10.14639/0392-100X-N2635
Objectives. Malignant minor salivary glands carcinomas (MiSGC) of the larynx and trachea are rare tumours and published evidence is sparse. We conducted a systematic review to describe shareable treatment strategies and oncological outcomes of these neoplastic entities. Methods. Full text English manuscripts published from January 1st 2000 to December 14th 2022 were included. Data on demographics, treatments and outcomes were collected. A pooled analysis of 5-year overall survival (OS) was performed. Results. Seventeen articles and 365 patients met the inclusion criteria. The most common subsites involved were subglottic and distal trachea. Adenoid cystic carcinoma was, by far, the most frequent histotype. The first-choice treatment strategy was surgery (86.8%), while adjuvant treatments were delivered in 57.4% of patients. Only 12.9% were treated with definitive radiotherapy with/without chemotherapy. The mean follow-up was 68.3 months. One hundred nine (34.9%) deaths were recorded and 62.4% were cancer-related. Five-year OS ranged from 20% to 100% and, at pooled analysis, it was 83% (range, 78%-87%). Conclusions. In case of MiSGC of the larynx and trachea, surgery remains the mainstay of treatment. Adjuvant treatments are frequently delivered. Survival estimates are good overall, but highly heterogeneous.
text/xml
1827-675X
2635
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Cesare Piazza
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ACTA Otorhinolaryngologica Italica
survival
Treatment and outcomes of minor salivary gland cancers of the larynx and trachea: a systematic review
Text.Serial.Journal
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2023-10-10
2023-05-04
2023-12-19
2023-12-19
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1
Cesare Piazza
2023/10/10
10.14639/0392-100X-N2635
365
Unit of Otorhinolaryngology – Head and Neck Surgery, ASST Spedali Civili of Brescia, Brescia, Italy; Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, School of Medicine, Brescia, Italy
1827-675X
survival
en
374
Treatment and outcomes of minor salivary gland cancers of the larynx and trachea: a systematic review
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ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43:365-374; doi: 10.14639/0392-100X-N2635




Review


Treatment and outcomes of minor salivary gland
cancers of the larynx and trachea: a systematic review
Trattamento dei tumori maligni delle ghiandole salivari minori della laringe
e della trachea e suoi risultati: revisione sistematica
Claudia Montenegro1,2, Davide Mattavelli1,2, Davide Lancini1, Alberto Paderno1, Elisa Marazzi1,2, Vittorio Rampinelli1,
Michele Tomasoni1, Cesare Piazza1,2
1
    Unit of Otorhinolaryngology – Head and Neck Surgery, ASST Spedali Civili of Brescia, Brescia, Italy; 2 Department of Medical and
Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, School of Medicine, Brescia, Italy


SUMMARY
Objectives. Malignant minor salivary glands carcinomas (MiSGC) of the larynx and tra-
chea are rare tumours and published evidence is sparse. We conducted a systematic review
to describe shareable treatment strategies and oncological outcomes of these neoplastic
entities.
Methods. Full text English manuscripts published from January 1st 2000 to December 14th
2022 were included. Data on demographics, treatments and outcomes were collected. A
pooled analysis of 5-year overall survival (OS) was performed.
Results. Seventeen articles and 365 patients met the inclusion criteria. The most common
subsites involved were subglottic and distal trachea. Adenoid cystic carcinoma was, by far,
the most frequent histotype. The first-choice treatment strategy was surgery (86.8%), while
adjuvant treatments were delivered in 57.4% of patients. Only 12.9% were treated with
definitive radiotherapy with/without chemotherapy. The mean follow-up was 68.3 months.
One hundred nine (34.9%) deaths were recorded and 62.4% were cancer-related. Five-year
OS ranged from 20% to 100% and, at pooled analysis, it was 83% (range, 78-87%).
Conclusions. In case of MiSGC of the larynx and trachea, surgery remains the mainstay of         Received: May 4, 2023
treatment. Adjuvant treatments are frequently delivered. Survival estimates are good over-       Accepted: June 10, 2023
all, but highly heterogeneous.                                                                   Published online: October 10, 2023

KEY WORDS: minor salivary gland tumors, larynx, trachea, treatment, survival                     Correspondence
                                                                                                 Davide Mattavelli
RIASSUNTO                                                                                        Unit of Otorhinolaryngology – Head and Neck Sur-
Obiettivi. I tumori maligni delle ghiandole salivari minori laringo-tracheali sono rari e i      gery, ASST Spedali Civili, University of Brescia,
                                                                                                 piazzale Spedali Civili 1, 25123 Brescia, Italy
dati pubblicati sono scarsi. Abbiamo condotto una revisione sistematica della letteratura
                                                                                                 Tel. +39 030 3995319
per descrivere le strategie di trattamento e i risultati oncologici.
                                                                                                 E-mail: davide.mattavelli@unibs.it
Metodi. Sono stati inclusi articoli in lingua inglese pubblicati dal 1° gennaio 2000 al 14
dicembre 2022. Abbiamo raccolto dati su trattamento e sopravvivenza ed è stata effettuata
un’analisi aggregata della sopravvivenza complessiva (OS) a 5 anni.                                How to cite this article: Montenegro C, Mat-
Risultati. Sono stati inclusi 17 articoli e 365 pazienti. Le sottosedi più frequentemente          tavelli D, Lancini D, et al. Treatment and out-
coinvolte sono risultate la sottoglottide e la trachea distale, mentre il carcinoma adenoido-      comes of minor salivary gland cancers of the
cistico si è confermato di gran lunga l’istotipo più frequente. La strategia di trattamento di     larynx and trachea: a systematic review. Acta
                                                                                                   Otorhinolaryngol Ital 2023;43:365-374. https://doi.
prima scelta è stata la chirurgia (86,8%) e il 57,4% dei pazienti ha ricevuto un trattamento
                                                                                                   org/10.14639/0392-100X-N2635
adiuvante. Solo il 12,9% è stato trattato con radioterapia o chemioradioterapia esclusive.
Il follow-up medio è stato di 68,3 mesi. Centonove (34,9%) pazienti sono deceduti, di cui il
                                                                                                 © Società Italiana di Otorinolaringoiatria
62,4% a causa della malattia. La sopravvivenza a 5 anni riportata varia dal 20% al 100%          e Chirurgia Cervico-Facciale
e nell’analisi aggregata è pari all’83% (range, 78-87%).
Conclusioni. Per i tumori delle ghiandole salivari minori laringo-tracheali la chirurgia è il                   OPEN ACCESS
trattamento di scelta, eventualmente associata a trattamenti adiuvanti. Le stime di soprav-
                                                                                                 This is an open access article distributed in accordance with
vivenza sono buone, ma altamente eterogenee.
                                                                                                 the CC-BY-NC-ND (Creative Commons Attribution-Non-
PAROLE CHIAVE: tumori delle ghiandole salivari minori, laringe, trachea, trattamento,            Commercial-NoDerivatives 4.0 International) license. The
                                                                                                 article can be used by giving appropriate credit and mentio-
sopravvivenza                                                                                    ning the license, but only for non-commercial purposes and
                                                                                                 only in the original version. For further information: https://
                                                                                                 creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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Introduction                                                     Selection criteria
                                                                 Only original papers in English, published in a peer-
The incidence of salivary glands carcinomas ranges from 4
                                                                 reviewed journal from January 1st, 2000 to December
to 135 cases per million per year: overall, 10-15% of cases
                                                                 14th, 2022, were considered. Exclusion criteria were: a)
arise in the minor salivary glands. Minor salivary glands can-
                                                                 impossibility to extrapolate specific data on treatments and
cers (MiSGC) are found mostly in the oral cavity and oro-
                                                                 survival of patients with MiSGC of the larynx or trachea
pharynx, while the larynx and trachea are seldom involved 1.
                                                                 from composite series; b) pediatric cohorts; c) series with
In particular, laryngeal MiSGC are extremely rare, account-
                                                                 less than or equal to 5 patients; d) non-human studies.
ing for less than 1% of all malignant tumors of this anatomi-
                                                                 Two authors (CM and EM) independently screened all ti-
cal site 2. The most common histotypes are adenoid cystic
                                                                 tles and abstracts, and full-texts were obtained for publi-
(ACC, 32-69%) and mucoepidermoid carcinomas (MEC,
                                                                 cations that fulfilled inclusion criteria. The references of
15-35%) 3. They often occur as submucosal masses found,
                                                                 all selected articles were reviewed to identify additional
in decreasing frequency, within the subglottis, supraglottis,
                                                                 relevant articles. Disagreements were solved by discussion
and glottis. Likewise, the incidence of primary tracheal car-
cinoma is extremely low (0.1 to 0.26 per million), account-      with a senior author (DM).
ing for only 0.1-0.4% of all cancers 4,5. Primary tracheal ACC
is the second most common malignant tracheal tumour after        Data extraction
squamous cell carcinoma 6 and accounts for approximately         The relevant features of each study included (publication
10-20% of all tracheal malignancies. Other salivary glands       year, country, study design, and period of observation) were
histotypes are exceedingly rare 6-8.                             collected along with demographics (age at presentation, gen-
Oncologic treatment modalities have substantially im-            der), pre-operative imaging, tumor features (site and subsite,
proved in the last decades. However, the rarity of these can-    histotype, TNM classification, perineural invasion [PNI],
cers hinders the definition of a standard of care and survival   lymphovascular invasion [LVI], grading, and margins sta-
analyses are flawed by the small size of published series,       tus), treatment modality and therapeutic intent (curative vs
often represented by anecdotal experiences and case re-          palliative), post-operative complications, mean follow-up,
ports. Moreover, larger cohorts sometimes gather tumours         deaths, recurrence rate (local, regional or distant), 5- and
from different sites without detailed data for the specific      10-year overall survival (OS), disease free survival (DFS),
site(s) of origin, thus limiting the information available for   local (LRFS), and distant recurrence free survival (DRFS).
laryngeal and tracheal MiSGC.                                    Two authors (CM and EM) independently extracted data
We carried out a systematic review on MiSGC of the larynx        from eligible articles and created a dedicated database. Da-
and trachea to describe treatment strategies and oncologi-       ta analysis was performed with Microsoft Excel. A pooled
cal outcomes.                                                    analysis on 5-year OS retrieved from the selected articles
                                                                 was performed to obtain a general estimate of this outcome.
Materials and methods
                                                                 Results
Objectives
The primary objective was definition of survival outcomes        General features
in patients affected by MiSGC of the larynx and trachea.         The initial search returned 3468 articles. Identification,
Secondary objectives were description of applied treatment       screening, and inclusions/exclusions are detailed in Figure 1.
modalities.                                                      A total of 17 articles, all based on retrospective series, with a
                                                                 total of 365 patients, were included in the present systematic
Search strategy                                                  review (Tab. I).
This systematic review was performed and reported in ac-
cordance with the Preferred Reporting Items for System-          Demographics and tumour characteristics
atic reviews and Meta-Analysis (PRISMA) checklist and            Demographics and tumour features are outlined in Table II.
statement recommendations 9. A comprehensive search on           Demographic characteristics were reported for all 365 pa-
PubMed, Web of Science, and Scopus was conducted on              tients. Mean age was 51.9 years (46.5 for tracheal and 53.6
December 14th 2022, using the following queries: “(Minor         for laryngeal localisation). The distribution was almost equal
salivary gland* OR salivary) AND (tumor* OR neoplasm*            between genders. The most commonly involved site was the
OR malignancy OR malignancies OR cancer* OR neopla-              trachea with a trachea to larynx ratio of 1.9:1 (235 tracheal
sia*) AND (Larynx OR laryngeal OR Trachea OR Tracheal            and 126 laryngeal MiSGC). Concerning the trachea, exclud-
OR laryngo-tracheal)”.                                           ing 14% of patients with no specific subsite reported, the



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                                                         Treatment and outcomes of minor salivary gland cancers of the larynx and trachea: a systematic review




Figure 1. Identification, screening, and exclusion/inclusion of publications in the present systematic review.




Table I. General features of the 17 articles included in the systematic review.
 First author           Publication year            Country            Study design            Observational period         No. of patients          Site
 Mahlstedt           19
                               2002                 Germany            Retrospective                1965-1998                      15              Larynx
 Albers     42
                               2004                   Usa              Retrospective                1992-2001                      8               Trachea
 Wang 18                       2006                  Taiwan            Retrospective                1981-2000                      11              Larynx
 Ganly 3                       2006                   Usa              Retrospective                1970-2003                      12              Larynx
 Moukarbel           17
                               2008                  Canada            Retrospective                1963-2005                      15              Larynx
 Lucioni        14
                               2008                   Italy            Retrospective                1990-2003                      6               Larynx
 Wurtz 12                      2010                  France            Retrospective                2005-2007                      6               Trachea
 Nielsen 11                    2012                 Denmark            Retrospective                1990-2007                      6               Larynx
 Zhang      2
                               2014                  China             Retrospective                2003-2010                      15              Larynx
 Liu   15
                               2015                  China             Retrospective                1998-2013                      6               Larynx
 Chen 22                       2015                  China             Retrospective                1995-2012                      52              Trachea
 Yang 20                       2016                  China             Retrospective                1995-2014                     109              Trachea
 Je    21
                               2017               South Korea          Retrospective                1994-2008                      22              Trachea
 Akbaba         16
                               2019                 Germany            Retrospective                2002-2009                      11              Larynx
 Högerle 13                   2019                 Germany            Retrospective                1991-2017                      38              Trachea
 Chen 23                       2020                China-Usa           Retrospective                2003-2014                      16              Larynx
 Lionello       10
                               2021                   Italy            Retrospective                1989-2020                      17              Larynx




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C. Montenegro et al.




Table II. Demographics and tumour features.                                        The most common histotype was ACC (88.9%), followed
 Characteristics                  Entire series          Larynx      Tracheal      by MEC (6.6%), with few cases of adenocarcinoma (AC,
 Patients, no.                              365          130           235         3.2%), adenosquamous carcinoma (ASCC, 0.8%), and my-
 Age, years (mean)                         51.9         53.6           46.5        oepithelial carcinoma (MC, 0.5%). The larynx showed a
 Gender, no.                                                                       higher degree of histologic variability: 90 ACC (69.2% of
   Male                                     183           75           108         all laryngeal cases), 23 MEC (18.2%), 12 AC (9.3%), 3
   Female                                   176           49           127         ASCC (2.3%), and 2 MC (1%) were reported. Conversely,
 Anatomic site, no.                                                                tracheal localisation was dominated by ACC (99.5% of all
   Trachea                                  235            -           235
                                                                                   tracheal cases) with only 1 MEC (0.5%). The TNM classi-
                                                                                   fication was reported in a few articles 2,3,10-19; in most cases
   Larynx                                   126          126            -
                                                                                   tumours were advanced, while nodal involvement was rare.
 Subsites, no.
                                                                                   PNI was observed in 57.3% of patients and LVI was present
   Supraglottis                              49          49              -
                                                                                   in 39.4% (all had laryngeal MiSGC). Tumour grading was
   Glottis                                   15          15              -
                                                                                   rarely reported. Resection margin status was detailed for
   Subglottis                                54          54              -
                                                                                   273 patients surgically treated and microscopically positive
   Transglottis                              12          12              -         (R1) in the majority (68.5%). Only 0.4% had macroscopic
   Trachea NOS                               51            -            51         positive margins (R2).
   Cervical trachea                          40            -            40
   Middle trachea                            60            -            60         Treatment
   Distal/carinal trachea                    84            -            84         Treatment modalities were described in all studies and are
 Histotypes, no.                                                                   detailed in Table III. Surgery was the most common choice.
   ACC                                     324           90            234         Three-hundred seventeen patients (64.4% tracheal and
   MEC                                       24          23             1          35.6% laryngeal MiSGC) were treated by different surgical
   Adenocarcinoma                            12          12             -          procedures according to the tumour site and histotype. For
   Adenosquamous carcinoma                   3            3             -          laryngeal malignancies, 59.2% underwent total laryngec-
   Myoepithelial                             2            2             -          tomy, 31.9% open partial horizontal laryngectomies or other
 pTNM, (no. of pts. with available data)                                           forms of partial laryngectomies, and 8% laryngo-tracheal
   T3-T4                                  51 (86)        28             23         resections and anastomoses, while only 0.9% underwent en-
   N+                                     16 (85)        16              0         doscopic resections. When the distal trachea was involved,
   M0                                   131 (142)        92             39
                                                                                   tracheal resection was associated with pulmonary resection
   M1                                    11 (142)         4             7
                                                                                   or lobectomy in 22 and 1 patient, respectively. Only one
                                                                                   study 12 reported on 6 patients treated by tracheal and carinal
 PNI-LVI, (no. of pts. surgically treated with available data)
                                                                                   replacement with aortic allografts.
   PNI+                                   47 (82)        35             11
                                                                                   Neck dissection was rarely performed (9.1% of patients),
   LVI+                                   13 (33)        13              -
                                                                                   and all had laryngeal malignancies. Out of 29 patients, only
 Margins, (no. of pts. surgically treated with available data)
                                                                                   for 10 and 2 patients the therapeutic or elective role of neck
   R0                                    76 (273)        34             42         dissection was respectively specified. Analysing patients
   R0 close                               9 (273)         7             2          who underwent surgery, 52% (119 tracheal and 46 laryngeal
   R1                                   187 (273)        36            151         tumours) were managed by adjuvant radiotherapy (RT), and
   R2                                     1 (273)         0             1          only 5.4% (12 tracheal and 5 laryngeal) by adjuvant chemo
NOS: not otherwise specified; ACC: adenoid cystic carcinoma; MEC: mucoepidermoid   RT (CRT): in almost all cases photons were delivered, while
carcinoma; PNI: perineural invasion; LVI: lymphovascular invasion.
                                                                                   only one patient was treated with carbon-ion RT (CIRT). Ne-
                                                                                   oadjuvant therapy was never performed. Only 12.3% of pa-
                                                                                   tients were treated by exclusive RT and 2 lesions (0.5%), one
most common anatomical region of origin was distal/cari-                           tracheal and one laryngeal, with concurrent CRT. Among
nal trachea (23%), followed by middle (16.4%), and cervi-                          these, only 6 tracheal MiSGC were treated with CIRT, and
cal trachea (10.9%). In contrast, the most common laryngeal                        the others with conventional RT.
subsite was the subglottis (14.9%), followed by supraglot-                         Post-operative complications were described for 176 pa-
tis (13.4%), and glottis (4.1%). Only 12 cases (3.3%) had a                        tients treated with surgery (55.5% of all patients treated
transglottic localisation. Data on pre-operative imaging was                       with surgery) with tracheal MiSGC 12,20-22 and included
reported for 204 cases and all underwent a CT scan.                                25.9% of non-fatal complications and one death for anas-



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                                                                Treatment and outcomes of minor salivary gland cancers of the larynx and trachea: a systematic review




Table III. Treatment strategies in the reported series of patients.
 First author     No. of patients         Site        Surgery       PL              TL     LTRA       ELR       TS          TS +             TS +            Adjuvant therapy
                                                                                                                         lobectomy        pulmonary
                                                                                                                                           resection
 Liu 15                       6               Larynx             6           2       4       0         0         0             0                0                   6 RT
 Chen 23                     16               Larynx            15           4      11       0         0         0             0                0               4 RT, 1 CRT
 Lionello 10                 17               Larynx            17           9       3       5         0         0             0                0                  3 CRT
 Zhang 2                     15               Larynx            13           4       9       0         0         0             0                0                   6 RT
 Nielsen 11                   6               Larynx             4           4       0       0         0         0             0                0                   2 RT
 Akbaba 16                   11               Larynx             6           3       3       0         0         0             0                0                   6 RT
 Lucioni 14                   6               Larynx             6           3       3       0         0         0             0                0                    0
 Moukarbel 17                15               Larynx            12           1       8       2         1         0             0                0                   8 RT
 Wang 18                     11               Larynx             9           2       7       0         0         0             0                0               3 RT, 1 CRT
 Mahlstedt 19                15               Larynx            15           2      13       0         0         0             0                0                   5 RT
 Ganly 3                     12               Larynx            10           2      6        2         0         0             0                0                   6 RT
 Yang 20                    109              Trachea            109          0       0       5         0        100            0                4                  73 RT
 Chen 22                     52              Trachea            48           0        0      5         0        30             0               13              12 RT, 12 CRT
 Wurtz 12                     6              Trachea             6           0        0      1         0         6             1                1                    0
 Je 21                       22              Trachea            13           0        0      0         0        8              0               4                   13 RT
 Högerle 13                 38              Trachea            20           0        0      -         0         -             -                -              1 CIRT, 12 RT
 Albers 42                    8              Trachea             8           0        0      0         0         8             0                0                   8 RT
PL: partial laryngectomy; TL: total laryngectomy; LTRA: laryngo-tracheal resection and anastomosis; ELR: endoscopic laryngeal resection; TS: tracheal surgery; RT: radiotherapy; CRT:
chemoradiotherapy; CIRT: carbon-ion radiotherapy.



Table IV. Post-operative complication.
 Author          No. surgical patients                   Site                                               Post-operative complication
                                                                                 Death               Yes                           Non-fatal complications
 Yang 20                          109                  Trachea                    1                   24        Unilateral recurrent laryngeal nerve palsy (9), anastomotic
                                                                                                                    stenosis (4), dyspnoea (2), granulation stenosis (2),
                                                                                                              permanent tracheostomy (2), pneumonia (2), emphysema (1),
                                                                                                                    tracheoesophageal fistula (1), incision infection (1)
 Chen 22                          48                   Trachea                    0                    5        Drinking cough (2), laryngeal nerve paralysis (1), tracheal
                                                                                                                                         stenosis (2)
 Wurtz 12                         6                    Trachea                    0                    5         Dehiscence anastomosis + sternoplasty for incomplete
                                                                                                                separation of the sternum (1), pneumonia + tracheotomy
                                                                                                                 and ventilatory support (1), necrosis of the graft (treated
                                                                                                               with transplantation) + tracheotomy and ventilatory support
                                                                                                                + oesophageal fistula (1), anterior spinal cord ischaemia
                                                                                                                 + purulent stent retention (required additional bronchial
                                                                                                              stenting) (1), sternal dehiscence (treated with sternoplasty) +
                                                                                                                                   ventilatory support (1)
 Je 21                            13                   Trachea                    0                   14      Tracheal stenosis (2), oesophagitis (3), pulmonary fibrosis (9)




tomotic problems (Tab. IV). No perioperative death was                                       tients died, and the most frequent cause of death was
described for laryngeal MiSGC.                                                               disease-related (62.4%) due to loco-regional recurrence
                                                                                             or distant metastasis. Laryngeal localisation was associ-
Follow-up and outcomes                                                                       ated with a slightly higher rate of cancer-related death
The follow-up time was available for 320 patients                                            (52.9% vs 47%). During follow-up, the recurrence rate
(mean, 68.3 months; range, 34-123). Patient status was                                       was 49.5%: local recurrence occurred in 25.7% of pa-
obtainable in 312 cases. One-hundred nine (34.9%) pa-                                        tients (40 with laryngeal and 16 with tracheal localisa-



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C. Montenegro et al.




tion), and distant metastasis in 23.8% (33 with laryngeal                                studies 13,17,18,20,21. Ten-year OS ranged from 43.2% 20 to
and 19 with tracheal tumours).                                                           81% 13 for the trachea, and from 46% 17 to 83% 18 for la-
Survival estimates in terms of 5- and 10-year OS, DFS,                                   ryngeal MiSGC, while 10-year DFS 20,21 was 20-28.7%. A
LRFS, RRFS, and DRFS were frequently unavailable. The                                    10-year LRFS of 83% was reported by Högerle 13.
available information is reported in Table IV. Based on the                              The same authors 13,20,21 reported specific oncologic outcomes
data collected 2,13,16-21,23, 5-year OS ranged from 20% to                               for patients with tracheal MiSGC treated with surgery and
100%. Good survival rates were described by Akbaba 16 for                                adjuvant RT. Outcomes are detailed in Table V.
laryngeal MiSGC (5-year OS 100%) and by Högerle 13 for
the trachea (5-year OS 95%). The worse 5-year OS (20%)                                   Discussion
was described by Zhang 2 reporting on laryngeal MiSGC.
Due to the scarcity of available data in the published lit-                              Due to the rarity of laryngeal and tracheal MiSGC, pub-
erature, we aimed to obtain an estimate of 5-year OS by                                  lished evidence is sparse and of low quality, being mostly
performing a pooled statistical analysis. The average 5-year                             represented by retrospective relatively small cohort studies
OS for laryngeal and tracheal MiSGC was 83%. The 95%                                     or even case reports. Accordingly, data on treatment and on-
confidence interval for the 5-year OS was calculated using                               cological outcomes are highly biased by the characteristics
a weighted mean based on the inverse of the standard errors                              of the series analysed, and therefore poorly generalisable. In
derived from individual study proportions, resulting in an                               this systematic review we aimed to provide a general picture
estimated range of 78-87%.                                                               of laryngeal and tracheal MiSGC, with particular focus on
Five-year DFS was reported in three laryngeal 16-18 and                                  treatment strategies and oncological outcomes.
two tracheal series 20,21, and ranged from 69% to 100% for
the larynx, and from 47.8% to 62% for the trachea. The                                   Patients and tumour features
5-year LRFS was 100% for the larynx 15 and 96% for the                                   Our review included 365 patients with an equal distribution
trachea 13. Five-year DRFS was reported only for tracheal                                between genders and a peak at diagnosis in the adult age.
MiSGC 13,21, and ranged from 52.6% to 69%.                                               A tracheal site was by far more frequent than a laryngeal
Ten-year oncological outcomes were available in fewer                                    one, and distal/carinal trachea and subglottis were the most


Table V. Oncologic outcomes.
 First            No. of     Site                               Histotype                                                 All treated patients
 author          patients
                                                                                                              5-year                                10-year
                                               ACC      MEC         AC            ASCC            OS      DFS      LRFS      DRFS       OS       DFS      LRFS      DRFS
 Yang 20               109        Trachea      109        0          0              0            88.7      62         -        -       43.2       20         -         -
 Je 21                  22        Trachea       22        0          0              0            81.8     47.8      100      52.6      54.2      28.7      70.2      33.5
 Högerle 13            38        Trachea       38        0          0              0             95        -        96       69        81         -        83        53
 Liu 15                  6         Larynx        6        0          0              0              -        -       100        -         -         -         -         -
 Chen 23                16         Larynx        8        4          2              2             60        -         -        -         -         -         -         -
 Zhang 2                15         Larynx        6        6          3              0             20        -         -        -         -         -         -         -
 Akbaba 16              11         Larynx       11        0          0              0            100      100       100        -         -         -         -         -
 Moukarbel 17           15         Larynx       15        0          0              0             64       69         -        -        49         -         -         -
 Wang 18                11         Larynx        4        3          3              1             71       83         -        -        63         -         -         -
 Mahlstedt 19           15         Larynx        6        5          4              0             47        -         -        -         -         -         -         -
                                                                                                                              Surgery + RT
                                                                                                              5-year                                10-year
                                                                                                  OS      DFS      LRFS      DRFS       OS       DFS      LRFS      DRFS
 Yang 20               109        Trachea      109        0          0              0            88.4     67.8       -         -       37.6       14        -         35
 Je 21                  22        Trachea       22        0          0              0            92.3     67.7      100      67.7      76.9      42.3      70.2      42.3
 Högerle 13            38        Trachea       38        0          0              0             84       -        100       65        84         -       100        65
 Liu 15                  6         Larynx        6        0          0              0              -       -        100        -         -         -        -          -
ACC: adenoid cystic carcinoma; MEC: mucoepidermoid carcinoma; AC: adenocarcinoma; ASCC: adenosquamous cell carcinoma; OS: overall survival; DFS: disease free survival; LRFS:
local recurrence free survival; DRFS, distant recurrence free survival; RT: radiotherapy.




370
                                              Treatment and outcomes of minor salivary gland cancers of the larynx and trachea: a systematic review




involved subsites, respectively. The diagnostic delay of these         ing to the site of origin is highly asymmetric, with a relevant
lesions is mirrored by the relevant prevalence of advanced             prevalence of R1 in the tracheal cohort (55% vs 13%).
tumours (T3-T4) and possibly explained by the indolent                 The relatively low rate of positive margins after laryngeal
and slow growth that often characterises MiSGC. Accord-                surgery is intriguing in view of the non-marginal rate of
ingly, symptoms such as dyspnoea are highly non-specific               conservative surgery (about one of three cases). Moreover,
and arise so gradually that the patient tends to overlook them         this value is far lower than those reported for sinonasal AC-
until they are extremely severe, while even specialists may            Cs, ranging from 60.6% to 65% 26. This discrepancy can be
initially misdiagnose such a clinical scenario as asthma.              explained by the anatomical complexity of the sinonasal
Radiological work-up mostly included CT scan due to its                district, which limits wide surgical excisions and offers var-
ability to assess the primary tumour location, extra-luminal           ious nervous and vascular bundles to tumour microscopic
extension, and regional/distant metastasis 24. Moreover, im-           escape. In contrast, the laryngeal box is a fairly well-con-
age acquisition is quicker, a pro that is extremely relevant in        fined anatomical compartment, with relatively few (and in-
case of pending airway problems, especially in critical con-           volved late) possible avenues for extra-laryngeal diffusion.
ditions or in presence of a tracheostomy which greatly ham-            The choice of RT alone or CRT without surgery is rare
pers MRI performance. Therefore, different from other loca-            and often reserved to patients with unresectable tumours
tions such as the sinonasal region, MRI can be considered a            or distant metastasis at diagnosis. The role of adjuvant
second-choice examination, required only in case of specific           RT has been debated in the literature over the past few
tumour extensions and clinically-relevant issues (demonstra-           years: adverse prognostic factors, such as positive or close
tion of cartilage involvement, perineural spread or extra-air-         surgical margins 27-30, high-grade malignant histology 27,30,31,
way soft tissues invasion, e.g. into digestive tracts).                PNI 30,32-34, and high T-N categories 27,35 are all indications
From a histological standpoint, apart from very few cases              for such a complementary treatment.
of MEC, rare laryngeal AC, ASCC and MC, ACC almost                     According to our data, about half of patients who under-
represents the totality of the series (88.9%): of note, this           went surgery received adjuvant RT (rarely CRT), due to the
trend is more pronounced than in other head and neck sites             high rate of R1 and pT3-T4 lesions. Conventional photon
(e.g., within the sinonasal region ACC represents about                therapy was mostly used, with few patients treated with
only two thirds of all MiSGC) 25. This predominance high-              CIRT, probably due to the relatively recent introduction of
ly impacted the delayed presentation of laryngo-tracheal               this treatment modality and its reduced overall availability
MiSGC (due to the indolent and slow growth typical of                  in many countries, compared to conventional photon RT.
ACC), surgical outcomes (high frequency of R1 margins),                Moreover, sound data about the real effectiveness of CIRT
pattern of tumour spread (high rate of PNI), and modes of              as adjuvant therapy for laryngeal and tracheal MiSGC are
recurrence (both local and distant).                                   still not available in the literature, and the risks of subse-
                                                                       quent stenosis or chondronecrosis at these sites are definite-
Treatment                                                              ly not negligible. Instead, several studies reported promis-
In our systematic review, the most common treatment                    ing results with proton beam therapy as adjuvant treatment
applied was surgery, with or without post-operative RT.                for nasopharyngeal ACC compared to photon RT 36 and in
In fact, 86.4% of patients were treated with surgery, and              association to conventional RT for oral cavity ACC, with
different procedures based on the site and level of inva-              good local control and relatively low toxicity 37.
siveness were described: from total or partial laryngec-               Post-operative complication rates reported in these studies
tomies to laryngo-tracheal resection and anastomosis.                  were generally low, but it should be noted that they mainly
Sometimes tracheal surgery was associated with pulmo-                  refer to tracheal procedures. Unfortunately, no detailed data
nary resections or lobectomy. Only one study 12 reported               about laryngeal surgery were provided. However, treatment-
6 cases of tracheal and carinal replacement with aortic al-            related mortality was anecdotal.
lografts. Conservative laryngeal surgical techniques were              Chemotherapy is mainly restricted to metastatic or relaps-
less often performed as first-choice treatment (36 cases               ing disease with limited success rate 38. In our systematic re-
compared to 67 total laryngectomies chosen especially                  view, few patients were treated with chemotherapy, but today
for high-grade MiSGC).                                                 new therapeutic strategies are taken in consideration, due to
Cumulative rate of positive margins (almost all microscopic,           the evolving understanding of biology of salivary glands tu-
R1) is high (68%), and in line with the vast prevalence of             mours. A precise diagnosis and knowledge of tumour muta-
ACC and its well-known tendency to develop PNI travelling              tions may lead to development of new treatments and person-
at distance from macroscopic site of origin of the tumour              alised medicine approaches. Indeed, on the top of traditional
itself. However, it is noteworthy that its distribution accord-        diagnostic tools, such as immunohistochemistry and fluores-



                                                                                                                                             371
C. Montenegro et al.




cence in situ hybridisation, the next-generation sequencing         were frequently collected, we were not able to find complete
approach has been successfully applied in recent years to           oncologic outcomes and, because ACC was the most com-
extend and refine our insights on salivary glands tumours 39,       mon represented histotype, most of the results were referred
carrying to the identification of previously unknown fusion         to this tumour. The pooled analysis was appliable only to
genes, potentially usable as diagnostic tools as well as novel      5-year OS for which we collected more data while, for the
targets for future therapeutic developments. For example,           other outcomes, for which very few details were available, it
MEC is associated to high level of EGFR expression with             could not be applied due to poor reliability.
poor prognosis and cetuximab has been used as a comple-
mentary therapy in low-grade tumours or as single therapy           Conclusions
in metastatic or recurrent MEC 40. ACC frequently presents
MYB altered pathway and molecular inhibitors are currently          MiSGC of the larynx and trachea are very rare tumours,
under development; in particular, multiple kinase inhibitors        often presenting as locally advanced and invasive diseas-
showed a promising response in advanced ACC 40,41.                  es. To date there are no guidelines about their treatment.
                                                                    Surgery followed by adjuvant (C)RT is the most common
Oncological outcomes                                                first-choice treatment. However, few studies are available
Mean follow-up was 68.3 months. In view of the notorious            in the literature and with a small number of patients or with
tendency of ACC to recur at 10, 15 or even 20 years after           insufficiently long follow-up. The literature shows that dis-
primary treatment, follow-up should be regarded as limited          tant metastases may occur up to more than 5 years after
and prompt the reader to cautiously interpret the survival          treatment. Multicentric prospective studies with long-term
outcomes reported herein.                                           follow-up are required to better define treatment strategies
In this regard, 62.4% of all deaths were caused by the              and possibly improve oncological outcomes.
disease, and laryngeal localisation was associated with a
higher rate of cancer-related death. The pattern of recur-          Conflict of interest statement
rence was typical of ACC, with a prevalence of local and            The authors declare no conflict of interest.
distant sites. Five-year OS was worse for laryngeal MiSGC
(Tab. IV), while 5-year OS collected for tracheal cases             Funding
ranged between 81.8% to 95%. On the other hand, 5-year              This research did not receive any specific grant from funding
                                                                    agencies in the public, commercial, or not-for-profit sectors.
DFS, described in only 5 studies (3 laryngeal 16-18 and 2
tracheal 20,21 series), was worse for tracheal malignancies
                                                                    Author contributions
(62% and 47.8% for the trachea compared to 100%, 83%,
                                                                    CM, DM, CP: study design, article selection, review draft-
and 69% for the larynx). This finding is in line with the
                                                                    ing and critical revision; CM, EM: article search and selec-
different rates of positive margins at these different sites.
                                                                    tion, data extraction; AP: pooled analysis and critical revi-
We also collected data on specific oncologic outcomes for
                                                                    sion; DL, MT, VR: critical revision of the article.
patients with tracheal MiSGC treated with multimodal thera-
py (surgery and adjuvant RT). While 5-year oncological out-
                                                                    Ethical consideration
comes are quite similar when considering all patients versus
                                                                    No formal ethics committee approval was required for this
those treated with surgery and RT, 10-year oncological out-
                                                                    article as it is based on already published clinical data from
comes improved with the use of multimodal therapy.
                                                                    other studies available in the literature.
Based on the data collected, surgery associated with RT had a
better impact on outcomes, mainly in terms of 5- and 10-year
LRFS and DRFS, and adjuvant RT may have also helped                 References
in delaying recurrence. Due to the limited data available, in       1
                                                                        Vander Poorten V, Hunt J, Bradley PJ, et al. Recent trends in the man-
order to obtain an estimate of 5-year OS, we performed a                agement of minor salivary gland carcinoma. Head Neck 2014;36:444-
                                                                        455. https://doi.org/10.1002/hed.23249
pooled analysis yielding a value of 83% (ranging from 78%           2
                                                                        Zhang M, Li KN, Li C, et al. Malignant minor salivary gland
to 87%). The same statistical analysis was not applicable to            carcinomas of the larynx. ORL J Otorhinolaryngol Relat Spec
the other outcomes due to the lack of precise data.                     2014;76:222-226. https://doi.org/10.1159/000368322
                                                                    3
                                                                        Ganly I, Patel SG, Coleman M, et al. Malignant minor salivary
Limitations                                                             gland tumors of the larynx. Arch Otolaryngol Head Neck Surg
                                                                        2006;132:767-770. https://doi.org/10.1001/archotol.132.7.767
The present systematic review has some limitations. Consid-         4
                                                                        Kumar NS, Iype EM, Thomas S, et al. Adenoid cystic carcinoma of the
ering all articles included, due to the rarity of these malignan-       trachea. Indian J Surg Oncol 2016;7:62-66. https://doi.org/10.1007/
cies and the considerable span of time in which these series            s13193-015-0453-5




372
                                                         Treatment and outcomes of minor salivary gland cancers of the larynx and trachea: a systematic review




5
     Honings J, van Dijck JAAM, Verhagen AFTM, et al. Incidence                   22
                                                                                       Chen F, Huang M, Xu Y, et al. Primary tracheal adenoid cystic car-
     and treatment of tracheal cancer: a nationwide study in the Nether-               cinoma: adjuvant treatment outcome. Int J Clin Oncol 2015;20:686-
     lands. Ann Surg Oncol 2007;14:968-976. https://doi.org/10.1245/                   692. https://doi.org/10.1007/s10147-014-0771-6
     s10434-006-9229-z                                                            23
                                                                                       Chen L, Deng W, Li C, et al. Clinical outcome and comparison be-
6
     Ning Y, He W, Bian D, et al. Tracheo-bronchial adenoid cystic carci-              tween squamous and non-squamous cell carcinoma of the larynx.
     noma: a retrospective study. Asia Pac J Clin Oncol 2019;15:244-249.               Acta Otolaryngol 2020;140:195-201. https://doi.org/10.1080/00016
     https://doi.org/10.1111/ajco.13162                                                489.2019.1700305
7
     Huo Z, Wu H, Li S, et al. Molecular genetic studies on EGFR, KRAS,           24
                                                                                       Zvrko E, Golubović M. Laryngeal adenoid cystic carcinoma. Acta
     BRAF, ALK, PIK3CA, PDGFRA, and DDR2 in primary pulmonary                          Otorhinolaryngol Ital 2009;29:279-282.
     adenoid cystic carcinoma. Diagn Pathol 2015;10:161. https://doi.             25
                                                                                       Ferrari M, Mattavelli D, Tomasoni M, et al. The MUSES∗: a prog-
     org/10.1186/s13000-015-0409-7                                                     nostic study on 1360 patients with sinonasal cancer undergoing en-
8
     Chan WL, Lee VHF, Siu SWK, et al. Inoperable adenoid cystic carci-                doscopic surgery-based treatment: ∗MUlti-institutional collaborative
     noma of trachea: complete remission after multi-modality treatment.               study on endoscopically treated sinonasal cancers. Eur J Cancer
     Hong Kong J Radiol 2014;17:203-207. https://doi.org/10.12809/                     2022;171:161-182. https://doi.org/10.1016/j.ejca.2022.05.010
     hkjr1413202                                                                  26
                                                                                       Michel G, Joubert M, Delemazure AS, et al. Adenoid cystic carci-
9
     Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement                    noma of the paranasal sinuses: retrospective series and review of the
     for reporting systematic reviews and meta-analyses of studies that                literature. Eur Ann Otorhinolaryngol Head Neck Dis 2013;130:257-
     evaluate healthcare interventions: explanation and elaboration. BMJ               262. https://doi.org/10.1016/j.anorl.2012.09.010
     2009;339:b2700. https://doi.org/10.1136/bmj.b2700                            27
                                                                                       Garden AS, Weber RS, Ang KK, et al. Post-operative radiation therapy
10
     Lionello M, Canal F, Presotto F, et al. Laryngeal adenoid cystic                  for malignant tumors of minor salivary glands. Outcome and patterns
     carcinoma: radical or conservative surgery? Am J Otolaryngol                      of failure. Cancer 1994;73:2563-2569. https://doi.org/10.1002/1097-
     2021;42:102974. https://doi.org/10.1016/j.amjoto.2021.102974                      0142(19940515)73:10<2563::aid-cncr2820731018>3.0.co;2-x
11
     Nielsen TK, Bjørndal K, Krogdahl A, et al. Salivary gland carcino-           28
                                                                                       Sadeghi A, Tran LM, Mark R, et al. Minor salivary gland tumors of the
     mas of the larynx: a national study in Denmark. Auris Nasus Larynx                head and neck: treatment strategies and prognosis. Am J Clin Oncol
     2012;39:611-614. https://doi.org/10.1016/j.anl.2012.02.003                        1993;16:3-8. https://doi.org/10.1097/00000421-199302000-00002
12
     Wurtz A, Porte H, Conti M, et al. Surgical technique and results of          29
                                                                                       van der Wal JE, Snow GB, van der Waal I. Histological reclassification
     tracheal and carinal replacement with aortic allografts for salivary              of 101 intraoral salivary gland tumours (new WHO classification). J
     gland-type carcinoma. J Thorac Cardiovasc Surg 2010;140:387-393.                  Clin Pathol 1992;45:834-835. https://doi.org/10.1136/jcp.45.9.834
     e2. https://doi.org/10.1016/j.jtcvs.2010.01.043                              30
                                                                                       Jenkins DW, Spaulding CA, Constable WC, et al. Minor salivary gland
13
     Högerle BA, Lasitschka F, Muley T, et al. Primary adenoid cystic car-             tumors: the role of radiotherapy. Am J Otolaryngol 1989;10:250-256.
     cinoma of the trachea: clinical outcome of 38 patients after interdis-            https://doi.org/10.1016/0196-0709(89)90004-5
     ciplinary treatment in a single institution. Radiat Oncol 2019;14:117.       31
                                                                                       Waldron CA, el-Mofty SK, Gnepp DR. Tumors of the intraoral mi-
     https://doi.org/10.1186/s13014-019-1323-z
                                                                                       nor salivary glands: a demographic and histologic study of 426 cas-
14
     Lucioni M, Marioni G, Libera DD, et al. Treatment of unusual or rare              es. Oral Surg Oral Med Oral Pathol 1988;66:323-333. https://doi.
     laryngeal nonsquamous primary malignancies: radical (total/extend-                org/10.1016/0030-4220(88)90240-x
     ed total laryngectomy) or conservative surgery? Am J Otolaryngol             32
                                                                                       Beckhardt RN, Weber RS, Zane R, et al. Minor salivary gland
     2008;29:106-112. https://doi.org/10.1016/j.amjoto.2007.02.007
                                                                                       tumors of the palate: clinical and pathologic correlates of
15
     Liu W, Chen X. Adenoid cystic carcinoma of the larynx: a report of six            outcome.     Laryngoscope   1995;105:1155-1160.  https://doi.
     cases with review of the literature. Acta Otolaryngol 2015;135:489-               org/10.1288/00005537-199511000-00003
     493. https://doi.org/10.3109/00016489.2014.990583                            33
                                                                                       Chen AM, Garcia J, Granchi P, et al. Base of skull recurrences after
16
     Akbaba S, Lang K, Bulut OC, et al. The role of organ- and func-                   treatment of salivary gland cancer with perineural invasion reduced
     tion-preserving radiotherapy in the treatment of adenoid cystic car-              by post-operative radiotherapy. Clin Otolaryngol 2009;34:539-545.
     cinoma of the larynx. Head Neck 2019;41:2208-2214. https://doi.                   https://doi.org/10.1111/j.1749-4486.2009.02036.x
     org/10.1002/hed.25678                                                        34
                                                                                       Gil Z, Carlson DL, Gupta A, et al. Patterns and incidence of neural
17
     Moukarbel RV, Goldstein DP, O’Sullivan B, et al. Adenoid cystic car-              invasion in patients with cancers of the paranasal sinuses. Arch Oto-
     cinoma of the larynx: a 40-year experience. Head Neck 2008;30:919-                laryngol Head Neck Surg 2009;135:173-179. https://doi.org/10.1001/
     924. https://doi.org/10.1002/hed.20802                                            archoto.2008.525
18
     Wang MC, Liu CY, Li WY, et al. Salivary gland carcinoma of the               35
                                                                                       Vander Poorten VL, Balm AJ, Hilgers FJ, et al. Stage as ma-
     larynx. J Chin Med Assoc 2006;69:322-325. https://doi.org/10.1016/                jor long term outcome predictor in minor salivary gland
     S1726-4901(09)70266-7                                                             carcinoma.       Cancer     2000;89:1195-1204.        https://doi.
19
     Mahlstedt K, Ussmüller J, Donath K. Malignant sialogenic tu-                      org/10.1002/1097-0142(20000915)89:6<1195::aid-cncr2>3.3.co;2-a
     mours of the larynx. J Laryngol Otol 2002;116:119-122. https://doi.          36
                                                                                       Akbaba S, Ahmed D, Lang K, et al. Results of a combination treat-
     org/10.1258/0022215021910078                                                      ment with intensity modulated radiotherapy and active raster-scan-
20
     Yang H, Yao F, Tantai J, et al. Resected tracheal adenoid cystic carcino-         ning carbon ion boost for adenoid cystic carcinoma of the minor sali-
     ma: improvements in outcome at a single institution. Ann Thorac Surg              vary glands of the nasopharynx. Oral Oncol 2019;91:39-46. https://
     2016;101:294-300. https://doi.org/10.1016/j.athoracsur.2015.06.073                doi.org/10.1016/j.oraloncology.2019.02.019
21
     Je HU, Song SY, Kim DK, et al. A 10-year clinical outcome of ra-             37
                                                                                       Lang K, Baur M, Akbaba S, et al. Intensity Modulated Radiotherapy
     diotherapy as an adjuvant or definitive treatment for primary tracheal            (IMRT) + Carbon Ion Boost for adenoid cystic carcinoma of the mi-
     adenoid cystic carcinoma. Radiat Oncol 2017;12:196. https://doi.                  nor salivary glands in the oral cavity. Cancers 2018;10:488. https://
     org/10.1186/s13014-017-0933-6                                                     doi.org/10.3390/cancers10120488




                                                                                                                                                        373
C. Montenegro et al.




38
     Shekar K, Singh M, Godden D, et al. Recent advances in the man-         sis and treatment. Cancers 2020;12:3107. https://doi.org/10.3390/
     agement of salivary gland disease. Br J Oral Maxillofac Surg            cancers12113107
     2009;47:594-597. https://doi.org/10.1016/j.bjoms.2009.07.006       41
                                                                             Corrêa TS, Matos GDR, Segura M, et al. Second-line treatment of
39
     Todorovic E, Dickson BC, Weinreb I. Salivary gland cancer in            HER2-positive salivary gland tumor: Ado-Trastuzumab Emtan-
                                                                             sine (T-DM1) after progression on trastuzumab. Case Rep Oncol
     the era of routine next-generation sequencing. Head Neck Pathol         2018;11:252-257. https://doi.org/10.1159/000488669
     2020;14:311-320. https://doi.org/10.1007/s12105-020-01140-4        42
                                                                             Albers E, Lawrie T, Harrell JH, et al. Tracheobronchial adenoid
40
     Porcheri C, Meisel CT, Mitsiadis TA. Molecular and cellular mod-        cystic carcinoma: a clinicopathologic study of 14 cases. Chest
     elling of salivary gland tumors open new landscapes in diagno-          2004;125:1160-1165. https://doi.org/10.1378/chest.125.3.1160




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