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British Journal of Oral and Maxillofacial Surgery 47 (2009) 587593

Leading article

Prognostic factors in malignant tumours of the salivary glands

Paul M. Speight a, , A. William Barrett b
a

Department of Oral & Maxillofacial Pathology, School of Clinical Dentistry, University of Shefeld, Claremont Crescent, Shefeld S10 2TA, United Kingdom b Department of Histopathology, Queen Victoria Hospital, Holtye Road, East Grinstead, West Sussex RH19 3DZ, United Kingdom Accepted 27 March 2009 Available online 5 May 2009

Abstract Salivary gland tumours are a relatively rare group of lesions best managed in specialist centres. We review some of the factors that inuence their prognosis. Clinical stage is the most important, with large malignancies having a poor prognosis regardless of histological grade and other features such as perineural invasion. Even high grade neoplasms may do well when they are small. A helpful guide to the management of salivary cancers is the 4 cm rule. 2009 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Keywords: Head and neck; Salivary gland diseases; Mouth neoplasms; Prognostic factors

Introduction Salivary gland tumours vary widely in their histological and clinical features, and are challenging to diagnose and manage.1 They are uncommon compared with squamous cell carcinomas (SCCs) of the oral cavity, and have an overall global incidence of 0.413.5 cases/100,000.2 Most are benign and the incidence of malignant salivary gland neoplasms ranges from 0.4 to 2.6 cases/100,000.36 We consider the factors that inuence the prognosis of malignant neoplasms of epithelial origin, which number 24 in the latest World Health Organization (WHO) classication of salivary gland tumours.7 In clinical practice, only ve salivary gland carcinomas are likely to be encountered with any degree of frequency; mucoepidermoid carcinoma, adenoid cystic carcinoma, carcinoma in pleomorphic adenoma, acinic cell carcinoma and, in the minor glands, polymor Corresponding author at: Department of Oral and Maxilofacial Pathology, School of Clinical Dentistry, University of Shefeld, Claremont Crescent, Shefeld S10 2TA, United Kingdom. Tel.: +44 0114 271 7951; fax: +44 0114 271 7894. E-mail address: p.speight@shefeld.ac.uk (P.M. Speight).

phous low grade adenocarcinoma.8 It is likely therefore that even specialist pathologists and surgeons will be required to diagnose and treat salivary gland cancers rarely, with some being encountered only once or twice in a working lifetime, if at all. However, many of the prognostic factors apply to all of them, with histological features providing additional information in only a few specic entities. In this review we consider clinical stage, use of histological grading where it is helpful, and perineural invasion, which is a characteristic nding in some salivary adenocarcinomas.

An overview of prognosis: stage compared with grade The latest WHO classication of tumour, node, metastasis (TNM) of salivary gland carcinomas7 is shown in Table 1. Stage IV is subdivided following the division of T4 into T4a (resectable tumours invading skin, mandible, ear canal, or facial nerve), and T4b (unresectable tumours invading the base of skull, pterygoid plates, or encasing the carotid artery). Although tumours up to 4 cm are allocated a T grade of T1 (2 cm or less) or T2 (>24 cm), any clinical or macroscopic

0266-4356/$ see front matter 2009 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

doi:10.1016/j.bjoms.2009.03.017

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P.M. Speight, A.W. Barrett / British Journal of Oral and Maxillofacial Surgery 47 (2009) 587593

Table 1 World Health Organization staging of salivary gland carcinomas.7 . Stage I II III Tumour 1 2 3 1, 2, 3 IVA IVB IVC 1, 2, 3 4a 4b Any Any Size 2 cm or less 24 cm <4 cm and/or extraparenchymal extension Node 0 0 0 1 2 0, 1, 2 Any 3 Any Metastasis 0 0 0 0 0 0 0 0 1

that are less than 4 cm (T1 or T2) do well regardless of histological type or grade.16 It has also been shown that adjuvant radiotherapy has a survival advantage for patients with tumours over 4 cm, but has little benet for those with smaller ones, which suggests that along with involved margins, tumours over 4 cm are an absolute indication for postoperative radiotherapy.15,16,18,22

Other prognostic indicators Many other prognostic indicators of variable importance have been reported. Several have proved to be important, including age,17,2326 site,17 involved margins24 and lymph node metastasis.16,17,26 Vander Poorten et al. devised a prognostic index for parotid cancer, which calculated a weighting of relevant factors using Cox proportional hazards regression analysis.24,27 Age was relatively unimportant preoperatively, with a weighting of 0.024. By contrast, size (T1T4) and nodal involvement (N0N3) were important and were weighted similarly (0.44 and 0.45, respectively), and the presence of pain (0.62) and invasion of skin (0.63) were more signicant still. However, the heaviest weighting (0.91) was assigned to paralysis of the facial nerve. Using the formula a score of 14 was derived and designated the PS1 index. A separate index (PS2) was calculated postoperatively using the same variables without the inclusion of pain, but with the addition of histological observations of involved margins (0.65), and perineural invasion (0.78). The index was validated on 231 parotid malignancies for recurrence-free survival at 5 years;27 both PS1 and PS2 produced a survival rate of 90% for a score of 1 and 40% for a score of 4. Scores of 2 and 3 were not as close, with rates of 70% and 59% for PS1, and 87% and 70% for PS2, respectively. Gender, tumour grade, site, number of metastatic lymph nodes, and extracapsular spread did not improve the prognostic power of the index.

evidence of extraparenchymal extension (invasion of soft tissue or nerve) upgrades it to T3 regardless of size. With regards to grade, the earlier classications of the Armed Forces Institute of Pathology (AFIP) divided all malignant salivary gland tumours into three grades; low, intermediate, and high,9 but this distinction did not appear in a later fascicle.10 Nevertheless oncologists invariably request an assessment of histological grade to assist in their planning of treatment. While there is evidence that histological grade is a guide to prognosis, it is more useful for some tumour types than others. Also, grade cannot be considered in isolation from clinical factors, and stage may be a better predictor of prognosis.1113 Extensive and signicant work on this topic from the Memorial Sloan Kettering Cancer Center has been reviewed by Spiro et al.14 Their data show that clinical stage, particularly tumour size (T), rather than histological grade is the critical factor in deciding the outcome of salivary gland cancer. Essentially, a stage III or IV tumour (more than 4 cm, with or without nodal involvement, and with or without extension) will do badly regardless of histological grade. Conversely, lesions in stages I and II (less than 4 cm) tend to do well. Low grade lesions have a better prognosis, but so do high grade lesions if they are in stage I or II.1518 This partly explains the apparent paradox that in one study of parotid malignancy the 10-year survival of low, intermediate, and high grade adenocarcinomas was 91%, 41%, and 50%, respectively.16 In this study the impact of high grade lesions on survival was only apparent if they were also large (stages III and IV). Similarly, patients with small, but high grade adenoid cystic carcinomas have a better prognosis than histological features suggest.14,19 In a study of mucoepidermoid carcinomas, overall survival at 5 and 10 years was 92% and 90%, respectively, but all the patients who died had had stage III or IV disease at diagnosis. The 5- and 10-year survival rates in this group of larger lesions was only 64% and 52% respectively.20 The 4 cm rule A widely used, but little reported guide to the management of salivary gland cancers is the 4 cm rule.21 Tumours

Grading of specic types of tumour Grading of salivary gland cancer is invariably subjective, but is based on knowledge of individual entities and the cellular and morphological features of individual tumours. Clinical experience supports the categorisation of tumours into families that show low and high grade types (Table 2). For example, the known behaviour of papillary cystadenocarcinomas warrants a classication of low grade, whereas salivary duct carcinomas are high grade. However, Table 2 shows that some cancers can be graded on their histological appearance. This includes mucoepidermoid carcinoma, adenoid cystic carcinoma, adenocarcinoma not otherwise specied (NOS), and primary SCC, all of which have low and high grade variants and in which grading is of prognostic value. However, the situation is confused when, for example, histologically intermediate grade mucoepidermoid carci-

P.M. Speight, A.W. Barrett / British Journal of Oral and Maxillofacial Surgery 47 (2009) 587593 Table 2 Grading of salivary gland adenocarcinomas after Cheuk and Chan13 . Low grade Polymorphous low grade adenocarcinoma Acinar cell carcinoma Basal cell adenocarcinoma Myoepithelial carcinoma Cystadenocarcinomas Epithelialmyoepithelial carcinoma Mucoepidermoid carcinoma Adenoid cystic carcinoma Adenocarcinoma NOS Squamous cell carcinoma Carcinoma ex-pleomorphic adenoma Salivary duct carcinoma Oncocytic carcinoma Undifferentiated carcinomas * * * * * * * * * * * * * * * * * * High grade

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Table 3 Grading of mucoepidermoid carcinoma using the scheme of Brandwein et al28 . (A) Histological features Histological feature Cystic component <25% Neural invasion Necrosis Mitoses >4/10 high power elds Prominent atypia Invasion in small nests and islands Lymphatic or vascular invasion Invasion of bone (B) Grading and scoring Grade I (low) II (intermediate) III (high) Total score 0 23 4+ Score 2 3 3 3 2 2 3 3

noma is categorised as a low grade tumour,13 or all adenoid cystic carcinomas are classed as intermediate grade.16 Both these neoplasms show histopathological variants that could be assessed as low, intermediate, or high. Adenocarcinoma NOS and primary SCC are graded in a similar way to extra salivary lesions according to the degree of differentiation. In the case of mucoepidermoid carcinoma, grading was traditionally based on a subjective assessment of the amount

Fig. 1. Mucoepidermoid carcinoma of the parotid. (a) Low grade lesion comprising scattered cysts with cellular mural thickenings present only focally (haematoxylin and eosin, original magnication 10) and (b) intermediate grade tumour where solid islands predominate over the cystic component (haematoxylin and eosin, original magnication 10).

of cystic change in the tumour, and on features of aggression or cytological atypia (Fig. 1). More recently, based on the AFIP experience, Goode et al.23 described a more objective scheme based on numerical scores given to histological features, which Brandwein et al.28 modied giving greater weight to features of invasion (Table 3). The latter group examined the inter-observer error of the two schemes and showed that the AFIP scheme tended to downgrade tumours, which may explain reported cases of aggressive behaviour in low grade lesions. In the AFIP series, grade 1 lesions in the major glands metastasised or caused death in 5% of patients,23 but with the modied grading scheme all grade 1 tumours were also stage I and none metastasised.28 All patients with grade 1 lesions were disease-free at 10 years, compared with roughly 70% with grade 2 lesions, and less than 40% with grade 3. The authors claimed that their grading scheme was better at allocating tumours to more realistic behavioural groups, but also found stage to be important. Over 90% of patients with stage I or II tumours were diseasefree at 10 years compared with less than 30% with stage III or IV disease. This suggests that although grade is important, stage still seems to be a better indicator of prognosis, a view shared by the AFIP.10 Polymorphous low grade adenocarcinoma is the only salivary tumour with a name that suggests its clinical behaviour. In most cases it affects the minor salivary glands and shares some histological appearances with the benign pleomorphic adenoma and the more aggressive adenoid cystic carcinoma, potentially posing a diagnostic problem. Both polymorphous low grade adenocarcinoma and adenoid cystic carcinoma may show cribriform morphology and perineural inltration (Fig. 2), and distinguishing between the two may be difcult in a small biopsy specimen. The distinction is important as it may affect treatment and prognosis. A recent study has shown that expression of minichromosome maintenance proteins in these lesions may be a useful discriminatory marker.29 In the

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P.M. Speight, A.W. Barrett / British Journal of Oral and Maxillofacial Surgery 47 (2009) 587593

Fig. 3. Papillary cystic pattern in a polymorphous low grade adenocarcinoma (haematoxylin and eosin, original magnication 100).

Fig. 2. Perineural invasion: (a) polymorphous low grade adenocarcinoma. Between the affected nerves (N) is a cribriform island (C) (haematoxylin and eosin, original magnication 100) and (b) adenoid cystic carcinoma of predominantly tubular morphology (haematoxylin and eosin, original magnication 20).

largest series of polymorphous low grade adenocarcinomas, which comprised 164 cases,30 98% of patients were either alive or had died with no evidence of recurrence, over a mean follow-up period of 115 months. However, despite its name up to a third of polymorphous low grade adenocarcinomas recur locally or metastasise to regional lymph nodes. Some morphological characteristics have been suggested to identify those tumours that may not, in fact, be low grade. For example, one study reported a signicant relation between a papillary cystic growth pattern (Fig. 3) and cervical lymph node metastasis.31 The relation between invaded margins and local recurrence was also signicant, but other clinicopathological variables, including tumour size, necrosis, mitotic rate, and bone and perineural invasion had no prognostic signicance. Unfortunately this introduces another subjective element, as focal areas of papillary cystic change are common in polymorphous low grade adenocarcinoma. Nevertheless, if papillary cystic change is prominent in a polymorphous low grade adenocarcinoma we alert the clinical team to the possibility of aggressive behaviour. We have previously discussed this issue and have suggested that this tumour should not be designated low grade, but should be called polymorphous adenocarcinoma.1

By comparison, the grading of adenoid cystic carcinoma is generally quite straightforward as it depends primarily on the morphological pattern of the tumour. Three patterns are recognised, namely cribriform, tubular, and solid, and tumours are categorised according to the predominant pattern (Fig. 2).13,32,33 The cribriform, multicystic or Swiss-cheese pattern is the most common and characteristic, and comprises 44% of all lesions with the tubular pattern in about 35% and solid in 21%.33,34 Most authorities agree that the solid adenoid cystic carcinoma is a high grade lesion, and it has been shown to have a higher rate of proliferation and greater expression of minichromosome maintenance proteins, which are markers of cell cycle progression.29 Solid lesions have reported recurrence of up to 100%, compared with 5080% for the tubular and cribriform variants.35 In some reports, no patients with the solid variant survived for 10 years.36 Reports vary about the behaviour of tubular and cribriform lesions. Perzin et al.34 reported that the tubular type have the best outcome with regard to recurrence and survival, but others found the cribriform pattern to be the most favourable.35 The AFIP categorise solid adenoid cystic carcinoma as high grade and both the tubular and cribriform types as intermediate grade.9 At the Memorial Sloan Kettering Cancer Center adenoid cystic carcinomas are graded according to the proportion of solid areas.36 Predominantly solid lesions are grade 3 (high), predominantly cribriform are grade 1 (low), and those with equal solid and cribriform or tubular areas are grade 2 (intermediate). Spiro et al. 19,36,37 generally dismiss the histological features of adenoid cystic carcinoma as important predictors of clinical behaviour, believing clinical factors (notably stage, large tumour size, and involvement of lymph nodes) to be more predictive of distant metastasis and ultimate prognosis. Grade was a deciding factor for 5-year, but not long term (1525 years) survival.36 Renehan et al.16 also regard histological features of little prognostic use. Unfortunately,

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regardless of grade or pattern, all adenoid cystic carcinomas have a protracted course and ultimately a poor outcome. Using the Memorial Sloan Kettering scheme, grade 1 and 2 lesions have similar outcomes at 5 years (roughly 85% survival), but at 10 years all grades do equally badly, with overall survival of less than 50%.36 Most adenoid cystic carcinomas are widely inltrative at diagnosis, invade bone early, and characteristically show perineural inltration. They typically recur frequently, and between 35% and 50% develop late distant metastases, usually to lung or bone, compared with only 10% with regional lymph node metastases.37,38 These factors and an unusually slow biological growth result in a relatively favourable 5-year survival, but poor longer term outcome. Age,39 positive surgical margins,4042 lymph node metastasis,43 and invasion of bone, vasculature, muscle, or extraglandular structures44 have all been implicated as adverse ndings in some (though by no means all) studies of adenoid cystic carcinoma. Most reports of this neoplasm also comment on the importance, or otherwise, of perineural inltration.

As implied by the prognostic index described above,24,27 clinical evidence of nerve invasion is a poor prognostic indicator. Such evidence may become manifest as paralysis, paraesthesia, deafness, diplopia, pain or tic. A review of 18 series reported between 1961 and 1999 suggested that clinical signs and symptoms of the involvement of nerves occurred in about 25% of patients with adenoid cystic carcinoma. However, the range was 286% for tumours at all sites and 957% of those affecting the parotid gland.46 Paralysis of the facial nerve is an important predictor of lymph node metastasis,52 and the gravity of VIIth nerve palsy was emphasised by Eneroth,53 who reviewed 378 parotid adenocarcinomas. While only 46 presented with this symptom, 77% of them developed metastasis and 98% died. In contrast, of the 332 patients with no evidence of involvement of the facial nerve there was metastasis in 27% and 33% died of their disease.

Summary and Conclusions The potential prognostic indicators in salivary gland cancers are stage, histological type and grade, involvement of nerves, site, age, gender, and status of surgical margins. In most studies stage and clinical evidence of nerve invasion are independent factors deemed to be of the greatest prognostic importance. Histological grade is a helpful guide in some neoplasms, and specic histological features may provide additional clues about unfavourable behaviour. T1 and T2 tumours less than 4 cm in size generally do well regardless of histological grade or any other features, and this rule has proved to be a useful clinical guide to behaviour and outcome.

Perineural invasion It is a paradox that perineural inltration is regarded as a sinister prognostic indicator, yet it is a characteristic and diagnostically useful feature of both polymorphous low grade adenocarcinoma and adenoid cystic carcinoma. It may also occur in any malignant neoplasm, is a feature of 27% of head and neck SCCs,45 and is a feature of most adenoid cystic carcinomas (Fig. 2). A review of 35 reports from 1961 to 1999 showed that perineural inltration occurred in roughly 60% of these tumours, though the range was 898%.46 Of these studies, 25 looked at prognosis and 14 showed that perineural inltration was associated with a poor prognosis. However, in four of these the prognosis was poor only if major named nerves external to the gland were involved, or nerves of a minimum diameter. The critical dimension was 0.25 mm or more in one study,47 and between 0.5 and 3.0 mm in another.48 In the former, invasion of nerves larger than this critical value correlated with tumour size and advanced clinical stage. Eleven of the 25 studies reported no association between perineural inltration and prognosis, but the number of cases in each series ranged from 21 to 198, and not all of them had applied statistical tests. A short period of follow-up could be criticised in others. Data on the signicance of histological perineural invasion is therefore equivocal. Some studies report it as signicant on univariate, but not on multivariate analysis.22,49,50 However, two studies have found it to be an independent factor in prognosis,42,51 and it is a means by which the tumour can grow along a plane of low tissue resistance. Even anatomical barriers can be breached since all are pierced by neurovascular bundles. It is particularly important when it occurs outside the main tumour mass, or causes clinical manifestations.

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