Lung adenocarcinoma with rapid progression and fatal outcome through spread through air spaces: an autopsy case report

Abstract

Background

Spread through air spaces (STAS), defined as tumor cell dissemination into alveolar spaces, is a prognostic factor for early-stage non-small cell lung cancer and is typically identified in surgical specimens from patients with early-stage disease. We describe a rare autopsy case of rapid progression with STAS in a patient with recurrent lung adenocarcinoma.

Case Description

A 70-year-old man with stage IA lung adenocarcinoma previously treated with stereotactic radiotherapy and multiple comorbidities, including chronic heart failure due to the dilated phase of hypertrophic cardiomyopathy, ventricular tachycardia treated with amiodarone, and diabetes mellitus, was admitted because of progressive dyspnea and respiratory failure. Computed tomography (CT) revealed bilateral ground-glass opacities with increased consolidation at the site of prior irradiation. Given the elevated liver attenuation on CT, amiodarone-induced pulmonary toxicity and pulmonary edema were initially suspected, the drug was discontinued, and diuretic therapy was intensified. Despite additional corticosteroid therapy and antibiotics for concurrent bacteremia, respiratory failure progressed and the patient died on hospital day 37. Autopsy revealed papillary adenocarcinoma with extensive STAS, characterized by tumor cell clusters floating within the airspaces in a micropapillary pattern, spreading bilaterally. Mucin staining revealed no abundant mucin in the cytoplasm, and thyroid transcription factor-1 was positive. No evidence of amiodarone-induced pneumonitis or significant pulmonary edema was observed.

Conclusions

To our knowledge, this is the first reported autopsy case of recurrent advanced lung adenocarcinoma with fatal respiratory failure in which extensive STAS was considered a major contributing factor. Clinicians should consider STAS as a potential mechanism of rapid deterioration in patients with known lung adenocarcinoma.

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Key findings

• Autopsy revealed extensive spread through air spaces (STAS) in a patient with recurrent lung adenocarcinoma and progressive respiratory failure.

What is known and what is new?

• STAS is a prognostic factor for early-stage non-small cell lung cancer and is typically identified in surgical specimens from patients with early-stage disease.

• This is the first reported autopsy case of recurrent advanced lung adenocarcinoma with fatal respiratory failure and STAS.

What is the implication, and what should change now?

• Clinicians should consider STAS as a potential mechanism of rapid deterioration in patients with known lung adenocarcinoma.

Introduction

Spread through air spaces (STAS) is a pattern of lung cancer invasion introduced in 2015 in the World Health Organization classification of lung cancer (1). STAS is defined as the spread of lung cancer cells into the alveolar air space in the lung parenchyma adjacent to the main tumor (2,3). Reportedly, 20 % to 40 % of surgically resected lung cancers show this pathological finding (3,4). STAS has been suggested as a potential prognostic factor for lung cancer. According to the analysis of 4,061 pathologic stage I non-small cell lung cancer specimens, STAS was an independent risk factor for poor recurrence-free survival (hazard ratio, 1.62) and overall survival (hazard ratio, 1.70) (4). Its presence might be considered in surgical assessment. Several studies have shown that STAS-positive patients who undergo lobectomy have significantly lower recurrence rates and better overall survival than those treated with segmentectomy or wedge resection, suggesting that lobectomy provides better oncological control for STAS-positive tumors (5,6). Thus, the emerging concept of STAS as a pattern of tumor spread in lung cancer is gaining importance for treatment selection and prognosis prediction.

STAS diagnosis requires evaluation of tumor margins and is therefore typically confirmed using surgical resection specimens that allow assessment of the entire tumor. Consequently, the clinical course of advanced or terminal lung cancers with STAS remains unclear. We report a case of lung adenocarcinoma that progressed rapidly to respiratory failure, and an autopsy revealed STAS. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0957/rc).

Case presentation

A 70-year-old man with chronic heart failure due to hypertrophic cardiomyopathy and diabetes mellitus presented with dyspnea, malaise, and anorexia, and was admitted to Niigata University Medical & Dental Hospital. His medical history was notable for several conditions. Four years earlier, he had developed pulseless ventricular tachycardia, undergone cardiac resynchronization therapy defibrillator implantation, and been started on amiodarone. During the same period, he had been diagnosed with stage IA lung adenocarcinoma of the right lower lobe, treated with stereotactic radiotherapy, and with an intraductal papillary mucinous neoplasm. One year prior to admission, he had undergone surgical resection of appendiceal and transverse colon cancers, and 3 months prior, he had been hospitalized for congestive heart failure.

On admission, the vital signs were as follows: blood pressure, 73/51 mmHg; pulse rate, 89 beats/min; body temperature, 36.7 ℃; and peripheral oxygen saturation (SpO₂)_, 89 % (room air). Arterial blood gas analysis revealed a pH of 7.40, partial pressure of carbon dioxide in arterial blood (PaCO₂) of 31 mmHg, partial pressure of oxygen in arterial blood (PaO₂) of 61.0 mmHg, and bicarbonate (HCO₃⁻) of 20.5 mmol/L, suggesting respiratory failure. Serologically, the patient had elevated liver enzymes, Krebs von den Lungen-6 (3,256 U/mL), surfactant protein-D (230.8 ng/mL), and B-type natriuretic peptide (208.8 pg/mL). The patient showed optimal blood levels of amiodarone and its metabolite, monodesethylamiodarone. Collagen autoantibody test, interferon-gamma release test, and β-D-glucan test yielded negative results.

Compared with computed tomography (CT) obtained 1 year before admission (Figure 1A), CT performed on admission revealed ground-glass opacities with partial interlobular septal thickening, mainly in the bilateral lower lobes. An increase in consolidation was observed in the right lower lobe following stereotactic radiotherapy (Figure 1B,1C). CT also showed an increase in liver CT values associated with amiodarone use.

Figure 1.

Images during clinical course. (A) CT 1 year before admission. (B) CT on admission. (C) Chest radiography on admission. (D) Chest radiography on day 13. (E) Chest radiography on day 24. CT, computed tomography.

Given the increased liver attenuation, interlobular septal thickening on CT, and elevated Krebs von den Lungen-6 levels, amiodarone-induced pulmonary toxicity and edema were suspected. Amiodarone was discontinued, and diuretic therapy was intensified. On the sixth day of hospitalization, bronchoscopy was planned to rule out lung cancer recurrence or infectious lymphangitis, and the patient consented to the procedure; however, it was canceled because of worsening respiratory failure, and corticosteroid therapy was initiated. On day 13, chest radiography demonstrated worsening ground-glass opacities in the left lower lung field (Figure 1D), and ceftriaxone (2 g/d) was initiated. Thereafter, no evidence of improvement was observed, and chest radiography on day 24 showed enlarged bilateral opacities (Figure 1E). Respiratory failure progressed, and the patient died on day 37. A pathological autopsy was performed to determine the cause of death.

Autopsy findings: Histologically, tumor cell infiltration with a predominantly papillary growth pattern and a minor micropapillary component (approximately 5%) was identified in the right lobe, corresponding to the infiltrative shadows (irradiated field) on CT (Figure 2A). Tumors had spread along the alveolar walls in both lungs, and tumor cell clusters floating within the airspaces in a micropapillary pattern were observed (Figure 2B-2D). These findings were consistent with those of STAS. D2-40 immunostaining confirmed that the intra-alveolar tumor cell clusters were not located within lymphatic spaces, and the clusters showed smooth, well-defined contours rather than the ragged edges characteristic of tissue-handling artifact. These findings support genuine STAS rather than lymphatic invasion or a sectioning artifact. Periodic acid-Schiff (PAS), diastase-digested PAS, and Alcian blue staining revealed no abundant mucin in the cytoplasm (Figure 2E-2G), whereas thyroid transcription factor-1 staining was positive (Figure 2H). Based on these findings, papillary adenocarcinoma with STAS was diagnosed. There was no clear evidence of amiodarone-induced interstitial pneumonia, and pulmonary edema was minimal, suggesting a limited contribution of cardiac failure to respiratory failure. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Niigata University (No. E2026-0007). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Figure 2.

Histological findings at autopsy. (A-D) Hematoxylin-eosin staining. (A) Primary tumor. (B) Upper right lobe. (C) Middle right lobe. (D) Lower left lobe. (E-H) Special staining of the primary tumor in the right lower lobe. (E) PAS staining. (F) Diastase-digested PAS staining. (G) Alcian blue staining. (H) Immunohistochemical staining for thyroid transcription factor-1. PAS, periodic acid-Schiff.

Discussion

Transairway metastasis in lung cancer is most common in invasive mucinous adenocarcinomas, which tend to present as multiple or diffuse shadows. Furthermore, case reports of rapid disease progression in invasive mucinous lung adenocarcinomas have been sporadically observed. However, in this case, special staining did not reveal abundant intracytoplasmic mucin, and mucin-producing lung adenocarcinoma was considered unlikely.

The presence of STAS has been almost exclusively demonstrated by surgical pathologic specimens from early-stage lung cancer (3). Furthermore, cases presenting with infiltrative lesions are rare; to date, only one such case of early-stage lung cancer treated with surgery has been reported (7). To the best of our knowledge, this is the first reported case of recurrent advanced lung cancer in which rapid progression was observed during the terminal phase, and STAS was identified at autopsy.

A retrospective study showed that pneumonia, pleural effusion, exacerbation of lung cancer, and pulmonary edema were the most common causes of respiratory failure in patients with terminal cancer, in that order (8). In this case, the clinical presentation included not only progression of lung cancer but also a broad range of differential diagnoses, including heart failure, amiodarone-induced pulmonary toxicity, and acute respiratory distress syndrome. Bronchoscopy was planned for further evaluation, but worsening respiratory failure precluded the procedure, limiting further diagnostic assessment. Consequently, the cause of the progressive respiratory failure could not be determined during the patient’s lifetime.

Conclusions

In conclusion, this case highlights the potential clinical significance of STAS, beyond its established pathological role. Extensive STAS may have contributed to the patient’s progressive respiratory failure, although its precise causal role could not be definitively established. Progression with STAS should be considered as a possible contributing factor in patients with rapidly worsening lung cancer, and careful radiological and pathological evaluation is warranted.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Niigata University (No. E2026-0007). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.