10.14639/0392-100X-N2466
Objectives. Head and neck adenosquamous cell carcinoma (HN-ASCC) is a rare, aggressive neoplasm, with limited data reported in the literature. The aim of this study was to assess tumour behaviour and prognostic factors impacting overall survival (OS) in a retrospective, single institution series. Methods. A retrospective study on patients affected by HN-ASCC who were treated surgically between 2002 and 2019 at the Department of Otorhinolaryngology – Head and Neck Surgery of the University of Brescia was conducted. Demographics, clinical data, OS, and relative prognostic factors were analysed. Results. The study included 32 patients, with a median age of 66 years, mostly males (84.4%) and untreated (68.8%). Adjuvant treatments followed surgery in 28.1% of patients. Compared to conventional SCC, ASCC showed a higher proportion of cases arising in the larynx (40.6%); no difference was found in other features. Advanced (pT3-4) local stage at presentation (p&nbsp;=&nbsp;0.023), perineural invasion (PNI, p&nbsp;=&nbsp;0.01), and positive margins (p&nbsp;=&nbsp;0.007) were independent negative prognostic factors for OS. Conclusions. HN-ASCC is a rare, aggressive cancer, most frequently arising in the larynx of elderly males, usually diagnosed in an advanced local stage. OS is generally poor, affected by local advanced stage, PNI, and positive resection margins.
text/xml
1827-675X
2466
en
Cesare Piazza
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
recurrence
Adenosquamous cell carcinoma of the head  and neck: a retrospective single institution series
Text.Serial.Journal
https://www.actaitalica.it/
43
Head and neck
2023-07-28
2023-01-08
2023-09-29
2023-10-02
310-316
1
Cesare Piazza
2023/07/28
10.14639/0392-100X-N2466
310
Department of Otorhinolaryngology – Head and Neck Surgery, ASST Spedali Civili, Department of Surgical and Medical Specialties, Radiological Sciences and Public Health, University of Brescia, School of Medicine, Brescia, Italy
1827-675X
recurrence
en
316
Adenosquamous cell carcinoma of the head  and neck: a retrospective single institution series
https://www.actaitalica.it/article/download/2466/1029
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43:310-316; doi: 10.14639/0392-100X-N2466




Head and neck


Adenosquamous cell carcinoma of the head
and neck: a retrospective single institution series
Carcinoma adenosquamoso del distretto testa-collo: studio retrospettivo monocentrico
Gabriele Zigliani1, Sara Migliorati1, Elisa Marazzi1, Mara Arcuri1, Michele Tomasoni1, Simonetta Battocchio2,
Alberto Paderno1, Davide Lancini1, Alberto Deganello3, Cesare Piazza1
1
 Department of Otorhinolaryngology – Head and Neck Surgery, ASST Spedali Civili, Department of Surgical and Medical Specialties,
Radiological Sciences and Public Health, University of Brescia, School of Medicine, Brescia, Italy; 2 Department of Pathology, ASST
Spedali Civili, University of Brescia, School of Medicine, Brescia, Italy; 3 Department of Otorhinolaryngology – Head and Neck
Surgery, IRCCS National Cancer Institute, Milan, Italy


SUMMARY
Objectives. Head and neck adenosquamous cell carcinoma (HN-ASCC) is a rare, aggres-
sive neoplasm, with limited data reported in the literature. The aim of this study was to
assess tumour behaviour and prognostic factors impacting overall survival (OS) in a retro-
spective, single institution series.
Methods. A retrospective study on patients affected by HN-ASCC who were treated surgi-
cally between 2002 and 2019 at the Department of Otorhinolaryngology – Head and Neck
Surgery of the University of Brescia was conducted. Demographics, clinical data, OS, and
relative prognostic factors were analysed.
Results. The study included 32 patients, with a median age of 66 years, mostly males
(84.4%) and untreated (68.8%). Adjuvant treatments followed surgery in 28.1% of patients.
Compared to conventional SCC, ASCC showed a higher proportion of cases arising in
the larynx (40.6%); no difference was found in other features. Advanced (pT3-4) local
                                                                                                     Received: January 10, 2023
stage at presentation (p = 0.023), perineural invasion (PNI, p = 0.01), and positive margins
                                                                                                     Accepted: April 1, 2023
(p = 0.007) were independent negative prognostic factors for OS.                                     Published online: July 28, 2023
Conclusions. HN-ASCC is a rare, aggressive cancer, most frequently arising in the larynx
of elderly males, usually diagnosed in an advanced local stage. OS is generally poor, af-            Correspondence
fected by local advanced stage, PNI, and positive resection margins.                                 Gabriele Zigliani
KEY WORDS: adenosquamous cell carcinoma, head and neck, survival, prognosis, recurrence              Department of Otorhinolaryngology – Head and
                                                                                                     Neck Surgery, ASST Spedali Civili, Department
                                                                                                     of Surgical and Medical Specialties, Radiological
RIASSUNTO                                                                                            Sciences and Public Health, University of Brescia,
Obiettivo. Il carcinoma adenosquamoso del distretto testa-collo (HN-ASCC) è una neoplasia            School of Medicine, piazzale Spedali Civili 1,
rara e aggressiva, con pochi dati riportati in letteratura. Lo scopo del presente lavoro è quello    25123 Brescia, Italy. Tel. +39 030 3995319
di valutare il comportamento di questa neoplasia e i fattori prognostici che ne influenzano la       E-mail: gabriele.zigliani@gmail.com
sopravvivenza cruda mediante uno studio retrospettivo su una serie monocentrica.
Metodi. Il lavoro, retrospettivo, ha reclutato pazienti affetti da HN-ASCC trattati chirur-            How to cite this article: Zigliani G, Miglio-
gicamente dal 2002 al 2019 presso la Clinica Otorinolaringoiatrica dell’Università degli               rati S, Marazzi E, et al. Adenosquamous cell
Studi di Brescia. Sono stati analizzati i dati demografici, clinici, di sopravvivenza cruda e          carcinoma of the head and neck: a retrospec-
i relativi fattori prognostici.                                                                        tive single institution series. Acta Otorhi-
Risultati. Lo studio ha incluso 32 pazienti di età mediana pari a 66 anni, per lo più maschi           nolaryngol Ital 2023;43:310-316. https://doi.
(84,4%), mai trattati prima (68,8%). Il trattamento adiuvante è stato somministrato dopo la            org/10.14639/0392-100X-N2466
chirurgia nel 28,1% dei casi. Confrontato col più frequente SCC, l’ASCC insorge maggiormente
                                                                                                     © Società Italiana di Otorinolaringoiatria
a livello laringeo (40,6%); non sono state riscontrate altre differenze. Lo stadio locale avanzato   e Chirurgia Cervico-Facciale
(pT3-4) alla diagnosi (p = 0,023), l’infiltrazione perineurale (p = 0,01) e i margini positivi
(p = 0,007) sono risultati fattori prognostici negativi indipendenti per la sopravvivenza cruda.
                                                                                                                    OPEN ACCESS
Conclusioni. L’HN-ASCC è una neoplasia rara, aggressiva, per lo più a origine laringea e
in pazienti anziani, maschi, in stadio localmente avanzato alla diagnosi. La sopravvivenza           This is an open access article distributed in accordance with
                                                                                                     the CC-BY-NC-ND (Creative Commons Attribution-Non-
cruda è solitamente scarsa e condizionata dallo stadio localmente avanzato, dalla presenza           Commercial-NoDerivatives 4.0 International) license. The
di invasione perineurale e dai margini positivi.                                                     article can be used by giving appropriate credit and mentio-
                                                                                                     ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: carcinoma adenosquamoso, testa-collo, sopravvivenza, prognosi,                        only in the original version. For further information: https://
recidiva                                                                                             creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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                                                                                         Adenosquamous cell carcinoma of the head and neck




Introduction                                                         cal, histopathological reports, and mortality registries were
                                                                     consulted. Demographics, clinical, tumour-, treatment-related
Head and neck adenosquamous cell carcinoma (HN-AS-
                                                                     characteristics, and information on follow-up were retrieved
CC) is a rare, aggressive neoplasm; the most frequently
                                                                     and collected in an anonymised database. Patients were fol-
involved site is the larynx, followed by the oral cavity, oro-
                                                                     lowed after surgery with a standard protocol, which involved
pharynx, hypopharynx, nasopharynx, and nasal cavity 1,2. It
                                                                     endoscopic examination every 2 months for the first year, 4
is usually diagnosed in the 6th and 7th decades with a male
                                                                     months during the second year, and 6 months thereafter. Ra-
prevalence 2-4. Due to its exceptional rarity, information
                                                                     diological evaluation (CT scan or MRI) of the head and neck
about its diagnosis, description, and treatment strategies
                                                                     was performed every 4 months in the first 2 years, 6 months
are based on case reports and small clinical series.
                                                                     from the third to the fifth year. Chest and abdomen CT scan (or
ASCC was first described by Gerughty et al. 5 in 1968, with
                                                                     a PET) was also obtained yearly.
80% of patients having distant metastasis at diagnosis; it has
                                                                     Data from a historic cohort of patients affected by Stage
been considered as a variant of mucoepidermoid carcinoma
(MEC) until Evans 6, in 1984, suggested that ASCC should be          II-IV SCC of the oral cavity, oropharynx, larynx and hy-
deemed as an independent histology due to its local aggres-          popharynx treated by upfront surgery at our Institution be-
siveness, early tendency to distant spreading, and poor progno-      tween 2009 and 2019, meeting the same inclusion/exclu-
sis 4,7. At histologic analysis, ASCC shows both squamous and        sion criteria of the ASCC cohort, were also retrieved.
adenomatous malignant components. The former usually pre-
                                                                     Statistical analysis
dominates, it can be in situ or invasive, and range from well to
                                                                     Variables included in the analysis were expressed in terms of
poorly differentiated. The latter have a tubular, alveolar, and/or
                                                                     median, interquartile range (IQR), range of values, and per-
glandular morphology. Mucin production is typically present,
but is not a requirement for diagnosis in the presence of true       centages. The main demographics (age at surgery, gender) and
gland formation 8. Perineural invasion is typically present 3.       pathological features (site of origin, pT, pN, margin status)
Despite the lack of scientific evidence, ASCC appears to             were compared between the cohorts of SCC and ASCC using
be strongly related to alcohol abuse and smoking habits,             Mann-Whitney, chi-square, and Fisher exact-tests, as appro-
although HPV may also take part in its pathogenesis 2,4.             priate. The time at risk was computed from the date of surgery
Symptoms are related to the site affected and include pain-          to the date of death, first relapse of disease (any site), or lat-
ful ulcers, hoarseness, dysphagia, dyspnoea, obstruction,            est available follow-up (censored data). Outcomes of interest
and haemoptysis 3. Histopathological differential diagnosis          were overall survival (OS), defined as the time from surgery to
includes muco-epidermoid carcinoma, adenoid squamous                 death from any cause, and relapse-free survival (RFS), defined
cell carcinoma, metastatic adenocarcinoma, necrotising               as the time from surgery to disease relapse (any site).
sialo-metaplasia, and squamous cell carcinoma 3.                     Univariate analysis was conducted using Cox proportional haz-
Because of its rarity, there are no specific guidelines for          ard model. Results were expressed as hazard ratio (HR) with
the management of ASCC. Most authors recommend ear-                  95% confidence intervals (CI). Survival curves and the rela-
ly and aggressive surgical resection followed by adjuvant            tive 95% CI were plotted using the Kaplan Meier method and
treatments 3,4, even though the beneficial role of radiation         compared with the log-rank test. Five-year survival estimates
therapy (RT) and associated chemotherapy (CHT) in the                and the relative 95% CI were reported at the univariate analy-
adjuvant setting has not been clearly demonstrated.                  sis. Multivariable analysis was conducted using a Cox propor-
                                                                     tional hazard model selecting the most relevant variables with a
Materials and methods                                                clinical application. Shoenfeld’s residuals were tested to assess
                                                                     the proportional hazard assumption. Multicollinearity between
A retrospective analysis of consecutive patients affected by         variables was excluded by testing the variance inflation factor
primary HN-ASCC who were treated surgically from Janu-               (vif); a vif < 5 was considered acceptable. Statistical analysis
ary 2002 to November 2019 was conducted at the Department            was performed using R (version 4.1.0, R Foundation for Statis-
of Otorhinolaryngology – Head and Neck Surgery, University           tical Computing, Vienna, Austria); p-values < 0.05 (two-tailed)
of Brescia, Italy. Inclusion criteria were: a) histopathologi-       were considered statistically significant.
cal diagnosis of HN-ASCC originating from the oral cavity,
oropharynx, larynx, hypopharynx, or sinonasal cavities per-
formed or confirmed at our Institution; b) primary or salvage
                                                                     Results
surgery with curative intent; c) availability of comprehensive       Clinical features
demographics and histopathological details. Patients with dis-       Thirty-two patients were included in the current study, and 27
tant metastasis at diagnosis were excluded. Clinical, radiologi-     (84.4%) were males; the median age at surgery was 66 years



                                                                                                                                     311
G. Zigliani et al.




(IQR = 11), ranging from 47 to 86 years. In 10 cases (31.2%),     Table I. Descriptive statistics of the cohort.
surgery was performed as salvage treatment for local recur-        Variables                                            N                %
rence after previous (CHT)RT (70%), surgery alone (20%),           Age (years)                       < 65               15             46.9
or surgery and adjuvant RT (10%). Among the 22 treatment-
                                                                                                     > 65               17             53.1
naïve patients receiving upfront surgery, data on pre-operative
                                                                   Gender                           Female               5             15.6
biopsy was available in 17 cases. Most patients were diagnosed
                                                                                                     Male               27             84.4
with conventional SCC (75%), whereas only 25% of cases
                                                                   Presentation                    Primary              22             68.7
were correctly diagnosed as ASCC from the beginning: in one
                                                                                                  Recurrence            10             31.3
case, pre-operative biopsy misdiagnosed ASCC for MEC. In 4
cases, pre-operative biopsy was not performed since transoral      Previous treatment              (CHT)RT               7              70
                                                                   (for recurrent ASCC)          Surgery + RT            1              10
base of tongue or transoral laryngeal microsurgery (TOLMS)
was scheduled, with frozen sections obtained intra-operatively                                   Only surgery            2              20
to confirm malignancy. For one patient, data on pre-operative      Subsite                        Sino-nasal             4             12.5
diagnosis was not available. The most involved site was the                                       Oral cavity            4             12.5
larynx (40.6%), followed by the oropharynx (21.9%), hy-                                           Oropharynx             7             21.9
popharynx, oral cavity, and sinonasal cavities (12.5% each).                                     Hypopharynx             4             12.5
Among treatment-naïve patients, 13 (59.1%) were cN0: in                                             Larynx              13             40.6
5 cases (38.5%) an elective neck dissection was performed,         pT classification                  pT1                6             18.8
with a rate of occult nodal metastasis of 40% (2 cases, both                                          pT2                9             28.1
classified as pN1); in the remaining 8 cases (61.5%), an ex-                                          pT3                6             18.8
clusive nodal recurrence with a disease-free interval (DFI)                                          pT4a               11             34.3
of 35 months was observed in only one patient (12.5%)              pN classification                  pN0               20             62.5
who was later successfully treated with surgery. Most tu-                                             pN1                4             12.5
mours were locally advanced (17 patients were diagnosed                                              pN2b                3              9.4
as pT3-4a, 53.1%), whereas the presence of nodal metasta-                                            pN3b                5             15.6
ses was observed in 37.5% of patients: 12.5% were classi-
                                                                   Presence of nodal                   No               19             59.4
fied as pN1, 9.4% as pN2b, and 15.6% as pN3b. Perineural           metastasis                         Yes               13             40.6
(PNI) and lympho-vascular invasion (LVI) were reported in
                                                                   Staging                             I-II             15             46.9
56.2% and 43.8% of cases, respectively. Surgical resection
                                                                                                     III-IV             17             53.1
with negative surgical margins (R0, with a distance from
                                                                   PNI                              Absent              14             43.8
the lesion > 5 mm for open surgery) was obtained in 18 cas-                                        Present              18             56.2
es (56.2%), while positive surgical margins were detected
                                                                   LVI                              Absent              18             56.2
in 14 (43.8%) patients. There were no R0 close margins.
                                                                                                   Present              14             43.8
Overall, adjuvant treatment was administered to nine pa-
                                                                   Margins                             R0               18             56.2
tients (28.4%). Among primary tumours, RT was performed
                                                                                                       R1               14             43.8
in 16.7%, whereas no case of re-RT after salvage surgery
                                                                   Adjuvant treatment                None               21              70
was recorded. Further details are available in Table I.
                                                                                                       RT                5             16.7
Overall survival and analysis of prognosticators                                                    CHTRT                4             13.3
Follow-up data were available for 30 patients, with a median                                     Missing data           (2)
follow-up of 39 months (range, 1-149). At the end of the study,   ASCC: adenosquamous cell carcinoma; CHTRT: chemo-radiotherapy; LVI: lympho-vascu-
                                                                  lar invasion; PNI: perineural invasion; RT: radiotherapy.
13 (43.4%) patients died of disease: all experienced recur-
rence, with a median DFI of 8.5 months (range, 3-41): loco-
regional recurrence occurred in 11 cases (36.7%), whereas         significantly associated with worse OS (Fig. 2). Multivariate
distant metastases were diagnosed in 2 (6.7%). Five-year OS       analysis confirmed PNI (HR = 7.81, p = 0.01), presence of pos-
and RFS were 49.3% (95% CI, 33.5%-72.5%) and 53% (95%             itive margins (HR = 7.80, p = 0.007), and pT3-4 (HR = 4.69,
CI, 36.1%-77.7%), respectively (Fig. 1).                          p = 0.023) as independent prognostic factors (Tab. II).
Univariate analysis according to OS showed that PNI
(HR = 4.62, p = 0.011), LVI (HR = 2.71, p = 0.052), pres-         Comparison of clinical features and prognosis
ence of positive resection margins (HR = 3.04, p = 0.026), and    of ‘conventional’ SCC and ASCC
advanced local disease (pT3-4, HR = 4.14, p = 0.018) were         Fourteen patients with treatment-naïve Stage II-IV ASCC of



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                                                                                                     Adenosquamous cell carcinoma of the head and neck




Figure 1. Kaplan Meier curves showing overall survival (OS) and recurrence free survival (RFS).


the oral cavity, oropharynx, larynx, and hypopharynx were                        Discussion
compared to an historic retrospective cohort of patients af-
                                                                                 The author who first described HN-ASCC suggested the ori-
fected by treatment-naïve conventional SCC and submit-
                                                                                 gin of such a rare lesion from sero-mucinous glands of the up-
ted to upfront surgery (n = 305). No significant differences
                                                                                 per aero-digestive tract 5. Evans 6 then ascertained the distinct
were found considering age at diagnosis (p = 0.686), gen-
                                                                                 histopathological features of ASCC, and Alos 10 described the
der (p = 0.994), margin status (p = 0.101), pT classification                    related immunohistochemical diagnostic criteria: CEA, CK7,
(p = 0.590), and presence of nodal metastasis (p = 0.684),                       and CAM5.2 reflect adeno-carcinomatous and glandular com-
whereas ASCC were significantly more common in the lar-                          ponents; CK20 is absent, while the squamous component ex-
ynx and rarely observed in the oral cavity compared to SCC                       presses CK5/6 and p63. Histopathological diagnosis based on
(p = 0.013). Further details are shown in Table III.                             small pre-operative biopsy can often be mistaken with MEC,
No significant differences between the cohorts of stage I-IV                     but mostly with SCC: this might be due to either the small por-
‘conventional’ SCC and ASCC (Fig. 3) were found both in                          tion of tissue picked up with biopsy (the glandular component
terms of OS (52.5%, 95% CI, 47.0%-58.8% vs 46.2%, 95%                            is always deeper than the SCC component, and therefore a
CI, 25.7%-83.0%; p = 0.576) and RFS (61.6%, 95% CI,                              superficial biopsy might lead to uncomplete diagnosis), and
56.0%-67.8% vs 51.3%, 95% CI, 29.6%-88.8%, p = 0.571).                           the uncommon occurrence of HN-ASCC.




Figure 2. Kaplan Meier curves showing overall survival (OS) according to pT classification (pT1-2 vs pT3-4), PNI (Pn0 vs Pn1), and surgical margins
(R0 vs R1).



                                                                                                                                                 313
G. Zigliani et al.




Table II. Univariate and multivariate analysis showing the prognostic role of demographics, treatment and pathological-related variables in terms of OS.
 Variables                                             Logrank test                      Cox proportional hazard                Cox proportional hazard
                                                                                              regression model                      regression model
                                                   5-year OS (95% CI)        P-value     HR (95% CI)           P-value         HR (95% CI)          P-value
 Age (years)                    < 65              52.4% (30.6%-89.6%)         0.316    1.67 (0.61-4.58)         0.323
                                > 65               46.8% (27.0%-81%)
 Gender                        Female             75.0% (42.6%-100%)          0.205    3.44 (0.45-26.23)        0.233
                                Male              44.4% (27.9%-70.6%)
 Presentation                  Primary            52.2% (33.7%-80.8%)         0.238    1.79 (0.68-4.76)         0.241       2.56 (0.62-10.60)        0.195
                                                  42.0% (18.4%-95.6%)
                             Recurrence           42.0% (18.4%-95.6%)
 Previous RT                     No               56.4% (37.4%-84.8%)         0.198    1.90 (0.71-5.12)         0.204        0.93 (0.18-4.76)        0.932
                                Yes               35.0% (14.3%-85.8%)
 Subsite                     Sino-nasal            100% (100%-100%)           0.844    1.10 (0.15-8.21)         0.922
                             Oral cavity          66.7% (30.0%-100%)         (2y-OS)   1.44 (0.19-10.70)        0.724
                            Oropharynx            57.1% (30.1%-100%)                    1.39 (0.26-7.20)        0.704
                            Hypopharynx           50.0% (18.8%-100%)                    1.10 (0.15-8.20)        0.922
                               Larynx             91.7% (77.3%-100%)
 pT                            pT1-2               73.3% (54%-99.5%)          0.010     4.14 (1.28-3.4)         0.018       4.69 (1.24-17.79)        0.023
                               pT3-4               19.4% (5.7%-65.6%)
 Nodal metastases                No               62.5% (28.1%-78.3%)         0.779    0.86 (0.32-2.34)         0.768        1.84 (0.46-7.31)        0.387
                                Yes               32.5% (32.5%-95.0%)
 PNI                            Pn0               76.6% (56.6%-100%)          0.006    4.62 (1.42-15.06)        0.011       7.81 (1.61-37.83)        0.010
                                Pn1               23.2% (8.75%-61.6%)
 LVI                            Lv0               62.2% (42.2%-91.7%)         0.044    2.71 (0.99-7.44)         0.052
                                Lv1               29.7% (11.7%-75.1%)
 Margins                         R0               66.2% (45.7%-95.8%)         0.021    3.04 (1.14-8.12)         0.026       7.80 (1.73-35.13)        0.007
                                 R1               30.8% (13.6%-69.5%)
 Adjuvant RT                     No               53.9% (35.5%-81.8%)         0.735    1.23 (0.38-3.96)         0.725
                                Yes               43.8% (18.9%-100%)
LVI: lympho-vascular invasion; PNI: perineural invasion; RT: radiotherapy.




Figure 3. Kaplan Meier curves comparing overall survival (OS) and recurrence free survival (RFS) between stage II-IV oral cavity, oropharyngeal, hypopharyngeal
and laryngeal SCC and ASCC.



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                                                                                                          Adenosquamous cell carcinoma of the head and neck




Table III. Differences in most relevant demographics and pathological variables between the retrospective cohorts of patients affected by treatment-naïve, Stage
II-IV primary ASCC and conventional SCC of the head and neck treated in our centre.
  Variables                                                                                ASCC                       SCC                       P-value
 Median age (range) - years                                                              67.5 (52-84)              67 (26-91)                   0.686
 Gender                             Female                                                3 (21.4%)                77 (25.2%)                   0.994
                                    Male                                                  11 (78.6%)              228 (74.8%)
 pT                                 pT1                                                      0 (0%)                 11 (3.6%)                   0.590
                                    pT2                                                    6 (42.9%)               84 (27.6%)
                                    pT3                                                    3 (21.4%)                70 (23%)
                                    pT4                                                   5 (35.7%)               139 (45.8%)
 Site                               Hypopharynx                                            3 (21.4%)               32 (10.5%)                   0.013
                                    Larynx                                                5 (35.7%)                94 (30.8%)
                                    Oral cavity                                            3 (21.4%)              164 (53.8%)
                                    Oropharynx                                            3 (21.4%)                15 (4.9%)
 Nodal metastasis                   No                                                     6 (42.9%)              157 (52.1%)                   0.684
                                    Yes                                                   8 (57.1%)               144 (47.9%)
 Extranodal extension               No                                                     5 (62.5%)               47 (34.3%)                   0.135
                                    Yes                                                   3 (37.5%)                90 (65.7%)
 Margins                            R0                                                    8 (57.1%)               158 (77.8%)                   0.101
                                    R1                                                    6 (42.9%)                45 (22.2%)


Historically, consensus in the previous literature reported that                  Mehrad et al. 12, evidence of HPV DNA or p16 was rarely re-
ASCC has a poor prognosis with a tendency for lymphatic                           ported, but better prognosis was hypothesised since no recur-
metastasis 11. Because of its rarity, retrospective series from                   rence was observed in these patients after adequate treatment.
the literature do not include a large number of patients, except                  The main contribution provided by our cohort study is that lo-
for the cohort study by Lee et al. (provided by the SEER da-                      cally advanced disease, and the presence of PNI and positive
tabase), with more than 200 cases collected over 40 years 7.                      margins of resection, are independently associated with worse
From 2002, our Institution had 32 patients diagnosed                              outcomes. Tumour staging has a strong impact on prognosis,
with ASCC, showing a large proportion of males, mostly                            as demonstrated by Lee et al. 7. In our cohort, patients affected
(81.2%) in their 7th-9th decades, confirming previous obser-                      by locally advanced disease, with tumor in pT3-4 categories,
vations reporting a higher incidence in the elderly 5,8, even                     showed a significant reduction of 5-year OS (19.4%) com-
if age appears to play a major negative role in survival, as                      pared to pT1-2 (73.3%), confirming its prognostic role as an
demonstrated by Lee et al. 7 Nevertheless ASCC can occur                          independent factor at multivariable analysis (HR = 4.69).
in younger patients, as previously reported 11-13. The relative                   Conversely, the presence of nodal metastasis, although a
frequency of the sites of origin was confirmed by our data,                       common occurrence (37.5%), was not associated with a
showing the larynx as the most involved site, followed by                         decrease in OS at either univariate or multivariate analysis.
the oropharynx, whereas the oral cavity, hypopharynx, and                         We did not find any report in the literature to confirm this
sinonasal tract were less frequently involved. Interestingly,                     unusual result; the exiguous number of patients involved in
the site of origin was the only feature that significantly dif-                   this study could also explain this discrepancy from previ-
fered from the historic cohort of conventional SCC, show-                         ous studies. Unfortunately, the rarity of this cancer histotype
ing a drastically higher and lower proportion of laryngeal                        makes comparison between larger series difficult to realise.
and oral cavity ASCC, respectively. No difference in terms                        As previously described by Sheahan 13 and Keelawat 1, pa-
of age, gender, margin status, pT and pN categories, five-                        tients with tumour showing PNI experienced a significant
year OS and RFS was found, although the small sample                              decrease in 5-year OS (23.2% vs 76.6%), thus confirming
size of our series limits us from drawing solid conclusions.                      it as an independent negative prognosticator at multivari-
We have not yet identified specific risk factors for the onset of                 ate analysis (HR = 7.81). PNI could explain both marked
this neoplasm; alcohol and smoking, as for conventional SCC,                      tumour aggressiveness and consequent poor prognosis,
can be however involved in laryngeal ASCC 2,4, while the role                     although Kass and colleagues 14 demonstrated that there
of HPV remains unclear. In the cohorts of Masand et al. 8 and                     was no difference in PNI on prognosis between ASCC and



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G. Zigliani et al.




conventional SCC. Even if statistical significance was not           Ethical consideration
met, the rate of positive margins was higher in the ASCC             This study was approved by the Institutional Ethic Commit-
group in comparison to the historical SCC cohort (43% vs             tee (CE Spedali Civili, Brescia) (protocol number: 4267).
22%), reinforcing the need of obtaining wider macroscopic            The research was conducted ethically, with all study proce-
margins in healthy appearing tissue when resecting ASCC.             dures being performed in accordance with the requirements
In fact, the presence of positive surgical margins was sig-          of the World Medical Association’s Declaration of Helsinki.
nificantly associated with a reduction in 5-year OS (30.8%
vs 66.2%), with an independent prognostic role at multi-             References
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AD: writing – review and editing.                                         org/10.1177/019459988108900218




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