Malignant Salivary Gland Tumors PDF

10 CHAPTER MALIGNA...

10 CHAPTER MALIGNANT TUMOURS OF THE SALIVARY GLANDS Vincent Vander Poorten and Patrick J. Bradley Introduction................................................................................. 131 Resected specimen: Histotyping, gradng and molecular studies.... 141 Incidence..................................................................................... 131 Specifics of the main histotypes................................................... 143 Risk factors for development of salivary neoplasms..................... 132 Post-operative radiotherapy......................................................... 146 Histogenetic theories for tumourigenesis..................................... 132 Radiotherapy and chemotherapy in unresectable disease............ 147 Clinical presentation and imaging workshop................................ 133 Treatment results and prognosis according to site....................... 147 Staging of salivary gland cancers................................................. 135 Complications of treatment.......................................................... 149 Pre-treatment histopathology typing............................................ 135 Conclusion................................................................................... 150 Surgical treatment....................................................................... 137 References.................................................................................. 151 SEARCH STRATEGY The data in this chapter may be updated by a Medline and Pubmed using the following keywords: salivary gland neoplasms, parotid gland, submandibular gland, minor salivary gland, carcinoma, review, management, molecular biology, pathology, surgery, radiotherapy and chemotherapy. INTRODUCTION INCIDENCE The broad pathological classification of malignant tumours Epithelial tumours account for the majority (95%) of malig- of the salivary gland comprises epithelial tumours, being nant salivary gland tumours, but are infrequently encoun- the most frequently encountered (> 80%), mesenchymal tered. Malignant salivary gland tumours are diagnosed in 4 tumors which are a very mixed group (< 20%), and hae- to 135 new patients per million in the population per year, matolymphoid tumours (lymphoma and plasmacytoma) the highest incidence being found in the Inuit community making up the remainder of the 2017 WHO classifica- of Greenland and the Canadian Arctic.1, 2 The incidence in tion. Epithelial salivary gland malignancies form one of the United States of America (USA) is 10 new patients per the most complex diseases in head and neck oncology, due million per year.3 For Europeans, the incidence is lower; to their low incidence and heterogeneity, both in micro- a Danish population-based study reported a comparable scopic appearance and clinical behaviour. A distinction crude incidence of 11 per million per year,4 with lower should be made between the paired major salivary glands incidences reported elsewhere in Europe (with Belgium, the (parotid, submandibular and sublingual) and the minor Netherlands, the UK and Finland having about 6–7 new salivary glands. The latter are unencapsulated seromu- cases per million per year).5–8 Ethnicity and geographical cinous glands distributed throughout the entire upper location presumably account for the observed differences aerodigestive tract, numbering between 500 and 1000, in incidence.2 Interesting data on the ‘population impact’ with the majority (< 90%) being located in the oral cavity of these cancers were published in the Netherlands in 1995, and oropharynx.1 where 89 new salivary gland carcinomas were diagnosed 131 132 Section 1: Head and Neck that year on a population of 15.5 million inhabitants (Netherlands Interdisciplinary Demographic Institute). HISTOGENETIC THEORIES When spread across the healthcare sectors, it was estimated FOR TUMOURIGENESIS that a General Practitioner would see one such patient in The normal histology of the salivary gland differs accord- 50 years of practice, an Otorhinolaryngologist would see ing to their anatomical location (major and minor glands) about one or two patients a year, and an average Head and and consists of different combinations and proportions Neck Oncology Centre about ten new patients a year.6 of the basic components, the acini and the ductal sys- As these malignancies occur at different anatomical loca- tem (Figure 10.1). Whereas the major glands have a true tions, incidence data are reported by anatomical site. Up to excretory ductal system, the minor salivary glands are 70% arise in the parotid gland4–6, 9 and typically 1–3% of composed of unencapsulated acini with a short or absent all head and neck carcinomas are reported to be parotid ductal system.11 carcinomas.10 The World Standard Population age-adjusted Serous acinus cells predominate in the parotid and the incidence of parotid carcinoma in Belgium in the period submandibular gland, and form only a minority of acini 2004–2005 was 6 for men and 4 for women per 106 person- in the sublingual gland. Mucous acinus cells are the main years, accounting for 3.9% of Belgian head and neck can- source of saliva in the sublingual and submandibular cers.5 Ten to 25% of salivary carcinomas arise in the minor glands, and are the only source of saliva in minor salivary salivary glands.4, 11 The rest are submandibular carcinomas, glands. with sublingual carcinomas being very rare. An example of The duct system consists of, in increasing diameter, the proportion is given by the population-based incidence intercalated ducts, striated ducts and excretory ducts. The per 106 person-years in the Southern Netherlands of 3.2 luminal cells in the ducts are well-differentiated epithe- parotid carcinomas for men and 1.9 for women, as com- lial cells. Abluminal cells, those not in contact with the pared to an incidence of 1.0 for men and 0.4 for women for lumen, consist of myoepithelial cells that are also found submandibular and sublingual malignancies.6 at the abluminal side of the acini, and pluripotent basal cells. 25, 26 RISK FACTORS FOR DEVELOPMENT Two theories have been proposed to explain the histo- genesis of the complicated appearance of normal salivary OF SALIVARY NEOPLASMS gland tissue and the complex ‘multicellular’ histologi- cal appearance of salivary gland tumours. The ‘multi- The influence of environmental and nutritional factors on cellular theory’ favours a transformation of the entire incidence has been studied in detail. Follow-up of atomic bomb survivors in Japan and atomic disaster survivors in Chernobyl12 reveals an increased incidence of both benign (Warthin’s tumour and pleomorphic adenoma) and Acini malignant (mucoepidermoid carcinoma) salivary gland tumours.13 The incidence of Warthin’s tumour is doubled and multicentric in smokers.14 Epstein—Barr Virus (EBV) Myoepithelial cells has been implicated in the genesis of bilateral Warthin’s tumours and undifferentiated parotid carcinoma.15, 16 Cytomegalovirus (CMV) infection may have a tenuous link to the development of mucoepidermoid carcinoma, both in mice and in humans.17 An inverse relationship exists between a diet rich in polyunsaturated fatty acids Intercalated and the registration of salivary cancers.18–23 A Danish ducts study found an increased risk of salivary cancer in workers involved with livestock feed processing, possibly related to naturally occurring mycotoxins produced by Aspergillus Striated spp. and are described as one of the most carcinogenic ducts substances known. 24 KEY POINTS The incidence of malignant salivary gland neoplasms in the western world is 7 to 12 per 1,000,000 person-years. Salivary malignancy increases with exposure to environ- Figure 10.1 Diagram of the normal salivary gland unit. One mental factors, low-dose ionizing radiation and a!atoxins. layer of myoepithelial cells invests the terminal secretory Smoking of cigarettes is related to development of ductoacinar unit – the intercalated duct and the acinus. Warthin’s tumours. Source: Tucker AS. Embryology and Clinical Anatomy. Salivary EBV infection may predispose to the development of Gland Disorders and Diseases: Diagnosis and Management. Warthin’s tumour and undifferentiated carcinoma. Bradley"PJ, and Guntinas-Lichius, (ed.) Reprinted by permission of Thieme Publishers.  10: MALIGNANT TUMOURS OF THE SALIVARY GLANDS 133 ducto-acinar unit and requires the various ‘differenti- ated’ cells to become ‘de-differentiated’, deranged in their growth pattern, resulting in the microscopically differ- 10 ent components observed in the various types of salivary gland tumours. 25 The ‘reserve cell theory’ states that both the normal salivary gland unit and the different tumour types are the result of differentiation of undifferentiated pluripotent precursor cells, and tumour cells originate from a problem in the normal differentiation process. The earlier in differentiation that a problem occurs, the more undifferentiated and ‘high-grade’ is the resulting salivary malignancy. The role of the precursor or ‘stem’ cell is attributed to the ‘epithelial basal ductal cells’ that rest on the base- ment membrane at the abluminal side of the ductal sys- tem. Originally, the ‘reserve cell theory’ was called the ‘bicellular’ reserve cell theory, distinguishing two types of reserve cells, one at the abluminal side of the intercalated ducts and another at the abluminal side of the excretory ducts. 26–28 The tumours originating from the interca- lated duct reserve cells are adenocarcinoma not other- wise specified (ACNOS), acinic cell carcinoma (AcCC), adenoid cystic carcinoma (AdCC), mixed malignant tumour and oncocytic tumours); those said to originate from the excretory duct reserve cells are mucoepidermoid Figure 10.2 Parotid cancer with skin invasion. Source: Prognosis in Head and Neck Cancer, Robert J Baatenburg de Jong, carcinoma (MEC), squamous cell carcinoma (SCC) and editor. V. Vander Poorten: Prognosis in patients with parotid salivary duct carcinoma (SDC). The reserve cell theory is carcinoma; Chapter 21, p 356. Reprinted by permission of supported by recent research indicating the common ori- Taylor and Francis. gin of both the epithelial, myoepithelial and the mesenchy- mal components of pleomorphic adenoma in exactly these and 25% have VIIN paresis or paralysis which is indepen- epithelial basal ductal cells. 29 dent of the tumour size. 30, 34–41 Rarely, the presentation can be insidious. The incidence of parotid carcinoma has been estimated to be as high as 6% in patients present- CLINICAL PRESENTATION ing with a lower motor neuron VIIN paralysis where no AND IMAGING WORKSHOP aetiology has been identified after initial MRI scans. This is more likely if the paresis has been slow in onset, pro- The majority of tumours (64–80%) arise in the parotid gressive in nature, shows no evidence of recovery, affects glands, of which 15–32% are malignant. Seven to 11% only isolated branches of the VIIN and if facial tics are arise in the submandibular glands with 41–45% being present.42, 43 malignant. Less than 1% occurs in the sublingual gland, The evaluation should include the size, extent, location where the majority (70–90%) are malignant. Minor sali- and the likelihood of the mass being benign or malig- vary gland tumours account for 9–23%, with +/– 80% nant. Imaging is strongly advised when the tumour mobil- being malignant.1, 30 ity is impaired, the tumour > 4 cm, the VIIN is clinically involved, and there are palpable cervical nodes.30, 44, 45 Magnetic resonance imaging (MRI) is superior to com- Parotid gland puterized tomography (CT) in evaluating parotid tumours The majority of parotid tumours present as asymptom- and allows better demonstration of the retromandibular atic, discrete pre-auricular or infra-auricular lumps. With parotid, the stylomastoid foramen area, VIIN invasion and 80–90% of parotid salivary tissue being located lateral to possible perineural extension.43, 44, 46 Conventional MRI is the facial nerve (VIIN), a similar proportion of all neo- complementary to fine-needle aspiration cytology (FNAC) plasms (benign and malignant) arise in the superficial in the pre-operative assessment of a parotid mass.47 lobe. A small percentage present only as a swelling of the Diffusion weighted MRI (DW-MRI) is considered to have soft palate or lateral oropharynx, 31 and 1% arise in the superior diagnostic efficacy in identifying malignancy accessory parotid gland (along the Stensen duct). 32 based on a specific diffusion pattern.48 Where malignancy About 1 in 4 parotid tumours are malignant33 and a is suspected, appropriate imaging should be performed to diagnosis of a malignancy is suggested by a rapid increase exclude distant metastases.49 Positron emission tomogra- in size, pain, associate cervical lymphadenopathy, fixa- phy/CT (PET-CT) imaging has high false-positive rates in tion of the salivary mass to deep structures or facial skin differentiating benign from malignant salivary disease as (Figure 10.2), or the presence of VIIN dysfunction. 30 Of common benign tumours (Warthin’s tumours and pleomor- patients presenting with parotid cancer, 44% have pain34 phic adenomas) demonstrate an increased FDG uptake.50 134 Section 1: Head and Neck Submandibular gland children MiSG cancers are low-grade and can frequently be excised with clear margins. 58 Akin to the normal distri- Most patients present with a slow-growing, painless mass bution of salivary glands, the most frequent sites of MiSG or swelling under the jaw or occasionally present with dis- cancer development are the oral cavity and oropharynx. tortion of the floor of the mouth, accompanied in excep- The most frequent primary site is the hard palate, where tional cases by skin invasion or ulceration or even more MiSG density is highest. The classical presentation is as a rarely with local nerve paresis or paralysis. The hypoglos- painless submucosal swelling, with fixation of the tumour sal nerve is most at risk, followed by the trigeminal nerve to the overlying mucosa. There may be a small central area and then the mandibular branch of the VII nerve. Thirty of ulceration. Some patients present complaining of their percent of patients complain of local pain suggesting local dentures not fitting comfortably as the tumour alters the tissue extension. 51 Cervical lymphadenopathy is present positioning of the dentures (Figure 10.3). When MiSG in 25% of patients. The median symptom duration in the tumours present in the nose and pharynx, most patients patient group of The Netherlands’ Cancer Institute was present with obstructive symptoms. Pain or paraesthesia 13.5 months, ranging from < 1 month to > 27 years. The as a complaint has been recorded in > 26% of patients11, 59 median duration of complaints may range from 3 years for and, when present, MRI is required to evaluate named low-grade malignancy to 6 months for high-grade malig- nerve invasion.60, 61 The presence of regional metastasis is nancy. 52–56 Evaluation of submandibular gland malignan- reported in 1 out of every 6 patients.11, 62, 63 cies by radiological imaging is similar to the principles for To estimate the anatomical involvement of the disease the parotid gland. process aiming to predict the likelihood of surgical man- agement it is mandatory that CT +/– MRI is performed. Recent reports suggest that the T-max (time to maximum Minor salivary glands (MiSG) contrast enhancement) in contrast to enhanced MRI scan- As MiSG are found throughout the entire upper aero diges- ning is helpful in differentiating benign from malignant tive tract, the signs and symptoms depend upon the ana- MiSG tumours.64 DW-MRI, which is of value for the tomical site involved. The majority of patients diagnosed pre-operative identification of malignancy based on the are in the 5th to 6th decade, but tumours have been docu- tissue-specific diffusion pattern of major salivary gland mented in children.11, 56, 57 Fortunately, when diagnosed in tumours, has not been studied specifically for MiSGC.48 (a) (b) Figure 10.3 (a) and (b) MiSGC of palate with ill-fitting denture. Source: Squamous cell cancer of the neck, Robert Hermans (ed). V."Vander Poorten: Epidemiology, pathology and clinical presentation: Chapter 1: p. 15. Reprinted by permission of Cambridge University Press.  10: MALIGNANT TUMOURS OF THE SALIVARY GLANDS 135 It can be questioned however whether this complex imag- TABLE 10.1 8th Edition (2017) UICC TNM classi#cation ing will yield any additional information, when, for MiSG tumours, an incisional diagnostic biopsy is necessary and and stage regrouping for major salivary gland malignancies 10 will provide the histological information needed to plan T – Primary Tumour further treatment. As stated above for major salivary gland cancers, PET with or without CT is useful for the Tx Primary tumour cannot be assessed exclusion of metastatic disease.65 T0 No evidence of primary tumour T1 Tumour 2 cm or less, without extraparenchymal extension* T2 Tumour > 2–4 cm, without extraparenchymal extension STAGING OF SALIVARY T3 Tumour > 4–6 cm, and/or extraparenchymal extension GLAND CANCERS T4a Tumour invades skin, mandible, ear canal and/or VIIth nerve involvement All patients should be staged as per the TNM system used T4b Tumour invades base of skull, and/or pterygoid plates and/ for major salivary gland cancers following evaluation or encases carotid artery (Table 10.1).66 Minor salivary gland cancers are staged as N – Regional Lymph Nodes per the anatomic site they originate in.11, 56, 59, 63, 67–69 The N1 Metastasis in a single ipsilateral node, 3 cm or less in use of a uniform classification system, such as the TNM, greatest dimension, without extranodal extension allows comparison of outcomes following different treat- ments to similar tumour stages. TNM components also N2a Single ipsilateral node > 3–6 cm, without extranodal extension have an independent prognostic role as shown by numer- ous studies, which help define and refine guidelines for N2b Multiple ipsilateral nodes < 6 cm treatment.10, 37, 41, 70–73 Similar to major salivary gland N2c Bilateral or contalateral nodes < 6 cm cancer, the TNM components and stage groupings for N3a Node(s) > 6 cm, without extranodal extension MiSG cancers have been found to be the strong prognos- N3b Single or multiple nodes, with extranodal extension** tic factors,11, 56, 63, 74–76 and many studies report that TNM overrules the histological grade.11, 56, 63, 68 Carrillo attrib- M – Distant Metastasis uted an additional independent prognostic value to grade M0 No distant metastasis for oral and oropharyngeal MiSG cancers, in addition to M1 Distant metastasis anatomical extent as reflected in UICC stage. 57, 77 Stage Grouping Stage 0 Tis N0 M0 KEY POINTS Stage I T1 N0 M0 The smaller the salivary gland, the less frequent a tumour Stage II T2 N0 M0 is likely to manifest, but when it does the more likely is the Stage III T3 N0 M0 tumour to be malignant. Parotid tumours T1, T2, T3 N1 M0 º rapid increase in size or volume, the presence of pain, Stage IVa T4A, N0, N1, N2M0 enlarged neck lymph nodes, #xation to deep struc- T1, T2, T3, T4a N2 M0 tures or skin, or VIIN dysfunction should alert a likely diagnosis of malignancy Stage IVb T4B any N M0 º tumour imaging aims to estimate the extent (summa- Any T N3 M0 rized in the TNM classi#cation), location and probabil- Stage IVc Any I any N M1 ity of malignancy º MRI scanning is mandatory to evaluate invasion of the * extraparenchymal extension is clinical or macroscopic invasion of soft VIIth nerve, #xation to the deep structures, location at tissues or nerve, other than those listed under T4a and T4b. Microscopic the stylomastoid foramen or deep lobe with the use of evidence alone does not constitute extraparenchymal extension for CT imaging to evaluate suspected bone invasion. classi#cation purposes. Reproduced with permission.66 Submandibular tumours, although frequently symptom- ** The presence of skin involvement or soft tissue invasion with deep less, are often malignant. #xation/tethering to underlying muscle or adjacent structures or clini- MiSG tumours commonly present at an advanced disease cal signs of nerve involvement is classi#ed as clinical extra nodal stage and their extent is summarized as per the TNM extension. Midline nodes are considered ipsilateral nodes. classi#cation for that anatomic location. Fine-needle aspiration cytology PRE-TREATMENT FNAC is an important tool in the diagnosis of salivary HISTOPATHOLOGY TYPING neoplasms. Accurate tumour typing is not to be expected as a routine, but when performed by an experienced cytol- Accurate characterization of the histology of any malig- ogist, FNAC is safe, associated with minimal morbidity nant tumour is a crucial part of the diagnostic workup. and is a reasonably accurate way to differentiate between This will confirm true salivary origin of the tumour and malignant and benign lesions (accuracy 79%).78–80 This permit appropriate treatment planning. information aids with the prioritization and timing of 136 Section 1: Head and Neck treatment, with the planning of the excision and possible TABLE 10.2 The WHO* 2017 Histologic Classi#cation of reconstruction, and allows for appropriate counselling. Malignant Salivary Gland Tumours204 Performing FNAC with ultrasound guidance (UgFNAC) not only helps with diagnosis of the primary tumour but Type WHO Abbreviation also aids with synchronously staging of the neck and is 1. Mucoepidermoid carcinoma MEC to be recommended.46 Immediate on-site processing and 2. Adenoid cystic carcinoma AdCC evaluation of the cellular quality of the aspirate should be 3. Acinic cell carcinoma provided, and if the aspirate is deemed unsatisfactory the FNAC can be repeated; this results in higher diagnostic 4. Polymorphous adenocarcinoma PAC accuracy.44, 81, 82 The real-life performance of this tech- 5. Clear cell carcinoma CCC nique can be deduced from a large French series of 1355 6. Basal cell adenocarcinoma BAC salivary gland FNACs which were correlated with sub- 7. Intraductal carcinoma sequent histological assessment, showing an 80.5% true 8. Adenocarcinoma, NOS positive rate, 4.6% suspicious lesions, 11.9% false nega- tives and 3% of uninterpretable samples.78 Even if the 9. Salivary duct carcinoma SDC FNAC suggests benign disease, removal of the tumour 10. Myoepithelial carcinoma for further histopathology analysis remains mandatory.83 11. Epithelial-myoepithelial carcinoma EMC Diagnostic accuracy of FNAC could be improved in the 12. Carcinoma ex pleomorphic adenoma future by implementing high throughput techniques such as cDNA microarrays on the aspirate to give a tumour- 13. Secretory carcinoma specific overview of overexpressed oncogenes and under- 14. Sebaceous adenocarcinoma expressed tumour suppressor genes.84 15. Carcinosarcoma 16. Undifferentiated carcinoma Incision biopsy 17. Large cell neuroendocrine carcinoma For MiSG tumours, FNAC can often correctly classify 18. Small cell neuroendocrine carcinoma the tumour as benign or malignant, but may be unable 19. Lymphoepithelial carcinoma to distinguish between subtypes or provide tumour grad- 20. Squamous cell carcinoma ing. Whereas incisional biopsy is not recommended for 21. Oncocytic carcinoma the diagnosis of major salivary gland tumours (except for large tumours with skin ulceration or infiltration), 22. Sialoblastoma (uncertain malignant potential) it is appropriate for MiSG locations, where the muco- * WHO: World Health Organization. Modi#ed from the WHO publication sal tumour is readily accessible for biopsy and will not to include only the malignancies. interfere with subsequent definitive treatment. Excisional biopsy of MiSG tumours has a high rate of positive mar- gins, makes orientation and margin assessment of the definitive resection specimen more difficult and is not to be recommended. The most important factor in the pre-operative evalu- ation is to obtain an accurate histopathologic subclassi- fication of the MiSGC (Table 10.2) and, when possible, an indication of the tumour grade. 85 The caveat to interpreting these biopsies is that many salivary gland tumour types have overlapping histological features. Without seeing the interface between the tumour and the surrounding normal tissue, invasion cannot be adequately assessed which complicates differentia- tion between benign and malignant tumours. Similar issues are encountered in interpreting FNAC where less information is to be obtained from individual cells, without the architecture. 86 Some tumours at presenta- tion will be at an advanced stage and the biopsy may be the only tissue sample obtained. Additional histo- logical prognostic features, such as perineural growth (Figure 10.4), lymphovascular invasion, and involved margins, can usually only be obtained from a resection Figure 10.4 Perineural spread of salivary cancer. Arrowhead demarcates perineurium, distended by tumour cells (arrow), specimen. Increasingly, molecular biological studies are compressing the nerve bundles (asterisk). Source: Hermans"R. performed, and many can be carried out also on the (ed.). Head and Neck Cancer Imaging, Vander Poorten V. incisional biopsy material. Epidemiology, risk factors, pathology and natural history of head and neck neoplasms; Chapter 1, p. 13.  10: MALIGNANT TUMOURS OF THE SALIVARY GLANDS 137 Core biopsy not resected should a lesser procedure be performed.33, 94, 95 There have been several recent reports discussing the added value of ultrasound-guided core biopsies (UGCB) Indeed, Armstrong et al. showed that the parotid lymph nodes are involved in 53% of elective neck dissections.96 10 Most pre-operatively intact nerves can be dissected mac- in salivary gland tumours, with some stating that GCB is roscopically free from the tumour. VIIN branches are so much more accurate than FNAC, that it should become only to be resected when pre-operatively paralyzed or the new standard.87, 88 There is, however, a theoretical peri-operatively invaded by or surrounded by tumour.97 increased risk for complications in the form of tumour More sensitive than clinical examination is electromyog- seeding (not clearly reported in the literature – but prob- raphy and this can be performed in suspected malignant ably strongly underreported) and, especially for parotid tumours to support in counselling the patient on the pos- tumours, the risk of facial nerve damage (not reported, sible need for nerve resection and reconstruction.98 There is but in the practice of one of the authors, two patients were consensus that microscopic disease left behind on a spared documented with VIIth nerve frontal branch damage fol- nerve branch can be controlled by the use of post-opera- lowing UGCB). As these complications are probably poorly tive radiotherapy.38, 71, 83, 97, 99, 100 Nerve sacrifice in these reported, and follow-up is frequently too short to know the instances often induces disproportionate morbidity at the real effect of tumour seeding, a recent meta-analysis find- expense of minor gain in tumour control.39, 97, 100 When the ing no difference between FNAC and USCB, has probably facial trunk or branch resection has been performed, fro- limited bearing.89 A balanced attitude is probably that, in zen section of the cut margins is recommended to avoid the clinical units where FNAC is quite accurate, USCB can be possibility of leaving tumour skip metastases. Immediate utilized when FNAC is equivocal or non-diagnostic.90, 91 cable grafting results in optimal functional outcomes. The greater auricular nerve (GAN) combines easy access, KEY POINTS good diameter and adequate arborization; 101, 102 for longer Pre-treatment cytological assessment should be defects the same donor nerve can be traced back to include performed for major salivary gland tumours should be cervical sensory branches. The sural nerve is a good alter- performed using FNAC; in selected instances UGCB can native.98 Electromyographic (EMG) signs of reinnervation be performed, and UGCB or incisional biopsy can be appear after 4.5 months, followed by the first movements considered when there is associated skin ulceration. about the 6th month. It can be up to 2 years before the final Incisional or punch-biopsy for MiSG tumours is the stan- dard of care. function is realized, usually a House-Brackman grade III to IV.98, 101, 102 Factors that negatively impact on the final result of nerve grafting include age > 60 years and the pres- ence and duration of the pre-operative VIIN dysfunction.98 SURGICAL TREATMENT Radiotherapy does not impair the final results of cable grafting: Brown et al. reported a House-Brackmann grade Parotid cancer III or IV in 69% of irradiated patients versus 78% of non- PRIMARY SITE irradiated patients (p = 0.54), and replicated previous reported experimental findings of 80% axon recovery in There is strong evidence that primary surgical excision both irradiated and non-irradiated facial nerves.102, 103 of parotid cancer is the treatment modality providing the best chance of cure.9, 71, 92 The extent of primary surgery NECK DISEASE is determined by the size of the lesion, the relationship to the VIIN and extraparotid tissue invasion. The majority N+ neck of parotid cancers (80%) are located in the superficial Parotid cancer related cN+ disease requires a comprehen- or lateral parotid lobe, with a normal functioning VIIN. sive (modified radical) neck dissection, removing levels I Performing the standard superficial or lateral parotidec- to V.104 Where appropriate, based on invasion or proxim- tomy would appear to be adequate in the majority of small ity to the metastatic disease, the non-lymphatic structures cancers. Until a prospective randomized evaluation proves (nerve XI, jugular vein or sternocleidomastoid muscle) may the oncological benefit of removing the deep lobe to need to be sacrificed.105 Recent studies corroborated this address occult metastatic disease, to date very little local ‘old knowledge’: pN+ involvement in a recent study from recurrence has been observed in tumours that are well the Memorial Sloan Kettering Cancer Center reached 52% localized in the superficial lobe and that are adequately in level I, 77% in level II, 73% in level III, 53% in level IV removed. It is very likely that the use of post-operative and 40% in level V.106 Also a comparable Korean study radiotherapy will also aid with the control of possible reported pN+ rates of 43% in level I, 90% in level II, 40% located microscopic deep lobe lymph node deposits.93 in level III, 57% in level IV and still 43% in level V.107 In Tumours < 4 cm, located in the parapharyngeal or pN+ patients, post-operative adjuvant radiotherapy to the deep lobe, or with VIIN involvement should have a more parotid and the ipsilateral neck doubles locoregional con- extended surgical procedure, such as a total or radical trol and improves survival.73, 105, 108–110 parotidectomy (Figure 10.5). The reasoning for a total parotidectomy is that in locally advanced, high-grade N0 neck parotid malignant salivary tumours, intraparotid lymph In patients with a cN0 neck at presentation, performing nodes may harbour metastatic disease and be overlooked or an elective neck surgery depends on the presence of the 138 Section 1: Head and Neck (a) (b) (c) (d) Figure 10.5 Extended radical parotidectomy with free flap reconstruction. (a) Outline of the resection for the patient referred to in Figure 10.2. (b) Following radical parotidectomy and radical neck dissection (modi#ed type I). (c) Monobloc resection specimen including skin and pinna. (d) Static facial nerve reconstruction using temporalis fascia – temporoparietal (e) fascia. (e) Gracilis free !ap reconstruction.  10: MALIGNANT TUMOURS OF THE SALIVARY GLANDS 139 risk factors for occult neck disease, but the alternative of level I-II-III neck dissection for none of the patients in the using elective radiotherapy is also shown to be effective in controlling neck disease.109 The authors routinely perform period 1939–1965 to 38% of the surgeries in the study period 1966–1982. In the Netherlands’ Cancer Institute, 10 frozen section of level II nodes at the commencement of the level I-II-III dissection comprising the submandibular the procedure and if these contain macrometastases, we gland was used, in the cN0 neck and absence of invasion of consider the neck as cN+ and proceed with a neck dissec- bone or floor of mouth, and accounted for 66% of opera- tion.41, 80, 83, 92 The recognized risk factors for the presence tive procedures in the period 1973–1983 and for 71% of the of occult neck disease are tumour size > 4 cm and histology procedures between 1984 and 1994.55 The current agree- with clinical high-grade behaviour, implying a 20% and ment is that for early stage, low-grade disease, the minimal 49% risk for occult nodal metastasis respectively.96, 109, 111 procedure that should be performed, should be complete Age > 54, perilymphatic spread and extraparotid exten- excision of the gland within a levels Ia and Ib lymph node sion, together correspond to a 95% risk.111 These high- dissection. For most other disease that is further cN0, a risk patients require elective neck treatment, be it neck level I-II-III elective dissection encompassing the subman- dissection or radiotherapy. Parotid AdCC rarely causes dibular gland is the recommended extent of surgery. This lymph node metastasis, so an elective neck dissection is operation should only be extended beyond the boundaries not really indicated in this high-grade malignancy.92 of the supraomohyoid dissection, if the local extension of Some authors propose a routine elective neck dissection the disease dictates so.53 Commonly there is cN+ disease, of for all parotid carcinoma patients; using this strategy and then a comprehensive neck dissection is mandated.119 Zbären finds a 22% occult rate and a better 5-year locore- gional control as compared to that of ‘an observation policy’, but the patients in this series did not receive radio- Sublingual gland cancer therapy.112, 113 Stennert reports even a 45% occult rate in AdCC is the most common malignant tumour of the sub- a large series of patients all of whom underwent neck dis- lingual gland (72%), followed by MEC, however other section.33 A Brazilian study reported a 37% occult metas- SGC have also been reported, usually as case reports. tases rate predicted by T-classification, severe desmoplasia The initial treatment should be surgery, performed after and histology (adenocarcinoma, undifferentiated carci- confirmation of histology and imaging, to encompass the noma, high-grade MEC, SDC and SCC, together resulting extent of the primary tumour. Tumours < 2 cm in size in a 68% occult rate).114 The surgical approach to the N0 and mobile may be resected intraorally but it is also rec- neck can be fine-tuned using pre-operative USgFNAC of ommended that the ipsilateral submandibular gland or the neck and the use of peri-operative frozen section. level I be removed, as the submandibular duct is likely The MD Anderson strategy is elective radiotherapy to to be resected. Tumours > 2 cm should receive an en-bloc the N0 neck in high-risk patients, relying on definitive resection, possibly using a ‘pull through’ procedure or a histopathology of the resected primary; this is appealing mandibulotomy approach. Performing an elective neck because the indications for elective neck treatment con- dissection (levels I–IIa) may facilitate such a surgical pro- cur with the indications for post-operative radiotherapy cedure in the N0 situation. In the N+ neck, a therapeutic to the primary, and also because pre- and peri-operative neck dissection such as a modified radical neck dissection typing of salivary carcinomas is very difficult (accuracy should be performed. Adjuvant post-operative radiother- 51–62%).111, 115 This means that the information required apy is indicated for patients with advanced stage disease to pre-operatively classify a parotid tumour as high (stage III/IV, high-grade tumours, perineural involvement, risk is often not available during elective surgery and at positive surgical margins, > 2 N+ lymph nodes and/or the time of decision to perform a neck surgery.44, 105, 115 pathological evidence of extracapsular extension.120 Furthermore, radiotherapy may still be indicated if a cN0 neck turns out to be pN+.93, 110 Only conducting a prospec- KEY POINTS tive randomized trial will answer the question whether an elective neck dissection (followed by radiotherapy if indi- The preferred treatment of parotid and submandibular cated) provides a better result than elective radiation alone gland cancer treatment is surgery. VIIN-preserving parotidectomy (allowing for microscopic to the cN0 neck. remnant disease if unavoidable – followed by radiother- apy) in a patient with a pre-operatively functioning VIIN is Submandibular gland cancer considered the standard of care. Gross tumour involvement of the VIIN requires nerve The standard treatment in the last decades has shifted resection followed by immediate cable grafting. from a rather aggressive and extended surgery as mono- The N+ neck requires surgery, the N0 neck should be treated electively surgically or by radiotherapy, depending therapy52, 63, 107, 116 to more limited and functional surgery, on the risk factors. tailored to the local pathological involved anatomy, supple- Post-operative radiotherapy improves locoregional con- mented by post-operative radiotherapy.53–55, 71, 117, 118 The trol depending on the prognostic factors present. typical standard operation included the submandibular For submandibular gland malignancy, the minimally gland in a radical neck dissection, often with en bloc exci- required surgery is a gland resection within a level I-II-III neck dissection (selective neck dissection); the indication sion of the floor of mouth and lower rim of the mandi- for post-operative radiotherapy follows that for parotid ble.52, 116 The move over time toward conservation surgery gland malignancy. was illustrated by Spiro et al.,71 who described the use of 140 Section 1: Head and Neck Minor salivary gland cancer (MiSGC) a therapeutic neck dissection in combination with wide excision of the primary. Resection of the primary palatal GENERAL CONSIDERATIONS tumour may require a palatal obturator or free-tissue The primary reconstruction, depending on the size and location of the surgical defect. The treatment of choice for MiSGC is wide local resection with tumour-free margins. Resectability is determined Oropharynx pre-operatively, based on clinical and imaging findings, the anatomical site of origin, the histology and the avail- There are few series focusing specifically on the orophar- able surgical expertise. These factors also determine the ynx, but the tongue base is the most common site of ori- extent of resection necessary and the functional implica- gin. In the Netherlands’ Cancer Institute series of patients tions of a resection. In all reported series, resection mar- the posterior tongue was the only oropharyngeal subsite gin status is one of the most important survival outcome involved.11 Like in the oral cavity, the most frequent his- prognostic factors that correlate strongly with both ana- tologies are AdCC and MEC (up to 60%), followed by tomical extent and histological type.11, 121, 122 ACNOS. Treatment – if feasible – is surgery, ranging from transoral laser microsurgery or transoral robotic The neck resections for smaller circumscribed lesions, to suprahy- oid release or mandibulotomy and free-flap reconstruc- Currently, surgical treatment of the neck is only indi- tions for the larger tumours. Most resected tumours will cated when 1) there is clinical or radiological evidence of require post-operative radiotherapy, which is detailed in regional metastasis (N+), or when 2) the risk of subclinical ‘Post-operative radiotherapy’ below. disease in a clinically negative neck exceeds 15–20% and when 3) the neck is surgically entered as an approach to Larynx the primary. Clinical N+ disease occurs in about 15% of patients.11, 123 MiSGs are found in the submucosa of the subglottis, Except in patients with high-grade cancers such as high- glottis (floor of the ventricle and the undersurface of grade mucoepidermoid carcinoma, the occult metastasis the anterior commissure) and supraglottis (especially rate is too low to justify elective surgical treatment.124, 125 in the aryepiglottic folds, and petiole of the epiglottis) Nasopharyngeal salivary cancers are also an exception, and account for about 1% of all tumours of the larynx, where a high rate of occult disease has been reported both benign and malignant. The most frequent laryn- following elective neck dissection in a series of patients geal MiSGC is subglottic AdCC, followed by MEC. amenable to surgery.126 For patients with pN+ disease, Typically, these laryngeal MiSGC are diagnosed at an post-operative radiotherapy improves locoregional control advanced disease stage when diagnosed, due to their and survival.73, 110 submucosal growth and large size at the time of pre- sentation. The treatment of choice is surgical resec- tion, with endoscopic resection, open partial and total SITE-SPECIFIC CONSIDERATIONS122 laryngectomy being the options. Post-operative radio- Oral cavity therapy should be considered in all patients especially The most common subsites are the palate, buccal mucosa, when unfavourable prognostic factors are present, or in retromolar trigone and upper lip, accounting for +/– 75% the case of cartilage, perineural or vascular invasion. of cases. The palate is the most common site (55%) with Laryngeal MiSGC patients frequently develop distant +/– 60% of these being malignant. In a series from the metastasis, usually to the lungs.128, 129 Netherlands’ Cancer Institute, 78% of minor salivary gland cancers were located in the oral cavity.11 In 149 patients Nose, paranasal sinuses and nasopharynx with palatal MSGT seen over a 46-year period at the MD AdCC is the most frequent MiSGC found in the nasal Anderson Cancer Center, malignant tumours were found cavity and paranasal sinuses and due to its advanced in 116 patients (78%), with 50% of these tumours on the stage at presentation results in a worse prognosis than hard and the other 50% on the soft palate. in any other site of the head and neck, implying local The majority (up to 90%) of the oral cavity MiSGC recurrences and early perineural and hematogenous are MEC, AdCC and PAC.122, 127 Akin to the growth spread; around 50% present with distant metastases. pattern, patients with MEC tend to have localized Locoregional control is better in those patients receiv- space-occupying lesions, which present at an earlier ing more radical primary surgery, with or without stage compared to patients with AdCC, which display an post-operative radiotherapy, but there is little data to infiltrative submucosal and perineural growth and are at support radical management over a more conservative an advanced disease stage when diagnosed. In the MD approach. Recent progress in surgery, including endo- Anderson series, extensive disease diagnosed locally by scopic resection, facilitates local surgical radicality and radiological imaging showed: local bone invasion 31%, improved surgical reconstruction that allows for timely the sinonasal cavities 31%, the sinonasal cavities 31%, and optimum post-operative radiotherapy. Use of the the pterygoid muscles 5%, the nasopharynx 3%, and gamma knife for residual or recurrent disease optimizes intracranially 3%, but only 3% presented with detect- the chances of cure and improves remaining quality of able cervical lymphadenopathy.75 The latter group need life. A significant number of patients have unresectable  10: MALIGNANT TUMOURS OF THE SALIVARY GLANDS 141 disease at presentation and are treated with primary and the margins status. Increasingly, molecular biological radiotherapy, explaining why the proportion of MiSGC at this subsite is overrepresented in reported series of markers are being identified and studies suggest that their usage may aid with a more accurate histologic diagnosis 10 AdCC from radiation oncology centres (e.g. 40% in the and prognosis.130, 85 University of Florida series). 63 For MiSGC located in the nasopharynx, the most com- mon histology is AdCC (94%), and rarely MEC (6%). Histologic typing: Light microscopy AdCC comprised 48% of a large surgical series (n = 23 and immunohistochemistry accumulated during 12 years), MEC 35% and ACNOS The primary histological diagnosis of SGCs is challeng- 17%. Like MiSGC located in the nose and paranasal ing, as can be seen in the 29% reclassification rate result- sinus, nasopharyngeal MiSGC presents late, typically at ing from a new histological classification system reported an advanced stage of disease with invasion of the skull by van der Wal et al.4, 122, 123, 131 and by a substantial base, cranial nerve paralysis and intracranial invasion. inter-observer variability between pathologists.60, 132 The Complex surgical resections (varying approaches have Netherlands’ Cancer Institute series displayed a 22% been described such as lateral infratemporal middle fossa, reclassification rate.11 Reclassification, interobserver vari- subfrontal, midfacial degloving, lateral rhinotomy, trans- ability, geographical variation and referral bias all con- oral palatal or maxillary swing approach), possibly trans- tribute to disparities in the published literature. Only a posing or resecting the carotid artery, resection of dura population-based study can give an accurate idea of the and dissection of cancer from the cavernous sinus, are only incidence of different histological types. possible in a minority of cases. These complex resections A clear relationship between histological type and demand that expertise for a wide variety of reconstructive biological behaviour is often lacking, as commented options be available, ranging from dural repair using tem- by Spiro30 and Leivo.134 In population-based stud- poralis fascia or a pericranial flap to vascularized flaps. ies, most major SGCs are AcCCs (15–17%), AdCCs Exceptionally for MiSGC, elective neck dissection reveals (16–27%), and MECs 14.5–19.2%). 8, 40 All 22 malig- occult metastatic disease in about 50% of the patients nant salivary tumour types have been described across with tumours in the nasopharynx.126 Post-operative most sites. In most studies of MiSGCs, AdCC (32–71%) radiotherapy is always required and will be detailed in and MEC (15–38%) account for the majority of histo- ‘Postoperative radiotherapy’ below. This strategy carries logical types and far outnumber the other histological 5- and 10-year disease-specific survival (DSS) rates of variants.11, 56, 57, 59, 60, 63, 67, 68, 73, 76, 134 –137 67% and 48% respectively. In non-resectable nasopharyn- The most critical aspect of pathological examination is geal AdCC radical primary external-beam photon radia- differentiating these tumours from benign entities, which tion seems a good option with a reported local control can demonstrate overlapping histologic features. The pro- rate of 45% at 5 years and 5- and 10-year survival rates portion of benign to malignant varies across series; those of 78% and 49%, respectively. Long-term complications with a higher percentage of malignant disease may suffer may be serious and are less expected with modern IMRT from referral bias seen at tertiary centres that are more techniques. likely to publish their results. 30, 63, 138 KEY POINTS Grading The optimum curative treatment for minor salivary gland tumours is surgery. Grading is a standard procedure that is performed as a The surgical approach and resection should be dictated surrogate marker for the biological behaviour within by the site of origin and can encompass the entire tumours of the same histological type. However, grading spectrum of head and neck surgical resective and suffers from poor inter- and intra-examiner consistency reconstructive procedures. and low independent prognostic power.11, 56, 131, 132, 139 Meaningful clear-margin surgery is often impossible to achieve at certain sites because of the extensive local A clear relationship between histological grade and bio- anatomical invasion by tumour at diagnosis (skull base logical aggressiveness is thus often lacking.133, 140 In addi- and perineural invasion); in these instances, primary tion, grading often has no therapeutic relevance as most radical radiotherapy may be the #rst and only choice of salivary gland cancers are treated similarly with surgery treatment available. and post-operative radiotherapy, with the exception of completely resected low-grade, low-stage MEC and poly- morphous low-grade adenocarcinoma, where post-opera- RESECTED SPECIMEN: HISTOTYPING, tive radiotherapy is not required.44 GRADNG AND MOLECULAR STUDIES Clinical grading combines information Salivary malignancies are categorized as per the 2017 WHO classification (featuring 22 different phenotypes: from histological type and grade Table 10.2). The characteristics that will also be reported To facilitate clinical use, the different histological sub- include the tumour grade, and describe negative features types are divided into low, intermediate and high grades such as perineural, vascular and perilymphatic invasion as shown in Box 10.1. 142 Section 1: Head and Neck Some of these proliferation markers have also been BOX 10.1 Grading of salivary gland investigated as therapeutic targets and these are tabu- malignancies based on clinical behaviour lated in Table 10.3. What follows is an overview of major Low: AcCC, PAC (formerly PLGA), and low-grade MEC advances in SGC molecular biology. Intermediate: AdCC and epithelial myoepithelial carcinoma High: High-grade MEC, SDC, carcinoma expleomor- Growth factor receptor proteins and their ligands phic adenoma, ACNOS and undifferentiated carcinoma Stem cell factor receptor (c-KIT, a transmembrane tyro- sine kinase), angiogenesis-related growth factor receptors (VEGFR, PDGFR, bFGFR, IL-8, PlGF , TGF!), nerve When one chooses to work with two groups the inter- growth factor (NGF), the ErbB/HER family of human mediate group is clubbed with the high-grade group for epidermal growth factor receptors (EGFR, also named the following reasons: AdCC is hard to cure often with HER-1 through -4 or ErbB-1 through -4), insulin-like a protracted clinical course, and epithelial myoepithelial growth factors IGF–I/II and receptor IGF-1R, and fibro- carcinoma is linked to a recurrence rate of 40% and a DSS blast growth factors 1 and 2 and fibroblast growth factor of only 60%.141, 142 It must be noted that this grade assign- receptor 1 belong to this category. c-KIT is detected in ment does not always parallel clinical behaviour. 80–94% of AdCC and in 100% of lymphoepithelial-like Despite these limitations, grading is still an essential SGCs and myoepithelial carcinomas, and in a subset of part of the workup and decision-making for the three other tumours as well. In AdCC, the relation between high most commonly encountered SGCs: AdCC,140, 143–145 c-KIT expression (> 50%) and grade remains unresolved. MEC132, 139, 146–150 and AcCC.85, 151, 152 As clinical grad- In one study this feature was significantly more common ing is strongly associated with other consistent prognostic in solid type AdCC but Freier et al.154 found the opposite: factors such as age11 and TNM-stage, 56, 140 it is often not high expression only in cribriform and tubular AdCC. retained in the final model in multivariate analysis. As for angiogenesis-related growth factor receptors, Lim et al.155 describe a prognostic value for vascular endothe- Molecular biology92, 122, 153 lial growth factor (VEGF) expression in many SGC. In multivariate analyses, VEGF expression was associated Protein products of various genes and their corresponding with advanced stage and with worse DSS. EGFR identi- genes in salivary gland cancers have been intensively stud- fication and overexpression parallels aggressiveness in ied to identify potential prognostic factors and treatment MEC, SDC, and AdCC. HER-2 has been found overex- targets. pressed in adenocarcinoma, undifferentiated carcinoma, AdCC, SDC and in 30% of MEC. Furthermore, it is a neg- PROGNOSTIC FACTORS ative prognostic marker in multivariate analysis, indepen- Cell cycle-based proliferation markers likely represent the dent of histopathological grade, tumour size and regional endpoint of the accumulation of genetic and epigenetic metastasis. On the other hand, in a recent study, ERBB1/ events that induce deranged growth, reflecting the num- CCND1/PIK3CA co-amplification was the most consis- ber of cells going through the cell cycle. The first subject tently observed pattern (29%). EGFR amplification cor- to interest cell biologists in SGC were silver-staining or related with distant metastasis, and the co-amplification argyrophylic nucleolar organizer regions (AgNOR); an pattern translated into a reduced survival. Aggressively increased AgNOR cluster to nucleolus volume reflects behaving AdCC also displays HER-3 expression. Recently proliferative activity and correlates with the degree of increased expression of NGF has been described in AdCC, malignancy. Other intensively studied factors include possibly accounting for its neurotropism. Fibroblast Ki-67 expression (anti-apoptotic nuclear antigen in pro- growth factors 1 and 2 and fibroblast growth factor recep- liferating cells), proliferating cell nuclear antigen expres- tor 1 are all overexpressed in salivary gland SGC. sion (PCNA, co-factor of DNA polymerase delta), human telomerase reverse transcriptase expression (hTERT) and TABLE 10.3 Molecular targets and corresponding TUNEL [terminal deoxynucleotidyl transferase (TdT)- therapies studied in salivary gland carcinoma mediated dUTP-biotin nick end labelling identifying Salivary gland DNA breaks in apoptotic cells] assays. In SGC, these Molecular target carcinoma type Molecular therapy proliferation markers correlate with optical grading and c-KIT AdCC imatinib have prognostic power in AdCC, AcCC, SDC and MEC. ErbB-1 All types cetuximab Importantly, their contribution is proven by remaining ge#nitib independent factors in multivariate models that include classical clinicopathological factors. The advantage of ErbB-2 All types trastuzumab lapatinib these proliferation indices is that they are not too expen- sive, widely applicable, correlate well with prognosis and VEGF -family AcCC axinitib thus could improve prognostic grouping. In this respect, NF B – proteasomes AdCC bortezomib Ki-67 staining is probably the best studied and most read- degrading its inhibitor (I- B)- ily available supplementary examination to aid in locating a specific SGC on the scale of biological aggressiveness. Reproduced with permission.92  10: MALIGNANT TUMOURS OF THE SALIVARY GLANDS 143 Cell cycle oncogenes the transcript Myb was found, suggesting this to be a The above-mentioned growth factor-receptor interac- tion activates cell cycle oncogenes. These include sex- potential target for new therapies. Proteins involved in DNA damage repair 10 determining region Y-box 4 (SOX-4), nuclear factor B (NF B), human rat sarcoma viral oncogene homo- p53 and ERCC1 (excision repair cross-complementation log (H-RAS), phosphatidylinositol 3 phosphate kinase/ group 1) belong in this category. p53 expression and p53 serine-threonine protein kinase Akt (PI3K/AKT), sar- mutations in AdCC are generally associated with worse coma (Schmidt-Ruppin A-2) viral oncogene homolog outcome, but a large Finnish multivariate analysis failed to (Src), signal transducer and activator of transcription 3 confirm additional value over a clinicopathological multi- (STAT3), mammalian target of rapamycin (mTOR, acti- variate model. This large study however did not focus on vated by AKT regulates protein synthesis depending on the AdCC subgroup but studied all histological types. nutrient availability), peroxisome proliferator-activated receptor gamma (PPARgamma), and cyclin D1. In a Proteins involved in apoptosis large microarray analysis of AdCC, Frierson et al. found The Bcl-2 group contains pro-apoptotic proteins such as that SOX-4 was the most significantly overexpressed Bax, Bad and Bak and anti-apoptotic proteins such as cell cycle oncogene.156 Furthermore, increased apoptosis Bcl-2, Bcl-xL and survivin. Low expression of Bcl-2 cor- following SOX-4 knockdown suggests that this onco- responds to higher apoptosis and thus better prognosis, gene exerts its activity via down-regulation of inhibitors whereas high Bcl-2 expression in SGC relates to poor of the NF B pathway (inhibitor protein (I- B)- ) and prognosis and advanced T and N classification. Nuclear by up-regulation of apoptosis inhibitors such as sur- survivin expression indicates SGC with worse prognosis. vivin. Mutations of H-RAS are observed in carcinoma ex-pleomorphic adenoma, in adenocarcinoma and in Proteins involved in cell-cell adhesion (hemidesmosome almost half of MECs, where the frequency of H-RAS proteins B180 and B230, E-cadherin, CDH12, -catenin), mutations parallels tumour grade. Cyclin D1 seems migration (matrix metalloprotease, heparanase) and frequently overexpressed in AdCC and MEC and cor- epithelial-mesenchymal transition (NBS-1 and snail) relates with prognosis. In MEC, high-cyclin D1 expres- Estrogen, progesterone and androgen receptors sion follows inactivation of secreted frizzled-related Estrogen receptors have been described in AdCC, whereas proteins (SFRPs) by hypermethylation. Nuclear pSTAT3 androgen receptors are the target of hormonal therapy in expression seems to play a role as tumour suppressor SDC. in the absence of EGFR, HER-2, and survivin in SGC. RUNX3, a tumour suppressor gene that, when active, Microarray technology gives a tumour-specific overview facilitates TGF-beta to play its apoptotic role, appears of over- and underexpressed tumour genes, and can silenced by hypermethylation in AdCC. RB1-inducible be used as a prognostic blueprint of a tumour. coiled-coil 1 (RB1CC1) is a positive regulator for the ret- inoblastoma tumour suppressor (RB1) pathway, and its This guides treatment for other tumours such as breast expression in SGC implies better prognosis, analogous cancer, but to date there have been only limited efforts to observations in breast cancer. Efforts are underway in SGC. An application of this strategy in AdCC resulted at targeting the PI3K/AKT pathway by blocking mTOR in the identification of a novel oncogene in salivary gland with temsirolimus. oncogenesis, AQP1, the transcription of which seems epi- Pleomorphic adenoma gene 1 (PLAG1) is a specific genetically regulated by (hypo-)methylation status. proto-oncogene found in a large percentage of pleomor- phic adenomas and is transcribed and overexpressed Viral aetiology following a t(3;8)(p21;q12) chromosome translocation EBV has been implicated in the genesis of bilateral resulting in !-catenin-promoter swapping. This causes Warthin’s tumours and undifferentiated SGC. CMV infec- deregulated expression of PLAG1 target genes by the tion in mice and in humans seems related to MEC devel- IGF-II/IGFIR mitogenic signalling pathway. Another opment. This awaits further validation in larger series, but fusion oncogene, MEC translocated 1 gene with exons the authors found the CMV protein expressed in almost 2–5 of the mastermind-like gene (MECT1-MAML2), all cases studied.17 Other viruses implicated in this disease t(11;19)(q14-21;p12-13) is transcribed into a fusion are HPV, human herpes virus 8 (HHV-8). protein that was initially thought to be exclusive for low-grade MEC. However, high-grade fusion-positive MEC cancers associated with advanced-stage lethal disease have now been described. For AdCC, a recur- SPECIFICS OF THE MAIN HISTOTYPES rent reciprocal translocation of t(6;9)(q22-23; p23-24) In population-based studies of parotid carcinoma, the resulting in fusion gene partners comprising MYB gene majority of carcinomas are AcCC (15–17%), followed by and the transcription factor NFIB (previously reported AdCC (16–27%) and MEC (14.5–19.2 %).8, 40 The distri- in AdCC of breast and, lacrimal and ceruminal glands) bution in submandibular gland cancer and MiSGC is dif- has now been described. In both fusion-positive and a ferent, with an emphasis on especially AdCC, more than subset of fusion-negative AdCCs, high expression of MEC and ACNOS (Table 10.4). 144 Section 1: Head and Neck TABLE 10.4 Distribution of the major histological tumour types in minor salivary gland carcinomas122* Authors No. of patients AdCC % MEC % ACNOS % CAN % Others % Spiro et al.56 378 34 34 21 1 10 Sadeghi et al.76 117 59 25 15 0 1 Garden et al.67 160 71 16 11 1 1 Anderson et al.68 95 43 26 26 3 0 Parsons et al.63 95 60 15 22 – – Chou et al.59 256 32 38 16 3 14 Jones et al.135 103 70 19 – 1 9 Le et al.58 54 59 13 28 – – Vander Poorten et al.11 55 40 16 16 6 16 Terhaard et al.73 157 42 23 22 6 6 Pires et al.136 546 15 52 9 9 15 Loh et al.158 171 47 23 19 – – Kruse et al.159 27 48 30 22 – – Kakarala et al.160 639 26 50 22 2 – Carrillo et al.57 77 45 30 15 4 6 Li et al.137 103 47 36 – 3 15 * Reproduced with permission. Acinic cell carcinoma (AcCC) influenced by clinical stage, histological grade, and surgi- cal margins, all strongly interrelated factors. In grading AcCC usually presents as a painless parotid lump and forms MEC, two- and three-tiered systems have been advocated. some 15–17% of parotid malignancies, yet they account for Batsakis et al.162 follow the suggestion of Healey et al.148 only 3% of all salivary gland tumours, indicating a clear for a three-tiered system, based mainly on the involved parotid predilection.162 Macroscopic pathology commonly cell types. Healey found in univariate analysis that recur- shows a solitary encapsulated lesion but multilobulation rence rates of low- and intermediate-grade carcinomas are does occur. This tumour arises from the acinic cells, but in quite similar with a recurrence rate of 6% and 20% for 75% of AcCC more than one cell type is seen and the histo- low- and intermediate-grade MEC respectively, vs. 78% logical patterns described include solid microcystic, papil- for high-grade carcinomas. The Armed Forces Institute lary cystic and follicular. All of these patterns may be seen of Pathology (AFIP) also proposed a three-tiered grad- in one individual tumour.162 AcCC is generally considered ing system, based on different criteria, and promoted a low grade and is considered to have the best survival rate, more quantitative approach but the clinical data support- but a high-grade aggressive subgroup (papillary cystic vari- ing this complicated grading system are not convincing. ety) has poorer prognosis.71, 152, 161 AcCC has a long natural Brandwein et al. showed a good correlation of these AFIP history and long-term follow-up is mandatory. Spiro found grades with stage and local control, but revealed a sig- that the cure rate continued to drop from 76% at 5 years nificant grading disparity among five experienced oral to only 55% at 15 years and other authors have found the pathologists using the ‘standard AFIP grading criteria’.132 same.156 Clearly, this can be an aggressive tumour that More appealing to clinicians are simpler two-tier grad- should be treated accordingly – early attempts at enucle- ing systems. Evans150 suggests that > 90% solid tumour in ation yield disastrous survival figures.163, 165 It is generally MEC indicates a high-grade histology, with only univari- accepted that one should not hesitate to use post-operative ate analysis supporting this; Ciccolallo et al. suggest that radiotherapy, which can only be omitted for low-stage > 90% epithelial cells should be interpreted as high-grade AcCC in absence of adverse prognostic factors.83, 92, 110 histology, supported by the observation that patients with low-grade tumours have a 5-year survival of 96% whereas high-grade tumours show a death rate 10 times this. Mucoepidermoid carcinoma (MEC)122 Recent large studies find no prognostic difference between Whereas AdCC is the most frequent MiSGC overall, low- and intermediate-grade MEC.167 To summarize, in MEC is the most frequent type at the intraoral subsite. clinical practice only the low-grade subgroup without MEC represents about 16–37% of all MiSGCs, but further negative prognostic features should be managed about 36–59% of intraoral MiSGCs. As in many salivary with surgery alone. In the intermediate-grade MEC group malignancies the tumour is formed of several cell types, many patients will have additional negative prognostic in MEC there are mucus-secreting cells, epidermoid cells factors (e.g. involved surgical margins or soft tissue inva- and intermediate cells. The prognosis of MEC is mainly sion) that will be an indication for adjuvant radiotherapy.  10: MALIGNANT TUMOURS OF THE SALIVARY GLANDS 145 Adenoid cystic carcinoma (AdCC)122 alarming to the oncologist and the patient, frequently AdCC demonstrates insidious growth over many years, with a tendency for local recurrence and distant metas- grow slowly. A Japanese study analyzed 30 patients where 21 had pulmonary metastases, 4 of these at presentation 10 and 17 during follow-up, and showed a cumulative inci- tasis despite aggressive therapy at the primary site. Some dence of distant metastasis in 100% of patients followed patients have severe pain due to nerve invasion, and in the for longer than 5 years, regardless of grade and initial parotid gland VIIN palsy may be evident. In a study from stage.173 The average tumour doubling time of a meta- Liverpool dealing with 108 patients with AdCC, nearly static deposit was just over one year, which is very slow, one-third occurred in the major salivary glands, and most compared with lung metastases from other cancers. This of the remainder involved the minor glands.168 Forty per tumour doubling time suggests that distant metastasis is cent of patients had oral cavity tumours and half of these often present long before the initial diagnosis of the pri- were in the hard palate. Of all tumours 41% were locally mary salivary gland tumour, and this obviously puts in advanced at presentation and 11% had distant metastases. perspective the limits of ablative surgery for AdCC in the Interestingly, revision of the pathology slides led to 15% head and neck. reclassification as PLGA. In the Netherlands’ series, 17% As stated above, AdCC can be graded histologically. of the parotid cancers were AdCC, as were 40% of the The scheme proposed by Szanto et al.144 indicates a pri- cancers of the submandibular gland. marily cribriform or tubular tumour as grade I; tumours AdCC thus mainly occurs in the MiSG, where it is with less than 30% solid component are grade II and the most common subtype (32–71%) and, as shown in tumours with greater than 30% solid component are Figure!10.2, occurs mostly in the palate followed by the grade III. In patients treated similarly, a solid histologi- paranasal sinuses (14–17%). This tumour will often be cal pattern of AdCC carries a worse prognosis in terms of diagnosed at an advanced stage, and due to the complex distant metastases and long-term survival on univariate anatomical area in the skull base region, complete exci- analysis. In multivariate analysis, when including stage sion is frequently impossible169 and further complicated by at presentation, this prognostic effect is less clear, yet a the propensity of AdCC for perineural extension, both in Brazilian study recently confirmed solid histology as an the MiSG, and in the parotid and submandibular glands, independent prognostic factor.174 where large nerves are closely adjacent to the tumour. This perineural growth is notorious for skip lesions, for example, in the VIIN, isolated AdCC deposits can be Polymorphous adenocarcinoma observed several centimetres from where tumour inva- sion apparently terminated, both on frozen section and (PAC; formerly polymorphous low- on later paraffin-section histology. The feature ‘perineural grade adenocarcinoma (PLGA))122 growth’ implies a worse prognosis. PAC, prior to 1983 considered a low-grade variant of A study from the University of Michigan showed 80% AdCC and initially also referred to as terminal duct ade- positive margins in operated skull base AdCC cases, even nocarcinoma, has a less aggressive biological behaviour with tumours where experienced surgeons pre-operatively compared to other types of adenocarcinoma. About 75% had the feeling they could resect the tumour with clear of these tumours arise from MiSGs. Major salivary gland margins.166 Every AdCC should be considered a ‘clini- involvement is relatively unusual. It most frequently arises cally high-grade malignant neoplasm’: the behaviour of on the palate. Despite the better prognosis, local recur- AdCC is relentless and the long-term course is marked rence even with negative margins, regional recurrence and by multiple local recurrences, uncommon regional and distant metastasis have all been described. Recurrence yet frequent distant metastatic spread to the lungs and can occur very late in follow-up: in one series, local bones. It is often said that cure is never achieved in this recurrences occurred at 15 years and regional recurrence disease. Sometimes optimistic 5-year survival rates are occurred at 20 years after initial treatment. Therefore, reported (e.g. 92% in an Australian series),169 but 10- the term ‘low-grade’ is omitted in the most recent WHO and 20-year survival rates continuously drop (e.g. in a classification, which now talks about ‘Polymorphous UK series 40% at 20 years and continuing to drop until Adenocarcinoma’. There are four histological patterns: 30 years; the actuarial primary site recurrence rate in that tubular, cribriform, papillary and lobular, and because study was 100% recurrence at 30 years,168 and 54% in of this variable appearance, P(LG)AC may be mistaken the Australian series). In a large European study, 10 years for pleomorphic adenoma or other benign tumours, and survival was 65%.171 for AdCC, due to comparable growth patterns and to AdCC uncommonly presents with lymph node metasta- the presence of neurotropism. Immunohistochemical and sis, and recently an interesting hypothesis has been devel- molecular biological studies may help to differentiate oped to explain this phenomenon. AdCC does produce these two lesions. only very limited amounts of VEGF-C, which translates into very few lymphatic vessels within the tumour due to a reduced interaction with VEGFR-3.172 AdCC frequently metastasizes to bone and liver, but Adenocarcinoma NOS most frequently to the lung, in approximately 70% of This histology also forms a large subgroup in major patients in most series. The latter metastases, although series (8–18% of parotid carcinoma), but this proportion 146 Section 1: Head and Neck depends on the effort by pathologists to revise the mate- carcinomas, Conley stated in the early 1970s52 that there rial. A substantial part of the tumours initially classified was no indication that irradiation should be given when as adenocarcinoma not otherwise specified (ACNOS) can an adequate operation has been performed; thus, only be specified as one of the subtypes in Table 10.2 upon revi- 12% of his patients were treated in a combined fashion, sion using modern histopathological techniques. 34, 40, 73 and there are reports of series advocating radiotherapy in Nonetheless, frequently the remaining ACNOS are aggres- less than 3% of surgically treated patients.116 In contrast, sive, with advanced locoregional extension at diagnosis in the Netherlands’ Cancer Institute series, 67% received and frequently implying perineural growth and positive combined treatment, as did 59% of patients in the resection margins.41 Princess Margaret Hospital series, Toronto, with signifi- cant reported improvement in locoregional tumour con- trol. 54 Post-operative radiotherapy to the primary tumour Carcinoma ex-pleomorphic adenoma used to be delivered by conformal wedged-pair beams to These tumours account for up to 5–25% of all SGC and a dose of 60 Gy44, 73, 110, 182, 183 but has been replaced by tend to arise in the major glands.9, 37, 112, 175 The risk of devel- 3-dimensional (3D) conformal radiotherapy and lately oping this carcinoma within a pre-existing pleomorphic intensity-modulated radiotherapy (IMRT), which is now adenoma increases with the time a pleomorphic adenoma considered the ‘standard of care’.184, 185 exists, to as much as 10% by 15 years. Carcinogenesis Radiotherapy is indicated in advanced stage disease seems associated with frequent earlier attempts at removal (stage III and IV) and in the presence of histopathologi- of a recurrent benign pleomorphic adenoma, the reason cal adverse prognostic factors. Lacking randomized trials, why optimal initial surgery is so much stressed upon in the evidence for this approach comes from retrospective trainee surgeons.177–179 The tumour may be malignant reports, with a bias of selecting prognostically nega- from onset or carcinomatous transformation can occur.179 tive patients for combined therapy, yet demonstrating In recurrent pleomorphic adenoma, the rate of carcinoma improved locoregional control in the combined treatment found ranges from 7% to 16%.177, 178, 180 In the 2005 group. 51, 70, 110, 185–187 The study of the Dutch Head and WHO classification, for the previous term ‘carcinoma Neck Oncology Cooperative Group illustrates this by a ex-pleomorphic adenoma’ a distinction is made between relative risk (RR) for local recurrence in surgical patients carcinoma in pleomorphic adenoma (which can be a nidus being 9.7 times the risk of patients receiving combined of non-invasive carcinoma in pre-existent pleomorphic surgery and radiotherapy. These findings are consis- adenoma or a true invasive carcinoma), the very rare and tent with the older matched pair analysis by Armstrong aggressive carcinosarcoma, and the metastasizing mixed et al., describing a significantly improved DSS and local tumour, in which metastases contain typical benign struc- control in patients with stage III and IV disease treated tures. The prognosis of a carcinoma in pleomorphic ade- with radiotherapy following resection.108 Post-operative noma is poor: the MSKCC cause-specific survivals for this radiotherapy can only be omitted for stage I-II lesions in disease are 40% at 5 years, 24% at 10 years and 19% at AcCC and low-grade MEC if complete resection does not 15 years.181 reveal other adverse pathological factors (close surgical margins, perineural or perilymphatic invasion, or recur- rent disease).41, 55, 83, 92 For high-risk major salivary gland KEY POINTS carcinomas, two reports recently documented the benefit The histopathological workup of SGC, i.e. typing of a post-operative platinum-based concomitant chemora- and grading, is among the most complex areas in diation scheme.188, 189 histopathology. This holds for the light microscopic, immunohistochemi- cal and molecular biological aspects of the histopatho- Minor salivary gland cancer logical workup. Once the MiSGC has been resected and pathologically Enormous advances in SGC molecular biology in the last two decades have resulted in better prognostic #ne- staged and graded, post-operative radiotherapy to the tuning, but to date have not resulted in advances in treat- primary site is recommended for most patients. Only in ment, nor in improved treatment results. ‘clear margin’ early stage disease (stage I and II) without lymphovascular or perineural invasion (a set of condi- tions usually restricted to low-grade variants), can post- operative radiotherapy be omitted without loss of disease POST-OPERATIVE RADIOTHERAPY control11, 73, 110, 122, 125 Adverse prognostic factors, such as positive or close surgical margins,67, 76, 125, 131 a high- Parotid and submandibular grade histology,60, 67, 125 perineural growth (particularly ‘named’ nerve invasion),75, 125, 190, 191 bone and muscle salivary gland malignancies invasion, paranasal sinus localization, and high T- and Following resection and classical histologic