Imaging manifestations of nuclear protein in testis carcinoma in the maxillary sinus with elevated alpha-fetoprotein: a case description and literature analysis

Introduction

Nuclear protein in testis (NUT) carcinoma is a rare and highly aggressive malignancy defined by rearrangement of the NUTM1 gene, most commonly involving BRD4, and typically arises in midline structures such as the head and neck, mediastinum, and thorax (1). It predominantly affects adolescents and young adults, and is characterized by rapid progression, early metastasis, and poor prognosis (2). Histologically, NUT carcinoma often presents as a poorly differentiated carcinoma with focal abrupt keratinization, whereas its imaging features are generally nonspecific and may overlap with those of other aggressive sinonasal malignancies (3,4). Serum alpha-fetoprotein (AFP) is classically associated with hepatocellular carcinoma and germ cell tumors, and its elevation in non-hepatic epithelial malignancies is uncommon (5,6). The significance of AFP elevation in NUT carcinoma remains uncertain. Here, we report a rare case of primary maxillary sinus NUT carcinoma with markedly elevated serum AFP and occult distant metastases detected on positron emission tomography/computed tomography (PET/CT), highlighting the diagnostic value of radiologic-pathologic correlation and the added value of PET/CT in whole-body staging evaluation of this highly aggressive tumor.

Case presentation

A 26-year-old male presented with a 1-month history of recurrent left-sided nasal obstruction and rhinorrhea beginning in February 2024. He was initially evaluated at an outside hospital, where paranasal sinus CT performed on March 8, 2024 revealed a mass that was initially considered a nasal polyp. He was subsequently admitted to our otolaryngology department on March 18, 2024, and nasoendoscopy demonstrated a mass in the left nasal cavity/middle meatus. No palpable cervical lymphadenopathy was identified on physical examination.

Laboratory investigations showed neutrophilia (NEUT% 75.8%), lymphopenia (LYM% 19.0%), and markedly elevated liver enzymes [alanine aminotransferase (ALT) 297 U/L, aspartate aminotransferase (AST) 121 U/L]. Serum AFP was markedly elevated at 873 ng/mL. Epstein-Barr virus serology was negative. Abdominal ultrasonography performed on March 14, 2024 demonstrated multiple hypoechoic lesions in the liver.

The contrast-enhanced magnetic resonance imaging (MRI) of the paranasal sinuses performed on March 15, 2024 (Figure 1) demonstrated a large (5.3 cm × 4.1 cm × 5.6 cm), ill-defined, heterogeneous soft-tissue mass centered in the left maxillary sinus, extending into the left nasal cavity, ethmoid, and sphenoid sinuses. The lesion showed isointense signal on T1-weighted imaging (T1WI), hyperintense signal on fat-suppressed T2-weighted imaging (T2WI), and heterogeneous enhancement with central non-enhancing necrotic areas. Extensive osseous destruction of the maxillary sinus walls was present, with superior extension toward the left orbit and invasion of the left masticator space, including the medial and lateral pterygoid muscles and temporalis muscle, as well as anterior extension into the left maxillofacial soft tissues. Orbital MRI was recommended by the ophthalmology team because of suspected orbital involvement, but the patient declined.

Figure 1 Magnetic resonance imaging findings of the primary lesion. The arrows indicate the primary maxillary sinus tumor lesion and its local extension. (A) Non-contrast-enhanced sagittal T1-weighted image showing a large soft-tissue mass centered in the left maxillary sinus. (B,C) Fat-suppressed coronal and sagittal T2-weighted images showing a heterogeneously hyperintense mass with small internal hypointense areas corresponding to necrotic foci. (D) Contrast-enhanced sagittal T1-weighted image demonstrating heterogeneous mild-to-moderate enhancement with central non-enhancing necrotic areas (red arrow). (E,F) Coronal and sagittal T1-weighted images showing superior extension into the left orbit, lateral extension beyond the maxillary sinus wall, and anterior extension into the left maxillofacial soft tissues.

On the same day, endoscopic surgical removal/biopsy of the left sinonasal lesion was performed, and tissue was submitted for histopathological examination. Initial histopathology revealed a poorly differentiated small round cell malignant tumor with a high nuclear-to-cytoplasmic ratio, frequent mitotic figures, focal necrosis, and abrupt keratinization (Figure 2A-2C). Because abrupt keratinization in an aggressive poorly differentiated midline tumor raised suspicion for NUT carcinoma, additional immunohistochemical analysis was performed. Immunohistochemistry showed diffuse nuclear positivity for NUT and positivity for CK, CK5/6, EMA, and partial positivity for P40 and P16, whereas synaptophysin, chromogranin A, S-100, desmin, SALL4, CD30, and lymphoid markers were negative. EBER in situ hybridization was also negative (Figure 2D). Based on the characteristic histomorphology and NUT immunohistochemical positivity, the diagnosis of NUT carcinoma was established. Molecular confirmation, such as fluorescence in situ hybridization or next-generation sequencing, was not performed in this case.

Figure 2 Histopathological and immunohistochemical findings of the left sinonasal lesion. (A,B) Hematoxylin and eosin staining (×200) showing tumor cells infiltrating in nests and sheets. (C) Hematoxylin and eosin staining (×400) showing poorly cohesive round-to-oval tumor cells with enlarged atypical nuclei, increased nuclear-to-cytoplasmic ratio, prominent nucleoli, frequent mitotic figures, and focal necrosis. (D) Immunohistochemical staining (×200) showing diffuse nuclear positivity for NUT in the tumor cells. NUT, nuclear protein in testis.

Because abdominal ultrasonography had already shown multiple liver lesions and the patient repeatedly declined further upper abdominal MRI and magnetic resonance cholangiopancreatography (MRCP) on March 18, 2024, whole-body ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT was performed on March 19, 2024 to facilitate systemic staging evaluation of this highly aggressive malignancy (Figure 3). PET/CT demonstrated intense hypermetabolism in the primary sinonasal tumor [maximum standardized uptake value (SUVmax) 14.4] with adjacent osseous involvement. Mildly hypermetabolic lymph nodes were observed in the left submandibular (level Ib, SUVmax 3.5) and left deep parotid regions. Importantly, PET revealed multiple hypermetabolic liver lesions (largest in segment VIII, 2.4 cm, SUVmax 8.8) and a metabolically active focus in the left proximal femur (SUVmax 3.2), both of which were occult on the non-contrast CT component. These findings indicated distant metastatic disease.

Figure 3 PET/CT findings of the primary lesion and metastatic lesions. The arrows indicate hypermetabolic lesions with increased FDG uptake on PET imaging. (A,B) CT images showing an irregular lobulated soft-tissue mass in the left maxillary sinus with adjacent osseous destruction. (C) PET image demonstrating markedly increased uptake in the primary lesion (SUVmax 14.4; red arrow). (D,E) CT and PET images of metastatic lymph nodes in the neck. (F,G) CT and PET images of hepatic metastases. (H,I) CT and PET images of metastasis in the proximal femur. CT, computed tomography; FDG, fluorodeoxyglucose; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

The patient was transferred to the hepatology department on March 21, 2024 because of persistent liver enzyme abnormalities and liver lesions on imaging, but he continued to decline upper abdominal MRI. After confirmation of the pathological diagnosis on March 27, 2024, radiotherapy was recommended on March 28, 2024; however, the patient refused treatment. He was discharged on April 1, 2024 and declined further antitumor therapy. No chemotherapy or palliative systemic treatment was administered because the patient declined further therapy. Subsequent telephone follow-up was unsuccessful, and the patient was lost to follow-up; therefore, long-term clinical outcome could not be determined.

Ethics and consent statement: all procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (approval No. G2025-22) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication could not be obtained because the patient was lost to follow-up and could not be contacted despite reasonable efforts. The manuscript has been sufficiently anonymized to minimize the risk of patient identification.

Discussion

NUT carcinoma is a rare and highly aggressive malignancy defined by rearrangement of the NUTM1 gene, most commonly involving BRD4, and tends to arise in midline structures such as the head and neck, mediastinum, and thorax (1-4). It can occur across a wide age range but predominantly affects adolescents and young adults, and is characterized by rapid local invasion, early distant metastasis, and poor survival (5-7). Because of its rarity and the lack of specific clinical manifestations, diagnosis is often delayed or initially mistaken for other poorly differentiated sinonasal malignancies.

In the present case, the primary tumor arose in the maxillary sinus and showed aggressive local behavior on MRI, including a large infiltrative soft-tissue mass, heterogeneous internal signal, necrotic components, marked bone destruction, and extension into adjacent sinonasal spaces, the orbit, and masticator space. These findings are consistent with the reported imaging appearance of NUT carcinoma, which is generally non-specific and often overlaps with other aggressive sinonasal tumors (8). Therefore, imaging alone is insufficient for definitive diagnosis. Nevertheless, in young patients with a rapidly progressive destructive sinonasal mass, especially when pathology shows a poorly differentiated small round cell or undifferentiated carcinoma with abrupt keratinization, NUT carcinoma should be considered in the differential diagnosis, and NUT immunohistochemical staining should be performed promptly.

Another key message of this case concerns the role of PET/CT in assessing disease extent. At presentation, AFP was markedly elevated and abdominal ultrasonography had already demonstrated multiple hypoechoic liver lesions. In routine clinical practice, contrast-enhanced upper abdominal CT or MRI would usually be considered for further characterization of such lesions. However, the patient repeatedly declined upper abdominal MRI/MRCP. Under these circumstances, and given the highly aggressive nature of the sinonasal tumor, whole-body ¹⁸F-FDG PET/CT was performed to provide additional information for systemic staging evaluation. PET/CT demonstrated metabolically active liver and femoral lesions that were occult on the non-contrast CT component, thereby expanding the assessment from a locally destructive sinonasal tumor to disseminated metastatic disease. Thus, in this case PET/CT did not serve as a disease-specific “standard staging” tool for NUT carcinoma, but rather provided complementary value in whole-body staging and metastatic assessment, particularly for detecting occult distant lesions when conventional imaging was incomplete and distant spread was clinically suspected (9,10).

Marked AFP elevation was another unusual finding in this patient. AFP is classically associated with hepatocellular carcinoma and germ cell tumors, whereas elevation in non-hepatic epithelial malignancies is uncommon (11-15). Elevated AFP has been described in a small subset of reported NUT carcinoma cases. D’Ambrosio et al. summarized six such cases reported before 2017 (12). To update the literature without reproducing previously published summary tables, subsequently reported AFP-elevated cases together with the present case are summarized in Table 1. Some reports have suggested a possible association between AFP elevation and disease behavior in NUT carcinoma; however, the available evidence is limited and the clinical significance of AFP remains unclear. In our patient, serum AFP reached 873 ng/mL; however, the source and significance of this elevation remain uncertain. Although abdominal ultrasonography and PET/CT suggested multiple liver lesions, no pathological confirmation of the liver lesions was obtained because the patient declined further upper abdominal MRI and subsequent treatment. Therefore, AFP in this case should be interpreted cautiously and regarded as a rare accompanying phenomenon rather than an established diagnostic, prognostic, or disease-monitoring biomarker.

As shown in Table 1, several reported AFP-elevated cases involved thoracic or mediastinal primaries and were associated with diagnostic confusion with germ cell tumors; however, the number of reported cases is small and the available clinical data are incomplete and heterogeneous. Exact AFP values and longitudinal follow-up were also inconsistently documented. In contrast, our patient had a maxillary sinus primary, making the present case particularly uncommon within this already rare subgroup. Therefore, although AFP elevation is a recurrent observation in a small subset of NUT carcinoma cases, its biological basis and clinical significance remain uncertain (12,16-20).

The imaging differential diagnosis of maxillary sinus NUT carcinoma includes other aggressive sinonasal malignancies such as squamous cell carcinoma, adenoid cystic carcinoma, extranodal NK/T-cell lymphoma, and poorly differentiated sinonasal undifferentiated carcinoma (21-25). However, these entities often overlap substantially on imaging, and histopathology remains essential. In our case, the combination of a rapidly invasive maxillary sinus mass in a young patient, abrupt keratinization on histology, and diffuse nuclear NUT positivity established the diagnosis.

This report has several limitations. First, molecular testing was not performed, and the diagnosis relied on histomorphology and immunohistochemistry. Second, the hepatic lesions were not pathologically confirmed. Third, the patient declined recommended treatment and was subsequently lost to follow-up, so long-term outcome data were unavailable. Despite these limitations, this case remains clinically meaningful because it illustrates the real-world diagnostic reasoning process, highlights the added value of PET/CT for detecting occult distant lesions, and draws attention to the rare but noteworthy finding of marked AFP elevation in NUT carcinoma.

Conclusions

NUT carcinoma should be considered in young patients with an aggressive sinonasal mass showing rapid local invasion, particularly when histopathology demonstrates a poorly differentiated malignant tumor with abrupt keratinization. In this case, MRI delineated the locally destructive extent of the maxillary sinus tumor, while ¹⁸F-FDG PET/CT provided important added value for whole-body staging evaluation by detecting occult distant lesions in the liver and proximal femur. Marked AFP elevation was a rare accompanying finding, but its mechanism and clinical significance remain unclear. Recognition of these features may help improve diagnostic suspicion and facilitate earlier comprehensive evaluation of this highly aggressive malignancy.

Acknowledgments

None.

Footnote

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0216/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 in accordance with the ethical standards of the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (approval No. G2025-22) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication could not be obtained because the patient was lost to follow-up and could not be contacted despite reasonable efforts.

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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