Advances in the treatment of salivary gland disease
Parotid lumps may pose a diagnostic dilemma that could be helped by classifying patients
into one of five groups. Many of the conditions that involve the parotid glands evolve insidiously, and diagnostic delay is a common problem.
Parotid gland disease can be broadly broken down into five categories: obstructive causes; infection; autoimmune disorders; underlying systemic disorders; and tumours. It is also helpful to consider the presenting symptoms in terms of either single or multi-gland involvement, and the type of swelling present (recurrent swelling, diffuse swelling or a well-defined lump – see table 1), as this information helps differentiation between the five diagnostic categories of disease.
Age also has a bearing on the likely cause of parotid disease: infective causes are more common in children; obstructive, inflammatory and benign tumours predominate in middle age; and cancerous lumps are prevalent in old age.
Two major advances in recent years have changed the management of salivary disease. First, stones can now be reliably retrieved by minimally invasive techniques, preserving gland function and avoiding traditional sialoadenectomy, although the service is restricted to a few specialised centres.
Second, there has been an appreciation in the surgical community that benign salivary tumours can be safely treated by procedures much less extensive than a superficial parotidectomy, with a commensurate reduction in morbidity.
In recent years the major advances in the management of salivary gland disease have taken place in the treatment of salivary gland stones and in surgery for salivary tumours.
Infective disease of the parotid gland
In the primary care setting, children are the main group of patients presenting with parotid infections. The most commonly occurring viral infection is mumps. Mumps has an incubation period of two to three weeks and subjects are contagious from five days prior to the onset of symptoms and for 10 days after symptoms appear.
The parotids are firm and tender, and the ducts indurated. The submandibular glands may also be involved and 25 per cent of cases can have unilateral swelling. Antiviral therapy is not indicated and the object of management is symptom control. Other viral infections that also affect the salivary glands include Coxsackie A and B, parainfluenza B and Epstein-Barr, but these are commonly associated with predisposing factors such as immune suppression or debilitating systemic disease.
Acute bacterial infections are usually associated with chronic obstruction of the parotid gland and are an acute exacerbation of a chronic infection. They are frequently precipitated by a flu-like illness or deterioration in health.
The symptoms are unmistakable, with all the features of infection (swollen, red tender gland), and pus may be milked from the duct orifice.
As the infected tissue is tightly bound by a thick coat of fascia the condition can be very painful and an acute episode of parotitis usually merits admission to hospital. Initial treatment is with broad spectrum intravenous antibiotics, and then once the symptoms have settled the underlying cause of the infection needs to be established and eliminated.
Much less commonly, an acute infection is linked either to diminished salivary gland function following local radiotherapy, Sjögren's disease or general debilitation.
A small group of children have been reported with recurrent sialoadenitis, usually accompanied by malaise and fever (recurrent sialoadenitis of childhood), and a sub-group of these patients appears to have an autoimmune disorder. As many as 18 recurrent episodes have been reported in a single individual.9 The pathogenesis is normally unknown and sialography simply shows sialectasis (dilated ducts). The condition has been reported to resolve spontaneously, but there is evidence that some patients may continue with problems into adulthood. Without an understanding of the disease process, treatment is symptomatic.
With infections of the parotid gland, particularly in the context of immigrant or immunosuppressed patients, the possibility of TB should be considered, as it may pose a diagnostic dilemma. In contrast to acute bacterial or viral infections involving the whole gland, these infections present as discrete indurated lumps, and can mimic a malignant tumour. In the immunocompromised, alcoholics and drug abusers, the suspicion of such an infection can be confirmed by fine needle aspiration cytology (FNAC) and polymerase chain reaction (PCR) to identify the causative organism.
Cat-scratch disease, actinomycosis and hydatid disease are also rare causes of localised swelling in the parotid region.
Autoimmune diseases The main group of patients with autoimmune disease are those with Sjögren's syndrome, who represent about 1 per cent of the adult population. This affects 10 times as many females as males, and has an average age of presentation of 50 years. Salivary gland enlargement is common with up to 80 per cent of patients affected.
In the parotid gland there is classically a replacement of glandular epithelium with focal or diffuse lymphocytic infiltrates associated with islands of proliferating duct epithelium. The infiltrating lymphocytes form follicles resembling the mucosa associated lymphoid tissue of the gastrointestinal tract. The resultant disruption of the gland architecture leads to reduced function, and the patients complain of a dry mouth and eyes, together with bilateral swelling of the parotid glands.
Patients without an associated connective tissue disorder are designated as having primary Sjögren's syndrome and those with a connective tissue disease, secondary Sjögren's. Diagnostic criteria for primary and secondary Sjögren's syndrome have been set out by the American-European Consensus Group.10 The classification system was devised to distinguish Sjögren's syndrome from cases presenting with sicca symptoms due to other causes. It is based on a system incorporating six points, including both subjective and objective assessments (see table 2, left).
In the early phase of the disease a sialogram will demonstrate dilated ducts with extravasation of minute amounts of dye into the surrounding gland parenchyma (punctate sialectasis), whereas in advanced disease, duct architecture is lost and small abscess cavities may form in the gland. Ultrasound is also sensitive, demonstrating
If the symptoms are severe the underlying autoimmune disease can be modulated with different combinations of systemic steroids and cytotoxic drugs such as azathioprine. In practice most patients do not require such therapy and can obtain at least some relief of symptoms with saliva substitutes and lubricant solutions for the eyes.
The lack of saliva increases the risk of dental caries and an ongoing regimen of preventative dental care should be considered.
An important complication of Sjögren's syndrome, and in particular primary Sjögren's, is that it predisposes to lymphoma development, with a risk of about 44 times that of the general population and an incidence of 5–10 per cent of patients.11 The pathology is similar to that of lymphomas at other mucosa associated lymphoid tissue (MALT) sites in the gut. Unlike other lymphomas in the head and neck that present with obvious bulky cervical lymphadenopathy, or in the case of extranodal lymphoma, as a discrete lump, these MALT lymphomas of the parotid frequently present with a clinical picture of an inflammatory disorder, as might be expected in a tumour that arises from an inflammatory condition.
They have an insidious onset, and fortunately are usually low grade. Both parotid glands are diffusely enlarged and the tissues feel rubbery to palpation
(see figure 1, page 48). The patients may report episodes of swelling and inflammation lasting a week or more without evidence of infection. In such circumstances it is prudent to seek a tissue diagnosis by parotid tail biopsy, which is easily accessible without the risk of damage to the facial nerve.
Systemic disorders affecting the parotid glands Patients with a variety of underlying medical problems may present with enlarged salivary glands. The mechanism underlying the enlargement is not clear but has no implications for
the health of the patient or the function
of the gland apart from cosmetic considerations. Both parotid glands are enlarged but feel normal to palpation, and here the term sialosis is used.
Bulimic patients may have prominent salivary glands if the glands become hypertrophic in response to systemic acid/base imbalance that occurs with chronic vomiting. The presence of enlarged glands is accentuated further if the patient is excessively thin.
Endocrine problems such as diabetes mellitus and diabetes insipidus, as well as thyroid disorders and acromegaly, can all result in such swelling. Cystic fibrosis, liver disorders and malnutrition are also incriminated in gland enlargement. The diagnostic dilemma is in ensuring these underlying medical problems are the cause and not missing other more sinister disorders, such as lymphoma (see figure 1, page 48).
stones and strictures
Obstructions Obstructive episodes, resulting from the blockage of the ductal system, occur mostly as a result of salivary stones, and to a lesser extent strictures and occasionally mucus plugs. Obstructions have been estimated to account for 50 per cent of major salivary gland disease.12
Obstructive episodes classically present with a sudden onset of swelling at meal times (meal-time syndrome). This symptom is pathognomonic of obstruction. The swelling, which may be associated with pain as a result of back pressure within the gland, develops over
a period of a few minutes and then resolves slowly over a matter of hours as the saliva seeps around the obstruction into the mouth.
The symptoms evolve insidiously,
with the mean time to presentation from first symptoms being approximately
five years. Typically the obstruction
lasts a week or more and then may be relieved for up to 6–12 months. Ultimately, the stagnant saliva becomes infected
and the gland shows signs and
symptoms of infection. Such infections are usually caused by ascending normal oral flora, and treatment with a broad spectrum antibiotic is normally
adequate, although a well established sialoadenitis may take up to three weeks to resolve.
Annually, 60 patients per million of the population are admitted to hospital for treatment of salivary obstruction at an estimated cost of more than £4 million.13 The peak incidence in salivary stones in the UK is in the 25–50 age group, and assuming the average life expectancy is
76 years, the prevalence for symptomatic sialolethiasis is 0.45 per cent.14
Approximately 80 per cent of stones are found in the submandibular gland, with the remainder in the parotid. There is no predilection by gender, and
bilateral disease occurs in only one patient in 100.13
The investigation of choice is a sialogram either alone or with ultrasound imaging.
Minimally invasive techniques In the past five years there has been a revolution in the management of salivary gland obstruction. Traditionally, obstructive disease has been treated by removing the offending salivary gland. Yet surgery carries a small but significant morbidity, with 2–4 per cent of patients suffering permanent injury to the facial, lingual and hypoglossal nerves.
This approach is no longer necessary, as a combination of minimally invasive techniques including salivary lithotripsy, basket retrieval, salivary endoscopy, balloon dilatation and minor intra-oral surgery retrieves 77 per cent of stones and successfully dilates 87 per cent of strictures.
In a consecutive series of 455 salivary stones treated at the Guy's salivary centre between 1994 and 2004, only 2 per cent of salivary glands were removed.14
Most stones arise in the submandibular glands and approximately 40 per cent are washed down the duct.14 Those at the duct orifice can be released easily by a simple surgical procedure, while the other mobile stones are removed by basket retrieval either under radiological or microendoscope control.
The remaining 60 per cent of submandibular stones lie in the hilum of the gland and can be targeted by the lithotripter with a 30 per cent chance of stone clearance.14 This takes on average six treatment sessions, each of an hour. However, removing these stones by an intra-oral surgical procedure either under local anaesthetic or day case surgery has proved more efficient, as it achieves 97 per cent clearance.14
Parotid gland stones are more amenable to lithotripsy, with 87 per cent of patients rendered symptom free, of which 50 per cent are cleared of stone.14 Small mobile fragments in the parotid can also be approached with baskets and endoscopes. The few stones that are either too big or too infected to be treated by lithotripsy can be removed surgically by a combined endoscope-directed technique that preserves the function of the gland with minimal risk to the facial nerve. In such situations, an endoscope is placed down the salivary duct until it contacts the stone. The light from the endoscope tip can then be
used to guide the surgeon accurately to the stone.
Salivary gland tumours
The aetiology of salivary gland neoplasia remains largely unknown. The strongest evidence for a single causative factor
is high-dose ionising radiation demonstrated in survivors of the atomic bombs of Hiroshima and Nagasaki, who had a higher risk of developing both benign and malignant salivary gland tumours compared with the general population.15
Several studies have also demonstrated an association with low dose radiation following the now abandoned technique of irradiating benign skin lesions or following the use of radioactive iodine. The risk, however, is low.
In recent years molecular research has identified some chromosomal abnormalities resulting in gene mutations specific to benign and malignant salivary gland tumours, but despite these developments there are still no definitive studies on genetic mechanisms responsible for tumour development.16
A population-based study conducted in Nottingham17 demonstrated that the overall tumour incidence for parotid, submandibular and minor salivary glands collectively was 8 per 100,000 per year of which 7.2 per cent represented benign disease and 0.8 per cent malignant. The latter is consistent with national cancer data figures. The data confirms the 10:1:1 rule – for every 100 salivary tumours in the parotid there will be 10 tumours in the submandibular gland, and 10 tumours in the minor salivary glands of the mouth.
In terms of site, the majority of tumours occur in the tail of the parotid (75 per cent), or the preauricular portion of the gland (12 per cent). The remainder either arise in the deep lobe (6 per cent), the accessory lobe anterior to the main gland (2 per cent) or fill most of the gland (5 per cent).18 The Nottingham study demonstrated the risk of cancer was less than previously reported, since only 6 per cent of parotid, 34 per cent of submandibular and 24 per cent of minor salivary glands prove to be malignant.
Clinical features of benign tumours More than 90 per cent of benign tumours are either pleomorphic adenomas or Warthin's tumours. The former has a female predominance of 1.6:1 and a median age of presentation of 47 years, but with a broad distribution from childhood to old age. It is a slow-growing neoplasm and there is normally a delay of two to three years before the patient presents for consultation.
Most pleomorphic adenomas are asymptomatic at presentation and
the features of a benign lump are normally easily discernible in the form of a well defined and mobile lump (see table 3, page 52).
The Warthin's tumour, in contrast, has a median age of presentation in the seventh decade of life; it has a reported association with cigarette smoking and is more common in males. It classically presents as a soft spongy or cystic mass in the tail of the parotid that helps to distinguish it from the pleomorphic adenomas.
Another feature of Warthin's tumour is that it may enlarge rapidly over a period of a few days, presumably due to the cystic component of the tumour. It is a curious lesion because 25 per cent of cases are multifocal but do not recur and it can be found in local lymph nodes, although it does not metastasise. It is a lymphoepithelial lesion and may not be a true neoplasm.
In children, an important cause of a unilateral parotid swelling is a haemangioma or lymphangioma. The consistency of these lumps is different from the firm pleomorphic adenoma and can be easily distinguished by ultrasound or contrast CT/MRI.
Another difference in children is that, although salivary neoplasms are uncommon (1.6–3.6 per cent of all salivary neoplasms) at this early age (<16 years),
a greater proportion (30–50 per cent)
are malignant compared with adults (probably 10–15 per cent).19 In view of this risk, parotid lumps in children that could be a salivary tumour should be evaluated by FNAC: the majority of such lumps are likely to be of inflammatory origin in this age group, and so a parotidectomy is avoided.
Also, if a malignant neoplasm is present the surgeon is forewarned so that a technique is adopted to try and avoid the need for postoperative radiotherapy with all its attendant effects on growth.
Modern management of benign parotid tumours Technological advances, particularly in the field of investigative medicine, have had a significant impact on the management of many conditions and the salivary glands are no exception. The introduction of both CT and MRI imaging and the ability to evaluate the lumps through FNAC have meant that the majority of benign tumours can be reliably delineated from malignant lesions. This has produced a change in surgical perspective towards more conservative surgery for the benign parotid lump.20,21 This is a new and important development in parotid surgery. Figure 2 shows before and after the surgical removal of a parotid lump.
The facial nerve dominates the management of parotid gland disease and superficial parotidectomy is no more than a dissection of the facial nerve. Up to 60 per cent of pleomorphic adenomas removed by this technique were in contact with the facial nerve and could only be dissected free at a capsular level.
However, the expected tumour recurrence following such minimal excision margins did not materialise. In large centres this experience produced confidence in a more conservative surgical approach; not surprisingly, post-operative morbidity (facial nerve injury, Frey's syndrome, neuroma and facial deformity) is proportional to the magnitude of surgery.
Consequently there is currently a shift away from superficial parotidectomy to either partial parotidectomy20 or local dissection of the lump (capsular dissection)22 without the added risk of recurrence (2 per cent at 10 years follow-up).23 In parotid disease, as with other branches of surgery, there has been a shift to less invasive procedures.
Malignant salivary gland disease Malignant salivary gland tumours are relatively uncommon and have a peak incidence in the sixth decade of life. The most common are the mucoepidermoid, adenoid cystic and adenocarcinomas. In populations with a high incidence of cutaneous malignancy of the head and neck, such as Australia, the most common form of parotid malignancy is now metastatic disease (see table 4).
In 1994, a total of 261,107 new cancers were registered in England and Wales.24 Head and neck cancer (mouth/throat, thyroid and salivary gland) constituted 7,216 cases (2.7 per cent) and of these 425 arose from the major salivary glands (approximately 70 per cent in the parotid), representing 5.8 per cent of head and neck cancers and 0.2 per cent of all cancers.
Because of the insidious nature of the disease, there is usually a delay of a year or more between the tumour appearing and medical advice being sought.25 This may have a disarming influence on the clinician, and even with high grade tumours the delay may still be in the order of nine months.
About half the cancers are small and appear relatively innocent on presentation, and the features typically associated with cancer (pain, facial nerve dysfunction or cervical lymphadenopathy) are fairly uncommon (10–20 per cent of patients). These features normally signify a high grade lesion or advanced disease and carry a commensurately poor prognosis.26
Modern management of parotid cancer As with benign disease the mainstay of treatment is surgery. Only 30 years ago the policy was for radical resection which included the facial nerve. This view has modified considerably in the intervening years. It is now appreciated that radiotherapy is effective in eradicating minimal residual disease after surgical resection and that salivary tumours are not radio-resistant. A more conservative attitude has been adopted with preservation of the facial nerve if it were not overtly infiltrated with tumour.
Surgical management relies mainly on the stage of the tumour rather than the histology. Spiro made an important observation in that survival results were clearly better for histologically low grade tumour; however, intermediate or high tumour histological grade had no real impact on survival unless the tumour was clinically high stage.27 This meant that as long as the tumour was small (Stage I or II) the grade/histology of the lesion had minimal predictive value on outcome.
The corollary from this observation is that surgery has to be tailored to each individual tumour and no blanket policy is appropriate. The 10-year disease specific survival rates for stage I, II and III/IV combined are 96, 61 and 17 per cent respectively.21
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