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Oral manifestations of

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S. . Porter,1 V. Mercadente2 and S. Fedele3 provide a succinct review of oral mucosal and disorders that may arise as a consequence of .

While the majority of disorders of the are centred upon the focus of therapy; and/or 3) the dominant cause of a lessening of the direct action of plaque, the oral tissues can be subject to change affected person’s quality of life. The oral features that an oral healthcare or damage as a consequence of disease that predominantly affects provider may witness will often be dependent upon the nature of other body systems. Such oral manifestations of systemic disease their clinical practice. For example, specialists of paediatric can be highly variable in both frequency and presentation. As and orthodontics are likely to encounter the oral features of patients lifespan increases and medical care becomes ever more complex with congenital disease while those specialties allied to disease of and effective it is likely that the numbers of individuals with adulthood may see manifestations of infectious, immunologically- oral manifestations of systemic disease will continue to rise. mediated or malignant disease. The present article aims to provide This article provides a succinct review of oral manifestations a succinct review of the oral manifestations of systemic disease of of systemic disease. It focuses upon oral mucosal and salivary patients likely to attend services. The review will focus gland disorders that may arise as a consequence of systemic upon disorders affecting the and salivary glands – as disease. these are tissues of greatest interest to practitioners of oral medicine. Disorders of almost any body system can adversely impact Although systemic disease relevant to oral medicine can impact upon upon the mouth. Oral manifestations may be: 1) the first, only the teeth and periodontal tissues or cause altered orofacial sensory or or most severe feature of systemic disease; 2) the principle motor function these fall out of the of the present review.

ORAL MUCOSAL MANIFESTATIONS Solitary The oral mucosa is perhaps the most likely oral tissue to be Longstanding solitary oral mucosal ulceration should always initially be compromised by acquired systemic disease. The following considered to reflect repeated local trauma or (usually oral sections will focus upon ulceration and white of the [OSCC; Fig. 1]). Of course many other disorders oral mucosa – as these are the most likely abnormal signs that that give rise to oral ulceration may initially manifest as single ulcers but will be observed by oral healthcare providers. over time they evolve into more extensive disease. Local oral mucosal trauma in relation to systemic disease can arise as a consequence of physical, Oral ulceration for example, movement disorders,1 or chemical causes, for example, the A plethora of local and systemic disorders can give rise to now rare instances of placing acidic at sites of oral pain, and the very ulceration of the oral mucosa (Table 1). rare examples of deliberate self-harm by swallowing caustic agents.2

1Institute Director and Professor of Oral Medicine, UCL Eastman Dental Institute; 2Research Clinician, UCL Eastman Dental Institute; 3Professor of Oral Medicine, UCL Eastman Dental Institute and Oral Theme, UCL NIHR Biomedical Research Centre

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Other rare causes of traumatic ulceration Table 1 Systemic causes of oral mucosal or gingival ulceration could be due to reduced pain and/or touch sensation as might occur in trigeminal Trauma Physical, chemical, radiation, thermal neuropathy secondary to metastatic deposits Behçet disease Disorders causing aphthous-like in the or less commonly , PFAPA syndrome, other autoinflammatory disorders ulceration , disease (for Others example, ), mellitus or Primary or recurrent drug therapy (for example, with anti-malarials Varicella-zoster virus Epstein-Barr virus and some regimens). In most (very rare) instances of suspected traumatic ulceration there Coxsackie virus will be an identifiable local and/or systemic Echovirus cause, the ulcers will not be causing notable Mycobacterium (and rarely mycobacteria other than tissue destruction and the surrounding oral tuberculosis [MOTT]) mucosa will be normal in appearance. Gram-negative infections (rare) Chronic mucocutaneous Malignancy of the mouth is typically OSCC related to lifestyle factors (tobacco, alcohol, (and occasionally other types) some betal nut preparations and Human vulgaris (and occasionally other types) papillomavirus oncogenic types),3 however, Dermatoses herpetiformis rare congenital disorders such as dyskeratosis Linear IgA disease 4 5 Epidermolysis bullosa acquisita congenita, Fanconi anaemia, as well as the multiforme acquired oral lichen planus,6 possibly 7 8 Neutropenia(s) scleroderma and are risk factors for Non-solid haematological : leukaemia(s) and myelopro- the development of this malignancy. In contrast liferative disorders Hematologic disorders to traumatic ulceration OSCC does not have Solid haematological malignancy: non-Hodgkin’s Haematinic deficiencies any identifiable local cause, may cause local Others destruction and have abnormal surrounding Crohn’s disease and related disorders Gastrointestinal disorders mucosa (eg speckling). Oral squamous cell carcinoma, and indeed most malignancies of the mouth, may just appear plain odd. Drugs Cytotoxics and very many others Other malignancies related to systemic Kaposi’s sarcoma disease include several types of non-Hodgkin’s Malignancy non- lymphoma (NHL) and Kaposi’s sarcoma (KS). Others Non-Hodgkin’s lymphoma usually presents as Others Hypoplasminogenaemia a mass or area of destructive ulceration of the , or gingivae, sometimes being driven by a background of (for example, HIV disease, iatrogenic ).9 Some types of oral NHL are almost specific for certain situations, for example, plasmablastic lymphoma tends to be associated with HIV disease,10,11 or may arise without obvious underlying cause, for example, Natural Killer T cel lymphoma (NKTCL).12 Oral KS tends to arise on the palate and/or gingivae, is blue, red or purple and does not blanche with local pressure. Prior to the advent of anti-retroviral therapy (ART) KS was the most common oral malignancy of HIV disease, but as the numbers of patients receiving this therapy have climbed there has been a substantial fall in the prevalence of this Fig. 1 Oral squamous cell carcinoma - Fig. 2 Recurrent aphthous - episodic oral tumour.13 Nevertheless, oral KS can be the probably one of the most significant causes of superficial oral mucosal ulceration in otherwise solitary ulceratin of the oral mucosa well children and adults first clinical manifestation of unknown (and advanced) HIV disease and can arise in patients receiving long-term immunosuppressive (eg tertiary disease), primary or secondary although extensive ulceration might be more therapy. Metastatic disease generally does not infection of Mycobacteria tuberculosis likely than single ulcers.18 give rise to ulcers of the mouth, although as or mycobacteria other than tuberculosis noted above can manifest within the mandible (MOTT)15,16 and systemic mycoses (eg Multiple ulcers as a swelling and/ or paraesthesia/anaesthesia.14 mucormycosis, aspergillosis, and Recurrent is the most Other rare causes of solitary ulceration paracoccidiodomycosis).17 Solitary ulceration common cause of multiple superficial of possible systemic origin include syphilis secondary to neutropenias are also possible, ovoid ulcers of the oral mucosa,19 but this is www.nature.com/BDJTeam BDJ Team 22 ©2018 British Dental Associati on. All ri ghts reserved.

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and/or gingival features similar to those of OLP, Table 2 Oral mucosal white patches associated with systemic disease although lesions of may not be bilateral Pseudomembranous candidosis (thrush) and may be more likely to affect the palate than Other mycoses Non-adherent Food debris OLP. Sun-ray pattern lesions that comprise a Furred central area of erosion or ulceration from which Drug-associated necrotic debris (for example, aspirin, cocaine) white linear areas radiate have been described on the oral mucosa of patients with lupus Papillomas ( – these are rarely of sexual origin) disease.26,27 White sponge naevus ( – sometimes associated with type I hypersensi- The pemphigoid group of immunobullous tivity disorders or ) disorders can give rise to bullae and/or Frictional keratosis (for example, as a consequence of abnormal orofacial movement) Adherent ulceration of the palatal, buccal or lingual Lichen planus 28 Lupus disorders surfaces. Desquamative is Oral hairy common.29 Intact blood or fluid-filled bullae Chronic mucocutaneous candidiasis may be observed in patients with pemphigoid Others (for example, the rare dyskeratosis congenita) disease as the immune-mediated attack is targeting of the zone (BMZ).30 Depending upon the type of 20 characterised by the patients being otherwise features. The uncommon autoinflammatory pemphigoid, patients may have blistering well (Fig. 2). The multisystem inflammatory syndrome of periodic , aphthous ulceration, and/or ulceration of other mucocutaneous disorder Behcet’s disease (BD) gives rise to near and adenitis (PFAPA) that sites with oral involvement being most likely identical oral ulcers as RAS but also comprises usually arises in pre-pubertal children gives with mucous membrane pemphigoid.31 The genital ulceration, , rise to episodes of superficial aphthous-like IgA dermatoses (for example, dermatitis and other cutaneous features, as well as a ulceration. Unlike RAS this disorder tends to herpetiformis [DH; often associated with plethora of other gastrointestinal, urogenital, spontaneously remit in the teenage years.21 gluten sensitive enteropathy] and linear IgA neural, musculoskeletal, cutaneous and vascular Other autoinflammatory diseases (that is, disease) can give rise to oral features similar periodic ) such as familial Mediterranean to those of pemphigoid.32–35 , often fever (FMF) may also sometimes give rise to employed for the treatment of DH (and superficial oral ulceration.22 sometimes for pemphigoid) may rarely cause Ulceration similar to RAS, but without the blue discolouration of the tongue secondary to same periodicity, can be a feature of anaemia of methaemoglobinaemia. almost any cause. An important diagnostic rule The pemphigus group, in particular is to always investigate for anaemia as being the (PV), characterised by cause of sudden onset superficial ulceration in the generation of a series of anti-epithelial an adult who does not have a history of RAS and , gives rise to highly superficial has no signs of common bullous disease (see ragged-bordered ulcers of the palatal, lingual later in article).23 and buccal mucosa as well as desquamative Several mucocutaneous disorders give rise to gingivitis (Fig. 3). The mouth is the first site of multiple areas of oral ulceration, lichen planus involvement of PV in about 50% of affected being without doubt the most common to do individuals and without therapy perhaps 95% of so. The ulceration of oral LP (OLP) is usually patients will develop oral lesions.36,37 Fig. 3 Superficial ulceration of pemphigus bilateral, has a background of different white Of concern has been the realisation that vulgaris - the most common type of patches and arises bilaterally on the buccal, bullous disease can arise on a background of pemphigus to affect the oral mucosae or gingivae lingual and/or gingival surfaces. Up to 40% systemic malignancy, this group of disorders of patients with OLP will also have cutaneous being termed or other mucosal features of LP.24,25 Lichen (PNP; sometimes also termed paraneoplastic planus usually arises without identifiable cause autoimmune multi-organ syndrome [PAMS]). although may rarely be secondary to About two thirds of the associated are – for example, β blockers, sulphonylureas, haematological (for example, non-Hodgkin’s some anti-malarials (eg, hydroxychloroquine lymphoma, chronic lymphocytic leukaemia for the management of lupus disease) and a and Castleman’s disease) although PNP has spectrum of other agents – when disease is been observed in association with sarcomas, termed lichenoid drug reaction (LDR), or is thymoma, lung and OSCC. The mouth, a manifestation of graft versus disease pharynx and larynx are usually the first sites (GvHD).24 Associations between LP and of involvement, although the conjunctivae and HCV disease are tenuous. Regardless of any genitals may also be affected. The oral features association with systemic disorders or therapy, are similar to those of PV, although there can OLP-like disease is considered potentially be notable labial involvement. Desquamative malignant, this cancer risk being independent gingivitis presumably occurs. Confusingly,

Fig. 4 Pseudomembranous candidiasis of known causative factors of OSCC or therapy oral lichen planus-like features can sometimes (thrush) of the oral mucosa of OLP.6 Lupus disease (for example, discoid arise in PAMS. Of concern PAMS can cause and systemic) may give rise to oral mucosal bronchiolitis obliterans and early death. The

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example, for the management of ). While Table 3 Other oral mucosal manifestations of systemic disease albicans is the most common species Granulomatous disease (for example, Crohns disease; ) associated with oral thrush, several other types • Cobblestoning may also give rise to this clinical feature, some of • Mucosal tags and/or nodules • ‘Stag horn’ type swellings of the floor of mouth which can be particularly insensitive or indeed • Swelling of the and/or face () resistant to antifungal therapy.41,42 Swellings Sturge Weber syndrome Neurofibromatosis type 1 Adherent white patches Cowden’s syndrome The most common causes of white patches Others of the mouth are local physical trauma, oral lichen planus (discussed earlier), Physiological (that is, racially based) Neurofibromatosis type 1 of unknown cause, epithelial or Albright syndrome neoplasia. Some of these can arise in association Laugier-Hunziker syndrome with systemic disease (for example, traumatic Haemochromatosis Incontinentia pigmenti keratosis secondary to cerebral palsy or Metastatic malignant lichen planus due to medication) and white (usually Hypoadrenocortical deficiency patches of the oral mucosa and to a lesser extent hypermelanotic) Infection of the adrenal cortex (eg, TB, CMV, others) Ectopic ACTH production (for example, with some lung malignancies) the gingivae may be a significant feature of Peutz-Jegher’s syndrome (usually per-oral rather than oral hyperpigmented areas) systemic disease. Perhaps the most important Drugs (rare, but many can do this – for example, buspulphan, , , of these is chronic mucocutaneous candidiasis others) (other types of pigmentation include central cyanosis (blue), Kaposi’s sarcoma [blue, (CMC), a group of often congenitally red purple] and congenital bilirubinaemias [brown – but usually on the gingivae only].) driven disorders characterised by recurrent mucocutaneous candidal infection.43 In CMC variable presentation of PAMS reflects the wide range of with different epithelial targets that may be generated.38 Finally, several ‘THE MOST COMMON CAUSES OF WHITE PATCHES groups of drugs may cause pemphigus-like disease, for example angiotensin converting OF THE MOUTH ARE LOCAL PHYSICAL TRAUMA, enzyme (ACE) inhibitors.39 (EM) can often give ORAL LICHEN PLANUS, HYPERKERATOSIS, rise to areas of irregular superficial ulceration of the mouth particularly the anterior oral mucosa. There can also be areas of non-specific EPITHELIAL DYSPLASIA OR NEOPLASIA.’ erythema, occasional vesicles or or desquamative-like gingivitis. Target-like lesions may very rarely arise on the oral mucosa. This receives – but in some instances EM disease can the complete spectrum of presentations of oral group of disorders includes EM minor, EM arise in the absence of drug therapy.40 candidal infection can occur (for example, major, Stevens Johnson syndrome and toxic pseudomembraneous, erythematous, chronic epidermal necrolysis syndrome (TENS) that White patches hyperplastic). Patients with autoimmune often, but not always, are secondary to an White patches of the oral mucosa can be polyendocrinopathy candidiasis ectodermal increasingly wide range of . The categorised clinically into adherent (that is, dystrophy (APECED) not only have chronic risk of EM type disease clearly increases with do not easily wipe off) and non-adherent. The candidal infection but may have diabetes the numbers of different drugs that a patient range of systemic disorders that can give rise to mellitus (which presumably will increase oral mucosal (and sometimes gingival) white the risk or severity of periodontitis), patches is summarised in Table 2. enamel hypocalcification (secondary to hypoparathyroidism) and hypermelanotic Non-adherent white patches pigmentation of the oral mucosa (secondary to Pseudomembranous candidiasis (thrush) autoimmune-driven destruction of the adrenal is a non-adherent white or cream coloured cortex).44–47 Late-onset chronic mucocutaneous non-adherent pseudomembrane that tends candidiasis (Good’s syndrome) is accompanied to arise on the posterior palate or pharynx, by thymoma, and bone although when disease is severe almost any marrow abnormalities and thus affected oral surface can be affected (Fig. 4). Thrush is individuals may have abnormal movement usually painless and typically reflects present or of the eyes, mouth and/or face.48 Chronic recent therapy with broad spectrum , mucocutaneous candidiasis may be considered or other immunosuppressants, to be a rare for OSCC.49 other or long standing There are many other potential oral oral dryness (for example, medication induced mucosal manifestations of systemic disease, Fig. 5 Oral dryness secondary to Sjögren’s or Sjögren’s syndrome). Thrush is perhaps as summarised in Table 3. Perhaps the most syndrome - this tongue is notably fissured and most commonly observed in patients receiving notable of these is Addisonian pigmentation. also has signs of mild oral lichen planus long-term inhaler therapy (for This is actually very rare but manifests as areas www.nature.com/BDJTeam BDJ Team 24 ©2018 British Dental Associati on. All ri ghts reserved.

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the parotid glands) and reduced salivary output Table 4 Non-neoplastic systemic causes of salivary gland swelling and importantly there is a risk of NHL of Unilateral Bilateral salivary glands.50 Acute suppurative associated with HIV infection tends to arise in late advanced disease Recurrent of childhood HIV salivary gland disease (and related disorders) although it may rarely be the first manifestation of a previously unknown HIV infection. and other causes of HCV sialadenitis There can be swelling and/or , the ductal obstruction former being most common in the parotid Sjögren’s syndrome (and associated Sjögren’s syndrome (and rarely bilateral non-Hodgkin’s lym- glands. Within the gland there is non-Hodgkin’s lymphoma) phoma) (sialadenitis) that is being driven by infection with BK polyomavirus (BKPyV).51,52 Multicystic IgG4 related disease IgG4 related disease lymphoepithelial lesions, sometimes termed cystic lymphoid (CLH) or benign Sarcoidosis Sarcoidosis lymphoepithelial (BLEL) or benign lymphoepithelial (BLEC), may also occur Chronic non-specific sialadenitis Sialosis in 6% of adults and 10% of children infected with HIV. Transformation to non-Hodgkin’s Xanthogranulomatous sialadenitis lymphoma is a rare of CLH. Other causes of salivary swellings of patients Amyloidosis Iodine containing contrast media and radioactive iodine with HIV disease include intraglandular Others Drugs (rare) , Kaposi’s sarcoma, NHL and acute suppurative sialadentis. As noted above Others sialolithiasis possibly secondary to ART has been documented and some HIV protease inhibitors can cause salivary gland enlargement ‘SALIVARY GLAND DISEASE ASSOCIATED WITH HIV of unknown cause. Salivary gland swelling (often only of the submandibular glands), sometimes with INFECTION TENDS TO ARISE IN LATE ADVANCED xerostomia, can arise in IgG4-related disease. This is a rare fibroinflammatory disorder DISEASE ALTHOUGH IT MAY RARELY BE THE characterised by elevated serum levels of IgG4 and multi-organ inflammation (lacrimal glands, pituitary gland, thyroid, , biliary FIRST MANIFESTATION OF HIV INFECTION’ tract, lungs, prostate gland and retroperitoneal cavity). The disease has predominantly been described in Asian patients (particularly from of hypermelanotic pigmentation of the buccal or therapies have been linked to this disorder Japan) but affected individuals have been mucosae. A similar appearance (together with including diabetes mellitus, hypertension reported in the Western World. In the past the palatal pigmentation) can arise with some small and/or chronic liver disease, nephrolithiasis, features were termed ‘Mikulicz’ disease’ ‘Kuttner cell carcinomas of the lung. hyperparathyroid disease and therapy with the tumour’ or ‘chronic sclerosing sialadenitis’.50,53 anti-HIV agent atazanavir.50 Sialosis (sometimes termed sialoadenosis) SALIVARY GLAND MANIFESTATIONS Acute suppurative sialadenitis that usually is an uncommon non-neoplastic and non- Disease of the salivary glands broadly manifests manifests as a painful swelling of one parotid inflammatory disorder possibly associated as local swelling and/or oral dryness (the gland is typically secondary to longstanding with some systemic disorders that give rise symptom of xerostomia). The disorders likely oral dryness such as Sjögren’s syndrome or to bilateral non-painful enlargement of the to give rise to salivary gland manifestations are radiotherapy-associated salivary gland disease. major salivary glands – typically the parotids. summarised in Tables 4 and 5. However, neonatal disease has been reported Xerostomia is not a common or dominant in association with prematurity, orogastric accompanying symptom. The precise cause is Salivary gland swelling feeding and/or immunodeficiency. In adults unknown although it may reflect a neuropathy Mucoceles of the minor salivary glands of the links with systemic disease have included by which unopposed sympathetic drive causes lower and sialolithiasis of the submandibular diabetes mellitus, HIV disease and a plethora of an increase in protein content within the gland are probably the most common causes surgical interventions, as well as the very rare acinar cells.54 This would perhaps explain the of swelling of the salivary glands. Mucoceles coprophagia (the consumption of faeces). association of sialosis with diabetes mellitus have no association with systemic disease and Mumps will often cause short-term salivary and perhaps hypothyroidism, , , swellings of the submandibular and/or gland swelling although, hopefully, the return alcoholism and other causes of hepatic sublingual glands akin to that of mucoceles, do of the high compliance with appropriate cirrhosis. Sialosis has also been observed in not seem to have any consistent association with will lessen the frequency of this and , the degree of salivary gland systemic disease, although have been observed the much more significant consequences of this enlargement possibly correlating with the in patients receiving ART. Sialolithiasis tends to disorder. virus (HCV) infection can frequency of bulimic symptoms and with levels arise de novo but a number of systemic disorders cause both salivary gland enlargement (typically of serum amylase.

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Table 5 Other oral of systemic disease relevant to oral medicine

Any disorder that increases the risk of painful dental caries Dental pain secondary to sickle cell disease (very rare) Trigeminal -like disease with: • Multiple sclerosis • Systemic •Osteopetrosis • Infection/tumours around the central parts of the Glossopharyngeal neuralgia-like disease with: Oral pain • Multiple sclerosis • Infection/tumours around the central or peripheral parts of the glossopharyngeal nerve. Post-herpetic neuralgia (rare in the mouth) arteritis Migrainous disorders Temporomandibular disorder (TMD) – like features with: • Ehler Danlos syndrome Persistent idiopathic facial pain (sometimes termed idiopathic facial pain) Others

Metastatic deposits Diabetes mellitus (diabetic neuropathy) Loss of sensation Connective tissue disease (eg, scleroderma, Sjogren’s syndrome, others) (trigeminal neuropa- Sickle cell disease thy) Familial dysautonomia Drugs (eg, anti-malarials) Others

Upper motor nerve: • Stroke • CNS malignancy • Others Facial weakness (usually unilateral) Lower motor nerve: • Lyme disease (Bartonella burgdoferi) • Meningioma//infections within the internal auditory meatus • Middle /temporal bone malignancy/destruction • Tumours/infection in other parts of the nerve Abnormal orofacial movement Trigeminal neuralgia-like disease (as above) Parkinson’s disease Orofacial dyskinesias Tardive dyskinesia (eg, secondary to some anti-psychotic agents). Note that metroni- dazole can cause tardive and other dyskinesias of the face Rabbit syndrome (secondary to drugs) Chin tremor (eg, with paroxetine)

Bulbar palsy (ie, lower motor) – malignancy/infection/trauma of lower CNS/base of Reduced/altered tongue movement skull/tongue Pseudobulbar palsy (ie, upper motor) – malignancy/infection of CNS, some types of motor neurone disease (also described in variant Creutzfeld Jakob disease)

Upper respiratory tract infection/malignancy Pulmonary TB, abcesses, bronchiectasis, malignancy Occasionally H. pylori-associated gastric erosion Trimethylaminuria Oral malodour Hypermethioninaemia Diabetic ketoacidosis End stage renal failure End stage hepatic failure Halitophobia/pseudohalitosis/olfactory reference syndrome (symptoms but no clinically detectable evidence of altered breath smell)

A wide range of drugs can cause salivary nicardipine, nifedipine, chlormethiazole, liability to caries, gingivitis (but perhaps not gland enlargement. Transient and mild acute methimazole, naproxen, nitrofurantoin, periodontitis), candida infection (for example, sialadenitis (sometimes termed ‘iodide mumps’) sulfadiazine, captopril, cytarabine, cimetidine, pseudomembranous, erythematous and angular can arise in response to iodine based contrast ranitidine, and thioridazine.59 chielitis), acute suppurative sialadenitis and media (for example, for percutaneous coronary reduced retention of upper full dentures. It can interventions).55–58 Similarly radioactive iodine, Oral dryness thus greatly lessen quality of life.50 used for the treatment of thyroid cancer, can The symptom of oral dryness does not always The most common cause of persistent oral cause salivary gland swelling and xerostomia accord with loss of salivary gland function, dryness is drug therapy – with late-aged patients that may arise within 24 hours of therapy indeed many individuals report some degree receiving polypharmacy being at greatest risk and persist for a few weeks. Other agents that of usually transient or mild oral dryness of this problem (Box 1). Medication-related may cause salivary gland enlargement include without objective evidence of reduced xerostomia reflects anti-cholinergic and/or l-asparaginase, clozapine, phenylbutazone, salivary gland function. Reduced salivary sympathomimetic actions, hence the drugs methyldopa, interferon alpha, oxyphenbutazone, function gives rise to dysarthria, , most commonly implicated in xerostomia are ramipril, trimethoprim/sulfamethoxazole, dysgeusia, some mucosal soreness, an increased tricyclic , , www.nature.com/BDJTeam BDJ Team 26 ©2018 British Dental Associati on. All ri ghts reserved.

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phenomena, while those with secondary of the literature. Br Dent J 2010; 208: 297–300. Box 1 Systemic causes of Sjögren’s syndrome may also have oral 3. Radoï L, Luce D. A review of risk factors for oral longstanding oral dryness manifestations of any accompanying connective cavity cancer: the importance of a standardized 61 Drugs (many) tissue disease. case definition.Community Dent Oral Epidemiol The oral features of primary or secondary 2013; 41: 97–109. Radiotherapy of the head and neck SS are those of oral dryness (as described 4. Ray J G, Swain N, Ghosh R, Richa, Pattanayak Sjogren’s syndrome and related disorders previously) and salivary gland enlargement Mohanty S. Dyskeratosis congenita with Chronic graft versus host disease due to the inflammation of the actual disease, malignant transformation. BMJ Case Rep 2011; IgG4 related disease episodes of acute suppurative sialadenitis 2011: DOI: 10.1136/bcr.03.2010.2848. Sarcoidosis and NHL. With regard to this last feature it is 5. Wong W M, Parvathaneni U, Jewell P D et al. Salivary gland agenesis important to appreciate that SS is a potentially Squamous cell carcinoma of the oral tongue HIV salivary gland disease malignant disorder having a 4.3% risk of in a patient with Fanconi treated with HCV sialadenitis malignancy with a standardised incident radiotherapy and concurrent cetuximab: a case Others (for example, longstanding anxiety, rate of 18.9. The tumours are usually low report and review of the literature. Head Neck ) grade marginal zone lymphoma (MALT), 2013; 35: E292–298. but can also be follicle centre, diffuse 6. Fitzpatrick S G, Hirsch S A, Gordon S C. The lymphoma (DBCL) or lymphoplasmacytoid malignant transformation of oral lichen planus lymphoma.62,63 and oral lichenoid lesions: a systematic review. J atropinics, beta-blockers and anti-histamines. Am Dent Assoc 2014; 145: 45–56. Morphine-derived agents cause oral dryness OTHER ORAL MANIFESTATIONS 7. Kuo C F, Luo S F, Yu K H et al. Cancer risk among and while often promoted as having less The present article has focused upon the impact patients with systemic sclerosis: a nationwide actions than the tricyclics, the of systemic disease on the oral mucosa and population study in Taiwan. Scand J Rheumatol selective serotonin reuptake inhibitors (SSRIs) salivary glands but a very wide range of other 2012; 41: 44–49. still cause some dry mouth. Some other newer symptoms and/or signs of systemic disease 8. Michalek A M, Mahoney M C, McLaughlin drug therapies including omeprazole, anti-HIV can arise in the mouth or adjacent face as a C C, Murphy D, Metzger B B. Historical and protease inhibitors, the consequence of disorders of non-oral structures contemporary correlates of syphilis and cancer. HIV inhibitor didanosine, (summarised briefly in Table 5). Int J Epidemiol 1994; 23: 381–385. 9. Triantafillidou K, Dimitrakopoulos J, Iordanidis ‘XEROSTOMIA IS THE MOST COMMON F, Gkagkalis A. Extranodal non-hodgkin of the oral cavity and maxillofacial region: a clinical study of 58 cases and review of PERSISTENT SIDE EFFECT OF RADIOTHERAPY the literature. J Oral Maxillofac Surg 2012; 70: 2776–2785 (RT) OF THE HEAD AND NECK’ 10. Porter S R, Diz Dios P, Kumar N, Stock C, Barrett A W, Scully C. Oral plasmablastic lymphoma in previously undiagnosed HIV disease. Oral Surg trospium chloride, elliptinium, and new CONCLUSION Oral Med Oral Pathol Oral Radiol Endod 1999; 87: generation may also cause drug- Oral features of systemic disease can be 730–734. induced xerostomia. helpful in the diagnosis and management 11. Castillo J J, Bibas M, Miranda R N. The biology Xerostomia is the most common persistent of the underlying disorder – and indeed the and treatment of plasmablastic lymphoma. Blood adverse side effect of radiotherapy (RT) of the oral symptoms may be those that most lessen 2015; 125: 2323–2330. head and neck, affecting up to 85% of patients.60 the quality of life of affected individuals. The 12. Al-Hakeem D A, Fedele S, Carlos R, Porter S. The prevalence of RT-induced xerostomia providers of primary oral healthcare have an Extranodal NK/T-cell lymphoma, nasal type. Oral varies with respect to RT field, dose, regimen, essential role in the management of patients who Oncol 2007; 43: 4–14. and technique. Although the introduction of may have oral consequences of systemic disease, 13. Patton L L. Oral lesions associated with human intensity modulated RT has led to a significant as they are often likely to be the first clinicians to immunodeficiency virus disease.Dent Clin North reduction in the frequency and severity of observe such abnormalities. They may not know Am 2013; 57: 673–698. this iatrogenic problem, many patients still exactly what the disease is but timely referral 14. Rao R S, Patil S, Sanketh D, Amrutha N. experience the consequences of irreversible of patients to specialist oral medicine units will Metastatic tumors of the oral cavity. J Contemp salivary gland dysfunction as a fall in salivary ensure that any potential oral manifestation Dent Pract 2014; 15: 263–271. outflow and altered salivary content. of systemic disease is managed quickly and 15. Ilyas S E, Chen F F, Hodgson T A, Speight P Oral dryness is a dominant symptom of appropriately to improve the patient’s quality of M, Lacey C J, Porter S R. Labial tuberculosis: a Sjögren’s syndrome (Fig. 5). This disorder is life. A simple rule to perhaps apply is: ‘it looks unique cause of lip swelling complicating HIV classified as primary disease in which there are different thus I will refer the patient to someone infection. HIV Med 2002; 3: 283–286. symptoms and signs of ocular and oral dryness who may know what to do.’ 16. Aoun N, El-Hajj G, El Toum S. Oral : an and secondary Sjögren’s syndrome in which uncommon site in primary tuberculosis. Aust there is also a connective tissue disorder – most 1. Compilato D, Corsello G, Campisi G. An unusual Dent J 2015; 60: 119–122. frequently rheumatoid or systemic traumatic ulceration of the tongue. J Paediatr 17. Iatta R, Napoli C, Borghi E, Montagna M T. lupus erythematosus. However, patients with Child Health 2012; 48: 1104–1105. Rare mycoses of the oral cavity: a literature primary Sjögren’s syndrome have a spectrum 2. Gilvetti C, Porter S R, Fedele S. Traumatic epidemiologic review. Oral Surg Oral Med Oral of other systemic, and often autoimmune chemical oral ulceration: a case report and review Pathol Oral Radiol Endod 2009; 108: 647–655.

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