Prognostic factors in malignant tumours of the salivary glands

doi:10.1016/j.bjoms.2009.03.017

British Journal of Oral and Maxillofacial Surgery

Volume 47, Issue 8, December 2009, Pages 587-593

https://doi.org/10.1016/j.bjoms.2009.03.017 Get rights and content

Abstract

Salivary gland tumours are a relatively rare group of lesions best managed in specialist centres. We review some of the factors that influence 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.

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 0.4–13.5 cases/100,000.² Most are benign and the incidence of malignant salivary gland neoplasms ranges from 0.4 to 2.6 cases/100,000.3, 4, 5, 6 We consider the factors that influence the prognosis of malignant neoplasms of epithelial origin, which number 24 in the latest World Health Organization (WHO) classification of salivary gland tumours.⁷ In clinical practice, only five 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, polymorphous 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 specific entities. In this review we consider clinical stage, use of histological grading where it is helpful, and perineural invasion, which is a characteristic finding in some salivary adenocarcinomas.

Section snippets

An overview of prognosis: stage compared with grade

The latest WHO classification 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 (>2–4 cm), any clinical or macroscopic evidence of

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 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 benefit 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,

Other prognostic indicators

Many other prognostic indicators of variable importance have been reported. Several have proved to be important, including age,17, 23, 24, 25, 26 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 (T1–T4) and nodal

Grading of specific 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 classification of low grade, whereas salivary duct carcinomas are high grade. However, Table 2 shows that some cancers can be

Perineural invasion

It is a paradox that perineural infiltration 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 infiltration occurred in roughly 60% of these tumours,

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 specific histological features may provide additional clues about unfavourable behaviour. T1 and T2 tumours less than 4 cm in

References (53)

J. Ostman et al.
Malignant salivary gland tumours in Sweden 1960–1989—an epidemiological study
Oral Oncol
(1997)
J.A. Pinkston et al.
Incidence rates of salivary gland tumors: results from a population-based study
Otolaryngol Head Neck Surg
(1999)
A.V. Jones et al.
The range and demographics of salivary gland tumours diagnosed in a UK population
Oral Oncol
(2008)
R.H. Spiro et al.
The importance of clinical staging of minor salivary gland carcinoma
Am J Surg
(1991)
R.H. Spiro et al.
Stage means more than grade in adenoid cystic carcinoma
Am J Surg
(1992)
K. Plambeck et al.
Mucoepidermoid carcinoma of salivary gland origin: classification, clinical–pathological correlation, treatment results and long-term follow-up in 55 patients
J Craniomaxillofac Surg
(1996)
R.B. Bell et al.
Management and outcome of patients with malignant salivary gland tumors
J Oral Maxillofac Surg
(2005)
D.E. da Cruz Perez et al.
Prognostic factors in head and neck adenoid cystic carcinoma
Oral Oncol
(2006)
A.S. Garden et al.
The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation
Int J Radiat Oncol Biol Phys
(1995)
H. Kokemueller et al.
Adenoid cystic carcinoma of the head and neck—a 20 years experience
Int J Oral Maxillofac Surg
(2004)

A.M. Chen et al.

Adenoid cystic carcinoma of the head and neck treated by surgery with or without postoperative radiation therapy: prognostic features of recurrence

Int J Radiat Oncol Biol Phys

(2006)

M. Huang et al.

Factors influencing survival rate in adenoid cystic carcinoma of the salivary glands

Int J Oral Maxillofac Surg

(1997)

D.E. Eibling et al.

Flow cytometric evaluation of adenoid cystic carcinoma: correlation with histologic subtype and survival

Am J Surg

(1991)

S. Pohar et al.

Malignant parotid tumors: presentation, clinical/pathologic prognostic factors, and treatment outcomes

Int J Radiat Oncol Biol Phys

(2005)

P.M. Speight et al.

Salivary gland tumours

Oral Dis

(2002)

G.L. Ellis et al.

Classification of salivary gland neoplasms

E.C. Sun et al.

Salivary gland cancer in the United States

Cancer Epidemiol Biomarkers Prev

(1999)

P. Koivunen et al.

Malignant epithelial salivary gland tumors in northern Finland: incidence and clinical characteristics

Eur Arch Otorhinolaryngol

(2002)

G.L. Ellis et al.

Salivary gland neoplasms: general considerations

G.L. Ellis et al.

Atlas of tumor pathology

Tumors of the salivary glands. Series 3, Fascicle 17

(1996)

R.H. Spiro

Salivary neoplasms: overview of a 35-year experience with 2807 patients

Head Neck Surg

(1986)

W. Cheuk et al.

Salivary gland tumours

R.H. Spiro

Factors affecting survival in salivary gland cancers

J.G. Armstrong et al.

Malignant tumors of major salivary gland origin. A matched-pair analysis of the role of combined surgery and postoperative radiotherapy

Arch Otolaryngol Head Neck Surg

(1990)

A.G. Renehan et al.

Clinico-pathological and treatment-related factors influencing survival in parotid cancer

Br J Cancer

(1999)

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The role of growth pattern and grading in guiding prognosis in locoregionally disease is well acknowledged, with high-grade ACC having a significantly lower 5-year DFS. Grading of the disease is based on histopathological components, considering tubular, cribriform and solid growth pattern, where the solid component characterizes a more aggressive disease [3,11,17–21]. Van Weert et al. confirmed the prognostic impact of grading of the disease and solid growth-pattern on 1-year OS also in the RM setting.
Adenoid cystic carcinoma (ACC) is a rare tumor, usually arising in the salivary gland, accounting for 1% of all head and neck cancers. ACC may have a long-term poor prognosis, as about 40% of radically treated patients will recur locoregionally and up to 60% will develop distant metastasis.
Factors influencing risk of recurrence have been well studied, but few data exist about prognostic factors in Recurrent/Metastatic (RM) setting. Moreover, treatment of RM ACC is often a challenge for clinicians, in the context of a rare disease, which may have an indolent clinical behavior or less frequently a quicker growth and with a paucity of available clinical trials.
This review critically analyzes pathological and molecular prognostic factors in RM ACC and make an overview on actual therapeutic choices and future direction of therapy.
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Due to disappointing results with chemotherapy, new approaches are under study, also on the basis of biomolecular research. Ongoing clinical trials are evaluating treatment targeting MYB and NOTCH1 alterations, immunotherapy or combination of targeted treatments and immune checkpoint inhibitors.
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Adenoid cystic carcinoma (ACC) is an aggressive, rare, malignant tumour that accounts for about 1% of all head and neck neoplasms and 10% of all salivary gland tumours. It is characterised by frequent local recurrences and distant metastases. Growth is slow but relentless, and progression poses a challenge to head and neck clinicians. Many small retrospective studies have described its clinical management, but the lack of multicentre, randomised, controlled trials has resulted in inconsistencies in management globally. We have focused on three key management-related controversies: the role of elective neck dissection (END) for the N0 neck; the role of adjuvant treatment or radiotherapy; and finally, the follow-up protocol, particularly cross-sectional surveillance imaging of the full body or chest computed tomography (CT) alone, and options for treatment if metastases are found. The paucity of published studies may reflect the inconsistencies that exist in the management of ACC of the head and neck in the UK. The collaboration of head and neck centres would, we think, help to correct the imbalance in these three domains of care.
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The great majority of salivary gland malignancies are primary tumors which have been often studied and reported (Ng-Cheng-Hin et al., 2018; Zbären et al., 2018). These tumors vary significantly in their histological and biological nature, yet most of them (approximately 90%) belong to well known groups such as mucoepidermoid carcinoma, acinic cell carcinoma, adenoid cystic carcinoma, adeno carcinoma, polymorphous low grade adeno carcinoma and salivary squamous cell carcinoma (Jones et al., 2008; De Oliveira et al., 2009; Speight and Barrett, 2009). However, there is another subset of malignant salivary tumors encountered by the clinician which is seldom discussed or studied, the non-primary malignant tumors (both metastatic and not metastatic) (Jackson et al., 2015; Wang et al., 2017; Mezei et al., 2018).
Most salivary gland malignancies are primary tumors, but in our medical center one of six is non-primary. The relative scarcity of such reports justifies studying them.
We studied patients' demographic and clinical parameters, salivary tumors/metastasis, diagnosis and treatment, and survival rates.
Of all our salivary malignancy patients over the last 22 years, 15% (18/119) had non-primary malignant tumors, all located in the parotid glands. Of these, nine had skin cancer (SCC), 3 malignant solid tumors and 6 hematological systemic malignancies. Four had concomitant second malignancy. Mean age was 70.2 ± 13.8 years, 66.7% of the patients were males, 27.8% were smokers, none reported alcohol use. The most prevalent diagnostic tools used were CT (16 patients), FNA (13) and PET-CT (12). Eleven of 18 patients died from the disease despite receiving therapy: 6 SCC patients, 2 CLL patients and all 3 with solid tumors. All four lymphoma patients survived as did another three SCC patients.
Chemotherapy and radiotherapy for systemic disease prolonged life rather than surgery. Patients with poor prognosis non-primary salivary tumors should be treated conservatively; surgery should be for those without widespread metastases or systemic disease. Sometimes a palliative patient may benefit from tumor debulking.
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CT and MRI imaging are considered the diagnostic tools of choice while other tools are available for the clinician as well. These include tissue analysis, FNA, US, PET-CT etc (Nagler and Laufer, 1997; Jones et al., 2008; De Oliveira, 2009; Speight and Barrett, 2009; Guzzo et al., 2010; Dwivedi et al., 2013). Yet it is unclear which tools are preferable for each type of tumor and whether use of a certain tool creates an advantage for the therapeutic outcome.
We examined systemic medical and demographic characteristics of patients diagnosed with salivary malignant tumors in order to better understand the pathogenesis of the disease. Of 101 patients who received definitive treatment for malignant salivary gland tumors in our medical center, 22 died with disease (DwD) and were compared with the remaining 79 patients (Other). Mean ages were 66.7 years (median 68.0) in DwD group and 58.7 years (median 59.0) in the Others. The difference is significant (p = 0.037). Mucoepidermoid carcinoma was the diagnosis in 27.3% of DwDs and 27.8% of the others, Adenoidcystic carcinoma in 36.4% vs 21.5%, SCC and Acinic cell carcinoma were diagnosed in 18.3% vs 7.6% and 4.6% vs 7.6%, respectively. Alcohol consumption, concomitant malignancies, and chronic illnesses other than hypertension, were similar in the two groups, but hypertension (63.6%) in the DwD group was significantly higher than in the Other group (26.6%), (p = 0.0010). Smoking was also significantly different between the two groups: 50% of the DwD vs. 27.9% of the Others group smoked cigarettes. Similar distribution of the various malignant tumors in both groups emphasizes the relative importance of systemic factors such as smoking, aging and hypertension, in the salivary carcinogenesis process.
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Leading articlePrognostic factors in malignant tumours of the salivary glands

Abstract

Introduction

Section snippets

An overview of prognosis: stage compared with grade

The 4 cm rule

Other prognostic indicators

Grading of specific types of tumour

Perineural invasion

Summary and Conclusions

Oral Oncol

Otolaryngol Head Neck Surg

Oral Oncol

Am J Surg

Am J Surg

J Craniomaxillofac Surg

J Oral Maxillofac Surg

Oral Oncol

Int J Radiat Oncol Biol Phys

Int J Oral Maxillofac Surg

Int J Radiat Oncol Biol Phys

Int J Oral Maxillofac Surg

Am J Surg

Int J Radiat Oncol Biol Phys

Salivary gland tumours

Oral Dis

Classification of salivary gland neoplasms

Salivary gland cancer in the United States

Cancer Epidemiol Biomarkers Prev

Malignant epithelial salivary gland tumors in northern Finland: incidence and clinical characteristics

Eur Arch Otorhinolaryngol

Salivary gland neoplasms: general considerations

Atlas of tumor pathology

Tumors of the salivary glands. Series 3, Fascicle 17

Salivary neoplasms: overview of a 35-year experience with 2807 patients

Head Neck Surg

Salivary gland tumours

Factors affecting survival in salivary gland cancers

Malignant tumors of major salivary gland origin. A matched-pair analysis of the role of combined surgery and postoperative radiotherapy

Arch Otolaryngol Head Neck Surg

Clinico-pathological and treatment-related factors influencing survival in parotid cancer

Br J Cancer

Leading article
Prognostic factors in malignant tumours of the salivary glands