Pulmonary metastasis of nasal cavity DEK::AFF2 squamous cell carcinoma: case report and diagnostic insights

Abstract

DEK::AFF2 fusion carcinoma is an emerging sinonasal tract non-keratinizing squamous cell carcinoma (SCC) variant, characterized by deceptively bland morphology, frequent local recurrence, and metastasis in a subset of cases. Owing to its histologic mimicry, misdiagnosis remains common. We report a case of DEK::AFF2 neoplasm exhibiting malignant histological evidence strictly confined to the pulmonary “metastatic” lesion despite persistent benign radiologic and pathologic features in six nasal cavity tumor resections over two decades in a 35-year-old male. The patient was initially diagnosed with inverted papilloma (IP) of the nasal cavity. Histopathologic reassessment of the lung lesions, however, demonstrated divergent morphology—hybrid SCC and IP-like components. Molecular studies (FISH, RNA-seq) confirmed identical DEK::AFF2 fusion in both nasal cavity and pulmonary tumors, supporting clonal spread. This case underscores that DEK::AFF2 sinonasal carcinomas can retain benign histology in primary and recurrent lesions while exhibiting overt malignancy in “metastatic” sites. For sinonasal papillomatous tumors, even if the primary tumor lacks overt malignant histological features, atypical clinical behaviors, such as persistent recurrence or development of distant similar lesions, should raise suspicion for DEK::AFF2 SCC. DEK FISH or RNA sequencing should be considered for definitive diagnosis when clinically indicated.

Introduction

DEK::AFF2 fusion carcinoma is a newly recognized subtype of non-keratinizing squamous cell carcinoma (NK-SCC) of the sinonasal tract [1]. Although a subset of cases exhibit deceptively bland morphology, these tumors are clinically aggressive, with frequent local recurrences and potential for distant metastasis [2–4].

Notably, some DEK::AFF2 SCCs may display papillary architecture and cytologically bland features in primary lesions, mimicking benign entities such as sinonasal inverted papilloma (SIP). Nonetheless, recurrent tumors often progress to overt malignancy, including expansive or destructive stromal invasion, and progressive cytologic atypia [2–4]. However, the natural history of DEK::AFF2 SCCs’ presentation as a long-standing “benign” papillary neoplasm without local malignant morphologic features (but subsequent distant metastasis) remains undocumented.

Here, we report the first case of DEK::AFF2 SCC in a 35-year-old man with a 20-year history of recurrent nasal cavity tumors previously diagnosed as SIPs, where malignant features emerged solely in pulmonary metastases, displaying a hybrid morphology of SCC and morphologically bland, inverted papillary neoplasm (IPN) resembling benign SIP.

Case presentation

A 35-year‐old man initially presented with a 5.0‐mm pulmonary mass, detected incidentally in the right midlung zone on chest radiography performed for an upper respiratory tract infection. Over a 5‐year follow-up period, computed tomography (CT) imaging revealed an increase in mass size to 10.0 mm (Fig. 1A). However, the patient remained asymptomatic, with no cough; sputum production; hemoptysis; chest tightness; shortness of breath; dizziness; or tinnitus.

Fig. 1.

Histopathological features and radiology image of pulmonary metastatic tumor and nasal cavity DEK::AFF2 SCC. A The pulmonary tumor was nodular and well-circumscribed (hematoxylin and eosin stain, × 20, black arrow). CT imaging showed a 10.0 mm pulmonary mass in the right midlung zone (A, lower right, white arrow). B MRI revealed a unilateral expansile nodular mass (white arrow, T2-weighted imaging, left) in the nasal cavity, exhibiting a cerebriform enhancement pattern post-contrast. The lesion originated from the lateral nasal wall, accompanied by bone remodeling and localized hypertrophy, with no definitive signs of adjacent tissue infiltration or destruction (white arrow, right). C The pulmonary nodular tumor was located adjacent to the small bronchi and bronchioles (diameter < 3.0 mm, black arrow) (hematoxylin and eosin stain, × 20). D Left-side areas exhibiting SIP-like morphology (one star).​ The regions on the right display nests and sheets of tumor cells with infiltrative growth (two stars), consistent with SCC (× 40). E SIP-like components lined with bland basaloid and eosinophilic-cytoplasmic squamous epithelia (× 200). F The area of SCC with invasive growth showing disordered cell arrangements without papillary structures (× 100). G SCC cells demonstrating prominent atypia and mitotic figures (1–2 per 10 high-power fields, white arrows) (× 200). H The tumor in the nasal cavity composed of elongated interconnected squamous epithelial cords with prominent downward endophytic growth (× 40); the tumor cells show a transition from basaloid morphology at the base to eosinophilic cytoplasm with bland nuclear features and minimal mitotic activity (lower left, ×400). SCC, squamous cell carcinoma; SIP, sinonasal inverted papilloma; CT, computed tomography; MRI: magnetic resonance imaging

The patient subsequently underwent video-assisted thoracoscopic surgery at a specialized chest hospital for resection of the posterior segment of the right lower lobe. Postoperative pathological examination confirmed the diagnosis of pulmonary SCC, with regions demonstrating an inverted papillary growth pattern. Considering the patient’s history, metastasis from the IPN of the nasal cavity could not be excluded, particularly considering the 20-year history of right nasal cavity IP, with five prior local resections due to recurrence. The patient denied any history of smoking and reported no family history of cancer.

The patient was referred to our institution for a pathology consultation regarding the pulmonary tumor and guidance for further treatment. To evaluate the potential relationship between the pulmonary and nasal cavity lesions, further assessments were performed. Nasal endoscopy revealed a moderately firm pink nodular mass with a wrinkled surface in the right nasal cavity, while magnetic resonance imaging (MRI) confirmed an occupying lesion consistent with recurrent SIP (Fig. 1B). The patient subsequently underwent a sixth endoscopic resection of the nasal cavity tumor at our institution.

Pathological features

Gross examination revealed a 1.6 × 1.3 × 1.2-cm pulmonary mass with well-defined borders and a tan-white appearance. Microscopically, the lesion was adjacent to small bronchi and bronchioles (< 3.0 mm in diameter) (Fig. 1A, C). Some areas displayed a papillomatous morphology (Fig. 1D, E), whereas other regions comprised nests and sheets of tumor cells with infiltrative growth, consistent with SCC (Fig. 1D, F). The papillomatous regions exhibited an inverted growth pattern, covered by non-keratinizing squamous epithelium that transitioned from basaloid cells at the base to cells with eosinophilic cytoplasm and maintained a bland morphology, with minimal mitotic activity (Fig. 1E); whereas SCC areas showed disordered cell arrangements and an absence of papillary structures (Fig. 1F). The SCC tumor cells were moderate in size, with scant-to-moderate cytoplasm, oval nuclei with moderate chromatin, and 1–2 nucleoli. Mitotic figures were observed at 1–2 per 10 high-power fields (Fig. 1G). Necrosis was not observed. Examination of the pulmonary tumor did not reveal atypical bronchial epithelial hyperplasia or other precursor lesions.

A review of pathological slides from the patient’s current nasal cavity tumor resection specimen, as well as those from the five previous resections, revealed classic SIP-like features. The tumor exhibited elongated, anastomosing ribbon-like papillae lined by squamous epithelium, demonstrating prominent endophytic growth with smooth outer contours. The papillae displayed a biphasic cellular population: basaloid cells at the lower layer and cells with moderate eosinophilic cytoplasm toward the surface. Notably, overlying ciliated columnar epithelium, acantholytic change, and neutrophilic infiltration were not identified. These lesions were cytologically bland, with few mitotic figures, and no evidence of malignancy in the histology (Fig. 1H).

Immunohistochemical staining

Pulmonary tumor cells were diffusely positive for P40 and cytokeratin5/6 (CK5/6) and negative for P16. Ki-67 expression was scattered in the basal layers of the SIP-like components (Fig. 2A), and reached approximately 5% of the classic SCC areas (Fig. 2B). Consistent with the IPN findings in the nasal cavity, CK7 positivity was confined to the surface layer of the pulmonary SIP-like components, with the basal layer remaining negative (Fig. 2C, D). Additionally, the pulmonary alveolar epithelium was positive for napsin A and thyroid transcription factor 1 (TTF-1; Fig. 2E, F).

Fig. 2.

Immunohistochemical staining of pulmonary metastatic tumor and nasal cavity DEK::AFF2 SCC. A Ki-67 expression scattered within the basal layer of the SIP-like components of the pulmonary tumor (× 100). B Approximately 5% of the tumor cells showed positivity for Ki-67 staining in the classic invasive SCC area (× 40). C CK7 positivity in the surface layer of the nasal cavity tumor (× 100). Right lower panel: CK7 (brown)/p63 (blue) dual stain. D Similar to observations in the nasal cavity tumor, CK7 positivity is observed in the surface layer of the pulmonary SIP-like components, but not in the basal layer (× 100). E & F Positive staining of the pulmonary alveolar epithelia stained for TTF-1. E: SIP-like components. F: invasive SCC components) (× 100).​ G & H FISH for the DEK gene revealed separated red/green signals (white arrows), confirming DEK rearrangement (×10,000). Orange arrows indicate tumor cells with intact DEK signals. G: Pulmonary metastatic tumor. H: Nasal cavity tumor. I Targeted RNA sequencing detected a DEK::AFF2 fusion transcript (DEKex7::AFF2ex9; chr6p22.3::chrXq28) in the nasal cavity tumor

Molecular analysis

Real-time PCR analysis targeting nine lung cancer-related genes (epidermal growth factor receptor [EGFR], v-Raf murine sarcoma viral oncogene homolog B1, anaplastic lymphoma kinase, c-ros oncogene 1, mesenchymal-epithelial transition factor, rearranged during transfection, Kirsten rat sarcoma viral oncogene homolog, human epidermal growth factor receptor 2, and neurotrophic receptor tyrosine kinase) revealed no driver mutations [5]. Fluorescence in situ hybridization (FISH) analysis revealed DEK gene rearrangement in both pulmonary and sinonasal tumors (Fig. 2G, H), whereas no FGFR3 gene rearrangement was observed.

DNA-based next-generation sequencing (NGS) covering 463 tumor-associated genes was performed on the patient’s pulmonary tumor, and no pathogenic alterations were identified [6]. RNA sequencing (RNA-seq) of the nasal tumor (549-gene fusion panel, including DEK, AFF2 and FGFR3-related fusions) identified a DEK::AFF2 rearrangement (DEKex7::AFF2ex9; chr6p22.3::chrXq28) (Fig. 2I). RNA-seq was not performed on the pulmonary tumor due to suboptimal RNA quality and the unavailability of additional tissue from the external consultation institution.

Diagnosis and treatment

The pulmonary lesion was diagnosed as a pulmonary metastatic nasal cavity DEK::AFF2 SCC. Following resection of the pulmonary and nasal cavity tumors, the patient received no additional treatment, and recurrence was not observed during the 9-month follow-up period.

Discussion

We describe a unique case of pulmonary metastatic DEK::AFF2 SCC in a young man with a 20-year history of recurrent nasal cavity tumors, notable for their absence of malignant morphology features, radiologic evidence in all six nasal cavity tumor resections, and malignant histological evidence being restricted to the distant metastatic lesion. To our knowledge, this represents the first documented instance of such a presentation.

DEK::AFF2 SCC is characterized by deceptively bland morphology, frequent local recurrence, and lymph node or distant metastasis in a subset of cases [1]. Misdiagnosis at initial presentation is common; in published cohorts, approximately 20%~30% cases were initially diagnosed as SIP or other benign entities [2, 4]. However, most cases demonstrated histologic evidence of malignancy, at least in recurrent lesions [1–4, 7–9]. In contrast, with regard to our patient’s nasal cavity tumors, a thorough histological evaluation of all six nasal cavity resections revealed no malignant histological indicators, including absent cytological atypia, broad papillary fronds, and expansile infiltrative growth patterns, and no destructive stromal invasion. Instead, the tumor cells consistently exhibited classic SIP features, demonstrating a differentiation phenomenon rather than monotonous cytomorphology: anastomosing ribbons of tumor cells with squamous differentiation, transitioning from basaloid cells at the base to cells with eosinophilic cytoplasm and CK7-positive surface cells with no significant acantholysis or tumor-infiltrating neutrophils/lymphocytes (Figs. 1H and 2E). These findings starkly contrast typical DEK::AFF2 SCC presentations [1, 4].

The diagnosis of metastatic nasal cavity DEK::AFF2 SCC was supported by multiple lines of evidence: the patient’s relatively young age (35 years), morphologic similarity between tumors (papillary architecture with bland morphologic features in both nasal cavity and pulmonary sites), DEK rearrangement confirmed by FISH, and demonstration of DEK::AFF2 fusion by RNA sequencing. Importantly, NGS of the pulmonary lesion revealed no additional oncogenic alterations, reinforcing its clonal relationship to the nasal cavity tumors.

The key differential diagnosis was primary pulmonary SCC arising from IP. However, the papillary tumor component in the patient’s lung differed from primary pulmonary IP, which usually occurs in large bronchi and presents as a hilar mass on X-ray, whereas the location in this case was adjacent to the small bronchi and bronchioles (Fig. 1A, C). Additionally, the presence of the same molecular genetic alteration (DEK::AFF2 fusion) confirmed that the lung tumor had originated from the nasal cavity tumor.

Potential dissemination routes from the nasal cavity to the lung include hematogenous and lymphatic spread. Repeated surgical resections of recurrent tumors may have facilitated metastasis by introducing tumor cells into the circulatory and lymphatic systems through compromised vessels. Airway implantation can not be entirely ruled out for the following reasons: (1) anatomical continuity between the airway and nasal cavity; (2) pulmonary solitary lesions being centrally located rather than peripheral on imaging; (3) six recurrent nasal cavity tumors completely lacking malignant histological and radiological features, and aggressive growth behavior; (4) the pulmonary tumor demonstrating indolent growth over 5 years, with microscopic features showing proximity to bronchioles and areas resembling the nasal cavity tumor’s IP-like architecture, alongside foci of overtly SCC, suggesting the possibility of an indolent neoplasm implantation and localized progression. General anesthesia-associated surgical manipulations, chronic unilateral obstruction, and coughing may have promoted tumor cell seeding. Although conclusive evidence is lacking, this rare mechanism warrants attention. Recognition of this potential pathway is clinically relevant, as airway-implanted lesions may behave differently from conventional stage IV hematogenous/lymphatic metastases.

This case demonstrates that tumors harboring DEK::AFF2 fusions may have absent malignant histologic features and imaging evidence in both primary and recurrent lesions. Notably, a recent report documented a parotid gland carcinoma with DEK::AFF2 fusion in a 13-year-old girl, exhibiting undifferentiated morphology and neuroendocrine phenotype, with only scattered p63/p40-positive cells [10]. While rare, existing cases reveal a broad morphologic spectrum associated with DEK::AFF2 fusion neoplasm, ranging from indolent IP-like appearing with or without dysplasia, low-grade papillary sinonasal carcinoma, and NK-SCC, to poorly differentiated/undifferentiated phenotypes. A critical question emerges for sinonasal tumors with DEK::AFF2 fusions: If the primary and recurrent lesions, as in this patient, show no histologic aggressive evidence until late-stage lung involvement, should they be universally classified as “carcinoma” based solely on molecular criteria? Alternatively, could a descriptive diagnosis (e.g., “sinonasal IPN with DEK::AFF2 fusion”) coupled with a prognostic commentary better reflect their biologic behavior? For such tumors, in addition to being diagnosed as DEK::AFF2 fusion SCC/carcinoma, a more detailed morphologic grading may be necessary to better predict prognosis. Although studies including our case have not identified additional genetic alterations in these tumors apart from DEK::AFF2, it remains unclear whether unknown epigenetic or proteomic factors contribute to the broad spectrum of morphological features observed in DEK::AFF2 fusion tumors. This issue requires pathologists and clinicians to collect additional cases with comprehensive clinicopathologic data, including follow-up outcomes, and conduct further studies for clarification.

The limitation of this case report is the short follow-up period. At present, only nine months have passed since the patient’s sixth nasal cavity tumor resection and lung tumor resection surgery. The patient has not received further treatment and remains disease-free. Whether the nasal cavity tumor will recur again and whether malignant morphologic or imaging evidence will develop in the future remains unclear.

Conclusion

This case emphasizes the need for integrating clinical history with detailed histopathological and molecular analyses in diagnosing DEK::AFF2 SCC. For sinonasal papillomatous tumors, even if the primary tumor lacks overt malignant histological features, atypical clinical behaviors, such as persistent recurrence or development of distant similar lesions, should raise suspicion for DEK::AFF2 SCC. DEK FISH or RNA sequencing should be considered for definitive diagnosis when clinically indicated.

Abbreviations

ALK

Anaplastic lymphoma kinase

BRAF

v-Raf murine sarcoma viral oncogene homolog B1

CK5/6

Cytokeratin 5/6

CK7

Cytokeratin 7

CT

Computed tomography

EGFR

Epidermal growth factor receptor

FISH

Fluorescence in situ hybridization

HER2

Human epidermal growth factor receptor 2

HPV

Human papillomavirus

IP

Inverted papilloma

IPN

Inverted papillary neoplasm

KRAS

Kirsten rat sarcoma viral oncogene homolog

MET

Mesenchymal-epithelial transition factor

MRI

Magnetic resonance imaging

NGS

Next-generation sequencing

NTRK

Neurotrophic receptor tyrosine kinase

NK-SCC

Non-keratinizing squamous cell carcinoma

PCR

Polymerase chain reaction

ROS1

c-ros oncogene 1

RT

Respiratory tract

SCC

Squamous cell carcinoma

SIP

Sinonasal inverted papilloma

TTF-1

Thyroid transcription factor 1

Authors’ contributions

Author Contributions: C.Y. contributed to original draft writing. L.M. was responsible for methodology and histopathological diagnosis. S.Z. performed CT image analysis. L.K. participated in validation and histopathological review. M.J. and Y.H. conducted molecular testing and data analysis. C.B. oversaw manuscript review, editing, and supervision. All authors critically reviewed and approved the final version of the manuscript.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Review Board/Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine. Written informed consent was obtained from the patient.

Consent for publication

The patient provided written informed consent for the publication of clinical details and images.

Competing interests

The authors declare no competing interests.