Group A
Tumor confined to the nasal cavity.
Sinonasal Undifferentiated Carcinoma
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Sinonasal Undifferentiated Carcinoma (SNUC)?
Section titled “1. What is Sinonasal Undifferentiated Carcinoma (SNUC)?”Sinonasal undifferentiated carcinoma (SNUC) is an extremely rare and rapidly progressive malignant tumor arising in the nasal cavity and/or paranasal sinuses, first reported by Frierson et al. in 1986. It is thought to originate from the Schneiderian epithelium lining the sinonasal tract. Histologically, it is defined as an undifferentiated carcinoma without squamous or glandular differentiation.
According to a Swedish study, SNUC accounts for 5.8% of all sinonasal tumors. A US study (318 cases) reported 62% male, 82.7% White, with peak incidence in the 50s 2). The age-adjusted incidence rate is extremely low at 0.02 per 100,000. The most common sites are the nasal cavity, ethmoid sinus, and maxillary sinus, with onset across a wide age range (40–85 years, most commonly in the 40s–50s) 2).
Q
What is the incidence rate of SNUC?
A
The age-adjusted incidence rate is 0.02 per 100,000, making it an extremely rare tumor. In a Swedish study, it accounted for 5.8% of sinonasal tumors, with a male predominance in the 50s. In Japan, squamous cell carcinoma is the most common (about 80%) among all malignant sinonasal tumors, with SNUC comprising only a small fraction.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”Subjective Symptoms
Section titled “Subjective Symptoms”- Nasal obstruction and epistaxis: The most common initial symptoms.
- Headache and facial pain: Occur with local tumor extension.
- Rapid symptom progression: Characterized by rapid progression over weeks to months, often mistaken for benign diseases (e.g., sinusitis), leading to delayed diagnosis.
- Diplopia: Often caused by abducens nerve palsy due to tumor invasion of the orbit or skull base1).
- Visual impairment and proptosis: Due to optic nerve compression within the orbit or direct orbital invasion by the tumor.
- Hyposmia: Occurs with ethmoid sinus or nasal cavity involvement2).
Clinical Findings
Section titled “Clinical Findings”- Large locally advanced lesion: Usually found as a mass >4 cm, with bone destruction and remodeling.
- Intracranial extension: Frequently observed, with possible invasion of the anterior cranial fossa2).
- Orbital invasion findings: Proptosis, restricted eye movement, eyelid swelling/ptosis, decreased visual acuity, visual field defects, conjunctival edema/hyperemia.
- Superior orbital fissure syndrome: When the tumor extends to the orbital apex, total ophthalmoplegia and sensory disturbance in the V1 distribution of the trigeminal nerve occur. Addition of optic nerve involvement leads to orbital apex syndrome.
- Cranial nerve palsy: Abducens nerve palsy (diplopia) is particularly common1).
- Cervical lymph node metastasis: Present in 10–30% of cases at initial diagnosis2).
- Stage: Over 60% are AJCC stage 3 or 4, with T4 diagnosis in 71–100%3).
Q
Are the initial symptoms similar to sinusitis?
A
Initial symptoms such as nasal obstruction, epistaxis, and headache are similar to chronic sinusitis, often leading to delayed diagnosis. Characteristic features of SNUC include rapid symptom progression (over weeks to months) and the appearance of ocular symptoms (diplopia, proptosis, visual loss) and cranial nerve palsy. When these are present, sinonasal malignancy should be strongly suspected.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”SNUC is a malignant tumor derived from the Schneiderian epithelium, but clear risk factors have not been established.
- Association with EBV (Epstein-Barr virus): An association with EBV has been suggested in Asian populations, but multiple reports indicate that EBV genome is not detected in strictly defined SNUC, making the association unlikely 1). EBV-positive cases may represent a different tumor with lymphoepithelial carcinoma-like features 1).
- Occupational exposure: Metal dust and textile fibers have been identified as general risk factors for sinonasal carcinoma, but there are no data specific to SNUC 1).
- Smoking: Some case reports note patients with a history of smoking, but a clear causal relationship has not been established 3).
- Molecular background: SMARCB1 (INI-1) gene loss and IDH2 codon 172 mutations have been identified as important molecular abnormalities defining subtypes of SNUC.
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”Imaging Diagnosis
Section titled “Imaging Diagnosis”CT: Shows a non-calcified mass with sinus obstruction, bone destruction, and bone remodeling. Contrast enhancement shows variable patterns. If orbital invasion with bone destruction is present, sinonasal malignancy is strongly suspected.
MRI Findings:
| Imaging Sequence | Typical Findings |
|---|---|
| T1-weighted (without contrast) | Homogeneous mass isointense to skeletal muscle |
| T2-weighted | Hyperintense relative to skeletal muscle |
| T1-weighted (with contrast) | Heterogeneous enhancement |
Benign mucoceles show homogeneous high signal on T2-weighted images, making differentiation relatively easy. Definitive diagnosis requires histopathological examination after biopsy; imaging alone is insufficient. Whole-body evaluation with PET-CT and contrast-enhanced CT is also performed.
Staging (Kadish classification)
Section titled “Staging (Kadish classification)”Group B
Tumor confined to the nasal cavity and paranasal sinuses.
Group C
Extension beyond the nasal cavity and paranasal sinuses, including invasion of the orbit, skull base, or brain parenchyma.
Modified stage D
With cervical lymph node metastasis or distant metastasis.
The higher the Kadish stage, the worse the prognosis.
Histopathological Diagnosis
Section titled “Histopathological Diagnosis”- Histological findings: Large fungating tumor, highly cellular proliferation with extensive necrosis, pleomorphic undifferentiated cells.
- Immunohistochemistry (IHC): Positive for CK7, CK8, CK8/18, CK19, pan-keratin. Negative for CK4, CK5/6, CK142).
- Confirmation of SMARCB1 (INI-1) deficiency: Loss of nuclear INI-1 expression is important for definitive diagnosis3). 72.5% of patients are initially misdiagnosed3).
Differential diagnosis: Squamous cell carcinoma, olfactory neuroblastoma, small cell undifferentiated neuroendocrine carcinoma, sinonasal lymphoepithelial carcinoma, mucosal malignant melanoma, hematolymphoid malignancies, rhabdomyosarcoma.
Q
What tests are necessary for a definitive diagnosis of SNUC?
A
Definitive diagnosis is based on histopathological examination after biopsy. Confirmation of IHC markers (positive for CK7, CK8, etc., negative for CK5/6, etc.) is essential. If SMARCB1 (INI-1)-deficient subtype is suspected, IHC for nuclear INI-1 expression should be added. Imaging (CT, MRI) is essential for assessing the extent of the lesion and treatment planning, but does not provide a definitive diagnosis.
5. Standard Treatment
Section titled “5. Standard Treatment”There is no established universal treatment strategy; various combinations of chemotherapy, radiotherapy, and surgical resection are used. If possible, total resection is desirable. For extensive intraorbital invasion, radiotherapy alone or triple therapy with chemotherapy plus surgery is selected.
Comparison of treatment outcomes:
| Treatment Strategy | Approximate 5-Year Survival Rate |
|---|---|
| Surgical resection + adjuvant chemoradiotherapy | 55.8% |
| Chemoradiotherapy alone | 42.6% |
| Negative resection margin | 75.3% |
| Metastatic disease | 18.6% |
Triple therapy (chemotherapy + radiotherapy + surgical resection) has a 5-year survival rate of 51% vs. 38% for other management. With IMRT, 59% vs. 16% without IMRT. A dose-response relationship has been reported: 73% with ≥60 Gy vs. 23%.
Chemotherapy regimens: Cyclophosphamide + vincristine + doxorubicin, or etoposide + cisplatin. Radiation dose of 50–65 Gy is recommended2).
A report from Japan (Miyata et al. 2022) described a case of unresectable T4bN0M0 SNUC of the left maxillary sinus in a 75-year-old woman treated with TPF induction chemotherapy (docetaxel 70 mg/m² + cisplatin 70 mg/m² + fluorouracil 750 mg/m² for 5 days) → VMAT 70 Gy/35 fractions → HDR-ISBT boost 16 Gy/4 fractions → nivolumab (240 mg/body every 2 weeks), achieving complete response at 2 months and disease-free survival for 2 years6).
Q
What is the most important factor affecting treatment outcomes?
A
Achieving a negative resection margin (R0 resection) is most important. The 5-year survival rate for negative margins is 75.3%, whereas all patients with positive margins died by 5 years. Triple therapy (chemotherapy + radiotherapy + surgery) and the use of intensity-modulated radiotherapy (IMRT) contribute to improved survival.
6. Pathophysiology and Detailed Pathogenesis
Section titled “6. Pathophysiology and Detailed Pathogenesis”SNUC is an undifferentiated carcinoma derived from the Schneiderian membrane epithelium, and molecular subtype classification is advancing.
SMARCB1-deficient type
Mechanism: Inactivation of the SMARCB1 tumor suppressor gene on chromosome 22q11.2 4). Loss of the core subunit INI-1 protein of the SWI/SNF complex impairs transcriptional regulation and cellular function 3).
Frequency: Approximately 3–6% of sinonasal carcinomas 3)4).
Prognosis: Particularly poor (median OS 22 months, mortality 45.3%, distant metastasis 49.3%) 3).
WHO classification: Classified as a subtype of SNUC in the 5th edition (2022) 3).
IDH2 mutant type
Mechanism: Mutations at codon 172 of IDH2 (e.g., R172K, R172S) result in neomorphic enzyme activity, producing 2-hydroxyglutarate (2-HG) from isocitrate instead of α-ketoglutarate 7).
Consequence: Accumulation of 2-HG → inhibition of histone demethylases and TET enzymes → global DNA hypermethylation 7).
Prognosis: Considered relatively favorable 7).
SMARCA4 (BRG1)-deficient type: Amigay et al. reported complete loss of SMARCA4 and reduced SMARCB1/INI1 expression in all 10 cases of SNUC 2).
Immune evasion mechanism: Reduced expression of major histocompatibility complex (MHC) promotes immune evasion 3). Upregulation of PRAME and BRCA1 may serve as theoretical targets for immunotherapy 3).
7. Latest Research and Future Perspectives (Investigational Reports)
Section titled “7. Latest Research and Future Perspectives (Investigational Reports)”Immune checkpoint inhibitors
Section titled “Immune checkpoint inhibitors”Trinh et al. administered dual immune checkpoint inhibition with pembrolizumab (200 mg) plus ipilimumab (1 mg/kg) to a 56-year-old woman with metastatic p16-positive SNUC after multiple lines of chemotherapy had failed 5). Marked improvement of liver metastases was achieved, but Grade IV polyneuritis and SIADH (immune-related adverse events) occurred, which improved with prednisone 1 mg/kg. The patient eventually died of COVID-19 four years after starting immunotherapy. It has been suggested that the addition of the COX-2 inhibitor celecoxib may have enhanced the immune response via IDO1 suppression 5).
In the first report of immunotherapy (anti-PD-1 agent tislelizumab) for SDSC (SMARCB1-deficient subtype), a 34-year-old man who received additional administration after surgery plus chemoradiotherapy had no recurrence and no distant metastasis at 2 years 3).
High-dose-rate interstitial brachytherapy (HDR-ISBT) boost
Section titled “High-dose-rate interstitial brachytherapy (HDR-ISBT) boost”There is a report from Japan on adding a brachytherapy boost for residual tumors after definitive chemoradiotherapy. Compared with proton and carbon ion therapy, it has the advantage of a steep dose gradient and less impact on normal tissues, and is technically feasible especially for maxillary sinus cancer 6).
Potential of molecular targeted therapy
Section titled “Potential of molecular targeted therapy”- IDH2 mutant type: Application of IDH inhibitors already approved for other cancers is expected 7).
- SMARCB1-deficient type: The potential of epigenetic therapies such as EZH2 inhibitors is being studied 3).
8. References
Section titled “8. References”- Kaifee SQ, Haq Y, Sadhar B. Non-Epstein-Barr virus sinonasal undifferentiated carcinoma presenting as diplopia and rhinorrhea. Cureus. 2024;16(1):e53185.
- Antoniades E, Cheva A, Constantinidis J, et al. Intracranially extended sinonasal undifferentiated carcinoma: a case report and literature review. Am J Case Rep. 2022;23:e935876.
- Zhang L, Gao AX, He YL, et al. Immunotherapy in SMARCB1 (INI-1)-deficient sinonasal carcinoma: two case reports. World J Clin Cases. 2023;11(32):7911-7919.
- Douglas JE, Kaufman AC, Rajasekaran K. Management of a unique sinonasal undifferentiated carcinoma subtype in the era of SARS-CoV-2. ORL. 2020. DOI:10.1159/000511713.
- Trinh JQ, Acosta C, Easwar A, et al. Durable and dramatic response to checkpoint inhibition combined with COX-2 inhibitor celecoxib in a patient with p16+ metastatic sinonasal undifferentiated carcinoma: a case study. Cancer Reports. 2024;7:e1915.
- Miyata Y, Murakami N, Honma Y, et al. Technical report: a high-dose-rate interstitial brachytherapy boost for residual sinonasal undifferentiated carcinoma. J Radiat Res. 2022;63(6):879-883.
- Burgermeister S, Stoykova S, Krebs FS, et al. Methylation-based characterization of a new IDH2 mutation in sinonasal undifferentiated carcinoma. Int J Mol Sci. 2024;25:6518.
- Ayyanar P, Mishra P, Preetam C, Adhya A. SMARCB1/INI1 deficient sino-nasal carcinoma: extending the histomorphological features. Head Neck Pathol. 2021;15:555-565.
- Ma S, Xia Y, Wang M, et al. SMARCB1 (INI1)-deficient sinonasal carcinoma with yolk sac differentiation, a case of long-term clinical remission after multiple rounds of radiotherapy. Diagn Pathol. 2025;20:102.