An extremely rare case of congenital pulmonary airway malformation (CPAM) and atypical adenomatous hyperplasia (AAH) with EGFR mutation in a five-year-old girl

Abstract

Background

Congenital pulmonary airway malformation (CPAM) is the most common congenital lung disorder. Atypical adenomatous hyperplasia (AAH) is a recognized precursor of lung adenocarcinoma. The co-occurrence of CPAM and AAH is exceedingly rare in pediatric patients.

Case presentation

We present a case of a five-year-old girl who had multiple cystic lesions in the left upper lobe and successfully underwent video-assisted thoracoscopic surgery (VATS). Histologically, the cystic lesions exhibited the typical characteristics of CPAM type 1, and an area of AAH measuring approximately 2 mm was incidentally identified. Next-generation sequencing (NGS) identified the EGFR exon 20 insertion (ex20ins) mutation. The patient remained well 13 months after resection and did not require additional treatment.

Conclusions

We report an extremely rare case of CPAM and AAH with EGFR mutation in a child. The oncogenic driver mutation EGFR may play a potential role in early lung adenocarcinogenesis in pediatric patients. Further studies with a larger number of cases and longer follow-up are required.

Introduction

Congenital pulmonary airway malformation (CPAM), formerly known as congenital cystic adenomatoid malformation (CCAM), is a developmental disorder of the lungs characterized by the abnormal growth of the pulmonary airways and alveoli. It is the most common cystic lung disease among infants and children [1, 2]. CPAMs are classified by the Stocker classification (types 0–4), based on macroscopic appearance and histopathological features [3], and CPAM type 1 is the most common type [4]. Mucinous cell clusters (MCCs) or atypical goblet cell hyperplasia (AGCH) in CPAM, which frequently harbor KRAS mutations [4–11], have been recognized as premalignant precursors for lung mucinous adenocarcinoma [4, 5, 12–14].

Atypical adenomatous hyperplasia (AAH) is defined by the atypical proliferation of alveolar epithelial cells (typically ≤5 mm), which grow along the surface of the preserved alveolar walls without invasion [15]. AAH has been reported to harbor driver mutations [16–18]. KRAS and EGFR mutations were identified in approximately 33% and 25% of 40 AAH cases, respectively [18], and BRAF mutations were detected in 23% (5/22) of the AAH cases [16]. AAH harbors some molecular alterations that have been observed in lung adenocarcinoma, supporting the concept that AAH is a precursor lesion of lung adenocarcinoma and an early event in lung adenocarcinogenesis.

The co-occurrence of CPAM and AAH is extremely rare in pediatric patients. Herein, we comprehensively characterize the clinicopathological features of a rare case of CPAM and AAH with EGFR mutation in a five-year-old girl.

Case presentation

A five-year-old girl was admitted to a local hospital with a diagnosis of pneumonia. She had been suffering from recurrent coughing and expectoration, accompanied by nasal congestion and purulent rhinorrhea. A chest Computed Tomography (CT) scan conducted one month ago revealed a cystic lesion in the left upper lobe. At our hospital, a subsequent chest CT scan demonstrated multiple cystic lesions in the left upper lobe (A, arrows). Subsequently, the patient successfully underwent video-assisted thoracoscopic surgery (VATS) of the left upper lobe, and there were no postoperative complications.

Histopathological examination of the resected cystic specimen exhibited the typical characteristics of CPAM type 1 ((Fig. 1B). Adjacent to the CPAM cyst lesion, there was a focal area (approximately 2 mm) of atypical hyperplasia of alveolar epithelium (Fig. 1B, circle), along with the mild-to-moderate atypical proliferation of type II pneumocytes and/or club cells lining the alveolar walls, without invasion at a high-power view (Fig. 1C). The immunohistochemical staining results (Fig. 1) demonstrated positive staining for CK7 and TTF-1, while CK5/6 staining indicated the absence of a basal cell layer. This area was diagnosed as AAH.

Fig. 1.

Radiological, histopathological and immunohistochemical characteristics. Chest CT revealed multiple cystic lesions in the left upper lobe (A, arrows). A low-power view of the resected lung specimen demonstrated congenital pulmonary airway malformation (CPAM) type 1 (B), and there was a focal area (approximately 2 mm) of atypical hyperplasia of the alveolar epithelium (B, circle), which along with the mild-to-moderate atypical proliferation of type II pneumocytes and/or club cells lining the alveolar walls, without invasion at a high-power view (C, magnification x200). Immunohistochemical staining demonstrated positive staining for CK7 and TTF-1, while CK5/6 staining did not detect the presence of a basal cell layer (Magnification x200)

Next-generation sequencing (NGS) was performed on DNA extracted from a formalin-fixed, paraffin-embedded (FFPE) block that contained both the AAH and the CPAM type 1 components. NGS analysis of eight lung cancer-related genes (EGFR, ALK, ERBB2, BRAF, MET, ROS1, RET and KRAS) was conducted by Guangzhou Burning Rock Biotech. The analysis identified EGFR exon 20 insertion (ex20ins) mutation, p.N771_P772insThr (c.2313_2314insACA). No pathogenic mutations were detected in the other seven genes.

Based on the morphological and immunohistochemical features as well as molecular analysis, the pathological diagnosis was CPAM and AAH. The patient remained well 13 months after resection and did not require additional treatment.

Discussion

In the present case, we report an extremely rare occurrence of CPAM type 1 and AAH in a 5-year-old girl. CPAM is the most common congenital lung disorder, with CPAM type 1 being the predominant subtype [5, 12–14, 19]. CPAM type 1 is known to harbor mucinous precursor lesions, such as mucinous cell clusters (MCCs) and atypical goblet cell hyperplasia (AGCH) [4, 5]. KRAS mutations predominantly occur in lung mucinous adenocarcinoma in pediatric patients with CPAM [5–11]. Chang, W. C. et al. [6] reported the largest series (n = 37) of mucinous adenocarcinomas arising in CPAM, all were mucinous types (21 in situ; 13 invasive), and three were mixed mucinous and non-mucinous adenocarcinoma, moreover, 90% (9/10) of the cases were tested for KRAS mutations. However, neither MCCs nor AGCH were observed in the present case. Given that the AAH and the CPAM type 1 components were adjacent, NGS analysis was conducted on these two lesions. No KRAS mutations were detected. Interestingly, NGS analysis identified EGFR ex20ins mutation. The absence of typical CPAM-associated precursor lesions, combined with the EGFR mutation, suggests that EGFR mutation probably represents an oncogenic event from the AAH component. This finding may indicate a distinct, non-mucinous adenocarcinogenic pathway driven by EGFR mutation in pediatric cases.

In the present case, AAH was an incidental microscopic finding adjacent to the cyst walls of the CPAM during the histological examination of resected specimens, AAH is characterized by the atypical proliferation of alveolar epithelial cells without MCCs or AGCH. The histopathological findings showed that the area of AAH was adjacent to the CPAM. The AAH may either originate from the CPAM or may represent the co-occurrence of two distinct lesions. Histologically, AAH needs to be distinguished from non-mucinous adenocarcinoma in situ (AIS) and reactive pneumocyte hyperplasia. AAH is a putative precursor of AIS. AAH typically measures less than 5 mm, while non-mucinous AIS usually measures larger than 5 mm. Reactive pneumocyte hyperplasia is secondary to parenchymal inflammation or fibrosis, where the alveolar lining cells are not the dominant feature and are more diffusely distributed. To date, no cases of pure non-mucinous lung adenocarcinoma with CPAM have been reported in the published literature.

Video-assisted thoracoscopic surgery (VATS) may be considered as the first choice in the surgical treatment of congenital lung malformations [20]. Thoracoscopic lobectomy for congenital cystic lung diseases in neonates was practicable, with good esthetic results in neonates and small infants [21]. AAH is typically undetectable, but larger AAH may appear as a small faint, ground-glass nodule without solid component on high-resolution chest CT (HRCT). AAH can be completely resected, and the disease-free survival rate of AAH is 100%. VATS may be a reliable option for early-stage pulmonary cancers in pediatric patients. Herein, we report a rare case of CPAM and AAH in a child who underwent successful VATS lobectomy and remained well 13 months post-resection without further treatment.

EGFR mutations, which are the common oncogenic driver mutations in non-small cell lung cancer (NSCLC), can guide targeted therapy and are closely linked to prognosis and treatment response, and are associated with lung adenocarcinoma, female gender, never-smoking, and Asian ethnicity [22]. EGFR exon 19 deletions and EGFR exon 21 L858R account for the vast majority, can benefit from EGFR tyrosine kinase inhibitors (TKIs). EGFR ex20ins are the third most common EGFR mutations, account for approximately 4% to 12% of EGFR mutations [23–25], relatively insensitive to first and second-generation EGFR TKIs, and may lead to a particularly poor prognosis. Riess et al. [23] analyzed 14,483 NSCLC cases and found EGFR ex20ins in 12% of EGFR mutations and 1.8% of all molecular alterations. Additionally, Chen et al. [26] revealed that patients with EGFR ex20ins were younger and more frequently diagnosed with stage IA disease. Righi, L. et. al [27] reported primary lung non-mucinous adenocarcinoma in three adolescent patients affected by bone sarcomas: AIS harbored the EGFR exon 19 deletion (p.E746_A750) and exon 20 insertion (p.D770 > GY); minimally invasive adenocarcinoma (MIA) had an EGFR exon 20 insertion/duplication (p.N771_H773DUP); invasive adenocarcinoma with metastatic lymph node had an EGFR exon 20 insertion/duplication (p.V767_A769DUP). Xu et al. [28] reported that somatic mutations were detected in 50% (9/18) of AAH cases, and the most frequently detected mutation was the EGFR mutation (4/9, 22.2%). In another cohort of 40 AAH cases, 25% (10/40) harbored EGFR mutations, and EGFR mutations are evenly distributed from AAH to invasive adenocarcinoma [18]. EGFR mutations in AAH with CPAM may represent an early oncogenic event in the present case. However, given the absence of invasive carcinoma and the limited follow-up, the risk of progression to adenocarcinoma remains speculative. Further studies with a larger number of cases and longer follow-up are needed.

Conclusion

The oncogenic driver mutation EGFR in AAH with CPAM may play a potential role in early adenocarcinogenesis in pediatric patients, and suggests the potential clinical significance of early intervention and long-term follow-up.

Abbreviations

CPAM

Congenital pulmonary airway malformation

AAH

Atypical adenomatous hyperplasia

VATS

Video-assisted thoracoscopic surgery

CT

Computed tomography

NGS

Next-generation sequencing

Authors' contributions

XL and PZ drafted the initial manuscript, and reviewed and revised the manuscript.; CZ and SY collected data, carried out the initial analyses. LJ and PZ conceptualized and designed the study, and critically reviewed the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding

This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0520000, 2024ZD0520004), and Qimingxing Research Fund for Young Talents of West China Hospital, Sichuan University (No.HXQMX0111).

Data availability

The original contributions of this study are included in the article. The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive for Human (GSA: HRA016763) in National Genomics Data Center, China National Center for Bioinformation.

Declarations

Ethics approval and consent to participate

The respective ethics committee of West China Hospital, Sichuan University, China (No.2020892) granted ethical approval for this retrospective study. The parents provided written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.