Clonal relationship in a rare pulmonary mixed tumor: shared ALK fusion in atypical carcinoid and adenocarcinoma—a case report

Introduction

Mixed neuroendocrine and non-neuroendocrine neoplasm (MiNEN) of the lung represents a well-recognized subtype. In the latest 5th edition of the World Health Organization (WHO) classification of Thoracic Tumors, they are described primarily as combinations of non-small cell lung cancer (NSCLC) with high-grade neuroendocrine carcinomas, including small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC) (1). By contrast, the coexistence of NSCLC with typical or atypical carcinoid (TC/AC) tumors is not recognized in this classification (1). Although multiple hypotheses have been proposed regarding the cell of origin, recent molecular-pathologic studies most strongly support a monoclonal model arising from a common progenitor cell, followed by clonal divergence and lineage bifurcation (2,3). This view is substantiated by the detection of shared driver alterations—such as KRAS, RET, BRAF, STK11, and NF1—across both components within the same tumor, implying acquisition of early trunk mutations in a common ancestor and subsequent differentiation into morphologically distinct lineages (2,3). Within this context, we recently encountered a rare MiNEN composed of AC and adenocarcinoma. NSCLC combined with TC or AC has been reported in only a minimal number of case reports. Since the initial description in 1998, fewer than 20 such cases have been documented in the literature, and only limited information is available regarding the pathogenesis of this unusual combination (4). Accordingly, we sought to delineate the molecular alterations underlying this mixed phenotype. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1427/rc).

Case presentation

Clinicopathologic findings

A 62-year-old man had been diagnosed with prostatic acinar adenocarcinoma [cT3bN1M1, Gleason score 9 (4+5)] by needle biopsy at an outside hospital 7 months earlier. Immunohistochemical staining of the prostate biopsy demonstrated positivity for high-molecular-weight cytokeratin, alpha-methylacyl-CoA racemase (AMACR), p63, and prostate-specific antigen (PSA), supporting the diagnosis of prostatic adenocarcinoma. The patient had a smoking history of approximately one pack per day for 30 years and had quit smoking one year prior to diagnosis.

After referral to our institution, the patient underwent initial staging with 68Ga-Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and high-resolution chest computed tomography (HRCT). The 68Ga-PSMA PET/CT demonstrated PSMA-avid malignancy in the prostate gland with seminal vesicle involvement, bone metastases involving the left sixth rib, left ilium, and sacrum, as well as regional and distant lymph node metastases. Additional suspicious findings included a possible lung metastasis in the left lower lobe and a possible metastatic lesion in the left intercostal muscle. At the same time, HRCT revealed a ground-glass opacity (GGO) lesion in the right upper lobe that was not clearly visualized on PET/CT.

He subsequently received radiotherapy and hormonal therapy (Eligard and apalutamide) at our institution. The serum PSA level decreased from 58.6 ng/mL before treatment to 0.05 ng/mL approximately six months after initiation of therapy, indicating a good biochemical response. The right upper lobe GGO lesion was closely followed during prostate cancer-directed systemic therapy; however, despite biochemical response, the GGO lesion demonstrated interval growth on follow-up HRCT. Accordingly, the patient underwent an anatomical right apical segmentectomy with concurrent systematic lymph node dissection for definitive diagnosis (Figure 1A). The resected lymph node stations included stations 2R (upper paratracheal), 4R (lower paratracheal), 7 (subcarinal), and 10 (hilar).

Figure 1 Radiologic and gross findings of the pulmonary tumor. (A) HRCT scan showing a nodule with ill-defined margins in the apical segment of the right lung (arrow). (B) Gross appearance of the resected specimen. The cut surface reveals a 1.4 cm × 1.2 cm gray-white, firm mass with ill-defined margins blending into the surrounding lung parenchyma. HRCT, high-resolution computed tomography.

The resected specimen measured 10.5 cm × 6.5 cm × 3.3 cm in a single piece. Gross examination revealed a 1.4 cm × 1.2 cm, gray-white, firm mass in the lung parenchyma with ill-defined margins that blended into the surrounding tissue (Figure 1B). Histologically, the tumor was composed of two distinct components, consistent with a MiNEN (Figure 2). The neuroendocrine component, comprising approximately 60% of the tumor, exhibited features of AC, consisting predominantly of spindle-shaped cells arranged in nests with occasional glandular patterns. Cytologic atypia was mild, with a mitotic count of 6–7 per 2 mm² (Figure 2). Tiny foci of necrosis were present (Figure 2). The Ki-67 labeling index was approximately 35%. Immunohistochemically, this component showed diffuse positivity for neuroendocrine markers, including chromogranin A, synaptophysin, and INSM1, and was negative for napsin A and thyroid transcription factor-1 (TTF-1) (Figure 2). The non-neuroendocrine component, which comprised approximately 40% of the tumor, was a well-differentiated, invasive, non-mucinous adenocarcinoma characterized by acinar and lepidic growth patterns. The invasive adenocarcinoma component measured 5.6 mm in diameter. Immunohistochemically, this adenocarcinoma component was positive for napsin A and TTF-1 and negative for the neuroendocrine markers, including chromogranin A, synaptophysin, and INSM1, showing a staining profile opposite to that of the AC component (Figure 2). Immunohistochemical staining for PSA was performed on the entire lung tumor and was negative, and p53 immunohistochemical analysis revealed a wild-type expression pattern in both tumor components. Eighteen regional lymph nodes were examined, and no metastatic tumor was identified. Based on the above findings, we diagnosed the tumor as MiNEN (AC + invasive non-mucinous adenocarcinoma).

Figure 2 Histopathologic and immunohistochemical features of the MiNEN. (A) The non-neuroendocrine component is a well-differentiated invasive non-mucinous adenocarcinoma exhibiting acinar and lepidic growth patterns (H&E stain, original magnification: ×200). (B) The neuroendocrine component, consistent with atypical carcinoid, consists predominantly of spindle-shaped cells arranged in nests (H&E stain, original magnification: ×200). (C) High-power view highlighting mitotic figures (indicated by red circles) (H&E stain, original magnification: ×400). (D) High-power view showing focal punctate necrosis within the atypical carcinoid component (H&E stain, original magnification: ×200). Immunohistochemical staining for TTF-1 shows positivity in the adenocarcinoma component (E, original magnification: ×200) and negativity in the atypical carcinoid component (F, original magnification: ×200). Staining for INSM1 shows negativity in the adenocarcinoma component (G, original magnification: ×200) and positivity in the atypical carcinoid component (H, original magnification: ×200). Immunohistochemical staining for ALK demonstrates strong, diffuse cytoplasmic positivity in both the adenocarcinoma component (I, original magnification: ×200) and the atypical carcinoid component (J, original magnification: ×200). H&E, hematoxylin and eosin; MiNEN, mixed neuroendocrine and non-neuroendocrine neoplasm.

The patient received five cycles of hormonal therapy with Eligard in combination with apalutamide. During follow-up, the patient’s serum PSA level remained suppressed at <0.03 ng/mL, indicating sustained biochemical control of prostate cancer. The lung tumor has been managed with active surveillance following surgical resection. On the most recent restaging evaluation, no evidence of recurrent or metastatic lung cancer was identified. Concurrently, the prostate cancer remained radiologically and clinically stable without signs of disease progression.

Molecular and immunohistochemical findings

This combination of MiNEN, consisting of an AC and an invasive non-mucinous adenocarcinoma, is an exceedingly rare entity. Therefore, we conducted next-generation sequencing (NGS) analysis on the Ion Torrent S5 XL platform with a 550-chip kit, employing the NGS gene panel Oncomine^® Comprehensive Assay Plus (Thermo Fisher Scientific, Waltham, MA, USA), which interrogates approximately 500 cancer-related genes, to determine the molecular characteristics of each distinct cell population. In the AC component, NGS identified multiple sequence variants, including single-nucleotide variants (SNVs) and small insertions/deletions, as well as a gene fusion event, KIF5B-ALK involving exon 24 of KIF5B and exon 20 of ALK, detected at the genomic level. Direct visualization of reads by integrative genomics viewer (IGV) confirmed the presence of the KIF5B(24)–ALK(20) fusion. The adenocarcinoma component harbored the same KIF5B(24)–ALK(20) fusion, which was likewise confirmed by IGV analysis, along with its own spectrum of sequence alterations. Consistent with these findings, copy number profiling demonstrated a characteristic ALK gene imbalance pattern in both tumor components, with a marked read imbalance starting from exon 20 onward, supporting the presence of an ALK rearrangement (Figure 3A,3B). These results confirm ALK rearrangement as a common genetic driver across the morphologically distinct tumor components in this case. In addition to the shared ALK rearrangement, both AC and adenocarcinoma components harbored mutations in the PMS1, PXDNL, TMEM132C, and NQO1 genes (Table S1). For validation of an ALK fusion, ALK (D5F3 clone) immunohistochemistry was performed, revealing strong, diffuse cytoplasmic positivity (3+) in both tumor components (AC and adenocarcinoma) (Figure 2).

Figure 3 Molecular analysis using NGS. (A) ALK gene imbalance plots derived from NGS data for each tumor component. A significant read imbalance in the ALK kinase domain (exon 20 onwards), consistent with the presence of an ALK fusion, is observed in both components, with an imbalance score of 4.682 in the atypical carcinoid component and 4.943 in the adenocarcinoma component. (B) IGV visualization of fusion reads identified by the targeted NGS panel, demonstrating a shared KIF5B(24)–ALK(20) fusion in both the atypical carcinoid and adenocarcinoma components. IGV, integrative genomics viewer; NGS, next-generation sequencing.

All procedures performed in this study were conducted in accordance with the ethical standards of the institutional committee and with the Declaration of Helsinki and its subsequent amendments. The requirement for patient consent for the publication of this case report and accompanying images was waived by the Institutional Review Board of Jeonbuk National University Hospital (IRB No. CUH 2025-09-007).

Discussion

MiNEN was first described in the 4th edition of the WHO Classification of Tumors of Endocrine Organs as a pancreatic neoplasm composed of both neuroendocrine and non-neuroendocrine components, each accounting for at least 30% of the tumor (5). The MiNEN category extended to the entire gastrointestinal tract in the 5th edition of the WHO Classification of Digestive System Tumors (6). In the 5th edition of the WHO Classification of Tumors of Endocrine and Neuroendocrine Tumors, the MiNEN category has been broadened to encompass all organ systems of the human body (7). In this latest edition, MiNENs are defined as mixed epithelial neoplasms consisting of both neuroendocrine and non-neuroendocrine components, each of which is morphologically and immunohistochemically distinct (7). In the latest edition of the WHO Classification of Thoracic Tumors, MiNENs are primarily described as tumors composed of NSCLC combined with a high-grade neuroendocrine carcinoma, such as LCNEC or SCLC.

In contrast, TC and AC tumors are not described as occurring in combination with NSCLC (8). However, although rare, several case reports have described tumors composed of mixed TC or AC and NSCLC components, with fewer than 20 such cases reported in the literature to date. The present case expands this limited spectrum by demonstrating a distinct combination of an AC component with an elevated Ki-67 index (approximately 35%) and a well-differentiated acinar lepidic adenocarcinoma component. Although LCNEC was considered in the differential diagnosis of the neuroendocrine component, given the relatively high proliferative index, the mitotic count and the presence of only focal necrosis were consistent with AC. In addition, the wild-type p53 expression pattern further supports AC rather than LCNEC, as LCNEC typically exhibits aberrant p53 expression. The clear morphologic and immunohistochemical distinction between the two components, with positive synaptophysin and INSM1 in the neuroendocrine portion and TTF-1 and Napsin A positivity in the adenocarcinoma, fulfills the diagnostic criteria for MiNEN. A review of the histopathologic findings from previously reported cases of mixed TC/AC and NSCLC is summarized in Table 1. In the NSCLC component, adenocarcinoma was the most common histologic type, while AC was the predominant subtype among the neuroendocrine tumor components. The proportion of each component varied widely, ranging from 10% to 90%, with AC representing the predominant neuroendocrine component in most reports.

Molecular profiling studies have revealed that the genetic landscape of MiNEN-associated TC/AC differs markedly from that of sporadic carcinoid tumors. Sporadic TC/ACs are typically characterized by low mutation burden with alterations in chromatin-remodeling and epigenetic regulator genes, such as MEN1, ARID1A, and EIF1AX (17). In addition, whole-exome sequencing has identified mutations in genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling (18). Notably, previous studies have reported that therapeutically relevant mutations are generally absent in lung sporadic TC and AC (19,20). Although reported MiNEN-associated TC/AC cases are limited, a review of those with available molecular data suggests that their mutational profiles differ substantially from those of sporadic TC/ACs (3,9,10,12,14). The gene alterations identified in previously reported cases are summarized in Table 2. These include mutations in KRAS, BRAF, STK11, and NF1, as well as gene rearrangements involving RET. Notably, many of these alterations overlap with those commonly detected in NSCLC and involve therapeutically targetable genes, underscoring their potential clinical relevance. Consistent with the molecular patterns observed in previously reported MiNEN-associated TC/AC cases, the neuroendocrine tumor component of our MiNEN exhibited an ALK rearrangement, a genetic alteration frequently reported in NSCLC (21). This finding further supports the notion that MiNEN-associated TC/ACs may share molecular features with NSCLC rather than with sporadic carcinoid tumors.

In the present case, NGS identified a KIF5B(24)–ALK(20) fusion in both the AC and adenocarcinoma components. ALK rearrangements are a well-established oncogenic driver in lung cancer, particularly in NSCLC, occurring in approximately 3–7% of cases, most frequently identified in tumors with adenocarcinoma histology (22,23). These rearrangements arise from chromosomal translocations that fuse the ALK kinase domain to various partner genes, resulting in constitutive ALK activation. Among the reported fusion partners, EML4 is the most common, whereas less frequent partners include KIF5B, TFG, KLC1, STRN, and others (24,25). ALK-rearranged lung cancers are highly responsive to next-generation ALK tyrosine kinase inhibitors, such as alectinib, brigatinib, and lorlatinib, highlighting the clinical importance of identifying ALK fusion events (11,26). KIF5B is a relatively rare ALK fusion partner in lung cancer compared with EML4, but it has been shown to drive oncogenic ALK signaling through constitutive dimerization mediated by the coiled-coil domains of KIF5B (13). Two major hypotheses have been proposed to elucidate the pathogenesis of MiNEN: the collision theory and the common precursor theory (27). The collision theory postulates that the neuroendocrine and non-neuroendocrine components arise independently from distinct progenitor cells and subsequently merge to form a single composite lesion through spatial convergence (27). In contrast, the common precursor theory suggests that both components derive from a single multipotent progenitor cell, which subsequently undergoes early clonal diversification and differentiation into distinct lineages during tumor progression (27). Molecular profiling studies have increasingly supported the common precursor theory. As summarized in Table 2, most reported cases of MiNEN-associated TC/AC have demonstrated shared driver alterations such as KRAS, BRAF, RET, STK11, and NF1 in both the neuroendocrine and non-neuroendocrine components (3,9,10,12,14). These findings suggest that MiNENs may represent a single neoplastic process that undergoes subsequent divergence into two distinct phenotypic lineages. Aligned with previous reports, in the present case, although a NOTCH1 mutation was identified exclusively in the NET component and an MSH3 variant was detected only in the adenocarcinoma component, both components shared a common ALK rearrangement along with identical variants in PMS1, PXDNL, TMEM132C, and NQO1. Most of the genetic alterations were therefore shared between the two, and our findings may provide an additional example supporting the common precursor model in the pathogenesis of MiNEN.

Prostate cancer metastasis should be considered in the differential diagnosis given the patient’s history of advanced prostate cancer. ALK alterations have been reported in prostate cancer, particularly in tumors with neuroendocrine differentiation, raising the possibility of metastatic disease with overlapping molecular features (22). However, multiple clinicopathologic and radiologic findings in the present case argue against this possibility. The GGO lesion was already present at the time of initial staging and demonstrated interval growth on follow-up imaging despite a marked biochemical response to prostate cancer-directed therapy, with serum PSA levels decreasing from 58.6 to 0.05 ng/mL approximately six months after treatment initiation. Furthermore, immunohistochemical staining showed that the entire lung tumor was negative for PSA, and the adenocarcinoma component exhibited pulmonary lineage differentiation with napsin A and TTF-1 positivity. Taken together with the presence of a shared ALK rearrangement and identical mutational profiles across both tumor components, these findings strongly support a primary pulmonary MiNEN rather than metastatic prostate cancer. From a clinical standpoint, our patient had already been diagnosed with metastatic prostate cancer, and systemic therapy was prioritized for its management. In contrast, the pulmonary MiNEN, which was detected at an early stage, did not require additional chemotherapy following surgical resection. Nevertheless, the identification of an ALK rearrangement in both components is of particular interest, as it represents a therapeutically targetable alteration commonly observed in NSCLC. Although experience with targeted therapy in MiNENs is limited, the presence of ALK fusion in both the neuroendocrine and non-neuroendocrine components raises the possibility that ALK inhibitors, such as alectinib or lorlatinib, could provide therapeutic benefit in similar cases. Future studies integrating molecular findings with clinical outcomes are needed to clarify the efficacy of targeted therapies in this rare tumor type.

Conclusions

In summary, we report a rare case of pulmonary MiNEN composed of AC and adenocarcinoma components, both of which harbor a common ALK rearrangement, as well as shared molecular alterations. Pulmonary MiNENs of this type are exceptionally rare and remain insufficiently defined in the current WHO classification. Although the 5th edition of the WHO Classification of Thoracic Tumors recognizes MiNENs composed of NSCLC and high-grade neuroendocrine carcinoma, combinations involving typical or AC tumors are not yet formally categorized. Our findings, together with accumulating molecular evidence, suggest that such cases may represent an underrecognized variant within the MiNEN spectrum. Expanding the current classification to include these low-grade combinations would help establish more precise diagnostic criteria and facilitate future molecular and clinical investigations. In our case, both components shared an identical ALK rearrangement and several common variants, supporting a monoclonal origin rather than a coincidental collision of two independent tumors. The identification of a targetable ALK fusion emphasizes the clinical importance of comprehensive molecular profiling, even in rare mixed tumors, and highlights the potential for applying targeted therapies in similar cases. Further accumulation of well-characterized cases and comprehensive genomic studies will be essential to refine the MiNEN classification, elucidate its pathogenesis, and enhance our understanding of this uncommon and heterogeneous tumor category.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1427/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1427/prf

Funding: This research was supported by Fund of Biomedical Research Institute, Jeonbuk National University Hospital.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1427/coif). The authors have no conflicts of interest to declare.

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 conducted in accordance with the ethical standards of the institutional committee and with the Declaration of Helsinki and its subsequent amendments. The requirement for patient consent for the publication of this case report and accompanying images was waived by the Institutional Review Board of Jeonbuk National University Hospital (IRB No. CUH 2025-09-007).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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