King Edward VII's Hospital, London

 

University College London Hospital (NHS base)

        

 

 

Researching, Developing & Teaching Minimally Invasive Head & Neck Surgery 

 

   
     

Major Salivary Gland Cancer   Professor Mark McGurk 2016

 

 

 

Introduction

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. 

Incidence

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 respectively. 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.

Distribution 

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

Pathology, Tumour Biology and Biomarkers

Salivary 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 .

Squamous Cell Cancer (SCC) of the Parotid Gland.

In 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

Grading

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. 

Investigation

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 MRI24,25.  Positron 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. 

Diagnostic Anomalies 

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. 

 

The 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 .

Principals of Treatment

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 .

 

 In many 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.

 

 Paradoxically 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 41.

 

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 adjuvant radiotherapy.

 

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. 

Outcome

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. 

Recurrent Disease. 

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 .

Conclusion

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. 

References

 

1 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.

2  Luukkaa H, Klemi P, Leivo I et al . Salivary gland cancer in Finland 1991-1996: an evaluation of 237 cases  Acta Otolaryngol 2005;125:207-214.

3 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

4 Office of National Statistics. Cancer Registrations  .www.ons.gov.uk/ons/rel/vsonl/cancer-statisticsengland/index.html)

5 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.

6  Bradley PJ, McGurk M. Incidence of salivary gland neoplasms in a defined UK population British Journal of Oral & Maxillofacial Surgery. 2013; 51(5):399-403.  

7 Spitz MR, Batsakis JG. Major salivary gland carcinoma. Descriptive epidemiology and survival of 498 patients. ArchOtolaryngol 1984;110:45–9.

8  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.

9 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 Publications, Amsterdam.1993

10     Spiro RH. Changing trends in the management of the salivary glands. Semin Surg Oncol 1995;1:, 240-5. 

11    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. 

12     Majewska 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.

13    Hunt JL. An update on molecular diagnostics of squamous and salivary glandtumors of the head and neck. Arch Pathol Lab Med. 2011 May;135(5):602-9.

14    Simpson RHW, Skalova A, Di Palma S, Leivo I. Recent advances in the diagnostic pathology of salivary carcinomas. Virchows Arch 2014; 465:371-384. 

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16     Keam 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): 2612-2617

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18    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.

19     Brandwein 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 2001; 25:835-845.

20    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.

21     Batsakis JG, Luna MA, El Naggar AK. Histopathological grading of salivary gland neoplasms: II. Acinic cell carcinoma. Ann Otol Rhinol Laryngol 1990;99:929-933.

22     Gallina E, Gallo O, Boccuzzi S, Paradiso P. Analysis of 185 submandibular glands excisions. Acta Otorhinolaryngol Belgium 1990; 44 (1): 7-10. 

23    Boccato P, Altavilla G, Blandamura S: Fine needle aspiration biopsy of salivary gland lesions: A reappraisal of pitfalls and problems. Acta Cytol1998; 42:888

24      Heran 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.

25    Imaizumi A,  Kuribayashi A, Okochi, K et al. Magnetic Resonance Imaging: Usefulness of the Parotid Duct Criterion, Acta Radiologica 2009; 50(7):806-811.

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27     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.

28     Mantsopoulos K; Velegrakis S; Iro H . Otolaryngology - Head & Neck Surgery2015; 152(6):1042-7.

29    Hemprich A, Schmidseder R. The adenoid cystic carcinoma. Special aspects of its growth and therapy. J Craniomaxfac Surg 1988; 16: 136-139.

30    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. 

31    Goh YH, Sethi DS. Submandibular gland excision: 5 year review. Journal of Laryngology and Otology 1998; 112 (3): 269-273.

32    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. 

33    Spiro RH (1998) Management of malignant tumours of the salivary glands. Oncology (Williston Park) 1998; 12: 671-83.

34    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.

35    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.

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39    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.

40    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. 

41    Kirkbride P, Liu FF, O’Sullivan B et al. Outcome of curative management of malignant tumours of the parotid glans. J Otolaryngol 2001:30:271-279.

42    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. 

43    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.

44    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; 36 (9): E91-3.

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