The fetal adenocarcinoma of the lung (FLAC), a rare subtype of pulmonary adenocarcinoma, was initially recognized by Kradin in 1982. The lesion earns its denomination due to morphologic resemblance to fetal lung during development [1]. It was later classified as a variant of invasive adenocarcinoma in the updated international multidisciplinary classification established in 2011 by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS). This classification formally subdivided FLAC into two subtypes: low-grade fetal adenocarcinoma (L-FLAC) and high-grade fetal adenocarcinoma (H-FLAC) [2]. The 2015 World Health Organization (WHO) classification of lung tumors recognizes FLAC as an independent subtype of lung adenocarcinoma [3].

As a rare disease, the epidemiology of FLAC remains poorly understood. According to both domestic and international data, FLAC accounts for approximately 0.1%–0.5% of all lung tumors [4, 5]. Due to its rarity and the limited clinical recognition of this entity, the risk of clinical misdiagnosis is notably high.

This study systematically analyzed 10 cases of pulmonary fetal adenocarcinoma, summarizing their clinicopathological features along with key diagnostic and differential diagnostic considerations. This study aims to enhance clinicians’ understanding of this disease and reduce the likelihood of clinical misdiagnosis.

FLAC is a relatively rare subtype of lung adenocarcinoma, accounting for only 0.1%–0.5% of all lung tumors [4]. In domestic reports, the prevalence of FLAC ranges from approximately 0.32%–0.54% [7, 8]. The tumor derives its name from its striking histological similarity to fetal lung epithelium at the embryonic stage (8–16 weeks of gestation). Initially described by Kradin in 1982, FLAC was later classified as a distinct subtype of invasive lung adenocarcinoma in the IASLC/ATS/ERS classification of 2011 [2]. The 2015 World Health Organization (WHO) classification of lung tumors recognizes FLAC as an independent subtype of lung adenocarcinoma [3].

FLAC can arise at any age. Literature indicates that L-FLAC is more common in younger patients, while H-FLAC predominantly affects elderly smokers [7, 9]. Among the 10 patients in this study, the 6 cases of L-FLAC exhibited a male-to-female ratio of 1:1, a mean age of 57.5 years, and 2 patients had a history of smoking. Early-stage disease (stage I) constituted 83.3% (5/6) of L-FLAC cases. The 4 H-FLAC cases also had a male-to-female ratio of 1:1, a mean age of 67 years, with 2 patients having a smoking history. Stage IIB disease accounted for 75% (3/4) of H-FLAC cases.

FLAC typically presents with non-specific clinical manifestations. In this study, only 4 of the 10 patients showed symptoms such as cough and sputum production, likely attributed to tumor location and growth rate [10, 11]. Imaging findings generally reveal a peripheral solid pulmonary mass, which may exhibit lobulation, spiculation, air bronchogram signs, bronchial truncation, and pleural traction in some cases, with contrast enhancement noted on enhanced scans [12]. However, these features are non-specific, complicating the distinction of FLAC from other lung tumors.

The diagnosis and grading of FLAC rely on pathological evaluation. Its core histological feature is the formation of glandular structures that resemble fetal lung airway epithelium, composed of non-ciliated columnar cells arranged in a pseudostratified manner, with cytoplasm rich in glycogen. Significant differences in cellular morphology, necrosis extent, and characteristic structures between L-FLAC and H-FLAC provide critical clues for grading diagnosis [4, 8]. Due to the heterogeneity of lung adenocarcinoma, the fifth edition of the WHO Classification of Thoracic Tumors specifies that a diagnosis of H-FLAC requires at least 50% of the tumor tissue to exhibit H-FLAC morphology to avoid misdiagnosing conventional adenocarcinoma with only minor fetal-like structures as H-FLAC [6]. All H-FLAC cases in our series met this WHO diagnostic criterion, with high-grade fetal components exceeding 50% of the lesion.

The immunophenotype of H-FLAC is characterized by positivity for TTF-1 and Napsin A, frequent overexpression or a null pattern of p53, and predominantly membranous β-catenin expression. Together with its molecular features, this suggests that H-FLAC should be regarded as a high-grade special subtype within the conventional lung adenocarcinoma spectrum rather than an entirely independent entity. This classification is further supported by the observation that H-FLAC often contains conventional adenocarcinoma components, such as lepidic, micropapillary, or solid patterns [13]. In contrast, L-FLAC exhibits a higher detection rate of CTNNB1 gene mutations, particularly activating mutations in exon 3, which are recognized as a characteristic molecular alteration of this subtype [4, 14]. Such mutations lead to impaired degradation of β-catenin, resulting in cytoplasmic accumulation and nuclear translocation, which produces a distinct nuclear/cytoplasmic immunohistochemical expression pattern. This also aberrantly activates the Wnt/β-catenin signaling pathway, driving the formation of characteristic morphological features of L-FLAC, such as morules [14]. As noted in previous reports, the nuclear/cytoplasmic expression pattern of β-catenin, combined with CTNNB1 mutation testing, aids in distinguishing L-FLAC, H-FLAC, and morphologically similar conventional adenocarcinomas. In our study, among the six L-FLAC cases, five showed nuclear and/or cytoplasmic β-catenin positivity, and one exhibited membranous staining with focal nuclear positivity. By contrast, all four H-FLAC cases demonstrated membranous β-catenin positivity. Although gene sequencing was not performed in this study, the β-catenin immunohistochemical findings align with the subtype-specific staining patterns previously described for L-FLAC and H-FLAC, further corroborating the documented differences in molecular pathways between these two tumor subtypes.

Concerning neuroendocrine differentiation, earlier studies indicated that approximately 80% of H-FLAC and a subset of L-FLAC express neuroendocrine markers [8, 15]. However, the results of the present study deviate from this observation, as all H-FLAC cases were negative for neuroendocrine markers. Conversely, focal positivity for CgA and Syn was noted in a subset of L-FLAC cases, consistent with findings reported by Bai et al. [16]. Regarding other markers, literature suggests that H-FLAC may express AFP, Glypican-3, and SALL4 [3, 17]. However, no AFP expression was detected in any of the cases within this group, and this negative finding may be attributed to the small sample size and tumor heterogeneity. SALL4 demonstrated focal or partial positivity in a subset of both L-FLAC and H-FLAC, indicating expression heterogeneity. A comprehensive diagnostic immunohistochemical panel for FLAC should include core markers such as TTF-1, β-catenin, p53, neuroendocrine markers (Syn, CgA), and oncofetal markers (AFP, SALL4, Glypican-3). This approach simultaneously facilitates diagnostic differentiation between L-FLAC and H-FLAC subtypes, identifies therapeutically relevant targets, and provides prognostic information. Additionally, future large-sample studies integrating multi-omics approaches are necessary to enhance the refinement of diagnostic criteria, molecular subtyping, and the relationship of FLAC with the conventional adenocarcinoma lineage.

Fetal adenocarcinoma of the lung (FLAC) harbors a molecular landscape distinct from that of classic-type lung adenocarcinoma. EGFR and KRAS gene mutations are well-established driver events in conventional lung adenocarcinoma but are relatively rare in L-FLAC [12]. Ma et al. analyzed the correlation between driver gene alterations and pathological subtypes in 3,012 primary lung adenocarcinomas, revealing that EGFR mutations predominate in invasive non-mucinous adenocarcinoma, while KRAS mutations are the primary alteration in invasive mucinous adenocarcinoma [18]. Li Sun et al. found that TP53 was the predominant mutated gene in all FLAC patients as well as patients with H-FLAC, whereas CTNNB1 mutations were most frequent in L-FLAC [19]. Some studies have detected KRAS and EGFR mutations in H-FLAC [5, 20], indicating potential molecular genetic heterogeneity among different grades of FLAC. In this study, molecular testing was performed on 5 patients (3 with L-FLAC and 2 with H-FLAC). Driver gene mutations were detected in two patients, both of whom had H-FLAC. One pure H-FLAC case exhibited an EGFR exon 19 deletion. This relatively rare molecular alteration aligns with prior case reports and supports genomic heterogeneity among H-FLACs. The other case, consisting of 60% H-FLAC and 40% conventional adenocarcinoma, harbored a KRAS G12C mutation. Since DNA was extracted from the bulk FFPE tissue block without microdissection to separately enrich the two histological components, we could not determine whether the KRAS G12C mutation arose from the high-grade fetal adenocarcinoma compartment or the classic-type lung adenocarcinoma compartment, and both possibilities remain. This represents a limitation of the present study. Future investigations may utilize microdissection to isolate distinct tumor components and clarify the clonal origin of such mutations. Notably, the EGFR and KRAS mutations identified herein may serve as potential therapeutic targets. Nevertheless, treatment response was not assessed in this cohort, and additional studies with larger patient cohorts are warranted for further validation of their clinical relevance.

Due to the absence of specific clinical manifestations and imaging findings, FLAC must be differentiated from several other entities both clinically and pathologically, including pulmonary adenosquamous carcinoma, acinar adenocarcinoma, pulmonary blastoma, and metastatic endometrial adenocarcinoma of the lung. (1) Conventional adenocarcinoma: Tumor cells may exhibit lepidic, acinar, or papillary growth patterns, lacking embryonic glandular epithelium and morule-like structures. (2) Pulmonary adenosquamous carcinoma: Composed of both adenocarcinoma and squamous cell carcinoma, the squamous component demonstrates intercellular bridges, keratinization, or keratin pearls, while FLAC comprises only an adenocarcinoma component. (3) Pulmonary blastoma: This tumor consists of malignant primitive epithelium and malignant mesenchyme. The primitive epithelial component is arranged in tubular structures lined by simple cuboidal cells, with mesenchyme comprising immature mesenchymal cells. The primitive epithelial component is distributed within the mesenchymal tissue, contrasting with FLAC, where the stromal component is benign, aiding in differentiation. Immunophenotypically, the epithelial component in pulmonary blastoma is positive for CK and epithelial membrane antigen (EMA), whereas the mesenchymal component is positive for vimentin. (4) Metastatic endometrial adenocarcinoma of the lung: Such cases often present with corresponding gynecological symptoms and a history of endometrial carcinoma, with imaging possibly revealing uterine or ovarian masses. The immunophenotype typically exhibits positivity for ER, PR, and vimentin, while TTF-1, Napsin A, and SP-B are generally negative. In contrast, FLAC is frequently positive for TTF-1.

No specific treatment exists for FLAC, and complete surgical resection remains the first-line treatment, followed by adjuvant chemotherapy or radiotherapy. In this study, all patients underwent lobectomy or segmentectomy with lymph node dissection. Three patients received postoperative chemotherapy with pemetrexed plus platinum. The follow-up duration ranged from 4 to 93 months, with a mean of 34.5 months. Throughout this follow-up period, all patients remained alive and well, with no evidence of tumor recurrence or metastasis.

In summary, FLAC exhibits distinct clinicopathological, immunophenotypic, and molecular characteristics. Given its extremely low incidence, recognition and comprehensive understanding of this rare tumor remain insufficient, leading to frequent missed diagnoses and misdiagnoses in clinical practice. Therefore, enhancing clinical awareness of FLAC is essential to improve diagnostic accuracy.

Several limitations of the present study should be acknowledged. As a single-center retrospective investigation with a relatively small sample size and incomplete molecular profiling due to the rarity of FLAC, rigorous statistical analysis was restricted, which may limit the generalizability of our findings. Additionally, PD-L1 immunohistochemical staining was not performed in this cohort, as long-term preservation of FFPE specimens may compromise the reliability of staining results. Despite these shortcomings, our study provides valuable supplementary evidence for clarifying the differential diagnosis, clinical management, and prognostic features of both L-FLAC and H-FLAC. Future large-scale, multicenter prospective studies with comprehensive molecular and biomarker assessments are warranted to validate our findings and deepen the understanding of this rare pulmonary malignancy.