Gingival Pathology

Anne Hegarty and Alison Rich

AbstractThe normal anatomy and physiology of theperiodontium is well known to dentists anddental specialists, as are the effects on theperiodontium of plaque-associated bacterialinfections. However, the gingivae may beinvolved in many other local and systemicconditions. The purpose of this chapter is todescribe some of the less common pathologicalconditions that may affect one or more of thecomponents of the periodontium and to discusshow clinicians can ensure these lesions arediagnosed and managed in a timely manner.

KeywordsGingival lesions • Periodontium • Periodontaldiseases and conditions • Non-plaque gingivalpathology • Immunological • Lichen planus •Infectious • Drug-induced • Leukoplakia •Erythroplakia • Neoplastic

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Gingival Lesions of Developmental/GeneticOrigin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Hereditary Gingival Fibromatosis . . . . . . . . . . . . . . . . . . . . 2Ligneous Gingivitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Gingival Hamartoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Reactive Gingival Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Gingival Epulides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Localized Juvenile Spongiotic Gingival

Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Peripheral Giant Cell Lesions . . . . . . . . . . . . . . . . . . . . . . . . . 9

Drug-Induced Gingival Lesions . . . . . . . . . . . . . . . . . . . . 11

Gingival Lesions of Infectious Origin . . . . . . . . . . . . . . 12Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Human Immunodeficiency Virus (HIV) Infection . . . . 12

Immune-Mediated Gingival Lesions . . . . . . . . . . . . . . . 13Oral Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Mucous Membrane Pemphigoid . . . . . . . . . . . . . . . . . . . . . . 14Linear IgA Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Pemphigus Vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Orofacial Granulomatosis and Oral Crohn’s

Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Granulomatosis with Polyangiitis (Wegener’s

Granulomatosis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Pyostomatitis Vegetans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Plasma Cell Gingivitis/Gingivostomatitis . . . . . . . . . . . . 19

A. HegartyConsultant in Oral Medicine, Sheffield Teaching Hospitals,Sheffield, UKe-mail: Anne.Hegarty@sth.nhs.uk

A. Rich (*)The Department of Oral Diagnostic and Surgical Sciences,University of Otago, Dunedin, Otago, New Zealande-mail: alison.rich@otago.ac.nz

# Springer International Publishing AG 2017C.S. Farah et al. (eds.), Contemporary Oral Medicine,DOI 10.1007/978-3-319-28100-1_15-1

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Cysts, Potentially Neoplastic and NeoplasticGingival Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Odontogenic Cysts and Neoplasms . . . . . . . . . . . . . . . . . . . 21Leukoplakia and Erythroplakia . . . . . . . . . . . . . . . . . . . . . . . 22Oral Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . 24Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Other Primary Malignant Neoplasms . . . . . . . . . . . . . . . . . 24Metastases to the Gingiva . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Conclusions and Future Directions . . . . . . . . . . . . . . . . . 27

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Introduction

Awide variety of lesions may arise from the oralmucosa, fibrous connective tissue, bone, andcementum of the periodontium. The commonestpathology is a result of bacterial infection and isvery well known to dental practitioners and iscovered in other chapters of this text and detailedin the classification of periodontal diseases andconditions (Table 1) (Armitage 1999). Rarer con-ditions, however, also present as gingival pathol-ogy. The pathogenesis of these non-plaque-relatedlesions and conditions comprises genetic, trau-matic, immunological, and neoplastic etiologiesincluding benign, malignant, and metastatic. Thischapter outlines these conditions, describing themin terms of four categories related to their patho-genesis: Genetic, Reactive, Immunological, andNeoplastic. Using this framework, and with care-ful consideration of both the clinical features anduse of appropriate special tests, should enablethe clinician to make a timely and accurate diag-nosis. Plaque-related gingival and periodontalconditions are covered in more detail in separatechapters on “▶Odontogenic Bacterial Infections”and “▶Odontogenic Pathology.” Given the widespread of conditions affecting the gingival tissues,more detailed exploration of conditions coveredin this chapter can also be found in separate chap-ters on “▶Oral Lichen Planus,” “▶White andRed Lesions of the Oral Mucosa,” “▶Oral Muco-sal Malignancies,” “▶Ora Ulcerative Lesions,”“▶Oral and Maxillofacial Viral Infections,” and“▶Oral Vesicular and Bullous Lesions” amongothers.

Gingival Lesions of Developmental/Genetic Origin

Hereditary Gingival Fibromatosis

Hereditary gingival fibromatosis is an uncommoncondition characterized by generalized extensivefibrous enlargement of the gingivae which have anormal or slightly paler color and which are firmto touch (Fig. 1). It is inherited, usually as anautosomal dominant trait, and is associated withmutation of the son-of-sevenless (SOS-1) genewhich encodes a guanine-nucleotide exchangefactor that is important for Ras activation andhence activation of various receptors relating tocell proliferation (Hart et al. 2002; Poulopouloset al. 2011). It may be associated with hyper-trichosis and/or sensorineural hearing loss(Hartsfield et al. 1985) with or without learningdisability and/or epilepsy (Witkop 1971). Carewith oral hygiene may be all that is required fortreatment, but surgical reduction may be neces-sary with recurrences to be expected.

Ligneous Gingivitis

Ligneous gingivitis, also known as destructivemembranous periodontal disease or (erroneously)amyloidaceous gingival hyperplasia, is anotherrare disorder that should be included in the differ-ential diagnoses for patients presenting withgeneralized or focal gingival enlargement in theabsence of the use of medications. Females areaffected more frequently than males (F:M ratio�3:1), and while the initial cases were reportedin people of Turkish ethnicity, it is now clear thereis a worldwide distribution (Sivolella et al. 2012).The gingival enlargement has a generalized nod-ular appearance with surface ulceration whichmay begin in childhood (Fig. 2). The soft tissuehyperplasia may be associated with significantalveolar bone loss and severe periodontal disease.Histological examination shows the deposition ofeosinophilic acellular material, demonstrated tobe fibrin, in the connective tissue (Fig. 3). Amy-loid is not present. A small number of patientshave similar conjunctival lesions, known as

2 A. Hegarty and A. Rich

Table 1 Classification of periodontal diseases and conditions (Armitage 1999)

I. Gingival diseases 3. Gingival diseases of fungal origin

A. Dental plaque-induced gingival diseasesa a. Candida-species infections

1. Gingivitis associated with dental plaque only 1. Generalized gingival candidosis

a. Without other local contributing factors b. Linear gingival erythema

b. With local contributing factors (See VIII A) c. Histoplasmosis

2. Gingival diseases modified by systemic factors d. Other

a. Associated with the endocrine system 4. Gingival lesions of genetic origin

1. Puberty-associated gingivitis a. Hereditary gingival fibromatosis

2. Menstrual cycle-associated gingivitis b. Other

3. Pregnancy associated 5. Gingival manifestations of systemic conditions

a. Gingivitis a. Mucocutaneous disorders

b. Pyogenic granuloma 1. Lichen planus

4. Diabetes mellitus-associated gingivitis 2. Pemphigoid

b. Associated with blood dyscrasias 3. Pemphigus vulgaris

1. Leukemia-associated gingivitis 4. Erythema multiforme

2. Other 5. Lupus erythematosus

3. Gingival diseases modified by medications 6. Drug-induced

a. Drug-influenced gingival diseases 7. Other

1. Drug-influenced gingival enlargements b. Allergic reactions

2. Drug-influenced gingivitis 1. Dental restorative materials

a. Oral contraceptive-associated gingivitis a. Mercury

b. Other b. Nickel

4. Gingival diseases modified by malnutrition c. Acrylic

a. Ascorbic acid-deficiency gingivitis d. Other

b. Other 2. Reactions attributable to

B. Non-plaque-induced gingival lesions a. Toothpastes/dentifrices

1. Gingival diseases of specific bacterial origin b. Mouthrinses/mouthwashes

a. Neisseria gonorrhea-associated lesions c. Chewing gum additives

b. Treponema pallidum-associated lesions 3. Other

c. Streptococcal species-associated lesions 6. Traumatic lesions (factitious, iatrogenic,accidental)

d. Other a. Chemical injury

2. Gingival diseases of viral origin b. Physical injury

a. Herpesvirus infections c. Thermal injury

1. Primary herpetic gingivostomatitis 7. Foreign body reactions

2. Recurrent oral herpes 8. Not otherwise specified (NOS)

3. Varicella-zoster infections

b. Other

II. Chronic periodontitisb VII. Periodontitis associated with endodontic lesions

A. Localized A. Combined periodontic-endodontic lesions

B. Generalized VIII. Developmental or acquired deformities andconditions

(continued)

Gingival Pathology 3

ligneous (woody) conjunctivitis. These patientsshould be investigated to exclude an associationwith inherited type 1 plasminogen deficiencysince hypoplasminogenaemia is present in a highproportion of cases (Schuster et al. 1997; Scullyet al. 2007; Sivolella et al. 2012). In cases with orwithout hypoplasminogenemia, surgical removalof the hyperplastic gingival tissue tends to befollowed by recurrence (Kurtulus et al. 2007;Sivolella et al. 2012). Topical and/or systemic

plasminogen supplementation has been attemptedwith variable success (Sivolella et al. 2012).

Gingival Hamartoma

Odontogenic gingival epithelial hamartoma(OGEH) is a rare benign hamartoma believed toarise from epithelial remnants of the dental lamina(rests of Serres) (Kitano et al. 1991). It usually

Table 1 (continued)

III. Aggressive periodontitisb A. Localized tooth-related factors that modify orpredispose to plaque-induced gingival diseases/periodontitis

A. Localized 1. Tooth anatomic factors

B. Generalized 2. Dental restorations/appliances

IV. Periodontitis as a manifestation of systemic diseases 3. Root fractures

A. Associated with hematological disorders 4. Cervical root resorption and cemental tears

1. Acquired neutropenia B. Mucogingival deformities and conditionsaround teeth

2. Leukemias 1. Gingival/soft tissue recession

3. Other a. Facial or lingual surfaces

B. Associated with genetic disorders b. Interproximal (papillary)

1. Familial and cyclic neutropenia 2. Lack of keratinized gingiva

2. Down syndrome 3. Decreased vestibular

3. Leukocyte adhesion deficiency syndromes 4. Aberrant frenum/muscle position

4. Papillon-Lefèvre syndrome 5. Gingival excess

5. Chediak-Higashi syndrome a. Pseudopocket

6. Histiocytosis syndromes b. Inconsistent gingival margin

7. Glycogen storage disease c. Excessive gingival display

8. Infantile genetic agranulocytosis d. Gingival enlargement (See I.A.3 and I.B.4)

9. Cohen syndrome 6. Abnormal color

10. Ehlers-Danlos syndrome (Types IV and VIII) C. Mucogingival deformities and conditions onedentulous ridges

11. Hypophosphatasia 1. Vertical and/or horizontal ridge deficiency

12. Other 2. Lack of gingiva/keratinized tissue

C. Not otherwise specified (NOS) 3. Gingival/soft tissue enlargement

V. Necrotizing periodontal diseases 4. Aberrant frenum/muscle position

A. Necrotizing ulcerative gingivitis (NUG) 5. Decreased vestibular depth

B. Necrotizing ulcerative periodontitis (NUP) 6. Abnormal color

VI. Abscesses of the periodontium D. Occlusal trauma

A. Gingival abscess 1. Primary occlusal trauma

B. Periodontal abscess 2. Secondary occlusal trauma

C. Pericoronal abscessaCan occur on a periodontium with no attachment loss or on a periodontium with attachment loss that is not progressingbCan be further classified on the basis of extent and severity. As a general guide, extent can be characterized asLocalized = �30% of sites involved and Generalized = >30% of sites involved. Severity can be characterized on thebasis of the amount of clinical attachment loss (CAL) as follows: Slight= 1 or 2 mm CAL, Moderate= 3 or 4 mm CAL,and Severe = �5 mm CAL

4 A. Hegarty and A. Rich

presents as an asymptomatic gingival lump inadults, mostly females. Histologically OGEHshows multiple islands and clusters of bland epi-thelial cells surrounded by condensed fibrous con-nective tissue, without significant hyalinizationtypical of epithelial-mesenchymal inductive inter-actions seen in odontogenic neoplasms (Fig. 4). Itis a completely innocuous lesion but is an impor-tant differential histological diagnosis for local-ized gingival lesions containing odontogenicepithelium when a diagnosis of a peripheral odon-togenic tumour is being considered (see below).

Reactive Gingival Lesions

Acute physical trauma to the gingiva is commonand is easily recognized by the patient and clini-cian, although low-level chronic trauma may notelicit a clear history. The first part of this sectionwill describe gingival reactions to various localirritants. The second part will describe reactionsof the gingival tissues to the use of some systemicmedications.

Fig. 1 Generalized extensive fibrous enlargement of thegingivae which may impede the eruption of teeth

Fig. 2 Irregular nodular gingival hyperplasia with super-ficial ulceration and erythema in a patient being investi-gated for ligneous gingivitis (destructive membranousperiodontal disease)

Fig. 3 Photomicrograph showing eosinophilic acellularCongo-red negative material, mostly fibrin, in the gingivalconnective tissue (arrow) in ligneous gingivitis

Fig. 4 Islands of bland epithelial cells within the fibrousconnective tissue of an odontogenic gingival epithelialhamartoma. These lesions usually present as an asymptom-atic gingival lump

Gingival Pathology 5

Gingival Epulides

Gingival epulis refers to a lump on the gingiva andincludes angiogranuloma (also known as vascularepulis or erroneously as pyogenic granuloma)(Fig. 5), pregnancy epulis (Fig. 6) and fibrousepulis (sometimes known as peripheral fibromadespite the fact the lesion is traumatic in origin)(Fig. 7). Angiogranuloma is a relatively commontissue response to localized irritation or traumaoften seen in the gingiva and presents as a local-ized swelling. It is a reactive inflammatory pro-cess filled with proliferating vascular channels,immature fibroblastic connective tissue, andscattered inflammatory cells. Pregnancy can

Fig. 5 Angiogranuloma presenting as a large gingivalpalatal lump associated with the upper central incisorteeth (11 and 21) in a 35-year-old female (a) with extensionto the labial aspect (b) causing separation of the upper

central incisors with a semi-lunar bone defect along thealveolar crest (c). (Images courtesy of Professor CamileFarah, Perth Oral Medicine & Dental Sleep Centre, Perth,WA, Australia)

Fig. 6 With pregnancy hormones circulating, vascularepulides can become extensive. In this situation, the termpregnancy epulis is often applied

6 A. Hegarty and A. Rich

predispose the patient to gingival hyperplasia andinduce a large localized vascular lesion (preg-nancy epulis), particularly when oral hygiene ispoor. A fibrous epulis, a localized hyperplasticfibrous gingival mass formed as a response tochronic irritation, shows much less vascularityhistolologically with more mature fibrous tissue

and little inflammation. Mineralization within afibrous epulis is relatively common and, in thesecases, the surface is often ulcerated. There may bedystrophic calcification or recognizable wovenbone or cementum (Fig. 7c). These are known asmineralizing or ossifying fibrous epulides toreflect their reactive nonneoplastic nature.

Fig. 7 Fibrous epulis between the lower left canine andfirst premolar teeth (33 and 34) (a). The surface mucosais of the same color and texture as surrounding tissue.(b) shows another fibrous epulis, in this case involvingthe labial gingiva of the lower left first and second molar

teeth (36 and 37), in a 14-year-old female. Histologicallythis was shown to contain mineralized areas within theconnective tissue similar to that shown in (c). (Clinicalimages courtesy of Professor Camile Farah, QueenslandOral Medicine & Pathology, Brisbane, QLD, Australia)

Gingival Pathology 7

For all gingival epulides management involvestreating the cause and usually requires excisionalbiopsy as definitive treatment and to confirmthe diagnosis. The excision should extend to peri-osteum, and the region should be thoroughlyscaled and root planed (Fig. 8). This is usuallycurative, but recurrences do occur. Althoughmany of these lesions can be excised without

extensive periodontal surgery with adequatehealing, occasionally coronally repositionedflaps are required to provide adequate tissuecoverage, healing, and esthetics. For pregnancyepulis, treatment is best deferred until after partu-rition when the vascularity of the lesion willregress.

Fig. 8 Surgical removal and debridement ofangiogranuloma. Angiogranuloma involving labial gingi-val margin between upper left central and lateral incisorteeth (21 and 22) (a). Lesion is excised completely down toperiosteum and periodontal tissues debrided thoroughly

without raising a flap (b). Healing at 2 weekspost-surgery (c). (Images courtesy of Professor CamileFarah, Queensland Oral Medicine & Pathology, Brisbane,QLD, Australia)

Fig. 9 Clinical presentation of localized juvenilespongiotic gingival hyperplasia involving the labial gin-giva of the upper right first and second incisors and canineteeth (11, 12, 13) in a 12-year-old female (a). (Imagecourtesy of Professor Camile Farah, Queensland Oral

Medicine & Pathology, Brisbane, QLD, Australia). Thesmall vessels in the superficial connective tissue are typi-cally dilated and engorged in this condition, contributing tothe clinical appearance (b)

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Localized Juvenile Spongiotic GingivalHyperplasia

Localized juvenile spongiotic gingival hyperpla-sia (LJSGH) is a painless solitary localized sessileor pedunculated swelling of the attached gingivaewith a characteristic bright red color (Fig. 9a). Itbleeds easily and usually affects the maxillaryanterior labial gingivae in children and adoles-cents. Histologically the lesion is covered bynonkeratinized epithelium with elongated reteridges with pronounced edema of the stratumspinosum and neutrophil exocytosis. Numeroussmall dilated blood vessels and a mixed inflam-matory cell infiltrate are conspicuous in the con-nective tissue papilla (Fig. 9b). Sometimes thesurface has a granular or papillary texture.LJSGH is considered to be a reactive lesion, butit is not simply a response to plaque (Darling et al.2007), and there is no convincing evidence tosupport a viral etiology (Argyris et al. 2015).The histological features and pattern of cyto-keratin expression in the epithelium of LJSGHare similar to that of junctional epithelium, ratherthan mature gingival epithelium, leading to thesuggestion that these lesions might represent exte-riorized junctional epithelium from the gingivalsulcus (Chang et al. 2008; Allon et al. 2016). Theexposed junctional-type epithelium is then

vulnerable to local irritants and the reactiveLJSGH ensues. Localized surgical excision withcareful scaling and root planning of the adjacentteeth is the treatment of choice (Chang et al.2008).

Peripheral Giant Cell Lesions

Peripheral giant cell lesions (giant cell epulis) arerelatively common and present as a red, bluish, orpurple gingival mass, sometimes ulcerated. Ini-tially they usually involve the buccal interdentalpapillae but they may extend lingually/palatallyand separate the adjacent teeth (Fig. 10a). Theyoccur over a wide age range with a reasonablyeven gender distribution. Peripheral giant celllesions are considered to be derived from cellsin the periosteum or periodontal ligament as areactive response to local trauma (Lester et al.2014). There have been reports of their develop-ment adjacent to dental implants (Hirshberget al. 2003; Brown et al. 2015). Histologicalexamination shows mononuclear cells and numer-ous multinucleated giant cells, thought to be ofosteoclastic origin, in vascular cellular connectivetissue (Fig. 10b). There have been numerousreports describing the immunohistochemical pro-files of mononuclear cells and giant cells in

Fig. 10 Peripheral giant cell granuloma of the gingivabetween the lower left first and second incisors (32 and33) causing displacement of tooth 32 lingually. (a) Thesurface mucosa is erythematous and easily traumatized(Image courtesy of Professor Camile Farah, QueenslandOral Medicine & Pathology, Brisbane, QLD, Australia).

Numerous multinucleate giant cells are present in vascularimmature fibrous connective tissue, typical of a giant celllesion (b). More mature fibrous tissue containing hemosid-erin and a mild chronic inflammatory cell infiltrate ispresent in the top right side of the photomicrograph

Gingival Pathology 9

peripheral and central giant cell lesions in antici-pation of variation in expression reflecting differ-ences in behavior and response to treatmentmodalities such as calcitonin, interferons, andbone resorption inhibitors (Tobón-Arroyaveet al. 2005; Kujan et al. 2015; Martins et al.2015). It is important that radiographs of theregion are obtained since, while these lesionscan cause minor resorption “cupping” of the adja-cent cortical bone, more extensive bony involve-ment indicates the presence of a central giantcell lesion with peripheral extension. A peripheral

giant cell lesion should be treated in the sameway as a fibrous epulis. Clinical review is recom-mended since recurrences do occur. The clinicaland histological appearance of the “browntumors” of hyperparathyroidism (Fig. 11) maybe the same as that of giant cell lesions andhence hyperparathyroidism should be excludedfor central giant cell lesions and for multiple orrecurrent peripheral lesions. The oral lesionsin these cases may not need surgical inter-vention once the parathyroid hormone levels arestabilized.

Fig. 11 Brown’s tumour of hyperparathyroidism pre-senting as a gingival lump on the maxillary alveolus (a).The lesion demonstrates a strongly enhancing soft tissuemass eroding bone within the right anterior maxilla

extending into the nasopalatine canal and into the overly-ing gingiva on MDCT (b) and MRI (c). (Images courtesyof Professor Camile Farah, Perth Oral Medicine & DentalSleep Centre, Perth, WA, Australia)

10 A. Hegarty and A. Rich

Drug-Induced Gingival Lesions

One of the most troublesome drug-induced gingivallesions is gingival enlargement, which may be somarked as to interfere with mastication and causeesthetic problems. Agents associated with gingivalenlargement include phenytoin (Fig. 12a),calcineurin inhibitors such as cyclosporine(Fig. 12b) and tacrolimus, and calcium channelblockers such as nifedipine, diltiazem, oxidipine,and amlodipine. A common link between thesedrugs is cation flux inhibition, leading to decreaseduptake of folate by gingival fibroblasts and subse-quent changes in matrix metalloproteinase metabo-lism and lack of collagenase activation. Thus, theexcess collagen formed in association with inflam-matory gingivitis cannot be degraded effectively(Brown et al. 1991; Brown and Arany 2014). Care-ful attention to oral hygiene remains an importanttreatment modality. The putative drug should bewithdrawn by the treating physician if possible,but regression of the gingival hyperplasia is oftenslow. Surgical debulking may assist but should notbe performed until after the drug has been ceased for

somemonths. If the drug cannot be altered, gingivalrecontouring, either by conventional surgery orlaser, may be helpful but is likely to relapse. Despitea number of reports recommending the use of top-ical or systemic folic acid supplementation, orazithromycin to manage drug-induced gingivalenlargement, there is currently insufficient evidenceto confirm their value (Brown and Arany 2014).

Drug-induced hyposalivation may be associatedwith increased susceptibility to cervical caries andgingivitis/periodontitis due to prolonged adherenceof plaque at the tooth-gingival interface (Lam et al.2009). Drug-induced hyposalivationmay be associ-ated with many medications, particularly antide-pressants and diuretics. Mouth-breathing has beenassociated with higher levels of plaque and gingivalinflammation (Wagaiyu and Ashley 1991).

Drug-induced oral ulceration has been reportedwith numerous medications (Scully and Bagan2004) and, in more recent times, secondary tonicorandil, a potassium channel activator used inthe treatment of unstable angina (Yamamoto et al.2011). Although more common on the tongue,lesions may affect the gingivae and edentulousridge mucosa (Fig. 13).

Fig. 12 Extensive gingival enlargement associated withthe use of phenytoin (a). Other drugs capable of inducingprofound gingival enlargement include cyclosporine (b)

and calcium channel blockers (c). (Image C courtesy ofProfessor Camile Farah, Perth Oral Medicine & DentalSleep Centre, Perth, WA, Australia).

Gingival Pathology 11

Gingival Lesions of Infectious Origin

Viral Infections

Herpes Simplex InfectionPrimary herpetic gingivostomatitis presents usu-ally in young children as a painful acute viralillness with intraoral vesicles and erythematous,swollen gingiva (Fig. 14). The generalized gingi-val involvement is a fairly constant and conspic-uous clinical feature of primary herpeticgingivostomatitis and may assist in distinguishingit from other viral infections that involve the oralmucosa such as herpangina and hand, foot andmouth disease. Treatment is usually symptomatic,ensuring adequate hydration, while an antiviralagent such as acyclovir (also known as acyclovir)may be necessary in immunocompromised hosts.Acyclovir is prescribed for primary herpeticgingivostomatitis at a dose of 200 mg five timesdaily for 5 days in adults and for a child, 1 monthto 2 years old, half the adult dose is given.Potential adverse effects include nausea,vomiting, rash and photosensitivity and veryrarely hepatitis, acute renal failure, neurologicalreactions, and hematological effects. Valaciclovir,a pro-drug of acyclovir, may be used if there areadverse effects to acyclovir is ineffective. A usualdose for adults is 500 mg twice daily for 5 days,and for children consultation with pediatric med-ical specialists is advised. Adverse reactions aresimilar to those related to acyclovir but

neurological reactions are more likely with higherdoses. Other herpesviruses, e.g., varicella-zosterrarely affects the gingiva, but if gingival herpeszoster does occur, treatment should take intoaccount the possibility of post-zosterosteonecrosis, since alveolar bone necrosis andtooth exfoliation is a rare complication of intraoralherpes zoster infection, particularly in immuno-compromised patients (Mendieta et al. 2005; Jainet al. 2010).

Human Immunodeficiency Virus (HIV)Infection

Antiretroviral therapy (ART) has dramaticallyimproved the management of patients infectedwith human immunodeficiency virus and hasreduced the incidence and severity of linear gin-gival erythema and necrotizing periodontitis aswell as intraoral neoplasms associated withacquired immunodeficiency syndrome (AIDS).Human papillomaviruses may induce a numberof lesions in patients with HIV/AIDS in-cluding gingival papillomas, warts, condylomaacuminatum, and focal epithelial hyperplasia(Fig. 15). Carbon dioxide laser treatment mayreduce the HPV-related lesions but the underlyingimmune impairment reduces its effectiveness(Limeres Posse and Scully 2016). Malignanttransformation in gingival papillary lesions inHIV/AIDS is rare. It is interesting to note that

Fig. 13 An area of ulceration in the maxillary buccalsulcus associated with the use of the potassium channelactivator nicorandil

Fig. 14 Pronounced gingival erythema with ulcerationaround the gingival margins in a patient with primaryherpetic gingivostomatitis

12 A. Hegarty and A. Rich

the incidence of HPV-associated malignancies inother sites, specifically anus and cervix, has notdeclined since the introduction of ART indicatingthat ART confers little benefit in the preventionand management of HPV-related pathology(Palefsky 2016).

Immune-Mediated Gingival Lesions

Oral Lichen Planus

Oral lichen planus (OLP) can present as white,red, and/or ulcerative lesions usually presentingbilaterally on the buccal mucosa, the lateral mar-gins of the tongue or the gingivae. White striated,papular, or plaque-like forms (Fig. 16) are oftenasymptomatic, but the atrophic and ulcerativeforms may cause significant discomfort. WhenOLP affects the gingivae and gives rise to gener-alized gingival erythema, desquamation, andedema, the term “desquamative gingivitis” maybe used (Fig. 17). This is a general term describinga clinical situation and is not a diagnosis. Becauseother conditions can have a similar clinicalappearance, biopsy is recommended to confirmthe diagnosis, but it is advisable to avoid a gingi-val biopsy if there are other sites of involvement,since the inflammatory infiltrate associated withconcomitant gingivitis may disrupt the typicalhistological features of OLP (Fig. 18) leading todifficulties in obtaining a definite diagnosis. Thecause of OLP is not fully understood, but it is

thought to represent a T cell-mediated immuneresponse to an unknown trigger, whereby cyto-toxic T-cells damage basal epithelial keratinocytes(Zhou et al. 2002), in a microenvironment wherethere is an altered balance of immune regulatorycells and signalling pathways (Firth et al. 2015;Sinon et al. 2016). OLP is considered a potentiallymalignant condition (Al-Hashimi et al. 2007), andit is prudent that patients be reviewed at regularintervals by an oral medicine specialist because ofan increased likelihood of oral squamous cellcarcinoma occurring in association with OLP,particularly of the atrophic or ulcerative variety.Treatment is aimed at relieving symptoms and isusually provided to patients with painful, erosive,and ulcerative forms of disease (Hegarty 2012;Ryan et al. 2014). Maintenance of good oralhygiene and attention to routine dental care shouldbe reinforced to patients. Due to the paucity ofrandomized controlled clinical trials to evaluatetherapies, there is a lack of strong evidencesupporting the effectiveness of any palliativetherapy for symptomatic OLP (Chan et al. 2000;Zakrzewska et al. 2005). Topical corticoste-roids are still considered first line therapy(Thongprasom et al. 2011). Preparations includebetamethasone sodium phosphate as amouthrinse, fluticasone propionate as spray,mouth rinse, or cream, beclomethasone spray,fluocinolone cream, and clobetasol ointment orcream, or dexamethasone mouth rinse. As OLPcan present as desquamative gingivitis, improve-ment and maintenance of oral hygiene should be a

Fig. 15 Multiple gingival papillomas in a patientwith AIDS

Fig. 16 Plaque-like lichen planus involving the posteriormandibular gingivae

Gingival Pathology 13

priority in the management of this disease, butpain may be a limiting factor to good oral hygienemeasures and therefore must be taken into account

when designing a preventive program for thesepatients (Scattarella et al. 2011; Hegarty 2012).Topical immunomodulators such as tacrolimusand cyclosporine may be useful second linetherapies in recalcitrant OLP (Elad et al.2010; Thongprasom et al. 2011). Systemic immu-nosuppressants that have been used successfullyin the treatment of recalcitrant symptomatic OLPinclude azathioprine, mycophenolate mofetil, andsystemic corticosteroids (Al-Hashimi et al. 2007;Ryan et al. 2014). The use of laser therapy andultraviolet light phototherapy has been reportedless frequently in the treatment of OLP with lim-ited effectiveness (Ryan et al. 2014). Topical aloevera, topical pimecrolimus, and oral curcuminoidsare the most promising of the new therapiesreported (Thongprasom et al. 2013). Other inter-esting modalities are topically applied thalido-mide and amlexanox. Regular monitoring ofpatients with OLP is recommended due to thepotentially malignant nature of the conditionalthough the optimum frequency of reviewappointments is uncertain (Mattsson et al. 2002;Ryan et al. 2014).

Mucous Membrane Pemphigoid

Mucous membrane pemphigoid (MMP) is a rarechronic blistering autoimmune disease, whereautoantibodies are formed against components of

Fig. 17 Another manifestation of gingival lichen planusis desquamative gingivitis. Usually there is buccal involve-ment but occasionally desquamative gingivitis may be theonly sign of oral lichen planus (a). (b) is another example

of gingival lichen planus manifesting as desquamativegingivitis. Histological examination of representative tis-sue is necessary to confirm the diagnosis

Fig. 18 This photomicrograph shows the important diag-nostic features of basal cell damage with the ingress oflymphocytes into the basal layers of the epithelium. Theinflammatory infiltrate is confined to the superficial con-nective tissue and is composed of lymphocytes andmacrophages

14 A. Hegarty and A. Rich

hemidesmosomes. Target antigens in MMPinclude bullous pemphigoid antigen 1 (BP 230)and 2 (BP180), and laminins (Chan et al. 2002)with antibodies to human α6 integrin being iden-tified as important in the pathogenesis of oralMMP (Rashid et al. 2006). The condition com-monly affects middle-aged and elderly femalesand the usual presentation is oral mucosal vesi-cle/bulla formation with or without gingivalinvolvement. Gingival involvement usually man-ifests as painful erythema with desquamation(Fig. 19), either spontaneously or followingminor trauma such as tooth-brushing. Blood orfluid-filled blisters may be seen. The diagnosisshould be confirmed by biopsy for routinemicroscopic evaluation and immunofluorescencewhere possible, understanding that a biopsy of analready ulcerated region is likely to provide anonspecific result and the typical subepithelialsplit, with intact basal keratinocytes remainingon the epithelial surface, will not be seen(Fig. 20). Perilesional and lesions early in theirevolution will show linear deposition of IgGand/or C3 in the basement membrane zone(Fig. 21). Because of potential ocular involve-ment, as shown in Fig. 22, an ophthalmologicalexamination should be organized given the riskfor blindness. Treatment of MMP may be difficultdue to the complexity of the disease, diversity ofpathogenic pathways seen, and the lack of largescale, well-controlled studies regarding therapy

for MMP (Chan et al. 2002; Di Zenzo et al.2014; Taylor et al. 2015). Patients with oral dis-ease including involvement of the gingivae canoften be managed with local therapies, namely,

Fig. 19 When mucous membrane pemphigoid involvesthe gingiva, the clinical appearance is frequently ofdesquamative gingivitis (a, b). It is exacerbated by plaque,but the painful gingivae cause difficulty with tooth

brushing. Careful attention to oral hygiene in conjunctionwith a dental hygienist is an important component of themanagement plan

Fig. 20 Biopsy from a perilesional area in mucous mem-brane pemphigoid shows separation of the entire epithe-lium from the underlying connective tissue, with an intactlayer of basal keratinocytes on the epithelial aspect of thesplit

Gingival Pathology 15

topical corticosteroids and calcineurin inhibitors(Taylor et al. 2015). With gingival involvement,avoidance of trauma and improvement of oralhygiene should be part of the management regime(Bagan et al. 2005). For gingival lesions applica-tion of topical therapy in a vacuum-formed cus-tom tray may be more effective (Bagan et al.2005). The choice of medication use in the treat-ment of MMP depends on the site, severity, andrapidity of progression. If gingival MMP is recal-citrant to local measures and topical therapies,systemic immunosuppressants and immunomod-ulators may be required. Azathioprine,

mycophenolate mofetil, methotrexate, cyclospor-ine, and cyclophosphamide have been used in themanagement of severe disease to reduce inflam-mation, and biological agents such as rituximabare used to reduce autoantibody production(Taylor et al. 2015). Dapsone and othersulphonamides which suppress neutrophil adher-ence modulate severe vesiculobullous disease(Bagan et al. 2005). Tetracyclines which haveanti-inflammatory and immunosuppressive activ-ity and nicotinamide have also been used success-fully in managing oral MMP (Chan et al. 2002;Bagan et al. 2005). Systemic corticosteroids eitheralone or combined with other systemic therapy areeffective in achieving rapid control of severe dis-ease; however, the adverse effects tend to limittheir long-term use (Bagan et al. 2005; Tayloret al. 2015).

Linear IgA Disease

Linear IgA disease is a rare chronic, subepithelialblistering disease that is associated with the pres-ence of linear deposits of IgA along the basementmembrane zone. Oral mucosal lesions may occursimilarly to oral MMP with gingival involvementrarely seen (Fig. 23). Management is similar tothat of MMP but should include exclusion ofinflammatory bowel disease (IBD), because ofits occasional association with linear IgA disease(Shipman et al. 2012).

Fig. 22 Some forms of mucous membrane pemphigoidinduce conjunctival scarring (ocular cicatricialpemphigoid), which, if untreated, can lead to blindness

Fig. 21 Part of a biopsy from a perilesional region mayalso be used for direct immunofluorescence or, as in thisphotomicrograph, immunohistochemistry, where a lineardeposit of IgG and/or C3 may be observed in the basementmembrane zone

Fig. 23 The clinical presentation of linear IgA disease, asseen in this clinical photograph, may involve the gingivaein a similar manner to mucous membrane pemphigoid

16 A. Hegarty and A. Rich

Pemphigus Vulgaris

Pemphigus vulgaris (PV) is a rare but importantautoimmune disease, which frequently first occursintraorally. Gingival involvement may be in theform of mild erythema, desquamative gingivitis,and/or ulceration (Fig. 24). Antibodies are formedagainst cell adhesion molecules, particularlydesmoglein 3 in the case of oral mucosal disease,leading to progressive bulla formation and subse-quent ulceration and desquamation. A biopsy ismandatory to confirm the diagnosis prior to theinstitution of systemic and topical immunosup-pressive therapy, but care should be taken withobtaining an adequate specimen since the tissue isfragile and the epithelium can easily be lost. Aperilesional site, not directly involving the gingi-vae, should be chosen if possible. Histology willshow an intraepithelial split with acantholysis(Fig. 25) and with direct immunofluorescence, arim of IgG may be seen around the suprabasalcells (Fig. 26). Early diagnosis of oral lesionsand hence early initiation of appropriate therapyappears to minimize the chance of later severecutaneous disease in some instances, in part byreducing the likelihood of epitope spread andintroduction of antibodies to desmoglein 1 (Endoet al. 2008). Treatment usually involves use ofsystemic immunosuppressants and benefits

Fig. 24 The oral manifestations of pemphigus vulgarismay be relatively localized in the early stages of the dis-ease, as in (a), but are very likely to become more wide-spread (b) with extensive oral mucosal involvement andinvolvement of other mucosae and skin unless effective

treatment is instigated. As noted in relation to mucousmembrane pemphigoid, careful control of oral hygiene isvery important and may reduce the amount of topicaland/or systemic medication required for disease control

Fig. 25 The histological features of intraoral pemphigusvulgaris are an intraepithelial clefting with acantholysis,leaving one to three layers of keratinocytes on the base-ment membrane

Fig. 26 Direct immunofluorescence in pemphigusvulgaris shows intercellular binding of IgG

Gingival Pathology 17

have been reported from use of systemic cortico-steroids, azathioprine, mycophenolate mofetil,plasmapheresis, intravenous immunoglobulins,methotrexate, and the monoclonal antibody toCD20 on B cells, rituximab (Black et al. 2005;McMillan et al. 2015; Cholera and Chainani-Wu2016). There is still a lack of evidence from goodquality clinical studies regarding best interven-tions for PV (McMillan et al. 2015; Cholera andChainani-Wu 2016). The response to treatmentvaries and the incidence of remissions in pemphi-gus is unclear (Black et al. 2005). If there isgingival involvement, local measures must beincluded in the management plan and attentionto improving and maintaining good oral hygieneand minimizing irritation is essential along withthe adjuvant use of topical immunosuppressivetherapies in the form of corticosteroids and/orcalcineurin inhibitors (Black et al. 2005).

Orofacial Granulomatosis and OralCrohn’s Disease

Orofacial granulomatosis (OFG) is a term used todescribe a group of conditions with a clinicalpresentation of diffuse swelling of the lower halfof the face, particularly the lips, hyperplasticmucosal tags in the buccal mucosa, and diffusegingival enlargement and/or erythema (Fig. 27).Biopsy shows non-caseating granulomata. A

proportion of these patients have underlyingCrohn’s disease or sarcoidosis. While the orallesions may pre-date gastrointestinal Crohn’s dis-ease where investigations have ruled out Crohn’sdisease or sarcoidosis, a search for an allergicetiology, particularly to cinnamonaldehyde andbenzoates, should be undertaken. Managementof OFG and oral Crohn’s disease is challenging.Topical and systemic immunosuppressantsincluding intralesional injections of triamcinolonehave been used successfully but many patientsrequire systemic interventions to achieve partialor complete remission of signs and symptoms.Topical corticosteroids and tacrolimus have beenreported to be beneficial, and systemic therapiesinclude systemic corticosteroids, azathioprine,thalidomide, methotrexate, and in recalcitrantcases biologic agents such as infliximab andadamilumab (monoclonal antibodies againstTNF-alpha) have been used (Hegarty et al. 2003;Kolho et al. 2011; Zbar et al. 2012; O’Neill andScully 2012). A cinnamon and benzoate-free diethas been reported to be beneficial and plays a rolein management of OFG (Campbell et al. 2011).Gingival erythema and enlargement can be man-aged additionally by attention to oral hygiene anddental scaling and debridement. If gingivalenlargement persists following treatment of thecondition, then surgical intervention may beappropriate in some cases (Bansal et al. 2015).

Fig. 27 Friable erythematous maxillary gingival tissuesextending to involve the attached mucosa in a 33-year-oldmale with biopsy proven Crohn’s disease (a). (b) showshyperplastic inflamed mandibular labial gingiva with

swelling of the upper and lower lips in a 4-year-old malewith orofacial granulomatosis. (Images courtesy of Profes-sor Camile Farah, Queensland Oral Medicine & Pathology,Brisbane, QLD, Australia)

18 A. Hegarty and A. Rich

Granulomatosis with Polyangiitis(Wegener’s Granulomatosis)

Granulomatosis with polyangiitis (GPA), previ-ously known as Wegener’s granulomatosis, is asevere systemic vasculitis affecting medium andsmall arteries (Falk et al. 2011; Wojciechowskaet al. 2016). It is characterized by necrotizinggranulomatous inflammation of the upper andlower respiratory tract with glomerulonephritis,although many systems may be involved.Approximately one third of patients with GPAwill have oral involvement, which, in a smallnumber of cases, can first manifest in the oralmucosa (Almouhawis et al. 2013). The gingivaeare the usual site of oral involvement, with thedevelopment of a characteristic reddish purplegranular hyperplasia, known as “strawberry gin-givitis” (Fig. 28) (Cohen and Meltzer 1981;Almouhawis et al. 2013). Diagnosis in clinicalpractice is based on a combination of the clinicalmanifestations suggestive of a vasculitis, a biopsyof the affected organ showing necrotizing granu-lomatous inflammation with vasculitis and thepresence in serum of anti-neutrophil cytoplasmicantibodies (ANCA) (Lutalo and D’Cruz 2014;Wojciechowska et al. 2016). The particularpattern of ANCA in GPA is cytoplasmic(c-ANCA), where the antibody binds to protein-ase 3 (Relle et al. 2016). Immunosuppression withcorticosteroids and cyclophosphamide is used toinduce remission with azathioprine and metho-trexate for remission maintenance. Rituximab(monoclonal antibody against CD20) is used forsevere GPA (Relle et al. 2016).

Pyostomatitis Vegetans

Pyostomatitis vegetans (PyoV) is a rare oral disor-der that may affect the gingivae and is associatedwith Inflammatory Bowel Disease (IBD), in par-ticular ulcerative colitis (Hegarty et al. 2004). It isconsidered a specific marker of disease activity inulcerative colitis (Lankarani et al. 2013). The termPyostomatitis vegetans was first introduced byMcCarthy in 1949 and considered the oral coun-terpart of pyoderma vegetans and since then more

than 50 cases have been reported (Hegarty et al.2004; Clark et al. 2016). Males are affected two tothree times more often than females with an aver-age age at presentation of 34 years (Lankarani et al.2013). Bowel disease may precede the onset oforal lesions by months or years. The conditionpresents as erythematous, thickened oral mucosawith multiple pustules and superficial erosions andmay involve the gingivae (Fig. 29), labial andbuccal mucosae, and palate. As vegetating lesionsprogress, the mucosa may develop thickened foldsparticularly in the labial and buccal mucosa(Hegarty et al. 2004). Immunological and micro-bial factors have been suggested as possible etio-logical factors (Femiano et al. 2009). Skin lesionsof pyoderma vegetans may appear at the same timeas oral lesions, and liver dysfunction has also beenreported in association with PyoV (Hegarty et al.2004). Histopathologically, PyoV is characterizedby intraepithelial and/or subepithelial abscessescontaining large numbers of eosinophils(Fig. 30). Peripheral eosinophilia is seen in up to90% of cases (Lankarani et al. 2013; Wu et al.2015). Topical and systemic corticosteroids arethe mainstay of treatment but medical and/or sur-gical treatment of any coexisting bowel diseasemay be effective in controlling oral lesions(Hegarty et al. 2004; Femiano et al. 2009;Lankarani et al. 2013).

Plasma Cell Gingivitis/Gingivostomatitis

Plasma cell gingivitis is a rare condition whichpresents as diffuse or more localized erythema andswelling of the gingiva (Fig. 31) characterized byinfiltration of polyclonal plasma cells into thesubepithelial gingival tissues (Fig. 32). Occasion-ally the plasma cell proliferation may extendbeyond the gingiva in which case the termsplasma cell gingivostomatitis, orofacialplasmacytosis, or oropharyngeal mucosalplasmacytosis are more appropriate (Tong et al.2008; Madhavarajan and Tighe 2015). The etiol-ogy is uncertain but thought to represent an immu-nological reaction to an allergen (Joshi and Shukla2015) such as components of toothpastes and

Gingival Pathology 19

Fig. 28 Granulomatosis with polyangiitis presenting asfriable erythematous gingiva in a 63-year-old female oninitial presentation (a), post-systemic prednisolone therapy(b), and post-systemic methotrexate and cyclophospha-mide therapy (c). Hematoxylin and eosin stained

histopathological specimen demonstrating widespreadnonspecific inflammatory infiltrate with extravasated redblood cells (d). (Images courtesy of Professor CamileFarah, Perth Oral Medicine & Dental Sleep Centre, Perth,WA, Australia)

20 A. Hegarty and A. Rich

tooth powders, chewing gum, and certain foods.Treatment is with topical and/or systemic immu-nosuppression, in addition to identification ofoffending agent and its exclusion where possible.

Cysts, Potentially Neoplasticand Neoplastic Gingival Lesions

Odontogenic Cysts and Neoplasms

Cysts and neoplasms peculiar to the odontogenictissues may present with gingival involvementwhen they arise in an intrabony site and expandor erode the cortical plate. Less commonly theselesions can arise within the soft tissues of thegingival complex such as the gingival cyst of theadult (Fig. 33). These occur most often as anasymptomatic elevated dome-like lesion in themandibular canine and premolar gingivae, with-out underlying bony involvement. The histologyshows a cyst with a thin epithelial lining, usuallywith focal epithelial thickenings known asplaques. Excision is curative.

Peripheral ameloblastoma (PA), also knownas extraosseous ameloblastoma is a type ofameloblastoma that occurs exclusively in the softtissues of the gingiva or edentulous alveolar areas,showing microscopic features of ameloblastomaand without bone involvement (Vered et al. 2017).It has a predilection for the lingual gingiva in thepremolar region of the mandible (Philipsen et al.

Fig. 29 Erythema of the gingivae with small irregularulcers and superficial necrosis in pyostomatitis vegetans

Fig. 30 The histological features of pyostomatitis vegetansinclude both epithelial hyperplasia and ulceration with char-acteristicmicroabscesses containing eosinophils and neutro-phils at the tips of the connective tissue papillae and withinthe epithelium, as shown in the photomicrograph

Fig. 32 Photomicrograph showing the intense plasma cellinfiltrate seen in the connective tissue in plasma cellgingivostomatitis

Fig. 31 The typical features of gingival erythema and swell-ing are seen in this clinical photograph of plasma cell gingivos-tomatitis (Image courtesy of Professor Camile Farah,Queensland Oral Medicine & Pathology, Brisbane, QLD,Australia)

Gingival Pathology 21

2001). PA can mimic nonspecific ulcerationand/or pyogenic granuloma/angiogranuloma clin-ically (Fig. 34a). It shares similar histologicalfeatures with intraosseous ameloblastomas andretains an unencapsulated and infiltrative histo-pathological growth pattern (Fig. 34b). However,the recurrence rate is lower, and PA is generallyregarded to be less aggressive than intrabonyameloblastomas.

Other benign odontogenic tumours such ascalcifying epithelial odontogenic tumour andadenomatoid odontogenic tumour very rarelyhave peripheral counterparts in the absenceof an intrabony component. Benign cementum-producing neoplasms such as benigncementoblastoma and cemento-ossifying fibroma,

as well as non-neoplastic bone lesions such asfibrous dysplasia and the osseous dysplasias,may also present as a diffuse swelling of thealveolar bone. These lesions are covered in moredetail in separate chapters on “▶OdontogenicPathology” and “▶Non-Odontogenic BonePathology.”

Leukoplakia and Erythroplakia

Oral potentially malignant lesions of the gingivainclude leukoplakia, erythroleukoplakia, anderythroplakia. Homogeneous and non-homogeneous leukoplakia may develop on thegingiva (Fig. 35) and are considered to be at risk

Fig. 33 A raised dome-shaped lump involving theattached mucosa betweenthe upper right first andsecond incisor teeth (11 and12) (a). Surgical removal ofthe lump reveals exposedroot of tooth 12 (b).Histologically the lesiondemonstrates a cyst with athin epithelial liningconsistent with a gingivalcyst of the adult (c). (Imagescourtesy of ProfessorCamile Farah, Perth OralMedicine & Dental SleepCentre, Perth, WA,Australia)

22 A. Hegarty and A. Rich

of malignant transformation. Less commonly,erythroplakia may be diagnosed which has ahigher malignant potential than leukoplakia(Fig. 36). Biopsy is necessary to establish thedegree of epithelial dysplasia (Warnakulasuriyaet al. 2011). Proliferative verrucous leukoplakia(PVL) is a rare form of leukoplakia which pro-gresses, often over many years, from a singlelocalized homogeneous leukoplakia to multiplewidespread nonhomogeneous verrucous leuko-plakic lesions with a high rate of change toverrucous and/or squamous cell carcinoma. It ischaracterized by extensive and multifocal whiteadherent lesions which frequently involve the gin-giva (Fig. 37), in addition to the palate and buccal

mucosa (Bagan et al. 2003; Gondalfo et al. 2009).The diagnosis can only be made retrospectivelyand the underlying etiopathogenesis is poorlyunderstood. PVL requires close monitoring, andadequate management is difficult. There is someevidence to suggest carcinoma arising in PVLhave a better prognosis than other intraoral carci-nomas (Akrish et al. 2015). Oral potentiallymalignant lesions are covered in more detail inseparate chapters on “▶White and Red Lesionsof the Oral Mucosa” and “▶Oral MucosalMalignancies.”

Fig. 34 Biopsy proven peripheral ameloblastoma pre-senting as a gingival lump on the lingual aspect of thelower left second premolar suggestive of anangiogranuloma (a). Hematoxylin and eosin stainedhistopathological specimen demonstrates islands of

ameloblastoma in direct continuity with surface epithelium(b). (Images courtesy of Professor Camile Farah, PerthOral Medicine & Dental Sleep Centre, Perth, WA,Australia)

Fig. 35 Diffuse leukoplakia involving the maxillary alve-olar mucosa and the labial mucosa

Fig. 36 Erythroplakia is relatively uncommon but is alesion with a high malignant potential. The clinical photo-graph shows an erythroplakia involving the maxillarygingivae

Gingival Pathology 23

Oral Squamous Cell Carcinoma

Over 90% of oral cancers are squamous cell car-cinomas and the gingivae or edentulous alveolarmucosa are sites that may be involved. Oral squa-mous cell carcinoma (OSCC) may present as apersistent nonhealing ulcer (Fig. 38a), a persistentwhite, red, or mixed white and red patch or anexophytic mass (Fig. 38b). Patients may beasymptomatic or present with pain, bleeding,altered sensation, difficulty eating, speaking,swallowing and/or cervical lymphadenopathy.OSCC, including gingival SCC, is seen mostfrequently in patients with a history of tobaccoand alcohol use, although gingiva was a relativelyfrequent site of carcinoma in elderly females whohad never smoked or drank alcohol (Dahlstromet al. 2008). Any lesion on the gingivae whichdoes not show significant resolution followingelimination of possible causes should be biopsiedwithin 3 weeks. A degree of urgency in manage-ment is advisable, because, while early gingivalSCC can usually be treated successfully by localsurgery, the proximity of the gingival soft tissuesto alveolar bone can lead to early bone involve-ment. Invasion of the underlying bone, particu-larly invasion of the mandibular canal, presents adifficult surgical problem and poor 5-year survival(Okura et al. 2016).

Lymphoma

Lymphoma is a term used to describe a heteroge-neous group of malignant disorders derived fromlymphoid cells and their precursors. ExtranodalHodgkin’s lymphoma is uncommon and most pri-mary oral lymphomas are B-cell non-Hodgkin’slymphoma (NHL), particularly diffuse large B cellNHL (Iguchi et al. 2012; Silva et al. 2016).Lymphoma is the second most common intraoralmalignancy after SCC (Epstein et al. 2001).Waldeyer’s ring is the most frequent oropharyn-geal site involved, but gingival lesions occur inotherwise healthy people (Fig. 39a, b), as well asin those with immunodeficiencies. A study of68 extranodal B cell NHL in the head and neckreported that 30 were intraoral; and the most fre-quent intraoral location was the gingiva (Baganet al. 2015). Gingival NHL may be associatedwith alveolar bone loss, edema, and pain mimick-ing dental periapical and/or periodontal infectionsand leading to a delay in diagnosis (Spataforeet al. 1989; Jessri et al. 2013). The conventionalhistopathology findings need to be interpretedalong with immunohistochemistry with a panelof appropriate antibodies and molecular investi-gations for various translocations (Fig. 40a, b).Prognosis is grade-dependent and ranges fromsustained long-term survival to a 5-year mortalityrate of around 60%. Hematologists are the pri-mary specialists involved in provision of treat-ment for lymphoma.

Other Primary Malignant Neoplasms

Rarely other primary oral malignant neoplasmsmay involve the gingivae. Oral malignant mela-noma usually presents as a pigmented lesion onthe gingivae or palate (Fig. 41a). It is an aggres-sive neoplasm derived from malignant transfor-mation of oral mucosal melanocytes. Early in itsevolution, it is likely to be a dark brown to blackirregular macule which progresses to a raisednodule with ulceration and soon involves theunderlying alveolar bone (Fig. 41b, c). An obser-vational study of 46 new cases involving intraoralmalignant melanoma emphasized their clinical

Fig. 37 Proliferative verrucous leukoplakia is a term usedto describe leukoplakias that progress from being solitarywith a relatively homogeneous surface to a verrucous sur-face, as shown in this Figure and then to verrucous and/orsquamous cell carcinoma. There are no particular clinicalor histological features that are specific to this condition; itis a diagnosis that is made retrospectively

24 A. Hegarty and A. Rich

Fig. 38 Persistent gingival ulcer which histologically wasfound to be a squamous cell carcinoma (a). Note theleukoplakia around the gingival margin of the adjacent

teeth. Gingival squamous cell carcinomas can present in avariety of forms including as an erythematous somewhatexophytic lesion as shown in (b)

Fig. 39 Intraorallymphomas may be part ofdisseminated disease, butthe first indication oflymphoma may bepresentation with a painlesssoft tissue swellinginvolving the gingivae, asshown in a, b, or posteriorhard palate

Fig. 40 (a) is a photomicrograph from an incisionalbiopsy of a gingival mass in a 63-year-old female andshows a dense infiltrate of neoplastic lymphoid cells

which were CD3 positive (b). The diagnosis was diffuselarge B-cell lymphoma

Gingival Pathology 25

and histological diversity. The greater majority ofthese were found in the maxillary mucosa withclinicians’ impressions of these varying frombenign fibrous growths to high grade malignan-cies. The histopathological features also variedwidely among cases, with two cell types pre-dominating, namely, epithelioid cells and spindlecells, often in combination. Only 53.1% demon-strated melanin pigmentation (Housley Smithet al. 2016).

Leukemia, a group of malignancies of hemo-poietic stem cells, may occasionally manifest asdiffuse gingival swelling when leukaemic cellsinfiltrate the gingival soft tissues (Fig. 42a, b).As the normal hemopoietic stem cells in thebone marrow are displaced by malignant cells,the oral mucosa, including the gingivae, mayshow evidence of neutropenia with increased sus-ceptibility to infection and ulceration and throm-bocytopenia with petechial hemorrhages and atendency to spontaneous or prolonged bleeding.

Kaposi sarcoma (KS), an AIDS definingmalignancy, may present as oral mucosal red,brown, or purple macules and/or swellingswhich may affect the gingivae (Fig. 43). Kaposisarcoma-associated herpesvirus (KSHV) is neces-sary for the development of KS which usuallyoccurs in a setting of immunosuppression(Chang et al. 1994; Dittmer and Damania 2016).This virus also causes other diseases in AIDSpatients, including multicentric Castleman’s dis-ease, a B cell lymphoproliferative disorder, andspecific lymphomas (Goncalves et al. 2017). Mostprimary KSHV infections are asymptomatic. Thevirus infects endothelial cells, epithelial cells, Bcells, monocytes and dendritic cells where itbecomes latent, but it can be reactivated andinduced to replicate in certain circumstances inresponse to severe T cell depletion or inactivation(Dittmer and Damania 2016; Goncalves et al.2017). The diagnosis is made by demonstratingKSHV in lesional spindle cells in a biopsy sample.

Fig. 41 Malignantmelanoma, confirmedhistologically from anincisional biopsy, involvingthe maxillary labialgingivae, with marginsmarked for excision (a) andcorresponding surgicalresection specimen (b). Thephotomicrograph showssheets of malignantmelanocytes with boneinvolvement (c)

26 A. Hegarty and A. Rich

While the incidence and mortality from Kaposisarcoma has dropped significantly since the use ofART, it remains the most common AIDS-associated malignancy in both developed anddeveloping nations (Wen and Damania 2010).

Metastases to the Gingiva

Metastases to the oral regions are rare and areusually associated with widespread metastatic dis-ease. Bony metastases are the most likely, partic-ularly to the mandible, but soft tissue metastasesdo occur, and in these instances the gingivalmucosa is the most common oral mucosal siteinvolved (Allon et al. 2014). An association has

been noted between gingival metastases and thepresence of teeth, leading to the suggestion thatcytokines related to periapical and periodontalinflammation facilitate the development of a suit-able niche for circulating tumour cells to thrive(Allon et al. 2014; Hirshberg et al. 2014). Themost common clinical presentation of a gingivalmetastasis is a painful swelling, with or withoutsurface ulceration, which rapidly increases in size.If bone is involved and the lesion is located in thevicinity of the inferior alveolar nerve, labial par-esthesia or anesthesia may develop. In theseinstances, radiographs are likely to show radiolu-cency with poorly defined margins. In males, themost common primary sites that metastases to theoral region are lung, kidney, liver, and prostate,and in females, metastases are most likely to befrom breast, female genital organs, kidney, andcolorectum (Hirshberg et al. 2014).

Conclusions and Future Directions

Gingival lesions may be of a simple local nature ormay be an indication of severe local or systemicdisease. Recognizing the signs and/or symptomsof gingival pathology will ensure prompt andappropriate management for the patient. Carefulclinical observation will continue to be critical tothe development of a clinical diagnosis for gingi-val pathology. However diagnostic techniques are

Fig. 42 Widespread gingival hyperplasia involving themaxillary andmandibular labial (a) andmandibular lingual(b) gingiva in a 48-year-old female patient with chronic

periodontal disease complicated by chronic leukemic infil-trates. (Images courtesy of Dr Marie Matias, Western Peri-odontics, Northbridge, WA, Australia)

Fig. 43 Prior to effective antiretroviral treatment innova-tions, intraoral Kaposi’s sarcoma was a relatively frequentoral manifestation of AIDS, usually involving the gingivaeor palate

Gingival Pathology 27

changing. Biopsy of a lesion for conventionalhistopathology remains the gold standard formost diagnoses, but this is often interpreted inconjunction with the results of immunofluores-cence and immunohistochemistry studies. Weare increasingly looking beyond the tissue archi-tecture and cellular features to study genetic andprotein-related biomarkers from lesional tissue,blood, and potentially saliva. The diagnosticapplications of saliva as a biofluid are beginningto be understood but reliable cost-effective tech-nology is not yet available.

Cross-References

▶Clinical Evaluation of Oral Diseases▶Clinical Immunology in Diagnoses of Maxillo-facial Disease

▶Diagnostic Imaging Principles and Applica-tions in Head and Neck Pathology

▶Head and Neck Malignancies▶LaboratoryMedicine and Diagnostic Pathology▶Non-odontogenic Bone Pathology▶Normal Variations in the Anatomy, Biology andHistology of the Maxillofacial Region

▶Odontogenic Bacterial Infections▶Odontogenic Pathology▶Oral and Maxillofacial Viral Infections▶Oral Lichen Planus▶Oral Manifestations of Systemic Diseases andTheir Treatments

▶Oral Mucosal Malignancies▶Oral Ulcerative Lesions▶Oral Vesicular and Bullous Lesions▶ Pediatric Oral Medicine▶ Pharmacotherapeutic Approaches in OralMedicine

▶ Pigmented Lesions of the Oral Mucosa▶White and Red Lesions of the Oral Mucosa

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