10.14639/0392-100X-suppl.1-41-2021-01
The term “sinonasal tumours” includes a large spectrum of diseases, which are characterized by heterogeneous biological behavior and prognosis, and located in a critical anatomic area. Diagnosis and treatment of sinonasal tumours require the contribution of different disciplines. A narrative review was performed to highlight the role of surgeons in contributing to a multidisciplinary approach to sinonasal tumours. Diagnosis and staging of sinonasal tumours is challenging and requires collaboration between surgeons, radiologists, and pathologists. The identification and management of critical extensions (orbital or intracranial encroachment, vascular abutment or encasement) is fundamental for successful treatment. Most cases of advanced sinonasal tumours can undergo surgical intervention by an adequately trained otorhinolaryngological team. The contribution of neurosurgeons and oculoplastic surgeons is required in selected scenarios. In rare circumstances, multidisciplinary reconstructive strategies can be indicated for complex tissue defects. Furthermore, a multidisciplinary approach is pivotal in the management of perioperative complications. While surgery remains the mainstay of treatment, the role of non-surgical adjuvant or even exclusive treatments is constantly expanding.
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Piero Nicolai
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ACTA Otorhinolaryngologica Italica
multidisciplinary treatment
When is a multidisciplinary surgical approach required in sinonasal tumours with cranial involvement?
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2021-05-14
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1
Piero Nicolai
2021/05/14
10.14639/0392-100X-suppl.1-41-2021-01
3
Section of Otorhinolaryngology, Head and Neck Surgery, University of Padua, “Azienda Ospedaliera di Padova”, Padua, Italy
1827-675X
multidisciplinary treatment
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When is a multidisciplinary surgical approach required in sinonasal tumours with cranial involvement?
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ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41(SUPPL.1):S3-S17; doi: 10.14639/0392-100X-suppl.1-41-2021-01




When is a multidisciplinary surgical approach required
in sinonasal tumours with cranial involvement?
Quando è indicato un approccio chirurgico multidisciplinare nei tumori naso-sinusali
con estensione cranica?
Marco Ferrari1,2,3, Diego Cazzador1, Stefano Taboni1,3,4, Maria Vittoria Trimarchi1, Enzo Emanuelli1, Piero Nicolai1
1
 Section of Otorhinolaryngology, Head and Neck Surgery, University of Padua, “Azienda Ospedaliera di Padova”, Padua, Italy;
2
 Technology for Health (PhD program), Department of Information Engineering, University of Brescia, Brescia, Italy; 3 University
Health Network (UHN) Guided Therapeutics (GTx) Program International Scholar, UHN, Toronto, Canada; 4 Artificial Intelligence in
Medicine and Innovation in Clinical Research and Methodology (PhD program), Department of Clinical and Experimental Sciences,
University of Brescia, Brescia, Italy


SUMMARY
The term “sinonasal tumours” includes a large spectrum of diseases, which are character-
ized by heterogeneous biological behavior and prognosis, and located in a critical anatomic
area. Diagnosis and treatment of sinonasal tumours require the contribution of different
disciplines. A narrative review was performed to highlight the role of surgeons in con-
tributing to a multidisciplinary approach to sinonasal tumours. Diagnosis and staging of
sinonasal tumours is challenging and requires collaboration between surgeons, radiologists,
and pathologists. The identification and management of critical extensions (orbital or in-
tracranial encroachment, vascular abutment or encasement) is fundamental for successful           Received: October 20, 2020
treatment. Most cases of advanced sinonasal tumours can undergo surgical intervention by          Accepted: January 15, 2021
an adequately trained otorhinolaryngological team. The contribution of neurosurgeons and
oculoplastic surgeons is required in selected scenarios. In rare circumstances, multidisci-       Correspodence
plinary reconstructive strategies can be indicated for complex tissue defects. Furthermore,       Marco Ferrari
a multidisciplinary approach is pivotal in the management of perioperative complications.         Section of Otorhinolaryngology, Head and Neck
While surgery remains the mainstay of treatment, the role of non-surgical adjuvant or even        Surgery, Department of Neurosciences, University
exclusive treatments is constantly expanding.                                                     of Padua, “Azienda Ospedaliera di Padova”
                                                                                                  via Giustiniani 2, 35128 Padua, Italy
KEY WORDS: sinonasal tumours, anterior skull base tumours, cranial involvement,                   E-mail: 1990marcoferrari@gmail.com
multidisciplinary team, multidisciplinary treatment
                                                                                                  Funding
                                                                                                  None.
RIASSUNTO
I tumouri nasosinusali includono un ampio spettro di neoplasie caratterizzate da un com-
                                                                                                  Conflict of interest
portamento biologico eterogeneo e dalla localizzazione in un distretto anatomico critico.
                                                                                                  The Authors declare no conflict of interest.
Diverse discipline mediche sono coinvolte nella diagnosi e nel trattamento di tali tumori.
Una revisione narrativa della letteratura è stata condotta per identificare i ruoli delle spe-
cialità chirurgiche che appartengono al gruppo multidisciplinare. La diagnosi e la stadia-          How to cite this article: Ferrari M, Cazzador
zione dei tumori nasosinusali richiede la collaborazione tra chirurghi, radiologi e patologi.       D, Taboni S, et al. When is a multidisciplinary
L’identificazione delle estensioni tumorali critiche è fondamentale per un corretto tratta-         surgical approach required in sinonasal tumours
mento. L’intervento chirurgico necessario per la maggior parte dei tumori nasosinusali              with cranial involvement?Acta Otorhinolaryngol
                                                                                                    Ital 2021;41(SUPPL.1):S3-S17. https://doi.
avanzati può essere eseguito da un team otorinolaringoiatrico con adeguato training. Il
                                                                                                    org/10.14639/0392-100X-suppl.1-41-2021-01
contributo di neurochirurghi e di specialisti in chirurgia orbitaria è necessario in scenari
selezionati. Nei casi di difetti chirurgici complessi possono essere necessarie strategie rico-
                                                                                                  © Società Italiana di Otorinolaringoiatria
struttive multidisciplinari. La collaborazione chirurgica multidisciplinare è essenziale per      e Chirurgia Cervico-Facciale
la gestione delle complicanze nel periodo perioperatorio. Nonostante la chirurgia rimanga
il trattamento principale, si sta affermando una vasta gamma di trattamenti non-chirurgici,                      OPEN ACCESS
adiuvanti o esclusivi.
                                                                                                  This is an open access article distributed in accordance with
PAROLE CHIAVE: tumori nasosinusali, tumori della base cranica anteriore,                          the CC-BY-NC-ND (Creative Commons Attribution-Non-
coinvolgimento cranico, gruppo multidisciplinare, trattamento multidisciplinare                   Commercial-NoDerivatives 4.0 International) license. The
                                                                                                  article can be used by giving appropriate credit and mentio-
                                                                                                  ning the license, but only for non-commercial purposes and
                                                                                                  only in the original version. For further information: https://
                                                                                                  creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                            S3
M. Ferrari et al.




Introduction                                                    surgical physicians alternatively lead case management de-
                                                                pending upon the specific phase and circumstances.
Ideally, sinonasal tumours should always be managed
through a multidisciplinary team (MDT) approach. In fact,
while most surgical procedures for advanced sinonasal           Pretreatment diagnosis
cancers are performed by a single-specialty surgical team,      Diagnosis of tumours of the sinonasal tract is a consider-
the path leading patients to the operating theater requires     able challenge to the pathologist. This is mostly due to the
a long list of surgical specialists and non-surgical physi-     rarity, pathological heterogeneity, and possible morpholog-
cians, whose contribution is variably needed based on the       ical similarity of different sinonasal tumours.
characteristics of each case. The need for multidisciplinary    An emblematic example is represented by “small round
management owes to the vast spectrum of diseases includ-        blue cell tumours”. This term was coined by Bridge et al. in
ed in the term “sinonasal tumours”, which are located in a      2010 and refers to tumours displaying a non-specific mor-
watershed area where the combined knowledge of different        phology, which consists of “monotonous population of un-
specialties and subspecialties is frequently a must.            differentiated tumour cells with relatively small-sized nu-
The benefit of using MDT approach has been thoroughly           clei and scant cytoplasm” 4. This non-specific morphology
and objectively demonstrated for head and neck cancers 1.       is potentially underlaid by a number of cancers including
The present article aims to highlight the surgical aspects of   adenoid cystic carcinoma (ACC), Ewing-family tumours,
a modern MDT approach to advanced sinonasal tumours.            human papilloma virus (HPV)-related, ACC-like carci-
Sinonasal cancer frequently represents a challenge due to       noma, non-keratinizing squamous cell carcinoma (SCC),
a number of critical issues, the most relevant being re-        lymphoepithelial carcinoma, NUT carcinoma, SMARCB1/
liability of diagnosis, extension towards the intracranial      INI1-deficient carcinoma, sinonasal undifferentiated car-
spaces, face and orbit, possibility to spare content of the     cinoma (SNUC), neuroendocrine carcinomas (NEC), mu-
orbital cavity, sensitivity to non-surgical treatments, ex-     cosal melanoma (MM), olfactory neuroblastoma (ONB),
pected treatment-related morbidity, and prognosis. There-       rhabdomyosarcoma, mesenchymal chondrosarcoma, and
fore, sinonasal cancers are frequently at the top of the list   other tumours 5. As a consequence, a rational investiga-
of malignancies requiring thorough multidisciplinary as-        tion through immunohistochemistry is essential to unveil
sessment. Similarly, some benign or borderline sinonasal        molecular hints that ultimately lead to correct diagnosis 5.
diseases that are usually treated by surgery might benefit      As for all pathological conundrums, information coming
from a MDT approach in view of some special charac-             from clinical history as well as endoscopic and radiologic
teristics they can display. The rarity of sinonasal tumours     findings can be of help to anticipate a diagnosis or at least
alongside with the willingness of patients to refer to cent-    estimate its reliability in the pretreatment setting 6,7.
ers with adequate experience lead most cases to concen-         Another challenge faced by the MDT is that knowledge of
trate into “superspecialized” centers. On one hand, this        sinonasal tumours has been evolving with an accelerating
implies that expertise in management of sinonasal tumours       pace 8. This concept is well exemplified by SNUC his-
cannot prescind from training in those centers where an         tology. Originally described by Frierson et al. in 1986 9,
adequate volume of cases is managed by an MDT. On the           SNUC soon raised the interest of many researchers and
other hand, cases diagnosed in centers with a low vol-          clinicians. Since its description, it has represented a di-
ume of sinonasal tumours should be cautiously managed           agnosis of exclusion, thus early acquiring the role of
and referral to or consultation with institutions with ac-      “wastebasket entity” which still characterizes SNUC 10.
knowledged experience should be considered as an act            However, refinements in molecular diagnostics and bio-
of medical responsibility 2. This is even more true when        logical understanding of sinonasal tumours progressively
considering that for the majority of sinonasal tumours the      led some cancers initially labelled under the umbrella of
actual chance to cure the patient relies on primary treat-      SNUC to be diagnosed based on an immunohistochemi-
ment, whereas recurrence is much more difficult to treat        cal identifier rather than by exclusion. SMARCB1/INI1-
irrespective of MDT experience 3.                               deficient carcinoma 11, SMARCA4-deficient carcinoma 12,
The professional figures who should ideally participate in      IDH2-mutant SNUC 13, HPV-related SNUC 14, and NUT
a MDT are summarized in Table I and clustered as “essen-        carcinoma 15 (formally not considered a SNUC subtype) 16
tial” and “required on a case-by-case basis” depending on       are the most relevant examples of this phenomenon.
how often they are consulted according to authors’ expe-        While providing new diagnostic tools, this process should
rience. Though surgeons are frequently the “quarterback”        also prompt pathologists and their MDTs to be updated
of the MDT approach to sinonasal tumours, different non-        on the constant advancements of diagnosis of sinonasal



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                                                               When is a multidisciplinary surgical approach required in sinonasal tumours with cranial involvement?




Table I. Members of the multidisciplinary team to treat advanced sinonasal tumours.
 Multidisciplinary team member                                   Role(s)
 Essential members
 Otorhinolaryngologist, head and neck surgeon                             Clinical diagnosis and pre-treatment biopsy
                                                                          Surgical excision and skull base reconstruction
                                                                          Pathologic staging*
                                                                          Clinical follow-up
 Radiologist, PET-trained physician                                       Tumour mapping and re-staging
                                                                          Pathologic staging*
                                                                          Radiologic follow-up
 Pathologist                                                              Preoperative pathologic diagnosis
                                                                          Postoperative pathologic evaluation of the surgical specimen
                                                                          Pathologic staging*
 Medical oncologist                                                       Neoadjuvant chemotherapy
                                                                          Concomitant chemotherapy
                                                                          Palliative chemotherapy
                                                                          Immunotherapy and biotherapy
 Radiation oncologist                                                     Definitive radiation therapy
                                                                          Adjuvant radiation therapy
                                                                          Palliative radiation therapy
                                                                          Referral to a particle therapy center
 Required on a case-by-case basis
 Neurosurgeon                                                             Management of cases with critical transcranial and/or orbital apex extension
                                                                          Bypass surgery
                                                                          Management of intracranial complications
 Plastic surgeon, surgeon with advanced plastic surgery training          Reconstruction of complex defects
 Ophthalmologist, oculoplastic surgeon, maxillofacial surgeon             Management of cases with advanced involvement of the orbit and/or lacrimal system
 Neuroradiologist, interventional radiologist                             Temporary occlusion test
                                                                          Endovascular occlusion/stenting of the internal carotid artery
 Anesthesiologist, critical care physician                                To anticipate complex cases from an anesthesiologic standpoint
                                                                          To support management of intraoperative and early postoperative complications
                                                                          To minimize early postoperative events potentially favoring failure of the skull base
                                                                          reconstruction (e.g. nausea, vomit, cough)
 Dentist/oral health consultant                                           To address dental/periodontal disease before radiation therapy
                                                                          Dental rehabilitation in patients who undergo midfacial bone reconstruction
 Psychiatrist, psychologist, mental health professional                   To diagnose and address mental health disorders
 Pediatrician, pediatric subspecialist(s)                                 To anticipate and manage age-related medical/surgical issues in pediatric patients
                                                                          To lead management of complex cases in syndromic patients
                                                                          To propose and manage complementary antiangiogenic and other medical therapies
 Geriatrician                                                             To anticipate and manage age-related medical/surgical issues in elderlies
 Endocrinologist                                                          To anticipate and manage surgery- and/or disease-related endocrinological disorders
 Hematologist                                                             To lead management of lymphoproliferative disorders
 Palliative medicine physician, pain management specialist                To lead management of patients for whom palliation is indicated
 Thoracic surgeon and other surgeons                                      To perform metastasectomy in carefully selected patients
 Prosthetic anaplastologist                                               To organize facial/orbital/nasal/palatal prosthetic rehabilitation
 Hyperbaric medicine physician                                            To indicate and organize hyperbaric oxygen therapy in patients with skull base
                                                                          radionecrosis, osteomyelitis, or similar disorders
* Pathologic staging is best performed in consensus between the pathologist, radiologist, and surgeon who performed the resection.


tumours and equip them with the most modern and prom-                                      even in referral centers. Mehrad et al. analyzed 500 consec-
ising staining methods.                                                                    utive cases of head and neck tumours and found 20 (4.0%)
Despite improvement in the understanding and definition of                                 had major diagnostic discrepancies (with “major” denot-
sinonasal tumours, diagnosis remains a challenge, as wit-                                  ing a “significant change in patient management and/or
nessed by the considerable rate of misdiagnoses observed                                   prognosis”), 4 (20.0%) of which were sinonasal tumours 17.



                                                                                                                                                                  S5
M. Ferrari et al.




Considering the prevalence of sinonasal tumours in their
series, the sinonasal tract was the site with the highest rate
of major diagnostic discrepancies (19.0% vs 0.0-8.3%).
Schreiber et al. reported on a series of 77 nasoethmoidal tu-
mours on which they analyzed diagnostic reliability of pre-
treatment biopsy 7. They found that the overall reliability
was 83.1%, with pretreatment diagnosis of SCC or miscel-
laneous tumours (i.e. “malignant neoplasm”, “mesenchy-
mal neoplasm”, “poorly differentiated carcinoma”, “undif-
ferentiated carcinoma not otherwise specified”, and NEC)
and sampling of a small volume of tissue being significant-
ly associated with the highest risk of misdiagnosis. On the
other hand, diagnosis of adenocarcinoma, MM, and ONB
was associated with high reliability (97-100%), which led
the authors to conclude that well-defined clinical scenarios
such as, respectively, wood or leather workers, elderly with
pigmented sinonasal lesions, and lesions centered in the ol-
factory cleft with a cystic component on the intracranial
aspect could be reasonably sampled in the outpatient clinic
under local anesthesia. Other presentations should warrant
ample sampling (i.e. at least 2 mL), which is best achieved       Figure 1. Computed tomography (A, B) and magnetic resonance imaging
under sedation or even general anesthesia. Similarly, Ganti       (C, D) of a mucinous, signet-ring cell, intestinal-type adenocarcinoma of the
et al. described 11/52 (21.2%) cases of discrepancy be-           right nasoethmoidal complex. Different imaging modalities allow depiction of
tween preoperative and postoperative histopathology over          tumour extension with respect to the most relevant adjacent compartments
                                                                  (i.e. orbital cavity, skull base).
a 4-year time span 18. In particular, they distinguished 4
(7.7%) cases of shift from benign to borderline/malignant
disease, 3 (5.8%) from a malignancy to another cancer with        Precise mapping of tumour extension is a pivotal step in
more aggressive behavior, and 4 (7.7%) from malignancy
                                                                  treatment planning, particularly in relation to orbit and
to a benign disease.
                                                                  skull base invasion (Fig. 1). The presence in the MDT of a
These data dispel doubts that pathologists should be an ac-
                                                                  head and neck radiologist with specific expertise in sinona-
tive member of MDTs treating sinonasal tumours. Not only
                                                                  sal tumours is therefore crucial 19.
is the pathologist in charge of providing pretreatment diag-
                                                                  Nasal cavity and paranasal sinuses are separated from the
nosis, but also in sharing its estimated reliability, potential
                                                                  orbit and the intracranial space by several bony laminae,
pitfalls, and most probable alternative diagnoses with the
                                                                  which are thought to serve as barrier against tumour spread.
MDT. As a final remark, the pathologist is also involved
in other essential phases of the diagnostic-therapeutic pro-      Computed tomography (CT) depicts changes and losses of
cess, which includes postoperative diagnosis, detection of        mineralization of bony structures 20,21. However, resorption
pathological risk factors, and pathological staging. In this      of the mineral content of a bony wall does not necessar-
regard, it is the authors’ opinion that definition of margin      ily imply that the tumour has invaded the adjacent com-
status and pathological staging should be the result of a         partment. In fact, the most effective barrier to neoplastic
teamwork from the MDT. In fact, both these processes re-          spread beyond sinonasal boundaries is known to be the
quire in-depth anatomical mapping of tumour extension,            periosteum 22. Therefore, knowledge of infiltration and/or
which cannot ignore a simultaneous analysis of imaging            transgression of the periosteum represents a critical infor-
and consultation with the surgeons who performed surgery.         mation for therapeutic planning. In this regard, MRI has an
                                                                  intrinsic advantage over CT. In fact, the cortical bone and
                                                                  periosteum can be adequately demonstrated as a single, ho-
Mapping of local extension of the tumour
                                                                  mogeneous hypointense layer, irrespective of bone miner-
through pretreatment imaging                                      alization 23. Similarly, the dura and bony skull base appear
Improvement of cross-sectional imaging, with special ref-         as a single hypointense layer in non-contrast-enhanced se-
erence to magnetic resonance (MRI), has been one of the           quences. The dura differs from extracranial periosteum be-
main evolutionary drivers in the field of sinonasal tumours.      cause it frequently reacts to an advancing lesion by signifi-



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                                                     When is a multidisciplinary surgical approach required in sinonasal tumours with cranial involvement?




cantly increasing its thickness and enhancement 24. Overall,                  mour from the signal of retained mucus or inflamed thick-
the biological heterogeneity of sinonasal tumours translates                  ened mucosa; 2) the second step is mapping gross tumour
into 4 different patterns of bone involvement 25: 1) bone re-                 extension: once the epicenter of tumour is located, its
modeling, with displacement and thinning of bony walls 26;                    3-dimensional extent should be analyzed systematically
2) cortical destruction, with interruption of the cortical                    including six “vectors of growth” (i.e. anterior, posterior,
bone layer; 3) permeative invasion, which is replacement                      medial, lateral, caudal, cranial); 3) the last step is inference
of medullary bone in the absence of obvious cortical in-                      of potential patterns of non-macroscopic spread based on
terruption; 4) medullary sclerosis, with fibrous-like tissue                  imaging findings (e.g. enhancement, signal replacement)
formation in the medullary portion of a bone structure.                       and clinical information (e.g. histology, primary versus re-
Once bony boundaries are transgressed, accurate description                   current presentation). The same authors suggested that the
of the stage of involvement of adjacent compartments be-                      radiologist joining the MDT should carry “hand luggage”
comes paramount. In fact, infiltration of adjacent compart-                   with 4 epistemic compartments 19: mastering of technical
ments such as the orbit, soft tissues of the face, and intracra-              solutions, knowledge of radiologic anatomy, understanding
nial space might dictate the need for neoadjuvant treatment,                  of information with practical implications for other MDT
the response to which cannot be adequately evaluated unless                   members, and awareness of different biological behaviors
the initial extension has been accurately staged.                             displayed by tumours of the sinonasal tract.
Maroldi et al. demonstrated that MRI is superior to CT in
predicting the absence of orbital invasion (negative predic-                  Preoperative embolization and preventive
tive value: 100% vs 75%, overall accuracy 96% vs 81%,
                                                                              measures against major vascular
respectively) 27. In a recent study, Ferrari et al. analyzed the
diagnostic performance of MRI in detecting the involve-                       complications
ment of single orbital structures: the adjusted diagnostic ac-                Resection of sinonasal tumours with a critical relationship
curacy was satisfactory (≥ 80.0%) for the bony layer, extra-                  to major vessels and/or intrinsic hypervascularity (Tab. II)
conal fat, and muscular layer, but suboptimal (< 80.0%) for                   represents a challenge 31. In fact, uncontrolled bleeding
the periorbit and intraconal compartment 28. Overall, MRI                     causes poor visualization, increases the risk of complica-
was confirmed to provide precious preoperative informa-                       tions such as cranial nerve injury, CSF leak, and rupture of
tion on orbit involvement, though with specific shortcom-                     major vessels, and limits the ability to completely remove
ings the MDT should be aware of. Another goal of imaging                      the tumour. Potential additional morbidity includes postop-
is to establish the depth of transcranial invasion 29,30. Differ-             erative anemia and blood transfusion-related issues. Even if
ent degrees of invasion through the anterior skull base can                   immediate corrective protocols are available, death is also a
be identified by analyzing the signal of dura, cerebrospinal                  possible consequence of unresolved massive intraoperative
fluid (CSF), brain, and tumour, which is best depicted by                     blood loss 32. Consequently, all sinonasal tumours display-
MRI 25. Finally, potential contraindications to surgery such                  ing hypervascularity and/or abutting or encasing a major
as encasement of internal carotid artery and involvement                      vessel should be discussed with and possibly managed by
of the cavernous sinus should be evaluated on preoperative                    an MDT including an interventional radiologist.
imaging.
In order to facilitate comprehensive radiologic evaluation                    Angiography and embolization
of sinonasal tumours, Maroldi et al. proposed a checklist                     Blood supply to the tumour can be surmised based on the
approach 19: 1) the first step consists of separating the tu-                 location and extent of the lesion. This particularly applies


Table II. Most common hypervascularized tumours of the sinonasal tract.
 Benign vascular tumours and tumour-like lesions                            Juvenile angiofibroma
                                                                            Hemangioma (lobular capillary hemangioma)
                                                                            Angioleiomyoma
                                                                            Sinonasal paraganglioma
 Vascular malformations                                                     Venous malformation (cavernous hemangioma)
 Borderline/low grade malignant tumour                                      Glomangiopericytoma
                                                                            Solitary fibrous tumour
 Primary malignant vascular tumours                                         Angiosarcoma
 Secondary hypervascularized tumours                                        Renal cell carcinoma




                                                                                                                                                      S7
M. Ferrari et al.




to juvenile angiofibroma (JA), which predominantly re-
ceives vascular supply from the external carotid artery but
can also be fed by branches arising from the internal carot-
id artery (ICA), especially in case of large lesions. Notably,
30% of JAs show a bilateral vascular supply, which increas-
es to almost 70% in advanced cases 33. Vascular feeders of
sinonasal paragangliomas 34, hemangiopericytomas 35, hae-
mangiomas 36, and other hypervascularized lesions 37,38 are
less well known given their rarity. Transarterial angiogra-
phy provides the MDT with a case-specific map of vascular
feeders, which enables estimation of intraoperative risks,
morbidity of embolization or ligation, and potential residu-
al vascularity following embolization.
Embolization is meant to reduce tumour vascularity through
the injection of particles, coils, liquid embolic agents, or
other substances. It can be performed through direct punc-
ture of the tumour and/or via an endovascular approach.
Traditionally, tumour embolization has been achieved via a
transarterial route (most commonly through the femoral ar-
tery) with superselective catheterization and embolization
of feeding vessels. Superselective catheterization of exter-
nal carotid branches not only depicts the vascular architec-
ture of the lesion, but also unveils potentially dangerous
anastomoses with the cerebral/orbital vasculature which
                                                                 Figure 2. Angiography of a case of right juvenile angiofibroma with feed-
can result in subtotal embolization or even dramatic com-        ers coming from both the internal and external carotid artery systems (A, B).
plications such optic nerve ischemia 39. Evaluation of the       Following combined transarterial (with polyvinyl alcohol particles) and transle-
contralateral carotid branches should be done to exclude         sional (with Onyx®) embolization of the lesion and transarterial closure of the
contribution to tumour blush, particularly when the tumour       ipsilateral maxillary artery, only minimal residual enhancement from internal
                                                                 carotid artery feeders can be observed (C, D).
extends beyond the midline 40. Direct puncture techniques
using liquid embolic agents (e.g. Onyx) have also been de-
scribed. They can be used in conjunction with transarterial      criterion of difficult, dangerous, or even impossible resect-
embolization or as a sole modality of embolization 41.           ability. Intraoperative rupture of the ICA has been reported
Timing is a crucial aspect of embolization. Therefore, co-       to occur in 28/7160 (0.4%) endoscopic procedures and its
ordination of different members of the MDT is essential          consequences ranges from death to non-lethal cerebrovas-
to guarantee a satisfactory result. Early resection follow-      cular events, pseudoaneurysm, carotid-cavernous fistula,
ing embolization (i.e. within 24 hours) may obscure the
                                                                 and need for vascular occlusion 45,46. Although one could
beneﬁts of the procedure by not allowing enough time for
                                                                 hypothesize that vessels-encroaching tumours should be
tumour devascularization to occur; on the other hand, wait-
                                                                 referred to radiation oncologists, vascular toxicity actually
ing too long following embolization can lead to tumour
                                                                 represents a major concern even in patients undergoing RT
revascularization or even dramatic consequences such as
tumour inflammation, infarction, and/or swelling. For these      that can considerably limit dose delivery in areas neighbor-
reasons, surgery should not be delayed beyond 48-72 hours        ing the vessel (Fig. 3). In this scenario, the expertise of a
following embolization 33,40,42,43. However, a complex case      neuroradiologist, interventional radiologist, and neurosur-
of JA treated with staged surgery performed 8 days after         geon might be game changing in selected cases.
trimodal embolization has been reported (Fig. 2) 44.             The first step is to adequately analyze the critical relation-
                                                                 ship to the vessel through CT/MRI angiography 19. The sec-
Measures against major vascular complications                    ond is to test the tolerance of a potential ICA occlusion
While the indications and contraindications to surgery for       through a temporary occlusion test, which can be achieved
sinonasal tumours have considerably evolved throughout           via external compression or transarterial balloon occlusion.
the last decades, abutment, encasement, and frank inva-          Tolerance can be evaluated through a combination of sever-
sion of the ICA have been invariably considered as a major       al techniques including clinical assessment, cross flow tim-



S8
                                                             When is a multidisciplinary surgical approach required in sinonasal tumours with cranial involvement?




Figure 3. ( A, B) The panel shows the case of a pseudoaneurysm of the para-
sellar, paraclinoid, and intracranial tracts of the right internal carotid artery in
a patient who was treated through 12C-carbon ion therapy for an unresectable
adenoid cystic carcinoma of the right sphenoid sinus.


ing, evoked potentials, and functional imaging. In patients
demonstrating adequate cross flow from the contralateral
vascular system, the decision on whether or not to perform
endovascular ICA occlusion prior to surgery should be
based on the estimated risk of intraoperative rupture, which
has a known lethality of roughly 7-15% 46,47, and possible
need for vessel removal as part of the resection 48. However,
preoperative endovascular ICA occlusion should not be in-
dicated carelessly, as the long-term effects of the procedure
are unknown. In patients who would not tolerate ICA oc-
clusion, adequate counselling on potential morbidity and
mortality is mandatory and strategies such as endovascular
flow diverter protective stenting or extracranial-to-intracra-
nial bypass surgery should be considered when surgery can
be staged or delayed while the patient undergoes double
antiplatelet therapy (Fig. 4) 49,50.

Intracranial tumour extensions exceeding
the rhinologist’s expertise
The definition of intracranial involvement is of utmost im-                            Figure 4. The panel summarizes the complex management of a case of re-
portance in planning treatment for sinonasal tumours. MRI                              current nasopharyngeal carcinoma. (A) An enhancing nodule corresponding to
with contrast enhancement plays a key role in the deline-                              the second local recurrence of nasopharyngeal carcinoma is identified in close
ation of the tumour-dura and tumour-brain interface. Spe-                              relationship with the anterior genu of the left petrous internal carotid artery.
                                                                                       (B) A temporary balloon occlusion test reveals that the closure of the left inter-
cifically, the disappearance of the three “sandwich” layers                            nal carotid artery would not be tolerated by the patient. (C-E) An extracranial-
with different signals at the anterior cranial fossa (ACF)                             to-intracranial vascular bypass (white arrows) from the left external carotid
floor (bone-periosteum, dura, and CSF) and/or the evidence                             artery to the left middle cerebral artery was harvested and the left internal
of brain edema surrounding the tumour on T2-weighted                                   carotid artery was closed transarterially (white asterisks). (F, G) A type 3 left na-
                                                                                       sopharyngeal endoscopic resection was completed and the ipsilateral internal
images are predictors of intracranial and brain invasion,                              carotid artery (black asterisks) was resected; the carotid canal (black dotted
respectively 25.                                                                       lines) was completely drilled out. (H, I) Follow-up imaging showing patency of
Historically, the gold standard in the treatment of sinona-                            the vascular bypass and viability of the right temporoparietal fascia flap (TPFF)
sal malignancies invading the ACF was anterior craniofa-                               employed to resurface the surgical cavity.
cial resection with or without adjuvant RT 51, with bilateral
intraorbital and/or optic nerve extension, massive brain                               of subfrontal-subcranial approach firstly developed by
infiltration, optic chiasm involvement, distant metastasis,                            Raveh 52,53, in the late ’90s endoscopic techniques were
and internal carotid artery encasement being considered                                introduced in adjunction to open approaches with favora-
as absolute contraindications. By evolving the concepts                                ble outcomes 54. The so-called cranioendoscopic approach



                                                                                                                                                                       S9
M. Ferrari et al.




(CEA) combines an endoscopic approach allowing tumour            significant blood loss, as may occur even for benign lesions
removal from the nasal side with a subfrontal craniotomy         like JA 60. Procedure staging would enable complete resec-
that gives wide exposure of the lesion and margin control        tion, minimizing the risks related to duration of surgery and
from above. Main indications for CEA are massive infiltra-       surgeons’ fatigue 61.
tion of the dura, in particular when the dura is involved in     Finally, surgeons must bear in mind that resectability of
proximity to the lamina papyracea or when dural resection        sinonasal tumours with intracranial extension is influenced
would extend far lateral over the orbital roof 55. Multidisci-   not only by the entity of brain and dural invasion itself, but
plinary parallel dissection performed by skilled neurosur-       also by the histological diagnosis, with poorly differenti-
gical and otorhinolaryngological teams in CEA, using the         ated/aggressive lesions benefitting mostly from multimodal
microscope and endoscopes respectively, offers accurate          treatment often including neoadjuvant therapy.
control of the resection with clear dural margins. Another
scenario that should prompt to consider CEA is the contact       Orbital tumour extensions exceeding
between tumour and brain, “even with possible limited in-
filtration” 54. Nowadays this can be probably considered a
                                                                 the rhinologist’s expertise
“relative” indication to CEA, or at least a condition man-       The degree of orbital encroachment is a key element for
dating an accurate case-by-case selection. During the last       planning treatment of sinonasal tumours. In the ’70s, ero-
two decades, in fact, the growing body of evidence in the        sion of the lamina papyracea by sinonasal cancers was con-
field of endoscopic approaches to the nose and paranasal         sidered as an indication to orbital exenteration 51. Over the
sinuses has paved the way for the first series of pure endo-     last decades, several groups have demonstrated the onco-
scopic transnasal brain resection in the context of sinona-      logic safety of orbit-sparing surgery in adequately selected
sal malignancies 56. In cases of limited brain invasion, the     cases 62-65; however, criteria guiding orbit-sparing surgery
proposed technique takes advantage of subpial dissection         still lack univocal consensus 66-69. Since the first proposal in
of the gyrus rectus and/or medial orbital gyrus, with the        the ’80s of sparing the orbit in tumours eroding the medial
aim of achieving negative margins of resection. This resec-      orbital bony wall by Perry et al. 63 and Scott McCary et
tion technique requires proper preparation and experience        al. 64, the decisional barriers to indicate the need for orbital
in open and endoscopic approaches to the ACF, including          exenteration has been settled to the involvement of extrinsic
adequate training in dissecting the bony and the dura layers     muscles, optic nerve, ocular bulb, and/or skin overlying the
in the context of transnasal craniectomies 57,58. A series of    eyelid, as described by Iannetti et al. in the early 2000s 70.
19 selected patients with clinically suspected brain infil-      More recently, endoscopic and endoscopic-assisted orbit-
tration (11 with pathologically-proven brain involvement)        sparing surgery was shown to be useful and oncologically
including different histologies (> 50% ONB) was recently         safe 71. Turri-Zanoni et al. described a multimodal treat-
published by the Brescia and Varese groups 56, showing           ment algorithm for sinonasal cancers with orbital invasion
that 3-year overall, local recurrence-free, and distance         based on histology-driven treatment and accurate staging
recurrence-free survivals were 65.5%, 81.8%, and 68.2%,          of the degree of orbital invasion through contemporary
respectively.                                                    preoperative imaging (Figs. 5, 6) 72. Poorly differentiated
Even in referral centers for endoscopic approaches to the        cancers without orbital apex involvement were submitted
ACF, open approaches to the anterior skull base find their       to neoadjuvant chemotherapy, which was continued up to a
place in case of wide dural involvement, especially with         maximum of 5 cycles in good responders. Patients achiev-
lateral extension or when the tumour abuts the optic chiasm      ing complete response or ≥ 80% reduction of initial tumour
or extends over the orbital roof reaching beyond the mid-        volume at the end of neoadjuvant chemotherapy were sent
pupillary line.                                                  for definitive chemoradiation; patients with less favorable
Massive extension of the tumour through the dura and             response to neoadjuvant chemotherapy underwent surgical
infiltration of falx/superior sagittal sinus and/or brain pa-    resection followed by adjuvant radiotherapy or chemora-
renchyma also requires an open approach. In addition, a          diotherapy. Patients whose general conditions prevented
critical relationship with neurovascular structures as well      chemotherapy and those affected by well differentiated
as infiltration of the anterior wall of the frontal sinus or     sinonasal cancers or chemoresistant tumours received pri-
massive frontal sinus involvement are contraindications for      mary surgery, which was followed by adjuvant treatment if
purely endoscopic approaches to the ACF 59. Furthermore,         mandated by risk factors identified at definitive histologic
staged surgery should be considered when the tumour can-         examination. The multimodal treatment algorithm maxi-
not be entirely accessed through a single approach that          mized the orbital preservation rate (76.6%) in patients with
might require extensive bone removal or be threatened by         orbit-encroaching sinonasal cancer. According to a recent



S10
                                                          When is a multidisciplinary surgical approach required in sinonasal tumours with cranial involvement?




Figure 5. The panel illustrates two cases of moderately differentiated squamous cell carcinoma of the right maxillary sinus (A, D), both receiving neoadjuvant
chemotherapy with taxane, cisplatin, and 5-fluorouracile as the primary treatment modality. The first tumour (A) had a partial response (B) and was therefore sent
for proton therapy, which resulted in a complete response (C). The second tumour (D) had progression of disease (E) and therefore mandated surgery including
total maxillectomy with orbital exenteration, middle and anterior craniectomy with dural resection (F), reconstruction of the defect through a multilayer skull base
plasty and an anterolateral thigh free flap, followed by adjuvant radiation therapy.


publication, patients receiving orbital ablation for a sinona-                      treatment in patients who will have an ominous prognosis
sal cancer unamenable to orbit-sparing surgery have a high                          irrespective of surgical aggressiveness. However, this ad-
probability of bearing nodal disease (29.8%), poor chances                          ditional step forward in surgical orbital preservation would
of surviving (5-year overall and disease-specific survival:                         be unfeasible without the contribution of oculoplastic sur-
27.8%), and high risk of experiencing a local relapse de-                           geons and/or maxillofacial surgeons trained in oculoplastic
spite aggressive surgery (5-year local recurrence-free sur-                         surgery.
vival: 44.6%) 28. These data should be considered as a “red                         Another unsolved challenge of sinonasal oncology is rep-
flag” for the MDT, with an indication to orbital ablation                           resented by sinonasal cancers macroscopically invading the
deserving thoughtful evaluation of potential alternatives.                          orbital apex. When invasion of the orbital apex is detected
The need to combine orbit sparing with functional pres-                             at preoperative imaging, 5-year overall survival probability
ervation and offer the patient an adequately experienced                            is as low as 15.0% in patients undergoing multimodal treat-
handling of orbital tissues justifies why an oculoplastic                           ment including orbital exenteration/clearance 28. Sugawara
surgeon should be part of the MDT. For instance, Shi et                             et al. reported a 5-year overall survival rate of 86.2% in 15
al. described the feasibility and oncologic adequacy of a                           patients with macroscopic orbital apex involvement treated
combined external and endoscopic en bloc orbit-sparing re-                          through an “extended orbital exenteration” 75. The surgical
section in malignancies arising from the lacrimal drainage                          procedure was performed by a multispecialty team com-
system 73. Recently, Fontes et al. reported on the satisfac-                        posed of neurosurgeons, head and neck surgeons, and plas-
tory functional outcome of surgical reconstruction of the                           tic surgeons. In addition to resection of the nasoethmoidal
medial rectus muscle after iatrogenic rupture during endo-                          box and anterior skull base, the authors removed the orbital
scopic transnasal sinus surgery 74. Based on these results                          apex as surrounded by its bony walls and sectioned the neu-
and keeping in mind the potential negative effects of ad-                           rovascular structures in their intracranial tracts through a
juvant treatment, one could hypothesize to partially resect                         transcranial approach. The obvious gain in overall survival
and primarily reconstruct a focally-invaded extrinsic ocular                        reported by Sugawara et al. should encourage one to offer
muscle. This approach could indeed reduce morbidity of                              multidisciplinary surgery by both head and neck and neu-



                                                                                                                                                              S11
M. Ferrari et al.




Figure 6. Panel showing three examples of surgical orbital preservation in patients affected by sinonasal cancers. (A, D) A right nasoethmoidal intestinal-type
adenocarcinoma encroaching the orbit with no interruption of the periorbit at preoperative imaging was resected through an orbit-sparing endoscopic approach.
(B, E) A recurrent adenoid cystic carcinoma located into the inferior aspect of the right orbital cavity was resected through an orbit-sparing transnasal endoscopic
prelacrimal approach. (C, F) A unifocal, left preseptal recurrence of intestinal-type adenocarcinoma was resected through an orbit-sparing rhinectomy extended
to the medial canthus and lacrimal sac.


rological surgeons to those unfortunate patients requiring                          facial skeleton, oral cavity, and/or scalp, which mandates
orbital ablation for an orbital apex-invading cancer.                               the use of more complex reconstructive strategies. Another
                                                                                    scenario that requires advanced plastic surgery expertise
Post-ablative defects requiring plastic                                             is when graft-based and vascularized local and regional
                                                                                    reconstructive strategies are unavailable or have already
surgical expertise                                                                  failed 82-86. In both circumstances, reconstruction with re-
The majority of resections for sinonasal tumours with cra-                          vascularized free flaps has been reported as an effective
nial involvement result in skull base defects that can be ef-                       strategy 87. A variety of free flaps have been used in patients
fectively reconstructed by an otorhinolaryngologist and/or                          requiring complex skull base reconstruction. According to
neurosurgeon through multilayer reconstruction possibly                             a recent systematic review, 1628 cases of skull base recon-
including a vascularized flap 76-79. Regional flaps such as the                     struction using free flap as the sole strategy or in combi-
pericranial or temporoparietal fascia flap can be used up-                          nation with other techniques have been reported, with the
front or left as backup options when the risk of postopera-                         large majority of cases including an anterior skull base de-
tive CSF leak is deemed high (Fig. 7) 80,81.                                        fect 88. Fasciocutaneous flap such as the anterolateral thigh
In rarer circumstances, the defect can be variably extended                         and radial forearm free flaps have been most frequently
to the external nose, orbit, midface, upper face, maxillo-                          employed, with bulkier myocutaneous flaps such as the



S12
                                                            When is a multidisciplinary surgical approach required in sinonasal tumours with cranial involvement?




                                                                                     ing a combination of tailored antibiotics, pentoxifylline,
                                                                                     alpha-tocopherol, and hyperbaric oxygen therapy 91-93.
                                                                                     Of note, it is the authors’ opinion that reconstruction of the
                                                                                     bony and dural defect in the skull base should adhere to
                                                                                     the principles of a multilayer technique to ensure watertight
                                                                                     closure before the free flap is in-set. It is indeed surmised
                                                                                     that this minimizes the chances of CSF leak, which can
                                                                                     subtly occur even though a thick layer of well vascular-
                                                                                     ized tissues covers the defect, but skull base closure is not
                                                                                     watertight. Considering this, it seems logical that a plastic
                                                                                     surgeon or head and neck surgeon with expertise in plas-
                                                                                     tic surgery be included in MDT for advanced sinonasal
                                                                                     tumours. Moreover, adequate briefing and planning of the
                                                                                     reconstruction is mandatory, with each surgical specialist
                                                                                     being in charge of different phases of reconstruction in-
                                                                                     cluding multilayer skull base reconstruction, flap harvest-
                                                                                     ing, in-set, and microvascular anastomoses (Fig. 8).

                                                                                     Intraoperative complications requiring
                                                                                     multidisciplinary management
                                                                                     Several intraoperative complications can occur during sur-
                                                                                     gery for advanced sinonasal tumours. The present para-
                                                                                     graph summarizes the main concepts on two important
                                                                                     events of which the MDT should be aware, namely intraop-
                                                                                     erative ICA rupture and neurogenic cardiovascular altera-
                                                                                     tions.
                                                                                     Injury of the ICA is a rare but potentially catastrophic in-
                                                                                     traoperative complication of endoscopic skull base surgery.
                                                                                     Wang et al. reported that an incidence of 0.016% to 1% was
                                                                                     estimated based on large endoscopic transnasal surgery se-
                                                                                     ries 94; AlQahtani et al. reported an in-depth analysis of 28
Figure 7. Panel illustrating the surgical management of a chondrosarcoma             cases of ICA injury out of 7160 endoscopic procedures,
of the nasal septum encroaching the anterior skull base. (A, B) Preoperative         with a resulting frequency of 0.4% 46.
imaging of the tumour. (C-E) Exemplificative steps of the endoscopic transna-        In case of intraoperative ICA rupture, the current opinion
sal resection of the chondrosarcoma. (F, G) Harvest of the pericranial flap and
preparation of the so-called “mailbox” for flap transposition towards the skull      is that bleeding should be temporarily controlled by na-
base defect. (H-J) Three-layer reconstruction of the skull base through grafts       sal packing possibly anticipated by an attempt at direct
of iliotibial tract and subcutaneous fat, which was lined with a pericranial flap.   endoscopic hemostasis by an adequately trained surgical
                                                                                     team 47,95. This explains why the anesthesiologist should
                                                                                     also be considered as part of the MDT. For instance, op-
rectus abdominis and latissimus dorsi flap being indicated                           timal blood pressure control is warranted in case of ICA
for very large defects. Bone-including free flaps have also                          injury 96, with arterial hypotension and hypertension be-
been reported for reconstruction requiring a rigid vascular-                         ing sequentially necessary to facilitate bleeding control
ized framework, with special reference to those harvested                            and ensure adequate collateral/contralateral flow towards
from the subscapular system due to its versatility in terms                          ischemic areas, respectively. Adequate preoperative brief-
of bony and soft tissue components 89,90. Skull base infec-                          ing with the anesthesiologist is therefore suggested in cases
tion and osteoradionecrosis also benefit from transfer of                            with potential ICA injury. Thereafter, the patient should be
non-infected, non-irradiated, (re-)vascularized tissue fol-                          moved to the angiography room and urgent occlusion test
lowing necrosectomy and debridement, which should be                                 followed by endovascular stenting and/or occlusion should
delivered in the context of a comprehensive therapy includ-                          be performed by an interventional radiologist 95,97,98.



                                                                                                                                                           S13
M. Ferrari et al.




                                                                                       the surgical procedure, a neurosurgeon, preferably trained
                                                                                       in bypass surgery, should be alerted when an operation at
                                                                                       risk of causing an intraoperative intracranial bleeding is
                                                                                       performed.
                                                                                       In case of endoscopic surgery involving any part of the
                                                                                       trigeminal nerve, adequate briefing with the anesthesiolo-
                                                                                       gist is also mandatory. In fact, trigeminal stimulation might
                                                                                       suddenly provoke dysrhythmia, hypotension, or even asys-
                                                                                       tole due to the trigemino-cardiac reﬂex 99,100. Management
                                                                                       of the trigemino-cardiac reflex is mainly based on preop-
                                                                                       erative risk evaluation, vigilance during anesthesia, effec-
                                                                                       tive communication for a rapid cessation of precipitating
                                                                                       stimuli, and prompt correction of cardiovascular changes.

                                                                                       Conclusions
                                                                                       The present narrative review highlighted that most cases
                                                                                       of advanced sinonasal tumours can be managed by an ad-
                                                                                       equately trained otorhinolaryngological team. However,
                                                                                       since a minor yet non-negligible case rate requires addi-
                                                                                       tional expertise, a systematic MDT discussion of sinonasal
                                                                                       tumours have, among others, the advantage of selecting pa-
                                                                                       tients requiring the intraoperative skills of neurosurgeons,
                                                                                       oculoplastic surgeons, and physicians with plastic surgery
                                                                                       training. As a final remark, one should consider that non-
                                                                                       surgical specialties participating in the MDT approach to
                                                                                       sinonasal tumours have been and are noticeably evolving.
                                                                                       As a consequence, the paradigms of treatment of sinona-
                                                                                       sal tumours, with special reference to cancers and selected
                                                                                       advanced benign tumours, are considerably changing. This
                                                                                       fact mandates approaching advanced sinonasal tumours
                                                                                       through a comprehensive MDT approach to provide the pa-
                                                                                       tient with the best possible treatment he/she can be offered.
Figure 8. Panel illustrating the complex surgical management of a recurrent
nasopharyngeal carcinoma located into the nasoethmoidal box (A, B) and ex-
tending to the right orbital apex through the posterior ethmoidal canal (white         References
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