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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 293-295

Who knows the nose? – The tale of esthesioneuroblastoma and sinonasal neuroendocrine carcinoma

1 Division of Medical Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, Maharashtra, India
2 Division of Hematology and Medical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA

Date of Submission05-Apr-2020
Date of Acceptance12-Apr-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Sewanti Limaye
Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Four Bungalows, Andheri West, Mumbai - 400 093, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_122_20

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How to cite this article:
Limaye S, Shreenivas A. Who knows the nose? – The tale of esthesioneuroblastoma and sinonasal neuroendocrine carcinoma. Cancer Res Stat Treat 2020;3:293-5

How to cite this URL:
Limaye S, Shreenivas A. Who knows the nose? – The tale of esthesioneuroblastoma and sinonasal neuroendocrine carcinoma. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Sep 19];3:293-5. Available from: http://www.crstonline.com/text.asp?2020/3/2/293/287202

Sinonasal malignancies are rare but aggressive cancers, mostly diagnosed at a locally advanced or advanced stage.[1] Surgery has remained the main treatment for this heterogeneous group of cancers; however, nearly one-third are locally advanced at presentation, preventing upfront surgical approach.[2] Prospective randomized data are deficient due to the limited number of cases and diversity of the histopathological subtypes, leading to distinctly different biological behaviors. The bigger responsibility is to understand the difference in pathology of the different kinds of paranasal cancers, comprehend the differences in prognosis and response to therapy, and tailor the treatments accordingly; multimodality therapy has emerged as an improved treatment approach.[3] Although prospective data are lacking, evidence, in the form of large-case series and retrospective reviews, is growing in favor of enhanced survival with induction/neoadjuvant chemotherapy (NACT) in the locally advanced cases.[4],[5],[6],[7],[8],[9],[10] Sinonasal malignancies with neuroendocrine differentiation are difficult to distinguish, and based on their histopathological characteristics and clinical behavior are categorized into sinonasal undifferentiated carcinomas, sinonasal neuroendocrine carcinomas (SNEC), esthesioneuroblastomas, and small-cell carcinomas. Kadish clinical staging and the Dulguerov system based on the TNM staging are utilized for tumor staging, and the Hyams histologic grading system is used for the pathologic grading of these tumors.[11]

Esthesioneuroblastoma or olfactory neuroblastoma is a rare type of cancer of the olfactory epithelium, with no specific etiology and no particular genetic predilection.[11] The largest dataset presented is a SEER data analysis of 311 patients, where the median age of presentation was 53 years with a slight male predominance. In this analysis, 54% of the patients had locally advanced disease, and 29% had regional or distant metastases.[12],[13] Presentation is mostly with symptoms such as difficulty breathing due to nasal obstruction, epistaxis, and anosmia, from 6 months to 1 year. Local invasion to the skull base, clivus, or orbital invasion are relatively common presentations that make surgical intervention difficult, if not impossible. Headache, ear pain, orbital or paraorbital pain, proptosis, diplopia, and blurred vision could also be presenting symptoms, due to local invasion.

SNEC is another subcategory of the sinonasal malignancies with neuroendocrine differentiation and a significant overlap of characteristics with esthesioneuroblastomas; the main differentiating factor is that the SNEC show a strong reactivity with both epithelial and neuroendocrine markers, whereas esthesioneuroblastomas show higher reactivity with neuroendocrine markers, but low or no reactivity to epithelial markers. In addition, most cases of SNEC are high-grade tumors, whereas esthesioneuroblastomas are mostly of a lower grade, but of a higher stage at presentation.[11]

As a result of the higher percentage of the sinonasal malignancies presenting with locally advanced and advanced disease, multimodality therapy is required and has been shown to increase the local control and survival. Multimodality treatment, including radiation in the adjuvant, definitive, or palliative setting and chemotherapy used concurrently with radiation or in the induction/neoadjuvant setting, forms the basis of therapy in most patients.[3] However, it has been shown in multiple previous reports that outcomes are inferior in patients who are unable to undergo primary surgical resection; such patients need to be treated with definitive chemoradiation upfront.[14] Even escalated doses of radiation alone are unable to overcome the compromise in the outcomes from the lack of a primary surgical approach.[15]

Neoadjuvant or induction chemotherapy has been shown to increase the response, local control, and resectability in locally advanced sinonasal malignancies. Cases where a complete response or partial response is seen after NACT, have been shown to have higher rates of survival.[9],[10] In one of the largest series of sinonasal neuroendocrine cancers, the 5-year outcome data were in favor of NACT, which was shown to enhance the survival in poorly differentiated tumors. The 5-year overall survival (OS) of 67 cases of esthesioneuroblastoma was 91.6%, and that of 22 cases of poorly differentiated SNEC was 42.6%.[16] The other interest in NACT is for the possibility of organ preservation, especially to reduce the rates of orbital exenterations; however, this needs to be studied better.[9],[10]

In the original article published in this issue by Patil et al., the authors have studied and reported on two such sinonasal malignancies with neuroendocrine differentiation: esthesioneuroblastoma and SNEC.[17] They analyzed the 5-year outcomes, including the progression-free survival (PFS), OS, and late adverse events, of 25 patients with locally advanced esthesioneuroblastoma or SNEC treated between August 2010 and August 2014 with NACT followed by local therapy at their center. The authors had previously published their 2-year outcomes for this cohort of patients.[7]

All these patients received two cycles of NACT consisting of cisplatin (33 mg/m 2 D1–D3) and etoposide (100 mg/m 2 D1–D3). Cisplatin was replaced with carboplatin (area under the curve-5 or 6) if the creatinine clearance was below 60 mL/min. Post 2 cycles, patients underwent response assessment in the multidisciplinary clinic, and then based on the response, either underwent surgical resection followed by adjuvant chemoradiation or radical chemoradiation or palliative radiation. The 5-year PFS in the esthesioneuroblastoma and SNEC cohorts was 63.5% (95% confidence interval [CI], 28.9–84.7) and 34.6% (95% CI, 10.1–61.1) (P = 0.1), respectively, and their 5-year OS was 91.7% (95% CI, 53.9–98.9) and 46.2% (95% CI, 19.2–69.6) (P = 0.024), respectively. Response to NACT was the only factor impacting PFS on the multivariate analysis (P = 0.033). Any grade late adverse event occurred in twenty patients (80%). Metabolic late adverse events, including any grade of hypertension, type 2 diabetes, and renal dysfunction, were seen in 19 patients (76%). Notably, the incidence of type 2 diabetes was 68%, as against the national reported incidence of 7.3% in a similar aged cohort, as per the authors.

The important contribution of the study to the existing literature on paranasal sinus tumors is that it adds to the database of outcomes for this rare group of patients. It especially sheds light on two distinct facts: first, that esthesioneuroblastoma and SNEC are two different entities with distinct histopathology characteristics, and different prognosis; second, the study underlines the benefit of induction/NACT for both of these tumor types (esthesioneuroblastoma more than SNEC) in the form of local responses, enhanced resectability, as well as improved PFS and OS. These results were noteworthy, considering nearly half of their patients had SNEC, which are known to have a poor prognosis, and almost all of their patients had T4 disease with proven poor outcomes.[7] Some limitations of the current study are the small numbers of two distinctly different histologies, retrospective nature of the review, lack of tumor biomarker testing, and correlation with outcomes (not even done retrospectively).

This analysis has a limited follow-up of 5 years; a longer follow-up will be needed to capture late recurrences described in this patient population and also to assess late adverse events beyond 5 years. There is a dearth of comparative data, especially in symptomatic locally advanced cases, to decide the exact primary strategy, and this study does not address that.

In this analysis of 25 cases of esthesioneuroblastoma (n = 12) and SNEC (n = 13), Patil et al. conclude that NACT in advanced sinonasal cancers is associated with an improvement in the 5-year outcomes. Late side effects, especially metabolic, were seen in a large group of these patients (80%) and should be evaluated during further follow-up. Ideally, one would desire a randomized prospective trial of NACT for definitive recommendations; however, in this very rare population of patients with heterogeneous histology this is not feasible, leaving the strategy hypothesis generating.[18] However, one would argue that there are enough data to inform therapeutic recommendations in the form of case series and retrospective reviews with a long-term follow-up, to underline the survival benefit from such a strategy.[4],[5],[6],[7],[8],[9],[10] Innovative research methods and novel clinical trial designs in the form of biomarker-enriched, umbrella, and basket trials are needed to help better answer this question further.

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Robin TP, Jones BL, Gordon OM, Phan A, Abbott D, McDermott JD, et al. A comprehensive comparative analysis of treatment modalities for sinonasal malignancies. Cancer 2017;123:3040-9.  Back to cited text no. 2
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Noronha V, Patil VM, Joshi A, Krishna MV, Dhumal S, Juvekar S, et al. Induction chemotherapy in technically unresectable locally advanced carcinoma of maxillary sinus. Chemother Res Pract 2014;2014:487872.  Back to cited text no. 5
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Patil VM, Joshi A, Noronha V, Sharma V, Zanwar S, Dhumal S, et al. Neoadjuvant chemotherapy in locally advanced and borderline resectable nonsquamous sinonasal tumors (Esthesioneuroblastoma and sinonasal tumor with neuroendocrine differentiation). Int J Surg Oncol 2016;2016:6923730.  Back to cited text no. 7
Ock CY, Keam B, Kim TM, Han DH, Won TB, Lee SH, et al. Induction chemotherapy in head and neck squamous cell carcinoma of the paranasal sinus and nasal cavity: A role in organ preservation. Korean J Intern Med 2016;31:570-8.  Back to cited text no. 8
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[PUBMED]  [Full text]  
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