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Accepted Manuscript

Sinonasal non-small cell neuroendocrine carcinoma the validity of histological


grading: Case report and a review of the literature

Shivesh Maharaj, Farzana Mahomed

PII: S2468-5488(18)30095-X
DOI: 10.1016/j.xocr.2018.07.009
Reference: XOCR 81

To appear in: Otolaryngology Case Reports

Received Date: 10 June 2018

Accepted Date: 25 July 2018

Please cite this article as: Maharaj S, Mahomed F, Sinonasal non-small cell neuroendocrine carcinoma
the validity of histological grading: Case report and a review of the literature, Otolaryngology Case
Reports (2018), doi: 10.1016/j.xocr.2018.07.009.

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Sinonasal non-small cell neuroendocrine carcinoma the validity of histological grading :


case report and a review of the literature

Dr Shivesh Maharaj, Dept of Otorhinolaryngology, University of the Witwatersrand

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Dr Farzana Mahomed, Dept Of Oral Pathology, University of the Witwatersrand

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Abstract

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Introduction:
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Paucity of reported cases and lack of significant follow-up preclude definitive statements

regarding the prognosis of sinonasal non-small cell neuroendocrine carcinoma (NSNEC). The
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validity of histologic grading as a prognostic indicator in sinonasal NSNEC is also not known.
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Case Report:
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We present a case of a primary moderately differentiated neuroendocrine carcinoma (atypical

carcinoid tumour) that showed unilateral involvement of the nasal cavity, maxillary sinus and
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sphenoid sinus. The tumor cells displayed fairly uniform round to oval stippled nuclei with

abundant granular, eosinophilic cytoplasm. There was positivity for neuroendocrine and

epithelial markers. The patient underwent surgery with post-operative adjuvant radiotherapy.

There has been no recurrence or distant metastasis in the 93-months since the patient’s initial

presentation.

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Conclusion

The role of histologic subtyping and grading as a potential prognostic indicator within the

sinonasal family of neuroendocrine tumors is discussed.

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Key words: Neuroendocrine carcinoma, Non-small cell neuroendocrine carcinoma, paranasal

sinus

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Introduction

In concordance with other organ systems, the spectrum of neuroendocrine neoplasia of the
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sinonasal tract has expanded over the years to include tumors with heterogenous histologic
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growth patterns that in the sinonasal complex have been denoted as well differentiated NEC or
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typical carcinoid, moderately differentiated NEC or atypical carcinoid, small cell carcinoma

neuroendocrine type and NEC “not otherwise specified”.1 Sinonasal small cell NECs usually
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have a poor prognosis frequently associated with local recurrence and distant metastases.1 For

the non-small cell NECs (NSNEC), the validity of histologic grading to predict biologic
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aggression in sinonasal NSNEC is not known. This report describes a case of sinonasal non-
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small cell neuroendocrine carcinoma (NSNEC) that satisfied the histologic criteria for a

moderately differentiated NEC or atypical carcinoid at this site. To our knowledge this is the

first paper that analyzes the role of histologic grading as a potential prognostic indicator in the

largest series of NSNEC thus far reviewed in the literature.

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Case report

A 65-year-old woman presented to the Charlotte Maxeke Johannesburg Academic Hospital in

September 2005 complaining of right nasal obstruction. On physical examination there was

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mild, non-tender elevation of the right nasal and malar area with very minimal proptosis of the

right eye. A right intranasal mass was evident on sinus endoscopy. Computed tomography (CT)

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scans of the paranasal sinuses showed an expansile mass occupying the right nasal cavity and

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involving the right lamina papyracea. The tumor caused a defect in the cribriform plate but did

not extend intracranially. The patient denied smoking or exposure to prior irradiation. Past

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medical history was not significant for previous malignancy. Biopsy specimens indicated
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neuroendocrine carcinoma with features reminiscent of an atypical carcinoid tumor. CT scans of

the chest and abdomen showed no lesions elsewhere in the body, stage AJCC (American Joint
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Committee on Cancer) T4N0M0. The patient subsequently underwent a right medial

maxillectomy and a right lateral rhinotomy (Figure 1). Post-operative radiotherapy was
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administered prophylactically to the main tumour bed and ipsilateral hemi-neck with radiation
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doses of 5400 cGy in 27 fractions and 3500 cGy in 14 fractions respectively within a 10-week

period. The patient’s serum chromogranin A levels are being monitored at 3-monthly intervals.
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There is no recurrent or metastatic disease at 7 years and 9 months follow-up.


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Pathological findings

The tumor was histologically characterized by a proliferation of relatively uniform round to

polygonal cells that were arranged in nests and small anastomosing trabeculae (Figure 2). The

mitotic rate, which was assessed in areas where the mitoses were most frequent after a general

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slide survey, yielded an average of 9 mitoses/10 high power fields (hpf) or 2mm2 (mitoses

ranged from 4-15/10 hpf, as counted in 100 hpf). Necrosis was absent. The tumor invaded the

surrounding tissue in an expansile fashion, extending to just beneath the surface epithelium but

without causing ulceration of the mucosa and where residual glands were notably incorporated

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into the tumor (Figure 3).

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Discussion

NSNEC are rare tumors of the sinonasal tract. We have been able to identify 68

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histomorphologically diverse cases that have been reported in the literature over a 36-year
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period. These cases have been reported under various names (typical carcinoid, atypical

carcinoid, malignant carcinoid, oncocytic carcinoid, goblet cell carcinoid, low-, intermediate-
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and high-grade neuroendocrine carcinoma, poorly differentiated intraepithelial neuroendocrine


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carcinoma, neuroendocrine carcinoma). In some of the earlier reports, the distinction between
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NEC and other neuroectodermal tumors was based on the findings on routine light microscopy

and/or electron microscopy alone.2-6 Sinonasal NEC, olfactory neuroblastoma and


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paraganglioma, however, may show overlapping histomorphologic features and

immunohistochemical study is essential for differentiating between these entities. For the
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purpose of diagnostic accuracy we therefore reviewed only those tumors that were positive for
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one/more neuroendocrine markers and further where the diagnosis of NEC was supported by

epithelial marker positivity.

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Of the 68 NSNEC that have been reported in the literature, 25 cases were described before the

advent of immunohistochemistry,2-4 3 tumors were not tested with an epithelial marker,5-7 1

tumor was both cytokeratin and epithelial membrane antigen negative,8 while in a further case a

cytological biopsy alone was performed.9 We consequently reviewed the clinical and pathologic

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characteristics of 38 cases in this rare group of tumors and add our case to the series (Table 1).

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Individuals in their fifth decade were generally affected (mean=54.4 years; median=54 years).

Twenty-five (64.1%) patients were male and 14 (35.9%) female. Presenting symptoms included

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epistaxis, facial pain, paralysis or dizziness. There was preferential involvement of the nasal

cavity. In the 14 cases, which specified the exact site/s involved by the sinonasal tumor, 5

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tumors were localized to the nasal cavity,10-13 in 6 cases there was concomitant involvement of
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the nasal cavity, ipsilateral maxillary and/or ethmoid sinus.7,14,15 In these instances it was

difficult to determine the specific origin of occurrence as the tumors were often locally
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advanced. Three tumours were confined either to the sphenoid or ethmoid sinus and 1 tumor
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extended into the nasopharynx.12,15,16 Primary NSNEC has been treated by resection, sinus
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endoscopy, radiosurgery, radiation and/or chemotherapy, although no specific guidelines exist.


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Based on the histologic grades that were rendered in 21 of the 39 reviewed cases (Table 1), 1
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tumor was categorized as an in situ NEC,10 4 cases corresponded to well differentiated or low-
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grade NEC,11,12,14,15 11 cases represented moderately differentiated or intermediate grade

NEC,12,15,17 while the 5 tumors that were classified as high-grade or poorly differentiated NEC

showed non-carcinoid morphology with histologic features that were analogous to pulmonary

large cell NEC7,13,16; a possible indication that this histologic subtype may occur at this site and

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therefore merits consideration for inclusion in the WHO classification of neuroendocrine

tumours of the nasal cavity, paranasal sinuses and nasopharynx.

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The validity of histologic grading to predict biologic aggression in sinonasal NSNEC has rarely

been investigated. There were 18 patients with NSNEC in the series of cases reported by

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Rosenthal et al.18 The histologic grades of tumor differentiation were, however, not described in

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the former study. In a series of 20 patients with sinonasal NEC recently reported by

Lickhacheva et al.17 which included 7 moderately differentiated and 13 poorly differentiated

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tumors, pathologic differentiation did not appear to be a critical factor in the clinical
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management of these patients. Well differentiated (low-grade) tumors were, however, not

analyzed and the poorly differentiated group was not exclusively of the non-small cell type.
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We undertook a descriptive analysis of NSNEC cases, where the histologic grade of the tumor
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was specified in the published report, in order to ascertain whether histologic grade has bearing

on the aggressiveness or metastatic potential of these tumors. Of the 4 low-grade tumors and 1
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in situ NEC, 4 patients were alive with no evidence of disease (mean follow up = 44.6 months)
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(Table 1), while 1 patient was alive with stable disease 7 years after the initial diagnosis.15 Of
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the 11 patients in the intermediate grade category, 6 patients experienced no adverse outcome

after the initial treatment and were alive without disease at the latest follow-up (mean follow-up

= 76.3 months) (Table 1). The other 5 patients in the intermediate category either developed

local recurrence (n=2), nodal (n=2) or distant metastases (n=1). Two of 11 patients in the

intermediate category died of disease.17 Two of the five patients with high grade tumors died of

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disease, while 1 patient is alive with disease (mean follow-up = 24.8 months) (Table 1). An

adverse outcome was encountered in 1/5 well differentiated, 5/11 moderately differentiated and

3/5 poorly differentiated sinonasal NSNEC. Although the number of reported cases is still too

few to draw definitive conclusions regarding whether histological separation is reflective of

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biologic heterogeneity in sinonasal NSNEC, there appears to be a trend of increased biologic

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aggression with increasing tumor grades. Future studies in larger populations are essential to

delineate the clinical relevance and prognostic significance of histologic grading in this rare

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group of neuroendocrine tumors. The use of additional prognostic parameters such as Ki-67

labeling index and TNM classification for sinonasal NSNEC also awaits future study.

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Funding
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This research received no specific grant from any funding agency in the public, commercial, or
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not-for-profit sectors.
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References

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1. Neuroendocrine tumours. Barnes L, Eveson JW, Reichart P, Sidransky D (Eds): World Health

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Organization classification of tumours. Pathology and genetics. Head and neck tumours, IARC

Press, Lyon 2005;135-139.

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2. Yamamoto K, Sakai S, Honda M, Hyo Y, Hoshiya T. Carcinoid tumor of the maxillary sinus.
AN
Jibi-Rinsho (Clin Oto-rhinol). 1975;68:965-971.

3. Kameya T, Shimosato Y, Adachi I, Abe K, Ebihara S, Ono I. Neuroendocrine carcinoma of


M

the paranasal sinus: a morphological and endocrinological study. Cancer. 1980;45:330-339.

4. Silva EG, Butler JJ, Mackay B, Goepfert H. Neuroblastomas and neuroendocrine carcinomas
D

of the nasal cavity: a proposed new classification. Cancer. 1982;50:2388-2405.


TE

5. Siwersson U, Kindblom LG. Oncocytic carcinoid of the nasal cavity and carcinoid of the lung

in a child. Pathol Res Pract. 1984;178:562-569.


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6. Contrucci RB, Holmes WF, Heffron T. Neuroendocrine tumors of the nose and upper airway.
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Ear Nose Throat J. 1985;64:235-238.


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7. Smith SR, Som P, Fahmy A, Lawson W, Sacks S, Brandwein M. A clinicopathological study

of sinonasal neuroendocrine carcinoma and sinonasal undifferentiated carcinoma. Laryngoscope.

2000;110:1617-1622.

8. Westerveld GJ, van Diest PJ, van Nieuwkerk EB. Neuroendocrine carcinoma of the sphenoid

sinus: a case report. Rhinology. 2001;39:52-54.

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9. Loo CK, Chin M, Farrell M, Wu XJ. Sinonasal neuroendocrine carcinoma: case report with

FNA findings. Pathology. 2006;38:181-184.

10. Watanabe K, Ogura G, Suzuki T. Intra-epithelial neuroendocrine carcinoma of the nasal

cavity. Pathol Int. 2003;53:396-400.

PT
11. Lee DH, Cho HH, Cho YB. Typical carcinoid tumor of the nasal cavity. Auris Nasus Larynx.

RI
2007;34:537-539.

12. Wang CP, Hsieh CY, Chang YL, Lou PJ, Yang TL, Ting LL, Ko JY. Postirradiated

SC
neuroendocrine carcinoma of the sinonasal tract. Laryngoscope. 2008;118:804-809.

13. Mendis D, Malik N. Sinonasal neuroendocrine carcinoma: a case report. Ear Nose Throat J.

2008;87:280-282.
U
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14. McCluggage WG, Napier SS, Primrose WJ, Adair RA, Toner PG. Sinonasal neuroendocrine

carcinoma exhibiting amphicrine differentiation. Histopathology. 1995;27:79-82.


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15. Weinreb I, Perez-Ordonez B. Non-small cell neuroendocrine carcinoma of the sinonasal tract
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and nasopharynx. Report of 2 cases and review of the literature. Head and Neck Pathol.
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2007;1:21-26.

16. Esposito F, Kelly DF, Vinters HV, DeSalles AA, Sercarz J, Gorgulhos AA. Primary
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sphenoid sinus neoplasms: a report of four cases with common clinical presentation treated with

transsphenoidal surgery and adjuvant therapies. J Neurooncol. 2006;76:299-306.


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17. Likhacheva A, Rosenthal DI, Hanna E, Kupferman M, Demonte F, El-Naggar AK. Sinonasal
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neuroendocrine carcinoma: impact of differentiation status on response and outcome. Head Neck

Oncol. 2011;3:32.

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18. Rosenthal DI, Barker JL Jr, El-Naggar AK, Glisson BS, Kies MS, Diaz EM Jr. Sinonasal

malignancies with neuroendocrine differentiation: patterns of failure according to histologic

phenotype. Cancer. 2004;101:2567-2573.

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Table 1 Sinonasal non-small cell neuroendocrine carcinoma: review of published reports

Author Age/ Tumor location Histopathologic subtype Treatment Outcome Follow-up


Gender of NEC

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McCluggage et al.14 73M Ethmoid sinus, NC, Goblet cell carcinoid Resection NED 3 months
maxillary sinus
Smith et al.7 58M NC, ethmoid sinus High grade (NOS) Resection, C DOD 14 months

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42M NC, ethmoid sinus High grade (NOS) Resection, C, R NED 31 months
34M NC, ethmoid sinus High grade (NOS) Resection, R Nodal metastasis, DOD 41 months
Watanabe et al.10 46F NC Intraepithelial NEC Radiosurgery NED 40 months

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Rosenthal et al.18 M (n=10) Not specified NEC (NOS) R and/or C and/or Nodal metastasis (n=2), 72.6% 5-yr
F (n=8) surgery distant metastasis (n=10) survival
Esposito et al.16 70M Sphenoid sinus High grade (LC) Subtotal removal AWD 18 months

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Lee et al.11 76M NC Typical carcinoid Sinus endoscopy NED 12 months
Weinreb and Perez- 67M Ethmoid sinus, NC Intermediate grade R NED 48 months

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Ordonez et al.15 34M Nasopharynx, Low grade None, tumour AWD 84 months
sphenoid sinus unresectable
Wang et al.12 67F NC Atypical carcinoid Surgery Local recurrence, NED 14 months

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63M NC Atypical carcinoid Surgery, C, R NED 16 months
42F Ethmoid sinus Typical carcinoid Surgery NED 84 months
Mendis et al.13

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73M NC Poorly differentiated Surgery, R NED 20 months
NEC, LC

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Lickacheva et al.17 22M NS Moderately differentiated Surgery, R NED 166 months
67F NS Moderately differentiated Surgery, C, R Dural metastases (21 mo), 56.2 months
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43F NS Moderately differentiated Surgery, R NED 31.3 months
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46M NS Moderately differentiated C, R NED 16.6 months
54M NS Moderately differentiated Surgery, C, R Nodal metastases (46 mo), 107 months
NED
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47M NS Moderately differentiated Surgery, R Nodal metastasis (125 mo), 172 months
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54M NS Moderately differentiated Surgery, C, R Local recurrence (80 mo), 119 months
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Current report 65F NC, maxillary sinus, Moderately differentiated Surgery, R NED 93 months
sphenoid sinus
NC nasal cavity, LC large cell, C chemotherapy, R radiation therapy, LR local recurrence, NED no evidence of disease, DOD died of disease,
AWD alive with disease, NS not specified, mo months

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Figure legends

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Figure 1. Post contrast computed tomography scan at 7-months post surgery showing no
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evidence of tumour recurrence.


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Figure 2. Low power view depicting a cellular infiltrate within the sinus mucosa (haematoxylin
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and eosin stain, original magnification X40). The surface respiratory epithelium is compressed
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and attenuated but not ulcerated by the tumour.


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Figure 3. Tumour comprises a compact arrangement of solid nests of fairly uniform polygonal

cells with round to oval nuclei and abundant granular eosinophilic cytoplasm (haematoxylin and

eosin stain, original magnification X400).

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