Sinonasal neuroendocrine carcinoma: a case report.

Abstract

Neuroendocrine carcinoma (NEC) is rare. We report a case of probable sinonasal NEC in a 73-year-old man who had presented with a history of right nasal obstruction, nasal discharge, and recurrent epistaxis. On examination, a red, friable, gelatinous, polypoid mass with a tendency to bleed was seen in the right nasal cavity. Computed tomography revealed that the lesion was confined to the right nasal cavity; coincidental or reactive opacification was seen in the adjacent sinuses. The final histologic evaluation of the excised biopsy specimens yielded a diagnosis of an invasive, poorly differentiated NEG probably a large-cell variant, with the differential diagnosis lying at a point somewhere between poorly differentiated large-cell NEC and high-grade olfactory neuroblastoma. The patient underwent a right lateral rhinotomy and medial maxillectomy followed by adjuvant radiotherapy. At 20 months of follow-up, he exhibited no sign of recurrence.

Introduction

Neuroendocrine carcinoma (NEC) was first proposed as a clinical entity by Silva et al in 19822 It is a rare malignant neoplasm that contains neurosecretory granules and lacks a neurofibrillary background. NEC is classified as well-differentiated, intermediately differentiated, and poorly differentiated; poorly differentiated NECs are subclassified as small-cell, intermediate-cell, and large-cell. In this article, we describe a case of an invasive, poorly differentiated sinonasal NEC, probably a large-cell variant.

Case report

A 73-year-old man presented with a 2-year history of right nasal obstruction with discharge and an 18-month history of right nasal epistaxis. He denied anosmia, pain, tearing, and diplopia, and he did not exhibit a neck mass or proptosis. His medical history included hypertension and polymyalgia rheumatica; for the latter, he was on long-term steroid therapy.

Examination revealed the presence of a red, friable, gelatinous, polypoid mass in the right nasal cavity. Findings on the remainder of the examination were unremarkable, and no cervical lymphadenopathy or cranial nerve palsies were identified. Findings on serologic testing--which included measurements of the complete blood count, renal function, liver function, and rheumatoid factor--were normal with the exception of a raised erythrocyte sedimentation rate of 26 mm/hr (range of normal: 1 to 12).

Examination under general anesthesia was performed, and a biopsy of the lesion was obtained. The examination revealed that the mass had arisen from the middle meatus and was attached to the middle turbinate. The lesion bled on contact. Computed tomography (CT) identified it as a soft-tissue mass that measured 2 to 3 cm in diameter. CT showed that the mass had expanded the right nasal cavity, a finding that suggested a chronic process rather than an invasive malignant process (figure 1,A). Some associated opacification was seen in the right frontal sinus, the right ethmoid sinuses, the left anterior and middle ethmoid sinuses, and both maxillary antra (figure 1, B and C). There was no cribriform plate invasion or intracranial extension.

The provisional histology, based on multiple pieces of tissue measuring 4 x 3 x 1 cm, was inconclusive, and therefore a second histopathologic opinion was sought. The second opinion was that the specimens represented an invasive, poorly differentiated NEC, probably a large-cell variant, with the differential diagnosis lying at a point somewhere between poorly differentiated large-cell NEC and high-grade olfactory neuroblastoma. The biopsy specimens contained part of an invasive, poorly differentiated malignant tumor that had infiltrated vascular turbinate tissue. No definitive neurophil, rosette/pseudorosette formation, or sustentacular pattern was seen on hematoxylin and eosin (H&E) staining (figure 2, A). There was also an absence of a central neurofibrillary matrix. The tumor cells expressed avid CD56, synaptophysin, and chromogranin A immunoreactivity (figure 2, B). The results of staining for cytokeratin (CK) 5/6, CK7, and epithelial membrane antigen were equivocal (figure 2, C). Stains were negative for vimentin, S-100 protein, melan-A, HMB-45, carcinoembryonic antigen, CAM 5.2, broad-spectrum cytokeratins, CK8/18/19, and CK20.

The patient underwent a right lateral rhinotomy and medial maxillectomy; a lateral rhinotomy incision with a Lynch extension was used. Lateral flaps were dissected to the inferior orbital nerve, and a medial flap was elevated over the right nasal bone. Orbital periosteum was dissected and moved laterally. The maxillary antrum was opened via the anterior wall with a gouge and hammer. An inferior incision was made though the inferior meatus to the posterior wall of the antrum, and the medial one-third of the orbital floor was excised. The lacrimal duct was identified and transected I cm from the sac; the sacrifice of the duct was necessary because of its proximity to the lateral edge of the tumor. A superior cut was made through the nasal bone toward the posterior aspect of the orbit, and the lateral wall was removed in a piecemeal fashion. The antrum was cleared. Anterior and posterior ethmoidectomies were carried out to clear the tumor. Diathermy, bone wax, and Surgicel were applied to achieve hemostasis.

The wound was closed and packed with a Whitehead's varnish nasal pack. (Whitehead's varnish is made up of a mixture of ether, iodoform, benzoin, storax, and tolu balsam. It is used for its antiseptic properties.) During the immediate postoperative period, the patient complained of diplopia secondary to extensive periorbital swelling; the diplopia subsided with conservative management. Two weeks postoperatively, the Whitehead's pack was removed under general anesthesia, and the patient received a course of adjuvant radiotherapy (55 Gy in 20 fractions over 1 month) delivered to the nose and paranasal sinuses.

Subsequent follow-up assessments were made with anterior rhinoscopy and flexible nasendoscopy. At 20 months postoperatively, the patient had shown no evidence of recurrence, and he had no complaints other than mild nasal crusting.

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Discussion

In this case, the final diagnosis of a probable large-cell sinonasal NEC was based on the tumor's appearance on light microscopy and its reactivity to immunohistochemical markers. In this way, we were able to distinguish sinonasal NEC from olfactory neuroblastoma and sinonasal undifferentiated carcinoma; all three are neuroectodermal tumors. These neuroectodermal tumors fall along a spectrum of disease:

* Olfactory neuroblastoma is nonepithelial and the most differentiated of the neuroectodermal tumors.

* Sinonasal undifferentiated carcinoma is the least differentiated and has the most tenuous neuroendocrine qualities.

* Sinonasal NEC lies along the spectrum somewhere in between. (2)

NEC is considered to be a less differentiated version of olfactory neuroblastoma because it has more epithelial carcinomatous features. In two-thirds of all cases, sinonasal NEC stains for epithelial markers such as low-molecular-weight cytokeratins and epithelial membrane antigen. In contrast, olfactory neuroblastoma does not generally express epithelial markers. (2) However, both NEC and olfactory neuroblastoma share neuroendocrine tendencies, and it has been postulated that both arise from basal progenitor cells in the olfactory mucosa. (1) A neoplastic proliferation of these cells is capable of developing into either NEC or olfactory neuroblastoma. An association between olfactory neuroblastoma and asbestos has been postulated. (3) This was not relevant to our case.

Both NEC and olfactory neuroblastoma express neuroendocrine markers such as synaptophysin and chromogranin, both of which were expressed in our case, as well as S- 100 protein, which was not. Bearing in mind that the presence of neuroendocrine markers makes a diagnosis of sinonasal undifferentiated carcinoma unlikely, there were specific findings in our case that favored a diagnosis of NEC over olfactory neuroblastoma. One of these findings was the absence of cribriform plate invasion. Also, olfactory neuroblastoma has a tendency toward rosette formation and a central neurofibrillary matrix, and these were absent in our patient. Another difference between the two is that NEC exhibits a diffuse pattern of S-100 expression, and olfactory neuroblastoma exhibits a sustentacular pattern (4)--but again, S-100 protein was not expressed in this case.

Radiologically, sinonasal NEC and sinonasal undifferentiated carcinoma are indistinguishable from olfactory neuroblastoma. Both entities can appear as an aggressive soft-tissue mass that invades adjacent bone rather than remodeling it. With smaller sinonasal NECs, the mass is usually polypoid and confined to one nasal cavity, as occurred in our patient.

In terms of tumor site, most sinonasal NECs and sinonasal undifferentiated carcinomas occur in the same sites as do olfactory neuroblastomas--that is, in the superior nasal cavity, the superior turbinate, and the ethmoid sinuses. Onlysinonasal NEC has been reported in the middle turbinate. (2)

There is clinical relevance in distinguishing between sinonasal NEC and olfactory neuroblastoma because the latter is typically more aggressive and invasive. However, more cases need to be described and analyzed before we can make any significant comments on the differences in prognosis.

No mete-analysis has been published on the optimal management of sinonasal NEC, but we do know that treatment of all neuroectodermal tumors should include adequate resection margins and adjuvant radiotherapy, which our patient received. For our patient, we chose an open approach for surgical resection because of the friable and bleeding nature of the tumor. The optimal management of olfactory neuroblastoma has been reported as a combination of surgical resection with adjuvant radiotherapy. (5) Resection can be accomplished via either an endoscopic or open approach. The role of chemotherapy and elective neck dissection remains unclear.

References

(1.) Silva EG, Butler JJ, MacKay B, Goepfert H. Neuroblastomas and neuroendocrine carcinomas of the nasal cavity: A proposed new classification. Cancer 1982;50(11):2388-2405.

(2.) Smith SR, Som P, Fahmy A, et al. A clinicopathological study of sinonasal neuroendocrine carcinoma and sinonasal undifferentiated carcinoma. Laryngoscope 2000;110(10 Pt 1):1617-22.

(3.) Olsen KD, DeSanto LW. Olfactory neuroblastoma. Biologic and clinical behavior. Arch Otolaryngol 1983;109(12):797-802.

(4.) Hirose T, Scheithauer BW, Lopes MB, et al. Olfactory neuroblastoma. An immunohistochemical, ultrastructural, and flow cytometric study. Cancer 1995;76(1):4-19.

(5.) Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: A mete-analysis and review. Lancet Oncol 2001;2 (11):683-90.

Dulani Mendis, MRCS, DOHNS; Nasser Malik, FRCS(Edin.), DLO

From the Department of ENT Surgery, Queen's Hospital, Burton-upon-Trent (Miss Mendis), and the Department of ENT Surgery, Royal Wolverhampton Hospitals (Mr. Malik), U.K.

Corresponding author: Miss Dulani Mendis, Department of ENT Surgery, Queen's Hospital, Belvedere Rd., Burton-upon-Trent, Derby DE 13 ORB, UK. Phone: [phone] (bleep 351); fax: [phone]; e-mail: [e-mail]