Management of baseline and new sub-solid nodules in CT lung cancer screening

KEYWORDS:

• Computed tomography
• lung cancer screening
• new nodule
• pulmonary nodule management
• subsolid nodule

1. Introduction

While reading thoracic CT examinations, three different subtypes of pulmonary nodules are differentiated based on the nodule’s density. Until now, most existing evidence concentrated on solid lung nodules. However, in recent years gradually more studies are published focusing on subsolid nodules including pure ground-glass (nonsolid) nodules (GGNs) and part-solid nodules. A GGN is defined as a circumscribed area of increased pulmonary attenuation with preservation of the bronchial and vascular margins. When part of the ground-glass opacity completely obscures the parenchyma, the nodule is defined as part solid.

In baseline rounds of CT lung cancer screening, part-solid nodules comprise a higher risk of malignancy than do solid nodules [1]. Management of subsolid nodules in lung cancer screening trials and incidentally detected subsolid nodules in clinical practice is based on nodule size and growth [2]. In most guidelines, no differentiation is made between subsolid nodules already present at a previous CT examination and new subsolid nodules. Recently, it was shown that new solid nodules detected in CT lung cancer screening have a significantly higher lung cancer probability at smaller nodule size compared to baseline solid nodules and need lower size cutoffs [3]. Some guidelines, such as the British Thoracic Society (BTS) guideline and Lung-RADS, have incorporated the higher malignancy risk in solid new nodules [4,5]. However, the question remains whether new subsolid nodules should be followed more aggressively as well.

2. Subsolid nodules detected at baseline and incident lung cancer screening

Several lung cancer screening trials have reported the prevalence of subsolid nodules.

In a large prospective cohort, the International Early Lung Cancer Action Program (I-ELCAP), it was found that at least one nonsolid nodule was detected in 4.2% of participants at baseline, and 5.0% had at least one part-solid nodule at baseline [6]. As far as we know, only I-ELCAP published separate reports on the prevalence of new GGNs and part-solid nodules.

A new GGN was detected in 0.7% (485/64,677) annual repeat screenings. Eleven new GGNs nodules were diagnosed as adenocarcinoma, all stage IA. In both baseline and new GGNs, lung cancer was diagnosed only in growing GGNs, and always was stage I, regardless of nodule size. Seventy-eight months (median) after lung cancer diagnosis, none of the patients had died from lung cancer. It was concluded that screen-detected GGNs either present at baseline or new at incidence screening can be followed safely with annual low-dose computed tomography (LDCT) [6].

In 0.8% (541/64,667) annual repeat screenings a new part-solid nodule was identified in the I-ELCAP [7]. Of these new part-solid nodules, 69.7% resolved or decreased in size at follow-up. Twenty-eight (5.2%) of the 541 new part-solid nodules were proven to be lung cancer, all stage IA adenocarcinoma. All lung cancers were retrospectively visible as GGNs in earlier screening rounds. The lung cancer survival rate of participants with a baseline or new part-solid nodule was 100% (median follow-up after baseline 89 months).

In the largest randomized-controlled lung cancer screening trial worldwide, the National Lung Screening Trial (NLST), at least one subsolid nodule (GGN and part solid not further specified) at baseline or follow-up screening (1 and 2 years after baseline) was detected in 9.4% of participants [8]. In that study, no distinction was made between baseline subsolid nodules and newly detected in incident screening rounds. A retrospective analysis on lung cancers detected in NLST participants with a positive baseline screen result showed an odds-ratio of 0.24 for lung cancer death for cancers arising from GGNs as compared to solid nodules [9].

The percentage subsolid nodules as reported by the NLST is much higher than the subsolid nodule prevalence reported in the largest European lung cancer screening study, the Dutch-Belgian randomized controlled lung cancer screening (acronym: NELSON) trial, in which 3.3% of participants were diagnosed with a subsolid nodule (234 participants) during either baseline screening or one of the three incidence screening rounds (1, 3, and 5.5 years after baseline) [10]. Lung cancer in all resected subsolid nodules has been diagnosed in stage I, apart from one invasive adenocarcinoma (stage IV, delayed resection because of a competing malignancy). During follow-up, none of the nonresected subsolid nodules progressed into a clinical relevant malignancy. Therefore, it was concluded that even bi-annual follow-up instead of immediate resection may be a safe option in the management of subsolid nodules. Also in this study, no differentiation was made between baseline and new subsolid nodules or between GGNs and part-solid nodules [10].

In the Multicentric Italian Lung Detection (MILD) trial, 56/1866 participants (3.0%) had 76 subsolid nodules at baseline (48 GGNs, 28 part solid) [11]. A quarter of the subsolid nodules resolved spontaneously and the majority of nodules remained stable. Five percent of the subsolid nodules were diagnosed as early stage adenocarcinoma after an active surveillance approach. To the best of our knowledge, data on new subsolid nodules detected in incidence screening rounds of the MILD trial have not been published.

2.1. Guidelines on subsolid nodules detected in daily clinical practice and in screening

Subsolid nodules not only are a regular finding in lung cancer screening participants, they are often incidentally detected in asymptomatic patients as well. Two commonly used guidelines on the management of incidentally detected subsolid nodules come from the Fleischner Society and the BTS [4,12]. Lung-RADS is used for the management of screen-detected subsolid nodules [5]. Issues in the classification of subsolid nodules comprise accurate differentiation between solid, part solid, and GGNs by the radiologist [13], and subsolid nodule size and growth determination. In contrast to measurements of solid nodules, software for semi-automated volume determination often fails measuring subsolid nodule’s size. Therefore, subsolid nodule’s size and growth determination are usually based on diameter measurements.

2.1.1. Fleischner Society

For clinical practice, the Fleischner Society recommends that solitary GGNs <6 mm do not generally require routine follow-up; however, for GGNs close to 6 mm follow-up at 2 and 4 years may be reasonable when considering nodule morphology or other risk-factors [12]. GGNs ≥6 mm should receive a follow-up within 6 to 12 months to confirm persistence and repeat scans subsequently every 2 years until 5 years follow-up. For part-solid nodules, the Fleischner Society recommends that nodules <6 mm do not necessitate routine follow-up, while nodules ≥6 mm should receive a follow-up within 3–6 months and annual LDCTs for 5 years. Persistent part-solid nodules with a solid component ≥6 mm are considered highly suspicious for lung cancer. In case of multiple subsolid nodules, management is recommended to be based on the most suspicious nodule, and in case of multiple nodules <6 mm a follow-up LDCT within 3–6 months is advised.

2.1.2. BTS guidelines

The current BTS guidelines do not distinguish GGNs and part-solid nodules [4]. Generally, subsolid nodules <5 mm are not recommended to receive routine follow-up. For subsolid nodules ≥5 mm it is recommended to perform a repeat LDCT within 3 months if no previous imaging exists. If unchanged, the Brock risk prediction tool is recommended to estimate the risk of malignancy [14]. Subsolid nodules with a low lung cancer risk (<10%) should receive follow-up LDCTs at 1, 2, and 4 years, while higher lung cancer risk may require diagnostic work-up. In case of growth or changes in morphology an aggressive diagnostic work-up is advised.

2.1.3. Lung-RADS

In Lung-RADS, management of screen-detected baseline and new GGNs/new part-solid nodules is distinguished [5]. Short-term follow-up LDCTs (3 or 6 months, lung cancer probability 1–15%) is advised for all GGNs with diameter >20 mm and part-solid nodules with diameter >6 mm (part-solid and nonsolid component combined) or any new part-solid nodule with solid component <4 mm at incident screening. More stringent follow-up using chest CT with or without contrast, PET-CT (when there is a ≥ 8mm solid component) or tissue sampling is recommended in case of a new or growing part-solid nodule with solid component ≥4 mm or a baseline part-solid nodule with solid component ≥8 mm.

3. Conclusion

Only limited information is available on the prevalence and lung cancer probability of subsolid nodules newly detected after baseline lung cancer screening. It remains unknown whether these results are comparable to new subsolid nodules in a European population, in which prevalence of subsolid nodules seems significantly lower. Nevertheless, current available evidence shows that malignant nonsolid nodules in baseline and new nodules typically have an indolent course and can be generally managed with follow-up by 1 or 2 years to identify nodule growth or increase in attenuation as a sign suspicious for invasive carcinoma, rather than immediate resection.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.