Fetal lung interstitial tumor (FLIT) is an exceptionally rare pediatric malignancy, first described by Dishop et al. [1] in 2010. FLIT is characterized by abnormal growths in the lungs, featuring immature air sacs surrounded by interstitial cells that resemble the fetal lung during the 20 to 24 weeks of gestation [2]. Among the most well-known perinatal tumors, such as pleuropulmonary blastoma (PPB), congenital peri-bronchial myofibroblastic tumor, inflammatory myofibroblastic tumor (IMT), and congenital or infantile fibrosarcoma, FLIT is a rare subclassification of lung tumors. It has recently been included in the International Classification of Diseases, 11th revision and the fifth edition of the World Health Organization classification of tumors [3,4]. The diagnosis of FLIT is still in the early stages of development. To date, only a few case studies have been published worldwide, and there have been no reports in Korea [5-7]. There has been a case report of FLIT expressing a novel alpha-2-macroglobulin (A2M)–anaplastic lymphoma kinase (ALK) fusion gene, which represents the only instance of molecular genetic analysis using next- generation sequencing (NGS) for FLIT thus far [8]. This study reports the first case of FLIT in Korea and aims to refine the diagnostic method for FLIT. It also seeks to improve the accuracy of prognostic assessments by examining ALK gene rearrangement through NGS.

An 18-month-old male child presented with symptoms of recurrent upper respiratory infections. He was delivered at 39+0 weeks of gestation via elective cesarean section, without any prenatal obstetric complications. A chest X-ray revealed a mass in the left lower lung zone (Fig. 1A). Subsequent chest computed tomography showed a 3.4-cm circumscribed, lobulated, enhancing mass in the left lower lobe, suggestive of a benign tumor such as an IMT (Fig. 1B–D). Positron emission tomography identified a mass with minimal hypermetabolism in the left lower lobe (maximum standardized uptake value of 1.1) (Fig. 1E). Percutaneous needle biopsy results were consistent with a benign papillary adenoma, leading to the decision for the child to undergo video-assisted left lower lobectomy. The chest drain, placed intraoperatively, was maintained until postoperative day 2. The patient was discharged on postoperative day 3 without any immediate postoperative complications.

Figure 1. Preoperative chest X-ray (A), coronal computed tomography (CT) angiography (B), axial CT angiography with the lung window, (C) and mediastinal window (D), showing a well-circumscribed solid mass with contrast enhancement in the left lower lobe. (E) Positron emission tomography reveals a minimally hypermetabolic lesion in the left lower lobe.

Upon macroscopic examination, a well-circumscribed, encapsulated white glistening mass measuring 3.3 cm in its largest diameter was observed (Fig. 2A). Microscopic analysis revealed an interstitial cell neoplasm characterized by a micropapillary pattern and evidence of capsular invasion (Fig. 2B). The neoplasm consisted of a dual-cell population, featuring bland-looking round to ovoid nuclei with clear cytoplasm, and was lined by type II pneumocytes (Fig. 2C). Immunohistochemical staining showed that the tumor was positive for vimentin and focally positive for smooth muscle actin and desmin (Fig. 2D–F). Periodic acid-Schiff (PAS) staining indicated the presence of cytoplasmic glycogen, which was subsequently confirmed by the elimination of the PAS stain with diastase digestion, verifying its glycogenic nature (Fig. 2G). The tumor also exhibited positivity for ALK, suggesting an ALK gene rearrangement (Fig. 3A). Further analysis using break-apart fluorescence in situ hybridization (FISH) demonstrated chromosomal rearrangement at the ALK locus 2p23 (Fig. 3B), and NGS confirmed a genomic breakpoint between exon 22 of A2M and exon 19 of ALK (Fig. 3C). Based on these histologic and molecular characteristics, the tumor was pathologically diagnosed as a FLIT.

Figure 2. Specimen of lobectomy and the histopathological features of fetal lung interstitial tumor. (A) The lobectomy specimen is a well-circumscribed, encapsulated, white, glistening tumor that is 3.3 cm in size. (B) A microscopic examination showing this encapsulated tumor with capsular invasion (arrow) and a micropapillary pattern (hematoxylin and eosin [H&E] stain, ×12.5) (C–E) The tumor contains a dual-cell population with vimentin-positive interstitial cells and epithelial membrane antigen (EMA)-positive pneumocytes lining the interstitium: (C) (H&E, ×400); (D) (Vimentin); (E) (EMA, ×100). (F) The tumor shows focal positivity for desmin (Desmin, ×160). (G) Periodic acid-Schiff (PAS) stain reveals cytoplasmic glycogen that is cleared by the D-PAS stain (inset) (PAS and D-PAS, ×400).

Figure 3. The identification of ALK gene rearrangement. (A) An immunohistochemical study revealed positivity for ALK (5A4) staining. (B) ALK fluorescence in situ hybridization using a break-apart ALK (2p23) probe; Green and red probe signals (green box) for detecting chromosomal rearrangement involving ALK. (C) A schematic diagram demonstrates the possible A2M::ALK fusion that was detected by RNA-based next-generation sequencing. ALK, anaplastic lymphoma receptor tyrosine kinase; A2M, a-2-macroglobulin.

This case report was approved by the Institutional Review Board (IRB) of Seoul National University Hospital (IRB no., H-2310-106-1478; IRB approval date: October 26, 2023), and the requirement for informed consent was waived.

FLIT is a rare respiratory neoplasm characterized by gestationally inappropriate fetal lung-like morphology with immature interstitial cells, initially described in 2010 by Dishop et al. [1]. The study examined 10 cases presenting as solid to microcystic masses resembling fetal lung tissue at 20–24 weeks of gestation and summarized their clinical and pathological features. The histological findings of FLIT, as described in this paper, include encapsulation by fibrous capsules and widened alveolar septa due to the proliferation of interstitial cells. The airspace size is variable, and the lining is composed of cubic cells. The pathology of our patient also featured encapsulation, sparse pneumocyte lining, and proliferative interstitial cells, which is consistent with the characteristics described [1]. A case report from India discussed a case of FLIT with a micropapillary pattern, suggesting that the proliferative patterns of FLIT may vary and are not limited to septal widening alone [9]. In 2014, a case report in Genes, Chromosomes, and Cancer documented the first instance of a FLIT case with ALK rearrangement and disruption at the 2p23 locus of the ALK gene, identified through FISH, and a fusion between A2M exon 22 and ALK exon 19, detected through sequencing. In our patient, FISH analysis revealed a similar pattern of ALK gene rearrangement with multiple signal segments, consistent with the previous case. Subsequent NGS confirmed the presence of the A2M-ALK fusion, a previously reported genetic anomaly, leading us to conclude that FLIT was the most reasonable diagnosis for our patient [8].

Since the clinical, pathologic, and immunohistochemical features of FLIT are primarily documented in case reports, established diagnoses and treatments remain underdeveloped. The lack of standardized diagnostic and treatment protocols necessitates careful consideration on a case-by-case basis. Moreover, there is a paucity of data to determine whether FLIT is a potential high-grade malignant neoplasm, similar to types II and III PPB, which require adjuvant chemotherapy and sometimes radiotherapy following surgical resection. In our patient, certain histological patterns, such as the micropapillary pattern and capsular invasion, which are typically associated with a poor prognosis generally, warrant vigilant follow-up, even in a case of FLIT. These findings should be approached with the possibility of malignancy in mind. It is notable that most reported cases of FLIT have shown a favorable prognosis, with no recurrences after resection. Although the initial prognosis has been promising since FLIT was first reported in 2010, diligent monitoring is essential to confirm the long-term outcomes for patients with FLIT [1]. If FLIT consistently exhibits a favorable prognosis, despite the presence of pathological features linked to poorer outcomes, achieving an accurate diagnosis is crucial to prevent unnecessary overtreatment. An accurate diagnosis of FLIT could mean that patients may benefit greatly from surgical resection alone.

In conclusion, FLIT is a rare bronchopulmonary tumor, and the prognosis is known to be good to date, but the clinical, radiological, histopathological, and genetic information is insufficient. An accurate differential diagnosis at the genetic level through NGS can guide appropriate management.

Author contributions

Conceptualization: ENK, CHK. Data curation: all authors. Formal analysis: all authors. Investigation: all authors. Methodology: all authors. Project administration: all authors. Resources: all authors. Software: all authors. Supervision: ENK, CHK. Validation: all authors. Writing–original draft: YJJ, SJ. Writing–review & editing: all authors. Approval of final manuscript: all authors.

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.