, was absent. VDT = volume doubling time, T2 = second annual CT examination, T1 = first annual CT examination, T0 = baseline CT examination (typically occurred shortly after NLST randomization), BAC = bronchioloalveolar carcinoma. a This case was included in another study [9] because this patient also had nonsolid nodules. b Length width. c The measurements of the largest nodule are shown here. The largest nodule was in the left upper lobe. Diagnosis of lung cancer was made before the first annual screening (T1) in four patients (cases 3, 4, 16, 17), before the second annual screening (T2) in 10 (cases 5, 6, 7, 8, 9, 11, 13, 14, 15, 18), and after the T2 screening in four (cases 1, 2, 10, 12). Considering all 18 cases, the average time from randomization to diagnosis was 18.6 months, and the average time from randomization to the last follow-up time was 79.2 months. On the last CT examination before diagnosis, the average diameter of the entire part-solid nodule was 17.4 mm (SD, 9.7), and the average diameter of the solid component was 9.2 mm (SD, 4.9). The diameter of the solid component at the last CT examination was less than 6 mm in diameter for four patients (cases 4, 10, 16, 18), between 6 and 10 mm in diameter for nine (cases 3, 5, 6, 7, 8, 9, 11, 13, 17), and larger than 10 mm for five (cases 1, 2, 12, 14, 15). The VDT could be calculated for 13 of the 18 patients with at least two available CT examinations that were performed before diagnosis. Two cases showed no change in the diameter of the entire nodule or of its solid component. The median VDT was 476 days based on the entire nodule diameter and 240 days based on the solid component alone. Screen-Detected Cases Manifesting as a Solid Nodule With Lung Cancer as Cause of Death Of the 67 patients with cancers that were reclassified as a solid solitary or dominant nodule according to the four reviewing radiologists, 14 (21%) died of lung cancer; the CT findings of these 14 patients are detailed in Table 3. The diagnoses were squamous cell carcinoma in five cases (cases S1, S4, S5, S8, AJR:208, May 2017 1015

Yip et al. TABLE 3: Screen-Detected Cases of Lung Cancer Manifesting as a Solid Nodule in Patients Who Died of Lung Cancer Within 12 Months of the Last CT Screening Examination According to the National Lung Screening Trial (NLST) Endpoint Process [16] Death Due to Lung Cancer No. of Days (mo) After Randomization CT Measurements a of Solid Mass or Nodule in Cancerous Lobe (mm) Case No. Lobe Cell Type Stage Death Lung Cancer Diagnosis Last CT Scan (T1/T2) First CT Scan (T0) VDT (d) Lymph Node Enlargement b Treatment S1 RUL SCC IIB 950 (31.7) 613 (20.4) T1, 6 6 (Growing solid nodule) 5 4 251 W, C S2 RUL ASC IV 507 (16.9) 455 (15.2) T1, 23 21 (Solid nodule growing around preexisting cyst) 6 5 60 W S3 RUL NSCLC IV 404 (13.5) 19 (0.6) 66 20 (Solid mass adjacent to large bulla) Yes (around cystic airspace) S4 LUL SCC IIIB 394 (13.1) 280 (28.6) 13 7 (Solid nodule adjacent to pleura) C S5 RUL SCC IIIB 1224 (40.8) 858 (28.6) T2, 57 27 (Growing solid mass and new solid nodule) 17 13 163 Yes M, B S6 RML AC IV 563 (18.8) 4 (0.1) 24 18 (Solid nodule with cavitation; right effusion; probable metastases) S7 U Carcinoma IV 1354 (45.1) 511 (17.0) T1, 34 26 (Growing left hilar solid mass; no part-solid nodules) R, C Yes C 28 25 711 Yes C S8 RUL SCC IIIA 64 (2.1) 37 (1.2) 57 53 (Solid mass with cavitation and thin nonsolid rim around mass) S9 LLL AC IA 1551 (51.7) 757 (25.2) T2, 31 11 (Solid nodule growing around cystic airspace) Yes None 22 10 62 L S10 RLL BAC IA 508 (16.9) 26 (0.9) 19 15 (Solid nodule) L, C S11 RLL AC IA 491 (16.4) 286 (9.5) 14 13 (Solid nodule with spiculations; no other nodules) S12 RUL and RML SCC IV 289 (9.6) 208 (6.9) 32 22 (Solid hilar mass obstructing RUL bronchus; atelectasis in RUL) L Yes R, C S13 LLL NSCLC IIIB 477 (15.9) 15 (0.5) 23 15 and 9 8 (2 Solid nodules around cyst) Yes R, C 149 L S14 RLL BAC IB 2081 (69.4) 989 (33.0) Images not available; T1 54 18 (Growing complex cystic airspace mass on coronal CT) and 16 8 (solid nodule showed growth around cystic airspace) 47 10 and 9 6 (Solid nodule seen at superior aspect of cystic airspace) Note The data presented here are the findings noted by the four reviewing radiologists. They reviewed the cancerous lobe on the screening CT examinations and reviewed the medical records for the lung cancer diagnosis and timing of the diagnosis. No part-solid nodules were identified in the lobes where the cancers were diagnosed. T2 = second annual CT examination, T1 = first annual CT examination, T0 = baseline CT examination (typically occurred shortly after NLST randomization), VDT = volume doubling time, RUL = right upper lobe, SCC = squamous cell carcinoma, W = wedge resection, C = chemotherapy, ASC = adenosquamous carcinoma, NSCLC = non small cell lung carcinoma, R = radiation, LUL = left upper lobe, M = mediastinoscopy, B = bronchoscopy, RML = right middle lobe, U = unknown, AC = adenocarcinoma, LLL = left lower lobe, L = lobectomy, RLL = right lower lobe, BAC = bronchioloalveolar carcinoma a Length width. b Lymph node enlargement was defined as mediastinal lymph nodes greater than 10 mm in the short axis. 1016 AJR:208, May 2017

Lung Cancers Manifesting as Part-Solid Nodules S12), adenocarcinoma in five (cases S6, S9, S10, S11, S14), adenosquamous carcinoma in one (case S2), and non small cell carcinoma or unknown carcinoma in three (cases S3, S7, S13). Of these 14 patients, mediastinal lymph node enlargement was seen at CT before lung cancer diagnosis in seven patients. The average diameter of the cancer was 18.7 mm (SD, 14.4) when first seen and was 24.1 mm (SD, 13.8) on the last CT study before diagnosis. At T0, seven of the 14 patients (cases S3, S5, S6, S7, S8, S12, S13) already had lymphadenopathy that could be identified on the CT scans and other findings of advanced disease (e.g., large mass, pleural effusion). Of the 14 cases, eight were diagnosed before the first annual screening (T1), three before the second annual screening (T2), and three after the T2 screening. The average time from randomization to diagnosis was 361 days (12.0 months). The median VDT of the six patients who had at least two CT examinations was 180 days. The average time from randomization to death was 776 days (25.9 months). In comparison with patients with lung cancers manifesting as a solitary or dominant part-solid nodule, a higher proportion of patients with lung cancer manifesting as a solid nodule died (21% [14/67] vs 0% [0/18], respectively; p = 0.03). The average followup time from randomization to the date of death or last follow-up was significantly longer among the 18 lung cancer cases manifesting as a solitary or dominant part-solid nodule than the 14 cases manifesting as a solid nodule (2375.1 days [79.2 months] vs 775.5 days [25.9 months], p < 0.0001). A C Discussion Among the 985 participants with a mixed nodule according to the NLST database, lung cancer was diagnosed in 88 as a result of a positive screening test. On review of the baseline (T0) and two annual screening CT examinations (T1 and T2) by four experienced radiologists, only 19 patients were found to have lung cancer manifesting as part-solid nodules or masses, whereas 67 patients were found to have lung cancer manifesting as a solitary or dominant solid nodule or mass and two patients were found to have lung cancer manifesting as a nonsolid nodule. Of the 18 patients with lung cancer manifesting as a part-solid nodule, all cases were stage I because none of the patients had mediastinal lymph node enlargement or metastases at surgery, the VDTs showed slow growth both Fig. 6 63-year-old man (case 19 in Table 2) with diagnosis of multifocal stage IV bronchioloalveolar carcinoma 751 days (25.0 months) after randomization. Slice thickness was 2 mm. A, CT scan obtained at baseline (time 0 [T0] = 0 days after randomization) shows multiple nonsolid, part-solid, and solid nodules in all five lobes. Largest partsolid nodule, which is in left upper lobe (LUL), measures 22 17 mm and its solid component measures 17 11 mm. B and C, All nodules showed growth on follow-up CT scans obtained 343 (B) and 736 (C) days after randomization. At second annual follow-up (C), largest part-solid nodule in LUL measures 35 26 mm and its solid component measures 30 12 mm. Mediastinal lymph nodes are not enlarged. B AJR:208, May 2017 1017

Yip et al. A B Fig. 7 64-year-old man (case 2 in Table 1) with diagnosis of adenocarcinoma, stage IB, in right upper lobe (RUL) 765 days (25.5 months) after randomization. Slice thickness was 2.5 mm. A, On CT scan obtained at baseline (time 0 [T0] = 15 days after randomization), part-solid nodule measures 45 33 mm (solid component = 13 12 mm). B, CT scan obtained 336 days after randomization shows nodule. C, CT scan obtained 735 days after randomization shows nodule is 47 40 mm (solid component = 27 14 mm). of the entire nodule and of its solid component in all cases for which VDT could be calculated, and none of the patients died of lung cancer. The average diameter of the solid component of the 18 cases at T0 was 6.3 mm (SD, 3.3). The average follow-up time was 79.2 months (> 6 years), and the average VDT was 4276 days, indicating the indolent nature of these lesions with slow growth and without dissemination. These findings differ from those of the 67 patients with lung cancer manifesting as a solitary or dominant solid nodule. Of these 67 patients, 21% (14/67) died before the end of a significantly shorter follow-up time. Similar findings have been reported previously. In the I-ELCAP report on 2892 lung cancer cases with part-solid nodules detected on 57,496 baseline screening studies and new part-solid nodules identified on 541 of 64,677 (0.8%) annual repeat screenings, workup led to diagnosis of adenocarcinoma in 107 [7]. At resection, 106 were pathologic stage I adenocarcinoma, and one was a partsolid nodule with a 12-mm solid component that had a single N2 lymph node metastasis [7]. Lung cancer specific survival for these 107 cases was 100%; median follow-up from diagnosis was 89 months (interquartile range [IQR], 52 134 months). Sone et al. [2] also reported a low fatality rate among cancers manifesting as part-solid nodules. They reported that one of 19 patients (5%) with partsolid nodules died compared with five of 22 (23%) patients with solid nodules who died. Their results are similar to what we found in this study of the NLST cases. In addition, Hasegawa et al. [26] reported on the VDTs of the Sone et al. cases, which were similar to those reported here. In 2014, Kadota and colleagues [27] reported on 1038 surgically resected adenocarcinomas and found that cases diagnosed as adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic-predominant adenocarcinoma (i.e., > 50% lepidic component) had no recurrence after resection. As the lepidic component decreased in size, the rate of recurrence increased. In a study of long-term survival rates of patients with lepidic adenocarcinomas diagnosed at CT screening, it was shown that survival was 100% as long as the lepidic component was 90% or more but survival decreased as the percentage of the lepidic component decreased below 90% [22, 28, 29]. All these results are consistent with the original A B Fig. 8 70-year-old man (case S14 in Table 3) with diagnosis of bronchioloalveolar carcinoma, stage IB, in right lower lobe (RLL) 989 days (33.0 months) after randomization. A, CT scan obtained at baseline (time 0 [T0] = 11 days after randomization) shows small solid nodule in superior aspect of complex cystic mass that measures 9 6 mm. Slice thickness was 1.0 mm. B, CT scan obtained at first follow-up (367 days after randomization) shows that nodule has markedly increased in size to 16 8 mm. Slice thickness was 2.0 mm. Nodule presumably continued to grow, although images from second follow-up are not available. Lobectomy was performed 33.0 months after randomization. C 1018 AJR:208, May 2017

Lung Cancers Manifesting as Part-Solid Nodules results of Noguchi et al. [5], which showed a decrease in survival with progressive tumor invasion as reflected by the increase in the solid component of the adenocarcinoma. It is important to identify the nodule consistency because the management and subsequent treatment of patients diagnosed with lung cancer should be tailored to reflect the biologic behavior of the nodules [30, 31]. The VDTs of the entire nodule and its solid component of the lung cancer cases manifesting as a solitary or dominant part-solid nodule are helpful because they illustrate the slow growth of these lesions. Further evidence of slow growth was that all the lung cancers manifesting as a part-solid nodule were identified on the initial baseline CT study at T0; however, diagnosis was not pursued for some time later because the average time to diagnosis was 18.6 months, all cases were still in stage I, and none of the patients died of lung cancer according to the NLST endpoint verification process. The results of this study and others suggest that part-solid nodules with solid components of less than 8 10 mm can be safely followed to assess for growth before invasive diagnostic workup as suggested by the I-ELCAP [18] and Lung Reporting and Data System (Lung-RADS) [32] protocols. Furthermore, management of part-solid nodules should focus on the size of the solid component because this focus allows more conservative management of part-solid nodules. The disagreement between the NLST radiologists and the four reviewing radiologists in terms of classifying consistency of nodules is striking. The discrepancies may be in part attributable to the scanning parameters used in NLST. It is now well accepted that to confidently characterize nodules as being either a nonsolid nodule or a part-solid nodule, it is best to acquire the CT images using thin slices of 1.25 mm or less to minimize the partial volume effect that can cause solid nodules to have a subsolid appearance, especially small ones. The importance of thin sections for classification has also been recognized by the Fleischner Society [33]. The partial volume effect occurs because the attenuations (in Hounsfield units) of each voxel reflect the average CT attenuation of the various parenchymal components included within the voxel. At the surface of the nodule, both soft tissue and air are included; when thicker CT slices are used, there is more lung parenchyma, which makes some voxels appear to have lower attenuation values. Thus, solid nodules may appear to be nonsolid or part-solid when they are not, particularly when the nodule is small (Fig. 5). Most of the disagreements, however, we think are because the NLST definition of mixed nodule also included masses that were considerably larger than 30 mm. In some of the cases, the cancer was called part-solid because the solid nodule or mass A B Fig. 9 69-year-old man (case S2 in Table 3) with diagnosis of adenosquamous carcinoma, stage IV, in right upper lobe 455 days after randomization. Slice thickness was 3.2 mm. A, CT scan obtained at baseline (time 0 [T0] = 5 days after randomization) shows small solid nodule adjacent to multiple cystic airspaces. B, CT scan obtained at first follow-up (364 days after randomization) shows solid nodule has increased in size to 23 21 mm. was adjacent to one or more cystic airspaces (Figs. 4, 8, and 9). In other cases, there was a thin nonsolid rim at the periphery of a large solid mass (Figs. 2 and 3) or cavitation within the solid mass (Fig. 3). Figures 4, 8, and 9 illustrate that, in the context of screening, cystic airspaces with walls that increase in thickness with adjacent small nodules should receive additional attention because these nodules are likely to be lung cancer. These cases have been previously reported in the context of screening [34]. A clear definition of part-solid nodules is important for management purposes, particularly when prior thin-section CT images documenting the progression from a nonsolid nodule to a part-solid nodule are not available. We [7, 18] and others [35, 36] have recommended that an upper limit be used in the definition. We suggest that an upper limit for the ratio of the diameters of the solid component of a part-solid nodule to the entire part-solid nodule should be less than 80% [7, 18]. If the diameter of the solid component is 80% or more, then the nodule should be classified as solid and managed accordingly. If we consider that there is at least some degree of partial volume effect around the surface of the nodule affecting at least the outer voxel, then this definition allows small nodules to be designated as solid. Also, when a nodule shows internal necrosis or cavitation (Fig. 3), is adjacent to a cystic airspace (Fig. 4), or grows around a cystic airspace, it should be classified as a solid nodule [18, 34]. The availability of large lung cancer screening databases allows review of the accumulated empirical evidence rather than basing management protocols on expert opinion or isolated cases. These retrospective reviews are now driving current management protocols as exemplified by the shift of the size threshold for a positive result for solid nodules on baseline screening from 5 mm [37] to 6 mm [38, 39] in I-ELCAP [7, 8], National Comprehensive Cancer Network [40], and Lung-RADS [41, 42] recommendations. The NLST data are particularly useful because all cases, regardless of whether diagnosis was pursued, were followed to the close of the study 4 6 years after being randomly assigned to CT screening in the trial and because the endpoint verification process determined whether the participant had died and, if so, the COD. Although we cannot know with certainty how many of the part-solid nodules identified in the NLST were ultimate- AJR:208, May 2017 1019

Yip et al. ly diagnosed with lung cancer as pathologic diagnosis during the NLST, we nevertheless were able to determine whether lung cancer death could be attributed to a cancer in a part-solid nodule. The main limitation in this study is that thicker CT images acquired in the NLST made it difficult in some cases to discriminate between subsolid and solid nodules. This issue has been recognized as a limitation, and thin-slice CT images are preferred for screening purposes [18, 33]. Also, selection of the cases relies heavily on the accuracy and completeness of information in the NLST database because only cases with a part-solid nodule in the cancerous lobe reported by the NLST were reviewed; however, great care was taken in developing the NLST protocol for reporting guidelines. Another limitation is the imprecise definition of mixed nodules, and we hope that this study provides evidence of the importance of adopting a precise definition. The descriptive definition of mixed nodules in the NLST protocol as a combination of soft-tissue and ground-glass components is too broad a definition to allow accurate differentiation of subtypes of nodules for management and prognostic purposes. An upper limit of either the size or the relative diameter of the solid component is also needed when only a single CT examination is available and it cannot be shown that the nodule has progressed from a nonsolid nodule to a part-solid nodule. This distinction is an important one in determining the management of the nodule, particularly in the context of CT screening. In conclusion, we think that this study adds further support toward taking a conservative approach in the management and treatment of patients with part-solid nodules especially when the solid component is small. To an extent, this strategy is already reflected in the updated I-ELCAP [18] and Lung-RADS [32] guidelines, which recommend focusing on the size of the solid component in the partsolid nodule instead of on the overall nodule size. For the future, the critical issue will be further refinements for the follow-up of partsolid nodules based on the size or volume of the solid component that allow a process of shared decision making in selecting appropriate management and treatment. Acknowledgments We thank the National Cancer Institute (NCI) for access to the NCI s data collected by the National Lung Screening Trial. The statements contained herein are solely those of the authors and do not represent or imply concurrence of or endorsement by the National Cancer Institute or National Institutes of Health. References 1. Henschke C, Yankelevitz D, Mirtcheva R, McGuinness G, McCauley D, Miettinen O; ELCAP Group. 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