Small nodules (≤ 6 mm in diameter) of multiple primary lung cancers: Prevalence and management

doi:10.21203/rs.3.rs-1327656/v1

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Small nodules (≤ 6 mm in diameter) of multiple primary lung cancers: Prevalence and management

https://doi.org/10.21203/rs.3.rs-1327656/v1

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Background: Synchronous multiple primary lung cancers associated with small non-dominant nodules are commonly encountered. However, the incidence, follow-up, and treatment of small non-dominant tumors have been but little studied. We explored the prevalence and management of small non-dominant tumors and factors associated with interval growth.

Methods: This observational, consecutive, retrospective single-center study enrolled patients diagnosed with synchronous multiple primary lung cancers and small non-dominant tumors (≤ 6mm in diameter) who underwent resection of the dominant tumor. The incidence, follow-up, and management of small non-dominant tumors and predictors of nodule growth were analyzed.

Results: There were 88 patients (12% of all lung cancer patients) with pathological diagnoses of synchronous multiple primary lung cancers. A total of 131 (18%) patients were clinically diagnosed with at least one small (≤ 6 mm in diameter) multiple primary lung cancer non-dominant tumor. 94 patients with 125 small-nodule non-dominant tumors clinically diagnosed as multiple primary lung cancers were followed-up for at least 6 months. A total of 29 (29/125, 23.2%) evidenced small pulmonary nodules (≤ 6 mm in diameter) that exhibited interval growth on follow-up computed tomography (CT). On multivariate analysis, a part-solid nodule (compared to a pGGN) (OR 1.23; 95% CI 1.08–1.40) or a solid nodule (compared to a pGGN) (OR 3.50; 95% CI 1.94–6.30) predicted small nodule interval growth.

Conclusions: We found a relatively high incidence of multiple primary lung cancers with small non-dominant tumors exhibiting interval growth on follow-up CT, suggesting that resection of non-dominant tumors at the time of dominant tumor resection, especially when the nodules are part-solid or solid, is the optimal treatment.

Multiple primary lung cancer

Non-dominant tumor

Comprehensive histological assessment

Interval growth

Lung cancer screening reduces lung cancer mortality in high-risk populations^1,2. Small, solitary pulmonary nodules must always be followed-up. The nodule size threshold for surgical resection is 6-8 mm³. Current multiple primary lung cancer (MPLC) guidelines emphasize management of the dominant tumor (DT). In the clinic, some MPLC patients exhibit DTs longer than 6–8 mm and non-dominant tumors (nDTs) shorter than 6 mm. No guideline aiding nDT selection and treatment is yet available.

Small nodules are commonly encountered during lung cancer screening and can develop into invasive cancers⁴. Nodule size and growth rate determine the nature of the nodule, and its management⁵. However, the use of only nodule dimensions is limited in terms of predicting whether small nodules can develop into advanced lung cancers^4,5. In MPLC patients with small nDTs, it remains unclear whether to resect MPLCs and nDTs at the same time or in separate operations. Here, we explored the prevalence of MPLC with small-nodule nDTs; the management strategy; and predictors of nodule growth.

We established a cohort of consecutive patients with non-small cell lung cancer who underwent radical resection from January 2018 to July 2020. Patients with sMPLCs and small nDTs (≤ 6 mm) who underwent DT resection were included in the study. We reviewed all computed tomography (CT) images. For patients with more than one pulmonary nodule, we also examined the medical records and pathology reports. The largest or most invasive nodule was the DT and the other nodules possible nDTs. The resected DTs had been pathologically diagnosed as primary lung cancers. The surgical procedures were based on tumor size, location, CT features, performance status, and pulmonary function. Solid and part-solid DTs were usually resected via lobectomy or segmentectomy. nDTs were always resected via segmentectomy or wedge resection. For patients exhibiting a poor pulmonary reserve or poor performance status, segmentectomy or wedge resection was selected instead of lobectomy.

Tumor morphology, size, and growth aided the clinical diagnosis and identification of benign and malignant lung nodules. The likelihood of malignancy correlates with both nodule size and growth rate, and any history of prior lung cancer or an extrathoracic malignancy. All MPLC diagnoses were reviewed by our multidisciplinary lung cancer team.

The pathologically diagnostic criterion for MPLCs was a comprehensive histological assessment (based on our previous work)⁶. Briefly, we semi-quantitatively evaluated the relative percentages of all histological subtypes (lepidic, acinar, papillary, micropapillary, and solid components) in 10% increments. Paired tumors exhibiting similar histological features were considered to be lung metastases, and those exhibiting different proportions of histological subtypes or features to be multiple primaries. Tumors presenting as adenocarcinomas in situ (AISs), minimally invasive adenocarcinomas (MIAs), or lepidic-predominant adenocarcinomas (LPAs), were considered to be multiple primaries. We performed a targeted gene panel test to distinguish multiple primaries from intra-pulmonary metastases.

The maximum diameters of all nodules were measured with electronic calipers using our institutional picture archiving and communication systems. Nodules were considered to exhibit interval growth if the axial size increased by ≥ 1 mm; this represents almost a volumetric doubling of a nodule ≤ 6 mm. Volumetric analysis was not available given the retrospective nature of the study. The study was approved by the Institutional Review Board and the Ethics Committee of the Fifth Hospital of Sun Yat-sen University and written informed consent was obtained from all patients.

Statistical analysis

The student t-test or the Mann-Whitney U test was used to compare continuous variables between the two groups and the chi-squared or Fisher exact test was employed to compare categorical variables. Covariates exhibiting P-values < 0.1 on univariate analysis were included in a multivariate logistic regression to investigate factors associated with nodule presence and growth. A two-tailed P-value < 0.05 was considered significant.

From January 2018 to July 2020, 735 patients underwent resection of primary lung cancers in our department. CT revealed that 257 (35%) had more than one nodule. Eighty-eight (12%) patients were pathologically diagnosed with synchronous MPLCs (sMPLCs).

Factors Associated With Mplcs

On multivariate regression, sex and nodule density were associated with MPLCs (Table 1). Such cancers were more common in women than men (odds ratio [OR] 2.49; 95% confidence interval [CI] 1.20–5.14). Multiple pure ground-glass nodules (pGGNs) were more likely to be MPLCs than were solid nodules (OR 1.36; 95% CI 1.13–1.31).

Table 1

Multivariate analysis of factors associated with multiple primary lung cancer
Predictors	OR (95% CI)	P value
female vs male	2.49 (1.20, 5.14)	0.013
Upper lobe vs middle or lower lobe	1.36 (0.97,1.91)	0.072
pGGN VS solid	1.36 (1.13, 1.31)	0.012

The Prevalence Of Small Pulmonary Nodules

A total of 177 (24%) patients evidenced small nodules on at least one CT examination. A total of 131 (18%) were clinically diagnosed with MPLC nDTs (≤ 6 mm), of which 43 in 37 (5%) patients underwent surgical resection. Thirty-eight were resected at the time of DT resection, and five during second operations after nodule growth was evident on follow-up CT. There was no perioperative mortality (30- or 90-day). In total, 32 (4.3%) patients with 35 (35/42, 83%) small nodules were pathologically diagnosed with MPLCs. Two patients had 3 small metastatic cancers; three had 5 small non-malignant nodules; 4 nodules were AISs, 9 were MIAs, and 22 were invasive adenocarcinomas. Overall, 88% (38/43) of resected small nodules were malignant.

Development Of Lung Cancer From Small Pulmonary Nodules

Overall, 94 patients with 125 nDTs suspected of being MPLCs were followed-up for at least 6 months. Of these, 17 underwent follow-up CT for ≤ 365 days and 77 follow-up CT for > 365 days. The median follow-up time was 530 days. Of these patients, 19 had 29 (29/125, 23.2%) small pulmonary nodules (≤ 6 mm) evidencing interval growth on follow-up CT (Supplementary Fig. 1-2) and 4 with 5 nodules underwent surgical resection; 3 were pathologically confirmed to have three MPLCs; 1 had two pulmonary nodules that were metastases from colon cancer; and 1 was pathologically diagnosed with MPLC via CT-guided core needle biopsy (several N2 lymph nodes were cancer-positive). The other 14 patients were followed-up (Table 2). The medium volume doubling time was 347 days. Figure 1 shows a patient with an MPLC and a 5-mm solid nodule in the right lower lobe that exhibited interval growth from 5 to 24 mm over 14 months, accompanied by multiple N2 mediastinal lymph node metastases. CT-guided core needle biopsy of the right lower lobe revealed an invasive adenocarcinoma. Comprehensive histological assessment diagnosed MPLCs.

Table 2

characteristics of non-dominant small nodules with interval growth
				Characteristics of dominant tumor			Characteristics of non-dominant tumor with interval growth
Patient ID	nodule ID	Gender	Number of tumors	Maximum diameter(mm)	CT characteristic	Histology	Baseline Diameter(mm)	Diameter of latest measurement (mm)	Volume double time (Day)	CT characteristic	Surgical resection	Histology
1	1	F	3	14*13	PSN	Ad	4	12	232	pGGN	Yes	Ad
2	2	F	5	15*13	PSN	Ad	3	14	157	SN	Yes	Ad
2	3						5	6	2012	pGGN	No	NA
3	4	M	2	10*8	PSN	Ad	4.5	10.5	295	PSN	Yes	Ad
4	5	M	2	20*18	PSN	Ad	4	5.5	353	PSN	No	NA
5	6	M	4	16*10	PSN	Ad	5.5	8	451	pGGN	No	NA
6	7	M	2	12*10	PSN	Ad	5	24	63	SN	No (core needle biopsy)	Ad
7	8	F	3	14*10	GGN	Ad	3.2	4.3	329	SN	No	NA
8	9	M	2	34*32	SN	Ad	4	8	186	SN	No	NA
9	10	F	3	14*14	GGN	Ad	2	10	84	SN	Yes	M
9	11						2	10	84	SN	Yes	M
10	12	F	5	41*32	PSN	Ad	4	8	280	pGGN	No	NA
10	13						3.0	5.6	379	PSN	No	NA
11	14	F	4	15*7	PSN	Ad	4.5	5.5	950	PSN	No	NA
12	15	F	2	12*11	pGGN	Ad	5	8	227	PSN	No	NA
12	16						3.8	6.8	234	SN	No	NA
13	17	F	7	7*6	PSN	Ad	2.7	4.8	450	PSN	No	NA
13	18						4.11	5.21	1399	SN	No	NA
14	19	F	10	29*15	PSN	Ad	3.4	5	524	PSN	No	NA
15	20	M	5	10*10	SN	Ad	4	6	1554	pGGN	No	NA
15	21						2.5	4	1554	pGGN	No	NA
16	22	F	2	11*5	PSN	Ad	2	6	376	SN	No	NA
17	23	M	3	22*17	PSN	Ad	4.4	7.2	354	SN	No	NA
18	24	F	3	9*8	PSN	Ad	5.5	8.9	347	PSN	No	NA
19	25	F	6	16*10	SN	Ad	4.2	5.8	906	SN	No	NA
19	26						3.8	6.3	292	SN	No	NA
19	27						3.9	6.6	292	SN	No	NA
19	28						4.5	8.1	292	SN	No	NA
19	29						3.6	5.9	396	SN	No	NA
M, Male; F, Female; PSN, Part-solid nodule; SN, Solid nodule; pGGN, Pure ground glass nodule; Ad, Adenocarcinoma; M, Metastasis.

Factors Associated With Pulmonary Nodule Growth

On univariate analysis, nodule density on CT [part-solid vs. pGGN (OR 4.18; 95% CI 1.12–14.94), solid vs. pGGN (OR 11; 95% CI 3.175–38.74)]; and a history of cancer (OR 5.5; 95% CI 1.24–24) were associated with nodule growth.

On multivariate analysis, a part-solid nodule vs. a pGGN (OR 1.23; 95% CI 1.08–1.40); a solid nodule vs. a pGGN (OR 3.50; 95% CI 1.94–6.30) were predictors of small nodules exhibiting interval growth (Table 3).

Table 3

Univariate and multivariate analyses for factors associated with interval growth of small nDTs
Independent variables	Univariate predictors		Multivariate predictors
Independent variables	OR(95%CI)	P value	OR(95%CI)	P value
age	0.43 (0.092, 2.024)	0.14
sex
Male	Reference
Female	0.59 (0.21, 1.63)	0.41
Smoke
None smoker	Reference
Current smoker	3.57 (1.09, 11.6)	0.03	1.06 (0.45, 2.48)	0.89
Former smoker	1.6 (0.53, 5.19)	0.37
CT density
Pure GGN	Reference
Part solid	4.18(1.12, 14.94)	0.03	1.23 (1.08, 1.40)	0.029
Solid	14.7(4.74, 46.09)	<0.001	3.50 (1.94, 6.30)	<0.001
Nodule margin
Regular	Reference
Irregular	2.2(0.37, 13)	0.19
Spiculated	2.73(0.76, 9.8)	0.06	1.08(0.98, 1.19)	0.11
Lobulated	0.93(0.17, 4.8)	0.46
Nodule location
Upper lobe
Middle or lower lobe	0.32(0.48, 1.26)	0.34
History of cancer	5.5(1.24, 24)	0.014	1.15(0.81, 1.6)	0.072

Overall, 12% of lung cancer patients were pathologically diagnosed with sMPLCs. When multiple nodules were evident on chest CT, females and those with multiple GGNs were more likely to have MPLCs. Of all patients, 18% were clinically diagnosed with MPLC and small nDTs. Of 43 such nDTs that were resected, 38 (88%) were malignant. Of all patients, 4.3% had small pathologically diagnosed MPLCs. Overall, 29 of 125 (23.2%) small nDTs evidenced interval growth on follow-up. Part-solid and solid nodules predicted nodule growth.

Given the widespread use of high-resolution chest imaging systems and lung cancer screening programs, patients with MPLCs are growing in numbers worldwide⁷. Any solitary small nodule ≤ 6–8 mm should be followed-up in terms of growth⁸. The clinical management of such patients varies by the risk of malignancy and (to some extent) the patient and the referring physician. For patients with multiple nodules, the Fleischner Society and National Cancer Comprehensive Network guidelines recommend that MPLC management should be based on the DT³; no recommendations for the selection and treatment of nDTs are made. When a patient exhibits a small nodule that raises a suspicion of an nDT, should we resect this along with the DT or during follow-up? No consensus has yet emerged. In this study, 4.3% of patients exhibited small, pathologically diagnosed MPLCs, 88% of resected small suspicious nodules were malignant and there was no operative mortality. Contemporaneous resection of the DT and a small suspicious nodule eradicates the tumor early and avoids the risk of advanced disease. Some patients may be unwilling to undergo a second operation or may be unfit. Also, resection of small suspected nDTs allows of precise diagnosis and staging, usefully guiding adjuvant therapy.

The probability of a malignant, small pulmonary nodule in those undergoing lung cancer screening is low and correlates with nodule size. In the NELSON trial, the lung cancer probability was 0.4% when the nodule diameter was < 5 mm, and 1.3% when the diameter was 5–10 mm⁹. In the National Lung Screening Trial (NLST), the lung cancer probability was 0.3% when the nodule diameter was 4–6 mm¹⁰. Munden et al.⁴ analyzed the NLST data and found that 42% of all participants had at least one CT-visible micronodule (less than 4 mm). In 13 cases, micronodules developed into lung cancer; the rate was thus 0.11% (13 of 11,326) of all subjects with micronodules.

However, the implications of small nodules in oncology patients are much more serious; it is not always practical to wait for a long time. Khokhar et al.¹¹ reported that 42% of pulmonary nodules were malignant among patients with prior extrapulmonary cancer histories. Hanamiya et al.¹² evaluated 308 patients with extrapulmonary carcinomas or sarcomas. At least one non-calcified pulmonary nodule was detected in 75% (233/308); 7% of all small nodules (< 5 mm) were malignant, as were 4% of nodules of 5–10 mm and 15% of those > 10 mm. In the present study, 35 of 42 (83%) resected suspected nDTs were MPLCs. Of 125 small nodules that were followed-up, 29 (23.2%) grew. Partially solid and solid nodules predicted nodule growth. Clinically suspicious MPLCs with small nDTs should undergo limited resection at the time of DT removal if the possible nDTs are ipsilateral to the DT and are part-solid or solid.

Resection of small possible nDTs raises the concern of overdiagnosis; such nodules may have not caused any clinical problems if not resected. In fact, the extent of overdiagnosis on lung cancer screening has been grossly exaggerated. Patz et al.¹³ reported that over 18% all lung cancers detected by low-dose (LD) CT during the NLST were overdiagnoses. However, this is likely an overestimate because of the potential lead-time bias associated with the LD CT arm. After extended follow up of NLST, the median follow-up times were 11.3 years for cancer incidence and 12.3 years for mortality. The lung cancer incidence in the LD CT arm was the same as that in the chest X-ray arm; the overdiagnosis rate was 3.1%¹⁴. Some overdiagnosis is inevitable when dealing with small nDTs. Resection of small suspicious nDTs avoids a second operation and the risk of advanced disease, at a cost of a small overdiagnosis rate.

Our work has several limitations. First, it was retrospective in nature; some recording bias may be inevitable. The criteria used to select small nodules for resection may differ among surgical teams. The sample size was relatively small and the risk of nodule growth may have been underestimated. The follow-up period may have been too short to detect progression of slow-growing cancers, particularly GGNs. However, we are the first to describe a relatively high incidence of MPLCs with small nDTs, no operative mortality, and predictors of interval growth.

MPLCs with small nDTs are rather common. Such nDTs can grow or trigger advanced disease. Contemporaneous resection of clinically suspicious MPLCs and small nDTs is recommended if the nDTs are located ipsilateral to the DTs, and when the nodules are part-solid or solid.

MPLC, Multiple primary lung cancer; DT, Dominant tumor; nDT, Non-dominant tumor; M, Male; F, Female; SN, Solid nodule; PSN, Part-solid nodule; pGGN, Pure ground glass nodule; AIS, Adenocarcinoma in situ; MIA, Minimally invasive adenocarcinoma; Ad, Adenocarcinoma; M, Metastasis

Ethics approval and consent to participate: The study was approved by the Institutional Review Board and the Ethics Committee of the Fifth Hospital of Sun Yat-sen University and written informed consent was obtained from all patients.

Consent for publication: Written informed consent was obtained from the patients for publication of this article.

Availability of data and materials: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Competing interests: All authors declare no competing interests.

Funding: This research had been partly supported by Science and Technology Planning Project for health care of Zhuhai City (No: ZH22036201210065PWC)

Authors' contributions: HC and WL: drafting and revising manuscript. XL and HZ: acquisition. XW and XW: analysis. YL and XL: interpretation of data. QC: design and approval. All authors read and approved the final manuscript.

Acknowledgements: Not applicable

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You are reading this latest preprint version

Small nodules (≤ 6 mm in diameter) of multiple primary lung cancers: Prevalence and management

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Version 1

Abstract

Figures

Introduction

Material And Methods

Statistical analysis

Results

Factors Associated With Mplcs

The Prevalence Of Small Pulmonary Nodules

Development Of Lung Cancer From Small Pulmonary Nodules

Factors Associated With Pulmonary Nodule Growth

Discussion

Conclusion

Abbreviations

Declarations

References

Supplementary Files

Status:

Version 1