10.14639/0392-100X-N2087
Objective. Biphenotypic sinonasal sarcoma (BSNS) is a rare low-grade cancer that was included from the 4th edition of WHO classification of head and neck tumours. The purpose of this study is to analyse clinical behaviour, pattern of recurrences and survival outcomes of this neoplasm.Methods. Retrospective review of patients affected by BSNS who were treated via an endoscopic- assisted approach in 6 European tertiary-care referral hospitals. Cases of BSNS described in literature since 2012 to date were fully reviewed, according to PRISMA guidelines.Results. A total of 15 patients were included. Seven patients were treated via an endoscopic endonasal approach, 4 with endoscopic transnasal craniectomy, and 4 via a cranioendoscopic approach. Adjuvant treatment was delivered in 2 cases. After a mean follow-up of 27.3 months, systemic metastasis was observed in 1 case; the 5-year overall survival and disease-free survival rates were 100% and 80 ± 17.9%, respectively.Conclusions. BSNS is a locally aggressive tumour with a low recurrence rate and encouraging survival outcomes if properly treated with surgical resection and free margins followed by adjuvant radiotherapy for selected cases. Endoscopic-assisted surgery is safe and effective as an upfront treatment within a multidisciplinary care protocol.
text/xml
1827-675X
2087
en
Paolo Castelnuovo
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
sinonasal cancer
Biphenotypic sinonasal sarcoma: European multicentre case-series and systematic literature review
Text.Serial.Journal
https://www.actaitalica.it/
42
Rhinology
2022-12-29
2022-03-23
2022-12-29
2023-01-16
545-553
1
Paolo Castelnuovo
2022/12/29
10.14639/0392-100X-N2087
545
Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria, 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
sinonasal cancer
en
553
Biphenotypic sinonasal sarcoma: European multicentre case-series and systematic literature review
https://www.actaitalica.it/article/download/2087/894
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:545-553; doi: 10.14639/0392-100X-N2087




Rhinology


Biphenotypic sinonasal sarcoma: European
multicentre case-series and systematic literature
review
Sarcoma bifenotipico nasosinusale: case-series europeo multicentrico e revisione
sistematica della letteratura
Mario Turri-Zanoni1,2, Gianluca Dalfino1, Matt Lechner3, Iacopo Dallan4, Paolo Battaglia1,2, Carla Facco5,
Francesca Franzi5, Giacomo Gravante1, Marco Ferrari6, Dimitrios Terzakis7, Amrita Jay8, Martin D. Forster9,
Andrea Luigi Ambrosoli10, Maurizio Bignami2,11, Christos Georgalas7, Philippe Herman12, Piero Nicolai6, Valerie J. Lund13,
Paolo Castelnuovo1,2
1
  Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria, 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 UCL Cancer Institute, University College London; Head and Neck Centre, University College
London Hospitals and Barts Health NHS Trust, London, UK; 4 ENT Unit, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy;
5
  Department of Pathology, ASST Sette Laghi, University of Insubria, Varese, Italy; 6 Section of Otorhinolaryngology-Head and
Neck Surgery, Department of Neurosciences, University of Padua, Azienda Ospedaliera di Padova, Padua, Italy; 7 Department of
Otorhinolaryngology-Head & Neck Surgery, Hygeia Hospital, Athens, Greece; 8 Department of Cellular Pathology, University College
London Hospitals NHS Foundation Trust, London, UK; 9 UCL Cancer Institute, London, United Kingdom; Department of Oncology,
University College London Hospitals NHS Foundation Trust, London, United Kingdom; 10 Department of Anesthesia and Intensive
Care, Filippo Del Ponte Hospital, ASST Sette Laghi, Varese, Italy; 11 Department of Otolaryngology Head and Neck Surgery,
University of Insubria, Como, Italy; 12 Department of Otolaryngology, Lariboisière University Hospital, Paris Diderot University, APHP,
Paris Sorbonne Cité, Paris, France; 13 Royal National Throat, Nose and Ear Hospital, UCLH Foundation Trust, London, United
Kingdom


SUMMARY                                                                                        Received: May 3, 2022
Objective. Biphenotypic sinonasal sarcoma (BSNS) is a rare low-grade cancer that was           Accepted: October 3, 2022
included from the 4th edition of WHO classification of head and neck tumours. The purpose
of this study is to analyse clinical behaviour, pattern of recurrences and survival outcomes   Correspondence
of this neoplasm.                                                                              Gianluca Dalfino
Methods. Retrospective review of patients affected by BSNS who were treated via an en-         Division of Otorhinolaryngology, Department of
doscopic-assisted approach in 6 European tertiary-care referral hospitals. Cases of BSNS       Biotechnology and Life Sciences, University of
described in literature since 2012 to date were fully reviewed, according to PRISMA guide-     Insubria, via Guicciardini, 9, 21100 Varese, Italy
                                                                                               Tel. +39 0332 278426. Fax +39 0332 278945
lines.
                                                                                               E-mail: gianluca.dalfino@gmail.com
Results. A total of 15 patients were included. Seven patients were treated via an endo-
scopic endonasal approach, 4 with endoscopic transnasal craniectomy, and 4 via a cranio-
endoscopic approach. Adjuvant treatment was delivered in 2 cases. After a mean follow-up         How to cite this article: Turri-Zanoni M, Dal-
of 27.3 months, systemic metastasis was observed in 1 case; the 5-year overall survival and      fino G, Lechner M, et al. Biphenotypic sinona-
                                                                                                 sal sarcoma: European multicentre case-series
disease-free survival rates were 100% and 80 ± 17.9%, respectively.
                                                                                                 and systematic literature review. Acta Otorhi-
Conclusions. BSNS is a locally aggressive tumour with a low recurrence rate and encour-          nolaryngol Ital 2022;42:545-553. https://doi.
aging survival outcomes if properly treated with surgical resection and free margins fol-        org/10.14639/0392-100X-N2087
lowed by adjuvant radiotherapy for selected cases. Endoscopic-assisted surgery is safe and
effective as an upfront treatment within a multidisciplinary care protocol.                    © Società Italiana di Otorinolaringoiatria
                                                                                               e Chirurgia Cervico-Facciale
KEY WORDS: anterior skull base, biphenotypic sarcoma, endoscopic endonasal surgery,
low-grade sarcoma, sinonasal cancer
                                                                                                              OPEN ACCESS

                                                                                               This is an open access article distributed in accordance with
RIASSUNTO                                                                                      the CC-BY-NC-ND (Creative Commons Attribution-Non-
Obiettivo. Il sarcoma nasosinusale bifenotipico (SNSB) è un raro tumore a basso grado,         Commercial-NoDerivatives 4.0 International) license. The
                                                                                               article can be used by giving appropriate credit and mentio-
incluso a partire dalla 4° edizione WHO dei tumori testa-collo. L’obiettivo di questo studio
                                                                                               ning the license, but only for non-commercial purposes and
è analizzare i tassi di sopravvivenza e i pattern di recidiva di questa neoplasia.             only in the original version. For further information: https://
Metodi. Revisione retrospettiva dei pazienti affetti da SNSB, trattati mediante approccio      creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                       545
M. Turri-Zanoni et al.




endoscopico in 6 centri di riferimento europei. È stata condotta inoltre una revisione sistematica della letteratura dal 2012 ad oggi, secondo
le linee guida PRISMA.
Risultati. Sono stati inclusi 15 pazienti (approccio endoscopico endonasale in 7 casi, craniectomia endoscopica transnasale in 4 casi, approc-
cio combinato transcranico in 4 casi). In 2 casi è stata somministrata radioterapia adiuvante. Dopo un periodo di follow-up medio di 27,3
mesi, è stato riscontrato un caso di metastasi a distanza; i tassi di 5-year Overall Survival e Disease-Free Survival erano 100% e 80 ± 17,9%,
rispettivamente.
Conclusioni. Il SNSB è un tumore localmente aggressivo con un basso tasso di recidiva e tassi di sopravvivenza incoraggianti se trattato con
asportazione chirurgica radicale con radioterapia adiuvante per casi selezionati. La chirurgia endoscopica ha dimostrato di essere sicura ed
efficace come trattamento iniziale all’interno di un protocollo di cura multidisciplinare.
PAROLE CHIAVE: base cranica anteriore, sarcoma nasosinusale bifenotipico, chirurgia endoscopica endonasale, sarcoma basso grado,
tumori maligni nasosinusali



Introduction                                                             Pre-operative work-up
                                                                         All patients underwent complete physical examination, nasal
Biphenotypic sinonasal sarcoma (BSNS) is a rare and re-
                                                                         endoscopy, routine blood counts, biopsy with histological ex-
cently introduced low-grade tumour that was initially de-                amination, neck ultrasound and total body contrast-enhanced
scribed by Lewis et al. in 2012 as “low-grade sinonasal                  CT scan. The local extension of disease was estimated using
sarcoma with neural and myogenic differentiation,” which                 multiplanar computed tomography (CT) scan and contrast-
remains a synonym for BSNS 1.                                            enhanced magnetic resonance imaging (MRI) in all cases.
These cancers were first included in the fourth edition of               All neoplasms were classified according to the WHO histo-
WHO classification of head and neck tumours in 2017. The                 logic classification (4th edition). BSNSs were staged using
recognition of BSNS as a distinct neoplasm helps with the                the AJCC cancer staging manual (8th edition).
categorisation of a heterogeneous group of tumours that
were previously classified together 2.                                   Treatment
A variety of sinonasal neoformations, including cellular                 All patients were treated using an endoscopic-assisted ap-
schwannoma, glomangiopericytoma, fibrosarcoma, leio-                     proach tailored to the extension of disease and ranging
myosarcoma, malignant peripheral nerve sheath tumour                     from an exclusive endonasal resection (EER) to expanded
(MPNST), synovial sarcoma, solitary fibrous tumours, and                 resection including the ethmoidal roof and dura of the ante-
fibromatosis may pathologically mimic BSNS. However,                     rior skull base (ERTC, endoscopic resection with transna-
the diagnosis of BSNS based on pathological features alone               sal craniectomy). Transnasal skull base reconstruction was
is not possible due to the potential for pathological overlap.           performed according to a multilayer technique using au-
Therefore, immunophenotyping and immunofluorescence                      tologous materials such as fascia lata or the iliotibial tract.
are essential for diagnosis 3. Being rare and recently in-               In cases of massive involvement of the dura over the orbital
troduced, there is no available data, on survival outcomes               roof or brain parenchyma infiltration, the endoscopic endo-
and standard of care. The purpose of this study is to re-                nasal technique was combined with an external transcranial
view a multicentre experience on patients treated at seven               approach (CER, cranio-endoscopic resection). No elective
European tertiary-care referral centres, to report prelimi-              neck treatment was performed due to the low-grade of the
nary data on clinical behaviour, pattern of recurrences and              neoplasm and the lack of evidence on this protocol. Adju-
survival outcomes of this rare clinical entity. Additionally,            vant irradiation of the surgical field was administered in
currently available protocols of multidisciplinary manage-               case of close or positive surgical margins or involvement of
ment were investigated, and the recent pertinent literature              non-resectable areas (cavernous sinus, orbital apex).
was reviewed.
                                                                         Pathological diagnosis
Study design                                                             Histopathological diagnosis was performed uniformly with
Patients affected by BSNS, who were treated via endoscop-                centralised review and only those cases which had the fol-
ic-assisted approaches between January 2013 and January                  lowing features were included in the present study: typi-
2021 in seven European tertiary-care referral University                 cal histopathological appearance, immunohistochemical
hospitals, were enrolled in this study. Inclusion criteria               analysis and fluorescence in situ hybridisation analysis.
were as follows: (1) neoplasm treated with curative intent;              Haematoxylin-eosin staining showed a submucosal spindle
(2) histology-proven BSNS; (3) at least 12 months of fol-                cell proliferation with “herringbone” fascicular pattern of
low-up for surviving patients.                                           growth, uniform nuclei, lacking significant pleomorphism



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                                                                                                                    Biphenotypic sinonasal sarcoma




                                                                                 Statistical methods
                                                                                 The main endpoints analysed were overall survival (OS)
                                                                                 and disease-free survival (DFS). OS was defined as the
                                                                                 time from surgical treatment to death from any cause. DFS
                                                                                 was defined as the time from surgical treatment to the first
                                                                                 observation of recurrence at any site or death from any
                                                                                 cause. The Kaplan-Meier method was used to estimate the
                                                                                 probability of OS and DFS. All analyses were performed
                                                                                 using IBM-SPSS statistical software, version 1.0.0.1347.

                                                                                 Literature review
                                                                                 Currently available clinical studies were selected through
                                                                                 searching on online English-language electronic databases
                                                                                 (Pubmed, Scopus, Web of Science, and Cochraine Library)
                                                                                 from January 2012 to January 2021, under Preferred Re-
                                                                                 porting Items for Systematic Reviews and Meta-Analysis
                                                                                 (PRISMA) guidelines. The Population, Intervention, Com-
                                                                                 parator, Outcome, and Study (PICOS) design was utilised
                                                                                 for this review. The keywords and search terms included
                                                                                 the following: biphenotypic sinonasal sarcoma OR low-
                                                                                 grade sinonasal sarcoma with neural and myogenic differ-
                                                                                 entiation OR low-grade sinonasal sarcoma. In addition, we
                                                                                 manually scanned the reference lists of the articles included
                                                                                 to identify the other potential studies. The articles included
                                                                                 in this review of the literature met the following inclusion
                                                                                 criteria: confirmed histopathological diagnosis with im-
                                                                                 munohistochemical and molecular studies; available data
                                                                                 on clinical presentation, treatments, follow-up period and
                                                                                 oncological status.


Figure 1. (A) Haematoxylin-eosin staining showing submucosal spindle cell        Case-series
proliferation with fascicular pattern of growth (20x); (B) Smooth muscle actin   A total of 15 patients, aged between 34 to 75 years (mean,
(SMA) staining showing concomitant expression of actin (20x); (C) S100 pro-
tein is positive with diffuse immunoreactivity (20x).                            54 years) were analysed. The female gender was more of-
                                                                                 ten affected, with a male to female ratio of 1:4 (Tab. I). The
                                                                                 clinical symptoms reported by patients were unilateral na-
and increased mitotic activity. Immunohistochemical posi-                        sal airway obstruction in 14 cases, unilateral epistaxis in 9
tivity for S100 protein (polyclonal AB) and smooth muscle                        cases, olfactory disfunction in 6 cases, and facial pain in 3
actin (SMA, clone 1A4) was used to confirm the diagnosis                         cases. Only one patient presented with diplopia and ocular
(Fig. 1). Furthermore, fluorescence in situ hybridisation                        motility impairment.
(FISH) analysis was performed to reveal the presence of                          Only one patient (1/15, 6.7%) has been formerly treated via
                                                                                 trans-facial surgery 10 years earlier in Peru for a sinonasal
PAX3-MAML3 fusion protein through t(2;4) translocation
                                                                                 sarcoma not otherwise specified (NOS) and this was also
(q35; q31.1).
                                                                                 the diagnosis on the pre-operative biopsy when the patient
                                                                                 was sent to our tertiary care referral centre. However, the
Follow-up                                                                        histology slides relating to both the previous surgical pro-
All patients were followed in accordance with a specific                         cedure and the pre-operative biopsy were examined by our
protocol which included endoscopic nasal examination,                            expert pathologists who were able to confirm a diagnosis
contrast-enhanced MRI of the head, neck US, and total                            of BSNS.
body CT scan at scheduled intervals, as previously de-                           The histological result of the preoperative biopsy was in
scribed 4. Follow-up data were available for all patients.                       line with the final diagnosis of BSNS in six cases (6/15,



                                                                                                                                             547
M. Turri-Zanoni et al.




Table I. Clinico-pathological features of the study population.                            In our sample, seven patients were treated with EER (7/15,
                                                                       BSNS                46.6%, Fig. 2), four patients were treated with ERTC
 Gender                                       Male                  3/15 (20%)             (4/15, 26.7%, Fig. 3) and four patients with CER (4/15,
                                             Female                12/15 (80%)             26.7%). Free-margin tumour excision was obtained in all
 Age                                         Range                 34-75 years             cases except two (2/15, 13.3%), where the resection mar-
                                              Mean                   54 years              gins were microscopically infiltrated (R1). The epicentre of
 Previous treatments                           Yes                  1/15 (6.7%)
                                                                                           the tumour was most frequently the ethmoid sinus (13/15,
                                                                                           86.7%), followed by the frontal sinus (3/15, 20%). Based
                                               No                 14/15 (93.3%)
                                                                                           on the final histology report, most cases were classified as
 Site of origin                             Ethmoid               13/15 (86.7%)
                                                                                           locally advanced tumour (pT4, 12/15 cases, 80%, Tab. I).
                                          Frontal sinus            2/15 (13.3%)
                                                                                           Adjuvant irradiation was performed in cases (2/15, 13.3%)
 Surgery                                       ER                  7/15 (46.6%)
                                                                                           with positive surgical margins using intensity modulated
                                              ERTC                 4/15 (26.7%)
                                                                                           radiation therapy (IMRT, 62 Gy).
                                               CER                 4/15 (26.7%)            During follow-up, only one patient (1/15, 6.7%) experi-
 Surgical margins                              R0                 13/15 (86.7%)            enced recurrence. This patient’s tumour was initially re-
                                               R1                  2/15 (13.3%)            sected with negative surgical margins, but she developed
 pT classification                              T2                  1/15 (6.7%)            local recurrence at the level of anterior skull base and orbit
                                                T3                 2/15 (13.3%)            after 35 months of follow-up. The patient was treated via
                                               T4a                 9/15 (66.7%)            CER with curative intent obtaining a free margin resection
                                               T4b                  3/15 (20%)             of the local recurrence. After 47 months of follow-up, she
 Adjuvant therapy                             None                13/15 (86.7%)            developed a second local recurrence involving the orbital
                                              IMRT                 2/15 (13.3%)            apex and cavernous sinus and was submitted to intensity
 Recurrence                                                         1/15 (6.7%)            modulated proton therapy (IMPT, 70 Gy). Surprisingly,
 Follow-up                                   Range                 6-80 months             lung metastasis was observed after 56 months of follow-
                                             Mean                  27.3 months             up, which was treated with lobectomy. The final histology
                                             Median                 18 months              report on the lung confirmed the diagnosis of BSNS, and
 Status                                       NED                 13/15 (86.7%)
                                                                                           confirmed by both immunohistochemical and FISH analy-
                                                                                           ses. The patient is currently alive with stable persistence
                                              AWD                  2/15 (13.3%)
                                                                                           of disease (cavernous sinus) after 80 months. After a mean
 OS                                          3-year                   100%
                                                                                           follow up of 27.3 months (median, 18 months; range, 6-80
                                             5-year                   100%
                                                                                           months), 13/15 (86.7%) patients are alive without evidence
 DFS                                         3-year                    80%
                                                                                           of disease. The 5-year OS rate was 100%, since no deaths
                                             5-year                    80%
                                                                                           occurred during follow-up. Conversely, the 5-year DFS
BSNS: biphenotypic sinonasal sarcoma; ER: endoscopic resection; ERTC: endoscopic
resection with transnasal craniectomy; CER: cranio-endoscopic resection; R0: free mar-     was 80 ± 17.9% (Fig. 4).
gin resection; R1: microscopic residual disease; IMRT: intensity modulated radiotherapy;
IMPT: intensity modulated proton therapy; NED: no evidence of disease; AWD: alive with     Literature review
disease; OS: overall survival; DFS: disease-free survival.
                                                                                           A total of 19 clinical studies were identified through
                                                                                           searches on online electronic databases, of which 16 were
40%), while a misleading diagnosis was found on pre-op-                                    selected (Fig. 5). A total of 122 cases were described in
erative biopsy in other cases: glomangiopericytoma (2/15,                                  the selected studies (Tab. II). However, the large major-
13.3%), malignant peripheral nerve sheath tumour (MPNST)                                   ity of studies were focused on histological diagnosis and,
                                                                                           therefore, clinical data (age, stage of disease, treatment
(1/15, 6.7%), NOS sarcoma (1/15, 6.7%), neurofibroma
                                                                                           strategy, follow-up, recurrence) were not fully available.
(1/15, 6.7%), synovial sarcoma (2/15, 13.3%) and inverted
                                                                                           Stage of disease was available for 7/122 cases in the litera-
papilloma (1/15, 6.7%). Of note, in one case (1/15, 6.7%) two                              ture and most were classified as locally advanced tumour
preoperative biopsies of the sinonasal lesion were performed,                              (T4a-T4b). Among cases with reported surgical technique,
but the histological result was negative for cancer and com-                               29.4% (5/17) underwent EER, 17.65% (3/17) ERTC and
patible with inflammatory tissue in both cases. Pre-operative                              17.65% (3/17) lateral rhinotomy. The most widely used
neck ultrasound and contrast-enhanced total body CT scan                                   surgical technique was CER in 35.3% (6/17) of cases.
ruled out the presence of satellite lymphadenopathies (N0)                                 Adjuvant treatments were performed in 17/122 (20.75%)
and distant metastasis (M0) in any patient.                                                of cases. In 13 cases (76.5%) adjuvant radiotherapy was



548
                                                                                                                              Biphenotypic sinonasal sarcoma




Figure 2. Endoscopic appearance of BSNS in right nasal fossa (A). Tumour mass after removal (B). Right nasal cavity after endoscopic resection (C).
BS: basisphenoid; IT: inferior turbinate; NS: nasal septum; black asterisk: tumour.




Figure 3. Preoperative MR angiography in axial (A), coronal (B) and sagittal (C) views revealed a mass arising from the right ethmoid. At 45 months, postopera-
tive MRI in axial (D), coronal (E) and sagittal (F) views revealed no recurrence of disease.



administered, while the remaining four (23.5%) received                           for 73/122 cases. In detail, the mean follow-up period was
chemo-radiotherapy. Follow-up information was provided                            54.6 months (range 2-336 months). Recurrences were ob-



                                                                                                                                                         549
M. Turri-Zanoni et al.




                                                                 Histologically, BSNS is characterised by a “herringbone”
                                                                 fascicular pattern, “staghorn” vessels and consistent immu-
                                                                 nohistochemical positivity for S100, smooth muscle actin
                                                                 (SMA), calponin and b-catenin. Moreover, it can also show
                                                                 variable expression of desmin, myogenin and factor XIIIa,
                                                                 while it is negative for cytokeratin and SOX10 7. The dou-
                                                                 ble phenotype stems from rearrangements in PAX3 gene, a
                                                                 transcription factor that normally promotes neural crest and
                                                                 skeletal muscle differentiation and which is particularly im-
                                                                 portant in the normal development of nasal structures. The
                                                                 original and predominant translocation identified in BSNS
                                                                 is t(2;4) (q35; q31.1), which results in a PAX3-MAML3
Figure 4. Kaplan-Meier disease-free survival analysis.           that appears to be specific for BSNS 8,9.
                                                                 Given its rarity, BSNS is often misdiagnosed, resulting in
                                                                 improper treatment planning. Unfortunately, endoscopic
                                                                 appearance and imaging of this tumour do not allow for ad-
                                                                 equate differential diagnosis. In some cases, it is possible to
                                                                 suspect a sinonasal malignant tumour, and in selected cases
                                                                 to postulate the possibility of sinonasal sarcoma based on
                                                                 endoscopic endonasal examination and specific radiologi-
                                                                 cal patterns. However, a specific diagnosis of BSNS can be
                                                                 only defined by an expert pathologist. In this regard, immu-
                                                                 nohistochemical analysis and fluorescence in situ hybridi-
                                                                 sation (FISH) are mandatory for appropriate characterisa-
                                                                 tion of this rare sinonasal sarcoma, which is crucial for an
                                                                 appropriate histology-driven multidisciplinary treatment 10.
Figure 5. Review process according to PRISMA guidelines.
                                                                 From a histological viewpoint, the differential diagnosis for
                                                                 BSNS includes cellular schwannoma, low-grade malignant
                                                                 peripheral nerve sheath tumour (MPNST), leiomyosarco-
served in 33.8% (25/74) of cases. None of these patients
                                                                 ma, fibrosarcoma, synovial sarcoma and glomangiopericy-
were reported to have distant metastases. At the time of the
                                                                 toma 7.
last follow-up, most of these patients (64/77, 83.1%) had
                                                                 Compared to other sinonasal sarcomas, BSNS shares a
no evidence of disease (NED); eight patients (8/77, 10.4%),
                                                                 similar clinical presentation, with aspecific symptoms, and
however, were alive with disease (AWD); in addition, four        a high propensity for local recurrence, while it differs in
patients (4/77, 5.2%) died for other diseases (DOD) and one      terms of clinical course and overall prognosis, especially
patient (1/77, 1.3%) died for other complications (DOC).         from high grade sarcomas which are characterized by in-
                                                                 creased rates of distant metastasis and poor prognosis.
Discussion                                                       In the literature, the treatment of choice for BSNS is free-
                                                                 margin surgical excision 11. Endonasal endoscopic surgery
The BSNS, also referred to as low-grade sinonasal sarcoma
                                                                 has been described as a safe, effective and minimally in-
with neural and myogenic differentiation, is a rare and re-
                                                                 vasive surgical approach in the management of sinonasal
cently described low-grade sarcoma that exhibits both neu-       malignant tumours 4. This was confirmed also by this multi-
ral and myogenic differentiation 1. BSNS typically arises        centre European experience for the treatment of BSNS. The
along the sinonasal tract, especially in the ethmoid sinus       endonasal endoscopic surgical approach, either exclusive
and nasal cavity. Clinically, it mainly affects women (M:F       or extended to the ethmoidal roof and dura of the anterior
ratio 1:3) and presents with non-specific symptoms such as       cranial fossa, allows appropriate excision of the disease
nasal airway obstruction, nasal congestion and epistaxis.        since the most frequently involved site in the origin of this
BSNS demonstrates a slowly progressive growth with local         tumour is the ethmoid sinus. An effective option for extend-
invasion and potential for local recurrences 5,6. Conversely,    ed tumours with anterior or lateral involvement of the fron-
distant metastasis is rare, as shown by the fact that no cases   tal sinus, infiltration of the dura far over the orbital roof, or
have been described in the literature thus far.                  presenting with an infiltration of the brain is a combined



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Table II. Review of literature and analysis of described cases.
 Author, year               No. of               No., location                 Staging     Surgical Adjuvant          Follow-up        Recurrence                    Status
                            cases                                                         treatment treatment (number of patients with
                                                                                                                available information)
Lewis, 2012 1                28                   19, ethmoid                    NA           NA           NA       Range 12-336 months (16)            7/16         14 NED
                                                                                                                                                       12 NA         2 DOD
                                                 8, nasal cavity
                                               1, sphenoid sinus
Powers, 2015 5                1           1, ethmoid and nasal cavity            T3         ERTC          None             10 months (1)                None          1 NED
Rooper, 2016     14
                             11                   4, ethmoid                     NA           NA           NA       Range 12-312 months (7)              2/7          6 NED
                                                                                                                                                        4 NA
                                                3, frontal sinus                                                                                                      1 DOD
                                                 3, nasal cavity                                                                                                     4 LOST
                                          1, ethmoid and nasal cavity
Cannon, 2016 15               3                                                  NA        1 ERTC         None         Mean 25 months (3)                1/3          2 NED
                                                                                            1 CER                                                                     1 AWD
                                          3, frontal, ethmoid and orbit                     1 None
Wong, 2016 6                  1         1, ethmoid and sphenoid sinus           T4a           ER         CH-RT             5 months (1)                 None          1 NED
Huang, 2016    7
                              7                 2, frontal sinus                 NA           NA         1 CH-RT     Range 3-132 months (4)              1/4          4 NED
                                                                                                                                                        3 NA
                                          3, ethmoid and nasal cavity                                                                                                3 LOST
                                                1, nasal septum
                                            1, upper nasal meatus
Fritchie, 2016 16             9           7, ethmoid and nasal cavity            NA           NA           NA              12 months (2)                 1/2          1 NED
                                                                                                                                                        7 NA
                                          1, ethmoid and frontal sinus                                                                                                1 AWD
                                     1, nasal cavity, oropharynx, skull base                                                                                         6 LOST
Lin, 2017 17                  1       1, ethmoid, sphenoid, frontal and         T4b          CER          None                   NA                      NA           1 DOC
                                      maxillary sinus with skull base and
                                           frontal lobe involvement
Hockstein, 2018 18            1                 1, frontal sinus                T4b          CER          None                   NA                      NA           1 NED
Kakkar, 2018     19
                              6           2, ethmoid and nasal cavity            NA      3 Only biopsy    None       Range 10-56 months (3)              2/3          1 NED
                                                                                                                                                        3 NA
                                               1, maxillary sinus                          3 Lateral                                                                  2 AWD
                                        1, maxillary and ethmoid sinus                    rhinotomy                                                                   1 DOD
                                     1, maxillary, ethmoid, sphenoid sinus                                                                                           2 LOST
                                          with intracranial extension
                                     1, maxillary, ethmoid sinus with dura
                                                   involvement
Chitguppi, 2018 20            1        1, ethmoid, nasal cavity and orbit       T4a           ER           RT                    NA                     None          1 NED
Andreasen, 2018        21
                              3                2, ethmoid sinus                  NA           NA          2 RT       Range 64-72 months (3)              1/3          3 NED
                                          1, ethmoid and nasal cavity
Miglani, 2019 22              5                                                  NA         3 CER         1 RT        Range 2-97 months (5)              2/5          4 NED
                                                                                             1 ER                                                                     1 AWD
                                          5, ethmoid and nasal cavity                      1 ERTC
Alkhunder, 2019       23
                              1                1, ethmoid sinus                  NA           ER          None             24 months (1)                None          1 NED
Le Loarer, 2019 24           41               14, nasal cavity                   NA           NA          8 RT      Range 11-185 months (25)            8/25         22 NED
                                             11 ethmoid sinus                                                                                          16 NA
                                     10 ethmoid and frontal sinus or skull
                                                   base
                                                   6 NA
Sethi, 2021 25                3        3, ethmoid, maxillary and frontal        3 T4a        3 ER         1 RT        Mean 22.5 months (2)              None          2 NED
                                           sinuses and nasal cavity

Present series               15                                                 1 T2                     2 CH-RT     Range 6- 80 months (15)            1/15          3 AWD
                                                                                2 T3                       1 CH                                                      16 LOST
                                                 13, ethmoid                    9 T4a
                                                2, frontal sinus                3 T4b
ER: endoscopic resection; ERTC: endoscopic resection with transnasal craniectomy; CER: cranio-endoscopic resection; RT: radiotherapy; CH-RT: chemoradiotherapy; NED: no evidence
of disease; AWD: alive with disease; DOC: dead of other causes; DOD: dead of disease; NA: not available.



                                                                                                                                                                          551
M. Turri-Zanoni et al.




approach, consisting in performing an endoscopic endona-          experienced multiple recurrences: two local recurrences
sal procedure in conjunction with an external transcranial        and one pulmonary metastasis, after 35, 47 and 56 months
approach (i.e., CER).                                             of follow-up, respectively. This anecdotal clinical case rep-
According to our literature review, data on surgical treat-       resents the first case of a systemic metastasis from BSNS
ment were available only for 17/122 cases (Tab. II), who          so far reported in literature. The difference observed be-
were treated using an endoscopic endonasal technique in           tween our case series and the literature in local recurrence
14/17 cases (82.3%), obtaining free-margin tumour resec-          rate might be explained by a limitation of this study, which
tion in 12/17 patients (70.6%). In our series, patients treated   is the short mean follow-up period of 27.3 months of our
with an endoscopic-assisted approach achieved free-margin         case series, compared to 54.6 months of mean follow-up
tumour resection in 13/15 cases (86.7%). In most (11/15,          for the patients reported in the studies selected through the
73.3%), the surgical technique was exclusively endonasal          literature review. On the other hand, only case reports or
with minimal impact on the quality of life of the patient.        retrospective studies based on the review of histological
Adjuvant treatment is a matter of debate in the literature        slides are available in the literature which resulted in a lack
since, to date, there are no universally accepted protocols       of complete data on each patient’s medical history. In the
for BSNS. Given their rarity, its low-grade biological be-        absence of reliable data, at present, it would be prudent to
haviour and the absence of prospective studies, the indica-       follow all patients closely, based on a follow-up protocol
tions for adjuvant treatments, at present, might be compa-        which includes contrast-enhanced MRI of the head every 6
rable to those used for low-grade mesenchymal tumours 12.         months and an annual total body CT scan, in order to detect
Adjuvant irradiation can be administered in case of posi-         possible recurrences as early as possible.
tive microscopic surgical margins and in case of perineural
spread and/or lymphovascular invasion. Postoperative radi-
                                                                  Conclusions
ation can be delivered using conventional photon radiother-
apy (e.g., IMRT) or by particle beam therapy (IMPT), es-          BSNS is a rare and a locally aggressive tumour, mostly in-
pecially for cases with positive surgical margins. Moreover,      volving the nasal cavity and paranasal sinuses. BSNS may
this innovative irradiation form has shown excellent local        invade the skull base and result in intracranial extension.
disease control rates not only in the postoperative setting       Endoscopic-assisted surgery proved to be safe and effec-
but also for inoperable cases. However, the use of heavy          tive as an upfront treatment within a multidisciplinary care
ion particle radiotherapy in the anterior skull base should       protocol. Adjuvant irradiation should be delivered in case of
be considered with caution, given the potential for toxic-        positive surgical margins and in case of persistence or recur-
ity (e.g. osteoradionecrosis) even after several years 13. The    rence of disease in non-resectable areas. A low mortality rate
role of chemotherapy in this cancer subtype is controversial.     was found in our series, as confirmed by data in literature.
Adjuvant cisplatin-based chemotherapy might be delivered          Although distant metastases are extremely rare, they are theo-
concomitant to irradiation in cases of macroscopic persis-        retically possible. Immunohistochemical analysis and molec-
tence of disease in unresectable critical sites. In our expe-     ular studies by expert pathologists are mandatory to confirm
rience, adjuvant radiotherapy was indicated in two cases          the correct diagnosis. Further clinical and molecular studies
(2/15, 13.3%) due to microscopic infiltration of the tumour       on larger case-series will be needed to better decipher the
resection margins, while adjuvant chemotherapy was never          biological behaviour of this disease and improve treatment
administered. In the studies examined in our literature re-       strategies for this rare subtype of sarcoma.
view, 17/122 (20.75%) patients were subjected to adjuvant
treatment. The indication for adjuvant radiotherapy in 10         Conflict of interest statement
cases (10/17, 58.8%) was for positive surgical margins. In        The authors declare no conflict of interest.
four cases (4/17, 23.5%) adjuvant chemo-radiotherapy was
indicated, but no specific details on indications and drugs       Funding
were provided.                                                    This research did not receive any specific grant from fund-
The recurrence patterns of this cancer are far from being         ing agencies in the public, commercial, or not-for-profit
completely elucidated due to the rarity of the neoplasm.          sectors.
Data emerging from the literature seem to support that this
sarcoma often relapses locally (33.8%) during follow-up,          Author contributions
while it is rarely associated with distant metastases. Con-       MT-Z and GD conceptualised and designed the review, per-
versely, in our series, we observed a very low recurrence         formed the literature search, collected and analyzed data
rate (1/15, 6.7%) and the only patient who relapsed had           and drafted the work. PC conceptualised the review, coor-



552
                                                                                                                           Biphenotypic sinonasal sarcoma




dinated the data collection and data analysis and critically                   10
                                                                                    Carter CS, East EG, McHugh JB. Biphenotypic sinonasal sarcoma:
revised the manuscript. ID, PB, GG, MF realised the fig-                            a review and update. Arch Pathol Lab Med 2018;142:1196-1201.
                                                                                    https://doi.org/10.5858/arpa.2018-0207-RA
ure and performed the statistical analysis. CF, FF took care                   11
                                                                                    Oren N, Vaysberg A, Ginat DT. Updated WHO nomenclature of head
of histopathological diagnosis, through a centralised case                          and neck lesions and associated imaging findings. Insights Imaging
review. ML, DT, CG, AJ, ALA, MDF, PH, PN, MB and                                    2019;10:72. https://doi.org/10.1186/s13244-019-0760-4
VJL shared their clinical cases and experience to analyze                      12
                                                                                    Patel TD, Vázquez A, Plitt MA, et al. A case-control analysis of
all study data. All authors approved the final manuscript                           survival outcomes in sinonasal carcinosarcoma. Am J Otolaryngol
                                                                                    2015;36:200-204. https://doi.org/10.1016/j.amjoto.2014.10.031
as submitted and agree to be accountable for all aspects of                    13
                                                                                    Hu W, Hu J, Huang Q, et al. Particle beam radiation therapy for sinon-
the work.                                                                           asal malignancies: single institutional experience at the Shanghai Pro-
                                                                                    ton and Heavy Ion Center. Cancer Med 2020;9:7914-7924. https://
Ethical consideration                                                               doi.org/10.1002/cam4.3393
This study was performed in compliance with the Hel-                           14
                                                                                    Rooper LM, Huang S-C, Antonescu CR, et al. Biphenotypic sinona-
                                                                                    sal sarcoma: an expanded immunoprofile including consistent nuclear
sinki Declaration and approved by the Institutional Re-                             b-catenin positivity and absence of SOX10 expression. Hum Pathol
view Board (Insubria Board of Ethics, approval number                               2016;55:44-50. https://doi.org/10.1016/j.humpath.2016.04.009
0033025/2015).                                                                 15
                                                                                    Cannon RB, Wiggins RH, Witt BL, et al. Imaging and outcomes for
Written informed consent was obtained from all patients                             a new entity: low-grade sinonasal sarcoma with neural and myo-
prior to any diagnostic or therapeutic procedure.                                   genic features. J Neurol Surg Rep 2017;78:e15-e19. https://doi.
                                                                                    org/10.1055/s-0037-1598198
                                                                               16
                                                                                    Fritchie KJ, Jin L, Wang X, et al. Fusion gene profile of bipheno-
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