10.14639/0392-100X-N1729
The purpose of this review is to analyse the very large number of studies (sometimes con- tradictory) on adenoid cystic carcinoma (ACC). This second part provides a critical analysis of various treatment described in the literature. Anywhere the primary tumour is located, the most common treatment for ACC is complete surgical resection, with or without post- operative radiotherapy (PORT), while conventional photon and/or electron radiotherapy alone and chemotherapy are commonly used in unresectable or metastatic disease. Fast neutron radiotherapy was used in the past with good local results, but the risk of late effects was high and tended to increase over time. Modern carbon-ion radiotherapy seems to be a valid option in selected cases. The quite universally accepted poor prognostic factors are advanced stage, perineural and intraneural invasion, involved margins, and initial presence or later development of neck metastases. The impact of histologic grade on prognosis is controversial. Owing to the long natural history of ACC, the follow-up for patients must be&nbsp;at least 10 years long.
text/xml
1827-675X
1729
en
Giulio Cantù
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
prognostic factors
Adenoid cystic carcinoma. An indolent but aggressive tumour. Part B: treatment and prognosis
Text.Serial.Journal
https://www.actaitalica.it/
41
Reviews
2021-09-14
2021-06-08
2021-09-15
2021-09-15
296-307
1
Giulio Cantù
2021/09/14
10.14639/0392-100X-N1729
296
Former Director of Otorhinolaryngology and Cranio-Maxillo-Facial Unit, Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori, Milano, Italy
1827-675X
prognostic factors
307
Adenoid cystic carcinoma. An indolent but aggressive tumour. Part B: treatment and prognosis
https://www.actaitalica.it/article/download/1729/650
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:296-307; doi: 10.14639/0392-100X-N1729




Review


Adenoid cystic carcinoma. An indolent but aggressive
tumour. Part B: treatment and prognosis
Carcinoma adenoide cistico. Un tumore indolente ma aggressivo.
Parte B: trattamento e prognosi
Giulio Cantù
Former Director of Otorhinolaryngology and Cranio-Maxillo-Facial Unit, Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori, Milano, Italy


SUMMARY
The purpose of this review is to analyse the very large number of studies (sometimes con-
tradictory) on adenoid cystic carcinoma (ACC). This second part provides a critical analysis
of various treatment described in the literature. Anywhere the primary tumour is located,
the most common treatment for ACC is complete surgical resection, with or without post-
operative radiotherapy (PORT), while conventional photon and/or electron radiotherapy
alone and chemotherapy are commonly used in unresectable or metastatic disease. Fast
neutron radiotherapy was used in the past with good local results, but the risk of late effects
was high and tended to increase over time. Modern carbon-ion radiotherapy seems to be a
valid option in selected cases. The quite universally accepted poor prognostic factors are
advanced stage, perineural and intraneural invasion, involved margins, and initial presence
or later development of neck metastases. The impact of histologic grade on prognosis is
controversial. Owing to the long natural history of ACC, the follow-up for patients must be
at least 10 years long.
KEY WORDS: adenoid cystic carcinoma, salivary gland tumors, head and neck cancer,
prognostic factors                                                                                Received: January 12, 2021
                                                                                                  Accepted: May 3, 2021
RIASSUNTO
                                                                                                  Correspondence
Il proposito di questa review è quello di analizzare il grande numero di studi (talvolta
                                                                                                  Giulio Cantù
contradittori) sul carcinoma adenoide cistico. Questa seconda parte presenta una ana-             via Milano 36, 20846 Macherio (MB), Italy
lisi critica dei vari trattamenti descritti in letteratura. Ovunque il tumore primitivo sia       E-mail: gcantu43@gmail.com
localizzato il trattamento più indicato è una resezione radicale con o senza radioterapia
postoperatoria. La radioterapia convenzionale con fotoni e/o elettroni e la chemioterapia         Funding
sono comunemente riservate ai casi inoperabili o metastatici. La radioterapia con neutroni        None.
è stata ampiamente utilizzata in passato con buoni risultati locali, ma il rischio di effetti
collaterali tardivi si è dimostrato alto e con tendenza ad aumentare nel tempo. Il moderno        Conflict of interest
trattamento con ioni carbonio si sta dimostrando una valida alternativa in casi selezionati.      The Author declares no conflict of interest.
I fattori prognostici negativi quasi universalmente accettati sono lo stadio avanzato, l’in-
vasione perineurale e intraneurale, i margini positivi e le metastasi linfonodali alla presen-      How to cite this article: Cantù G. Adenoid
tazione o successive. Il valore prognostico del grading istologico è controverso. Stante la         cystic carcinoma. An indolent but aggressive
lunga storia naturale del carcinoma adenoide cistico il follow-up dei pazienti deve essere          tumour. Part B: treatment and prognosis. Acta
almeno di 10 anni.                                                                                  Otorhinolaryngol Ital 2021;41:296-307. https://
                                                                                                    doi.org/10.14639/0392-100X-N1729
PAROLE CHIAVE: carcinoma adenoide cistico, tumori ghiandole salivari, carcinoma
testa e collo, fattori prognostici                                                                © Società Italiana di Otorinolaringoiatria
                                                                                                  e Chirurgia Cervico-Facciale

Treatment                                                                                                        OPEN ACCESS

                                                                                                  This is an open access article distributed in accordance with
                                                                                                  the CC-BY-NC-ND (Creative Commons Attribution-Non-
Surgery                                                                                           Commercial-NoDerivatives 4.0 International) license. The
Anywhere the primary tumour is located, the most common treatment for ad-                         article can be used by giving appropriate credit and mentio-
                                                                                                  ning the license, but only for non-commercial purposes and
enoid cystic carcinoma (ACC) is complete surgical resection. For the breast,                      only in the original version. For further information: https://
surgery is either a lumpectomy or a simple, radical or modified radical mas-                      creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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tectomy, with or without adjuvant radiation therapy 1,2. The     rifice also in patients without preoperative facial weakness
mainstay of treatment for ACC of the tracheobronchial tree       and T2 tumour 12. However, beyond these extremisms, an
is surgical resection. When the radical resection (R0) is        Italian multicentre study demonstrated that total parotidec-
over risky or may cause mortal complication, the R1 resec-       tomy with or without facial nerve sacrifice was performed
tion (close margins) with adjunctive therapy is acceptable       in 79% of patients with malignant tumours between 1993
for patients to obtain a promising prognosis 3,4. The same       and 2003 13. Conservative total parotidectomy was the most
indications are valid also for the skin 5 and female genital     common operation in the study by Boahene et al. 14 Also in
system 6.                                                        the United Kingdom National Multidisciplinary Guidelines
Surgery is the primary treatment for ACCs arising from           one can find the following sentence: “For small, low-grade
major and minor salivary glands of the head and neck. In         superficial tumours a partial parotidectomy may suffice but
the National Comprehensive Cancer Network (NCCN)                 otherwise a total conservative parotidectomy is advocat-
Guidelines 2019 7 one may find this: “The major therapeu-        ed” 15. One must wonder which improvement of radicality
tic approach for salivary gland tumors is adequate and ap-       may give the resection of few uninvolved glandular acini
propriate surgical resection. Surgical intervention requires     of the deep lobe after having dissected with difficulty the
careful planning and execution, particularly in parotid tu-      tumour from some branches of the facial nerve. Certainly,
mour surgery because the facial nerve is in the gland”. Cer-     this resection implies a greater manipulation of the nerve
tainly, the two adjectives (adequate and appropriate) have       and a higher incidence of facial nerve dysfunction during
been carefully chosen because the radical resection of a         the first postoperative period than superficial parotidecto-
parotid tumour according to the usual rules (free margins        my 16.
≥ 5 mm) is often impossible without the sacrifice of some        The resection of an ACC of the submandibular gland is ap-
branches of the facial nerve. Owing to the complex branch-       parently less problematic, but the surgeon must avoid some
ing and connections of the facial nerve within the parotid,      possible pitfalls. First of all, the gland is surrounded by sev-
a quite small ACC of the superficial lobe of the gland can       eral lymph nodes which may be involved by the ACC. Allen
often approach or come into contact with a branch of the         et al. 17 demonstrated that “when lymph node involvement
nerve. A real radical resection would entail the sacrifice of    does occur, it does not result from embolic lymph node me-
this branch. However, the facial nerve is aesthetically and      tastasis; rather, a direct invasion of the lymph node from
functionally so important that almost all authors agree with     tumour in the perinodal soft tissue occurs”. In a following
the preservation of the nerve when it is possible to dissect     study, Bosch et al. 18 demonstrated that there was a higher
it from the tumour. “The facial nerve should be sacrificed       incidence of neck metastases in ACC of the submandibu-
(and possibly repaired) if there is preoperative nerve in-       lar gland in comparison with the parotid gland and it was
volvement with palsy or if there is direct invasion of the       due to direct extension of the tumour from the gland to the
tumour into the nerve where the tumour cannot be sepa-           adjacent nodes rather than by a classic embolic metastasis.
rated from the nerve” 7. The aforesaid surgical behaviour        For this reason, Batsakis wrote: “In surgical procedures it is
is a compromise between one of the dogmas of oncologic           best to remove the entire nodular and glandular contents of
surgery (clean margins) and aesthetic and functional re-         the submandibular compartment rather than perform par-
sults. Most published studies on head and neck ACC do not        tial excision of the gland” 19. Secondly, it is almost always
report margins status. I found only three studies reporting      possible to preserved the hypoglossal nerve because of its
this datum 8-10. Garden et al. 8 found that 83/198 patients      deep location in the submandibular triangle, but the lingual
(42%) had microscopic positive margins and an additional         nerve is often approached or involved by the tumour be-
55 (28%) had close or uncertain margins. In the study by         cause it crosses the anterior portion of the gland, which lies
Erovic et al. 9, positive surgical margins (i.e. tumour ex-      along its duct. Batsakis 19 reported a particularly high rate
tending to the inked margin of specimen) were identified in      of local recurrence of ACC of the submandibular gland.
38.9% of patients who underwent parotidectomy for malig-         Also for ACCs of paranasal sinuses surgical resection
nant tumours and in 12/20 (60%) patients with ACC. In the        (when possible) with postoperative radiotherapy is the best
study by Lee et al. 10 there was a 50.82% rate of closed or      treatment. The surgical procedure most commonly per-
positive surgical margins.                                       formed is maxillectomy with varying degrees of resection
In the light of the aforesaid uncertain radicality, the debate   of the ethmoid sinus; the resection must be extended to the
between superficial or total parotidectomy is rather point-      orbit and to the skull base when it is necessary. Unfortu-
less. Nevertheless, in the past century some authors ad-         nately, many patients present with very advanced tumours,
vocated total parotidectomy for all benign and malignant         so making difficult to achieve clean margins. In the series
tumours 11, and radical parotidectomy with facial nerve sac-     by Michel et al. 20 65% of operated patients had positive



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G. Cantù




surgical margins on histological examination of the opera-       ing was correct in 68% and 71% of the cases, respectively.
tive specimen. The same rate of positive margins is report-      Therefore, they settled the question suggesting “a routine
ed by Miller et al. 21. Cantù et al. 22 achieved clean margins   END in all primary carcinomas of the parotid glands. The
in 56.5% in a series of patients with very large maxillary       neck dissection can easily be incorporated into the surgi-
ACC invading the middle cranial fossa (T4b).                     cal approach with practically no additional morbidity and
The surgical approach for the resection of an ACC of the         only a slight increase in operative time” 32. I believe that
oral cavity depends on the subsite of the tumour. The hard       the spinal accessory nerve does not enjoy this statement.
palate is the most commonly involved subsite in almost all       Other authors demonstrated that the rate of regional metas-
published series 23-26. Owing to the infiltrative submucosal     tases is quite low and does not justify a systematic elective
grown of ACC, it can infiltrate the underlying bone and          neck dissection 33. A review of 18 studies involving 2993
invade the sinonasal cavities. The resection of the tumour       patients demonstrated that ACCs of minor salivary gland
may require a subtotal or total maxillectomy.                    have a higher cervical lymph node metastases rate in com-
The most common site of origin of ACCs of the oropharynx         parison with major salivary glands. Therefore, the authors
is the base of tongue. For rare small tumours it may be pos-     suggested that END might be applied only to ACC of minor
sible a transoral resection or, nowadays, a transoral robotic    salivary glands 34. On the contrary, a review on the manage-
resection. On the contrary, a pull-through or a mandibul-        ment of minor salivary gland carcinoma concluded that the
otomy approach is required for the frequent large tumours        occult metastasis rate, as evidenced by the appearance of
involving both the base and the mobile tongue. In these          metastasis in the untreated N0 neck, is too low to justify
cases a reconstruction with pedicled or microvascular free       END, except in patients with high-grade cancers such as
flaps is mandatory.                                              high-grade MEC 35. Another review concluded that only in
Partial laryngectomy is rarely possible for the resection of     some oral and oropharyngeal locations does occult nodal
ACCs of the larynx. Unfortunately, total laryngectomy is         involvement approach > 20%, reaching the level normally
the most frequent surgical treatment.                            used to justify END 36.
Considering that the surgical treatment of the neck is in-       The peculiarity of this controversy is that all authors re-
dicated when there is clinical evidence of regional metas-       port quite the same rate of neck node metastases in cN0
tasis or when the resection of the primary tumour implies        neck (between 13% and 20%). Different opinion lies in
a trans-cervical approach, the management of a clinically        considering high or low these rates. Moreover, some stud-
node-negative neck (N0) in this context remains controver-       ies demonstrated that every type of neck dissection implies
sial, mainly for malignancies of the parotid gland. Should       possible iatrogenic damage (mainly to the spinal accessory
an elective neck dissection (END) be performed or is a           nerve) 37-39. Therefore, the most important question is: how
wait and watch policy safe and adequate? This question has       much END in cN0 patients can improve the overall (OS)
been a contentious issue spanning five decades. In fact, En-     and/or disease free survival (DFS)? Unbelievably, almost
eroth et al advocate radical neck dissection for all tumours,    all authors did not find any difference between patient
even without clinically involved lymph nodes, except for         treated and those observed. “END of cN0 patients does not
low grade MEC 27. On the contrary, some other authors 19,28      provide any benefit on event free survival, which suggests
demonstrated that only the high-grade adenocarcinomas,           that its application on such patients is not necessary” 33.
MEC, and carcinomas ex pleomorphic adenoma manifest              “There was no significant enhanced survival in the group
a significant lymphatic spread. The question is not yet          of patients who underwent END” 40. “Although END is as-
solved. Also in more recent years, many authors advocate         sociated with a prolonged regional recurrence-free period,
END only for high stage (T3/T4) and/or high grade tu-            its influence on final outcome or survival is still controver-
mours (salivary duct carcinoma, adenocarcinoma, and high         sial” 41. “In the majority of patients (65%), the neck was
grade MEC) 10,29-31. Almost always ACC is left in an doubt-      observed rather than treated electively, with no impact on
ful position.                                                    overall survival. These data support our policy of reserv-
However, there is an unsolved problem: while it is easy to       ing END only for those histologic diagnoses that carry the
know preoperatively the stage of the tumour, it is often im-     highest risk of nodal metastases, as well as for selected pa-
possible to know its grade and, sometimes, even its histol-      tients whose primary tumour resection might be facilitated
ogy. As above mentioned, FNAC has a low diagnostic po-           by lymphadenectomy” 42. As sometimes happens, one can
tential for tumour typing and grading. Zbären et al. 32 found    find controversial conclusions in two analyses of the same
that in their series the tumour typing and grading by FNAC       series. “Our findings support the consideration of END in
was accurate in 50% and 45%, respectively. Moreover, even        patients with ACC of the oral cavity” 43. “Statistical analy-
with intraoperative frozen section tumour typing and grad-       sis showed no survival advantage for patients who under-



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went END compared with those who did not” 44. The real           included in END or extent of therapeutic neck dissection
value of END in N0 ACC has been stated by the following          for parotid malignancies.
sentence. “Although END itself did not have beneficial ef-       An interesting study by Chisholm et al. 47 tried to solve the
fects on distant metastasis or survival, END can provide         question. The objective of their study was to ascertain the
valuable staging and prognostic information” 10.                 distribution pattern or topography of cervical nodal metas-
Fortunately, two studies with large series of patients made      tases from primary parotid carcinomas. They reviewed 474
a good contribution to settle the question of END for pa-        articles reporting neck metastases and found only 2 studies
rotid malignancies. Lim et al. 45, analysing a series of 86      reporting the topography of nodal disease in cN0 patients
patients with parotid cancer, demonstrated that using in-        undergoing prophylactic neck dissection 48,49. The data from
traparotid lymph node metastasis status to predict cervical      these 2 series were combined with their own data to form
nodal metastasis resulted in a sensitivity and specificity       a virtual series of 66 cases of primary parotid carcinoma
of 70% and 90.6%, respectively (positive predictive value        with cervical nodal spread. The results demonstrated that
of 87.3%). However, a recent review on this topic raised         the overall distribution of cervical disease in primary pa-
the objection that intraparotid lymph node metastasis may        rotid carcinoma is diffuse: level I 28%, level II 59%, level
not be first echelon lymph nodes for regional spreading in       III 52%, level IV 38%, and level V 41%. Moreover, 17%
all cases. “It is imaginable that if the tumour is located in    of patients had single nodes (N1 or N2a), levels I and V
the far inferior part of parotid gland, level IIa or IIb lymph   were only involved in conjunction with other levels, level
node metastasis might regularly occur without intraparot-        IV was involved by itself in 2 cases, one patient had level
id lymph node metastasis” 46. The study by Erovic et al. 9       II and IV disease without any involvement in the interven-
overcame this objection. In their series of 215 patients with    ing level III. The authors concluded that these data point
parotid cancer, all patients underwent parotidectomy and         away from the use of the often recommended supraomohy-
resection of the lymph nodes surrounding the inferior lobe       oid neck dissection as an oncologically safe procedure in
(periparotid nodes). These lymph nodes were macroscopi-          therapeutic END for primary parotid carcinomas, because
cally examined and enlarged nodes were sampled and, if           the diffuse distribution of cervical nodal metastases does
frozen section examination confirmed metastases, an ap-          not support a high echelon neck dissection or radiotherapy
propriate neck dissection was performed. Lateral neck me-        fields limited to the upper chain in the management of cer-
tastases were more common in cases with positive peripa-         vical nodal disease.
rotid nodes than in those that did not. In addition, almost      Among frequent, and sometimes late, distant metastases
half of the patients with a positive periparotid node were       (DM) the most commonly involved site is the lung 50,51.
staged clinically as being N0. Thus, a decision for END          Moreover, lung metastases are distinct from other sites be-
may be made at the time of surgery on identifying a peri-        cause they often progress slowly and show symptoms only
parotid node and evaluating for metastases on frozen sec-        after a long time, unlike the behaviours of distant metasta-
tion analysis. Interestingly, periparotid nodal metastases       ses in other organs. Lung metastases in ACC are asympto-
were most commonly noted with salivary duct carcinomas           matic and lung function can be retained for a long period
(61%). This was followed in frequency by adenocarcinoma          of time 52. Hence, is their surgical resection worthy? The
(22.7%), MEC (17.9%), acinic cell carcinoma (8.2%), car-         opinions about this treatment are conflicting. Spiro 53 in
cinoma ex pleomorphic adenoma (6.7%), and ACC (3.9%).            1997 wrote: “Considering that lung metastases are usually
Another unsolved question is the appropriate type of neck        multiple, and prolonged survival without treatment is not
dissection for parotid malignancies. Apart from the histori-     unusual, resection of pulmonary metastases may be hard
cal treatment with prophylactic radical neck dissection 27,      to justify in ACC patients based on the limited experience
in more recent years most authors advocate a selective neck      thus far reported”. On the contrary, Locati et al reported a
dissections for cN0 cases. “Levels II to IV were regularly       series of 20 patients with lung metastases and concluded
removed for parotid tumours, levels I to III for subman-         that lung metastasectomy provided a prolonged freedom
dibular and sublingual tumours, and levels I to IV for minor     from progression in a high selected subset of patients with
gland tumors” 29. “If performed, END should be limited to        ACC (patients with a disease-free interval ≥ 36 months, ≤ 6
levels I-III of the ipsilateral neck since occult metastases     metastases, and monolateral lung involvement) 54. A more
are exclusively located within these neck regions” 41. Un-       recent study on 109 patients from the International Reg-
fortunately, all these statements are not supported by undis-    istry of Lung Metastases demonstrated that lung metasta-
putable proofs. Due to the rarity of parotid malignancies,       sectomy should be considered as a therapeutic option to
the data on topography of nodal disease is scarce. Hence,        achieve local control of disease when 2 conditions are met:
there is no consensus as to which nodal levels should be         (a) complete surgical resection is feasible and (b) the time



                                                                                                                            299
G. Cantù




to pulmonary relapse after primary tumour treatment is            of neck control at 5 years in the two groups was quite the
greater than 36 months 55.                                        same (97% vs 98%). A following study by the same centre
                                                                  concluded that elective nodal irradiation should be consid-
Radiotherapy                                                      ered for primary sites located in lymphatic-rich regions,
Postoperative radiotherapy (PORT) is almost always used           namely the submandibular gland 66.
for ACC. As far as 1977, Osborn 56 wrote: “All cases were         Mendenhall et al. 57 investigated the efficacy of RT alone
treated by varying combinations of surgery and irradiation,       in the treatment of head and neck ACC. They started by
the former usually preceding the latter though not neces-         saying that “comparison of the efficacy of RT alone with
sarily of a radical nature in the first instance”. Since then,    that of surgery and RT is hampered by selection bias; pa-
many other authors confirmed this indication. Mendenhall          tients with early-stage lesions that are resectable tend to
et al. used PORT, regardless of margin status and site of the     undergo surgery, whereas those with advanced, unresect-
tumour, in essentially all cases, except for the occasional       able cancers tend to be treated with RT alone. The 10-year
patient with a grade 1 T1N0 lesion resected with widely           outcomes after RT vs surgery and RT were as follows: local
negative margins 57. Other authors concluded that PORT            control, 43% vs 91%; absolute survival, 42% vs 55%; and
“with a dose of at least 60 Gy is indicated for patients with     cause-specific survival, 48% vs 71%” 57.
T3-4 tumours, incomplete or close resection, bone inva-           In 1987, Catterall et al. 67 first presented a series of 65 ad-
sion, perineural invasion, and pN(+)” 58. Also the analysis       vanced or recurrent salivary glands tumour treated by fast
of thousands cases from the SEER by Mahmood et al. dem-           neutron radiotherapy. Local control and 5-year survival
onstrated that PORT is associated with improved survival          rates were 72% and 50%, respectively. After then, some
for high-grade and/or locally advanced malignant major            other studies on neutron radiotherapy for head and neck
salivary gland tumours 59. The same conclusion has been           ACC have been published. The results were encouraging in
drawn by Safdieh et al. analysing as many as 4,068 major          almost all the patients. However, a study presenting a large
salivary glands malignant tumours from the NCDB 60. Lee           series of 84 patients with ACCs of minor salivary glands
et al. 61 analysed 1,784 cases of ACC from the NCDB and           reported that: “Patients without involvement of the cavern-
concluded that PORT for salivary ACC was associated with          ous sinus, base of skull, or nasopharynx (51 patients) had a
improved survival even for those with early-stage disease.        5-year actuarial local-regional control rate of 59%, whereas
Moreover, they found that there was no survival benefit           local-regional control was significantly lower (15%) for pa-
for intensity modulated radiotherapy (IMRT) over three-           tients with tumours involving these sites” 68. A following
dimensional radiation therapy. Garden et al. 8 demonstrated       paper presented a very large series of patients with sali-
that patients with positive margins had an improved likeli-       vary glands neoplasms treated with curative intent using
hood of local control with RT doses of 56 Gy or more (88%         fast neutron radiotherapy after previous surgical resection.
vs 40%). However, it is worth noting that some of these           Of the 279 cases of the series (ACCs 68%), 263 had evi-
studies 58-60 analysed all salivary malignant tumours, and        dence of gross residual disease, 141 and 138 had tumours
that two studies using national population-based data dem-        of the major and minor salivary glands, respectively. Pa-
onstrated that PORT does not significantly affect patient         tients without skull base invasion had a statistically signifi-
survival outcomes 62,63.                                          cant improvement in cause-specific survival 69. Two studies
Another vexed question is whether and when it appears jus-        compared neutron to conventional photon and/or electron
tified the inclusion of the neck in the fields of radiotherapy.   radiotherapy for the treatment of advanced salivary gland
Obviously, all authors agree with PORT on the neck in             tumors 70 and, in particular, salivary glands ACC 71. Both
cases with cervical lymph node metastases, mainly in cases        studies demonstrated a statistically significant difference in
with extracapsular spread 64. On the contrary, elective neck      the local-regional control (56% vs 17%, and 75% vs 32%),
RT on cN0 neck is more controversial. Authors supporting          although no improvement in survival was seen. Most stud-
END underline that negative nodal findings will allow the         ies did not report the rates of late complications of neu-
postoperative radiation field to be limited to the primary        tron radiotherapy. A study on 140 cases found that post-
site 32. Other authors advocate performing a neck dissection      treatment trismus occurred in 56%, acute mucositis and
only in cases of a clinically or radiologically determined        xerostomia occurred in approximately 88% and 89% of
presence of lymph node metastases and support the view            patients, respectively, and osteoradionecrosis was reported
that radiation therapy is adequate for treating subclinical       in 5.7% of patients 72. In the version 2.2019 of the NCCN
disease 65. However, in the series of ACC with a clinically       guidelines for head and neck tumours 7, there is the follow-
negative neck presented by Mendenhall et al. 57, 33 patients      ing statement: “Results from a retrospective cohort study
were observed, and 55 received elective neck RT. The rates        including 545 patients with salivary gland tumours treated



300
                                                                                                       Adenoid cystic carcinoma




between 1997 and 2010 showed better local control and           neutron therapy as a general solution for salivary glands
survival outcomes with neutron therapy, relative to photon      cancers due to the diminishing demand, concerns regard-
therapy 73. However, risk of late effects with neutron ther-    ing methodologic robustness of randomised trial data, and
apy is high and tends to increase over time, with estimates     closure of all but one center in the United States” 7.
as high as 20% at 9 years. The panel no longer recommends       The second heavy particle therapy is proton radiotherapy.




  Treatment

  Surgery
  • Wherever the primary tumour is located, the most common treatment for ACC is complete surgical resection ±
    postoperative radiotherapy (PORT).
  • Owing to the complex branching and connections of the facial nerve within the parotid, also a quite small ACC of
    the superficial lobe of the gland can often approach or come into contact with a branch of the nerve. Therefore, the
    radical resection of a parotid tumour according to the usual rules (free margins ≥ 5 mm) is often impossible without
    the sacrifice of some branches of the nerve. Microscopic positive or close margins were between 40% and 70% in
    some important studies reporting these data.
  • In the light of the often uncertain radicality, the debate between superficial or total parotidectomy is rather point-
    less because one must wonder which improvement of radicality may give the resection of few uninvolved glandular
    acini of the deep lobe after having dissected with difficulty the tumour from some branches of the facial nerve.
  • For the submandibular gland the limit of radicality may be the lingual nerve and, in the paranasal sinuses, the exten-
    sion of the tumour to the skull base and along the II branch of the trigeminal nerve.
  • The surgical approach for the resection of an ACC of the oral cavity depends on the subsite of the tumour. The resec-
    tion of a tumour of the hard palate may require a subtotal or total maxillectomy. For rare small tumours of the base
    of the tongue it may be possible a transoral resection or, nowadays, a transoral robotic resection. On the contrary,
    a pull-through or a mandibulotomy approach is required for large tumours involving both the base and the mobile
    tongue. In these cases a reconstruction with pedicled or microvascular free flaps is mandatory.
  • The surgical treatment of the neck is indicated when there is clinical evidence of regional metastasis or when the
    resection of the primary tumour implies a trans-cervical approach. On the contrary, the management of cN0 neck
    remains controversial, mainly for malignancies of the parotid gland.
  • The resection of the frequent lung metastases should be considered as a therapeutic option to achieve local control
    of disease when 2 conditions are met: (a) complete surgical resection is feasible and (b) the time to pulmonary re-
    lapse after primary tumour treatment is greater than 36 months.

  Radiotherapy
  • PORT is almost always used for ACC, mainly for patients with T3-4 tumours, incomplete or close resection, bone
    invasion, perineural invasion, and pN+. However, two studies using national population-based data demonstrated
    that PORT does not significantly affect patient survival outcomes.
  • Radiotherapy alone is generally used for patients with advanced, unresectable tumours, with low rates of local
    control.
  • Two studies demonstrated an improvement in the local-regional control using fast neutrons or protons in compari-
    son with conventional photon and/or electron radiotherapy. However, risk of late effects with neutron therapy is
    high and tends to increase over time.
  • The most recent heavy particle therapy is carbon ion radiotherapy (CIRT), that demonstrated to be a good option
    for unresectable or uncompleted resected ACC.

  Chemotherapy and targeted therapy
  • A review of 114 publications on chemotherapy and targeted therapy concluded that the reported response rates were
    low and response duration generally short lived.



                                                                                                                          301
G. Cantù




The first proton beam accelerator used for therapeutic ser-        Prognostic factors and outcomes
vice was that of Loma Linda University (1990). Proton
                                                                   Because of the relative rarity of ACC, it is highly unlikely
radiotherapy has demonstrated a good local control of the
                                                                   that the various prognostic factors and treatment options
disease and a better toxicity profile compared to neutrons.
                                                                   could be compared in a clinical trial. Moreover, it is dif-
However, the series of patients treated with protons are
                                                                   ficult to learn indisputable data on outcomes from the lit-
smaller than those with neutron, and present almost only
                                                                   erature because many studies report DFS and OS only at
ACC involving the skull base and lacrimal gland 74-76. Bhat-
                                                                   5 years, that is a too short follow-up. It is well known that
tasali et al. 77 presented a small series of 9 patients with un-
                                                                   the natural history of ACC is characterised by an indolent
resectable head and neck ACC receiving definitive proton
                                                                   growth rate and a high likelihood of hematogenous late dis-
RT and concurrent cisplatin, and concluded that this treat-
                                                                   semination. In the series presented by Mendenhall et al. 57,
ment is a good options for these patients.
                                                                   the cumulative percentage of recurrences observed at vari-
The last heavy particle therapy is carbon ion radiotherapy
                                                                   ous points in time after treatment were: 5 years, 73%; 10
(CIRT). The first centre offering CIRT has been open in
                                                                   years, 91%; 15 years, 96%; 20 years, 98%; and 25 years,
1994 in Chiba (Japan). Among several types of ion species,
                                                                   100%. Eneroth et al. 82, in a historical study, reported the
carbon ions were chosen for cancer therapy because they            following rates of determinate survival for parotid ACC: 5
were judged to have the most optimal properties in terms           years, 73%; 10 years, 39%; 15 years, 21%; and 20 years,
of superior physical and biological characteristics 78. As of      13%. In the more recent study by Ellington et al. 62 the
March 2010, 5,196 patients have been treated at the Chiba          overall 5-year, 10-year, and 15-year survival estimates for
centre. Nowadays, CIRT has become a well-known non-                all stages were 90.34%, 79.88%, and 69.22%, respectively.
invasive local treatment for solid cancer. Unfortunately, few      All historical and recent studies demonstrated that advanced
other centres offering carbon ion radiotherapy have been           stage is the worst prognostic factor. Spiro et al. 83 found that
opened in the world, among which there is the CNAO in              the cumulative 10-year OS was 75%, 43%, and 15% for
Pavia (Italy). By pathological type, CIRT is effective against     stage I, stage II, and stage III-IV patients, respectively. The
non-squamous cell types of tumours for which photon                disease specific survival at 10 years was as high as 94% in
beams are minimally effective, including adenocarcinoma,           patients with stage I disease. In more recent years, Marci-
ACC, hepatocellular carcinoma, malignant melanoma,                 now et al. 84 and Mays et al. 85 reported very similar results
bone, and soft-tissue tumors 78. CIRT is also a good option        for ACC of both major and minor salivary glands 84, and for
for retreatment of inoperable recurrent salivary gland             ACC of the sinonasal cavity 85.
tumours with acceptable rates of acute and late toxicity 79.       The impact of histologic grade on prognosis is controver-
                                                                   sial. Many studies demonstrated a worse prognosis for
Chemotherapy and targeted therapy                                  cases with solid histological type in comparison with tu-
In a review on the reported efficacy of various chemother-         bular type 20,85-87, while other studies demonstrated just the
apy regimens and molecular therapies on recurrent/meta-            opposite 19,83. However, it is proper to specify that the 3 his-
static salivary gland ACC, Dodd and Slevin 80 examined             tologic component of ACC (cribriform, tubular, and solid)
114 publications on chemotherapy and possible molecular            are often mixed in the tumour. In fact, Mays et al. 85 found
targets of therapy, including KIT, epidermal growth fac-           solid variant in 38% of their 160 cases, but only 10% of pa-
tor receptor (EGFR), human epidermal growth receptor-2             tients revealed predominantly solid type histology. Finally,
(HER-2), oestrogen and progesterone receptors, proliferat-         Seethala 88, wondering the usefulness of the grading, wrote:
ing cell nuclear antigen (PCNA), Ki-67 and the p53, bcl-2          “While prognostically useful, it is unclear whether grad-
and SOX-4 genes. The conclusions of the authors were that          ing of ACC is useful in patient management. Regardless
the reported response rates to combination chemotherapy            of grade, all ACCs are treated with surgery plus irradiation
were low and response duration generally short lived.              because locally they are aggressive and ‘high risk’”.
Moreover, no standard chemotherapy regimen could be                Perineural invasion (PNI) has turned out to be a bad prog-
recommended. However, Andry et al. 81 reported that for            nostic factors in most studies 8,84. Marcinow et al. 84 identi-
recurrent and/or metastatic cancer, polychemotherapy (cis-         fied PNI as a poor prognostic factor for DFS, but not for
platin based) gives a 25% response rate in ACC and should          OS. They hypothesised that the lack of significant impact
be used when the disease is overtly in progression. The            on OS in these patients may be secondary to the indolent
response to targeted therapies with anti-EGF (epidermal            nature of ACC with frequent recurrences but overall good
growth factor) receptor molecules, antiangiogenic agents           long-term survival. Garden et al. 8 found that PNI was an
and tyrosine kinase inhibitors is also low.                        adverse prognostic factor only when a major (named) nerve



302
                                                                                                              Adenoid cystic carcinoma




was involved. Amit et al. 89 reported that PNI by itself was         Eskander et al. 95 analysed 17 studies examining a volume-
not predictor of outcome, whereas intraneural evidence of            outcome relationship in the treatment of patients with head
cancer was independent histologic sign of poor survival.             and neck cancer with meta-analysis for long-term survival
Few studies analysed the impact of involved margins in               results, and found that high-volume hospitals and high-vol-
ACC of the head and neck, and, mainly, the impact of                 ume surgeons have better overall survival than low-volume
close margins. Almost all studies found positive margins             hospitals and surgeons, respectively. These data support
to significantly worsen survival. However, many authors              the concept of centralisation of complex surgical proce-
consider positive and close margins jointly in follow-up as-         dures at centres able to meet minimum volume thresholds
sessment. Moreover, which is the required width of normal            to improve patient outcomes. Ciccolallo et al. 94 found that
tissue around the tumour for ACC? In head and neck squa-             10-year survival in Eastern Europe (56%) was lower than
mous cell carcinoma (SCC), margins that are < 5 mm are               in Northern Europe (69%) and hypothesised that “multi-
defined as close. Some recent studies demonstrated that the          disciplinary specialist care is well developed in much of
commonly used cut-off of 5 mm for a close margin lacks               Northern and Western Europe, whilst in some Eastern Eu-
an evidential basis in predicting local recurrence for head          ropean countries cancer services are often provided by un-
and neck SCC, and that local recurrence-free survival was            specialised professionals and access to imaging (CT, MRI)
significantly affected only with surgical margins ≤ 2.2 mm           or enrolment in clinical trials may be limited”.
in patients with oral tongue SCC 90,91. Hence, it is correct         The initial presence or later development of neck metasta-
to take the parameter of 5 mm for ACC? To the best of                ses is generally considered to be an unfavourable prognos-
my knowledge, only two studies analysed specifically the             tic factor for head and neck squamous cell carcinomas, and
impact of close margins in ACC of the head and neck. In              also for ACCs 84,94,96. The presence of subclinical or clini-
a series of 198 patients, Garden et al. 8 found that 18% of          cal nodal metastases in ACCs, that rarely have a regional
patients with positive margins developed local recurrences,          spread, is the effect of an intrinsic biological aggressive-
compared to 9% of patients with close or uncertain mar-              ness of the tumour, and may be a predictive factor for dis-
gins, and 5% of those with negative margins (p = 0.02). In           tant metastases.
an International collaborative study of 507 patients, Amit et        Like all head and neck cancers, also for ACC older age and
al. 92 demonstrated that positive margins are associated with        comorbidities significantly correlate with worse DFS and
the worst outcome, whereas negative and close margins are            OS in most studies 62,84,94. The impact of sex in the clini-
associated with improved outcome, regardless of the dis-             cal outcome of head and neck ACC is controversial. The
tance from the tumour. The presence of close margin status           largest epidemiologic studies seem to suggest that women
resulted in similar outcome as negative margins for ACC of           have better prognosis compared with men 62,94. According
all sites examined except the oral cavity.                           Ellington et al.: “The sex-specific survival differences raise
The primary site of ACC has been reported as a prognostic            the possibility that hormonal influences may be at play. In
factor by most previous studies, with minor salivary gland           addition, it is plausible that women could be more apt to
tumours having a worse prognosis when compared to ma-                adhere to the treatment plan or tolerate the treatment” 62.
jor salivary gland tumours. However, among minor gland               However, in another study, female sex was a prognostic
ACCs, some studies found significantly worse survival in             factor for higher rate of ACC recurrence 84. The study by
tumours originating in the sinonasal cavity in comparison            Ellington et al. also revealed a better prognosis among
with those originating in any other area of the head and             married individuals compared with a combined group that
neck, like the oral cavity 8,85,92,93. There is a plausible expla-   included never married, widowed, divorced, and separat-
nation for this difference. A radical resection of a tumour          ed patients 62. The association between marital status and
of the paranasal sinuses is often limited by the proximity           outcome is a previously described phenomenon reported
to skull base, restricting the limit of resection 22,92. As proof    across several cancer sites.
of this surgical difficulties, Mays et al. demonstrated that         As previously discussed, ACC is an indolent but aggres-
those patients with tumour epicentre in a sinus had worse            sive tumour with a high incidence of DM. In fact, about
OS than other subsites of epicentre on both univariate anal-         10-15% of patients have DM at presentation 62 and distant
ysis and multivariate analysis 85. ACCs of the breast and            metastatic spread will occur in approximately half of the
skin have favourable prognosis with excellent survival 93,           patients 97. Sung et al. 98 found that DM occurred in 48% of
unlike those of the tracheobronchial tree 94.                        patients and developed more frequently in patients with tu-
The “surgeon” and “hospital” factors have not been taken             mours of the solid histologic subtype than in patients with
into account in most studies. The resection of a large ACC           tubular or cribriform subtypes. Moreover, DM occurred
is a difficult challenge, especially in the paranasal sinuses.       less frequently in the minor salivary glands of the sinona-



                                                                                                                                 303
G. Cantù




  Prognostic factors and outcomes
  • Because of the relative rarity of ACC, it is highly unlikely that the various prognostic factors and treatment options
    could be compared in a clinical trial. Moreover, many studies report the overall survival only at 5 years,which is too
    short. In a recent study on ACC of the head and neck, the overall 5-year, 10-year, and 15-year survival estimates for
    all stages were 90.34%, 79.88%, and 69.22%, respectively.
  • The advanced stage, the perineural and intraneural invasion, the primary site, involved margins, and the initial pres-
    ence or later development of neck metastases have been reported to be bad prognostic factors by most studies. The
    impact of histologic grade on prognosis is controversial.



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