Hereditary Gingival Fibromatosis (HGF)

Hereditary Gingival Fibromatosis (HGF)

• Clinical presentation: Slow, progressive gingival overgrowth with varying degrees of manifestation. May present in an isolated fashion or part of a syndrome. Gingival enlargement is typically of normal coloration and non‐ulcerated.
• Cause: Association with mutation of the Son of Sevenless gene SOS1 and SOS2 (however not in all cases). Gingival expansion as a result of accumulation of extracellular matrix protein.
• Diagnosis: Clinical examination, biopsy, medical history, family history and laboratory tests.
• Ddx: Drug induced gingival hyperplasia and leukemia.
• Histopathology: Epithelial hyperplasia with elongated thin rete pegs extending into hypo‐vascular fibrous connective tissue containing numerous collagen fibers, oriented in variable directions.
• Management: Non‐surgical management entails scaling, root planing, and oral hygiene instruction. Surgical management involves gingivectomy.

Infections of Bacterial Origin

Necrotizing Periodontal Diseases

• Clinical: Patient presents with painful and erythematous gingiva and “crater‐like” necrosis in interdental papillae with ulceration. The lesions may be hemorrhagic and disseminate a strong foul odor. Consider the spectrum of lesions which vary depending on both localization of lesion and predisposing factors i.e. necrotizing‐gingivitis, ‐periodontitis, ‐stomatitis, and noma.
• Cause: Due to bacterial infection by species that include Treponema, Selenomonas, Fusobacterium, and Prevotella intermedia. Immunosuppression, poor oral hygiene, smoking, stress, and poor nutrition are strongly associated with infection.
• Diagnosis: Clinical features and bacterial culture.
• Ddx: Primary herpetic gingivostomatitis, vesiculobullous diseases, and gonorrhea.
• Histopathology: Ulceration with necrotic tissue and prominent acute and chronic inflammatory cells in connective tissue stroma. Bacterial colonies are also noted.
• Management: Supportive care and pain control with debridement to remove debris and plaque. Consider antibiotics (Figure 4.1).

Gonorrhea

• Clinical: Rare oral manifestation of sexually transmitted disease with areas of erythema and ulceration of gingiva with a pseudomembranous coating. Oropharyngeal lesions appear markedly erythematous with scattered pustules. Lesions develop within one week of contact with infectious individual. This infection is associated with pelvic inflammatory disease and gonococcal ophthalmia neonatorum.
• Cause: Sexually transmitted infection caused by the bacterial organism Neisseria gonorrhea.
• Diagnosis: Culture of organism, gram stain of purulent material demonstrates gram negative diplococcic, and nucleic acid amplification tests (NAATs).
• Ddx: Necrotizing periodontitis (typical odor is not present in gonorrhea).
• Management: Symptomatic treatment of oral lesions after confirming patient is receiving care from physician with appropriate antibiotics.

Syphilis

• Clinical: Sexually transmitted disease with possible oral manifestations which vary in presentation depending upon stage.
  1. ○ Primary: Presents with the highly infectious usually painless chancre that may occur at any oral mucosal site including the gingiva (resolves in approximately two to eight weeks).
  2. ○ Secondary: Diffuse skin eruptions are the hallmark of this stage. Orally presents with elevated mucous patches and condylomata lata (2–12 weeks after primary lesion).
  3. ○ Tertiary: This stage may occur as many as 30 years after the secondary stage. Oral lesions include areas of granulomatous inflammation termed gumma, which results in significant ulceration (more common on palate and tongue).
  4. ○ Also consider congenital syphilis infection and oral manifestation of Hutchinson incisors and mulberry molars.
• Cause: Infection with spirochete bacterium Treponema pallidum.
• Diagnosis: Clinical features, histopathology, dark field microscopy of a smear and lab tests (i.e. venereal disease research lab (VDRL) test, rapid plasma reagin [RPR] test).
• Ddx: Depending upon stage the lesions may resemble various other oral pathologic processes.
  1. ○ Primary: The lesion may resemble the non‐healing ulceration differential (traumatic ulcer, squamous cell carcinoma, tuberculosis ulcer, deep fungal ulcer).
  2. ○ Secondary: Mucous patches may resemble leukoplakic patches.
  3. ○ Tertiary: Palatal gumma may mimic sequelae from cocaine use, malignancy, or mucormycosis infection.
• Histopathology: In primary and secondary syphilis the oral lesions show ulceration with exocytosis of neutrophils with a dense chronic inflammatory infiltrate in the connective tissue stroma. Of note is the perivascular lymphoplasmacytic infiltrate. With special stain (Warthin Starry, silver stain) or immunohistochemistry, the spirochete organisms can be seen in surface epithelium. In tertiary lesions the organisms are difficult to ascertain however ulceration and granulomatous inflammation is noted.
• Management: Intramuscular Penicillin G.

Tuberculosis

• Clinical: Chronic granulomatous infectious disease, which usually affects the lungs. Secondary hematogenous spread from the lungs or rarely primary infection may lead to non‐specific oral lesions. The most common manifestation however is a painful non‐healing ulcer on the lateral tongue.
• Cause: Infection with Mycobacterium tuberculosis.
• Diagnosis: Biopsy, sputum culture, chest X‐ray, Mantoux test, and systemic signs.
• Ddx: Traumatic ulcer, major aphthous ulcer, squamous cell carcinoma, deep fungal ulcer, syphilitic ulcer.
• Histopathology: Epithelioid histiocytes surrounding a central necrotic zone accompanied by multinucleated giant cells and lymphocytes. Special stain with Ziehl–Neelsen to demonstrate acid‐fast bacilli.
• Management: Six month course of antibiotics (isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin).

Streptococcal Gingivitis

• Clinical: Diffuse gingival inflammation and bone loss considered unassociated with plaque formation.
• Cause: Infection with streptococcal strains.
• Diagnosis: Culture of organism if regular phases of periodontal treatment are not providing resolution.
• Ddx: Other forms of periodontal disease.
• Management: Antibiotics with mechanical debridement.

Infections of Viral Origin

Hand, Foot, and Mouth Disease

• Clinical: Viral illness which usually presents in young children. The patient may display signs of fever, malaise, lack of appetite, and sore throat. Painful oral ulcers start to develop in the back of the mouth along with a rash/vesicles on the palms and soles.
• Cause: Most commonly Coxsackie virus A16, which is a type of Enterovirus.
• Diagnosis: Clinical presentation.
• Ddx: Herpetic gingivostomatitis, herpangina.
• Histopathology: Epidermal necrosis, infiltrate of lymphocytes along epithelial interface with connective tissue and extensive edema.
• Management: Self‐limiting condition which lasts 7–10 days in most cases therefore supportive treatment to alleviate pain and prevent dehydration.

Primary Herpetic Gingivostomatitis

• Clinical: Initial herpes simplex virus infection which results in shallow ulcers on both keratinized and non‐keratinized mucosa with systemic signs and symptoms (fever, lymphadenopathy, myalgia). More common in children.
• Cause: Herpes simplex virus type 1 (or type 2).
• Diagnosis: Cytologic smear, tissue biopsy, antibody studies, viral culture.
• Ddx: Other viral infections, necrotizing ulcerative periodontitis and erythema multiforme in some cases.
• Histopathology: Infected keratinocyte cells display balloon degeneration and nuclear changes consisting of margination of chromatin, multinucleation, and nuclear molding. The ulcer is composed of a fibrin membrane with viable and necrotic neutrophils.
• Management: Self‐limited condition which resolves in approximately 10 days without scarring. Palliative treatment with adequate hydration, nutrition, and consideration given to pain relief.

Recurrent Herpes Simplex

• Clinical: Recurrent unilateral ulcers which occur on the skin of the lip (termed herpes labialis) and intraorally on the keratinized mucosa. Extraorally, the ulcerations initially appear as a cluster of vesicles which eventually open and finally crust over. Intraorally, crops of coalescing ulcers are seen. Prodromal symptoms may be present before clinical evidence of lesions. Atypical presentation of lesions may occur in HIV infected individuals.
• Cause: Reactivation of herpes simplex virus infection which is latent in the trigeminal ganglion. Triggers include exposure to sunlight, trauma, fever, and stress.
• Diagnosis: Clinical diagnosis if features are classic or cytologic smear/tissue biopsy.
• Ddx: Extraorally, may resemble impetigo (not unilateral). Intraoral recurrent herpes is usually distinct but may resemble localized necrotizing ulcerative gingivitis or traumatic ulcers.
• Histopathology: Infected keratinocyte cells display acantholysis, balloon degeneration, and nuclear changes consisting of margination of chromatin, multinucleation, and nuclear molding. The ulcer is composed of a fibrin membrane with viable and necrotic neutrophils.
• Management: Self‐limited condition which heals without scarring. 1% penciclovir cream may be useful for extraoral lesions if applied during prodrome and for intraoral lesions consider systemic antivirals such as valacyclovir.

Oral Hairy Leukoplakia

• Clinical: Opportunistic infection by Epstein Barr virus (EBV) which results in a non‐wipeable white lesion with corrugated vertical folds on lateral tongue.
• Cause: Immunosuppression (HIV infection or organ transplant patients) leading to EBV infection.
• Diagnosis: Biopsy and microscopic evaluation.
• Ddx: Frictional keratosis, tongue chewing, leukoplakia.
• Histopathology: Thickened parakeratin with surface projections overlying a “balloon cell” layer containing cells with excess cytoplasm. These cells display nuclear clearing and margination of chromatin in the pattern of a circular string of beads.
• Management: Treatment is usually not needed however lesions may be removed for esthetic reasons.

Human Papilloma Virus Infection

• Clinical: The squamous papilloma is an asymptomatic oral lesion caused by low risk human papilloma virus (HPV). This exophytic growth presents with papillary projections and either a pedunculated or sessile base. The common locations are the tongue and soft palate.
• Cause: Low risk human papilloma virus (types 6 or 11) causing a benign neoplasm of squamous cells.
• Diagnosis: Microscopic examination.
• Ddx: Verruca vulgaris (cutaneous wart), condyloma acuminatum (genital wart), and occasionally a giant cell fibroma that has a similar bosselated surface.
• Histopathology: Proliferation of squamous epithelial cells in a papillary manner with fibrovascular cores (Figure 4.2). Other features include evidence of a viral cytopathic effect consisting of koilocytes and binucleated cells.
• Management: Surgical excision.

Chicken Pox (Varicella) and Zoster

• Clinical: Chicken pox or varicella is a viral infection that usually affects children and results in a pruritic maculopapular skin rash with associated systemic symptoms (headache, fever, malaise). In later stages, the lesions become vesicles and pustules which rupture and become crusted. The oral manifestation includes intraoral vesicles. In zoster or “shingles” there is a reactivation of the latent virus present in the dorsal root ganglion or trigeminal ganglion. The rash is distributed in a unilateral manner and presents with pain. In zoster, oral manifestations are rare however vesicles, bone necrosis, and tooth loss may occur in the affected area.
• Cause: Varicella zoster virus.
• Diagnosis: Clinical features, cytology, PCR, culture, antibody titers.
• Ddx: Rare oral gingival lesions resemble primary HSV infection.
• Histopathology: Cytology displays identical viral cytopathic effect as seen in HSV (i.e. nuclear margination of chromatin, molding of cells and multinucleation).
• Management: Supportive treatment (may consider antivirals in certain cases).

Molluscum

• Clinical: Commonly presents as pruritic, umbilicated papules on the skin of the face and trunk, rarely intraorally. More frequent in children and immunocompromised individuals. Sexually transmitted in adults.
• Cause: Poxvirus.
• Diagnosis: Clinical features, biopsy with microscopic examination.
• Ddx: Cryptococcus, verruca vulgaris, condyloma acuminatum.
• Histopathology: Viral cytopathic effect in epithelial cells leads to intracytoplasmic eosinophilic inclusions (Henderson‐Paterson bodies or molluscum bodies).
• Management: May regress within 6‐9 months or may be removed surgically.

Infections of Fungal Origin

Candidiasis

• Clinical: Opportunistic oral infection by the commensal fungal organism Candida albicans that results in five main presentations.
  1. Pseudomembranous candidiasis: White, wipeable curd‐like plaques that occur most commonly on the buccal mucosa, palate, and tongue in immunosuppressed or individuals taking broad‐spectrum antibiotics. Symptoms may include a burning sensation.
  2. Erythematous candidiasis: Red areas that may be a result of antibiotic use, xerostomia, or steroid inhalers (palate). The tongue may display patchy depapillation of the filiform papillae. The lesions may include symptoms of a burning sensation. This category also includes median rhomboid glossitis that presents as a well‐defined central area of atrophy on the dorsal tongue infected with candida which is asymptomatic.
  3. Denture stomatitis: Erythematous lesion localized to denture‐bearing areas due to continuous wear of denture. May present with petechiae to diffuse redness (Figure 4.3).
  4. Chronic hyperplastic: Uncommon form of candidiasis which presents as a non‐wipeable white lesion. The hyperplastic response of the mucosa is a result of the presence of candida organisms. Common on the anterior buccal mucosa.
  5. Angular cheilitis: Candida infection presents with cracking and erythema at the commissures that are usually bilateral. The loss of vertical dimension may predispose the area to constant moisture which leads to the infected fissured lesions.
• Diagnosis: Clinical features and cytologic smear (Figure 4.4) or biopsy with microscopic evaluation after PAS stain (Figure 4.5)
• Ddx (number corresponds with type of candidiasis): 1. Materia alba, 2. & 3. Erythroplakia, localized inflammatory response, 4. Frictional keratosis, leukoplakia (dysplasia/squamous cell carcinoma), 5. Nutritional deficiencies (iron, B12, folic acid).
• Histopathology: Increased thickness of parakeratin layer containing neutrophilic microabscesses and candida hyphae. There is also elongation of epithelial rete ridges and a chronic inflammatory cell infiltrate in the connective tissue.
• Management: Antifungal medication (nystatin or clotrimazole).

Histoplasmosis

• Clinical: Rare intraoral presentation of solitary ulceration with firm borders due to extrapulmonary disseminated infection.
• Cause: Histoplasma capsulatum.
• Diagnosis: Biopsy and microscopic examination, culture, serology.
• Ddx: Squamous cell carcinoma.
• Histopathology: Granulomatous inflammation comprised of epithelioid histiocytes containing fungal organisms (Figure 4.6). GMS special stain used to highlight presence of fungal organisms.
• Management: Amphotericin B or itraconazole antifungal medications.

Aspergillosis

• Clinical: Inhaled spores lead to various clinical presentations. Noninvasive form presents as an allergic fungal sinusitis or fungal ball (aspergilloma). Invasive form may present as disseminated disease or a localized intraoral lesion with a diffuse gray or violaceous hue.
• Cause: Aspergillus flavus and Aspergillus fumigatus.
• Diagnosis: Biopsy and microscopic examination or culture.
• Ddx: Other fungal infection, malignancy.
• Histopathology: Branching (acute angle) septate hyphae with fruiting bodies.
• Management: Debridement for non‐invasive disease (corticosteroids are also added for allergic fungal sinusitis). Debridement, voriconazole, and amphotericin B for invasive aspergillosis.

Hypersensitivity Reactions

Contact Allergy/Allergic Contact Mucositis

• Clinical: Erythematous and edematous lesions that may form vesicles and ulcers or appear lichenoid as a result of direct contact with allergens such as dental materials, toothpaste, chewing gum, food additives, and cinnamon. Symptoms include burning, itching, and stinging.
• Cause: Direct contact with allergen.
• Diagnosis: Consider history and perform allergy testing or possible biopsy in certain clinical situations.
• Ddx: Lichen planus, epithelial dysplasia.
• Histopathology: Lesions may present with interface mucositis and deeper perivascular inflammatory infiltrate with occasional eosinophils. Lichenoid type lesions display areas of hydropic degeneration of the basal cell layer and a dense band like infiltrate of lymphocytes and plasma cells subjacent to the basal cells. A deeper perivascular lymphoid infiltrate may also be seen.
• Management: Removal of allergen, antihistamines, or topical corticosteroids.

Plasma Cell Gingivitis

• Clinical: The gingival epithelium takes on a bright red hue and displays generalized involvement. Pain is associated with the condition especially if hot, spicy, and acidic foods are contacted.
• Cause: Allergy or idiopathic.
• Diagnosis: Histopathology combined with clinical features.
• Ddx: Desquamative gingivitis lesions.
• Histopathology: Hyperplasia of the mucosa in a psoriasiform manner with an intense plasma cell infiltrate in connective tissue stroma.
• Management: Allergy testing or dietary history to rule out offending agent. May consider topical steroids.

Erythema Multiforme

• Clinical: Acute self‐limiting condition with abrupt onset that presents with oral mucosal and/or skin lesions. The diffuse oral lesions are usually large ulcerations on the buccal/labial mucosa and lateral tongue. A characteristic hemorrhagic crusting of the vermilion of the lip and “target lesions” (concentric erythematous rings) on the skin may also be seen. This condition is most commonly seen in young adults.
• Cause: Uncertain but most likely hypersensitivity reaction to preceding herpes simplex or Mycoplasma pneumonia infection, drugs, or idiopathic.
• Diagnosis: Clinical features and history. May consider biopsy to rule out other conditions since histopathology is not pathognomonic.
• Ddx: Paraneoplastic pemphigus and other vesiculobullous disorders may present similarly. Stevens Johnson syndrome and toxic epidermal necrolysis are similar however more severe in presentation and most likely due to drug exposure.
• Histopathology: The epithelium displays necrosis of basal cells and the presence of intercellular and intracellular edema. There is also intraepithelial and subepithelial vesicle formation with exocytosis of inflammatory cells. A mixed infiltrate of lymphocytes, neutrophils, and occasional eosinophils is seen in the submucosa. A perivascular inflammatory infiltrate is also noted in the connective tissue.
• Immunofluorescence: Non‐specific.
• Management: Try to identify and avoid the probable etiologic agent. Usually self‐limiting (lasts two to four weeks), however, may consider steroid or antiviral for recurrent cases. Maintain hydration and use topical anesthetic for pain during eating.

Autoimmune Diseases of Skin and Mucous Membranes

Pemphigus Vulgaris

• Clinical: Autoimmune vesiculobullous condition more common in adults 50–60 years old. Autoantibodies develop toward epithelial intercellular bridges and results in loss of cell to cell adhesion. This condition manifests clinically as painful skin and oral vesicles and bullae which quickly rupture to form ulcers. Clinical manifestation on the gingiva is called desquamative gingivitis.
• Cause: Binding of autoantibodies (IgG) to desmoglein‐3 which is a component of desmosomes.
• Diagnosis: Biopsy (including intact epithelium) and consider a positive Nikolsky sign (formation of a bulla on normal mucosa with gentle lateral pressure) may also be noted.
• Ddx: Mucous membrane pemphigoid, erythema multiforme, erosive lichen planus, and paraneoplastic pemphigus.
• Histopathology: Acantholysis of the epithelium with an intact basal cell layer attached to the underlying connective tissue. Only the basal layer cells are attached to the basement membrane zone by hemidesmosomes and appear as a “row of tombstones.” Loose rounded acantholytic cells are noted in the intraepithelial clefts which are termed Tzanck cells (Figure 4.7).
• Direct immunofluorescence: IgG, IgM, and C3 are demonstrated in the intercellular spaces (“fishnet pattern”).
• Indirect immunofluorescence: Positive.
• Management: High dose steroids and immunosuppressives.

Mucous Membrane Pemphigoid

• Clinical: Autoimmune vesiculobullous condition more common in adults 50–60 years old. Autoantibodies develop toward a component of the basement membrane. This results in painful vesicles and bullae that rupture to leave large ulcerations that heal with scarring. Gingival lesions are clinically termed desquamative gingivitis. Ocular involvement may cause significant complications.
• Cause: Binding of autoantibodies (IgG, C3) to a component of the basement membrane (epiligrin) or a component of hemidesmosomes (alpha‐6 integrin).
• Diagnosis: Biopsy (including intact epithelium), a positive Nikolsky sign may also be noted.
• Ddx: Pemphigus vulgaris, erosive lichen planus, bullous pemphigoid (skin usually, BP180 and BP230 are antigens), linear IgA bullous dermatosis (deposition of IgA along basement membrane, mostly in skin), angina bullosa hemorrhagica (rare with blood filled vesicles), and epidermolysis bullosa acquisita (mostly skin, type 7 collagen is antigen).
• Histopathology: The epithelium separates from the connective tissue at the basement membrane (sub‐epithelial cleft) (Figure 4.8). The superficial connective tissue displays a chronic inflammatory infiltrate.
• Direct immunofluorescence: Linear pattern of deposition of IgG and C3 at basement membrane.
• Treatment: Topical steroids, immunosuppressives, referral to ophthalmologist.

Lichen Planus

• Clinical: Chronic T‐cell mediated autoimmune disease which affects both the skin and oral mucosa. The condition is more commonly seen on the buccal mucosa, tongue, and gingiva in people older than age 40. The buccal lesions are usually bilateral in presentation. Two main forms exist: reticular and erosive. The reticular form presents with lace‐like white lesions (Wickham striae) (Figure 4.9). On the dorsal of the tongue the white lesions are plaque like in appearance. The erosive form presents with pain, atrophy, and ulceration. Radiating white striae tend to rim the ulcerations. The erosive form is clinically termed desquamative gingivitis (Figure 4.10) when present on the attached gingiva. The skin lesions are described as purple, pruritic papules.
• Cause: T‐cell mediated disease.

• Diagnosis: Clinical features may be distinct in the reticular form however biopsy (including intact epithelium) is usually indicated for erosive form.
• Ddx: Clinical ddx: Lichenoid drug reaction (similar reaction as a result of systemic medication), graft versus host disease, epithelial dysplasia, mucous membrane pemphigoid, lupus erythematosus. Histopathologic ddx: Lichenoid drug reaction, graft versus host disease, lupus erythematosus, chronic ulcerative stomatitis, oral mucosal cinnamon reaction.
• Histopathology: The epithelium may show varying levels of parakeratosis and appear hyperplastic or atrophic depending on the form. Sub‐epithelial separation may be noted in the erosive type. Hydropic degeneration of the basal cell layer of the epithelium associated with a dense band‐like infiltrate of T‐lymphocytes is seen (Figure 4.11). “Saw‐tooth” rete ridges (Figure 4.11), colloid bodies (eosinophilic degenerating keratinocytes), and melanin incontinence may also be present.
• Direct immunofluorescence: Non‐specific with shaggy band of fibrinogen at basement membrane zone.

  Management: No treatment is needed for the reticular form. Topical corticosteroids may be used for the symptomatic erosive form. Warn patient of waxing and waning nature of disease.

Chronic Ulcerative Stomatitis

• Clinical: Immune mediated condition affecting older women with ulcerations on tongue or buccal mucosa in a manner similar to erosive lichen planus. Desquamative gingivitis may also be a feature.
• Cause: Studies suggest autoantibodies to the nuclear protein deltaNp63alpha cause a disruption in the attachment of epithelium to connective tissue.
• Diagnosis: Biopsy with direct immunofluorescence.
• Ddx: Erosive lichen planus (chronic ulcerative stomatitis does not respond well to steroid treatment).
• Histopathology: Similar to lichen planus.
• Direct immunofluorescence: Autoantibodies (IgG) to the nuclei of stratified squamous epithelial cells in basal and parabasal regions.
• Management: Hydroxychloroquine if lesions do not respond to steroid treatment.

Paraneoplastic Pemphigus

• Clinical: Vesiculobullous disorder that affects patients with a neoplasm such as lymphoma or leukemia. Clinically appears similar to pemphigus vulgaris however there is a diverse presentation.
• Cause: Precise mechanism is unknown; however antibodies to plakin family of desmosomal components have been identified in cases.
• Diagnosis: Tissue biopsy.
• Ddx: Pemphigus vulgaris, erythema multiforme (crusting of lips is similar), mucous membrane pemphigoid (eye scarring is similar), lichen planus (skin lesions are similar)
• Histopathology: A combination of features seen in pemphigus vulgaris and lichen planus (suprabasilar separation with acantholysis and vacuolization of basal cells with a lymphoid infiltrate).
• Direct immunofluorescence: Intercellular deposition of IgG and complement, with a granular deposition of complement at basement membrane.
• Indirect immunofluorescence: Positive.
• Treatment: Systemic steroids and immunosuppressive therapy are attempted however the morbidity and mortality rate is high.

Recurrent Aphthous Ulcers

• Clinical: Most common type of oral ulceration which appears on the movable non‐keratinized mucosa. Young adults are affected most frequently. The three types include: (i) Minor, (ii) Major, and (iii) Herpetiform
  1. Minor aphthous presents as a circular ulcer less than 1.0 cm with a white fibrin pseudomembrane and an erythematous halo. Commonly presents on buccal and labial mucosa. There may be a prodrome and healing occurs in one to two weeks without scarring.
  2. Major aphthous ulcers are larger than 1.0 cm and extend deeper into the submucosa. These ulcers require more time to heal and heal with scarring.
  3. Herpetiform aphthous ulcers are the rarest type and appear as crops of coalescing ulcers similar to recurrent herpetic ulcers (on fixed mucosa). Healing occurs in one to two weeks.
• Cause: Possible T‐cell mediated immune reaction causing epithelium to ulcerate.
• Diagnosis: Clinical features and exclusion of other diseases, biopsy is non‐specific.
• Ddx: (i) Minor aphthous‐Ulcers in systemic disorders, (ii) Major aphthous‐Squamous cell carcinoma, traumatic ulcer, deep fungal and tuberculosis ulcer, (iii) Herpetiform aphthous‐Herpetic ulceration (consider location).
• Histopathology: Ulcerated mucosa consisting of a fibrin membrane entrapping viable and necrotic neutrophils. Increased vascularity and an infiltrate of acute and chronic inflammatory cells are noted.
• Management: No treatment usually. May consider topical anesthetics or steroids. Systemic steroids may be used in major aphthous cases.

Graft versus Host Disease

• Clinical: Adverse reaction after allogeneic bone marrow transplantation to treat conditions such as leukemia, lymphoma, and multiple myeloma. Clinically oral lesions affect the tongue, labial mucosa, and buccal mucosa and may appear similar to lichen planus. Ulcerations and atrophy of the mucosa are noted.
• Cause: Engrafted cells start attacking cells in donor environment.
• Diagnosis: Consider clinical history and histopathology.
• Ddx: Lichen planus and potentially malignant lesions.
• Histopathology: Similar to lichen planus with less inflammation.
• Management: Topical corticosteroids, topical anesthetics (for comfort).

Granulomatous Inflammatory Conditions

Crohn’s Disease

• Clinical: Type of inflammatory bowel disease with immune mediation affecting any part of the gastrointestinal tract. Oral manifestations include “cobblestone” appearance to mucosa and linear ulcers in buccal vestibule. Erythematous macules and plaques may be seen on the gingiva. May see pyostomatitis vegetans or yellow‐white pustules on mucosa. Also noted is an increased frequency of periodontal disease.
• Cause: Unknown.
• Diagnosis: Based on clinical features and histopathology.
• Ddx: Histopathology resembles orofacial granulomatosis and Melkersson–Rosenthal syndrome.
• Histopathology: Non‐necrotizing granulomatous inflammation.
• Management: Oral lesions are treated with topical or intralesional steroids however usually resolve with overall treatment of condition.

Sarcoidosis

• Clinical: Granulomatous disorder that affects multiple organ systems. Uncommon oral manifestations include swelling, areas of granularity, and ulcerations. Most commonly affected intraoral soft tissue sites include buccal mucosa and gingiva.
• Cause: Unknown.
• Diagnosis: Clinical features, histopathology, lab analysis, and radiographic evaluation (intraosseous lesions also possible).
• Ddx: Perform special stains to rule out fungal and bacterial infections.
• Histopathology: Granulomas composed of epithelioid histiocytes with a rim of lymphocytes.
• Management: Corticosteroids and chemotherapeutics (in resistant cases).

Epulides

Irritation Fibroma/Fibrous Epulis

• Clinical: Smooth surfaced nodular lesion composed of connective tissue with overlying normal mucosal coloration (Figure 4.12). Irritation fibromas may be sessile or pedunculated and may occur anywhere in the oral cavity. The most common location is the buccal mucosa. A variation includes the epulis fissuratum that occurs in association with a denture flange.
• Cause: Reactive proliferation after traumatic injury or irritation. Some possible etiologies include calculus, ill‐fitting denture, overhanging restoration, or tissue injury from biting.
• Diagnosis: Consider clinical location and antecedent trauma. Biopsy is performed to obtain definitive diagnosis and rule out soft tissue tumor.
• Ddx: Other mesenchymal derived soft tissue tumor.
• Histopathology: Surface epithelium overlying a mass of dense fibrous connective tissue composed of collagen bundles.
• Management: Conservative surgical excision.

Peripheral Ossifying Fibroma

• Clinical: Exophytic pink to erythematous firm mass which presents exclusively on the gingiva. The lesion may be ulcerated.
• Cause: Most likely a reactive proliferation of periodontal ligament derived tissue in response to local irritation.
• Diagnosis: Biopsy and microscopic evaluation.
• Ddx: Peripheral giant cell granuloma, pyogenic granuloma, irritation fibroma, and peripheral odontogenic fibroma.
• Histopathology: Cellular fibrous proliferation with scattered bone and cementum‐like calcifications (Figure 4.13).
• Management: Local surgical excision down to periosteum and thorough scaling of adjacent teeth to prevent possible recurrence.

Pyogenic Granuloma

• Clinical: Erythematous nodule with frequent ulceration which may present anywhere in the oral cavity. Lesion tends to bleed easily due to vascular proliferation. May be sessile or pedunculated. Also called a “pregnancy tumor” when the lesion occurs during pregnancy.
• Cause: Possibly develops in response to trauma or irritants such as calculus.
• Diagnosis: Biopsy and microscopic evaluation.
• Ddx: Peripheral ossifying fibroma, peripheral giant cell granuloma, irritation fibroma, peripheral odontogenic fibroma, and malignant tumors in some cases.
• Histopathology: Vascular proliferation that resembles granulation tissue with an abundance of endothelial lined channels (Figure 4.14). The overlying epithelium may be ulcerated with a fibrin membrane entrapping viable and necrotic neutrophils. A mixed infiltrate of acute and chronic inflammatory cells is noted in the edematous stroma. When the vessels appear to be organized into lobules the term “lobular capillary hemangioma” is used.
• Management: Local surgical excision down to periosteum and thorough scaling of adjacent teeth to prevent possible recurrence.

Peripheral Giant Cell Granuloma

• Clinical: Exophytic red to blue firm mass which presents exclusively on the gingiva with a tendency to bleed easily. The lesion is more common in adults between 30 and 45 with a female predilection. These lesions may be ulcerated and may cause superficial resorption of the underlying bone.
• Cause: Most likely a reactive proliferation in response to local irritants.
• Diagnosis: Biopsy and microscopic evaluation.
• Ddx: Peripheral ossifying fibroma, pyogenic granuloma, irritation fibroma, and peripheral odontogenic fibroma.
• Histopathology: Proliferation of mononuclear spindle cells with numerous multinucleated giant cells set in abundant hemorrhage (Figure 4.15).
• Management: Local surgical excision down to periosteum and thorough scaling of adjacent teeth to prevent possible recurrence.