Diseases of the Tongue PDF

Clinics in Dermatology (2016) 34, 458–469 Diseases of the tongue Aaron R. Mangold, MD a,⁎, Rochelle R. Torgerson, MD, PhD b , Roy S. Rogers III, MD a a Department of Dermatology, Mayo Clinic, Scottsdale, AZ b Department of Dermatology, Mayo Clinic, Rochester, MN Abstract The tongue is a complex organ involved in speech and expression as well as in gustation, mastica- tion, and deglutition. The oral cavity, along with the tongue, are sites of neoplasms, reactive processes, and infections, and may be a harbinger of systemic diseases. This review includes both common and rare dis- eases that occur on the tongue, including: vascular and lymphatic lesions (infantile hemangiomas and oral varices), reactive and inﬂammatory processes (hairy tongue, pigmented fungiform papillae of the tongue, benign migratory glossitis, and ﬁssured tongue), infections (oral hairy leukoplakia, herpes simplex and varicella-zoster virus infections, human papillomavirus, and candidiasis), premalignant lesions (leukoplakia and erythroplakia), malignant lesions (squamous cell carcinoma, Kaposi sarcoma, and lymphoproliferative diseases), and signs of systemic disease (nutritional deﬁciency and systemic amyloidosis). © 2016 Elsevier Inc. All rights reserved. Introduction glands are often surrounded by muscle. Long, tortuous sublin- gual veins are located on the ventral surface of the tongue. The tongue is a complex organ involved in speech and ex- pression as well as in gustation, mastication, and deglutition. The oral cavity and the tongue are sites of neoplasms, reactive Vascular and lymphatic lesions processes, and infections and may be a harbinger of systemic diseases.1 The tongue is a complex set of sensory papillae Infantile hemangiomas and muscles (Figure 1). Taste buds are distributed along the dorsal surface of the tongue. There are three forms of taste Infantile hemangiomas (IHs) are benign vascular neo- buds: fungiform (anterior), circumvallate (posterior dorsum), plasms and are the most common soft tissue tumors in child- and foliate papillae (posterior lateral). The ﬁliform papillae hood. In white, non-Hispanic infants, IHs are seen in 1-2% are devoid of sensory ﬁbers and are not true taste buds. There of newborns and 10-12% of 1 year olds.2 They are more prev- is no submucosa on the tongue, and muscle is present superﬁ- alent in girls and most commonly affect the head and neck re- cially. Lingual tonsils are present at the posterior dorsum as gion. Risk factors include low-birth-weight infants, multiple well as the posterior lateral tongue. Lingual salivary glands gestation, and placental abnormalities. IHs proliferate during are located in the anterior ventral (glands of Blandin-Nuhn) the ﬁrst year of life, and 90% involute by 10 years of age.3 and posterior dorsal tongue (glands of von Ebner). These The majority of growth of IHs is seen in the ﬁrst 2 months of life.4 Most IHs are simple and run a benign course with in- ⁎ Corresponding author. Tel.: 480-301-8508. volution and minimal cosmetic disﬁgurement. Although oral E-mail address: [email protected] (A.R. Mangold). IHs are rare relative to the skin, they represent one of the most http://dx.doi.org/10.1016/j.clindermatol.2016.02.018 0738-081X/© 2016 Elsevier Inc. All rights reserved. Diseases of the Tongue 459 Fig. 1 General anatomy of the tongue. common lesions in the oral cavity of children and often affect disease.12 When seen in younger individuals, one should think the tongue, buccal mucosa, and lips.5–7 The oral IHs are of of Fabry disease, as well as hereditary hemorrhagic telangiec- particular concern due to frequent trauma, the risk of bleeding, tasia. Oral varicosities most commonly involve the ventral ton- and the possibility of airway compromise.8 gue and are characterized by tortuous, asymptomatic, IHs come in three general varieties: superﬁcial, deep, and compressible veins (Figure 2). Thrombosis has been rarely re- mixed pattern. Superﬁcial IHs are characterized by frambesi- ported within the varices and may result in episodic pain and form, red papules, with lobulated plaques and nodules. Deep erythema.13,14 Oral varices are commonly seen on the lip, as IHs are often a blue, subcutaneous papule or nodule with over- venous lakes, but are rare on the buccal mucosa. Treatment lying telangiectasia or veins. The clinical differential diagnosis is not necessary; however, conservative excision of cosmeti- is dependent on the tumor depth and includes pyogenic granu- cally concerning varices is often effective. Due to venous loma, angiosarcoma, and other vascular tumors. Fully formed drainage of the tongue into the internal jugular, sclerotherapy tumors at birth are more likely to be a noninvoluting congeni- should not be used. tal hemangioma (NICH), rapidly involuting congenital hem- angioma (RICH), or partially involuting congenital hemangioma (PICH). The clinical course as well as GLUT-1 negativity, found in NICH, RICH, and PICH, will help differ- entiate these from IHs. The treatment of IHs is dependent on the risk of compro- mise of vital organs and structures as well as cosmesis. Oral propranolol is now Food and Drug Administration approved for IHs and has become the gold standard for treatment.9 Re- sponse rates for propranolol are 98% with a goal dose of 2 mg/kg/day and 6 months of therapy. Although laser therapy is effective for treating IHs, it may not be appropriate for intraoral disease.10 Other treatment options include corticoste- roids, interferon alpha, and vinca alkaloids. Oral varices Oral varices are a common developmental anomaly noted in older adults.11 The etiology of oral varicosities remains un- Fig. 2 Vascular anomalies: oral varices. Oral varices are most com- known. Although the data are controversial, there may be an monly seen sublingually and are characterized by asymptomatic, tor- association with old age, smoking, and cardiovascular tuous vessels. 460 A.R. Mangold et al. Reactive and inﬂammatory processes of the tongue, acanthosis nigricans, and, rarely, hypertrophic herpes simplex virus infections. Pseudo–hairy black tongue Hairy tongue is often secondary to bismuth salicylate (Figure 3, b). Oral hairy leukoplakia (OHL) is strongly associated with immuno- suppression and has adherent plaques. Unless there are stigmata Hairy tongue (HT), also known as furred tongue, is the re- of underlying disease or symptoms, such as pain, no additional sult of retention hyperkeratosis of the ﬁliform papillae on the workup is needed. In refractory or atypical cases, a biopsy and anterior two thirds of the dorsal aspect of the tongue.15 HT is variably reported in the literature with rates as low as 0.5% cultures or polymerase chain reaction testing for bacteria, fun- gus, and herpes simplex virus may be warranted. and as high as 11.3%.16 There appears to be a male predomi- HT is commonly asymptomatic and self-resolving. Due to nance, as high as 3 to 1, and increased prevalence in older in- its unsightly appearance, patients often wish to pursue treat- dividuals, 40% in those older than 60 years.16 Normal papillae ment. First-line treatment is aimed at reducing the risk factors are 1 mm in length; however, in HT there is defective desquama- and improving hygiene by regular brushing of the tongue with tion of cells in the central column of the ﬁliform papillae, causing a simple dentriﬁce or using 1.5% hydrogen peroxide (5–10 an increase in length 10 to 20 times normal17 (Figure 3, a). strokes daily) with a hard toothbrush. Second-line therapies in- Black HT, seen in the spectrum of HT, occurs when bacteria are trapped in the ﬁliform papillae and produce porphyrins clude topical retinoids, antifungals, and keratolytics.21 Oral therapy with antifungals, antibiotics, and antivirals should be causing a brown or black color. The presence of other mi- reserved for refractory cases with positive cultures. More im- crobes, such as Candida, can exacerbate this condition. Solid portantly, when the disease is refractory or persistent, an alter- food acts to naturally debride the tongue, whereas irritants native diagnosis, an associated systemic disease, or oral stimulate hyperplasia of the tongue. HT is more common in malignancy should be considered. those with poor oral hygiene, smokers, drug users, mouth breathers, those on low-ﬁber diets, and febrile patients. Interest- ingly, HT has rarely been reported in patients with HIV infec- Pigmented fungiform papillae of the tongue tions, graft-versus-host disease, or internal malignancies.18–20 HT can be exacerbated by drugs, the most common being Pigmented fungiform papillae of the tongue (PFPT) is often antibiotics and medications that induce xerostomia, including confused with black HT. PFPT is normal variant most com- atypical antipsychotics, antidepressants, and anticholinergics.18 mon in darkly pigmented individuals and has been reported Clinically, HT is characterized by hairlike projections on in one fourth to one third of African Americans.22 PFPT is the dorsal tongue that can be scraped off. Although the original thought to be secondary to pigment-laden macrophages in name, black HT, implies that the tongue is black, the color can the fungiform papillae. The papules of PFPT are nonprogres- range from black-brown to green-yellow. Due to the previous- sive and appear in infancy. PFPT is characterized clinically ly stated risk factors and the overgrowth of microbes, it is not by monomorphic brown papules on the tip and lateral aspects surprising that HT is associated with halitosis. of the tongue (Figure 4). The areas of pigmentation are well The differential diagnosis of HT includes: pseudo–hairy demarcated and conﬁned to the individual fungiform papillae. black tongue, oral hairy leukoplakia, premalignant leukoplakia The differential diagnosis of PFPT includes amalgam tattoo, and squamous cell carcinoma, pigmented fungiform papillae Peutz-Jeghers syndrome, chronic adrenal insufﬁciency, Fig. 3 a, Hairy tongue. Classic hairy tongue is characterized by elongation of the ﬁliform papillae with furlike quality. b, Pseudo–hairy black tongue. Pseudo–hairy black tongue has similar black hyperpigmentation to classic black hairy tongue but lacks the elongation of the ﬁliform papillae. Diseases of the Tongue 461 rare.33 It occurs on nonlingual sites, typically the buccal and palatal mucosa, with invariable tongue involvement.34 The major clinical differential diagnosis includes psoriasis, reactive arthropathy, lichen planus (LP), lupus erythematosus, graft- versus-host disease, median rhomboid glossitis, leukoplakia, ﬁssured tongue, and chronic herpes simplex virus infection. BMG is often asymptomatic, with up to 1 in 4 individuals experiencing burning pain or sensitivity to foods.31 The symp- tomatic areas tend to occur in the atrophic patches. Although there are no rigorous studies, the mainstay of treatment for symptomatic BMG is similar to that of plaque psoriasis with potent topical corticosteroids as well as topical calcineurin in- hibitors.35 The use of systemic immunosuppressants, such as Fig. 4 Pigmented fungiform papillae of the tongue is characterized cyclosporine, has also been reported.36 by monomorphic, darkly pigmented fungiform papillae. Fissured tongue neuroﬁbromatosis type I, melanocytic nevus, melanoma, and Fissured tongue (FT) is a normal variant seen in up to 20-30% black HT.23 No treatment is necessary; patient reassurance of of the population, characterized by an increased number of ﬁs- the benign nature of the condition is adequate. sures and grooves at the central and lateral aspects of the ton- gue16,37 (Figure 6). More severe ﬁssuring is often referred to Benign migratory glossitis as “lingua plicata.” This condition is idiopathic, more common in older individuals, and thought to be a reactive pro- Benign migratory glossitis (BMG), also known as geo- cess.24,26,37 FT is more common in individuals with geographic graphic tongue and annular transient patches of the tongue, tongue, as well as those with psoriasis.38 FT is the most com- is a benign, inﬂammatory condition that affects all age groups. mon tongue ﬁnding, seen in up to one third of patients with BMG affects 1-2% of the population, is more common in psoriasis.28,39 Other associations include Down syndrome, young patients, and often diminishes with age.24–27 The etiol- Melkersson-Rosenthal syndrome, pernicious anemia and macro- ogy of BMG remains elusive. BMG is more common in peo- glossia, pachyonychia congenita, and Cowden syndrome.40–43 ple with psoriasis, up to 14%, and some argue that BMG is an oral manifestation of psoriasis.28–30 BMG is characterized by an annular arrangement of alter- nating raised, hyperkeratotic plaques and smooth, atrophic patches31 (Figure 5). Filiform papillae are absent in the atro- phic, red patches.32 The lesions are dynamic and change over hours, creating a “migratory pattern,” and more often involve the dorsolateral aspect of the tongue.31 BMG often has a wax- ing and waning course. Ectopic BMG, geometric stomatitis, is Fig. 6 Fissured tongue is characterized by a central groove with Fig. 5 Benign migratory glossitis is characterized by multiple, cir- smaller radiating grooves. This patient has an incidental bite ﬁbroma cinate, atrophic red plaques with a white, raised border. on the right lateral tongue. 462 A.R. Mangold et al. Clinically, FT is characterized by multiple, asymptomatic 2- to can occur on any mucosal surface and is most common on the 3-mm grooves and ﬁssures on the dorsal surface of the ton- lips and gingiva.59 The three major forms of intraoral HSV in- gue.37 There is often a midline groove with smaller, symmetric fections are acute herpetic gingivostomatitis, recurrent radiating grooves.37 The differential diagnosis also includes intraoral herpetic stomatitis, and herpetic geometric glossitis. concomitant infections. Unless harbingers of underlying sys- The clinical differential diagnosis includes LP; graft-versus-host temic disease are present, no workup is necessary. disease; ﬁssured tongue; recurrent aphthous stomatitis; hand, There is no effective treatment for FT; however, we recom- foot, and mouth disease; erythroplakia; and herpangina.60,61 mend good oral hygiene with brushing deep into the ﬁssures to Clinically, acute herpetic gingivostomatitis is characterized remove debris, lessen the microbial burden, and reduce halito- by fever, sore throat, malaise, and tender adenopathy.60 The le- sis.44 If pain is present, the possibility of a systemic disease or sions resemble aphthae with grouped, superﬁcial vesicles that concomitant infection and therapy should be targeted at reduc- rupture and form shallow red ulcers61 (Figure 7, a). Acute her- ing inﬂammation or eradication of the infection. petic gingivostomatitis is often self-limited; however, treat- ment with oral antivirals will hasten the resolution.59 A 10- day course of valacyclovir, famciclovir, or acyclovir is appro- priate, with valacyclovir and famciclovir being preferred due Infectious conditions to ease of administration, 2 to 3 times daily. Therapy should be initiated in the ﬁrst 72 hours of onset. Oral hairy leukoplakia Herpetic geometric glossitis, a unique form of recurrent HSV infection described in 1993,62 is classically described Oral hairy leukoplakia is characterized by hyperkeratotic as linear and symmetric striations and ﬁssures of the dorsal as- white plaques and is often unilateral on the lateral aspect of pect of the tongue in an immunocompromised individual, al- the tongue. The plaques are asymptomatic and cannot be though there are rare reports of herpetic geometric glossitis wiped off with gauze. The disease was originally described in immunocompetent patients as well63 (Figure 7, b). This during the HIV epidemic in 1984, is still one of the most spe- condition is characterized by exquisite tenderness and pain ciﬁc oral manifestations of HIV, and may herald more progres- within the atrophic and uniquely branched and ﬁssured le- sive disease.45–47 Oral lesions are very common in HIV and sions.62,64 The branched ﬁssures of herpetic geometric glossi- are indicative of the degree of immunosuppression. OHL has tis are analogous to the dendritic ulcerations of corneal been described in other immune-compromised states: solid or- herpetic infections.64 When examining the tongue in these gan transplant, corticosteroid usage, and malignancy.48 OHL cases, one should carefully examine for small foci of tradition- is an Epstein-Barr virus (EBV)–related disease that is driven al vesicles of HSV infections. Conﬁrmatory testing can be per- by immunosuppression49–52; however, immunosuppression formed with polymerase chain reaction ampliﬁcation of viral and EBV are necessary but not sufﬁcient for disease, because DNA.65 Therapy with systemic antiviral drugs is essential OHL occurs in only 25% of HIV patients.53 Other modulating and should be guided by cultures and clinical response.59 In factors include host response, age, local irritants, and concom- cases of recurrent and refractory disease in an immunocompro- itant infections.53 mised host, one should test for resistance and consider a reduc- Clinically, OHL is characterized by adherent, corrugated tion in immunosuppression. white plaques on the lateral aspect of the tongue.47,53 The dis- ease course is often chronic and dependent on the immune sta- tus of the individual. The clinical differential diagnosis Herpes zoster virus infections includes HT, hypertrophic candidiasis, LP, leukoplakia, and squamous cell carcinoma.47 Varicella-zoster virus, HHV-3, can produce two entities: Although OHL is often asymptomatic, has no malignant varicella (chickenpox) and varicella-zoster (shingles). Chick- potential, and does not require treatment, the underlying HIV enpox occurs in childhood with a 30% lifetime risk of shingles infection should be treated or the immunosuppressed states in affected individuals.66 The lifetime risk of shingles, as well should be modiﬁed. First-line topical treatment of OHL in- as age of onset, is dependent on immune status, with an in- cludes topical retinoids, podophyllin, and acyclovir, as well creased lifetime risk in the immunosuppressed as well as an as treatment for such exacerbating factors as Candida with earlier onset.66 There is often a prodrome of dysesthesias, gentian violet and other antifungal agents.54,55 Systemic anti- followed by vesiculation. Shingles is characterized by a local- virals typically diminish OHL within 1 to 2 weeks, but the dis- ized and unilateral eruption following the anatomic distribu- ease often ﬂares on discontinuation due to persistent latent tion of a single sensory nerve ganglion. Although shingles is virus as well as viral resistance.51,56–58 uncommon in the mouth, involvement of the mandibular (V3) branch of the trigeminal nerve can result in blistering Herpes simplex virus infections and ulceration of the tongue, ﬂoor of the mouth, mandibular gingiva, and buccal mucosa.67–71 Oral vesiculation is often ac- Primary and recurrent herpes simplex virus (HSV) infec- companied by facial involvement. Patients report having tions, secondary to human herpesvirus 1 (HHV-1) or HHV-2, odontalgia, dysgeusia, and ageusia.71 Diseases of the Tongue 463 Fig. 7 Herpes simplex virus. a, Acute herpetic gingivostomatitis is characterized by a vesiculobullous eruption, which may be associated with adherent hyperkeratosis and hemorrhage. This severe case occurred in the setting of immunosuppression. b, Herpetic geometric glossitis is clas- sically described as linear and symmetric striations and ﬁssures of the dorsal aspect of the tongue. Although classic eruptions can be diagnosed easily, atypi- squamous papilloma, and focal epithelial hyperplasia. The cal cases without vesiculation or with ulceration and necrosis clinical differential diagnosis of HPV-induced epithelial bring in a broader differential diagnosis. The clinical differen- changes includes squamous papilloma, condyloma acuminata, tial diagnosis may include: secondary syphilis; herpetic geo- exophytic squamous cell carcinoma, keratoacanthoma, exo- metric glossitis; burning mouth syndrome; cytomegalovirus phytic verrucous carcinoma, focal epithelial hyperplasia, and ulcers; EBV-mucocutaneous ulcers; hand, foot, and mouth verruciform xanthoma.78 disease; eosinophilic ulcer of the oral mucosa (EUOM); pem- Oral verrucae are rare, relative to cutaneous disease, and are phigus; mucous membrane pemphigoid; and even epithelial caused by HPV types 1, 2, 4, 26, 27, and 57.78 The verrucous carcinoma.72,73 Varicella-zoster virus polymerase chain reac- papules most commonly occur on the lips, tongue, and gingi- tion testing remains the most sensitive and speciﬁc method vae. Clinically, oral verrucae are characterized by exophytic, of diagnosis; however, culture should be considered in sessile, or pedunculated lesions. Although treatment is not immune-compromised patients to evaluate for resistance.74 necessary, local destruction with cryosurgery, electrosurgery, In atypical cases, a biopsy should be performed to conﬁrm and carbon dioxide lasers is often effective. For refractory or the diagnosis and rule out other entities. In cases with an atyp- atypical lesions, surgical excision is preferred. ical presentation, one should consider testing for an immune- Condyloma acuminata may be caused by HPV types 6 and suppressed state such as HIV. 11 and high-risk strains.79 They are most commonly found in Oral antivirals remain the standard of care. Early interven- the genital region of young adults; however, oral lesions, on tion within 72 hours of onset decreases the disease severity, the lips and tongue in particular, can occur in individuals en- but the beneﬁt in preventing postherpetic neuralgia is un- gaging in oral sex. Clinically, these lesions are indistinguish- clear.75 Although most studies suggest treating with antivirals able from other forms of HPV verrucae. Similar treatment in the ﬁrst 72 hours, treatment after this window of time is also modalities to oral verruca may be used. High-risk phenotypes, appropriate, especially in patients at high risk for complica- as well as high degrees of dysplasia, require more aggressive tions. For a more detailed review on dosing and duration for treatment.80–82 Prevention and risk reduction of condyloma varicella-zoster virus infections, please see Comprehensive and HPV-related cancers can be achieved with safe sex prac- Dermatologic Drug Therapy, Chapter 10, Systemic Antiviral tices, as well as HPV immunization. The new Gardasil 9 vac- Agents.76 cine protects against HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 and, in the United States, is recommended for everyone 9 to 26 Human papillomavirus infections years of age.83 Human papillomavirus (HPV) is responsible for a large Candidiasis number of epithelial diseases occurring on cutaneous and mu- cosal sites. Most commonly, HPV causes cutaneous verrucae. Oral candidiasis is most commonly caused by Candida Oral HPV is present in approximately 7% of the adolescent albicans.84 Median rhomboid glossitis is a unique form of can- and adult population in the United States, and 1% of the pop- didiasis that is characterized by large rhomboidal, atrophic pla- ulation harbors the high-risk strain HPV type 16.77 HPV types ques on the posterior-central tongue anterior84 (Figure 8). 16, 18, 31, 33, and 52 are associated with an increased risk of Median rhomboid glossitis is likely a reactive process to head and neck malignancy.78 The four major low-risk oral Candida and occurs more commonly in adults. The surface HPV diseases are oral verruca vulgaris, condyloma acuminata, of the tongue may be lobulated or smooth, and the lesions 464 A.R. Mangold et al. examination, including candidiasis, LP, lupus erythematosus, graft-versus-host disease, BMG, white sponge nevus, friction- al hyperkeratosis, nicotinic stomatitis, and squamous cell car- cinoma (SCC).87,93,94 When an entity has white plaques and cannot be identiﬁed further clinically, the term leukoplakia is often used pending a histopathologic analysis.90 For the pur- pose of this section, we will use leukoplakia as a clinical path- ologic correlation representing a white plaque clinically, with the absence of pathologic ﬁndings of other diseases and which may or may not have dysplasia. Leukoplakia is the most common chronic disease in the mouth and represents 85% of all keratotic lesions.92 Leukopla- kia increases in frequency with age, is associated with smok- ing, and commonly occurs on the tongue.92,95–97 Infectious risk factors include HPV, Candida, HIV, and syphilis. Squa- mous atypia may be found when a Candida infection is pres- ent. Although leukoplakia may be premalignant, dysplasia is not required for diagnosis. Up to 7% of cases of leukoplakia will show severe dysplasia on initial biopsy.92 Clinically, leu- Fig. 8 Median rhomboid glossitis is characterized by large rhom- koplakia is characterized by adherent, white plaques.90,92 The- boidal, atrophic plaques on the posterior-central tongue. se plaques should be palpated because tenderness and induration are signs of malignancy. The ﬂoor of the mouth, as well as the ventral surface of the tongue, are commonly in- are always anterior to the circumvallate papillae. The plaques volved. A complete oral examination should be performed be- are often asymptomatic. Median rhomboid glossitis may be cause leukoplakia can be associated with multifocal disease. confused with BMG; however, the plaques of median rhom- The overall risk of malignant transformation varies between boid glossitis are not dynamic. Treatment with topical or oral 2-3% per year, with long-term risk as high as 18%.89,96 Risk antifungals is effective.85–87 factors for malignant transformation include old age, location on the tongue, speckled leukoplakia, a history of smoking or betel nut chewing, and high-grade dysplasia on initial biopsy.89,95,97 Premalignant lesions Treatment of leukoplakia may be difﬁcult. A recent Cochrane review found no clear evidence for any treatment re- Leukoplakia gime preventing malignant transformation of leukoplakia.98 Close monitoring, best with serial photography, and frequent Leukoplakia is a misused term that refers to a phenotype, a biopsies for malignant transformation are necessary. Treat- white patch or plaque, that cannot be classiﬁed as any other ment options are dependent on the degree of dysplasia. Highly disease87–92 (Figure 9). Leukoplakia is therefore a clinically atypical lesions often require surgical removal or other de- descriptive term and, in itself, does not denote malignant structive methods: electrocautery, cryosurgery, or laser abla- potential. Other entities have white plaques on clinical tion. These methods will reduce the tumor burden, but recurrences are common and the rate of overall progression to malignancy is unaffected.98,99 Adjuvant ﬁeld therapy with imiquimod, ﬂuorouracil, and photodynamic therapy may be appropriate to reduce the disease burden. Long-term follow- up, every 3 to 6 months for 2 to 3 years, is necessary to detect malignant transformation.89 Erythroplakia Erythroplakia is a rare and poorly deﬁned premalignant condition with a higher rate of progression to invasive SCC than leukoplakia.100 Erythroplakia is a provisional diagnosis that refers to a clinical phenotype that cannot be classiﬁed as Fig. 9 Leukoplakia is characterized by a slightly elevated, white a speciﬁc clinical entity (Figure 10). For the purpose of this plaque. This patient had extensive benign leukoplakia. section, erythroplakia will only refer to purely red lesions Diseases of the Tongue 465 perform a biopsy early in the disease course, and perform re- peat biopsies in refractory oral inﬂammatory diseases. SCCs can appear as exophytic masses or endophytic and indurated ulcers. Clues to the diagnosis include longstanding lesions, ir- regular and ulcerated papules, nodules, and plaques that ex- tend above the normal epithelium. The lesions often have an indurated quality. The most common sites are the posterior lat- eral and ventral surface of the tongue.107 The ﬂoor of the mouth is the second most common location, whereas SCC of the dorsal surface of the tongue is rare. Multimodal therapy with surgical excision, chemotherapy, or radiation remains the standard of care.108 Recurrence is high in oral SCC; therefore, long-term monitoring is required. In Fig. 10 Erythroplakia is characterized clinically by a poorly mar- cases of multiply recurrent disease or ﬁeld cancerization, che- ginated red plaque. In this case, a biopsy revealed this to be an inva- moprevention with retinoids, topical chemotherapy, and pho- sive squamous cell carcinoma. todynamic therapy should be considered. Kaposi sarcoma and will exclude lesions of speckled leukoplakia, often classi- ﬁed as high-risk leukoplakia. It is unclear if erythroplakia de- Kaposi sarcoma (KS) is a rare vascular malignancy in an velops from leukoplakia or if it arises de novo. Erythroplakia endemic population; however, the epidemic form of KS be- is most common in older individuals, and risk factors include came a more common ﬁnding with the HIV/AIDS epidem- chewing tobacco and alcohol.101 Clinically, erythroplakia is ic.109 KS is the most common malignancy associated with described as a red, velvety patch. Oral mucosal erythroplakia HIV. KS is a virus-associated malignancy with invariable in- commonly occurs on the ﬂoor of the mouth and rarely on the fection with HHV-8.110,111 Four patterns of KS are seen: clas- tongue and buccal mucosa.102 The lesions may be atrophic sic, African/endemic, immunosuppressive, and HIV/AIDS and in some cases erosive. As with leukoplakia, a complete related. Oral KS most often affects the hard and soft palate, oral examination should be performed. The rate of malignant gingiva, and dorsal tongue with plaques or tumors of colora- transformation may be as high as 50%.103 tion ranging from nonpigmented to brown-red or violet.109 All erythroplakic lesions should be biopsied because SCC Oral KS is most common in HIV-related KS and may be the or SCC in situ are the most common diagnoses. Erythroplakia only area of involvement in 25% of cases.109 Oral KS may is a diagnosis of exclusion; in addition to malignancy, the most be the ﬁrst sign of an occult HIV infection. The differential di- important differential diagnosis are lupus erythematosus, LP, agnosis for oral KS includes pyogenic granuloma, benign vas- and erythematous candidiasis. When erythroplakia is present cular malformations, bacillary angiomatosis, and drug- in LP, it considered a high-risk feature for malignant degener- associated hyperplasia (most commonly on the gingiva).109 ation.104,105 Treatment options include surgical removal as For focal lesions, locally destructive methods, including cryo- well as other destructive methods: electrocautery, cryosurgery, therapy, topical alitretinoin, intralesional chemotherapy, and or laser ablation. Recurrence is common, and long-term excision, are effective. For later-stage disease, chemotherapy follow-up is necessary. or radiation is reasonable.112–114 Lymphoproliferative diseases Malignant neoplasms Eosinophilic ulcers of the oral mucosa can occur in adults, Squamous cell carcinoma as well as in infants (Riga-Fede disease). The pathogenesis is unknown but is thought to be trauma related, with the tongue SCC is the most common oral malignancy and is a signiﬁ- as the most common location.115 Clinically, the lesion starts cant worldwide health issue.88,106 Oral SCC is more common as a single nodule, enlarges, ulcerates centrally, and develops in men and in those older than age 40. Extrinsic risk factors in- rolled borders.115 In children, EUOM is often trauma associat- clude tobacco, alcohol, and sun exposure (if on the lip). Intrin- ed and resolves with the cessation of trauma. Histologically, sic risk factors include immunosuppression, longstanding EUOM are characterized by a polymorphous inﬂammatory in- inﬂammation, LP, HPV infection, HIV infection, and nutri- ﬁltrate with eosinophils and, more recently noted, a clonal tional deﬁciencies.88 The overall prognosis of SCC of the oral population of CD30-positive cells.116–118 This has led some cavity is worse than SCC of the skin. to speculate that EUOM represent a variant of CD30-positive The clinical presentation of oral SCCs is highly variable; lymphoproliferative disease. No treatment is necessary be- therefore, one should maintain a high index of suspicion, cause the lesions tend to spontaneously resolve within a few 466 A.R. Mangold et al. months. A biopsy is often performed to rule out malignancy. If the tip and lateral aspect of the tongue and eventually spread to in- lesion is nonresolving or increasing in size, one should consider volve the entire tongue surface. Iron supplements will often re- anaplastic large cell lymphoma as an alternative diagnosis. verse these changes. Plummer-Vinson syndrome is associated EBV-mucocutaneous ulcers, as well as EBV-associated with the triad of dysphagia, iron deﬁciency anemia, and esoph- lymphoproliferative diseases, occur in transplant patients.119 ageal webs.126 The major clinical ﬁndings are atrophic glossi- Histologically, the ulcerations are characterized by a polymor- tis, angular cheilitis, and koilonychia. Patients with Plummer- phous inﬂammatory inﬁltrate with immunoblasts, Hodgkin- Vinson syndrome are at increased risk of oropharyngeal SCC like cells, and apoptotic bodies.72 Like EUOM, EBV- and require long-term follow-up. mucocutaneous ulcers are CD30 positive; however, EBV- B-complex deﬁciencies (B1, B2, B3, B6, and B12) can result mucocutaneous ulcers may not resolve spontaneously and in tongue changes with eventual atrophy and even ulceration. may require a decrease in immunosuppression. These changes are indistinguishable from diseases of malab- sorption and iron deﬁciency. Niacin (B3) deﬁciency, pellagra, is associated with distinctive clinical features, including diar- rhea, photo-distributed dermatitis, and dementia. Cyanocobal- Signs of systemic disease amin (B12) deﬁciency also has unique hematologic and neurologic ﬁndings. The recognition and treatment of B12 de- Nutritional deﬁciency ﬁciency is critical because it is a reversible cause of bone mar- row failure and neurologic disease.122 Pernicious anemia is the Oral changes are often the ﬁrst clinical sign of a nutritional most common cause of B12 deﬁciency and is secondary to an- deﬁciency.1 The clinical changes may not correlate with the tibodies against intrinsic factor with destruction of gastric pari- disease severity and may be nonspeciﬁc. In some cases, there etal cells.122 Other populations with B12 deﬁciency include the may be no clinical ﬁndings other than symptoms of a burning elderly, vegetarians, and chronically ill individuals. Clinically, or sore mouth.120 Additionally, problems with malabsorption, burning pain on the tongue is often present before physical such as occur in patients with celiac disease, can result in nu- changes to the tongue, which may be mistaken for burning tritional deﬁciencies.121 A detailed dietary history of gastroin- mouth syndrome.127 As the disease worsens, there is a progres- testinal symptoms is required when a patient is suspected of sive, beefy red change to the tongue. Late-stage disease is char- having a nutritional deﬁciency. In early disease, the tongue pa- acterized by atrophy of the ﬁliform and fungiform papilla and a pillae initially redden and may enlarge. In late disease, the ton- smooth, glistening appearance.123 Taste and smell alteration gue takes on an atrophic and smooth, beefy red occurs in late disease. Measurement of B12, methylmalonic ac- appearance122,124 (Figure 11). Other cutaneous and neurologic id (elevated and the most sensitive test of B12 deﬁciency), and clues can be used to narrow the differential diagnosis.122 Panel homocysteine is used to conﬁrm vitamin B12 deﬁciency.122 testing for nutrients is often required.123 Treatment consists of Oral or subcutaneous B12 replacement is necessary. replacement of the deﬁcient vitamins and improved nutritional status. The two major entities discussed here are atrophic glossitis Systemic amyloidosis in association with iron deﬁciency and B-complex deﬁciency. Changes to the tongue and oral mucosa are common in red Systemic amyloidosis is a heterogeneous disease character- blood cell disorders. Iron deﬁciency anemia is common and ized by the deposition of amyloid in various organs. Amyloid often has early manifestations with atrophy of the ﬁliform and fungiform papillae.124,125 The atrophy may begin on the Fig. 12 Macroglossia can be diagnosed clinically with scalloped Fig. 11 Atrophic glossitis occurs in the setting of nutritional deﬁ- impressions on the lateral border of the tongue secondary to the com- ciency. In this case, the patient had pernicious anemia as well as angu- pression of the tongue on the teeth. This case was secondary to sys- lar cheilitis. temic amyloidosis. Diseases of the Tongue 467 light chain is the most common form of systemic amyloidosis 20. Farman AG. Hairy tongue (lingua villosa). J Oral Med. 1977;32:85-91. and most often occurs in individuals older than age 65.128 21. Langtry JA, Carr MM, Steele MC, Ive FA. Topical tretinoin: a new treatment for black hairy tongue. Clin Exp Dermatol. 1992;17:163. Most patients have an underlying plasma cell dyscrasia. Areas 22. Holzwanger JM, Rudolph RI, Heaton CL. Pigmented fungiform papillae commonly involved are the kidney, heart, peripheral nerves, skin, of the tongue: a common variant of oral pigmentation. Int J Dermatol. gastrointestinal tract, and oral cavity. Oral lesions predominantly 1974;13:403-408. affect the tongue, causing macroglossia in 15% of patients, along 23. Romiti R, Molina De Medeiros L. Pigmented fungiform papillae of the tongue. Pediatr Dermatol. 2010;27:398-399. with purpura and bullae128 (Figure 12). In systemic amyloid- 24. Halperin V, Kolas S, Jefferis KR, et al. The occurrence of Fordyce osis, the tongue has a woody quality on palpation and may spots, benign migratory glossitis, median rhomboid glossitis, cause airway obstruction. The major prognostic indicator of and ﬁssured tongue in 2,478 dental patients. Oral Surg Oral Med systemic amyloidosis is the degree of cardiac involvement.128 Oral Pathol. 1953;6:1072-1077. The treatment of systemic amyloidosis is centered on treating 25. Meskin LH, Redman RS, Gorlin RJ. 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