Rare Fetal Lung Adenocarcinoma Traced Across Ten Tumor Cases

A rare lung cancer that mimics the developing fetal lung has been dissected in detail by pathologists in China, who analyzed ten cases diagnosed at a single hospital over eight years. The tumor, known as fetal adenocarcinoma of the lung, or FLAC, accounts for roughly 0.1 to 0.5 percent of all lung tumors and takes its name from its striking resemblance to fetal lung tissue at the pseudoglandular stage of development, between eight and sixteen weeks of gestation. The new study, published in Pathology and Oncology Research, divided the ten tumors into six low-grade and four high-grade cases and mapped out their clinical, microscopic, immunohistochemical and molecular characteristics in what the authors describe as an effort to reduce the high risk of clinical misdiagnosis that comes with such a rare entity.

The patients were treated at Linyi People’s Hospital in Shandong province between January 2017 and December 2024. All diagnoses were confirmed by two associate chief physicians or specialists with higher professional titles, working from surgical specimens fixed in formalin, embedded in paraffin and stained with hematoxylin and eosin. The researchers applied the 2011 international multidisciplinary classification established by the IASLC, ATS and ERS, along with the WHO classification of thoracic tumors, to sort the cases into the two recognized grades. Because the sample was small and the study was descriptive, no inferential statistical tests were performed; the team summarized the data using frequencies, percentages, medians and ranges.

The clinical picture was strikingly quiet. Six of the ten patients, or 60 percent, had no symptoms at all, with their tumors discovered incidentally during routine health check-ups. The remaining four presented with cough, sputum production or blood-streaked sputum. In the low-grade group, three men and three women ranged in age from 33 to 66 years, with a median of 57.5 years, and their tumors measured from 0.9 to 6.0 centimeters across, with a mean of 2.7 centimeters. The high-grade group comprised two men and two women aged 51 to 76 years, median 67 years, with tumor diameters from 1.5 to 5.5 centimeters, mean 2.8 centimeters. Two patients in each group had a history of smoking, and early-stage disease was far more common among the low-grade cases, with stage I accounting for five of six, while stage IIB described three of the four high-grade tumors.

Imaging added little specificity. Every lesion was peripheral and appeared as a solitary solid nodule or mass-like soft tissue density with clear margins, sometimes showing lobulation and spiculation. Air bronchogram signs appeared within the lesions, and bronchial truncation was noted in a subset of cases. Contrast-enhanced CT scans revealed variable degrees of enhancement. The authors note that these features overlap with those of many other lung tumors, which complicates any attempt to distinguish FLAC from more common pulmonary malignancies on imaging alone.

Under the microscope, the tumors lived up to their name. The neoplastic cells resembled fetal lung airway epithelium, forming glandular, papillary, cribriform or sheet-like growth patterns. They were non-ciliated columnar cells arranged in a pseudostratified fashion, with clear or eosinophilic cytoplasm rich in glycogen and subnuclear or supranuclear vacuoles, resembling secretory endometrium. In the low-grade cases, nuclei were small, uniform and mildly atypical, with fine granular chromatin, inconspicuous nucleoli and rare mitotic figures; punctate necrosis and morule-like structures were present. The high-grade tumors told a different story: nuclei were enlarged, pleomorphic and markedly atypical, mitotic figures were readily identified, morules were typically absent, and multifocal necrosis was observed. All four high-grade cases met the WHO criterion requiring the high-grade fetal component to exceed 50 percent of the lesion; two were pure high-grade, while one contained 60 percent high-grade tumor with conventional adenocarcinoma patterns and another 70 percent with a different mix of conventional components.

Gross and pathological examination also revealed differences in aggressiveness. Among the four high-grade cases, three showed invasion of the visceral pleura and one patient had lymph node metastasis with spread through air spaces. In the six low-grade cases, two invaded the visceral pleura, and no lymph node or vascular invasion was noted. Maximum tumor diameter across all cases ranged from 0.9 to 6.0 centimeters, with a mean of 2.8 centimeters, and cut surfaces appeared gray-white or gray-yellow with a soft consistency, no capsule and relatively clear margins, growing adjacent to the visceral pleura. Gross necrosis was observed in one case.

Immunohistochemistry sharpened the divide between the two grades. TTF-1 was positive in all ten tumors. Napsin A was positive in three of three low-grade cases tested and in two of four high-grade cases. The most telling marker was beta-catenin: five of six low-grade tumors showed nuclear and/or cytoplasmic positivity, and the sixth showed membranous staining with focal nuclear positivity, whereas all four high-grade tumors displayed purely membranous expression. The authors explain that in low-grade FLAC, activating CTNNB1 mutations, particularly in exon 3, impair degradation of beta-catenin, causing cytoplasmic accumulation and nuclear translocation that aberrantly activates the Wnt/beta-catenin pathway and drives the formation of morules. Gene sequencing was not performed in this study, but the staining patterns align with subtype-specific patterns previously described. p53 staining showed a wild-type pattern in five of six low-grade cases and one of four high-grade cases, with overexpression in one case of each grade and a null pattern in the remaining two high-grade tumors. Neuroendocrine markers diverged from earlier literature: chromogranin A and synaptophysin were focally positive in one of five low-grade cases each but negative in all high-grade cases, whereas earlier studies had suggested that roughly 80 percent of high-grade FLAC express neuroendocrine markers. SALL4 and glypican-3 showed focal or partial positivity in subsets of both grades, while p40, CK5/6, AFP and PR were negative in the examined cases, and the Ki-67 proliferation index ranged from 5 to 50 percent in low-grade tumors and 20 to 80 percent in high-grade ones.

Molecular testing, performed on five cases using ARMS-PCR and next-generation sequencing, detected driver mutations in two patients, both with high-grade disease. One pure high-grade tumor harbored an EGFR exon 19 deletion, a relatively rare alteration in this subtype that the authors say aligns with prior case reports and supports genomic heterogeneity among high-grade FLACs. The other case, which consisted of 60 percent high-grade and 40 percent conventional adenocarcinoma, carried a KRAS G12C mutation. Because DNA was extracted from the bulk tissue block without microdissection, the team could not determine whether that mutation arose from the high-grade fetal component or the conventional adenocarcinoma component, and both possibilities remain open, a limitation the authors flag explicitly. The three low-grade cases tested showed no rearrangements or mutations in ALK, ROS1, BRAF or other genes. The authors suggest that the EGFR and KRAS mutations identified may serve as potential therapeutic targets, though treatment response was not assessed in this cohort.

Treatment followed a consistent path. All ten patients underwent lobectomy or segmentectomy along with lymph node dissection, and three received postoperative chemotherapy with pemetrexed plus platinum. Follow-up ranged from 4 to 93 months, with a mean of 34.5 months. During that period, all patients remained alive and well, with no evidence of recurrence or metastasis, although the authors caution that some patients had follow-up of only four to six months. The authors state that no specific treatment exists for FLAC and that complete surgical resection remains the first-line approach, followed by adjuvant chemotherapy or radiotherapy when given.

The study carries clear limitations. It was a single-center retrospective investigation with a small sample and incomplete molecular profiling, and PD-L1 immunohistochemical staining was not performed because long-term preservation of specimens may compromise staining reliability. The authors call for future large-scale, multicenter prospective studies with comprehensive molecular and biomarker assessments. They also outline the differential diagnoses that pathologists must consider, including conventional adenocarcinoma, pulmonary adenosquamous carcinoma, pulmonary blastoma and metastatic endometrial adenocarcinoma, each distinguished by specific morphological and immunophenotypic features. For a tumor so rare that recognition remains insufficient and misdiagnosis frequent, the ten-case series offers a detailed reference point: a distinctive morphology, a beta-catenin staining pattern that separates the grades, and a favorable short-term outlook after complete resection.

Subject of Research: Clinicopathological features of ten cases of fetal adenocarcinoma of the lung

Article Title: Analysis of clinical and pathological characteristics of 10 cases of fetal lung adenocarcinoma

Article References: Qiu, Y., Liu, W., Jin, Q., Sun, X., Wang, Y., & Zhang, N. (2026). Analysis of clinical and pathological characteristics of 10 cases of fetal lung adenocarcinoma. Pathology & Oncology Research, 32, Article 1612579. https://doi.org/10.3389/pore.2026.1612579

Image Credits: AI Generated

DOI: 10.3389/pore.2026.1612579

Keywords: fetal adenocarcinoma of the lung, lung adenocarcinoma, low-grade FLAC, high-grade FLAC, immunohistochemistry, beta-catenin, TTF-1, EGFR exon 19 deletion, KRAS G12C, surgical resection, retrospective study, rare lung tumors