Introduction
Nasopharyngeal carcinoma (NPC) is a malignancy originating in the epithelial lining of the nasopharynx. It is strongly associated with Epstein-Barr virus (EBV) infection, particularly the non-keratinizing and undifferentiated subtypes, and has a distinct geographical distribution, being more prevalent in Southeast Asia, the Middle East, and North Africa [ 1 , 2 ]. While local symptoms, such as nasal obstruction, epistaxis, or cervical lymphadenopathy, are common, distant metastasis at presentation can also occur, most frequently to the bone, liver, and lungs [ 3 ]. However, initial presentation with extensive symptomatic osseous metastases, including calvarial lesions with intracranial extension, is unusual and can pose a significant diagnostic challenge, often mimicking other primary or metastatic bone diseases. This case report describes an atypical presentation of NPC in an approximately 60-year-old female who presented with extensive osseous metastases, including a symptomatic calvarial lesion leading to intracranial involvement, and subsequent spinal cord compression risk. We highlight the diagnostic pathway, multidisciplinary management approach, and the importance of considering NPC in the differential diagnosis of widespread osteolytic lesions, even in non-endemic regions. This case is unique due to the constellation of extensive bone involvement as the primary manifestation, and contributes to the understanding of NPC’s diverse clinical spectrum.
Case Report
Patient Information
An approximately 60-year-old female, with no significant prior medical history related to malignancy, presented with a chief complaint of a progressively enlarging lesion on her left forehead over 6 months. Initially, it was a painless nodule, but it had become tender over time. She also reported experiencing bilateral headaches, described as a dull, persistent ache with a sensation of pressure behind the eyes, which intensified with activity. Over the 4 months leading up to presentation, she noticed progressive swelling in the left forehead, extending toward the posterior ear, which was intermittently tender without erythema or drainage.
Clinical Findings
On physical examination, the patient exhibited a 3–4 cm soft, minimally tender mass on the superior left side of the forehead. A firm, nonmobile, sub-centimeter lesion was also noted posterior to the left ear. The overlying skin was intact, with no signs of infection or discoloration. Neurological examination was initially unremarkable, apart from the reported headaches.
Timeline
The patient’s symptoms (forehead lesion, headaches) developed over 6 months before seeking medical attention. Diagnostic investigations commenced upon presentation, followed by surgical intervention for the calvarial lesion. Radiation therapy and systemic therapy were initiated subsequently. Follow-up occurred over several months, documenting initial response and eventual decline.
Diagnostic Assessment
The diagnostic evaluation began with magnetic resonance imaging (MRI) of the brain, which identified enhancing lytic lesions in the left frontoparietal calvarium, measuring approximately 33.1 mm by 67 mm in length, accompanied by intracranial extension and breach of the cortical bone ( Fig. 1 ). These findings were highly suggestive of an aggressive pathology.
Subsequent computed tomography (CT) of the chest, abdomen, and pelvis revealed multiple abnormalities: a lytic lesion on the T4 vertebral body ( Fig. 2 ), intrahepatic and extrahepatic biliary ductal dilatation, bilateral adrenal adenomas, and a right upper lobe pulmonary nodule. These findings were nonspecific for identifying a primary malignancy.
Positron emission tomography combined with CT (PET/CT) was pivotal. It detected a hypermetabolic mass in the posterior nasopharynx and the right fossa of Rosenmüller, with a maximum standardized uptake value (SUV max ) of 25.4, strongly indicative of a primary tumor ( Fig. 3 ). The PET/CT scan also confirmed extensive fluorodeoxyglucose (FDG)-avid osseous metastases involving the skull, thoracic vertebrae (including T4 and T7), scapula, and ribs, consistent with advanced systemic disease.
Histopathological analysis of biopsy specimens from the calvarial lesion, and subsequently from its surgical excision, revealed poorly differentiated squamous cell carcinoma invading bone and adjacent soft tissues. Immunohistochemical staining for EBV-encoded small RNAs using in situ hybridization showed 90% positivity in tumor cells. This finding conclusively established the diagnosis of EBV-associated metastatic NPC.
The differential diagnosis initially considered, given the lytic bone lesions, included multiple myeloma (excluded by lack of confirmatory serum protein electrophoresis and imaging features), metastatic disease from common primaries (breast, lung, kidney), primary bone malignancy (e.g., osteosarcoma, less likely given age and radiological features), and infectious causes (e.g., osteomyelitis, excluded by lack of systemic symptoms or granulomatous findings). The diagnostic challenge lay in the atypical presentation, with no overt nasopharyngeal symptoms until advanced imaging pinpointed the primary site and pathological confirmation. The final diagnosis was stage IVC (T4 N0 M1) EBV-associated poorly differentiated NPC with extensive osseous and intracranial metastases. Prognosis was deemed poor due to the advanced stage.
Therapeutic Intervention
The patient’s management involved a multidisciplinary approach.
Surgical Intervention
The symptomatic calvarial lesion was surgically excised. This provided symptomatic relief from local pain and pressure, confirming the histopathological diagnosis.
Radiation Therapy
Palliative radiation therapy was administered to the thoracic spine lesions, particularly targeting the T7 vertebral involvement, which posed an imminent risk of spinal cord compression. This aimed to alleviate pain and prevent neurological complications.
Systemic Therapy
A systemic regimen comprising gemcitabine, cisplatin, and toripalimab was initially recommended by the multidisciplinary oncology team, consistent with guidelines for the treatment of advanced NPC. However, after a detailed discussion regarding potential benefits and adverse effects, the patient opted to forgo traditional chemotherapy. She elected for a regimen consisting of the immune checkpoint inhibitor toripalimab, administered at (240 mg IV every 3 weeks), and denosumab (120 mg subcutaneously every 4 weeks) to manage skeletal metastases. She only received two dosages of the mentioned regimen as she decided to be hospice and passed away shortly after. This decision highlighted the importance of patient autonomy in treatment planning.
Follow-Up and Outcomes
Initially, the patient experienced partial symptomatic relief, particularly in spinal pain control and functional mobility, following radiation therapy and the initiation of immunotherapy. However, over the subsequent months, her clinical condition progressively deteriorated. She developed profound fatigue, worsening generalized metastatic pain, and significant reductions in functional capacity. Intervention adherence was good for the chosen regimen; tolerability was initially acceptable but overshadowed by disease progression. Adverse events were primarily related to disease progression rather than direct drug toxicity, though fatigue could have been multifactorial. Considering the relentless disease advancement, comprehensive and empathetic discussions were held with the patient and her family. Her care plan was fully aligned with her preferences, emphasizing comfort and dignity. Ultimately, her care transitioned to hospice and palliative services, focusing on optimal symptom management and maintaining quality of life during the terminal stage of her illness.
Discussion
This case illustrates an unusual and diagnostically challenging presentation of NPC, characterized by extensive osseous metastases with intracranial extension as the initial dominant feature, in the absence of typical early symptoms of NPC. The diagnostic journey underscores the importance of maintaining a broad differential for lytic bone lesions and the utility of comprehensive imaging, particularly PET/CT, in identifying an occult primary malignancy. The definitive diagnosis hinged on histopathological examination of the metastatic lesion and the crucial finding of EBV positivity, a hallmark of NPC [ 4 ].
The management strategy aligned with National Comprehensive Cancer Network (NCCN) guidelines for metastatic NPC, which recommend systemic therapy and palliative measures for symptomatic lesions [ 5 ]. While platinum-based chemotherapy combined with gemcitabine is a standard first-line option, the emergence of immune checkpoint inhibitors has transformed the therapeutic landscape for recurrent or metastatic NPC. Pembrolizumab, often in combination with chemotherapy, has shown subsequent line immunotherapy in this setting [ 5 ]. The patient’s choice of pembrolizumab and denosumab, rather than chemotherapy, highlights a growing trend where patient preferences and quality of life significantly impact treatment decisions in advanced cancer. Denosumab was used appropriately for the management of bone metastases and the prevention of skeletal-related events.
Strengths of this case report include the detailed clinical and radiological documentation of an atypical NPC presentation, as well as adherence to a multidisciplinary treatment approach. A limitation is the lack of long-term follow-up on the specific immunotherapy regimen due to rapid disease progression, which is common in widely metastatic NPC. Furthermore, while EBV DNA levels are valuable prognostic and monitoring biomarkers in NPC, serial monitoring was not extensively detailed in this acute presentation and rapid decline phase [ 6 ].
This case reinforces that NPC should be considered in patients presenting with metastatic squamous cell carcinoma of unknown primary, especially with EBV positivity, regardless of their geographic origin or initial lack of nasopharyngeal symptoms. The multidisciplinary approach, integrating surgery for symptomatic relief, palliative radiotherapy, and systemic immunotherapy, was critical.
Conclusion
This case of NPC with extensive initial bone and intracranial metastases highlights the diverse manifestations of this disease. A prompt and thorough investigation, including EBV testing, is vital for an accurate diagnosis. While the prognosis for such advanced presentations remains challenging, integrating modern systemic therapies, such as immunotherapy, tailored to patient preference and clinical context, alongside palliative measures, forms the cornerstone of management.
Statement of Ethics
Ethical approval was not received for this human study because Case reports are exempt from the Institutional Review Board (IRB), and informed consent was obtained. Case reports are exempt from IRB review, and we ensured that informed consent was obtained from all patients, reinforcing our commitment to ethical standards in research. Case reports are exempt from IRB review, and informed consent was obtained from patients. All adult participants provided written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for publication of the details of their medical case and any accompanying images. Written informed consent was obtained from the patient (signed by patient) for publication of this case report and any accompanying images. Publication of this case includes de-identified clinical details and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000547582 ).
Conflict of Interest Statement
The authors declare no conflicts of interest.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Mariana Marrero Castillo was involved in the conception of the report, data collection, and drafting of the manuscript. Anil Ananthaneni and Kavitha Beedupalli were involved in the patient’s clinical management and manuscript review. Benedict Amalraj provided radiological, figure preparation, and drafting of the manuscript. All authors read and approved of the final manuscript.
Funding Statement
This study was not supported by any sponsor or funder.
Data Availability Statement
The data that support the findings of this study are not publicly available due to patient confidentiality and ethical restrictions. De-identified data may be available from the corresponding author upon reasonable request.
References
1. Jiromaru R, Nakagawa T, Yasumatsu R. Advanced nasopharyngeal carcinoma: current and emerging treatment options. Cancer Manag Res. 2022;14:2681–9.
2. Argirion I, Zarins K, Suwanrungruang K, Pongnikorn D, Chitapanarux I, Sriplung H, et al. Subtype specific nasopharyngeal carcinoma incidence and survival trends: differences between endemic and non-endemic populations. Asian Pac J Cancer Prev. 2020;21(11):3291–9.
3. Pisani P, Airoldi M, Allais A, Valletti PA, Battista M, Benazzo M, et al. Metastatic disease in head & neck oncology. Acta Otorhinolaryngol Ital. 2020;40(Suppl 1):S1–86.
4. Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet. 2005;365(9476):2041–54.
5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) . Head and neck cancers version 2.2025: January 17, 2025; 2025.
6. Chan AT, Teo PM, Johnson PJ. Nasopharyngeal carcinoma. Ann Oncol. 2002;13(7):1007–15.
Associated Data
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are not publicly available due to patient confidentiality and ethical restrictions. De-identified data may be available from the corresponding author upon reasonable request.