Eur Arch Otorhinolaryngol DOI 10.1007/s00405-014-3035-1
Rhinology
Critical analysis of recurrences of esthesioneuroblastomas: can we prevent them? Marion Montava · Benjamin Verillaud · Romain Kania · Elisabeth Sauvaget · Damien Bresson · Julien Mancini · Sébastien Froelich · Philippe Herman
Received: 5 March 2014 / Accepted: 25 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Esthesioneuroblastoma (ENB) involving the anterior skull base is a rare malignant tumour derived from the olfactory epithelium. The gold standard of surgical treatment is currently craniofacial resection (CFR), which allows efficient removal of the tumour but entails significant morbidity. To reduce morbidity combined with good visualization of tumour limits removal, endonasal endoscopy resection (EER) has developed. The objective of this work was (1) to describe the EER surgical procedure, the morbidity, and the limitations of this endoscopic approach as compared with CFR, (2) analyse recurrences to define risk factors of recurrences and (3) to discuss a therapeutic decision algorithm. Retrospective series of
M. Montava Aix Marseille Université, IFSSTAR, LBA, UMR-T 24, 13344 Marseille, France M. Montava (*) APHM, Hôpital Nord, Service d’oto-rhino-laryngologie et chirurgie cervico-faciale, Chemin des bourrely, 13915 Marseille Cedex 20, France e-mail: marion.montava@ap‑hm.fr B. Verillaud · R. Kania · E. Sauvaget · P. Herman APHP and EA REMES, Paris-VII University, Sorbonne Paris Cité, Hôpital Lariboisière, Service d’oto-rhino-laryngologie et chirurgie cervico-faciale, Paris, France D. Bresson · S. Froelich APHP, Paris-VII University, Sorbonne Paris Cité, Hôpital Lariboisière, Service de Neurochirurgie, Paris, France J. Mancini Aix Marseille Université, Inserm, IRD, UMR_S 912 SESSTIM, 13385 Marseille, France J. Mancini APHM, Hôpital La Timone, BioSTIC, 13385 Marseille, France
18 patients with ENB endoscopically treated in a university tertiary referral centre over 13 years. Fifteen of those underwent radiotherapy. Epidemiological data, clinical and imaging findings, histology, treatment modalities and outcome of patients were studied. Mean follow-up was 31 months. Morbidity was mainly related to radiotherapy. Three recurrences were detected: one bone and one sylvian metastasis, and a local recurrence in a patient not irradiated. One recurrence spread through leptomeningeal propagation. Dural extension and frontal invasion were significantly associated with recurrences (p = 0.001 and p = 0.019, respectively). Patients with dural extension or frontal invasion should receive aggressive treatment. With a low rate of perioperative morbidity and efficient local control, EER seems to be a promising approach for selected cases of ENB. Keywords Olfactory neuroblastoma · Esthesioneuroblastoma · Endoscopic resection · Anterior skull base · Recurrence
Introduction Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is an uncommon malignant neuroectodermal tumour believed to arise from the olfactory epithelium of the sinonasal tract. It accounts for approximately 6 % of nasal cavity/paranasal sinus cancers [1, 2]. Since Berger et al.’s [3] first description of ENB in 1924, more than 1,000 cases of ENB have been reported in the world literature, mostly as single or small case reports. Surgery and radiotherapy remain main treatment modalities [4], although chemotherapy has been increasingly administered [5].
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Surgery of ENB classically requires craniofacial resection (CFR), which combines transcranial (bifrontal craniotomy) and transfacial approaches [4]. CFR has been the gold standard for the removal of ENB [6, 7], followed by radiotherapy [8]. However, this technique entails significant morbidity, such as pneumatocele, cerebral oedema, cerebral abscess, cerebrospinal fluid (CSF) leakage, meningitis, stroke, frontal syndrome sequel and even a fatal outcome [9]. Furthermore, there is no consensus regarding adjuvant radiotherapy and optimal dose delivery to the tumour bed. Esthesioneuroblastoma is thought to originate from the midline of the upper airway. Midline tumours are easily accessible by an endonasal endoscopic resection (EER), as reported by a significant number of publications [10–12]. However, in 50–75 % of ENB, the anterior skull base may be involved by the tumour, which requires partial or total anterior skull base resection [13]. Over the last 15 years, surgical techniques for ENB have evolved from CFR to include endoscopically assisted craniofacial resections, and more recently, purely endoscopic skull base resections based on expanded ethmoidectomy with transnasal craniotomy and anterior skull base resection. Indications and contraindications of EER have evolved according to tumour extension of ENB. Limits of EER are still questioned; however, there seems to be a consensus about the areas that the tumours should not reach in order to consider EER [11]. This study focused on endoscopically removed ENB, with partial or total removal of the anterior skull base. Based on our experience and a review of the literature, the aim of this work was: (1) to describe the EER surgical procedure, the morbidity, and the limitations of this endoscopic approach as compared with CFR; (2) to analyse tumour control and recurrences in order to evaluate prognostic factors; and (3) to propose a therapeutic decision algorithm.
Materials and methods This work reports on a retrospective study of consecutive cases of ENB treated endoscopically in a university tertiary referral centre over 13 years (2000–2013). Cases seen for a relapse or a recurrence after treatment with curative intent in another institution as well as cases with tumours considered as non-resectable were excluded from this study. Cases operated through CFR were also excluded. Workup All patients were clinically investigated for sinonasal, ocular and neurological symptoms, as well as cervical lymph nodes. Nasal endoscopy was performed in all cases, with biopsy under local anaesthesia on an out-patient basis.
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Eur Arch Otorhinolaryngol
Tumours were staged histologically according to Hyams [14], which may predict aggressivity and chemosensitivity of the lesion [15]. Computed tomography (CT), magnetic resonance imaging (MRI), and body scan or positron emission tomography (PET) were performed to stage the disease and elaborate treatment modalities in multidisciplinary committee. CT was performed with acquisition for navigation system. Tumours were staged according to the “Union Internationale Contre le Cancer” [International Union Against Cancer (UICC)] (2002), the Dulguerov’s TNM classification [16], the Kadish classification [17], and the Kadish classification modified by Morita et al. [8]. All patients received treatment according to the tumour board of our institution. All data were stored in the database of the institution following informed consent of the patients. Treatment strategy Cases of ENB with invasion of the frontal sinus, massive extension to the cerebral parenchyma, spread of the tumour above the orbits, or lysis of anterior facial skeleton were considered ineligible for EER. Neck metastasis, if present, were treated simultaneously by neck dissection. Surgery was followed by conformational radiotherapy and recently with intensity-modulated radiotherapy (IMRT). In the beginning of this series, radiotherapy was avoided for low-grade tumours or when margins especially the superior margin were free of disease [8], while it became systematic in the last period. Neoadjuvant chemotherapy (cisplatin [CDDP]–5-fluorouracile [5-FU]) was used as concomitant treatment, prior to and once during radiotherapy, for large or high-grade tumours [18, 19]. Surgical procedure for EER Surgical strategy was based on centripetal resection and was performed with dedicated instruments (Draf set from Karl Storz GmbH & Co. KG, Tuttlingen, Germany), powered instrumentation (Medtronic, Inc., Minneapolis, MN, USA) and navigation (Digipointeur, Collin, France). Surgery started with the definition of the inferior limits of the resection with a laser diode (anterior wall of the sphenoid or rhinopharynx posteriorly, nasal septum medially, lateral wall of the nasal fossa and frontal process of the maxilla anteriorly). Sections were taken and frozen to ensure tumour-free margins. Eventually, debulking of the lesion was performed to enlarge the field of vision and visualize the roof of insertion of the tumour. Dissection was then performed laterally along the orbit in a subperiosteal plane until the ethmoid roof was reached. Small lesions were removed by a unilateral procedure removing one cribriform plate. Most lesions were approached bilaterally after contralateral ethmoidectomy, Draf III procedure (frontal
Eur Arch Otorhinolaryngol
drill-out) [20] anteriorly and removal of the anterior wall of the sphenoid posteriorly. The dura was then exposed by drilling the roof of the ethmoid. Ethmoidal arteries were coagulated. The crista galli had to be removed before proceeding with the dural resection, which started on the lessaffected side. After sectioning the falx cerebri, the skull base specimen was gently pushed down, which allowed for exposure of the dura from above and resection on the most affected side. The olfactory bulbs were identified and the olfactory peduncles transsected. The skull base specimen was taken out through the nose or through the mouth. If the tumour adhered to the periorbit, the latter was resected at the end of the procedure, and sections showing limits were frozen. Duraplasty was performed with three layers of fascia lata successively fashioned intracranially and intradurally for the first layer, intracranially and extradurally for the second and extracranially for the third, with fibrin glue. Utmost care was given to the positioning of these layers, which had to be watertight. A sheet of Silastic® or conversely a balloon was placed to support the duraplasty for five days. Patients underwent postoperative CT within 24 h to visualize the adequate placement of the duraplasty, eliminate any postoperative bleeding and/or haematoma and assess the amount of pneumocephalus. During hospital stay CT was repeated in case of headache. Follow‑up Follow-up was based on regular endoscopic control of the nasal cavity (every 3 months during the first year, then every 4 months during 3 years, then annually), as well as sequential MRI. Statistical analysis Symptoms prevalence and recurrence rate were calculated by percentages. The follow-up interval was calculated by month, from the date of surgery to the date of the last follow-up. Overall survival and disease-free survival were calculated by the Kaplan–Meier method. The prognostic value of the variables studied in our series on disease-free survival was investigated by univariable analysis (log-rank test). A p value 60 years
Not significant Not significant
0.214 0.840
UICC classification T1-2 vs T3-4 Not significant T1-3 vs T4 Not significant T1-4a vs T4b Not significant Dulguerov’s TNM classification T1-2 vs T3-4 Not significant
Fig. 2 Imaging of patients with recurrence tumour, MRI on T1-weighted sequences. This coronal slice shows recurrence on olfactory bulb (Table 2, patient 2)
area, which was considered as non-surgically resectable and therefore, treated by chemotherapy. The initial tumour invaded extensively the dura mater, with frontal sinus extension and neck metastasis. After chemoradiotherapy, an anterior skull base defect, due to fascia lata necrosis and revealed
0.685 0.911 0.294 0.638
T1-3 vs T4 Significant Kadish classification modified by Morita
0.001
A–B vs C–D A–C vs D Kadish classification A–B vs C Hyams classification I–II vs III–IV I–III vs IV Neck metastasis Tumour extension Sphenoid
Not significant Not significant
0.984 0.294
Not significant
0.984
Not significant Not significant Not significant
0.984 0.452 0.294
Frontal sinus Orbit Anterior cranial fossa Dura mater Treatment Radiotherapy Chemotherapy
Not significant
0.810
Significant Not significant Not significant
0.019 0.199 0.391
Significant
0.001
Not significant
0.294
Not significant
0.452
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by streptococcus meningitis, was closed surgically with pericranial flap by endoscopy approach. This patient died 19 months after first surgery of uncontrolled metastasis. Prognostic factors for disease‑free survival Dulguerov’s T4 stage, dural extension and frontal sinus extension were the three significant variables significantly associated with poor disease-free survival (p = 0.001, p = 0.001 and p = 0.019, respectively). Disease-free survival was neither significantly influenced by the other variables studied in our series or correlated with the staging of the other classification systems (Table 2).
Discussion We aimed to investigate the results of EER for ENB, a rare sinonasal malignancy that often involves the anterior skull base and evaluate this strategy of treatment as an alternative to CFR for selected cases in terms of morbidity and efficiency. We retrospectively studied 18 cases of ENB that were removed endoscopically with partial or total removal of the anterior skull base. The major findings of this work were that dural extension, T4 Dulguerov and frontal sinus extension were significantly associated with recurrences. Although this was not a randomized study, EER seems to be a promising approach for managing selected cases of ENB, with a low rate of perioperative morbidity and efficient local control of the disease. Morbidity and efficiency CFR followed by radiotherapy entails significant morbidity [6, 9]. Surgery was followed by conformational radiotherapy and recently with intensity-modulated radiotherapy (IMRT). In the beginning of this series, radiotherapy was avoided for low-grade tumours or when margins especially the superior margin were free of disease [8], while it became systematic in the last period. Neoadjuvant chemotherapy (cisplatin [CDDP]–5-fluorouracile [5-FU]) was used as concomitant treatment, prior to and once during radiotherapy, for large or high-grade tumours [18, 19]. In this institution, frontal osteitis was observed during the time period of this study in two cases following radiotherapy, which required surgical excision of the bony flap and prolonged antibiotics. For EER, extended brain radionecrosis occurred in one patient, possibly related to inappropriate doses of radiotherapy (72 Gy), as for the case of the two necrosis of duraplasty which developed in patients having received 66 Gy. Therefore, while there is no consensus on the optimal dose delivery to the tumour bed, the observed complications suggest that doses should not exceed 65 Gy.
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The advent of IMRT may contribute to deliver homogeneous doses and preserve surrounding healthy tissue. Three recurrences were observed: one late local recurrence (olfactory bulb), one patient with metachronous spinal bones metastasis and one patient with early meningeal metastasis. Neither sinus nor orbit recurrence was observed. The single local recurrence occurred in a patient who experienced a recurrence on the olfactory bulb (Table 1, patient 1): he had obviously received at the beginning of this series inadequate resection. At the time of a unilateral endoscopic procedure, the cribriform plate had been drilled without resection of the bulb, and without radiotherapy. Nowadays all patients undergo bilateral procedure with complete removal of the anterior skull base, and radiotherapy is systematic. Noteworthy, one case presented intradural metastasis related to dissemination through CSF (Table 1, patient 3). Dural extension significantly affected disease-free survival, probably because of leptomeningeal propagation. This prognostic factor could be identified on preoperative MRI: indeed there was an absolute correlation between MRI data, surgical observations and pathologic data in our analysis. Patients with dural extension should receive aggressive surgical treatment, and the potential benefit of perioperative or adjuvant chemotherapy has to be validated in the future. In our study, Dulguerov’s T4 stage was significantly correlated with disease-free survival. Indeed dural extension was staged T4 and was correlated with a poor prognosis. Other classification systems were not statistically correlated with prognosis in this study possibly because of the limited number of patients. The main prognostic factor for overall survival and disease-free survival reported in the literature is clinical stage at the time of diagnosis [16, 21, 22]. Still other authors have questioned in the past the prognosis value of ethmoid cancer classification systems [23]. It is noteworthy that tumour extension to the frontal sinus was statistically associated with a poor prognosis, which points at an obvious limitation of the EER. However, the single patient whose tumour recurred had an intradural invasion, and recurrence occurred not locally but due to leptomeningeal diffusion. Limits of the exclusive endonasal approach Over the last 15 years, surgical indications for endoscopy have changed due to ongoing progress in cameras, devices and techniques. The aim of the endoscopic approach is to perform complete tumour removal with free margins, to cause minimal morbidity, to reduce the duration of hospitalization, and eventually to reduce the cost of care with the same tumour control as it would be achieved by CFR. Most specialized surgical teams are now convinced by the benefits of this technique, so that it would now hardly be feasible to elaborate a randomized prospective study comparing CFR versus EER. However, EER has obvious limitations in
Eur Arch Otorhinolaryngol
the case of sinonasal tumours: spread of the tumour inside the frontal sinus or invasion of the dura laterally above the orbits require a classic subfrontal approach; similarly, invasion of the facial skeleton requires a transfacial approach. At last it is questionable whether a wide intradural extension should be addressed endoscopically. However, apart from those rare cases, endoscopy may become the approach of choice for advocated ENB. As evidenced here and in other works, the endoscopic vision allows to precisely define the limits of the mucosal and bony resection, and eventually to perform periorbit resection if needed. Furthermore, skull base resection can be safely performed without conventional craniotomy and subsequent displacement of the frontal lobes. Still cerebrospinal fluid dissemination might represent a challenge for both approaches, EER and CFR, as evidenced by the cases of meningeal metastasis. Whether intradural recurrences are related to the behaviour of the tumour or to seeding at the time of surgery is still unclear. At last the case of the patient with an olfactory bulb recurrence suggests that, at least in the case of ENB, surgery should systematically remove the olfactory bulbs, a concept that was raised decades ago [24]. Nowadays all patients undergo bilateral procedure with complete removal of the anterior skull base (cribriform plates with dura, olfactory bulbs and eventually cerebral parenchyma), systematically followed by IMRT at 60–65 Gy. Therapeutic decision algorithm In this series, cases of ENB with invasion of the frontal sinus, massive extension to the cerebral parenchyma, spread of the tumour above the orbits, or lysis of the anterior facial skeleton have been considered ineligible for EER, a concept which reaches a consensus today [11]. Neck metastasis, if present, have been surgically treated simultaneously. Chemotherapy seems warranted for highgrade tumours (Hyams III–IV), for dural extension, for frontal sinus invasion, and in the presence of metastasis. At last the complications observed after the combination of surgery and radiotherapy support a dose of postoperative external beam therapy not exceeding 65 Gy. Place of endoscopic surgery The place of endoscopic surgery in the treatment of ENB was the subject of a meta-analysis based on 361 patients operated between 1992 (date of the first known publications on endoscopic surgery) and 2008 [10]. The authors found better survival rates (overall and disease-free survival) after endoscopic surgery than after open surgery. This study, however, has numerous limitations including the limited number of patients and the length of follow-up in the endoscopic
treatment group. Additional bias in this analysis comes from the fact that most of the tumours treated with an open surgical approach were Kadish stages C and D, whereas most tumours resected endoscopically were Kadish stages A and B. The authors concluded that endoscopic surgery is possible but must be reserved to less advanced tumours [10]. In another study of endoscopically resected ENB [25], 23 patients were retrospectively reviewed, 19 of whom had primary tumours and 4 of whom underwent revision surgery for recurrent tumours. The modified Kadish staging at presentation for the primary 19 patients was stage B (58.9 %), stage C (26.3 %), stage A (10.5 %), and stage D (5.3 %). Complete resection and negative intraoperative margins were achieved endoscopically in 17 of the 19 primarily treated patients. The mean follow-up for the primary treated cases was 45.2 months, and all patients except one with recurrent disease at presentation had no evidence of disease at their last follow-up [25]. Gallia et al. [26] published their series of nine patients with a mix of Kadish A–D tumours undergoing a purely endoscopic resection followed by radiotherapy. In each case negative margins were obtained, and all patients were disease free at the last clinic visit, although follow-up only averaged 27 months [26]. Most recently, Song et al. [27] compared the treatment results according to various treatment modalities. Endoscopic surgery for advanced ENB showed successful survival results compared with non-endoscopic surgery, and limited morbidities. In this study, modified Kadish classification best predicted disease-free survival for ENB. The number of studies comparing EER with CFR for advanced tumours is insufficient at the present time [12], and the limitations of the endoscopic approach have to be kept in mind when dealing with malignant tumours. ENB has a long natural history, often with late local and regional recurrence as well as distant metastases. Recurrent disease is often very treatable, with long-term success and prolonged survival, so extended follow-up is appropriate to detect and treat it appropriately [28]. Rimmer et al. [28] validated a follow-up protocol based on the long-term outcomes and recurrence rates in patients who had undergone surgical treatment for ENB (CFR or EER). Lifelong follow-up was proposed with both clinical examination and MRI scanning every 4 months for the first 2 years, every 6 months for a further 3 years, then every 9 months for life [28]. Still the results of expanded endoscopic surgery seem promising, both in terms of survival and in terms of quality of life [29, 30].
Conclusion This patient series adds to the growing experience of expanded endonasal endoscopic surgery in the treatment of skull base malignancies. ENB is a rare and challenging
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malignant tumour with few large studies having long-term follow-up to provide agreement in staging and treatment. Although this series is not randomized, the low rate of perioperative morbidity as well as the efficiency of EER in terms of tumour removal and local control advocates the use of EER for selected cases of ENB. Conflict of interest The authors declare that they have no conflicts of interest concerning this article.
References 1. Svane-Knudsen V, Jørgensen KE, Hansen O, Lindgren A, Marker P (1998) Cancer of the nasal cavity and paranasal sinuses: a series of 115 patients. Rhinology 36:12–14 2. Skarsgard DP, Groome PA, Mackillop WJ et al (2000) Cancers of the upper aerodigestive tract in Ontario, Canada, and the United States. Cancer 88:1728–1738 3. Berger L, Luc R, Richard D (1924) L’esthesioneuroepitheliome olfactif. Bull Assoc Fr Etude Cancer 13:410–421 4. Broich G, Pagliari A, Ottaviani F (1997) Esthesioneuroblastoma: a general review of the cases published since the discovery of the tumour in 1924. Anticancer Res 17:2683–2706 5. Chao KS, Kaplan C, Simpson JR et al (2001) Esthesioneuroblastoma: the impact of treatment modality. Head Neck 23:749–757 6. Patel SG, Singh B, Polluri A et al (2003) Craniofacial surgery for malignant skull base tumors: report of an international collaborative study. Cancer 98:1179–1187 7. Wang C-C, Chen Y-L, Hsu Y-S, Jung S-M, Hao S-P (2005) Transcranial resection of olfactory neuroblastoma. Skull Base 15:163–171 (discussion 171) 8. Morita A, Ebersold MJ, Olsen KD, Foote RL, Lewis JE, Quast LM (1993) Esthesioneuroblastoma: prognosis and management. Neurosurgery 32:706–714 (discussion 714–715) 9. Ganly I, Patel SG, Singh B et al (2005) Craniofacial resection for malignant paranasal sinus tumors: report of an International Collaborative Study. Head Neck 27:575–584 10. Devaiah AK, Andreoli MT (2009) Treatment of esthesioneuroblastoma: a 16-year meta-analysis of 361 patients. Laryngoscope 119:1412–1416 11. Lund VJ, Stammberger H, Nicolai P et al (2010) European position paper on endoscopic management of tumours of the nose, paranasal sinuses and skull base. Rhinol Suppl 22:1–143 12. Soler ZM, Smith TL (2012) Endoscopic versus open craniofacial resection of esthesioneuroblastoma: what is the evidence? Laryngoscope 122:244–245 13. Suarez C, Llorente JL, Fernandez De Leon R, Maseda E, Lopez A (2004) Prognostic factors in sinonasal tumors involving the anterior skull base. Head Neck 26:136–144
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Eur Arch Otorhinolaryngol 14. Hyams VJ (1988) Olfactory neuroblastoma. Tumours of the upper respiratory tract and ear. In: Hyams V, Batsakis J, Michaels L (eds). Armed Forces Institute of Pathology, Washington DC, pp 240–248 15. McElroy EA Jr, Buckner JC, Lewis JE (1998) Chemotherapy for advanced esthesioneuroblastoma: the Mayo Clinic experience. Neurosurgery 42:1023–1027 discussion 1027–1028 16. Dulguerov P, Calcaterra T (1992) Esthesioneuroblastoma: the UCLA experience 1970–1990. Laryngoscope 102:843–849 17. Kadish S, Goodman M, Wang CC (1976) Olfactory neuroblastoma. A clinical analysis of 17 cases. Cancer 37:1571–1576 18. Fitzek MM, Thornton AF, Varvares M et al (2002) Neuroendocrine tumors of the sinonasal tract. Results of a prospective study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy. Cancer 94:2623–2634 19. Kim D-W, Jo Y-H, Kim JH et al (2004) Neoadjuvant etoposide, ifosfamide, and cisplatin for the treatment of olfactory neuroblastoma. Cancer 101:2257–2260 20. Draf W, Weber R (1993) Endonasal micro-endoscopic pansinusoperation in chronic sinusitis. I. Indications and operation technique. Am J Otolaryngol 14:394–398 21. Jethanamest D, Morris LG, Sikora AG, Kutler DI (2007) Esthesioneuroblastoma: a population-based analysis of survival and prognostic factors. Arch Otolaryngol Head Neck Surg 133:276–280 22. Bachar G, Goldstein DP, Shah M et al (2008) Esthesioneuroblastoma: the Princess Margaret Hospital experience. Head Neck 30:1607–1614 23. Cantù G, Solero CL, Miceli R et al (2005) Which classification for ethmoid malignant tumors involving the anterior skull base? Head Neck 27:224–231 24. Harrison D (1984) Surgical pathology of olfactory neuroblastoma. Head Neck Surg 7:60–64 25. Folbe A, Herzallah I, Duvvuri U et al (2009) Endoscopic endonasal resection of esthesioneuroblastoma: a multicenter study. Am J Rhinol Allergy 23:91–94 26. Gallia GL, Reh DD, Salmasi V, Blitz AM, Koch W, Ishii M (2011) Endonasal endoscopic resection of esthesioneuroblastoma: the Johns Hopkins Hospital experience and review of the literature. Neurosurg Rev 34:465–475 27. Song CM, Won T-B, Lee CH, Kim D-Y, Rhee C-S (2012) Treatment modalities and outcomes of olfactory neuroblastoma. Laryngoscope 122:2389–2395 28. Rimmer J, Lund VJ, Beale T, Wei WI, Howard D (2013) Olfactory neuroblastoma: A 35-year experience and suggested followup protocol. Laryngoscope. Epub ahead of print 29. Cusimano MD (1999) Quality-of-life assessment in patients with lesions of the cranial base. Skull Base Surg 9:259–264 30. Castelnuovo P, Lepera D, Turri-Zanoni M et al (2013) Quality of life following endoscopic endonasal resection of anterior skull base cancers. J Neurosurg 119:1401–1409
Rhinology
Critical analysis of recurrences of esthesioneuroblastomas: can we prevent them? Marion Montava · Benjamin Verillaud · Romain Kania · Elisabeth Sauvaget · Damien Bresson · Julien Mancini · Sébastien Froelich · Philippe Herman
Received: 5 March 2014 / Accepted: 25 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Esthesioneuroblastoma (ENB) involving the anterior skull base is a rare malignant tumour derived from the olfactory epithelium. The gold standard of surgical treatment is currently craniofacial resection (CFR), which allows efficient removal of the tumour but entails significant morbidity. To reduce morbidity combined with good visualization of tumour limits removal, endonasal endoscopy resection (EER) has developed. The objective of this work was (1) to describe the EER surgical procedure, the morbidity, and the limitations of this endoscopic approach as compared with CFR, (2) analyse recurrences to define risk factors of recurrences and (3) to discuss a therapeutic decision algorithm. Retrospective series of
M. Montava Aix Marseille Université, IFSSTAR, LBA, UMR-T 24, 13344 Marseille, France M. Montava (*) APHM, Hôpital Nord, Service d’oto-rhino-laryngologie et chirurgie cervico-faciale, Chemin des bourrely, 13915 Marseille Cedex 20, France e-mail: marion.montava@ap‑hm.fr B. Verillaud · R. Kania · E. Sauvaget · P. Herman APHP and EA REMES, Paris-VII University, Sorbonne Paris Cité, Hôpital Lariboisière, Service d’oto-rhino-laryngologie et chirurgie cervico-faciale, Paris, France D. Bresson · S. Froelich APHP, Paris-VII University, Sorbonne Paris Cité, Hôpital Lariboisière, Service de Neurochirurgie, Paris, France J. Mancini Aix Marseille Université, Inserm, IRD, UMR_S 912 SESSTIM, 13385 Marseille, France J. Mancini APHM, Hôpital La Timone, BioSTIC, 13385 Marseille, France
18 patients with ENB endoscopically treated in a university tertiary referral centre over 13 years. Fifteen of those underwent radiotherapy. Epidemiological data, clinical and imaging findings, histology, treatment modalities and outcome of patients were studied. Mean follow-up was 31 months. Morbidity was mainly related to radiotherapy. Three recurrences were detected: one bone and one sylvian metastasis, and a local recurrence in a patient not irradiated. One recurrence spread through leptomeningeal propagation. Dural extension and frontal invasion were significantly associated with recurrences (p = 0.001 and p = 0.019, respectively). Patients with dural extension or frontal invasion should receive aggressive treatment. With a low rate of perioperative morbidity and efficient local control, EER seems to be a promising approach for selected cases of ENB. Keywords Olfactory neuroblastoma · Esthesioneuroblastoma · Endoscopic resection · Anterior skull base · Recurrence
Introduction Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is an uncommon malignant neuroectodermal tumour believed to arise from the olfactory epithelium of the sinonasal tract. It accounts for approximately 6 % of nasal cavity/paranasal sinus cancers [1, 2]. Since Berger et al.’s [3] first description of ENB in 1924, more than 1,000 cases of ENB have been reported in the world literature, mostly as single or small case reports. Surgery and radiotherapy remain main treatment modalities [4], although chemotherapy has been increasingly administered [5].
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Surgery of ENB classically requires craniofacial resection (CFR), which combines transcranial (bifrontal craniotomy) and transfacial approaches [4]. CFR has been the gold standard for the removal of ENB [6, 7], followed by radiotherapy [8]. However, this technique entails significant morbidity, such as pneumatocele, cerebral oedema, cerebral abscess, cerebrospinal fluid (CSF) leakage, meningitis, stroke, frontal syndrome sequel and even a fatal outcome [9]. Furthermore, there is no consensus regarding adjuvant radiotherapy and optimal dose delivery to the tumour bed. Esthesioneuroblastoma is thought to originate from the midline of the upper airway. Midline tumours are easily accessible by an endonasal endoscopic resection (EER), as reported by a significant number of publications [10–12]. However, in 50–75 % of ENB, the anterior skull base may be involved by the tumour, which requires partial or total anterior skull base resection [13]. Over the last 15 years, surgical techniques for ENB have evolved from CFR to include endoscopically assisted craniofacial resections, and more recently, purely endoscopic skull base resections based on expanded ethmoidectomy with transnasal craniotomy and anterior skull base resection. Indications and contraindications of EER have evolved according to tumour extension of ENB. Limits of EER are still questioned; however, there seems to be a consensus about the areas that the tumours should not reach in order to consider EER [11]. This study focused on endoscopically removed ENB, with partial or total removal of the anterior skull base. Based on our experience and a review of the literature, the aim of this work was: (1) to describe the EER surgical procedure, the morbidity, and the limitations of this endoscopic approach as compared with CFR; (2) to analyse tumour control and recurrences in order to evaluate prognostic factors; and (3) to propose a therapeutic decision algorithm.
Materials and methods This work reports on a retrospective study of consecutive cases of ENB treated endoscopically in a university tertiary referral centre over 13 years (2000–2013). Cases seen for a relapse or a recurrence after treatment with curative intent in another institution as well as cases with tumours considered as non-resectable were excluded from this study. Cases operated through CFR were also excluded. Workup All patients were clinically investigated for sinonasal, ocular and neurological symptoms, as well as cervical lymph nodes. Nasal endoscopy was performed in all cases, with biopsy under local anaesthesia on an out-patient basis.
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Tumours were staged histologically according to Hyams [14], which may predict aggressivity and chemosensitivity of the lesion [15]. Computed tomography (CT), magnetic resonance imaging (MRI), and body scan or positron emission tomography (PET) were performed to stage the disease and elaborate treatment modalities in multidisciplinary committee. CT was performed with acquisition for navigation system. Tumours were staged according to the “Union Internationale Contre le Cancer” [International Union Against Cancer (UICC)] (2002), the Dulguerov’s TNM classification [16], the Kadish classification [17], and the Kadish classification modified by Morita et al. [8]. All patients received treatment according to the tumour board of our institution. All data were stored in the database of the institution following informed consent of the patients. Treatment strategy Cases of ENB with invasion of the frontal sinus, massive extension to the cerebral parenchyma, spread of the tumour above the orbits, or lysis of anterior facial skeleton were considered ineligible for EER. Neck metastasis, if present, were treated simultaneously by neck dissection. Surgery was followed by conformational radiotherapy and recently with intensity-modulated radiotherapy (IMRT). In the beginning of this series, radiotherapy was avoided for low-grade tumours or when margins especially the superior margin were free of disease [8], while it became systematic in the last period. Neoadjuvant chemotherapy (cisplatin [CDDP]–5-fluorouracile [5-FU]) was used as concomitant treatment, prior to and once during radiotherapy, for large or high-grade tumours [18, 19]. Surgical procedure for EER Surgical strategy was based on centripetal resection and was performed with dedicated instruments (Draf set from Karl Storz GmbH & Co. KG, Tuttlingen, Germany), powered instrumentation (Medtronic, Inc., Minneapolis, MN, USA) and navigation (Digipointeur, Collin, France). Surgery started with the definition of the inferior limits of the resection with a laser diode (anterior wall of the sphenoid or rhinopharynx posteriorly, nasal septum medially, lateral wall of the nasal fossa and frontal process of the maxilla anteriorly). Sections were taken and frozen to ensure tumour-free margins. Eventually, debulking of the lesion was performed to enlarge the field of vision and visualize the roof of insertion of the tumour. Dissection was then performed laterally along the orbit in a subperiosteal plane until the ethmoid roof was reached. Small lesions were removed by a unilateral procedure removing one cribriform plate. Most lesions were approached bilaterally after contralateral ethmoidectomy, Draf III procedure (frontal
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drill-out) [20] anteriorly and removal of the anterior wall of the sphenoid posteriorly. The dura was then exposed by drilling the roof of the ethmoid. Ethmoidal arteries were coagulated. The crista galli had to be removed before proceeding with the dural resection, which started on the lessaffected side. After sectioning the falx cerebri, the skull base specimen was gently pushed down, which allowed for exposure of the dura from above and resection on the most affected side. The olfactory bulbs were identified and the olfactory peduncles transsected. The skull base specimen was taken out through the nose or through the mouth. If the tumour adhered to the periorbit, the latter was resected at the end of the procedure, and sections showing limits were frozen. Duraplasty was performed with three layers of fascia lata successively fashioned intracranially and intradurally for the first layer, intracranially and extradurally for the second and extracranially for the third, with fibrin glue. Utmost care was given to the positioning of these layers, which had to be watertight. A sheet of Silastic® or conversely a balloon was placed to support the duraplasty for five days. Patients underwent postoperative CT within 24 h to visualize the adequate placement of the duraplasty, eliminate any postoperative bleeding and/or haematoma and assess the amount of pneumocephalus. During hospital stay CT was repeated in case of headache. Follow‑up Follow-up was based on regular endoscopic control of the nasal cavity (every 3 months during the first year, then every 4 months during 3 years, then annually), as well as sequential MRI. Statistical analysis Symptoms prevalence and recurrence rate were calculated by percentages. The follow-up interval was calculated by month, from the date of surgery to the date of the last follow-up. Overall survival and disease-free survival were calculated by the Kaplan–Meier method. The prognostic value of the variables studied in our series on disease-free survival was investigated by univariable analysis (log-rank test). A p value 60 years
Not significant Not significant
0.214 0.840
UICC classification T1-2 vs T3-4 Not significant T1-3 vs T4 Not significant T1-4a vs T4b Not significant Dulguerov’s TNM classification T1-2 vs T3-4 Not significant
Fig. 2 Imaging of patients with recurrence tumour, MRI on T1-weighted sequences. This coronal slice shows recurrence on olfactory bulb (Table 2, patient 2)
area, which was considered as non-surgically resectable and therefore, treated by chemotherapy. The initial tumour invaded extensively the dura mater, with frontal sinus extension and neck metastasis. After chemoradiotherapy, an anterior skull base defect, due to fascia lata necrosis and revealed
0.685 0.911 0.294 0.638
T1-3 vs T4 Significant Kadish classification modified by Morita
0.001
A–B vs C–D A–C vs D Kadish classification A–B vs C Hyams classification I–II vs III–IV I–III vs IV Neck metastasis Tumour extension Sphenoid
Not significant Not significant
0.984 0.294
Not significant
0.984
Not significant Not significant Not significant
0.984 0.452 0.294
Frontal sinus Orbit Anterior cranial fossa Dura mater Treatment Radiotherapy Chemotherapy
Not significant
0.810
Significant Not significant Not significant
0.019 0.199 0.391
Significant
0.001
Not significant
0.294
Not significant
0.452
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by streptococcus meningitis, was closed surgically with pericranial flap by endoscopy approach. This patient died 19 months after first surgery of uncontrolled metastasis. Prognostic factors for disease‑free survival Dulguerov’s T4 stage, dural extension and frontal sinus extension were the three significant variables significantly associated with poor disease-free survival (p = 0.001, p = 0.001 and p = 0.019, respectively). Disease-free survival was neither significantly influenced by the other variables studied in our series or correlated with the staging of the other classification systems (Table 2).
Discussion We aimed to investigate the results of EER for ENB, a rare sinonasal malignancy that often involves the anterior skull base and evaluate this strategy of treatment as an alternative to CFR for selected cases in terms of morbidity and efficiency. We retrospectively studied 18 cases of ENB that were removed endoscopically with partial or total removal of the anterior skull base. The major findings of this work were that dural extension, T4 Dulguerov and frontal sinus extension were significantly associated with recurrences. Although this was not a randomized study, EER seems to be a promising approach for managing selected cases of ENB, with a low rate of perioperative morbidity and efficient local control of the disease. Morbidity and efficiency CFR followed by radiotherapy entails significant morbidity [6, 9]. Surgery was followed by conformational radiotherapy and recently with intensity-modulated radiotherapy (IMRT). In the beginning of this series, radiotherapy was avoided for low-grade tumours or when margins especially the superior margin were free of disease [8], while it became systematic in the last period. Neoadjuvant chemotherapy (cisplatin [CDDP]–5-fluorouracile [5-FU]) was used as concomitant treatment, prior to and once during radiotherapy, for large or high-grade tumours [18, 19]. In this institution, frontal osteitis was observed during the time period of this study in two cases following radiotherapy, which required surgical excision of the bony flap and prolonged antibiotics. For EER, extended brain radionecrosis occurred in one patient, possibly related to inappropriate doses of radiotherapy (72 Gy), as for the case of the two necrosis of duraplasty which developed in patients having received 66 Gy. Therefore, while there is no consensus on the optimal dose delivery to the tumour bed, the observed complications suggest that doses should not exceed 65 Gy.
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The advent of IMRT may contribute to deliver homogeneous doses and preserve surrounding healthy tissue. Three recurrences were observed: one late local recurrence (olfactory bulb), one patient with metachronous spinal bones metastasis and one patient with early meningeal metastasis. Neither sinus nor orbit recurrence was observed. The single local recurrence occurred in a patient who experienced a recurrence on the olfactory bulb (Table 1, patient 1): he had obviously received at the beginning of this series inadequate resection. At the time of a unilateral endoscopic procedure, the cribriform plate had been drilled without resection of the bulb, and without radiotherapy. Nowadays all patients undergo bilateral procedure with complete removal of the anterior skull base, and radiotherapy is systematic. Noteworthy, one case presented intradural metastasis related to dissemination through CSF (Table 1, patient 3). Dural extension significantly affected disease-free survival, probably because of leptomeningeal propagation. This prognostic factor could be identified on preoperative MRI: indeed there was an absolute correlation between MRI data, surgical observations and pathologic data in our analysis. Patients with dural extension should receive aggressive surgical treatment, and the potential benefit of perioperative or adjuvant chemotherapy has to be validated in the future. In our study, Dulguerov’s T4 stage was significantly correlated with disease-free survival. Indeed dural extension was staged T4 and was correlated with a poor prognosis. Other classification systems were not statistically correlated with prognosis in this study possibly because of the limited number of patients. The main prognostic factor for overall survival and disease-free survival reported in the literature is clinical stage at the time of diagnosis [16, 21, 22]. Still other authors have questioned in the past the prognosis value of ethmoid cancer classification systems [23]. It is noteworthy that tumour extension to the frontal sinus was statistically associated with a poor prognosis, which points at an obvious limitation of the EER. However, the single patient whose tumour recurred had an intradural invasion, and recurrence occurred not locally but due to leptomeningeal diffusion. Limits of the exclusive endonasal approach Over the last 15 years, surgical indications for endoscopy have changed due to ongoing progress in cameras, devices and techniques. The aim of the endoscopic approach is to perform complete tumour removal with free margins, to cause minimal morbidity, to reduce the duration of hospitalization, and eventually to reduce the cost of care with the same tumour control as it would be achieved by CFR. Most specialized surgical teams are now convinced by the benefits of this technique, so that it would now hardly be feasible to elaborate a randomized prospective study comparing CFR versus EER. However, EER has obvious limitations in
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the case of sinonasal tumours: spread of the tumour inside the frontal sinus or invasion of the dura laterally above the orbits require a classic subfrontal approach; similarly, invasion of the facial skeleton requires a transfacial approach. At last it is questionable whether a wide intradural extension should be addressed endoscopically. However, apart from those rare cases, endoscopy may become the approach of choice for advocated ENB. As evidenced here and in other works, the endoscopic vision allows to precisely define the limits of the mucosal and bony resection, and eventually to perform periorbit resection if needed. Furthermore, skull base resection can be safely performed without conventional craniotomy and subsequent displacement of the frontal lobes. Still cerebrospinal fluid dissemination might represent a challenge for both approaches, EER and CFR, as evidenced by the cases of meningeal metastasis. Whether intradural recurrences are related to the behaviour of the tumour or to seeding at the time of surgery is still unclear. At last the case of the patient with an olfactory bulb recurrence suggests that, at least in the case of ENB, surgery should systematically remove the olfactory bulbs, a concept that was raised decades ago [24]. Nowadays all patients undergo bilateral procedure with complete removal of the anterior skull base (cribriform plates with dura, olfactory bulbs and eventually cerebral parenchyma), systematically followed by IMRT at 60–65 Gy. Therapeutic decision algorithm In this series, cases of ENB with invasion of the frontal sinus, massive extension to the cerebral parenchyma, spread of the tumour above the orbits, or lysis of the anterior facial skeleton have been considered ineligible for EER, a concept which reaches a consensus today [11]. Neck metastasis, if present, have been surgically treated simultaneously. Chemotherapy seems warranted for highgrade tumours (Hyams III–IV), for dural extension, for frontal sinus invasion, and in the presence of metastasis. At last the complications observed after the combination of surgery and radiotherapy support a dose of postoperative external beam therapy not exceeding 65 Gy. Place of endoscopic surgery The place of endoscopic surgery in the treatment of ENB was the subject of a meta-analysis based on 361 patients operated between 1992 (date of the first known publications on endoscopic surgery) and 2008 [10]. The authors found better survival rates (overall and disease-free survival) after endoscopic surgery than after open surgery. This study, however, has numerous limitations including the limited number of patients and the length of follow-up in the endoscopic
treatment group. Additional bias in this analysis comes from the fact that most of the tumours treated with an open surgical approach were Kadish stages C and D, whereas most tumours resected endoscopically were Kadish stages A and B. The authors concluded that endoscopic surgery is possible but must be reserved to less advanced tumours [10]. In another study of endoscopically resected ENB [25], 23 patients were retrospectively reviewed, 19 of whom had primary tumours and 4 of whom underwent revision surgery for recurrent tumours. The modified Kadish staging at presentation for the primary 19 patients was stage B (58.9 %), stage C (26.3 %), stage A (10.5 %), and stage D (5.3 %). Complete resection and negative intraoperative margins were achieved endoscopically in 17 of the 19 primarily treated patients. The mean follow-up for the primary treated cases was 45.2 months, and all patients except one with recurrent disease at presentation had no evidence of disease at their last follow-up [25]. Gallia et al. [26] published their series of nine patients with a mix of Kadish A–D tumours undergoing a purely endoscopic resection followed by radiotherapy. In each case negative margins were obtained, and all patients were disease free at the last clinic visit, although follow-up only averaged 27 months [26]. Most recently, Song et al. [27] compared the treatment results according to various treatment modalities. Endoscopic surgery for advanced ENB showed successful survival results compared with non-endoscopic surgery, and limited morbidities. In this study, modified Kadish classification best predicted disease-free survival for ENB. The number of studies comparing EER with CFR for advanced tumours is insufficient at the present time [12], and the limitations of the endoscopic approach have to be kept in mind when dealing with malignant tumours. ENB has a long natural history, often with late local and regional recurrence as well as distant metastases. Recurrent disease is often very treatable, with long-term success and prolonged survival, so extended follow-up is appropriate to detect and treat it appropriately [28]. Rimmer et al. [28] validated a follow-up protocol based on the long-term outcomes and recurrence rates in patients who had undergone surgical treatment for ENB (CFR or EER). Lifelong follow-up was proposed with both clinical examination and MRI scanning every 4 months for the first 2 years, every 6 months for a further 3 years, then every 9 months for life [28]. Still the results of expanded endoscopic surgery seem promising, both in terms of survival and in terms of quality of life [29, 30].
Conclusion This patient series adds to the growing experience of expanded endonasal endoscopic surgery in the treatment of skull base malignancies. ENB is a rare and challenging
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malignant tumour with few large studies having long-term follow-up to provide agreement in staging and treatment. Although this series is not randomized, the low rate of perioperative morbidity as well as the efficiency of EER in terms of tumour removal and local control advocates the use of EER for selected cases of ENB. Conflict of interest The authors declare that they have no conflicts of interest concerning this article.
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