Sinonasal undifferentiated carcinoma (SNUC) is an extremely rare, highly aggressive malignancy of the nasal cavity and paranasal sinuses. It has only relatively recently been recognized as a separate entity and was first described extensively by Frierson in 1986.1 Since early symptoms mimic benign nasal or sinus disease, and since SNUC is a rapidly expanding tumour, patients often present with advanced disease. Over 50% of the patients have intraorbital and/or intracranial extension of the tumour on presentation, while approximately one third have distant metastases.2,3 A cure rate of less than 20% is generally reported in the literature, with most patients dying within 1.5 years of onset of the disease. Although SNUC is very rare, it is important to be aware of this neoplasm and to differentiate it from other small or medium cell tumours, because early recognition may result in treatment success with aggressive therapy. A case of SNUC of the nasal cavity and ethmoid complex is presented with a discussion of the clinical symptoms, diagnostic modalities, and treatment of this disease.
Case Report
A 53-year-old caucasian male reported to our clinic with a progressive left-sided nasal obstruction and anosmia of 5 months' duration. He also complained of recurrent epistaxis and diplopia but denied pain. His past medical history was unremarkable. He was a nonsmoker and non-drinker who was employed as a stockbroker. Physical examination showed a firm mass over the left medial canthus measuring 3 x 3 cm. Proptosis of his left eye was present. His left nasal cavity was entirely filled by an exophytic mass. No palpable cervical adenopathy was identified. The laboratory survey was within normal limits. A CT scan (Figs. 1A and B) showed a large soft-tissue mass filling the left nasal cavity and ethmoid complex. The mass had eroded the left medial orbital wall and roof and the right medial orbital wall, and extended superiorly through the cribriform plate to involve the dura.
Biopsy of the left nasal cavity mass (Figs. 2 and 3) showed a poorly differentiated tumour with rounded hyperchromatic pleomorphic nuclei and numerous mitoses (2 M/HPF). Necrosis was seen throughout the tumour; viable areas showed closely packed sheets of cells. Immunohistochemistry revealed intense focal positivity for low molecular-weight cytokeratin (CAM 5.2) and positivity for neuron-specific enolase.
On the basis of the characteristic histologic, clinical, and radiologic findings, we diagnosed SNUC of the left nasal cavity/ethmoid complex. The patient was treated with a regimen of CAPABLE chemotherapy (Cyclophosphamide, Adriamycin, Doxorubin, Cisplatin, Methotrexate, and Bleomycin) for 5 months, with partial response, followed by radiation with a total dose of 60 Gy. Although remarkable regression was observed; residual tumour was present, and 6 months after initiation of therapy, a craniofacial resection was performed including a maxillectomy, orbital exenteration, and excision of skin. Intraoperative frozen sections showed all margins to be free of tumour. A free rectus abdominis flap was used for reconstruction. However, the patient developed a recurrence within 2 months and died shortly thereafter.
Discussion
Presenting signs of SNUC usually include nasal obstruction, rhinorrhea, and facial pain, and are commonly mistaken for a cold or sinusitis. By the time patients present to an otolaryngologist, symptoms frequently include epistaxis, proptosis, cranial nerve palsies, periorbital swelling, or diplopia.1-3 The onset of symptoms is rapid: generally only a few months,4 like the patient reported.
If the diagnosis of SNUC is considered, a CT scan of the head, including the brain, is obligatory, and, if necessary, supplemented by MRI. CT scanning will frequently show extensive bony erosions and extension of the disease that is much greater than would be expected from the clinical course.3 On MRI, intracranial and intraorbital extension can well be visualized, while SNUC characteristics include an isointensity with gray matter on T^sub 1^-weighed images, slight hyperintensity compared with gray matter on T^sub 2^-weighed images, and irregular enhancement with gadolinium.5 Once the diagnosis is confirmed, at least a chest x-ray should be performed, but a CT scan of the abdomen and a bone scan should be considered.
The histologic differential diagnosis of small/ medium-sized tumours like SNUC includes lymphoma, melanoma, rhabdomyosarcoma, lymphoepithelioma, poorly differentiated adenoid cystic carcinoma, neuroendocrine carcinoma, and olfactory (esthesioneuroblastoma), the latter two being the most difficult to distinguish histologically from SNUC.1,2 Usually, the combination of light microscopy and the clinical status will be enough to establish the diagnosis, but occasionally, immunohistochemistry or electron microscopy can be helpful.
On light microscopy, SNUC consists of small- to medium-sized cells that form nests, sheets, and trabeculae. The cells have a high nuclear-cytoplasm ratio, and numerous mitoses. The nuclei are round to oval and are moderately pleomorphic. These are usually extensive necrosis and vascular invasion. There is no 100% consistency on immunohistochemistry, but the tumours usually react positively with antibodies to cytokeratin, negatively with S100 and LCA (leukocyte common antigen), and variably with epithelial membrane antigen and neuron-specific enolase.1 Neuroendocrine carcinoma, on the other hand, has spindle-shaped or polyclonal cells, a low mitotic rate, and only focal necrosis, and shows little nuclear anaplasia, while esthesioneuroblastoma also show less mitotic activity, necrosis, and vascular invasion, and have intercellular neurofibrils and often Homer Wright rosettes, absent in SNUC. They often contain Schwann's cells visible on electron microscopy or immunohistochemistry (S-100 positivity).1
The pathogenesis of SNUC is unknown. Environmental causes and smoking are unlikely to contribute but, due to the low incidence of SNUC, difficult to rule out. It has been suggested that the Epstein-Barr virus (EBV) might contribute to the development of SNUC. In situ hybridization studies6,7 have shown that tumour cells of approximately one third of the patients with SNUC tested positive for EBV; however, in one of these studies,6 this only occurred in Asian patients.
SNUC has been reported to occur in patients who had been treated with radiation for retinoblastoma.2,8 Greger et al.8 found a deletion at the RB-1 locus of chromosome 13 in SNUC cells that was not present in normal cells, and although it can not be ruled out that this mutation was radiation induced, it is suggested that mutations at the RB-1 locus may be involved in the formation or progression of ectodermal tumours.
SNUC has a very poor prognosis. An initial report by Levine et al.2 suggested a cure rate of less than 10% with radiotherapy and chemotherapy, or radiotherapy alone. Later reports3,4 showed that an improved 5-year survival rate could be achieved in patients with early-- stage disease (no intracranial involvement, no distant metastasis) if treated aggressively. Also, patients with a SNUC primary arising in the nasal cavity appear to do better than patients with a SNUC of the paranasal sinuses.4 However, this may be due to earlier symptoms leading to earlier discovery of the disease.
Deutsch et al.3 suggested a treatment regimen of cyclophosphamide, doxorubicin (Adriamycin), and vincristine, and radiotherapy (50 Gy), followed by surgical resection in patients without distant metastasis or extensive intracranial involvement.
Conclusion
Although SNUC is a rare, aggressive neoplasm with a poor prognosis, it is important that otolaryngologists be aware of the clinical symptoms, diagnostic modalities, and optimal treatment. Diagnosis is often made by the combination of clinical, pathologic, and radiographic findings. Preoperative radiation, and chemotherapy with surgical resection to those with locally invasive disease is the treatment of choice and has improved the long-term prognosis of SNUC.
References
1. Frierson HF, Mills SE, Fechner RE, et al. Sinonasal undifferentiated carcinoma. An aggressive neoplasm derived from scheiderian epithelium and distinct from olfactory neuroblastoma. Am J Surg Pathol 1986; 10:771-779.
2. Levine PA, Frierson HF, Steward FM, et al. Sinonasal undifferentiated carcinoma: a distinctive and highly aggressive neoplasm. Laryngoscope 1987; 97:905-908.
3. Deutsch BD, Levine PA, Stewart FM, et at. Sinonasal undifferentiated carcinoma: a ray of hope. Otolaryngol Head Neck Surg 1993; 108:697-700.
4. Gallo O, Graziani P, Fini-Storchi O. Undifferentiated carcinoma of the nose and paranasal sinuses. An immunohistochemical and clinical study. Ear Nose Throat J 1993; 72: 588-590.
5. Pitman KT, Lassen LF. Pathologic quiz case 2. Arch Otolaryngol Head Neck Surg 1995; 121:1201, 1203.
6. Gallo O, Lollo SD, Graziani P, et al. Detection of Epstein-- Barr virus genome in sinonasal undifferentiated carcinoma by use of in situ hybridization. Otolaryngol Head Neck Surg 1995; 112:659-664.
7. Lopategui JR, Gaffey MJ, Frierson HF, et al. Detection of Epstein-Barr viral RNA in sinonasal undifferentiated carcinoma from Western and Asian patients. Am J Surg Pathol 1994; 18:391-398.
8. Greger V, Schirmacher P, Bohl J, et al. Possible involvement of the retinoblastoma gene in undifferentiated sinonasal carcinoma. Cancer 1990; 66:1954-19S9.
Received 04/28/97. Received revised 04/28/97. Accepted for publication 09/OS/97.
Jeroen D.F. Kerrebijn, Linda Tietze, and Jeremy L. Freeman: Department of Otolaryngology/Head and Neck Surgery; David Mock: Department of Laboratory Medicine; Mt. Sinai Hospital, Toronto, Ontario.
Supported by the Saul A. Silverman Family Foundation, and Temmy Latner Dynacare, Toronto, Ontario. Address reprint requests to: Dr. Jeremy L. Freeman, Department of Otolaryngology/Head and Neck Surgery, Mt. Sinai Hospital, Suite 401, 600 University Avenue, Toronto, ON MSG 1X5.
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