+++
Ulcerative Conditions
++
The oral ulcer appears as a yellow–white papule or plaque of fibrin (often referred to as a “pseudomembrane”), usually with a surrounding red rim. It does not appear crusty because of the wet environment. Such lesions are always painful unless the ulcer represents a squamous cell carcinoma (SCC), which is often painless. Several conditions fall into this category and only the most common will be discussed here (eTable 76-1.2).
++
+++
Recurrent Aphthous Ulcers/Stomatitis (“Canker Sores”)
++
Recurrent aphthous ulcer (RAU) is a T-cell-mediated disorder and tumor necrosis factor (TNF)-α plays an important role in its occurrence.2 There is usually a family history of aphthous ulcers and there is a significant association with a number of HLA-haplotypes.3 Stress, systemic illness, and local trauma predisposes to their occurrence in susceptible individuals.
++
Aphtheiform ulcers are aphthous-like in their appearance and history but they may occur sometimes on the dorsum of the tongue if they are a result of hematinic deficiency or inflammatory bowel disease. RAU are seen in all patients with Behçet disease and may precede other findings by years. Behçet disease, a vasculitic disorder, has a predilection for Turkish and Japanese populations and is associated with an increase in HLA-B51.4 In periodic fever-adenopathy, pharyngitis, aphthae (PFAPA) syndrome, ulcers are often so severe that children miss days at school.5,6 Patients with other systemic or skin conditions and aphthous ulcers form part of the “complex aphthosis” syndrome and include those with MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome (eTable 76-1.2). Approximately 3% of patients with RAU have gluten-sensitive enteropathy7 and some show sensitivity to foods and sodium lauryl sulfate.
++
Idiopathic RAU occurs in 15%–20% of the population beginning in the second decade of life and the disease generally becomes less severe over the age of 50. Patients often report the sensation of a small nodule beneath the epithelium before the ulcer appears. The painful yellow–white ulcers are surrounded by an erythematous halo.
++
There are four clinical forms of RAU and these are always painful:
++
Minor ulcers (<1 cm, 1–10 at each episode lasting 1–2 weeks) (Fig. 76-3A); this is by far the most common form.
Major ulcers (>1 cm lasting several weeks and healing with scarring) (Fig. 76-3B).
Herpetiform ulcers (<1 cm, usually 0.1–0.5 cm each, >10 clustered ulcers at each episode, lasting 1–2 weeks (Fig. 76-3C).
Severe aphthous ulcers where patients have minor ulcers but with continuous ulcerations with minimum or no ulcer-free days for months.
++
++
Idiopathic RAU are almost always confined to the nonkeratinized mucosa. They may occur on the nonattached gingiva, but generally do not cross the mucogingival junction onto the attached gingiva, except in some cases of RAU major.
+++
Differential Diagnosis and Laboratory Studies
++
Traumatic lesions must be considered because the oral cavity is subject daily to mechanical trauma (such as mastication) (eTable 76-1.2). However, traumatic ulcers are not the same as RAU, although patients with RAU readily develop ulcers at sites of trauma. A history of trauma and the nonepisodic nature of the condition help to differentiate between traumatic ulcers and those of RAU. Chemotherapy-associated ulcers are not generally considered aphthous ulcers but rather chemotherapy- and neutropenia-associated (similar to cyclic neutropenia); they also tend to occur on the nonkeratinized mucosa. Herpetic ulcers in healthy patients occur intraorally on the keratinized mucosa of the gingival margin and the palate. However, in immunocompromised patients, they may resemble RAU, especially RAU major in patients with HIV disease. Culture and biopsy (Box 76-1) are indicated in such patients. Lesions of chronic recurrent oral erythema multiforme must also be considered in the differential diagnosis. Oral manifestations of Crohn disease and other gastrointestinal conditions are discussed below.
++
++
The biopsy is nonspecific and shows only a fibrin membrane with acute and chronic inflammation and granulation tissue, but may exclude an infectious etiology.
+++
Management and Prognosis
++
Any positive findings should be followed up. For example, it may be useful to keep a food diary and to change toothpaste to one that does not contain sodium lauryl sulfate. In most cases, the work-up is negative.
++
The treatment for minor RAU is topical steroids (Table 76-1) or intralesional steroid injection if the ulcers are large and persistent, especially those of aphthous major or in patients with HIV disease. Topical agents that may be useful include cyanoacrylate (Soothe-N-Seal; Colgate Palmolive, NY) and anti-inflammatory agents such as amlexanox 5% paste (Aphthasol, Uluru, Texas), 2 mg amlexanox mucoadhesive disc (Oradisc, Uluru, Texas), or tetracycline oral rinse. Lesions may also be cauterized with 28%–50% sulfuric acid and sulfonated phenolics (Debacterol, Epien Medical Inc.) or with silver nitrate (shaving sticks). Topical anesthetics in paste form are available over-the-counter, in particular benzocaine of varying strengths. Systemic therapy with prednisone for a few weeks and maintenance with pentoxifylline may reduce the number, duration and size of ulcers, and reduce the number of episodes. In appropriate patients, thalidomide therapy is extremely effective, although patients often develop irreversible neuropathy with long-term use. Other agents that are variably efficacious include colchicine and azathioprine.
+++
Oral Ulcerative Lesions Associated with Gastrointestinal Disease
++
The most common bowel diseases associated with oral ulcers are Crohn disease, ulcerative colitis, malabsorption syndromes leading to hematinic deficiency, and celiac disease.8
++
Oral lesions are seen in up to 20% of patients with Crohn disease if nonspecific mucogingivitis is excluded.9 Ulcers of Crohn disease typically present as linear lesions along the maxillary and mandibular vestibule/sulcus (Fig. 76-4A). In addition, patients often also present with papulous folds of tissues, swelling of the lips (indistinguishable from cheilitis granulomatosa), and cobblestoning of the mucosa.10 Other manifestations of Crohn disease include severe and diffuse erythema and inflammation of the mucosa, sometimes associated with Staphylococcus aureus infection (Fig. 76-4B).11 A reliable finding is a dusky-red firm area of the perivermilion skin that has a slight pitted, “orange peel” appearance.
++
++
Pyostomatitis vegetans (oral analog of pyoderma gangrenosum) associated with inflammatory bowel disease presents as “snail-track” ulcers of the oral mucosa.12 Dental enamel defects (enamel hypoplasia) are associated with celiac disease in children.13
+++
Differential Diagnosis and Laboratory Studies
++
Oral ulcers ultimately associated with inflammatory bowel disease may predate gastrointestinal lesions by years in up to 60% of patients,10 so that absence of gastrointestinal symptoms does not exclude this etiology. Elevated tissue transglutaminase and the presence of endomysial antibodies support the diagnosis of celiac disease.
++
A biopsy of oral lesions of Crohn disease shows granulomatous inflammation or while pyostomatitis vegetans shows acantholysis.
+++
Management and Prognosis
++
In the absence of gastrointestinal findings, treatment is with topical steroid therapy and in severe cases, prednisone for rapid control of lesions with maintenance on topical steroids or other anti-inflammatory agents similar to the protocol for management of idiopathic aphthous ulcers.14 If gastrointestinal disease is active, this should be brought under control first and oral ulcers may then resolve.
++
Oral manifestations generally wax and wane with the severity of systemic disease.
+++
Chemotherapy-Associated Ulcerative Mucositis
++
Damage from chemotherapy agents is mediated via production of cytokines, cytokine modulators, and stress responders, leading to apoptosis of dividing epithelial cells.15 Ulcers are potential portals for bacteremia and septicemia, particularly because patients are also often neutropenic. Depending on the regimen, 25%–30% of patients develop this complication. Agents often associated with such lesions include cytarabine and cisplatin, especially when combined with radiation.
++
These ulcers are generally located on the nonkeratinized sites and in particular the buccal mucosa and ventral tongue. They begin within 3–5 days of the start of chemotherapy and generally resolve when absolute neutrophil counts recover, usually a course of 7–10 days. Lesions are extremely painful and may measure several centimeters in size.16
+++
Differential Diagnosis and Laboratory Studies
++
Recrudescent herpes simplex virus (HSV) infection is common in immunocompromised patients such as patients with cancer and, unlike in healthy hosts, often occurs on nonkeratinized sites. Hence, patients who undergo hematopoietic stem cell transplantation, if seropositive for HSV antibodies, are prophylactically placed on antiviral agents during their hospital course. However, a positive culture may represent shedding of HSV in the oral fluids and saliva rather than true recrudescence within the ulcers.
++
Deep fungal infections and cytomegalovirus infection may all present with large ulcers on the mucosa, but these generally do not heal with recovery of neutrophil counts.
++
Radiation to the head and neck leads to severe erythema, inflammation, and ulceration (radiation mucositis).17,18
++
In patients who have received allogenic hematopoietic transplants, persistence of oral ulcers after engraftment may herald the development of acute graft-versus-host disease. In such situations, involvement of the keratinized tissues of the tongue dorsum and hard palate is not uncommon.
+++
Management and Prognosis
++
Ulcers are self-limiting and therapy is directed toward pain control and prevention of septicemia from bacterial ingress into the oral wounds.19 Patients are often treated with granulocyte-colony-stimulating factor to reduce the period of neutropenia and this has reduced the frequency of such ulcers.
++
Topical analgesia such as viscous lidocaine and systemic analgesia (especially narcotics) is the mainstay of pain control. Although chlorhexidine is often used for decontamination, its high alcohol content makes patient compliance poor. Other oral decontamination rinses contain nystatin and antibiotics.
+++
Traumatic Ulcerative Granuloma (Traumatic Ulcerative Granuloma with Stromal Eosinophilia, Eosinophilic Ulcer of the Tongue)
++

This condition is likely caused by trauma (possibly repeated) that leads to a penetrating injury and inflammation involving the underlying skeletal muscle. Although only 50% of patients give a history of trauma, this condition has been experimentally induced in dogs using physical trauma.
++

Traumatic ulcerative granuloma is a not uncommon condition. In children, it usually occurs in the first year of life with eruption of the mandibular deciduous incisors that traumatize the ventral surface of the tongue (Riga–Fede disease). In adults, the most common location is the lateral or ventral tongue.
20,21 As a disease strongly associated with muscle injury, it may arise anywhere in the oral cavity with underlying muscle. Lesions may raise suspicion of oral cancer because of presentation as a nonhealing, often painless ulcer and sometimes fungating mass (
eFig. 76-4.1). There may be bilateral synchronous lesions and they may recur. Some traumatic ulcerative granulomas develop from other ulcerative conditions [e.g., recurrent aphthous major, HIV ulcers, and ulcerative lichen planus (LP)] that are repeatedly traumatized.
++
+++
Laboratory Studies and Differential Diagnosis
++

The most important differential diagnosis is squamous cell carcinoma (SCC). Any neoplasm arising in the deep tissues of the lateral border of the tongue (such as from salivary gland of soft tissues) may become traumatized and ulcerated.
++

Biopsy is usually indicated and shows myositis associated with a proliferation of histiocyte-like mononuclear cells and many eosinophils. Although some cases seem to represent CD30
+ lymphoma, even lesions monoclonal for CD30
+ cells heal uneventfully.
22–24
+++
Management and Prognosis
++

TUG is best treated with excision or intralesional steroid injections. Some lesions will resolve after the biopsy. Lesions may recur or new lesions may appear elsewhere.
25
+++
Ulcerative Viral Infections
++

Acute primary viral infections in the oral cavity that result in ulcers include those caused by coxsackievirus, enterovirus, and Herpesviridae.
26 All are associated with fever, malaise, sore throat, and usually lymphadenopathy. Coxsackievirus infection (including infection by enterovirus-70) often occurs in seasonal epidemics in schoolchildren and takes several oral forms. Herpangina tends to present with ulcers in the posterior oral cavity and pharynx, while ulcers of hand-foot-mouth disease may be found anywhere in the oral cavity, usually but not always with attendant skin lesions. Lymphonodular pharyngitis is characterized by the occurrence of a sore throat and numerous pinkish-yellow lymphoid nodules in the oropharynx.
++

Herpes virus infections take various forms depending on the virus involved (
Table 76-2).
26 Only 20%–40% of patients infected with HSV develop recrudescent lesions. However, asymptomatic shedding occurs with high frequency and is the most common cause of transmission. The ulcers of primary HSV and recrudescent oral HSV (including herpes labialis) are clustered and coalescent (
Figs. 76-5A–76-5C), while recrudescent HSV in immunocompromised hosts may present as a single aphtheiform ulcer.
27 Herpes labialis has distinct stages starting with a prodrome of tingling, then formation of a papule, vesicle, crust, and resolution. During the healing stage of HSV infection on the tongue dorsum, lesions are often depressed granulating ulcers with sharply demarcated borders, a condition referred to as “herpetic geographic glossitis.”
++
++
++

Oral recrudescent varicella-zoster virus usually presents as clustered ulcers affecting one side of the mouth but atypical findings may be noted in patients who are immunocompromised.
+++
Differential Diagnosis and Laboratory Studies
++

Erythema multiforme and vesiculobullous disorders may result in multiple ulcers, but these are not usually small and coalescent. Vesiculobullous disorders are chronic, relapsing, and recurrent (see below).
++

The presence of HSV in cultures and by direct fluorescent antibody testing must always be correlated with clinical findings because HSV sheds in the saliva and oral secretions. The identification of multinucleated giant epithelial in a cytologic smear or in a tissue biopsy at the edge of the ulcer is typical for a herpes infection and immunohistochemical or in situ hybridization studies are then confirmatory.
+++
Management and Prognosis
++

Patients need supportive care for fever and pain (topical and systemic analgesics), as well as hydration.
++

Primary oral HSV and recrudescent HSV in immunocompromised hosts should be treated with
acyclovir or
valacyclovir within the first 1–3 days to reduce viral shedding and shorten disease course. However, after that period of time, it is unclear if antiviral drugs are effective. Once formed, ulcers take several days to resolve regardless of antiviral therapy. Recrudescent HSV may be treated with episodic therapy or prophylactic therapy. Herpes labialis may often be prevented or aborted by sunscreen use. Recrudescent lesions, at first prodrome of tingling, may be treated with topical
acyclovir (5% cream),
penciclovir (1% cream),
docosanol (10% cream),
valacyclovir (2 g twice daily for 1 day), or even a single dose of
famciclovir (1,500 mg).
28
+++
Deep Fungal Infections
++
Zygomycosis is a broad term used to describe fungal infections caused by organisms in the phylum Zygomycota. These include infections caused by organisms in the family Mucorales with organisms in the genera Mucor and Rhizopus. These are unusual infections, seen usually in patients who have diabetes mellitus (usually ketoacidotic) or are immunocompromised, and are often life threatening. Organisms are inhaled and spread into the adjacent sinuses, eroding through the bone, sometimes presenting on the palate as a necrotic ulcer, a condition also referred to as rhinocerebral zygomycosis.29 Aspergillus infections are seen in neutropenic patients, especially those with leukemia and tend to present as necrotic soft tissue and bony lesions of the gingiva, while histoplasmosis, coccidioidomycosis, blastomycosis, and paracoccidioidomycosis are seen in areas where such infections are endemic such as in South America and in patients with HIV/AIDS.30–33
++
Unlike candidiasis, deep fungal infections usually present as necrotic ulcers because they are angioinvasive organisms that cause vascular thrombosis and ischemia. The most common location for rhinocerebral zygomycosis is the palate, although fungal infections in immunocompromised patients may occur at any site in the mouth.
+++
Differential Diagnosis and Laboratory Studies
++
Deep fungal infections involving the palate or maxilla are an important differential diagnosis for the clinical entity “midline destructive disease.” Other conditions that fall into this category include NKT-cell lymphoma, other infections such as tertiary syphilis, granulomatosis with polyangiitis (Wegener disease), cocaine use, and epithelial malignancy of surface or salivary gland origin.34 A biopsy readily distinguishes among these entities.
++
Because these are deep infections, a swab culture may not capture any organisms. A biopsy shows the presence of hyphae. It is useful to submit part of the harvested tissue in saline for speciation in a microbiology laboratory.
++
A biopsy shows necrosis and inflammation. The morphology of hyphae seen on special stains, together with culture results, confirms the diagnosis.
+++
Management and Prognosis
++
Treatment is with systemic antifungal agents such as liposomal amphotericin and triazole antifungal agents such as fluconazole, itraconazole, and posaconazole, often with surgical debridement.35 Mortality is often high in poorly controlled infection. Reducing environmental exposures is a particularly important prophylactic measure for immunocompromised patients.
+++
Ulcers from Vascular Compromise and Vasculitides
++

Ulcers from vascular compromise that occur in the oral cavity tend to occur acutely and two are well recognized: (1) ulcers after injection of local anesthesia, and (2) ulcers from necrotizing sialometaplasia.
++

Dental anesthetics generally contain 1:50,000 or 1:100,000
epinephrine. The most common location for ulcers caused by dental anesthetics is the hard palatal mucosa after a greater palatine block.
21 Within 1–2 days of the procedure, an ulcer, usually 1–2 cm, develops around the area of the introduction of the anesthesia (
eFig. 76-5.1). Over a period of a few days, the ulcers resolve.
++
++

Vascular compromise may lead to necrotic ulcers in necrotizing sialometaplasia, an infarction of salivary gland tissue that presents first with a slight swelling followed by break down of the mucosa leading to an ulcer with sharply demarcated margins, and then resolution over a period of weeks.
36,37 Infrequently, cases may be bilateral,
38 or associated with bulimia.
39
+++
Differential Diagnosis and Laboratory Studies
++

The fairly superficial nature of these ulcers, their sharp border, relatively small size, and short duration differentiates this from long-standing ulcers of systemic vasculitides and lesions of “midline destructive disease” (see below).
++

In general, lesions caused by dental anesthesia are rarely biopsied. Lesions of necrotizing sialometaplasia show infarction of salivary glands and squamous metaplasia of ducts.
+++
Management and Prognosis
++

Lesions of acute vascular compromise are short-lived and generally resolve spontaneously. However, larger and more persistent lesions may be amenable to topical or intralesional steroid therapy.
+++
Granulomatosis with Polyangiitis (Wegener Disease)
++

Signs of systemic vasculitides in the oral cavity rarely occur in the absence of significant skin findings and patients usually present with an established diagnosis for management of mucosal lesions. The exception is granulomatosis with polyangiitis (Wegener's).
++

Granulomatosis with polyangiitis (Wegener's) presents in its full expression with involvement of the upper respiratory tract and oral mucosa with necrotizing granulomas, and involvement of small-to-medium-sized vessel with necrotizing vasculitis.
40 Necrotizing glomerulonephritis is common. It falls under the larger category of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides that also include microscopic polyangiitis, Churg–Strauss syndrome, and renal-limited vasculitis,
41 granulomatosis with polyangiitis (Wegener disease) is associated with HLA-DPB1. Autoantibodies are directed against granules of neutrophils and lysosomes of monocytes. There is a strong association of nasal carriage of
Staphylococcus aureus and increased risk for relapsing disease.
41 There is a limited form of the disease that affects only the upper airways and oral cavity.
++

Oral findings are the first presentation in approximately 6%–13% of patients.
42,43 Patients are usually adults and present with painful, necrotic ulcers of the oral mucosa, in particular the hard palate. This disease is one of the differential diagnoses for “midline destructive disease” (see below). A classic presentation is that of “strawberry gingivitis” where the gingiva has a pebbly, erythematous, and hyperplastic appearance with petechia.
+++
Differential Diagnosis and Laboratory Findings
++

“Midline destructive disease” is a term used to describe progressive, necrotic, and ulcerative lesions of the palate that may represent a variety of conditions such as lymphoma (especially NKT-cell lymphoma), deep fungal infection, tertiary syphilis, ulcers from
cocaine use, malignancies of the salivary glands, and SCC either of oral origin, or from the sinuses.
34 Location of these fairly large ulcers on the palate generally rules out aphthous ulcers but recrudescent herpetic stomatitis must be considered.
++

Swollen, diffuse, erythematous gingival overgrowth raises several other differential diagnoses (
eTable 76-2.1).
++
++

Indirect immunofluorescence testing reveals the presence of ANCA in a cytoplasmic (cANCA) pattern usually ELISA positive for antibodies against proteinase-3, while the perinuclear (pANCA) pattern is associated with ELISA positivity for antibodies against myeloperoxidase. The c-ANCA pattern is particularly important in granulomatosis with polyangiitis (Wegener disease).
44
++

A biopsy reveals geographic necrosis, necrotizing granulomas, and vasculitis.
+++
Management and Prognosis
++

Patients are treated with high-dose
prednisone and cytotoxic therapy such as
cyclophosphamide usually for many months.
45 Treatment and/or maintenance with
methotrexate,
azathioprine, and
mycophenolate mofetil mitigates toxicity of prolonged
cyclophosphamide use. Surgical reconstruction may be necessary if there has been extensive tissue destruction. The use of
rituximab for refractory disease has recently been found to be useful.
45,46
+++
Necrotic Bone Conditions
++

There is no fibrin clot overlying the lesion; rather, necrotic bone is exposed. The etiologies include vascular compromise (such as in osteoradionecrosis and postherpes zoster infections), physical and chemical trauma (such as chronic
cocaine use), and suppression of bone turnover (bisphosphonate-associated osteonecrosis of the jaws).
47–49
++

Depending on the etiology, there is some variation in the clinical presentation. “Benign sequestration of the lingual plate” is putatively caused by trauma. The lesion is generally only 3–5 mm in size, not painful, and occurs in healthy individuals, usually male.
++

In contrast, lesions associated with bisphosphonate use (both oral and intravenous preparations) occur in older patients being treated for osteoporosis, multiple myeloma, or metastatic cancer to the bones. The size of the exposed bone varies from several millimeters to several centimeters, and lesions may be painless or painful (
eFig. 76-5.2A). Approximately 60% of lesions appear after oral surgical procedures such as a tooth extraction. Infection with
Actinomyces or
Eikenella are not uncommon.
47
++
++

Osteoradionecrosis is associated with head and neck radiation, usually with doses greater than 60 Gys.
50 Clinically, it resembles bisphosphonate-associated lesions (
eFig. 76-5.2A).
+++
Differential Diagnosis and Laboratory Studies
++

See above for the differential diagnosis.
++

CT scans and dental imaging studies are useful for delineating extent of disease.
++

The biopsy reveals necrotic bone usually with extensive bacterial colonization with/out abscesses.
+++
Management and Prognosis
++

Once the bone is removed in “benign sequestration of the lingual plate,” the mucosa heals. The other conditions tend to be more severe, involve larger areas of necrotic bone, and are more difficult to treat; the bone exposure may be present for years. Management is directed at removal of necrotic bone, treatment of active infections, and reduction of symptoms. This may include using antimicrobial rinses (such as chlorhexidine), systemic antibiotics, nonsurgical sequestrectomy, debridement, surgical resection, and/or hyperbaric
oxygen therapy.
51,52
++
It is important to distinguish truly white lesions from ulcerated or necrotic lesions that usually have a creamy-yellow color.
++
Many well-recognized oral lesions are white, ranging from developmental lesions such as white sponge nevus, to infections such as candidiasis, to immune-mediated disorders such as lichen planus (LP) and to frictional keratoses such as morsicatio mucosae oris (Table 76-3). Such lesions, with specific clinical and histologic findings, are not properly termed “leukoplakia.”
++
++
True leukoplakias tend to be well demarcated at least around part of the lesion, are frequently dysplastic at first biopsy, and carry a significant potential for developing into SCC over time. White sponge nevus and reactive white lesions are discussed online.
++
White sponge nevus is an extremely rare condition, inherited in an autosomal dominant fashion. It affects the oral and genital mucosa, usually in a symmetric and often multifocal pattern, due to mutation in keratin K4 or K13 that results in keratin instability and abnormal keratin aggregation.53 Spontaneous mutations have been reported.
++
Patients develop poorly demarcated, diffuse, painless white plaques on the oral mucosa, usually the buccal mucosa and tongue, usually within the first two decades of life.21,54
+++
Differential Diagnosis and Laboratory Studies
++
Other conditions that may appear similar clinically include hereditary benign intraepithelial dyskeratosis, another rare mucosal disorder that occurs in a racial isolate in South Carolina,55–57 and pachyonychia congenita.58–60 Oral lesions of dyskeratosis congenita are true leukoplakias occurring in approximately 65% of patients and are usually dysplastic.61,62
++
Biopsy or exfoliative cytology is always indicated and shows perinuclear eosinophilic condensations (representing abnormal keratin aggregation) and distinguishes it from other mucosal disorders discussed below.
+++
Management and Prognosis
++
There is no treatment for white sponge nevus, although some have reported resolution with antibiotics, in particular tetracycline.63 It is postulated that tetracycline affects the keratinization process and inhibits epithelial proliferation.
+++
Reactive White Lesions
++
These very common conditions are caused by very mild topical injury caused by smoking or other mild contact injury such as strong toothpastes and alcoholic mouth rinses. The following white lesions are in ascending order of severity of injury beginning with changes caused by intracellular edema and swelling to those resulting in keratoses.
++
Many dentists classify leukoedema as a developmental malformation but it is likely a reactive lesion. It occurs in 20%–70% with habits such as using tobacco, coca, or marijuana to >90% of dark-skinned individuals mainly because the whiteness of the lesion shows up more clearly on pigmented mucosa.54,64
++
Lesions are usually bilateral on the buccal mucosa or ventral tongue and consist of painless, fine grayish white, opalescent reticulations. They are not well demarcated, but diffuse. Stretching the mucosa completely eliminates these fine lines since this is not a keratotic lesion, but rather caused by intracellular edema of damaged superficial keratinocytes.21
+++
Differential Diagnosis and Laboratory Findings
++
Reticular LP may look similar but they are more densely white and do not disappear on stretching the mucosa.
++
A biopsy shows typical findings of keratinocyte edema or hydropic degeneration.
+++
Management and Prognosis
++
No treatment is necessary since these lesions are benign although advice on smoking cessation may be warranted.
++
This is a common oral condition, where the injury to the tissue is slightly more severe than in leukoedema causing actual degeneration and detachment of the superficial keratinocytes. The offending agents are mouthwashes and toothpastes that are caustic [in particular Listerine (Pfizer Pharmaceutical, NY) mouthwash that contains 27% alcohol as well as eucalyptol and menthol].
++
This is generally a condition of adults. Patients will often report that their mouth is “peeling.” Lesions present as painless sloughs of desquamated tissue that lie in thin ribbons on the mucosa and can be removed without pain or discomfort to the patient, with normal-appearing, pink underlying tissue.65 Since the keratinized tissues are somewhat protected from the adverse effects of such topical agents, it is generally the nonkeratinized tissues that are involved. A helpful sign is a background of leukoedema with faint reticulations.
+++
Differential Diagnosis and Laboratory Studies
++
While some bullosing disorders may form such sloughs, those lesions are almost always painful or sensitive, and may bleed. Lack of symptoms is key to the diagnosis of this condition coupled with the typical history.
++
A biopsy shows desquamating strips of surface keratinocytes.
+++
Management and Prognosis
++
Patients should discontinue the use of the offending dentrifrice, or change to a less caustic agent.
+++
Morsicatio Mucosae Oris (Pathominia Mucosae Oris, Chronic Bite Injury)
++
This is a yet more intense local factitial injury to the oral mucosa, caused by a chewing habit, leading to reactive keratosis and benign epithelial hyperplasia. It occurs in 3% of the population.66 Any other factitial injury either from an unusual habit, or the rough edge of an appliance may lead to a similar lesion.
++
MMO appears as white papules and plaques on either side of the linea alba on the buccal mucosa, lower labial mucosa, or the lateral tongue, usually caused by raking of the teeth over the mucosa.67 Patients may or may not be aware of this habit (especially if this is a nighttime habit). Lesions have a shaggy, rough surface, are poorly demarcated, and occasionally may show evidence of erythema and/or ulceration where the “chewing” has been more intense (eFig. 76-5.3A and 76-5.3B).
++
+++
Differential Diagnosis and Laboratory Studies
++
Candidiasis, some lesions of LP, hairy leukoplakia, and some leukoplakias and erythroleukoplakias may look similar but a biopsy will provide a definitive diagnosis. Such factitial injury may be superimposed upon an underlying condition such as dysplasia or LP, making the diagnosis even more challenging.
++
A biopsy shows varying degrees of parakeratosis with impetiginization and benign epithelial hyperplasia.
+++
Management and Prognosis
++
No further management is necessary. These lesions are benign and have no malignant potential. The use of night guards or appliances to break the habit has not been shown to be helpful.
+++
Benign Alveolar Ridge Keratosis (Bark, Oral Lichen Simplex Chronicus)
++
BARK is a very common condition that was recently defined histologically. It occurs primarily on the keratinized mucosa of the gingiva and hard palate as a reaction to frictional trauma. It is the oral equivalent of lichen simplex chronicus.
++
BARK presents as poorly demarcated, painless white papules and plaques, often with a rough surface, usually less than 1 cm in greatest dimension (eFig. 76-5.4). The most common location is the retromolar pad (at the site of previously extracted wisdom teeth) and other areas where teeth have been extracted.68,69 It is not necessary for the opposing teeth to contact the mucosa, since crushing of food against the alveolar ridge that had been previously protected by a tooth is sufficient.
++
+++
Differential Diagnosis and Laboratory Studies
++
Leukoplakia, especially verrucous leukoplakia is a very important differential diagnosis and a biopsy should always be performed if the lesion shows signs of sharp demarcation or is extensive. More worrisome, verrucous leukoplakia, a dysplastic lesion, also has a rough surface and is usually greater than 1 cm.
++
A biopsy shows typical features of lichen simplex chronicus. BARK is closely related to MMO (described above), another frictional keratosis. It is possible that BARK being located on the keratinized mucosa that is closer in histology to the skin, takes on the more typical histologic characteristics of lichen simplex chronicus (LSC).
+++
Management and Prognosis
++
No treatment is necessary once the histopathologic diagnosis has been established. If a denture is the source of frictional irritation, this should be adjusted accordingly.
++
Nicotinic stomatitis is not caused by nicotine as its name suggests but rather by heat, usually from pipe smoking. A similar condition may be seen in patients who reverse smoke, that is, hold the lighted end of the cigarette in the mouth, as is the habit in some South Indian and Southeast Asian populations. It has also been noted in patients who habitually drink very hot beverages.
++
The palate of adult patients is the site most often affected. It is diffusely white with red, punctuate areas representing the openings of salivary ducts. It is usually not a painful lesion although severe cases may be sensitive to hot and spicy foods, and lesions are usually symmetric and diffuse.21,54
+++
Differential Diagnosis and Laboratory Studies
++
Leukoplakia and candidiasis of the palate may both mimic nicotine stomatitis.
++
A biopsy shows hyperkeratosis with benign epithelial changes and importantly, inflammation of excretory salivary ducts that exhibit squamous metaplasia. This diagnosis is difficult if the ducts are not included in the biopsy specimen.
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Management and Prognosis
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Lesions may resolve if the habit is discontinued. The risk for malignant transformation has not been well documented. However, the development of raised, indurated areas should raise suspicion for malignant transformation.
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Smokeless Tobacco Keratosis
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This is a lesion that results from a combination of direct contact toxicity of the smokeless tobacco on the mucosa (early lesions), and from effects of carcinogens within the snuff, namely tobacco-associated nitrosamines (late lesions that represent true leukoplakias). Not all smokeless tobaccos are alike. Snuff may be moist or dry and in general moist Swedish snuff (“snus”) is lower in nitrosamines than moist and dry snuff from the United States.70 Toombak, snuff from Ethiopia, has the highest levels of nitrosamines of all.71 In many Asian countries, snuff and smokeless tobacco is mixed with other substances such as spices and importantly areca nut, which contains another potent carcinogen, the alkaloid arecoline.72
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Over the last 10–15 years, there has been increased interest in using smokeless tobacco as a risk reduction measure in subjects who have difficulty discontinuing cigarette smoking because the risk of developing cancer (oral and other cancers) is reduced.73,74
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The lesions are located where the snuff is placed, usually the mandibular sulcus/vestibule, between the teeth and the buccal mucosa. The area looks grayish white, opalescent, and wrinkled, often with fissures.21,54
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Lesions are generally painless and poorly demarcated (eFig. 76-5.5).
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Differential Diagnosis and Laboratory Studies
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The diagnosis includes leukoplakia, candidiasis, and BARK. Aspirin is much more caustic and causes necrosis and ulceration, rather than this delicate white lesion.
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Biopsy reveals thin parakeratosis, intracellular edema, and devitalization of superficial keratinocytes. Any other agent that is locally irritating and slightly caustic may cause this clinical appearance.
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Management and Prognosis
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Most early lesions are primarily caused by contact injury and are reversible if the habit is discontinued. However, the development of a dense white plaque or erythema may signal transformation to malignancy and these areas should be biopsied. The rate of malignant transformation is only 1%–2% compared with cigarette smoking.
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Fungal infections are extremely common in the oral cavity and the most common causative agent is Candida albicans. Approximately 20%–30% of the population are carriers. In immumnocompromised hosts, other species such as C. tropicalis, C. dubliniensis, C. glabrata, and C. kruseii should also be considered, as some of these may be resistant to conventional therapy. Predisposing factors include hyposalivation (see Section “Xerostomia” and “Hyposalivation”), immunocompromise, topical steroid therapy (for treatment of oral lesions or as inhalers), and antibiotic therapy.
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Oral candidiasis may present in various forms (Table 76-4) (Figs. 76-6A–76-6B).1,21 Lesions are almost always painful and dentures act as fomites.75 Although C. albicans is the most common pathogen in denture-associated candidiasis, C. glabrata is found in 30% of cases.76
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Differential Diagnosis and Laboratory Studies
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An important differential diagnosis is hairy or coated tongue. This is not a candidal infection, although cultures may grow Candida in carriers. These lesions are almost always painless and do not involve mucosa other than tongue dorsum, unusual for candidiasis. It is caused by hyperplasia and hypertrophy of the filiform papillae of the tongue, with retention of keratinaceous debris as a result of hyposalivation and poor oral intake. Patients therefore are often ill, dehydrated, and on antibiotic therapy, further adding to the suspicion that the lesions represent candidiasis.
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Culture is not particularly useful for diagnostic purposes since many individuals are carriers. However, culture is important if speciation or sensitivity is required, or to identify carriers prior to the start of long-term steroid therapy. A potassium hydroxide preparation using scrapings from oral lesions is a good way to identify infection. Biopsies show typical candidal organisms.
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Management and Prognosis
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Patients who have dry mouths from polypharmacy or substantial damage to salivary glands (such as from radiation) are prone to develop recurrent candidiasis and are particularly difficult to manage. Nystatin rinses and clotrimazole troches contain caries-inducing sugars and should be used long-term only with careful monitoring by the dentist. The use of cholinergic agents such as pilocarpine or cevimeline helps to restore some secretory function of salivary glands and may reduce the frequency of candidiasis.
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Epstein–Barr virus (EBV) infections in the oral cavity may present as a primary infection (infectious mononucleosis). Hairy leukoplakia is an unusual presentation of recrudescent EBV in the oral cavity, where this normally lymphotropic virus is present within the epithelium.
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This manifests as a painless, white plaque usually located on the lateral border of the tongue in immunocompromised patients, and in particular, those with HIV/AIDS and after organ transplantation.77,78
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Typically, these present as white linear lesions running perpendicular to the long axis of the tongue but when more advanced, may extend onto the dorsum and present as a plaque (Fig. 76-7). Lesions are usually asymptomatic and usually superinfected with Candida. Infrequently, hairy leukoplakia has been reported in healthy individuals.79
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Differential Diagnosis and Laboratory Studies
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Lesions of MMO and candidiasis often occur on the lateral tongue and may appear similar.
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Both cytologic smears and biopsies show characteristic findings and the presence of EBV can be confirmed by in situ hybridization.
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Management and Prognosis
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The presence of hairy leukoplakia may be the first indication that a patient is infected with HIV. In patients with established HIV/AIDS, hairy leukoplakia is usually associated with a low CD4 count and high viral load.77 Treatment with an antifungal medication (see Section “Candidiasis”) will resolve the associated candidiasis and treatment with antiretroviral therapy results in resolution.
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Oral LP is an immune-mediated disorder and an interface stomatitis characterized by T-cell destruction of the basal cells of the epithelium, possibly as a result of altered antigen presentation on these cells, mediated by TH1 cytokines. Interferon-α production is thought to mediate lesions involving the oral cavity only while TNF-α may mediate systemic disease.80 Whether this is a disease in and of itself or whether it represents a “final common pathway” of mucosal reaction is unclear at this time. Many local and systemic conditions predispose to the development of such “lichenoid lesions” in the oral cavity. The term “lichenoid” used here to describe reticulated, often erythematous and/or ulcerated lesions, usually bilateral and symmetric. Unfortunately, many erythroleukoplakias that are by definition red and white lesions but usually without significant reticulation are also clinically described as “lichenoid” by some investigators, causing confusion and leading to the concept of LP as a premalignant lesion.
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Local lichenoid reactions may develop as a result of contact injury to amalgam restorations or cinnamic aldehyde from chewing gum. Medications implicated in the development of oral LP include antihypertensive agents (especially hydrochlorthiazide), some hypoglycemic agents, allopurinol, sulfasalazine, carbamazepine, and the new biological agents.80–82 It is often impossible to differentiate either clinically or histologically, between lesions of idiopathic LP and lichenoid hypersensitivity reactions.83
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Other conditions associated with oral lichenoid lesions include hepatitis C in Mediterranean races and this is associated with HLA-DR684,85; chronic graft-versus-host disease, and lupus erythematosus.86,87
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Oral LP occurs in 1%–2% of the population in the United States and affects females more than males, usually those in the fifth decade of life and older. Three clinical forms are noted—(1) keratotic/reticular, (2) erythematous/erosive, and (3) ulcerative—and these often occur in combination.21,54 The most recognizable is the keratotic/reticular form (Wickham striae) that is usually not painful. This is symmetric in distribution and reticulations almost always occur on the buccal mucosa and tongue although any oral mucosal site may be affected (Figs. 76-8A and 76-8B). Lesions on the dorsum of tongue tend to be subtle and more papular with atrophy of filiform papillae giving the tongue a white cast and smooth appearance (Fig. 76-8C). The erythematous or erosive form is usually painful and this is particularly common as a primary presentation on the gingiva (clinically desquamative gingivitis).88 LP on the gingiva is also noted in the gingival–genital syndrome.89 Ulcerative LP usually occurs in association with the other two forms. The finding of intact blisters (bullous LP) is rare in the oral cavity because it is a trauma-intense environment. Concomitant skin involvement is noted only in 10%–15% of patients.
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A controversial entity is the so-called “plaque-type LP.” If this lesion occurs as a unilateral plaque without reticulations, it should be considered a leukoplakia. If it occurs within an established, typical symmetric oral LP, it should be considered “leukoplakia developing within LP.” In either case, biopsy is indicated to exclude dysplasia or malignancy.
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Several scoring systems have been developed for evaluating the severity of disease but none are universally accepted.90–92
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Differential Diagnosis and Laboratory Studies
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Many conditions may result in the development of LP and lichenoid reactions. However, the most important is erythroleukoplakia. It can be differentiated from oral LP in that it is not usually definitively reticulated (although it may have subtle linear areas), is usually asymmetrically distributed, and often presents at a high-risk site for cancer such as the ventral tongue unilaterally. It is strongly associated with dysplasia and carcinoma (see below). Other lesions include candidiasis and contact stomatitis such as to chewing gum.
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Chronic ulcerative stomatitis is an entity that resembles erythematous/erosive LP but is associated with antibodies directed against δNp63α.93 Direct immunofluorescence studies reveal nuclear binding of keratinocytes in the basal and lower one-third of the epithelium. Serum immunoglobulin (Ig) G can be detected using guinea pig esophagus as substrate and an ELISA is now available.94
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The reticulated white areas on the buccal mucosa may sometimes resemble MMO. Erythematous LP lesions on the gingiva are often indistinguishable from other diseases presenting as desquamative gingivitis such as mucous membrane pemphigoid, hypersensitivity reaction, or plasma cell gingivitis. Pure ulcerative lesions without reticulations are more likely to be aphthous ulcers.
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Diagnostic histopathologic findings for oral LP, are squamatization of basal cells and a lymphocytic band at the interface. Direct immunofluorescence studies show shaggy fibrinogen and often IgM at the interface and IgM staining of colloid bodies.
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Management and Prognosis
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Management of oral LP and lichenoid lesions involves pain control and treatment with topical steroids and other anti-inflammatory agents (Table 76-1).95 Gingival lesions are effectively treated with topical steroids held in a stent. Systemic therapy with prednisone (at 1 mg/kg for 1 week with a fairly rapid taper) or hydroxychloroquine should be instituted in severe cases and topical therapy started concomitantly.
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Localized, unliateral lesions may respond to removal of dental restorations and a short course of topical steroids. Disease remission occurs in <10% of cases.
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The rate of malignant transformation (often given as 1% every 5 years) is controversial because some studies do not correct for confounding factors such as smoking, while other included erythroleukoplakias, leukoplakias (diagnosed as “plaque-type” LP), and proliferative leukoplakia in the group of “lichenoid” lesions. Classic, bilaterally symmetric, reticulated LP has a very low malignant potential.96
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Leukoplakia and Erythroplakia
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This is one of the more challenging diagnostic entities of oral mucosal disease. Leukoplakia is defined as a “white plaque of questionable risk having excluded other (known) diseases or disorders that carry no increased risk for cancer.”97 It is a clinical diagnosis only and modified once the histopathologic diagnosis is known. For example, what may appear to be a provisional diagnosis of leukoplakia on the buccal mucosa may histopathologically prove to be MMO as a final definitive diagnosis. Frictional keratosis is NOT a leukoplakia and the only two histologically well-defined frictional keratoses are (1) MMO and (2) BARK. Because frictional injury is very common in the oral cavity and usually presents as a hyperkeratosis, it is likely that many so-called leukoplakias actually represent nonspecific frictional keratoses that are not MMO or BARK.
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Leukoplakias occur in 2%–4% of the population.98 Any lesion that carries a provisional diagnosis of leukoplakia must be biopsied because approximately 20%–50% of these lesions are dysplastic or cancerous at the time of biopsy.99,100
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Leukoplakia is strongly associated with smoking and/or alcohol ingestion. Other predisposing factors are similar to those for oral cancer and will be discussed below.
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Leukoplakia is more common in adult males. It presents as a painless, white plaque that may be homogenous or nonhomogenous.97 It may occur anywhere in the oral cavity and generally shows areas that are sharply demarcated from the surrounding mucosa (Fig. 76-9). Homogenous leukoplakia may show areas of fissuring. Nonhomogenous leukoplakia have areas of erythema (erythroleukoplakia), rough, warty areas (verrucous leukoplakia), or nodular areas; they have a higher association with dysplasia and carcinoma, as do lesions on the floor of mouth, ventral tongue, and soft palate.101,102
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Proliferative verrucous leukoplakia (PVL)103,104 tends to occur in middle-aged females and, as its name suggests, tends to spread or proliferate over the mucosa over time, and is usually multifocal (eFigs. 76-9.1A–76-9.1C). It is associated with smoking in less than 30% of cases. Patients are usually diagnosed with this condition one to two decades after the first appearance of the white lesion. Areas of it may become verrucous, although not invariably, and other areas may appear red, in which case the term proliferative erythroleukoplakia may be appropriate. Approximately 70%–100% of cases develop SCC over time.103,105 These lesions are particularly difficult to diagnose because patients often have had multiple biopsies over many years, and each time, the diagnosis is one of “hyperkeratosis” only without evidence of dysplasia.
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Oral erythroplakia, although a red lesion, will be discussed here because of its high associated dysplasia. It is an uncommon lesion and in its pure form presents as a painless, red, sometimes velvety plaque of the oral mucosa (eFig. 76-9.2). More than 90% of cases are associated with dysplasia or carcinoma at the time of diagnosis.106,107 It is much more common to see it in combination with leukoplakia (erythroleukoplakia).
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Differential Diagnosis and Laboratory Studies
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The clinical differential diagnosis list for leukoplakia is long (Table 76-3). However, sharp demarcation at least one border is a helpful finding and usually excludes an inflammatory/reactive lesion. A biopsy should be performed for any white lesion if the etiology cannot be established with confidence on clinical grounds.
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Approximately 20%–50% of leukoplakias are dysplasias or carcinoma at the time of biopsy.100,101,106,108 However, 5%–18% of lesions diagnosed as “benign hyperkeratosis,” when followed over time, transform to carcinoma.99,102,108 This is particularly true of lesions of proliferative leukoplakia where multiple biopsies show “benign hyperkeratosis” until many years later when overt dysplasia or carcinoma develops.
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Research using microarrays and other techniques to better characterize the genome of these lesions will shed light on this in coming years. The concept of “oral” or “squamous intraepithelial neoplasia” similar to “cervical intraepithelial neoplasia” has not received acceptance although it is likely a useful concept to adopt.
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Management, prognosis, and risk of progression to oral SCC are discussed online.
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There is controversy as to whether leukoplakias should be excised.109 Some suggest that small leukoplakias should be excised, while extensive lesions could be managed with multistage stripping.110 While some clinicians and pathologists believe that mild dysplasias may just be observed since some of these regress, it is likely that some of these “regressing mild dysplasias” represent only keratotic lesions with reactive atypia. True dysplasias are intraepithelial neoplasias that have not yet become invasive. If such lesions can be removed without excessive morbidity, this seems prudent.
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Options for the 50%–80% of cases diagnosed as “benign hyperkeratosis,” include periodic rebiopsy or excision. It is suggested that “benign hyperkeratoses” that are not clearly frictional or reactive in nature and are in high-risk sites be narrowly excised and followed and that recurrent lesions be excised with a margin of several mm. Because leukoplakia is a clinicopathologic entity, it is important that the clinician work with a pathologist who is experienced in the diagnosis of reactive and nonreactive oral keratotic lesions.
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Smoking cessation counseling should always be part of the overall management strategy for patients who smoke.