Our recommendation of 1-year follow-up is based on the knowledge that lung cancers manifesting as nonsolid nodules have slow growth rates, that all were stage I adenocarcinomas, and that survival was 100% despite substantial time between the initial identification and treatment.
Abstract
Purpose
To address the frequency of identifying nonsolid nodules, diagnosing lung cancer manifesting as such nodules, and the long-term outcome after treatment in a prospective cohort, the International Early Lung Cancer Action Program.
Materials and Methods
A total of 57 496 participants underwent baseline and subsequent annual repeat computed tomographic (CT) screenings according to an institutional review board, HIPAA-compliant protocol. Informed consent was obtained. The frequency of participants with nonsolid nodules, the course of the nodule at follow-up, and the resulting diagnoses of lung cancer, treatment, and outcome are given separately for baseline and annual repeat rounds of screening. The χ2 statistic was used to compare percentages.
Results
A nonsolid nodule was identified in 2392 (4.2%) of 57 496 baseline screenings, and pathologic pursuit led to the diagnosis of 73 cases of adenocarcinoma. A new nonsolid nodule was identified in 485 (0.7%) of 64 677 annual repeat screenings, and 11 had a diagnosis of stage I adenocarcinoma; none were in nodules 15 mm or larger in diameter. Nonsolid nodules resolved or decreased more frequently in annual repeat than in baseline rounds (322 [66%] of 485 vs 628 [26%] of 2392, P < .0001). Treatment of the cases of lung cancer was with lobectomy in 55, bilobectomy in two, sublobar resection in 26, and radiation therapy in one. Median time to treatment was 19 months (interquartile range [IQR], 6–41 months). A solid component had developed in 22 cases prior to treatment (median transition time from nonsolid to part-solid, 25 months). The lung cancer–survival rate was 100% with median follow-up since diagnosis of 78 months (IQR, 45–122 months).
Conclusion
Nonsolid nodules of any size can be safely followed with CT at 12-month intervals to assess transition to part-solid. Surgery was 100% curative in all cases, regardless of the time to treatment.
© RSNA, 2015
Introduction
The nonsolid nodule was a rare finding at chest imaging before the computed tomographic (CT) era but is now commonly identified on CT images of the chest (1–3). It can be a manifestation of inflammation, infection, or fibrosis, but it can also be a precursor of adenocarcinoma (atypical adenomatous hyperplasia) or adenocarcinoma proper (1–6). Its management remains challenging as assessment by using morphologic appearance and growth is difficult as nodule contours tend to be very irregular and margins ill-defined, which makes measurements quite imprecise and irreproducible. In addition, cancers manifesting in such nodules may initially grow internally, thus increasing their CT attenuation without increasing their overall size (7,8). Even positron emission tomography (PET) imaging is generally not useful, and fine-needle aspiration biopsy is highly operator and cytologist dependent and often not definitive.
Beyond these diagnostic challenges, important clinical questions have been raised as to whether and when pathologic diagnosis needs to be pursued in nonsolid nodules, as lung cancer manifesting in such a nodule has been shown to be slow growing (4,9–11) and likely to be a candidate for overdiagnosis. Several guideline organizations have recently made management recommendations (12,13), but these are based primarily on consensus opinion.
We address the frequency of identifying nonsolid nodules, diagnosing lung cancer manifesting as such nodules, and the long-term outcome after treatment in a large prospective cohort, the International Early Lung Cancer Action Program (I-ELCAP).
Materials and Methods
This report draws from the database of the screenings in the I-ELCAP collaboration, which was performed under an institutional review board–approved, Health Insurance Portability and Accountability Act–compliant common protocol at participating institutions from 1992 to 2013 (14,15). Informed consent was obtained. This study is limited to the baseline and annual repeat screenings performed between January 1, 2001 and December 31, 2013. Annual repeat screenings are defined as screenings performed 7–18 months after the prior screening and are pooled. January 1, 2001 was chosen as the start date as low-dose thin-section CT images were being acquired at 2.5 mm or less and after June 2002 at 1.25 mm or less. Included were all participants with follow-up imaging who were 40 years and older and current, former, and never smokers with no prior diagnosis of lung cancer who underwent CT screening following the I-ELCAP protocol (14,15). Median pack-years of smoking was 32. The median age of the participants at baseline screening was 59 years; it was 60 and 59 years for men and women, respectively (P < .0001).
A nonsolid nodule was defined as a nodule that does not obscure the underlying lung parenchyma and in which the only solid components are blood vessels, identified by their branching structure (3). When a nonsolid nodule develops nonvascular solid components, it is called a part-solid nodule. In instances of more than one nonsolid nodule, the focus was on the largest one of these. Size was expressed as the average of nodule length and width on the image that represented the largest cross-sectional area of the nodule. A nonsolid nodule was considered to have grown if it increased in its overall size or developed solid components (15). Each case with a nonsolid nodule was followed to determine whether the nodule resolved, decreased in size, remained stable, or grew in size or developed a solid internal component. As change in nonsolid nodules was difficult to assess, the focus was on two categories of change: resolved or decreased and stable or grew. The size measurements were based on the original measurements made by experienced radiologists at each of the collaborating sites who had received training in the identification and measurement of such nodules and who have been invited to our collaborative conferences held every 6 months since 2000 (16).
In 2001, the I-ELCAP protocol for baseline screenings recommended annual low-dose CT scans for all participants with nonsolid nodules smaller than 8 mm in diameter and 3-month follow-up for all nonsolid nodules 8–14 mm; if no growth was seen, follow-up at first annual repeat screening was recommended (14). For cases with nodules 15 mm or larger, immediate biopsy or PET scan was an additional option. The recommendation for a new nonsolid nodule at annual repeat screening that was 3 mm but less than 5 mm was follow-up CT in 6 months; if it was 5 mm or larger, the recommendation was follow-up CT in 1 month, and if at follow-up CT no growth was seen, annual follow-up was recommended. If growth was identified at a malignant rate, biopsy or PET was recommended prior to surgery. If the biopsy or PET finding was negative, follow-up low-dose CT in 3 months was recommended (14,15). If there were other solid or part-solid nodules, the workup was determined by the largest noncalcified nodule that met the requirements for a positive result. Recommended acquisition of follow-up CT studies was the same as for the baseline and annual repeat screenings.
The protocol was updated in January 2011 with the new recommendation that participants with only nonsolid nodules of any size be followed up with annual screenings, whether identified at baseline or annual repeat rounds of screening (15). This recommendation for nonsolid nodules has remained unchanged in the further update in 2014 which set a new threshold of 6 mm for the workup of part-solid and solid nodules found at the baseline round of screening (17). If, at annual repeat screening, the nonsolid nodule developed a solid component within it, short-term follow-up or biopsy was recommended; otherwise, annual follow-up was recommended. However, as always, the final decision about the follow-up was left to each participant and his or her physician, and the actual follow-up was documented. Reminder letters and calls for follow-up and repeat screening were part of the protocol and were prompted by the management system which was also used to document any procedures that were performed.
Diagnosis of malignancy was based on cytologic findings from a nonsurgical biopsy or on the pathologic specimen obtained from surgical resection according to the standard definitions provided by the World Health Organization. For this article, the updated classification for adenocarcinoma proposed by Travis et al (18,19) was used. The updated definitions replace adenocarcinoma with bronchioloalveolar features with adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma. The lesion was classified as invasive adenocarcinoma if there was invasion of the stroma. When the lesion had atypical cells meeting appropriate pathologic criteria, no invasion in the pathologic specimen, and it was smaller than 5 mm in overall size, it was classified as atypical adenomatous hyperplasia, a precursor lesion of adenocarcinoma. If no malignant cells were identified in the pathologic specimen, the diagnosis was classified as not malignant. Biopsy findings, whether by fine-needle aspiration or bronchoscopy, do not provide information about the extent of parenchymal invasion. Thus, the cytologic diagnosis may be lung cancer, atypical bronchioloalveolar proliferation (a nonspecific classification that includes possible diagnoses of atypical adenomatous hyperplasia, AIS, minimally invasive adenocarcinoma, or adenocarcinoma with lepidic predominance) (15), or nonmalignant (eg, inflammation, fibrosis, infection).
All instances were identified in which a pathologic diagnosis of a nodule that initially manifested as a nonsolid nodule was pursued together with the resulting diagnoses. All cases of diagnosed lung cancer were reviewed (C.I.H., more than 25 years of experience; D.F.Y., more than 25 years of experience) to confirm the initial CT appearance and its consistency when the cancer was ultimately diagnosed and the diameter of the solid component when it was first identified and at last follow-up CT prior to treatment (Fig 1). The time from the initial detection to the development of a solid component at CT, if present, was also documented.
Figure 1a:
CT images in a 68-year-old smoker show (a) a nonsolid nodule (17 × 13 mm) in the left upper lobe at baseline screening, (b) the nodule remained nonsolid at follow-up 2 years later, and (c) a solid component emerged at follow-up 9 years later. At that time, it was resected, and the final diagnosis was 2.1-cm invasive adenocarcinoma.
Figure 1b:
CT images in a 68-year-old smoker show (a) a nonsolid nodule (17 × 13 mm) in the left upper lobe at baseline screening, (b) the nodule remained nonsolid at follow-up 2 years later, and (c) a solid component emerged at follow-up 9 years later. At that time, it was resected, and the final diagnosis was 2.1-cm invasive adenocarcinoma.
Figure 1c:
CT images in a 68-year-old smoker show (a) a nonsolid nodule (17 × 13 mm) in the left upper lobe at baseline screening, (b) the nodule remained nonsolid at follow-up 2 years later, and (c) a solid component emerged at follow-up 9 years later. At that time, it was resected, and the final diagnosis was 2.1-cm invasive adenocarcinoma.
A case was classified as a baseline cancer if the nodule was identified at the baseline round, regardless of when diagnosis occurred, and it was classified as an annual cancer if it was first identified at annual round, even when at review it could be identified in retrospect. The clinical stage of the diagnosed lung cancer and, if resected, its pathologic stage and any invasion beyond the stroma was documented according to the protocol (15). To ensure that all lung cancer cases had at least 1 year of follow-up, lung cancer–specific survival was determined, and follow-up of the diagnosed cancers was from the time of diagnosis to end of follow-up, December 31, 2014, date of death, or loss to follow-up, whichever came first.
Statistical analyses were performed by using a statistical package (SAS, version 9.2; SAS Institute, Cary, NC). Percentages, medians, and interquartile ranges (IQRs) were calculated as needed. The χ2 test was used to compare percentages. A P value less than .05 indicated a significant difference.
Results
Baseline Round of Screening
Among the 57 496 participants who underwent the baseline screening, at least one nonsolid nodule was identified in 2392 (4.2%), while 17 356 (30.2%) of the 57 496 had at least one solid nodule and 2892 (5.0%) of the 57 496 had at least one part-solid nodule. Among these 2392 cases of nonsolid nodules, the frequency according to size of the largest nonsolid nodule and follow-up is given in Table 1; 84% (2020 of 2392) were 9 mm or smaller in diameter. These 2392 cases were pooled into two categories as to whether the nodule resolved or decreased or remained stable or grew.
Table 1.
Frequency of Nonsolid Nodules and Diagnoses of Lung Cancer Identified in 2392 of 57 496 Participants at Baseline CT Screening according to Size of Largest Nonsolid Nodule
Note.—Data are numbers of nodules.
*AAH = atypical adenomatous hyperplasia, a diagnosis made on histologic specimens. ABP = atypical bronchioloalveolar proliferation, a diagnosis made on cytologic specimens.
The nonsolid nodule (largest) resolved or decreased in 26% (628 of 2392) of cases and remained stable or grew in 74% (1764 of 2392). Of the 2392 cases, 78% (1860 of 2392) had a single nonsolid nodule, while 22% (532 of 2392) had more than one, and the frequency of resolution or decrease in size was 27% (506 of 1860) and 23% (122 of 532), respectively.
There were no interim, symptom-prompted diagnoses of lung cancer manifesting as a nonsolid nodule. Pathologic diagnosis was pursued in 82 cases, which led to a diagnosis of lung cancer in 73 (3.1%) of the 2392 cases with a nonsolid nodule, or in 0.13% of the 57 496 baseline screenings, all in nonsolid nodules that were stable or grew (Table 1). Among the 1764 cases in which the nonsolid nodules were stable or growing, median time to pathologic diagnosis was 20 months (IQR, 6–45 months), which was not significantly different from the median follow-up of 17 months (IQR, 12–37 months; P = .45) of those cases that had no pathologic diagnosis. In 19 (26%) of the 73 cancer cases, a solid component emerged within the nonsolid nodule (median time, 25 months; IQR, 13–40 months). Once the solid component emerged, it was typically followed to assess growth, in some cases for multiple years, and the median size of the solid component at CT prior to treatment was 5 mm (IQR, 4–8 mm).
Among the 1764 cases in which the nonsolid nodule persisted or grew (median follow-up, 17 months), the largest nodule was smaller than 6 mm in diameter in 1063 cases, and pathologic diagnosis was pursued in 12 and adenocarcinoma was diagnosed in nine; it was 6–9 mm in 439 cases, and diagnosis was pursued in 24 and adenocarcinoma was diagnosed in 20; it was 10–14 mm in 164 cases, and diagnosis was pursued in 28 and adenocarcinoma was diagnosed in 27; it was 15–30 mm in 92 cases, and diagnosis was pursued in 16 and adenocarcinoma was diagnosed in 15; and, it was 31 mm or larger in six, and diagnosis was pursued in two and both led to the diagnosis of adenocarcinoma (Table 1, Fig 2).
Figure 2:
Graph shows the likelihood of diagnosing a lung cancer manifesting in a nonsolid nodule, separately in the baseline (blue) and annual repeat (red) rounds of CT screening.
Of the 73 diagnosed cases of lung cancer, 72 underwent resection and one was treated by using radiation therapy 29 months after baseline screening. Median time from baseline CT scan to treatment was 20 months (IQR, 6–41 months). Of the 73 baseline cancers, 36 were diagnosed within the first 18 months and the remaining 37 later as shown in Table 2. All 73 cases were stage I adenocarcinoma, of which 65 (89%) were invasive, including all 19 that developed a solid component. The remaining eight (11%) were AIS. Local invasion beyond the stroma occurred in two cases among the 19 cases that had developed a solid component (Table 3), one with bronchiolar invasion (diameter of solid component, 9 mm) and the other with an angiolymphatic invasion (diameter of solid component, 8 mm); they were resected 29 and 58 months after baseline screening, respectively. Additional AISs were identified in the pathologic specimen in four cases, and an incidental carcinoid was identified in another case, none of which were previously identified at CT. Among those in whom pathologic diagnosis was pursued, the rate of lung cancer diagnoses was essentially the same for those with a solitary nonsolid nodule as it was for those with more than one nodule (52 [3%] of 1860 vs 21 [4%] of 532, respectively; P = .17). In three of the 532 participants with more than one nonsolid nodule, diagnosis was pursued in the smaller nodule while the largest one remained stable. Among the 73 cases of lung cancer, a synchronous second primary lung cancer was diagnosed in three cases with another solid nodule and in two with another part-solid nodule.
Table 2.
Length of Follow-up from Baseline When the Nonsolid Nodule Was First Identified to End of Follow-up or Resection
Note.—Data are numbers of nodules.
*One atypical bronchioloalveolar proliferation, four atypical adenomatous hyperplasia, four cases of inflammation and/or fibrosis.
†Two cases with angiolymphatic or bronchiolar invasion.
Table 3.
Diagnosed Lung Cancers That Transitioned from Nonsolid to Part-Solid Nodules Prior to Treatment according to Baseline or Annual Repeat Screening
Note.—Data are numbers of nodules.
Annual Repeat Rounds of Screening
Among the 64 677 annual repeat screenings, at least one new nonsolid nodule was identified in 485 (0.7%), while 2379 (3.7%) of the 64 677 had at least one new solid nodule and 541 (0.8%) of the 64 677 had at least one new part-solid nodule. Median time from the baseline CT to emergence of a new nonsolid nodule was 24 months (IQR, 13–39 months). Among these 485 cases, the frequency according to size of the largest nonsolid nodule and follow-up is given in Table 4; 76% (369 of 485) were 9 mm or smaller.
Table 4.
Frequency of Nonsolid Nodules and Diagnoses of Lung Cancer Identified in 485 of 64 677 Annual Repeat Screenings according to Size of Largest Nonsolid Nodule
Note.—Data are numbers of nodules.
*AAH = atypical adenomatous hyperplasia, a diagnosis made on histologic specimens. ABP = atypical bronchioloalveolar proliferation, a diagnosis made on cytologic specimens.
Follow-up of the 485 cases showed that the nonsolid nodule (largest) resolved or decreased in 66% (322 of 485) of cases and remained stable or grew in 34% (163 of 485). Of the 485 cases, 90% (437 of 485) had a single nonsolid nodule, while 10% (48 of 485) had more than one, and the frequency of resolution or decrease in size was 65% (283 of 437) and 81% (39 of 48), respectively.
There were no interim, symptom-prompted diagnoses of lung cancer manifesting as a nonsolid nodule. Pathologic diagnosis was pursued in 15 cases with a new nonsolid nodule, and lung cancer was diagnosed in 11 (2.3%) of the 485 cases with a new nonsolid nodule, that is, in 0.017% of the 64 677 annual repeat screenings, all in nonsolid nodules that were stable or growing (Table 4). Among the 163 cases in which the nonsolid nodules were stable or growing, the median time to pathologic diagnosis was 14 months (IQR, 4–40 months) from when it was first identified, which was not significantly different from the median follow-up of 20 months (IQR, 10–39 months; P = .31) for those cases that had no pathologic diagnosis. A solid component emerged in three (27%) of the 11 cases, 11, 15, and 37 months after the nonsolid nodule was first identified (Table 3). The nodule was followed to further assess growth prior to resection, and the size of the solid component at CT prior to resection was 3, 7, and 12 mm, respectively.
Among the 163 cases in which the nonsolid nodule persisted or grew, the largest nodule was smaller than 6 mm in diameter in 89, and pathologic diagnosis was pursued in two; adenocarcinoma was diagnosed in both. The largest nodule was 6–9 mm in 42, and diagnosis was pursued in six and adenocarcinoma was diagnosed in four; it was 10–14 mm in 29, and diagnosis was pursued in seven and adenocarcinoma was diagnosed in five. No malignancies were diagnosed in new nonsolid nodules 15 mm or larger (Table 4, Fig 2).
All 11 diagnosed cases of lung cancer underwent resection. Median time from the initial identification of the nodule to treatment was 14 months (IQR, 4–50 months). Of the 11 cancers, six were diagnosed within the first 18 months, and the remaining five were diagnosed later as shown in Table 5. All 11 cases were stage I adenocarcinoma, of which nine (82%) were invasive, including two of the three that had transitioned to become part-solid, and the remaining two (18%) of the 11 cases were AIS. None had invasion beyond the stroma. In two cases, an additional AIS was identified in the pathologic specimen that had not been identified at CT. Among those in whom pathologic diagnosis was pursued, the rate of lung cancer diagnoses was essentially the same for those with new solitary nonsolid nodule as it was for those with more than one nodule (10 [2%] of 437 vs 1 [2%] of 48; P > .99); diagnosis was pursued in only one of the 48 participants with more than one new nonsolid nodule, and adenocarcinoma was diagnosed in the smaller nodule while the larger one remained stable. None of the lung cancer cases had a synchronous diagnosis of another primary cancer in a solid or part-solid nodule.
Table 5.
Length of Follow-up from When Nonsolid Nodule Was First Identified to End of Follow-up or Resection
Note.—Data are numbers of nodules.
*One atypical bronchioloalveolar proliferation, one atypical adenomatous hyperplasia, two cases of inflammation and/or fibrosis.
Treatment and Survival
Treatment of the 84 (73 + 11) cancer cases was with lobectomy in 55, bilobectomy in two, sublobar resection in 26, and radiation therapy in one, and the median time to treatment from initial identification was 19 months (IQR, 6–41 months). At retrospective review, all cancers were identified in growing nodules, some of which grew very slowly (Tables 2, 5). Regardless of the size when treated, time to treatment, emergence of a solid component, or type of treatment, the lung cancer–specific survival rate of the 84 diagnosed cases of lung cancer was 100% with a median follow-up since diagnosis of 78 months (IQR, 45–122 months). None has had a recurrence.
Nonmalignant diagnoses were made in nine cases in the baseline round and four in the annual repeat rounds. Of the 13 cases, seven were resected, and the diagnosis was atypical adenomatous hyperplasia in five, inflammation in one, and fibrosis in one; for the six cases that were not resected, the biopsy diagnosis was atypical bronchioloalveolar proliferation in two and inflammation and/or fibrosis in four. All 13 have been followed up and are alive with the median follow-up time of 99 months (IQR, 45–136 months).
Discussion
In the I-ELCAP cohort undergoing annual CT screening for lung cancer, the frequency of nonsolid nodules in the baseline round was low, as only 4.2% (2392) of the 57 496 participants had such a nodule. Pathologic diagnosis was pursued in 82 of the 2392 cases, and it resulted in the diagnosis of lung cancer in 73 (1.3 cases of lung cancer per 1000 baseline screenings). In annual repeat screenings, the frequency was more than five times lower than in baseline screenings, as a new nonsolid nodule was identified in only 0.7% (485) of the 64 677 annual repeat rounds. Diagnosis was pursued in 15 of the 485 cases, of which 11 had a diagnosis of lung cancer (0.17 per 1000 annual repeat screenings). The diagnosis of all 84 (73 + 11) identified cases of lung cancer was stage I adenocarcinoma. The median time from initial identification of the cancerous nodule to treatment was 19 months (IQR, 6–41 months). The nonsolid nodule had become part-solid in 22 cases, and the median time from initial identification of the nonsolid nodule to emergence of the solid component was 24 months (IQR, 13–39 months). Regardless of the tumor size, extent of invasion when treated, time to treatment, or type of treatment, lung cancer–specific survival rate was 100% with a median follow-up since diagnosis of 78 months (IQR, 45–122 months). The absence of interim, symptom-prompted diagnoses and absence of cancers manifesting as nonsolid nodules larger than 15 mm in annual repeat rounds provide further support of the indolent nature of these cancers (Fig 2). The total number of cancers manifesting as nonsolid nodules remains unknown as the diagnosis was only ascertained among those in whom pathologic diagnosis was pursued, and thus, the true frequency with which lung cancer would be diagnosed in the various size categories is also unknown. With continued annual screening, additional slow-growing cancers may yet be diagnosed.
The implication of the long-term survival of 100%, regardless of the cancer size or time to treatment, is that there is no added benefit to earlier invasive diagnostics and treatment of these cancers. It is notable that in 62 of the 84 cases, the nodule remained nonsolid, even at retrospective review, and yet pathologic evidence of stromal invasion was present in 52 (84%) of the 62. Therefore, whether the invasion remained invisible as it did not manifest as a solid component on CT images, or invasion led to development of a solid component on CT images, follow-up at 1-year intervals did not decrease long-term survival.
Some have recommended that repeat imaging be performed in less than 1 year (12,13), while others including I-ELCAP (15) have recommended follow-up in 1 year as long as the nodule(s) remains nonsolid. Recently, in the context of screening, the LungRads guidelines by the American College of Radiology (20) also recommended 1-year follow-up for nonsolid nodules with average diameter smaller than 20 mm. The rationale for short-term follow-up imaging in less than 1 year, including outside of the context of screening where follow-up may be more difficult to manage, is premised on two important concerns—first that cancers manifesting in nonsolid nodules might progress rapidly and second the anxiety caused by waiting 1 year. Our recommendation of 1-year follow-up is based on the knowledge that lung cancers manifesting as nonsolid nodules have slow growth rates, that all were stage I adenocarcinomas, and that survival was 100% despite substantial time between the initial identification and treatment. The concern about patient anxiety is a challenging one involving issues of quality of life and utilization of resources, namely excessive CT scans, unnecessary biopsies, and surgery that would have no effect on the patient outcome. However, some reassurance that this can be managed is demonstrated by the analysis of the anxiety caused by false-positive findings in the context of screening where it was found that it had minimal long-term effect (21,22).
Concern of overdiagnosis is an important consideration in the context of any cancer screening. In March 2012, the National Cancer Institute convened a working panel to develop a strategy for cancer screening, particularly in regard to indolent or overdiagnosed lung, prostate, and breast cancers (23). This report recommended that companion diagnostics (eg, molecular markers) be used to identify indolent or low-risk lesions and that the word cancer be replaced by IDLE (indolent lesions of epithelial origin) lesions with the anticipation that elimination of the word cancer would remove the fear that this term evokes. This approach recognizes the heterogeneous nature of cancers ranging from very aggressive to those that are essentially benign. We support this recommendation and note that until validated molecular markers become available, CT imaging is ideally suited for differentiating among lung cancers of different levels of aggressiveness. As shown in this report, CT allows for identification of a solid component within the nonsolid nodule sufficiently early so that delay in treatment did not alter prognosis.
With CT screening gaining widespread acceptance, the anticipated shift to more frequent diagnoses of early stage lung cancer increases the concern for identifying the most appropriate treatment. Nonrandomized trials have shown equivalence between lobectomy and limited resection for cancers manifesting as part-solid and solid nodules smaller than 30 mm (24–26), and there are ongoing randomized surgical trials comparing lobectomy with limited sublobar resection for cancers manifesting in such nodules. The role of nonsurgical therapy for these lesions, such as radiation (27) or image-guided ablative therapy, are not yet well explored. However, there are no ongoing randomized trials for lung cancer manifesting as nonsolid nodules. Our findings suggest that until the nodule becomes part-solid, there may be no need for any treatment at all, and under circumstances where treatment may be considered necessary, the most appropriate treatment has not been defined.
The major limitation of our study was that not all nonsolid nodules that demonstrated stability or growth were pursued for diagnosis, so that the actual frequency of cancer manifesting as a nonsolid nodule is unknown. However, there was no significant difference in the follow-up time of those who had pathologic diagnosis and those who did not, and therefore it was unlikely that an aggressive cancer was missed. In addition, the large majority of these were smaller than 10 mm where further diagnostic pursuit is challenging. The main point being that among those cases with nonsolid nodules that do not have pathologic diagnosis, it is unlikely that if there were cancers that they would be more aggressive than those already diagnosed. Presumably, the diagnosed cases were among the more aggressive ones, as at retrospective review, they all had demonstrated growth, developed solid components, or had some other reason prompting pathologic diagnosis. Nodule measurements relied on those made by a single radiologist so that the interobserver variability is not known, but it is well recognized that there is considerable measurement variability between radiologists. For this reason, the nonsolid nodules that remained stable or grew were pooled as it was difficult to reliably assess stability or growth of these nodules.
In summary, our findings support the safety of annual repeat scans for individuals with only nonsolid nodules and that pathologic diagnosis should be pursued only when a solid component develops. Earlier treatment of these cancers when they were either small or had not yet developed a solid component would have provided no additional benefit. However, in light of the many factors to be considered for these challenging nodules, this report highlights the need for shared decision making, which is considered an essential and well-accepted component of all screening programs.
Advances in Knowledge
■ Newly seen nonsolid nodules at annual repeat screening resolve or decrease more frequently than those seen at baseline screening (66% [322 of 485] vs 26% [628 of 2392], P < .0001).
■ In 64 677 annual repeat screenings, no lung cancer was diagnosed among the 31 participants with a newly seen nonsolid nodule that was 15 mm or larger.
■ All lung cancers manifesting in nonsolid nodules were stage I adenocarcinomas, and the long-term lung cancer–specific survival was 100%, regardless of the time from initial identification to treatment (median, 19 months; interquartile range, 6–41 months).
Implication for Patient Care
■ Nonsolid nodules of any size can be followed for growth yearly, rather than more frequently, as lung cancers diagnosed among them are slow growing.
Acknowledgments
Acknowledgments
The I-ELCAP Investigators: Mount Sinai School of Medicine, New York, NY: Claudia I. Henschke, Principal Investigator, David F. Yankelevitz, Rowena Yip, Dongming Xu, Mary Salvatore, Raja Flores, Andrea Wolf; Weill Cornell Medical College: Dorothy I. McCauley, Mildred Chen, Daniel M. Libby, James P. Smith, Mark Pasmantier; Cornell University: A. P. Reeves; CBNS, City University of New York at Queens College, Queens, NY: Steven Markowitz, Albert Miller; Fundacion Instituto Valenciano de Oncologia, Valencia, Spain: Jose Cervera Deval; University of Toronto, Princess Margaret Hospital, Toronto, Canada: Heidi Roberts, Demetris Patsios; Azumi General Hospital, Nagano, Japan: Shusuke Sone, Takaomi Hanaoka; Clinica Universitaria de Navarra, Pamplona, Spain: Javier Zulueta, Juan de Torres, Maria D. Lozano; Swedish Medical Center, Seattle, Wash: Ralph Aye, Kristin Manning; Christiana Care, Helen F. Graham Cancer Center, Newark, Del: Thomas Bauer; National Cancer Institute Regina Elena, Rome, Italy: Stefano Canitano, Salvatore Giunta; St Agnes Cancer Center, Baltimore, Md: Enser Cole; LungenZentrum Hirslanden, Zurich, Switzerland: Karl Klingler; Columbia University Medical Center, New York, NY: John H.M. Austin, Gregory D. N. Pearson; Hadassah Medical Organization, Jerusalem, Israel: Dorith Shaham; Holy Cross Hospital Cancer Institute, Silver Spring, Md: Cheryl Aylesworth; Nebraska Methodist Hospital, Omaha, Neb: Patrick Meyers; South Nassau Communities Hospital, Long Island, NY: Shahriyour Andaz; Eisenhower Lucy Curci Cancer Center, Rancho Mirage, Calif; Davood Vafai; New York University Medical Center, New York, NY: David Naidich, Georgeann McGuinness; Dorothy E. Schneider Cancer Center, Mills-Peninsula Health Services, San Mateo, Calif: Barry Sheppard; State University of New York at Stony Brook, Stony Brook, NY: Matthew Rifkin; ProHealth Care Regional Cancer Center, Waukesha & Oconomowoc Memorial Hospitals, Oconomowoc, Wis: M. Kristin Thorsen, Richard Hansen; Maimonides Medical Center, Brooklyn, NY: Samuel Kopel; Wellstar Health System, Marietta, Ga: William Mayfield; St Joseph Health Center, St. Charles, Mo: Dan Luedke; Roswell Park Cancer Institute, Buffalo, NY: Donald Klippenstein, Alan Litwin, Peter A. Loud; Upstate Medical Center, Syracuse, NY: Leslie J. Kohman, Ernest M. Scalzetti; Jackson Memorial Hospital, University of Miami, Miami, Fla; Richard Thurer, Nestor Villamizar; State University of New York, North Shore-Long Island Jewish Health System, New Hyde Park, NY: Arfa Khan, Rakesh Shah; The 5th Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China: Xueguo Liu; Mercy Medical Center, Rockville Center, NY: Gary Herzog; Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan: Diana Yeh; National Cancer Institute of China, Beijing, China: Ning Wu; Staten Island University Hospital, Staten Island, NY: Joseph Lowry, Mary Salvatore; Central Main Medical Center: Carmine Frumiento; Mount Sinai School of Medicine, New York, NY: David S. Mendelson; Georgia Institute for Lung Cancer Research, Atlanta, Ga: Michael V. Smith; The Valley Hospital Cancer Center, Paramus, NJ: Robert Korst; Health Group Physimed/McGill University, Montreal, Canada: Jana Taylor; Memorial Sloan-Kettering Cancer Center, New York, NY: Michelle S. Ginsberg; John Muir Cancer Institute, Concord, Calif: Michaela Straznicka; Atlantic Health Morristown Memorial Hospital, Morristown NJ: Mark Widmann; Alta Bates Summit Medical Center, Berkeley, Calif: Gary Cecchi; New York Medical College, Valhalla, NY: Terence A.S. Matalon; St Joseph’s Hospital, Atlanta, Ga: Paul Scheinberg; Mount Sinai Comprehensive Cancer Center, Miami Beach, Fla: Shari-Lynn Odzer; Aurora St Luke’s Medical Center, Milwaukee, Wis: David Olsen; City of Hope National Medical Center, Duarte, Calif: Fred Grannis, Arnold Rotter; Evanston Northwestern Healthcare Medical Group, Evanston, Ill: Daniel Ray; Greenwich Hospital, Greenwich, Conn: David Mullen; Our Lady of Mercy Medical Center, Bronx, NY: Peter H. Wiernik; Baylor University Medical Center, Dallas, Tex: Edson H. Cheung; Sequoia Hospital, Redwood City, Calif: Melissa Lim; Glens Falls Hospital, Glens Falls, NY: Louis DeCunzo; Atlantic Medical Imaging, Atlantic City, NJ: Robert Glassberg; Karmanos Cancer Institute, Detroit, Mich: Harvey Pass, Carmen Endress; Rush University, Chicago, Ill: Mark Yoder, Palmi Shah; Building Trades, Oak Ridge, Tenn: Laura Welch; Sharp Memorial Hospital, San Diego, Calif: Michael Kalafer; Newark Beth Israel Medical Center, Newark, NJ: Jeremy Green; Guthrie Cancer Center, Sayre, Pa: James Walsh, David Bertsch; Comprehensive Cancer Centers of the Desert, Palm Springs, Calif: Elmer Camacho; Dickstein Cancer Treatment Center, White Plains Hospital, White Plains, NY: Cynthia Chin; Presbyterian Healthcare, Charlotte, NC: James O’Brien; University of Toledo, Toledo, Ohio: James C. Willey
The screenings in the I-ELCAP pooled database has been supported in part by National Institutes of Health R01-CA-63393l and R01-CA-78905; Department of Energy DE-FG02-96SF21260; The City of New York, Department of Health and Mental Hygiene; New York State Office of Science, Technology and Academic Research (NYSTAR); American Cancer Society; Institute de Salud Carlos III, Spain (PI10/01652, PI07/0792, RD12/0036/0062); The Starr Foundation; The New York Community Trust; The Rogers Family Fund; The Foundation for Lung Cancer: Early Detection, Prevention, and Treatment (primary source from an unrestricted gift in 2000-2003 from the Vector Group, the parent company of Liggett Tobacco); Dorothy R. Cohen Foundation, Jacob and Malka Goldfarb Charitable Foundation; Auen/Berger Foundation; Berger Foundation; Mills Peninsula Hospital Foundation, Tenet Healthcare Foundation; Ernest E. Stempel Foundation; Early Diagnosis and Treatment Research Foundation, Academic Medical Development Corporation; Columbia University Medical Center, Empire Blue Cross and Blue Shield; Eastman-Kodak; General Electric; Weill Medical College of Cornell University; Cornell University; New York Presbyterian Hospital; Swedish Hospital; Christiana Care Helen F. Graham Cancer Center; Holy Cross Hospital; Eisenhower Hospital; Jackson Memorial Hospital Health System; Evanston Northwestern Healthcare.
Received November 6, 2014; revision requested December 30; revision received February 23, 2015; accepted March 17; final version accepted March 24.
Supported in part by the Flight Attendant Medical Research Institute (FAMRI).
Funding: This research was supported by the National Institutes of Health (grants R01-CA-63393l and R01-CA-78905).
Disclosures of Conflicts of Interest: D.F.Y. Activities related to the present article: none to disclose. Activities not related to the present article: serves on the scientific advisory board (unpaid) for Give-A-Scan, Lung Cancer Alliance; and is named inventor on a number of patents and patent applications relating to the evaluation of diseases of the chest including measurement of nodules. Some of these, which are owned by Cornell Research Foundation (CRF), are nonexclusively licensed to General Electric. As an inventor of these patents, D.F.Y. is entitled to a share of any compensation which CRF may receive from its commercialization of these patents. Other relationships: none to disclose. R.Y. disclosed no relevant relationships. J.P.S. disclosed no relevant relationships. M.L. disclosed no relevant relationships. Y.L. disclosed no relevant relationships. D.M.X. disclosed no relevant relationships. M.M.S. disclosed no relevant relationships. A.S.W. disclosed no relevant relationships. R.M.F. disclosed no relevant relationships. C.I.H. Activities related to the present article: none to disclose. Activities not related to the present article: none to disclose. Other relationships: is a named inventor on a number of patents and patent applications relating to the evaluation of pulmonary nodules on CT scans of the chest which are owned by Cornell Research Foundation (CRF). Since 2009, C.I.H. does not accept any financial benefit from these patents including royalties and any other proceeds related to the patents or patent applications owned by CRF; is the President and serves on the board of the Early Diagnosis and Treatment Research Foundation. I receive no compensation from the Foundation. The Foundation is established to provide grants for projects, conferences, and public databases for research on early diagnosis and treatment of diseases. Recipients include, I-ELCAP, among others. The funding comes from a variety of sources including philanthropic donations, grants and contracts with agencies (federal and nonfederal), imaging and pharmaceutical companies relating to image processing assessments. The various sources of funding exclude any funding from tobacco companies or tobacco-related sources.
Abbreviations:
- AIS
- adenocarcinoma in situ
- I-ELCAP
- International Early Lung Cancer Action Program
- IQR
- interquartile range
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