10.14639/0392-100X-N2375
Objective. Endoscopic endonasal surgery is effective in the treatment of sinonasal cancers. However, in cases of well-differentiated locally advanced neoplasms as well as recurrences, the most appropriate treatment is debated. The purpose of this study is to report a monoinstitutional experience on craniofacial surgery performed in a tertiary-care referral centre. Methods. This was a retrospective analysis of 90 patients treated with transcranial and/ or transfacial resection for sinonasal cancer between 2010 and 2020. Outcome measures included overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS) and recurrence-free survival (RFS). Results. The 5-year OS, DSS and DFS were 48.2%, 60.6% and 28.7%, respectively. Factors correlated with prognosis were pT-classification (p = 0.002), histotype (p = 0.012) and dural involvement (p = 0.004). Independent prognostic factors were orbital apex infiltration (p = 0.03), age (p = 0.002) and adjuvant therapy (p = 0.03). Conclusions. When endoscopic endonasal surgery is contraindicated and chemoradiotherapy is not appropriate, craniofacial and transfacial approaches still represent an option to consider, despite the non-negligible morbidity.
text/xml
1827-675X
2375
en
Mario Turri-Zanoni
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
treatment outcome
Surgical management of advanced sinonasal cancer: a 10-year mono-institutional experience
Text.Serial.Journal
https://www.actaitalica.it/
44
Skull base surgery
2024-04-22
2022-11-14
2024-04-23
2024-04-23
128-137
1
Mario Turri-Zanoni
2024/04/22
10.14639/0392-100X-N2375
128
Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria, ASST Sette Laghi, Ospedale di Circolo Fondazione Macchi, Varese, Italy; Head and Neck Surgery & Forensic Dissection Research Center (HNS&FDRc), Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
1827-675X
treatment outcome
en
137
Surgical management of advanced sinonasal cancer: a 10-year mono-institutional experience
https://www.actaitalica.it/article/download/2375/1088
44
ACTA OTORHINOLARYNGOLOGICA ITALICA 2024;44:128-137; doi: 10.14639/0392-100X-N2375




Skull Base Surgery


Surgical management of advanced sinonasal
cancer: a 10-year mono-institutional experience
Giorgio Sileo1, Alberto Daniele Arosio1, Alessia Lambertoni1, Paolo Battaglia1,2, Maurizio Bignami2,3, Mario Cherubino4,
Luigi Valdatta4, Paolo Antognoni5, Davide Locatelli6, Paolo Castelnuovo1,2, Mario Turri-Zanoni1,2
1
 Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria, ASST Sette Laghi,
Ospedale di Circolo Fondazione Macchi, Varese, Italy; 2 Head and Neck Surgery & Forensic Dissection Research Center
(HNS&FDRc), Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy; 3 Division of Otorhinolaryngology,
Department of Biotechnology and Life Sciences, University of Insubria, ASST Lariana, Ospedale Sant’Anna, Como, Italy; 4 Division
of Plastic and Reconstructive Surgery, Department of Biotechnology and Life Sciences, University of Insubria, ASST Sette Laghi,
Ospedale di Circolo Fondazione Macchi, Varese, Italy; 5 Division of Radiation Oncology, ASST Sette Laghi, Ospedale di Circolo
Fondazione Macchi, Varese, Italy; 6 Division of Neurosurgery, Department of Biotechnology and Life Sciences, University of Insubria,
ASST Sette Laghi, Ospedale di Circolo Fondazione Macchi, Varese, Italy


SUMMARY
Objective. Endoscopic endonasal surgery is effective in the treatment of sinonasal cancers.
However, in cases of well-differentiated locally advanced neoplasms as well as recurrences,
the most appropriate treatment is debated. The purpose of this study is to report a mono-
institutional experience on craniofacial surgery performed in a tertiary-care referral centre.
Methods. This was a retrospective analysis of 90 patients treated with transcranial and/
or transfacial resection for sinonasal cancer between 2010 and 2020. Outcome measures
included overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS)
and recurrence-free survival (RFS).
Results. The 5-year OS, DSS and DFS were 48.2%, 60.6% and 28.7%, respectively. Fac-
tors correlated with prognosis were pT-classification (p = 0.002), histotype (p = 0.012) and
dural involvement (p = 0.004). Independent prognostic factors were orbital apex infiltration
(p = 0.03), age (p = 0.002) and adjuvant therapy (p = 0.03).
Conclusions. When endoscopic endonasal surgery is contraindicated and chemoradiother-
apy is not appropriate, craniofacial and transfacial approaches still represent an option to
consider, despite the non-negligible morbidity.
KEY WORDS: craniofacial surgery, paranasal sinus, cancer, skull base, treatment outcome          Received: November 14, 2022
                                                                                                 Accepted: November 28, 2023

                                                                                                 Correspondence
                                                                                                 Giorgio Sileo
Introduction                                                                                     E-mail: sileo.giorgio@gmail.com
It is commonly accepted that a combination of surgery and radiotherapy is the
mainstay in the management of well-differentiated sinonasal cancer 1-3. Tradi-                     How to cite this article: Sileo G, Arosio
tionally, because of the complexity of the sinonasal anatomy and close proximity                   AD, Lambertoni A, et al. Surgical manage-
                                                                                                   ment of advanced sinonasal cancer: a 10-year
with orbit and brain, craniofacial surgery has been regarded as the standard treat-                mono-institutional experience. Acta Otorhi-
ment to obtain ‘en-bloc’ resection 4,5. Over the past two decades, with advances                   nolaryngol Ital 2024;44:128-137. https://doi.
in endoscopic endonasal surgical techniques and skull base reconstruction meth-                    org/10.14639/0392-100X-N2375
ods, minimally-invasive surgery has emerged as an alternative to an open surgi-
                                                                                                 © Società Italiana di Otorinolaringoiatria
cal approach, with the advantages of lower post-operative morbidity and higher                   e Chirurgia Cervico-Facciale
quality of life than open surgery 2,6,7. On the other hand, the appropriateness of
endoscopic endonasal surgery has been questioned especially when managing                                       OPEN ACCESS

locally-advanced cases, thus opening a diatribe between supporters of the two                    This is an open access article distributed in accordance with
                                                                                                 the CC-BY-NC-ND (Creative Commons Attribution-Non-
techniques. What is universally accepted is that a free-margins resection should                 Commercial-NoDerivatives 4.0 International) license. The
be obtained in patients considered suitable for surgery after a multidisciplinary                article can be used by giving appropriate credit and mentio-
                                                                                                 ning the license, but only for non-commercial purposes and
consultation. The surgical technique used to reach such a primary goal should                    only in the original version. For further information: https://
be based on the local extension of tumour and the patient’s general conditions.                  creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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                                                                                                                                               Surgery for advanced sinonasal cancer




The purpose of this study is to report a mono-institutional                                      according to the 8th edition of the “TNM classification of
experience on craniofacial surgery performed in a tertiary-                                      malignant tumours” for sinonasal cancer 8.
care referral centre renewed for endoscopic endonasal ap-                                        Histological classification was adapted to the 4th edition of
proaches, to offer a reappraisal of current evidence on indi-                                    the “WHO classification of head and neck tumours” 9.
cations and contraindications for traditional open surgery.
                                                                                                 Participants
Materials and methods                                                                            A cohort of 90 patients treated with a transcranial and/or
                                                                                                 transfacial approach was identified through electronic med-
Design and setting                                                                               ical records review.
Medical records of patients treated for sinonasal malignan-
cies via transcranial and/or transfacial approaches between                                      Pre-operative work-up and surgical technique
April 2010 and May 2020 at a tertiary-care referral Institu-                                     Local extension of disease was assessed by multiplanar
tion were retrospectively reviewed. Patients with (a) missing                                    computed tomography (CT) scan and contrast-enhanced
relevant data (e.g., pre-operative imaging, follow-up); (b) un-                                  magnetic resonance imaging (MRI) in all cases. Based on
resectable cancer; (c) distant metastases at presentation and                                    pre-operative radiological exams no involvement of unre-
(d) less than 12 months of follow-up were excluded.                                              sectable areas was apparent. All patients underwent pre-
Demographic data, tumour characteristics, imaging studies,                                       operative nasal endoscopy and biopsy. Neck ultrasound
surgical reports, previous treatments, and adjuvant therapy                                      and total body contrast-enhanced CT scan and/or positron
were collected and reviewed. All cases were re-classified                                        emission tomography (PET) scan were obtained to rule out




 Alt: anterolateral thigh free flap; T: tumour; black arrows: erosion of the anterolateral maxillary wall; black asterisks: infiltration of the right temporalis muscle; white arrows: mesh
 plate used to reconstruct the right orbital floor.

Figure 1. Pre-operative CT (A and D) and MRI scans (B, T2W; C, T1W contrast enhanced) in coronal sections show a right maxillary squamous cell carcinoma
eroding the anterolateral maxillary bony walls (black arrows in A and D), extending into the premaxillary soft tissues and infiltrating the infratemporal fossa and the
temporalis muscle (black asterisks in B and C). MRI scans in coronal views (E, T2W; F, T1W contrast enhanced) performed one year after transfacial surgery. The
patient is currently alive without disease at 5 years after treatment.



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G. Sileo et al.




 Alt: anterolateral thigh free flap; T: tumour; white arrows: mesh plate used to reconstruct the right orbital floor.

Figure 2. A 54-year-old woman affected by right maxillary sinus squamous cell carcinoma G1 involving the infratemporal fossa, parotid gland, temporalis muscle
and subcutaneous premaxillary soft tissues (T4aN0M0). (A) Clinical appearance, with noticeable right premaxillary swelling; (B) Intra-operative surgical planning
of skin incisions; (C) Intra-operative appearance of the surgical defect resulting after the transfacial resection (right selective neck dissection of the neck levels I
to IV, right radical parotidectomy, “en bloc” excision of the neoplasm by radical maxillectomy with extension to overlying skin, temporalis muscle and ramus of the
mandible. Reconstruction was performed with an anterolateral thigh free flap and a mesh plate was used for the orbital floor (white arrows in C). The patient un-
derwent post-operative radiotherapy. (D) Post-operative outcome after 2 years of follow-up.


regional or systemic spread, respectively. Surgical resec-                                       classified as exclusive local recurrence (T+, N-, M-), re-
tion was tailored to the local extension of disease (Figs. 1-2,                                  gional recurrence (T±, N+, M-) and distant recurrence (T±,
Tab. I). Transfacial surgery included orbital exenteration,                                      N±, M+). OS was defined as the time from surgery to the
total maxillectomy, facial skin excision and/or total rhinec-                                    last follow-up or death for any cause. DFS was defined as
tomy. Transcranial surgery was required in case of intracra-                                     the time from surgery to the first relapse at any site or death
nial extension, massive involvement of the frontal sinus, or                                     for any causes. LRFS, RRFS and DRFS were defined as
infiltration of its posterior wall. Skull base reconstruction                                    time from surgery until relapse at local, regional or distant
was performed whenever required.                                                                 sites, respectively.

Multimodal therapies and neck management                                                         Data analysis
Patients with locally advanced poorly-differentiated can-                                        Survival probability was assessed using the Kaplan-Mei-
cers were submitted to induction chemotherapy, accord-                                           er survival analysis and the log rank test was performed
ing to histology-driven protocols 10,11. Lymphovascular or                                       to compare survivals. A multivariate proportional hazard
perineural invasion and T3-T4 categories were considered                                         Cox-regression was used for the same endpoints (OS, DFS,
indications for adjuvant radiotherapy (RT) 1 and concurrent                                      LRFS, DRFS). Results are presented in term of hazards ra-
cisplatin-based chemoradiotherapy (CRT) was adminis-                                             tios (HR), 95% confidence intervals (CIs), and p values. All
tered in cases with positive surgical margins 12.                                                statistical tests were two-tailed and statistical significance
Patients affected by high-grade advanced stage epithelial                                        was considered when p value ≤ 0.05. IBM SPSS software,
sinonasal cancers submitted to reconstruction with free flap                                     version 25 (Chicago, IL, USA), was used to perform all
were treated with elective neck dissection, since the surgical                                   statistical analysis.
field was already approached for the vascular anastomosis. In
the other cases requiring elective neck treatment but without
                                                                                                 Results
the need of surgical reconstruction, an elective neck irradia-
tion was preferred. Clinically-positive neck lymph nodes were                                    Clinical and pathological characteristics of the population
treated with therapeutic neck dissection. All patients were ad-                                  During the 10-year time span, a total of 502 patients were
dressed to standardised clinical-radiological follow-up 6.                                       treated for sinonasal cancer. Among these, 41 patients
                                                                                                 (8.2%) affected by poorly differentiated histologies re-
Main outcome measures                                                                            ceived non-surgical based treatment with concurrent CRT,
Overall survival (OS), disease-free survival (DFS) and re-                                       and 371 patients (73.9%) underwent endoscopic endonasal
currence-free survival (RFS) were analysed. Relapses were                                        resection, while the remaining 90 cases (17.9%) were treat-



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Table I. Indications and contraindications, according to the authors’ opinion, for surgical approaches based on anatomical sites involved.
 Site                           Endoscopic endonasal resection            Trans-cranial resection              Trans-facial                Unresectable
                                                                                                                resection
 Maxillary sinus and                Involvement of medial maxillary wall,                         -                    Involvement of lateral and/or                    -
 palate                                         orbital floor                                                         inferior walls, hard and/or soft
                                                                                                                             palate involvement
 Frontal sinus                      Lesion abutting into the sinus; lesions        Origin from the upper half             Erosion of the anterior                       -
                                     originating from the lower half of the        of the sinus; erosion of the            wall; forehead skin or
                                   sinus with adequate anatomy (large AP                  posterior wall                    subcutaneous tissue
                                      diameter and interorbital distance)                                                       involvement
                                                                                    Small AP diameter and
                                                                                      interorbital distance
                                                                                   Massive involvement of the
                                                                                              sinus
                                                                                   Massive lateral supraorbital
                                                                                     attachment in laterally
                                                                                       pneumatised sinus

 Sphenoid sinus                        Involvement of the anterior wall                Posterior planum                               -                    Involvement of posterior/
                                                                                    sphenoidale involvement                                                    lateral wall and/or
                                                                                                                                                             cavernous sinus, optic
                                                                                                                                                            chiasm, cavernous ICA
 ITF/PPF/UPS                       PPF involvement; limited ITF extension                         -                      Massive ITF involvement,             Parapharyngeal ICA
                                                                                                                           masticatory space                     encasement
                                                                                                                               involvement
 Orbit                             Erosion of lamina papyracea (grade 1)                          -                    Invasion of the anterior 2/3          Orbital apex (grade 4)
                                                                                                                                (grade 3)
                                     Invasion of periorbital layer and/or
                                   focal invasion of extraconic periorbital
                                                fat (grade 2)
 Brain and dura                      Limited dural infiltration; olfactory          Dural infiltration extended                       -                    Massive brain infiltration
                                    bulb involvement; focal midline brain            laterally over the orbital
                                                  invasion                         roofs or posteriorly beyond
                                                                                       planum sphenoidale
                                                                                         Brain infiltration
 Skin                                                    -                                        -                       Facial skin involvement                       -
AP: anteroposterior; AW: anterior wall; FS: frontal sinus; ICA: internal carotid artery; ITF: infratemporal fossa; PPF: pterygopalatine fossa; UPS: upper parapharyngeal space.



ed with a transcranial or transfacial approach and included                                    Treatment and complications
in the study. The male to female ratio was 2.5:1 and the                                       The type of surgical resection and surgical margin status
mean age of the population was 61.2 years (range, 4-83;                                        are provided in Table II. Overall, 27 transcranial and 63
median, 65.5). Table II summarises histology distribution,                                     transfacial resection were performed. Reconstruction of
previous treatments and TNM classification of the patients                                     the surgical defect was required in 51 patients (56.7%) and
enrolled. A total of 25 patients affected by pT2-3 tumours                                     performed as follows: anterolateral thigh flap in 33 cases
                                                                                               (36.7%), temporal muscle flap in 7 cases (7.7%), fibula free
were not manageable with endonasal surgery due to hard
                                                                                               flap in 4 cases (4.4%), radial forearm flap in 3 cases (3.3%),
palate infiltration in 18 maxillary cancers (pT2 in 10 cas-
                                                                                               vastus lateralis free flap in 2 cases (2.2%), scapular tip free
es and pT3 in 8 cases with simultaneous involvement of                                         flap and medial sural artery perforator flap in one case each
ethmoid) and subcutaneous premaxillary soft tissue infil-                                      (1.1%). Skull base reconstruction was performed in 27 pa-
tration in 3 maxillary cancers (staged as pT3). Furthermore,                                   tients (30%), using pericranial flap in 14 cases and multi-
in 4 patients submitted to salvage surgery after CRT the                                       layered technique with either flaps or grafts in 13 cases.
final histology report resulted in a pathological downstage                                    Peri-operative complications occurred in 31 patients
of disease compared to the pre-operative radiological stage.                                   (34.4%): free flap failure (9 cases, 29%); bleeding (6 cases,



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Table II. Clinicopathological characteristics of the study population.
 Variable                                                                  N/tot (%)                      N/TCR (%)                       N/TFR (%)
 Age (years)
   Mean [range]                                                          61.2 [4-83]                    63.1 [27-83]                     60.5 [4-82]
 Gender
   Male                                                                  64/90 (71.1)                   23/27 (85.2)                     41/63 (65.1)
   Female                                                                26/90 (28.9)                    4/27 (14.8)                     22/63 (34.9)
 Previous treatments
   Surgery                                                               16/90 (17.8)                    4/27 (14.8)                      12/63 (19)
   Surgery + radiotherapy                                                10/90 (11.1)                     2/27 (7.4)                      8/63 (12.7)
   Chemo-radiotherapy                                                     9/90 (16.6)                     2/27 (7.4)                      7/63 (11.1)
 pT classification
   T2                                                                    10/90 (11.1)                          -                         10/63 (15.9)
   T3                                                                    15/90 (16.7)                     1/27 (3.7)                     14/63 (22.2)
   T4a                                                                    36/90 (40)                     3/27 (11.1)                     33/63 (52.4)
   T4b                                                                   29/90 (32.2)                   23/27 (85.2)                       6/63 (9.5)
 N classification
   N0                                                                    87/90 (96.7)                    27/27 (100)                     60/63 (95.2)
   N1                                                                     3/90 (3.3)                           -                           3/63 (4.8)
 Tumour site of origin
   Ethmoid sinus                                                         24/90 (26.7)                   11/27 (40.7)                     13/63 (20.6)
   Frontal sinus                                                          7/90 (7.8)                     6/27 (22.2)                      1/63 (1.6)
   Maxillary sinus                                                       48/90 (53.3)                    4/27 (14.8)                     44/63 (69.8)
   Nasal septum                                                           6/90 (6.7)                      2/27 (7.4)                       4/63 (6.3)
   Olfactory cleft                                                        4/90 (4.4)                      1/27 (3.7)                       3/63 (4.8)
   Pterygoid                                                              1/90 (1.1)                           -                           1/63 (1.6)
 Histologic group
   Squamous cell carcinoma                                               38/90 (42.2)                     10/27 (37)                     28/63 (44.4)
   Intestinal-type adenocarcinoma                                        13/90 (14.4)                    8/27 (29.6)                      5/63 (7.9)
   Other epithelial tumours                                              20/90 (22.2)                     1/27 (3.8)                     19/63 (30.3)
   Malignant soft tissue tumours                                         10/90 (11.1)                    3/27 (11.1)                      7/63 (11.1)
   Mucosal melanoma                                                       6/90 (6.7)                      2/27 (7.4)                       4/63 (6.3)
   Olfactory neuroblastoma                                                3/90 (3.3)                     3/27 (11.1)                           -
 Surgery
  Radical maxillectomy                                                   39/90 (43.3)                          -                          39/63 (62)
  Orbital exenteration                                                   12/90 (13.3)                          -                          12/63 (19)
  Cranio-endoscopic resection                                            12/90 (15.6)                   12/27 (44.4)                           -
  Combined approaches                                                     27/90 (30)                    15/27 (55.6)                      12/63 (19)
  Skull base reconstruction                                               27/90 (30)                     27/27 (100)                           -
  Neck dissection                                                        17/90 (18.9)                     2/27 (7.4)                     15/63 (23.9)
  Reconstruction                                                         51/90 (56.7)                   11/27 (40.7)                     40/63 (63.5)
 Surgical margins
  Negative                                                               62/90 (68.9)                   12/27 (44.4)                     50/63 (79.4)
  Positive                                                               28/90 (31.1)                   15/27 (55.6)                     13/63 (20.6)
 Adjuvant treatment
  Exclusive radiotherapy                                                 51/90 (56.7)                     17/27 (63)                      34/63 (54)
  Exclusive chemotherapy                                                  4/90 (4.4)                      1/27 (3.8)                      3/63 (4.8)
  Chemo-radiotherapy                                                       9/90 (10)                     4/27 (14.8)                      5/63 (7.9)
 Recurrence
  Overall recurrence rate                                                39/90 (43.3)                   15/27 (55.6)                      24/63 (38)
  Local (T+, N0, M0)                                                     19/90 (21.1)                    4/27 (14.8)                     15/63 (23.8)
  Regional (T±, N+, M0)                                                   7/90 (7.7)                      2/27 (7.4)                      5/63 (7.9)
  Distant (T±, N±, M+)                                                   13/90 (14.4)                    9/27 (33.4)                      4/63 (6.3)
 Status
  NED                                                                     36/90 (40)                     4/27 (14.8)                     32/63 (50.8)
  AWD                                                                     18/90 (20)                     6/27 (22.2)                      12/63 (19)
  DOD                                                                    28/90 (31.1)                   13/27 (48.2)                     15/63 (23.9)
  DOC                                                                     8/90 (8.9)                     4/27 (14.8)                      4/63 (6.3)
AWD: alive with disease; DOC: dead of other causes; DOD: dead of disease; M: distant disease; N: regional disease; NED: no evidence of disease; T: local disease;
TCR: transcranial resection; TFR: transfacial resection.



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                                                                                                                                               Surgery for advanced sinonasal cancer




19.3%); fever, pneumocephalus and donor site morbidity (3                                        Survival analysis
cases respectively, 9.7%); cerebrospinal fluid (CSF) leak,                                       After a mean follow-up of 32.8 months (range, 1-125; me-
meningitis and pneumonia (2 cases respectively, 6.4%);                                           dian, 26), only 36 patients (40%) were alive without evi-
deep vein thrombosis (one case, 3.2%). The mean time in-                                         dence of disease (Tab. II). Five-year OS, DSS and DFS
terval for complications was 8.3 days (range, 1-28, median,                                      were 48.2%, 60.6% and 28.7%, respectively. Five-year
9), categorised as early (within 15 days) in 21 cases, and                                       LRFS, RRFS and DRFS were 59.4%, 83.2% and 70.8%,
                                                                                                 respectively.
late (after 15 days) in 10 cases.
                                                                                                 The main prognosticators observed were pT classification,
Most of the patients received adjuvant treatment (64 cases,
                                                                                                 surgical margins status, dural infiltration, and orbital apex
71.1%, Tab. II), whereas 26 patients did not as it was not
                                                                                                 infiltration, which were associated with reduced survival
indicated after multidisciplinary discussion for several rea-                                    rates in terms of OS, DFS and DSS (Tab. III, Fig. 3). Histo-
sons: surgery performed as salvage treatment after previous                                      pathological classification was associated with significant
RT or CRT (14 cases, 15.5%); radical resection performed                                         differences only in terms of DFS (p = 0.012). No significant
for an early-stage cancer (i.e. pT2) in 9 cases (10%); multi-                                    differences in survivals between patients treated with trans-
ple comorbidities with compromised performance status in                                         facial and transcranial resection were observed in univari-
2 cases (2.2%); patient’s refusal in one case (1.1%).                                            ate analysis.


Table III. Survival analysis of the study population: univariate analysis of OS, DFS, DSS, LRFS and DRFS.
 Variable                        Overall survival       Disease free survival         Disease specific    Local recurrence free                              Distant recurrence free
                                                                                          survival               survival                                            survival
                                   5-yr OS         p value       5-yr DFS        p value         5-yr DSS        p value      5-yr LRFS        p value       5-yr DRFS         p value
 pT classification                                 0.011*                         0.002*                         0.023*                         0.124                           0.029*
  pT2-T3                             70.9                           49.8                           79.9                           69.6                          86.3
  pT4a                               56.8                           24.0                           61.5                           56.4                          64.4
  pT4b                               34.6                           13.1                           43.8                           47.9                          63.4
 Surgical margins                                  0.001*                         0.001*                         0.001*                        0.010*                           0.166
  Negative                           63.7                           38.9                           72.5                           63.6                          72.9
  Positive                           29.1                            8.9                           35.8                           47.4                          67.5
 Histology                                          0.099                         0.012*                          0.112                         0.186                           0.007*
  SCC                                43.8                           34.2                           56.2                           76.7                          69.8
  ITAC                               53.8                           24.6                           65.3                           55.5                          61.5
  Other epithelial tumour            56.9                           18.2                           56.9                           27.3                          87.1
  MSTT                               56.3                            NA                             75                             NA                           66.7
  Melanoma                           33.3                            NA                            33.3                           66.7                          22.2
  ONB                                100                            33.3                           100                            66.7                          100
 Adjuvant treatment                                 0.648                         0.109                           0.682                        0.007*                           0.169
  No                                 50.2                            NA                            56.3                           31.6                          86.3
  Yes                                 53                            35.3                            62                            70.1                          65.8
 Dural infiltration                                0.001*                         0.004*                         0.002*                         0.316                           0.029*
  Negative                           62.1                           34.9                           62.8                           63.4                          74.4
  Positive                           26.4                           11.6                           33.4                           41.9                          42.8
 Orbital apex infiltration                         0.001*                         0.001*                         0.001*                        0.001*                           0.031*
  Negative                           59.9                           34.9                           69.7                           63.7                          74.5
  Positive                           17.8                            NA                            19.4                            NA                           50.8
 Surgical approach                                  0.096                         0.401                           0.404                         0.237                           0.089
   TFR                               23.8                           29.8                           61.2                          53.6                           77.6
   TCR                               47.3                           26.5                           59.9                          72.3                           55.9
DFS: disease-free survival; DRFS: distant recurrence-free survival; ITAC: intestinal-type adenocarcinoma; LRFS: local recurrence-free survival; MSTT: malignant soft tissue tumour; NA:
not applicable; ONB: olfactory neuroblastoma; OS: overall survival; SCC: squamous cell carcinoma; TCR: transcranial resection; TFR: transfacial resection; *Statistically significant values.




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G. Sileo et al.




 DFS: disease-free survival.

Figure 3. Kaplan-Meier curves for DFS according to pT classification, surgical margins, histopathologic classification, adjuvant treatment, dural and orbital apex
infiltration.


Recurrence analysis                                                                as a protective factor, significantly reducing the global risk
The total recurrence rate was 43.3% (39/90 patients, Tab. II)                      of recurrence (HR 0.51 in DFS; HR 0.28 in LRFS). Finally,
with a mean time to recurrence of 18.5 months. Local re-                           age was confirmed to be an independent prognostic factor
currence was the most frequent pattern of relapse (19/39                           in terms of OS. Type of surgical resection (transcranial or
cases, 48.7%). Distant sites of failure were multi-organ (6                        transfacial) was not tested on multivariate analysis because
cases), brain (3 cases), liver (2 cases), lungs and bones (one                     of the lack of statistical significance in univariate analysis.
case each). Treatment of recurrences was surgically-based
in 15/39 cases (38.5%) and non-surgical (RT and/or CRT)                            Discussion
in 13/39 cases (33.3%), while 11/39 (28.2%) patients were
addressed to best supportive care.                                                 The management of sinonasal malignancies has signifi-
The main factors associated with recurrence risk are sum-                          cantly evolved during the last decades 1,3. Histology-driven
marised in Table III. Orbital apex infiltration was signifi-                       protocols are now recognised as the standard of care, which
cantly associated with increased risk of local and distant                         contributed to the reduction of surgical resection as an up-
failures; dural infiltration, pT and histopathologic clas-                         front treatment strategy, particularly in the case of poorly
sification were associated with increased risk of systemic                         differentiated neoplasms 1,12. Moreover, the growing experi-
dissemination of disease; finally, positive surgical margins                       ence acquired in sinonasal endoscopic surgery has prompt-
were associated with increased risk of local recurrences.                          ed a wide diffusion of endoscopic resection in the surgical
                                                                                   management of these cancers and the concept of “oriented
Multivariate analysis                                                              disassembling” of the lesion has definitely proved its va-
On multivariate analysis (Tab. IV), orbital apex infiltration                      lidity in terms of oncological safety, with outcomes com-
was associated with significantly increased risk of death and                      parable to those of the classical “en bloc” resection 6. In
recurrence (HR 2.53 in OS; HR 4.92 in DFS; HR 6.01 in                              the last decade, the progressive development of endoscopic
LRFS). Moreover, the delivery of adjuvant treatment emerged                        techniques has allowed to manage difficult regions such as



134
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Table IV. Survival analysis of the study population: multivariate analysis of OS, DFS, and LRFS.
 Variable                                    Overall survival                      Disease-free survival                           Local recurrence-free survival
                                   5-yr OS         HR (95% CI)           p value 5-yr DFS           HR (95% CI)      p value    5-yr LRFS     HR (95% CI)      p value
 Age (continuous)                                1.05 (1.01-1.08)         0.002*                  1.01 (0.99-1.03)    0.08                  1.00 (0.98-1.02)    0.67
 Surgical margins                                1.67 (0.71-3.89)          0.23                   1.58 (0.83-2.99)    0.15                  1.34 (0.51-3.55)    0.54
  Negative                           63.7                                                  38.9                                   63.6
  Positive                           29.1                                                   8.9                                   47.4
 Adjuvant treatment                              1.04 (0.47-2.29)          0.91                   0.52 (0.29-0.95)   0.03*                  0.28 (0.12-0.66)   0.004*
  No                                 50.2                                                   NA                                    31.6
  Yes                                 53                                                   35.3                                   70.1
 Dural infiltration                              2.11 (0.95-4.69)          0.06                   1.24 (0.61-2.54)    0.54                  1.05 (0.34-3.18)    0.92
  Negative                           62.1                                                  34.9                                   63.4
  Positive                           26.4                                                  11.6                                   41.9
 Orbital apex infiltration                       2.53 (1.08-5.94)          0.03*                  4.92 (2.20-11.01) < 0.0005*               6.01 (1.78-20.31) 0.004*
   Negative                          59.9                                                  34.9                                   63.7
   Positive                          17.8                                                  NA                                      NA
CI: confidence interval; HR: hazard ratio. *Statistically significant; NA: not available




the frontal sinus 13, various areas of the maxillary sinus 14,15,                                 gins, dural invasion and orbital apex infiltration were sig-
the infratemporal fossa 16 and orbit 17.                                                          nificantly associated with reduced survival rates in terms
Data from the present analysis confirm this trend over time,                                      of OS, DFS and DSS (Tabs. III-IV). Achieving negative
considering that in the last 10 years only 90 patients were                                       surgical margins is significantly more important than the
treated with transcranial or transfacial approaches com-                                          way a tumour is removed (en bloc vs piecemeal resection),
pared to 371 patients (73.9%) treated by endoscopic endo-                                         and therefore it should be the surgical goal regardless of
nasal resection.                                                                                  the technique chosen, whenever possible. Dural and intrac-
Nonetheless, traditional transcranial and transfacial proce-                                      ranial extension have been recognised as the most adverse
dures are still indicated in selected cases and can be used                                       prognostic factors 21. Our study is in line with this trend,
not only as primary treatment for locally-advanced cases,                                         even though the role of dural invasion was not significant in
but also as salvage procedures for local failures in sites that                                   multivariate analysis, suggesting that other elements might
are no longer manageable with minimally-invasive tech-                                            act as confounding factors. On the contrary, orbital apex
niques 18. This is confirmed by the present series, where                                         invasion resulted as a high-risk negative prognostic factor
more than half of the patients were treated for recurrent or                                      for almost all the survival endpoints, in both univariate and
persistent disease (52 cases, 57.8%).                                                             multivariate analysis. In particular, orbital apex infiltration
After a mean follow-up time of 32.8 months, 5-year sur-                                           significantly worsens outcomes because a free-margin re-
vival rates in the present study were 48.2%, 60.6%, 28.7%                                         section is virtually impossible, regardless of the type of sur-
for OS, DSS, and DFS, respectively. Survival rates from                                           gery performed 5, and results of the present study support
the largest series available are similar to those of the pre-                                     this evidence (Tab. IV).
sent study, with 5-year OS and DSS rates being 53.6% and                                          The total recurrence rate of the present series was 43.3%
59.9%, respectively 19. Moreover, a recent review 20 con-                                         with a mean time to recurrence of 18.5 months, with 5-year
firmed this trend, reporting median 5-year OS 54% and me-                                         LRFS, RRFS and DRFS being 59.4%, 83.2% and 70.8%,
dian 5-year DSS 60%. These data corroborate the appropri-                                         respectively. Ganly et al. 22 reported 5-year RFS rates of
ateness of the treatments provided in the present series, but                                     45.8%, with median time to recurrence of 7 months, while
also emphasise that there is still space for improvement of                                       Higgins et al. 23 reported a 5-year locoregional control rate
outcomes, considering that only small progresses in sur-                                          of 48%. In line with previous series 19,21, local recurrence
vival rates have been observed in the last decades when                                           was the most frequent pattern of relapse (19/39 cases,
considering advanced-stage sinonasal cancers.                                                     48.7%), followed by distant failure (13/39, 33.3%).
Survival analysis confirmed the role of the most recognised                                       Analysis of RFS showed that dural infiltration (p = 0.029)
prognosticators: pT classification, status of surgical mar-                                       and pT classification (0.029) were the factors associated



                                                                                                                                                                    135
G. Sileo et al.




with increased risk of systemic dissemination of disease.           of the armamentarium of the head and neck surgeon in or-
This was also the case of histopathologic classification            der to increase the chances to obtain radical resection in
(p = 0.07), as 4/6 patients affected by mucosal melanoma            advanced-stage disease and in selected cases of local recur-
developed metastases and died of disease. Positive surgi-           rences involving sites that are not amenable to endoscopic
cal margins were associated with increased risk of local re-        salvage surgery.
currence in univariate analysis (p = 0.01). With regards to
adjuvant treatments, our results suggest that post-operative        Conflict of interest statement
radiotherapy might correlate with improved locoregional             The authors declare no conflict of interest.
control: this confirms that in appropriately selected high-
risk cases adjuvant treatments might lower the risk of death        Funding
and recurrence 24.                                                  This research did not receive any specific grant from fund-
When dealing with open craniofacial surgery, postopera-             ing agencies in the public, commercial, or not-for-profit
tive morbidity deserves mention. This type of surgery is, in        sectors.
fact, associated with non-negligible rates of complications
with an average mortality of 4% as demonstrated by König            Author contributions
et al. 20.                                                          GS: conceptualisation, formal analysis, investigation, data
Among 1193 patients studied, Ganly et al. 25 reported a             curation, writing original draft, visualisation; ADA: con-
postoperative mortality rate of 4% and morbidity rate of            ceptualisation, investigation, writing original draft; PB:
33%. Except for the absence of treatment-related deaths,            resources, supervision; MB: resources, supervision; MC:
our study showed a perioperative complication rate                  resources, supervision; LV: resources, supervision; PA: re-
(34.4%) in line with those already mentioned. Complica-             sources, supervision; DL: resources, supervision; PC: con-
tions were more frequently represented by free flap failure         ceptualisation, investigation, resources, supervision; MTZ:
(9 cases, 29%), followed by bleeding requiring revision (6          conceptualisation, investigation, resources, supervision,
cases) and intracranial complications. This highlights that         writing review & editing.
expanding the surgical field can increase the chances to ob-
tain radical removal in tumours that are not amenable to en-        Ethical consideration
doscopic endonasal resection, but at a cost of increased risk       The study was approved by the Institutional Review Board
of mortality and morbidity: it should always be discussed           (Insubria Board of Ethics, approval number 0033025/2015).
pre-operatively with the patient and balanced considering           The research was conducted ethically, with all study proce-
performance status, comorbidities and residual quality of           dures being performed in accordance with the requirements
life.                                                               of the World Medical Association’s Declaration of Helsin-
This study has some limitations that should be mentioned.           ki. Written informed consent was obtained from each par-
First, it is based on a retrospective analysis of patients treat-   ticipant/patient for study participation and data publication.
ed over a 10-year period, with intercurrent changes that in-
evitably introduced bias in the analysis. Second, a signifi-
cant heterogeneity was observed in the study, considering
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