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Sialadenosis of the salivary glands
British Journal of Plastic Surgery [ 1995 ), 48. 419~.22 © 1995 The British Association of Plastic Surgeons
BRITISH
JOURNAL
OF
PLASTIC
/~ll~)
SURGERY
Sialadenosis of the salivary glands S. A. Pape*, R. I. MacLeodt, N. R. McLean* and J. V. Soames? * Departnwnt o f Plastic and Reconstr,ctive Surgery, Newcastle General Hospital and t Department of Oral Pathology, The Dental Hospital, Newcastle upon Tyne, UK S U M M A R Y. Sialadenosis (sialosis) is an uncommon, non-inflammatory condition which usually causes bilateral, diffuse enlargement of the salivary glands, particularly the parotid. We present a series of 7 patients with sialadenosis. Two had bilateral and 4 unilateral parotid involvement. One patient had unilateral submandibular gland sialadenosis. One patient had bilateral parotid and bilateral submandibular gland sialadenosis. The clinicopathological features and management of the condition are reviewed.
Sialadenosis (or sialosis) has been defined as a noninflammatory disease causing recurrent, bilateral swelling of the salivary glands, particularly the parotids, which may or may not be associated with pain. '-3 The swelling is unrelated to meals and there is no particular sex predominance. The condition usually begins between the ages of 20 and 60 years, may persist for more than 20 years 4 and may cause problems in diagnosis both clinically and histopathologically. The aetiology is unknown but is thought to be due to a peripheral neuropathy of the autonomic nerve supply of the salivary glands leading to disordered secretory activity in acinar cells) -8 In 50 % of cases the disease is associated with underlying systemic factors including endocrine disorders such as diabetes, malnutrition, alcohol abuse and drugs. ''9 We have previously reported a rare case of unilateral sialadenosis of the parotid gland in association with aplasia of the contralateral parotid. '° In this paper we report on the clinicopathological features of a further seven patients and review current concepts of the clinicopathological features and management of sialadenosis.
more of the major salivary glands. One patient was found to have diffuse enlargement of the parotid region when he presented with an intra-oral squamous cell carcinoma. Two patients had bilateral and 4 had unilateral parotid swelling. Two patients had involvement of the submandibular glands, one unilaterally and the other bilaterally in association with bilateral parotid swelling (Fig. 1). There were 4 males and 3 females, aged between 21 and 67 (mean 46.7) years at presentation. The duration of symptoms varied between 6 months and 2 years (mean 12.4 months). In 2 patients, no underlying condition could be found but 5 had a history of excessive alcohol consumption (more than 14 units of alcohol per week for females and more than 21 units per week for males). None were diabetic. In order to establish the diagnosis and to exclude other causes of salivary gland swelling, blood samples were sent for full blood count, urea and electrolytes, erythrocyte sedimentation rate, fasting blood glucose, liver function tests, alpha 1 antitrypsin, serum angiotensin converting enzyme, rheumatoid factor and autoantibody screen. Two patients had elevated gamma glutaryltransaminase levels. All other parameters were normal. Sialography (Fig. 2), fine needle aspiration cytology and CT scans (Fig. 3) were also performed. The diagnosis of sialadenosis was established by these methods in 4 of the 7 patients. In the other 3 patients,
Clinicopathological findings We have reviewed a series of 7 patients with sialadenosis confirmed by histology (Table 1). In 6 cases, the presenting complaint was diffuse swelling of one or
Table 1 Summary of clinical details Glands #wolved
Submandibular
Parotid
I 2 3 4 5 6 7
Age (.years) 67 21 65 26 39 51 58
Sex
Underlyh~g condition
Right
Left
Right
Left
Treatment
F F M M M M F
Alcohol Alcohol Alcohol None Alcohol Alcohol None
+ + + + + +
+
+
+ +
Excision left submandibular gland Bilateral superficial parotidectomy None None Left superficialparotidectomy Left superficial parotidectomy Left superficialparotidectomy
+ 419
420
British Journal of Plastic Surgery
Fig. I Figure l--Case 2. Tile typical hamster-like appearance of a patient with sialadenosis affecting both parotid and both submandibular glands.
Fig. 4 Figure 4~lA) Section of normal parotid gland. IB) Section of parotid gland affected by sialadenosis. The acinar cells are enlarged and packed with secretory granules. (Haernatoxylin and eosin: original magnification x 10.)
an open biopsy was necessary. In each case. this showed enlarged acini and acinar cells, two to three times their n o r m a l diameter, with basally situated nuclei and, in most cases, densely g r a n u l a r cytoplasm (Fig. 4).
Patients with a history of alcohol abuse were counselled and advised to reduce their alcohol consumption.
Fig. 2"
Fig. 3
Figure 2--Sialogram of parotid gland showing the thin. hair-like duct system in sialadenosis. Figure ~ - C T scan showing bilateral parotid enlargement, more marked on the left. Note the decreased density of the gland tissue and the obvious interlobular septa, which are strongly suggestiveof sialadenosis.
Sialadenosis of the salivary glands Five patients underwent surgery to the involved glands. In four, a superficial parotidectomy was performed because of the cosmetic deformity caused by the swollen gland. One year postoperatively, only one of these patients has recurrent glandular swelling, which causes some cosmetic deformity, but the patient has declined further surgery at present. One patient has died from alcoholic liver disease. Discussion
Sialadenosis is a distinct clinical and pathological entity, characterised by diffuse, usually bilateral swelling of the salivary glands? -3 In other series, it has been found to affect the parotid glands most commonly./'2 The differential diagnosis includes sialadenitis, obstruction due to salivary calculi, sarcoidosis, autoimmune connective tissue diseases (such as Sj6gren's syndrome), tumours and cysts/'4 In half of the patients, sialadenosis is associated with an underlying disease which may be endocrine, metabolic or neurogenic in origin/ Associated endocrine disorders include diabetes insipidus, acromegaly, diabete~ mellitus, hypothyroidism, pregnancy and adrenal disorders/'°'H Nutritional disorders such as pellagra, 4 beriberi, 4 kwashiorkorfl anorexia nervosa 12 and bulimia ~3 are also associated with parotid swelling and chronic malnutrition is thought to be the aetiological factor in alcohol-associated sialadenosis.T M Diabetic patients have an increased incidence of sialadenosis and it is more common in elderly diabetics with long-standing disease.4. H Neurogenic causes of sialadenosis include antihypertensive drugs (e.g. guanethidine~5"]~), psychotropic drugs (e.g. thioridazine ~7) and sympathomimetic drugs used for asthma (e.g. isoprenaline]8-2~), even when inhaled/2 Experimental work has suggested that the cause of sialadenosis is a peripheral autonomic neuropathy of the salivary glands. 5-7 The secretory cycle of the normal acinar cell is controlled by neurostimulation via alpha and beta receptors on the cell membrane. Both beta 1 and beta 2 agonists have been shown to induce salivary gland enlargement in rats? -7 Neurohormonal interference on the receptor site appears to cause an aberrant intracellular secretory cycle and this leads to either excessive stimulation or inhibition of the secretion of salivary granules. In the clinical situation, investigations should be directed towards confirming the diagnosis, excluding other causes of salivary gland swelling and detecting associated disorders. Blood analysis will screen for diabetes, alcoholic liver disease, sarcoidosis and autoimmune connective tissue disorders. Specific vitamin levels may be requested if deficiency is suspected. Fine needle aspiration cytology may confirm the diagnosis of sialadenosis~3'24 but requires the assistance of an experienced cytologist. The main value of aspiration cytology is in the exclusion ofa tumour and the assessment of acinar size. On cytology, mean acinar diameter greater than 62 microns is diagnostic of sialadenosis/3 Sialography will exclude calculi and may show
421 characteristic appearances of a thin, hairline salivary duct system, caused by extrinsic pressure due to parenchymal swelling, T M If the enlargement is pronounced, the proximal ducts may not be visualised at all. However, these appearances are non-specific and may be mimicked by diffuse, infiltrative processes such as granulomatous and auto-immune diseases and lymphomas/7 Scintigraphy often shows increased uptake and retention of Technetium (Tc99 m) in the salivary tissues in sialadenosis. However, this is neither consistent nor diagnostic. 4 The appearances on CT scanning are more specific/s'29 Initially, simple glandular enlargement is seen. Later, the density of the gland is reduced, due to fatty degeneration. Prominent septa of soft tissue density also appear, corresponding to fibrosis of the interlobular septa? ° Biopsy of the affected gland may be necessary to prove the diagnosis of sialadenosis. The characteristic feature is acinar enlargement, with an acinar cell diameter of 50 to 70 microns, compared with 30 to 40 microns in normal glands?' The cytoplasm of the swollen cells is packed with enzyme granules and the nucleus is displaced towards the base of the cell. Individual fat cells may be seen in the interstit[um of the lobules but there is no inflammatory infiltration/ Electron microscopy shows degenerative changes within the autonomic innervation of the salivary tissue affecting the postganglionic sympathetic neurones. These include a loss of neurosecretory granules, destruction of the mitochondria, hydropic swelling of the axoplasm and rupture of the axolemma, Lipid droplets and pigment granules are seen in the cytoplasm of Schwann cells of degenerated axons?' 31 The treatment of sialadenosis is often unsatisfactory and correction of the underlying condition may not result in the resolution of salivary gland enlargement. Surgical resection of the affected gland remains the mainstay of treatment but any remaining salivary tissue may continue to enlarge. Tympanic neurectomy has been performed in an attempt to interrupt the parasympathetic innervation of the parotid gland? ~ Early results are good but the effect is lost within 3 years in the majority of patients, presumably as a result of reinnervation. Although there is experimental evidence that catecholamines such as isoprenaline can reproduce the pathological features of sialadenosis, 18-2~ betablockers have been ineffective?4 Recently, pilocarpine has been shown to be beneficial in the treatment of bulimic patients with sialadenosis, when administered orally?3 Further studies are required to assess its value in patients with sialadenosis from other causes. In conclusion, sialadenosis should be considered in the differential diagnosis of patients presenting with diffuse enlargement of a salivary gland. In our patients, contrary to most other reported series, the disease was not always bilateral or symmetrical. Present treatments are unsatisfactory because they do not address the underlying cause of the condition, namely the degenerative changes of the autonomic innervation of the salivary glands. Surgery should only be undertaken when the cosmetic deformity is unacceptable.
BRITISH
JOURNAL
OF
PLASTIC
/~ll~)
SURGERY
Sialadenosis of the salivary glands S. A. Pape*, R. I. MacLeodt, N. R. McLean* and J. V. Soames? * Departnwnt o f Plastic and Reconstr,ctive Surgery, Newcastle General Hospital and t Department of Oral Pathology, The Dental Hospital, Newcastle upon Tyne, UK S U M M A R Y. Sialadenosis (sialosis) is an uncommon, non-inflammatory condition which usually causes bilateral, diffuse enlargement of the salivary glands, particularly the parotid. We present a series of 7 patients with sialadenosis. Two had bilateral and 4 unilateral parotid involvement. One patient had unilateral submandibular gland sialadenosis. One patient had bilateral parotid and bilateral submandibular gland sialadenosis. The clinicopathological features and management of the condition are reviewed.
Sialadenosis (or sialosis) has been defined as a noninflammatory disease causing recurrent, bilateral swelling of the salivary glands, particularly the parotids, which may or may not be associated with pain. '-3 The swelling is unrelated to meals and there is no particular sex predominance. The condition usually begins between the ages of 20 and 60 years, may persist for more than 20 years 4 and may cause problems in diagnosis both clinically and histopathologically. The aetiology is unknown but is thought to be due to a peripheral neuropathy of the autonomic nerve supply of the salivary glands leading to disordered secretory activity in acinar cells) -8 In 50 % of cases the disease is associated with underlying systemic factors including endocrine disorders such as diabetes, malnutrition, alcohol abuse and drugs. ''9 We have previously reported a rare case of unilateral sialadenosis of the parotid gland in association with aplasia of the contralateral parotid. '° In this paper we report on the clinicopathological features of a further seven patients and review current concepts of the clinicopathological features and management of sialadenosis.
more of the major salivary glands. One patient was found to have diffuse enlargement of the parotid region when he presented with an intra-oral squamous cell carcinoma. Two patients had bilateral and 4 had unilateral parotid swelling. Two patients had involvement of the submandibular glands, one unilaterally and the other bilaterally in association with bilateral parotid swelling (Fig. 1). There were 4 males and 3 females, aged between 21 and 67 (mean 46.7) years at presentation. The duration of symptoms varied between 6 months and 2 years (mean 12.4 months). In 2 patients, no underlying condition could be found but 5 had a history of excessive alcohol consumption (more than 14 units of alcohol per week for females and more than 21 units per week for males). None were diabetic. In order to establish the diagnosis and to exclude other causes of salivary gland swelling, blood samples were sent for full blood count, urea and electrolytes, erythrocyte sedimentation rate, fasting blood glucose, liver function tests, alpha 1 antitrypsin, serum angiotensin converting enzyme, rheumatoid factor and autoantibody screen. Two patients had elevated gamma glutaryltransaminase levels. All other parameters were normal. Sialography (Fig. 2), fine needle aspiration cytology and CT scans (Fig. 3) were also performed. The diagnosis of sialadenosis was established by these methods in 4 of the 7 patients. In the other 3 patients,
Clinicopathological findings We have reviewed a series of 7 patients with sialadenosis confirmed by histology (Table 1). In 6 cases, the presenting complaint was diffuse swelling of one or
Table 1 Summary of clinical details Glands #wolved
Submandibular
Parotid
I 2 3 4 5 6 7
Age (.years) 67 21 65 26 39 51 58
Sex
Underlyh~g condition
Right
Left
Right
Left
Treatment
F F M M M M F
Alcohol Alcohol Alcohol None Alcohol Alcohol None
+ + + + + +
+
+
+ +
Excision left submandibular gland Bilateral superficial parotidectomy None None Left superficialparotidectomy Left superficial parotidectomy Left superficialparotidectomy
+ 419
420
British Journal of Plastic Surgery
Fig. I Figure l--Case 2. Tile typical hamster-like appearance of a patient with sialadenosis affecting both parotid and both submandibular glands.
Fig. 4 Figure 4~lA) Section of normal parotid gland. IB) Section of parotid gland affected by sialadenosis. The acinar cells are enlarged and packed with secretory granules. (Haernatoxylin and eosin: original magnification x 10.)
an open biopsy was necessary. In each case. this showed enlarged acini and acinar cells, two to three times their n o r m a l diameter, with basally situated nuclei and, in most cases, densely g r a n u l a r cytoplasm (Fig. 4).
Patients with a history of alcohol abuse were counselled and advised to reduce their alcohol consumption.
Fig. 2"
Fig. 3
Figure 2--Sialogram of parotid gland showing the thin. hair-like duct system in sialadenosis. Figure ~ - C T scan showing bilateral parotid enlargement, more marked on the left. Note the decreased density of the gland tissue and the obvious interlobular septa, which are strongly suggestiveof sialadenosis.
Sialadenosis of the salivary glands Five patients underwent surgery to the involved glands. In four, a superficial parotidectomy was performed because of the cosmetic deformity caused by the swollen gland. One year postoperatively, only one of these patients has recurrent glandular swelling, which causes some cosmetic deformity, but the patient has declined further surgery at present. One patient has died from alcoholic liver disease. Discussion
Sialadenosis is a distinct clinical and pathological entity, characterised by diffuse, usually bilateral swelling of the salivary glands? -3 In other series, it has been found to affect the parotid glands most commonly./'2 The differential diagnosis includes sialadenitis, obstruction due to salivary calculi, sarcoidosis, autoimmune connective tissue diseases (such as Sj6gren's syndrome), tumours and cysts/'4 In half of the patients, sialadenosis is associated with an underlying disease which may be endocrine, metabolic or neurogenic in origin/ Associated endocrine disorders include diabetes insipidus, acromegaly, diabete~ mellitus, hypothyroidism, pregnancy and adrenal disorders/'°'H Nutritional disorders such as pellagra, 4 beriberi, 4 kwashiorkorfl anorexia nervosa 12 and bulimia ~3 are also associated with parotid swelling and chronic malnutrition is thought to be the aetiological factor in alcohol-associated sialadenosis.T M Diabetic patients have an increased incidence of sialadenosis and it is more common in elderly diabetics with long-standing disease.4. H Neurogenic causes of sialadenosis include antihypertensive drugs (e.g. guanethidine~5"]~), psychotropic drugs (e.g. thioridazine ~7) and sympathomimetic drugs used for asthma (e.g. isoprenaline]8-2~), even when inhaled/2 Experimental work has suggested that the cause of sialadenosis is a peripheral autonomic neuropathy of the salivary glands. 5-7 The secretory cycle of the normal acinar cell is controlled by neurostimulation via alpha and beta receptors on the cell membrane. Both beta 1 and beta 2 agonists have been shown to induce salivary gland enlargement in rats? -7 Neurohormonal interference on the receptor site appears to cause an aberrant intracellular secretory cycle and this leads to either excessive stimulation or inhibition of the secretion of salivary granules. In the clinical situation, investigations should be directed towards confirming the diagnosis, excluding other causes of salivary gland swelling and detecting associated disorders. Blood analysis will screen for diabetes, alcoholic liver disease, sarcoidosis and autoimmune connective tissue disorders. Specific vitamin levels may be requested if deficiency is suspected. Fine needle aspiration cytology may confirm the diagnosis of sialadenosis~3'24 but requires the assistance of an experienced cytologist. The main value of aspiration cytology is in the exclusion ofa tumour and the assessment of acinar size. On cytology, mean acinar diameter greater than 62 microns is diagnostic of sialadenosis/3 Sialography will exclude calculi and may show
421 characteristic appearances of a thin, hairline salivary duct system, caused by extrinsic pressure due to parenchymal swelling, T M If the enlargement is pronounced, the proximal ducts may not be visualised at all. However, these appearances are non-specific and may be mimicked by diffuse, infiltrative processes such as granulomatous and auto-immune diseases and lymphomas/7 Scintigraphy often shows increased uptake and retention of Technetium (Tc99 m) in the salivary tissues in sialadenosis. However, this is neither consistent nor diagnostic. 4 The appearances on CT scanning are more specific/s'29 Initially, simple glandular enlargement is seen. Later, the density of the gland is reduced, due to fatty degeneration. Prominent septa of soft tissue density also appear, corresponding to fibrosis of the interlobular septa? ° Biopsy of the affected gland may be necessary to prove the diagnosis of sialadenosis. The characteristic feature is acinar enlargement, with an acinar cell diameter of 50 to 70 microns, compared with 30 to 40 microns in normal glands?' The cytoplasm of the swollen cells is packed with enzyme granules and the nucleus is displaced towards the base of the cell. Individual fat cells may be seen in the interstit[um of the lobules but there is no inflammatory infiltration/ Electron microscopy shows degenerative changes within the autonomic innervation of the salivary tissue affecting the postganglionic sympathetic neurones. These include a loss of neurosecretory granules, destruction of the mitochondria, hydropic swelling of the axoplasm and rupture of the axolemma, Lipid droplets and pigment granules are seen in the cytoplasm of Schwann cells of degenerated axons?' 31 The treatment of sialadenosis is often unsatisfactory and correction of the underlying condition may not result in the resolution of salivary gland enlargement. Surgical resection of the affected gland remains the mainstay of treatment but any remaining salivary tissue may continue to enlarge. Tympanic neurectomy has been performed in an attempt to interrupt the parasympathetic innervation of the parotid gland? ~ Early results are good but the effect is lost within 3 years in the majority of patients, presumably as a result of reinnervation. Although there is experimental evidence that catecholamines such as isoprenaline can reproduce the pathological features of sialadenosis, 18-2~ betablockers have been ineffective?4 Recently, pilocarpine has been shown to be beneficial in the treatment of bulimic patients with sialadenosis, when administered orally?3 Further studies are required to assess its value in patients with sialadenosis from other causes. In conclusion, sialadenosis should be considered in the differential diagnosis of patients presenting with diffuse enlargement of a salivary gland. In our patients, contrary to most other reported series, the disease was not always bilateral or symmetrical. Present treatments are unsatisfactory because they do not address the underlying cause of the condition, namely the degenerative changes of the autonomic innervation of the salivary glands. Surgery should only be undertaken when the cosmetic deformity is unacceptable.