Nasopharyngeal carcinoma (NPC) occurs worldwide, but shows a particularly high incidence in the Western Pacific region and is one of the most common malignant tumors in China and Southeast Asia (1). In China, NPC also exhibits a distinct geographic distribution, with Guangdong province being a high-incidence area (2). NPC arises from epithelial cells that line the surface of the nasopharynx and its aggressive nature is characterized by early dissemination to regional lymph nodes. About 40% of patients present with cervical lymphadenopathy at initial diagnosis (3), and 60 to 90% develop cervical lymph node metastases during the disease course, with an orderly progression along the lymphatic network and a relatively low incidence of skip metastasis. The nodal regions most frequently affected are the retropharyngeal lymph nodes and the level II cervical lymph nodes (4,5). In addition, distant metastases are common, most commonly affecting the bones, lungs, liver and distant lymph nodes (6). Due to the anatomical inaccessibility of the nasopharynx and the nonspecific nature of early symptoms, most patients are diagnosed at an advanced stage, indicating a poor prognosis. In an intensity-modulated radiotherapy-treated validation cohort, the American Joint Committee on Cancer (AJCC) 8th edition staging system demonstrated stage-dependent prognostic discrimination, with 5-year overall survival rates ranging from >90% for stage IIA to ~70% for stage IV disease (7). This underscores the critical importance of early and accurate diagnosis. NPC inguinal lymph node metastasis (ILNM) is rare and has been scarcely reported in the literature, with an incidence of ~0.9% (8). The current study presents a case of NPC with ILNM encountered in clinical practice.

A 67-year-old woman from Guangdong first presented to the Affiliated Hospital of Guangdong Medical University (Zhanjiang, China) in July 2022 with a history since April 2022 of enlarged left cervical lymph nodes, intermittent headaches, dizziness, occasional nasal bleeding, tinnitus and hearing loss in the left ear. The patient had no significant medical history, including no history of gynecological disorders, pelvic inflammatory disease, or prior pelvic or lower extremity surgery. The patient also denied smoking and alcohol consumption. Physical examination showed a Karnofsky performance status score (9) of 90, with a hard, fixed lymph node measuring 2.0x2.0 cm at level II of the left cervical chain, without tenderness. Baseline complete blood count and hepatic/renal function tests were within normal limits. Nasal endoscopy revealed a shallow left pharyngeal crypt and thickening of the mucosa. A biopsy confirmed non-keratinizing carcinoma (Fig. 1). Magnetic resonance imaging (MRI) indicated mucosal thickening in the left pharyngeal region, with invasion into adjacent muscles, suggesting NPC. Enlarged lymph nodes were observed in the left retropharyngeal, level IIb and level III regions (Fig. 2). Positron emission tomography (PET)/CT performed in July 2022 showed increased glucose metabolism in the left pharyngeal area and cervical lymph nodes, indicating probable metastasis, but without liver, lung or bone involvement. Reactive hyperplasia was considered for some right cervical regions, left supraclavicular lymph nodes (SCLNs) and ILNs. Baseline plasma Epstein-Barr virus (EBV) DNA assay was negative. The patient was diagnosed with non-keratinizing carcinoma of the nasopharynx [T2N1M0, stage IIA, 8th edition of the AJCC staging system]. In July 2022, the patient received induction chemotherapy with docetaxel 75 mg/m² and cisplatin 75 mg/m². However, due to the development of grade IV leukopenia and neutropenia following chemotherapy, only 1 cycle of treatment was completed. Subsequently, the patient received radical concurrent chemoradiotherapy (CCRT) using volumetric modulated arc therapy, with prescribed doses of 69.96 Gy/33 fractions to the planning gross tumor volume of the nasopharynx and left cervical lymph nodes, 60.06 Gy/33 fractions to planning target volume 1 (PTV1) and 54.12 Gy/33 fractions to PTV2. Concurrent chemotherapy with cisplatin 80 mg/m², every 3 weeks (Q3W) was administered for 2 cycles. Post-CCRT MRI in September 2022 showed a complete response in the primary tumor and partial response in the cervical lymph nodes.

In March 2023, the patient returned with low back pain and bilateral inguinal lymphadenopathy. PET/CT showed multiple hypermetabolic lesions in the left supraclavicular, mediastinal, retroperitoneal, bilateral iliac and inguinal regions, as well as widespread bone involvement, consistent with metastases (Fig. 2). Inguinal fine-needle aspiration biopsy (FNAB) confirmed metastatic non-keratinizing carcinoma; the histopathological features were identical to those of the primary nasopharyngeal lesion, supporting the diagnosis of regional lymph node metastasis (Fig. 1) (Data S1). The patient was restaged as (rT0N3M1, stage IVB, AJCC 8th edition) and received 4 cycles of tislelizumab plus gemcitabine/cisplatin, achieving a partial response. Due to renal impairment related to cisplatin, cisplatin was switched to oral S-1 (a combination of tegafur, gimeracil and oteracil potassium) at a dose of 40 mg/m² twice daily on days 1-14, Q3W, for 2 additional cycles. The patient also underwent palliative radiotherapy to the thoracolumbar spine (30 Gy/10 fractions) in August 2023 and bilateral inguinal nodes (66 Gy/33 fractions) in October 2023; the latter was discontinued after 27 fractions due to myelosuppression. Maintenance S-1 continued, but the patient's overall condition subsequently declined, and management was shifted to primarily palliative and supportive care, with irregular follow-ups performed; the entire clinical course is summarized in Fig. 3 (last follow-up in March 2024).

The patient of the present study initially presented with non-keratinizing NPC (T2N1M0, stage IIA, AJCC 8th edition staging system) and received standard CCRT, yet subsequently developed inguinal and bone metastases. This case highlights the mechanisms of distant nodal spread in NPC and the diagnostic challenges they pose.

At initial diagnosis, the patient's PET/CT scan indicated positive lymph nodes only in the left upper neck, without significant enlargement in the lower neck or retroperitoneum. Although the ILN were enlarged, their low metabolic activity on PET/CT led to the diagnosis of reactive hyperplasia. ILNs are important regional lymphatic stations involved in immune surveillance and lymphatic drainage from the lower extremities, perineum, external genitalia and the distal anal canal. Based on these drainage patterns, ILNM are commonly associated with malignancies of the external genitalia, anal canal, vulva, penis, lower-extremity or trunk skin, and, less commonly, low rectal adenocarcinoma (10,11). However, PET/CT showed no tumors in these areas. Reactive lymphadenopathy (LAD) may be due to infectious, immune-mediated or neoplastic causes, all of which warrant PET/CT evaluation to inform biopsy decisions. Similar diagnostic pitfalls have been reported: In one patient with NPC, ¹⁸F-fluorodeoxyglucose PET/CT and MRI suggested bilateral cervical metastases, yet pathology revealed only reactive lymphoid hyperplasia; notably, ⁶⁸Ga-fibroblast activation protein inhibitor PET/CT showed no abnormal uptake in these nodes, suggesting that this novel tracer may aid in distinguishing reactive from metastatic LAD (12). It may be suggested that in patients with suspected reactive LAD, antitumor therapy can be initiated while closely monitoring the nodal response. If nodes show interval enlargement or progressive hypermetabolism on PET/CT, biopsy should be pursued without delay, as this indicates resistant malignant involvement rather than reactive hyperplasia. Even in the absence of regression, biopsy remains prudent to rule out occult metastatic disease, as reactive nodes may also persist after chemotherapy.

Distant metastasis of NPC to the ILNs is rare. Although the ‘seed and soil’ hypothesis (13) provides a general framework for organ-specific dissemination, imaging findings in this patient are more plausibly consistent with retrograde lymphatic spread through the supraclavicular-thoracic duct-retroperitoneal axis, rather than selective introduction into the inguinal microenvironment. In the present case, the left SCLN, initially interpreted as reactive hyperplasia on baseline PET/CT, was later highly suggestive of metastasis on follow-up PET/CT (Fig. 2G). This progression provides critical information on the likely route of inguinal dissemination. According to the retrograde metastatic pathway, tumor cells that drain from the nasopharynx into the cervical lymphatic system can reach the thoracic duct through the SCLN. When normal antegrade flow to the venous angle is obstructed, either due to tumor burden or lymphatic damage, malignant cells can reflux retrograde through the lymphatic trunks, descending into the mediastinum, retroperitoneum, and finally the pelvic and inguinal regions (14,15). Of note, subphrenic lymph node involvement-including inguinal metastasis-has been identified as an independent adverse prognostic factor in NPC (hazard ratio: 1.72, 95% CI: 1.02-2.90, P=0.038) (8). Clinically, the present case serves as a cautionary reminder: In patients with NPC and SCLN involvement, a high index of suspicion for occult subphrenic metastases should be maintained, even when inguinal lymphadenopathy exhibits only mild hypermetabolic activity on PET/CT. Persistent or progressive enlargement of the supraclavicular or inguinal nodes, regardless of low maximum standardized uptake values, warrants timely FNAB to rule out occult tumor spread. Early identification of this retrograde route may prompt more intensive initial systemic therapy and prevent the clinical understaging observed in this patient.

In addition, tumor cells can disrupt normal lymphatic structures, leading to remodeling of the lymphatic vessels. Lymphatic vessels lack the tight junctions and surrounding basement membrane layers commonly found in blood vessels, making them more fragile than blood vessels and thus weakening the barrier against tumor cell spread (16). Extracapsular invasion (Fig. 2C and D) observed in the cervical lymph nodes of the patient was associated with an increased risk of local recurrence or distant metastasis.

The N classification is an important prognostic factor for NPC, particularly with regard to distant metastasis-free survival. In the 8th edition of the AJCC staging system, stage N is based on the size and location of the nodes, although the number of metastatic lymph nodes more precisely reflects tumor burden (17). The N1 category is highly heterogeneous: Certain patients with N1 disease have outcomes comparable to those with N0 disease, whereas others experience markedly worse prognoses due to adverse nodal characteristics (18). Patients such as the one described in the present study, who exhibit extranodal extension of the cervical lymph nodes, cannot be classified as low-risk patients along with the stage N0, confirming that such a nodal phenotype warrants close surveillance for occult spread beyond initial imaging.

Longitudinal plasma EBV-DNA monitoring revealed an undetectable level at baseline (<500 copies/ml), with a transient mild elevation during the course that subsequently resolved, and a marked surge to 9.91x10⁵ copies/ml in September 2023, long after widespread metastases had been confirmed. Other serial measurements remained negative or borderline. Although EBV-DNA is well established as a sensitive marker for NPC surveillance (19-21), this trajectory illustrates that low-level or transient elevations do not exclude metastasis, particularly via lymphatic spread, and thus should not delay biopsy of suspicious nodes.

In summary, the patient was initially diagnosed with T2N1M0; however, the presence of high-risk factors for distant metastases was not recognized. The absence of timely ILN biopsy led to clinical understaging of the disease. This underestimation of tumor burden resulted in the delivery of suboptimal initial therapy (definitive chemoradiotherapy alone, without systemic immunotherapy or intensified regimen), which ultimately contributed to early disease progression rather than sustained remission. In retrospect, the inguinal lesions represented occult metastases that were not appreciable on baseline PET/CT due to their low metabolic activity. In newly diagnosed patients with inguinal LAD, it is crucial to definitively determine their nature. PET/CT and FNAB can aid in diagnosis and help avoid missing occult metastases.