Cancers that arise from the parotid and submandibular
gland have a similar natural history and the two glands can be addressed as a
single entity with distinctions imposed by local structures such as the facial
nerve. Salivary gland cancer is uncommon ( 1x 106 annum) but
paradoxically it is a topical surgical subject. Even in an established cancer centre individual experience is limited.
The situation is compounded by the long natural history of these cancers
with decades of follow up required to obtain informative data. This combination reinforces the status quo. One development that has
occurred over the last 2 decades has been the recognition that size, and tumour
grade are more important than histological type in determining outcome.
Parotid and submandibular cancers have an annual
incidence of 1 - 1.1 and 0.2- 0.3
cases per 106 population 1,2,3,4,5
In the English population of 54.7 million, only 2 children between 1-9y, and 9
between 10-19y developed a major salivary cancer in 2014. A rise in incidence
occurs abruptly at about 30-40y and continues with increasing age ( Fig I).
Delayed diagnosis is a feature of
salivary cancer with an average delay of about 6-8m from symptom recognition to
diagnosis. This period is longer for the indolent tumours such as acini cell and
adenoid cystic carcinoma were the delays are typically 10-15m1,2.
The distribution of salivary neoplasms (benign &
malignant) adheres to the 10:1:1 rule (10 parotid tumours, 1 submandibular, 1
minor salivary gland). What
is new is the estimated risk of malignancy at each site. A study extending over
2 decades showed the risk of malignancy in the parotid and submandibular glands
was 10% & 30% respectively6 .
Salivary cancer has been categorised into 24 types but
in practical terms the big four are adenoid cystic ( ~ 26%), mucoepidermoid ( ~17%), acinic cell
(~ 14%) and adenocarcinoma NOS(11%) 1,2,6 . Despite subtle differences in the distribution of histological types
between the parotid and submandibular gland 7 (more adenoid cystic
carcinoma in the latter) the outcome is similar 8,9,10
Biology and Biomarkers
tissue has a propensity for pleomorphism. The
current classification recognises 13 varieties of benign and 24 malignant
epithelial neoplasms 11. A
classification should denote tumour types with a distinct natural history.
Treatment can then be tailored to these characteristics. Rarity and lack of long follow up means this element is missing in new
classifications. Certain gene translocations have been identified in specific
salivary cancers; MECT1-MAML2 in mucoepidermoid carcinoma, MYB-NFIB in adenoid
cystic carcinoma, ETV6-NTRK3 in mammary analogue secretory adenoma12,13.
The hope is that the molecular changes may in time offer targets for therapeutic
intervention14 . Proliferation markers, appear to have prognostic
potential but their therapeutic role remains unclear. Unfortunately salivary
gland cancers have not proved susceptible to targeted molecular therapy as yet15,16,17
Cell Cancer (SCC) of the Parotid Gland.
the context of major salivary gland cancer the occurrence of primary SCC is an
anomaly. It follows none of the pattern describe by typical salivary cancers. By
comparison it is aggressive, it rapidly infiltrates the salivary gland and has a
proclivity for early lymphatic metastasis. The surgical response has to be rapid
for any delay adds further threat to the facial nerve.
These cancers are common in elderly males18
Tumour grading is an important prognostic factor but is
derived from 3 different sources, two are subjective in nature. The first arises
from histological evaluation of tumour architecture. The features then have high
and low grade biological properties attributed to them. This process can only
usefully identify high and low grade mucopepidermoid carcinomas 19 20,21.
The second is to use the natural history to define aggression -high grade ( MEC,
SDC, SCC, Ca ex pleomorphic adenoma,
adenoma NOS) , Intermediate ( ACC,
epithelial myoepithelial carcinoma) and low grade groups (ACN, polymorphous
low-grade and low grade MEC). The
final and by far the most relevant method of judging biological nature is to use
clinical features. Tumour that grow rapidly or are attached to local structure,
invade nerves or have metastasis have aggressive biological qualities
irrespective of their histological grade or tumour type. These features are now
built into the Staging system (Table 1). The recognition that tumour grading has 3 origins is important because
the term is used interchangeably in daily practice without acknowledgement of
the different values of the term.
The initial investigation of choice for salivary gland
lumps is US. It reliably establishes if a mass arises from the salivary gland or
adjacent structures 23*. It
is prudent to sample masses in the parotid and in particular submandibular gland
by US guided FNAC or true cut biopsy23 and is especially useful in
unveiling low grade malignant tumours masquerading as benign lumps 24.
CT or MRI are used routinely to assess malignant lumps
in the salivary glands. Initially there was little difference in diagnostic
ability between CT and MRI but gradually MRI has superseded the latter. They
also provide additional information on the status of the neck and chest. The problem of visualising the nerve has been solved by high resolution
emission tomography ( PET) does not distinguish between benign and malignant
salivary tumours. It has a role in advance or recurrent disease where
dissemination of tumour is expected and wide local spread is encounter. In is more accurate than CT at delineating the edge of the tumour when
the lesion is surrounded by scar tissue or oedema 26.
There are 3 clinical scenarios where misdiagnosis of a
salivary cancer is a recurring theme. Approximately 40% of salivary cancers are
indolent in nature. Malignancy features slowly appear as the lesion enlarges.
Error is with small tumours. A positive message for the minimally invasive
surgeon, who may encounter these lesions inadvertently, is
that this group of cancers rarely recur or pose a threat to the patient27,28 .
The second diagnostic pitfall relates to ACC. It has a
propensity to throw beads of cells around peripheral nerves. This can result in intermittent neurogenic pain29,30 and
divert attention to the tempromandibular joint (TMJ). If a neurotic label is attributed, then delayed diagnosis is the rule.
final recurring problem is the low threshold for submandibulectomy in some units22,31.
About a third of patients referred with submandibular masses are referred after
inadequate primary treatment32 with survival reduced by 20% compared to the parotid gland. This negative
effect is reversed if the patients has an appropriate surgical intervention as
their first procedure 33,34,35,5 .
A feature of salivary gland cancer is that treatment
has to be tailored to each patient. A
wide range of factors have been linked to outcome, the most important are size
of tumour , clinical grade (soft tissue and nerve invasion, pain, fixity), node
status, male gender and age. The histological type of tumour is not as important as previously
perceived. These factors have been incorporated into a useful predictive model
that provides prognostic data on individual patients with parotid cancer 36
instances theoretical concepts and nuances of treatment are overtaken by
practical issues. The prognostic cut off point is set at 4cm. In the absence of
any features of local invasion, nerve involvement or metastasis then these
tumours represent biologically indolent tumours with a good prognosis. Especially when small, they masquerade as benign lumps. Small tumours
even if high grade by histological type still do well and this observation
extends to ACC37.
it is the small malignant salivary tumours (Stage
I &II) that pose a treatment dilemma. Here is an opportunity to de-escalate
treatment. Most authors recommend total parotidectomy for high-grade tumours,
tumours of the deep lobe or tumours greater than Stage I. But as early as 1975 Spiro reported that 58% of malignant parotid tumours
treated primarily in their institution has less than a total parotidectomy.38
Mamelle proposed that for low grade
T1 tumours in the lower pole of the parotid a procedures less than a superficial
parotidectomy may be adequate to maintain optimum outcome39
In contrast an argument has been made for total
parotidectomy, in case of metastasis to deep intra parotid lymph nodes 40.
The threat from intra parotid lymph nodes has not materialised. To temper
the discussion, clinical experience demonstrates a low local recurrence rate for
primary tumours in the parotid treated with less than a total parotidectomy.
This might be explained by the low threshold for adjuvant radiotherapy at this site
Recently attention has turned to management of the N0
neck. It is increasingly apparent the incidence of occult metastasis in the neck is quite high ( ~25%) even
for histological low grade or T1 & II disease 42,43. The dilemma
applies mainly to parotid tumours (submandibular cancers are removed with some
form of neck dissection) and only really in patients with Stage I & II
disease. Until techniques for
sampling the parotid and neck, such as sentinel node biopsy, become the norm 44 then clinical judgment utilising risk factors for metastasis (histological
type – salivary duct carcinoma, high grade mucoepidermoid carcinoma,
adenocarcinoma NOS, SCC anaplastic disease-, age and possibly new biological
markers) will govern treatment.
In Stage ,III & VI disease the treatment options
are limited. It is almost always necessary to have wide exposure to give
adequate access to the tumour. This dictates some form of neck dissection and
resolves the dilemma of the neck. In
terms of the facial nerve, evidence of facial nerve weakness gives a licence to
remove the nerve in part or in total and repair it directly. With respect to
early disease, any tumour > 1cm in diameter is inevitably close to the nerve.
The rule is to preserve a functioning nerve but the excision margins will be
close. Hence a low threshold for
In summary the management protocols for Stage 3 & 4
salivary cancer do not pose an intellectual problem. Parotid
cancers are dealt with by total parotidectomy and , submandibular cancers by
wide excision of the submandibular triangle as dictated by the size and
character of the tumour. In both instances the primary resection should be
complimented by some form of neck dissection and adjuvant RT. It is the stage 1 & II cancers that are more challenging from a
planning perspective. It is here that SNB would resolve the emerging dilemma of
how to manage the neck . A low threshold for adjuvant radiotherapy seems to
guard against local recurrence and the routine total parotidectomy.
The size of the primary tumour at presentation is all important to
outcome1235. In the Dutch & Danish studies1,3 overall disease free survival was 55% & 58% respectively at 10y
with a loco-regional failure over the same period of 33% and 23% respectively. In modern practice where the threshold for adjuvant RT is
low, the most frequent failure involves distant metastasis1. Both
increasing T and N disease predicted for distant metastasis.
The prospect of salvaging recurrent disease depends on tumour stage
and grade at initial presentation45. Recurrent cases should be
restaged into groups 1: consisting of mobile, low grade tumours without lymphadenopathy and
group 2 containing fixed tumours, lymphadenopathy or high grade
histology. The division into these two groups is highly predictive of survival.
Patients with distant metastasis have a bleak outlook with few patients
surviving 5 years. The occasional patient with metastatic adenoid cystic
carcinoma living with disease for an extended period is so uncommon that they
become part of folk law. The reality is that survival at 1,3 and 5 years is 69%, 35% and 14% respectively46
The Stage of disease is the most
important factor to govern treatment and outcome as it incorporates both size
and clinical biological grade of the tumour. The histological type of disease is
subsidiary to stage. Stage I &
II disease has a good prospect of cure. In salivary gland cancer size is
important ( <4cm). In modern
oncological practice there is no longer a difference in survival between parotid
and submandibular gland cancers. The historical discrepancy has been eliminated
by appropriate initial therapy. In
both the parotid and submandibular gland, the best prospect of cure lies with
the initial treatment. Relatively few patients are amenable to salvage unless
the disease is low stage and indolent at presentation. A low threshold for
adjuvant radiotherapy has resulted in good loco-regional control of disease with
distant metastasis being the most common site of relapse.
Bjorndal K, Krogdahl A, Hamilton M et al. Salivary gland cancer in Denmark 1990-2005: a national study of
incidence, site and histology. Results of the Danish head and neck cancer group
(DAHANCA) Oral Oncol 2011; 47:677-682.
H, Klemi P, Leivo I et al . Salivary gland cancer in Finland 1991-1996: an
evaluation of 237 cases Acta
Terhaaard CH, Lubsen H, Vander Tweel I, et
al . (Salivary gland carcinoma: independent prognostic factors for locoregional
control, distant metastasis, and overall survival; results of the Dutch head and
neck oncology cooperative group. Head neck 2004; 26: 681-69
of National Statistics. Cancer Registrations .www.ons.gov.uk/ons/rel/vsonl/cancer-statisticsengland/index.html)
Wahlberg P, Anderson H, Biorklund
A. et al . Carcinoma of the parotid and submandibular glands—a study of 2465
patients. Oral Oncology2002;38: 706–713.
Bradley PJ, McGurk M.
Incidence of salivary gland neoplasms in a defined UK population British Journal
of Oral & Maxillofacial Surgery. 2013;
Spitz MR, Batsakis JG. Major salivary gland carcinoma. Descriptive
epidemiology and survival of 498 patients. ArchOtolaryngol 1984;110:45–9.
Spiro RH, Armstrong J,
Harrison L, Geller NL, Lin S-Y, StrongEW. Carcinoma of major salivary glands.
Arch OtolaryngolHead Neck Surg 1989;115:316–21.
Spiro RH. Prognostic variables. Johnson JT, Didolkar MS eds
in Head and neck cancer VIl, III
Proceedings of the 3rd International Conference on Head & Neck
Cancer,pp619-25 Elsevier Science
RH. Changing trends in the management of the salivary glands. Semin Surg Oncol
Barnes, L., Eveson, J.W., Reichart, P., Sidransky, D. World health
classification of tumour: Pathology and Genetics of Head and Neck Tumours. Third
edition.’Lyon: IARC Press; Vol 9 : 2005.
H, Skalova A, Stodulski D et al. Mammary
analogue secretory carcinoma of salivary glands: a new entity associated with
ETV6 gene rearrangement. Virchows Arch 2015; 466: 245-254.
Hunt JL. An update on molecular diagnostics of squamous and
salivary glandtumors of the head and neck. Arch Pathol Lab Med. 2011
Simpson RHW, Skalova A, Di Palma S, Leivo
I. Recent advances in the diagnostic pathology of salivary carcinomas. Virchows
Arch 2014; 465:371-384.
JA, Kies MS, Glisson S et al Phase II study of gefitinib in patients with
advanced salivary gland cancer. Head & Neck. 201;
B, Kim SB, Shin SH, Cho BC et al Phase 2 study of dovitinib in patients with
metastatic or unresectable adenoid
cystic carcinoma. Cancer 201; 121(15):
Poorten V, Bradley PJ, Takes RP, Rinaldo A, Woolgar JA, Ferlito A.Diagnosis and
management of parotid carcinoma with a special focus on recent advances in
molecular biology. Head Neck. 2012 Mar;34(3):429-40.
Chen MM, Roman SA, Sosa JA, Judson BJ. Prognostic factors for
squamous cell cancer of the parotid gland: analysis of 2104 patients. Head &
Neck 2015; 37(1), 1-7.
MS, Ivanov K, Wallace DI et al. Mucopepidermoid carcinoma: a clinic-pathological
study of 80 patients with special reference to histological grading. Am J Pathol
Cruz Perez DE,Abreu AlvesF, Nobuko
Nishimoto I et al. Prognostic factors in head and neck adenoid cystic carcinoma.
Oral Oncol. 2006;64(11):1592-97.
JG, Luna MA, El Naggar AK. Histopathological grading of salivary gland neoplasms:
II. Acinic cell carcinoma. Ann Otol Rhinol Laryngol 1990;99:929-933.
E, Gallo O, Boccuzzi S, Paradiso P. Analysis of 185 submandibular glands
excisions. Acta Otorhinolaryngol Belgium 1990;
Boccato P, Altavilla G, Blandamura S: Fine needle aspiration
of salivary gland lesions: A reappraisal of pitfalls and problems.
Acta Cytol1998; 42:888
F, Chandra A. Investigation of salivary gland lumps. In Controversies in the
management of salivary gland disease. Ed M McGurk & J Combes. Oxford
University Press 2013 p 41-54.
Imaizumi A, Kuribayashi
A, Okochi, K et al. Magnetic Resonance Imaging: Usefulness of the Parotid Duct
Criterion, Acta Radiologica 2009; 50(7):806-811.
Henriques de Figueiredo B; Barret O; Demeaux H et al Comparison
between CT and FDG-PET defined tumour volumes for radiotherapy planning in head
and neck cancer. Radiotherapy
& Oncology 2009; 93(3):479-82.
M McGurkM,Thomas BL,Renehan AG.
Extracapsular dissection for clinically benign parotid lumps: reduced morbidity
without oncological compromise. Br J Cancer. 2003; 89:1610-1613.
Velegrakis S; Iro H
. Otolaryngology - Head & Neck Surgery2015;
Hemprich A, Schmidseder R. The adenoid cystic
carcinoma. Special aspects of its growth and therapy. J Craniomaxfac Surg 1988;
Laine FJ, Sen ME, Braun IF, Nadel L, Som PM.
Perineural tumor extension through the foramen ovale: evaluation with MR
imaging. Radiology 1990; 174: 65-71.
Goh YH, Sethi DS. Submandibular gland
excision: 5 year review. Journal of Laryngology and Otology 1998;
Camilleri IG, Malata CM. McLeanNR, Kelly
CG.. Malignant tumours of the submandibular glands: a 15 year review. Br j
Plastic Surg 1998;51 (3):181-185.
Spiro RH (1998) Management of malignant
tumours of the salivary glands. Oncology (Williston Park) 1998; 12: 671-83.
Renehan A, Gleave EN, Hancock BD, Smith P,
McGurk M Long term follow up of over 1000 patients with salivary gland tumours
treated in a single centre. Br J Surgery 1998;83:1750-4.
Vander Poorten VLM, Balm AJM, Hilgers FJM, Tan IB, Loftus-Coll BM,
Keus RB, et al. Prognostic factors for long term results of the treatment of
patients with malignant submandibular gland tumors. Cancer 1999;85:2255–64.
Vander Poorten V, Hart A, Vauterin T et al
(2009) Prognostic index for patients with parotid cancer : international
external validation in a Belgian-German database . Cancer 2009;65:2515-20.
Spiro RH, Huvos AG. Stage means more than grade in adenoid cystic carcinoma. AM J
Spiro RH, Huvos AG, Strong EW Cancer of the
parotid gland. A clinic-pathalogic study of 288 primary cases. Am J Surg 1975;130:452-35.
Mamelle G. Total versus partial
parotidectomy. In Controversies in the management of salivary glands disease. Ed
M McGurk , J Combes. Oxford University Press, 2013 p194-202.
Boahene DK, OlsenKD, Lewis JE, Pinheiro AD,
Pankratz VS, Bagniewski SM. Mucoepidermoid carcinoma of the parotid gland: the
Mayo clinic experience. Arch Otolaryngology Head Neck Surg 2004:130,849-856.
Kirkbride P, Liu FF, O’Sullivan B et al.
Outcome of curative management of malignant tumours of the parotid glans. J
Klussmann JP, Ponert T, Murller RP, Dienes
HP, Guntinas-Lichius O. Patterns of lymphnode spread and its influence on
outcome in resectable parotid cancer. EJSO 2008; 34: 932-937.
Ettl T, Gosau M, Berockhoff G et al.
Predictors of cervical lymph node metastasis in salivary gland cancer. Head and
Neck 1014; 36 (4) 517-23.
Schilling C, Gnanasegrtan G, McGurk M.
Three-dimensional imaging and navigated sentinel node biopsy for primary parotid
malignancy: New application in parotid cancer management. Head & Neck 2014;
Spiro RH & Renehan A. Can recurrent salivary cancers be
salvaged? In Controversies in the
management of salivary gland disease. Ed M McGurk J Combes. Oxford Univ Press
2013, p 168-176
Gallo O, Meccariello G & Renehan A. Factors predicting distant
metastasis and subsequent management In Controversies in the management of
salivary gland disease. Ed M McGurk J Combes. Oxford Univ Press 2013, p 178-193.