Targeted Intraoperative Molecular Imaging Detects Nonpalpable Lung Lesions During Surgery

A novel imaging technique using the folate analog tracer FA-S0456 was able to detect small, nonpalpable lung lesions otherwise undetectable by traditional means during resection surgery.

Clinical use of intraoperative molecular imaging (IMI) during oncologic surgeries may provide greater insight regarding nonpalpable tumors, occult disease, and positive tumor margins in patients with lung lesions, according to a study published in JAMA Surgery.

In 40 patients examined, margins detected by IMI were almost identical to those found on final pathology (coefficient of determination, R2= 0.9593). In addition, the method was able to identify 2 margins in nonpalpable tumors that were considered clinically unacceptable with a high probability of recurrence.

“This trial demonstrates that IMI can improve the surgical management of patients with nonpalpable pulmonary lesions by identifying occult tumors and cancer-positive margins that may have been missed by conventional surgical methods,” wrote the study investigators who were led by Gregory T. Kennedy, MD.

In this single-center study, patients with T1 lung lesions suspicious for malignant neoplasm with radiographic evidence of ground glass opacity with or without solid component were enrolled from May 2017 through June 2020. Six to 24 hours prior to surgery, patients were administered the folate analog tracer FA-S0456 intravenously at 0.025 mg/kg. Following surgical removal of tissue that was identified by thoracoscopic visualization and finger palpation, specimens were examined ex vivo by IMI for margins less than 0.5 cm needing additional parenchyma removal.

Nonpalpable lesions (n = 18) were smaller than palpable lesions (n = 22; 1.41 cm vs 1.6 cm, respectively) and were deeper from the pleural surface (0.57 vs 0.32), but not to a statistically significant degree.

Conventional surgical techniques localized 22 tumors (55%) versus IMI at 36 lesions (90%). Palpable lesions were fluorescent in vivo at a higher rate than nonpalpable lesions (95.4% vs 83.3%, respectively). Three nonpalpable lesions that were not localized for resection required either a generous wedge resection in 1 case or formal lobectomy in 2.

Thirty-five out of 40 lesions were palpable by back-table analysis using traditional means versus 39 of 40 by IMI. One lesion undetectable by either method required repeated sectioning for identification, revealing a 2.5-cm deep adenocarcinoma.

As lesion depth increased the mean fluorescence intensity (MFI) decreased, with surface lesions having greater MFI versus lesions 1 cm or deeper in vivo (P = .003) and ex vivo (P = .02). Signal-to-background fluorescence ratios, defined as the MFI of the lesion over the MFI of the background, were not significantly different for lesions stratified by palpability.

Fifteen of the 40 tumor lesions were able to be localized by IMI alone with patients undergoing minimally invasive wedge resection, sparing the need for open-chest surgery, segmentectomy, or lobectomy.

The investigators noted that IMI provided unique benefits for 2 patients whose tumors were not palpable but had detectable margins by IMI, allowing for real-time assessment and further re-resection.

Patient characteristics revealed a majority female cohort (65%) with a median age of 66.5 years (interquartile range [IQR], 62-72). Most patients were former smokers (75%) with a 28.6 mean pack-year history. Mean lesion size was 1.52 cm (IQR, 1.10-1.60) with a mean depth from the pleural surface of 0.43 (IQR, 0-0.625). Invasive carcinomas accounted for most lesions (67.5%) with fewer tumors having adenocarcinoma in situ (15%), squamous cell carcinoma (5%), small cell (5%), and benign (7.5%) histology.

The investigators noted that optical imaging represents a safe and accurate method for localization and margin assessment of solid tumors in general, with these results showing its potential for use in nonpalpable tumors. Of note, roughly 40% of patients with nonpalpable tumors herein had clinical management altered in response to findings by IMI.

“IMI localized tumors or quantified margins in lesions that were indistinguishable from normal lung parenchyma by visual inspection or palpation,” wrote the investigators. “IMI facilitated removal of the lesion by a small wedge resection, rather than a lobectomy, which would have involved resection of a large amount of normal lung parenchyma in patients who often have compromised baseline pulmonary function.”

Limitations of the study include its exploratory, nonrandomized design and small sample size. For IMI to be used in a broad range of tumor types, additional target tracers will need to be developed as FA-S0456 specifically targets only those malignant cells that overexpress folate receptor-a.


Kennedy GT, Azari FS, Bernstein E, et al. targeted intraoperative molecular imaging for localizing nonpalpable tumors and quantifying resection margin distances. JAMA Surg. Published August 25, 2021. doi:10.1001/jamasurg.2021.3757