Continuing Medical Education

Tuberculosis Verrucosa Cutis Presenting as an Annular Hyperkeratotic Plaque

Shahbaz A. Janjua, MD; Amor Khachemoune, MD, CWS; Sabrina Guillen, MD

GOAL To understand cutaneous to better manage patients with the condition

OBJECTIVES Upon completion of this activity, dermatologists and general practitioners should be able to: 1. Recognize the morphologic features of cutaneous tuberculosis. 2. Describe the histopathologic characteristics of cutaneous tuberculosis. 3. Explain the treatment options for cutaneous tuberculosis. CME Test on page 320.

This article has been peer reviewed and approved Einstein College of Medicine is accredited by by Michael Fisher, MD, Professor of Medicine, the ACCME to provide continuing medical edu- Albert Einstein College of Medicine. Review date: cation for physicians. October 2006. Albert Einstein College of Medicine designates This activity has been planned and imple- this educational activity for a maximum of 1 AMA mented in accordance with the Essential Areas PRA Category 1 CreditTM. Physicians should only and Policies of the Accreditation Council for claim credit commensurate with the extent of their Continuing Medical Education through the participation in the activity. joint sponsorship of Albert Einstein College of This activity has been planned and produced in Medicine and Quadrant HealthCom, Inc. Albert accordance with ACCME Essentials.

Drs. Janjua, Khachemoune, and Guillen report no conflict of interest. The authors discuss off-label use of , , , and . Dr. Fisher reports no conflict of interest.

Tuberculosis verrucosa cutis (TVC) is a form evolving cell-mediated immunity. TVC usually of cutaneous tuberculosis that results from acci- begins as a solitary papulonodule following a dental inoculation of tuberculosis trivial injury or trauma on one of the extremi- in a previously infected or sensitized individ- ties that soon acquires a scaly and verrucous ual with a moderate to high degree of slowly surface. The , which is usually persistent, expands slowly over several months or years with or without central clearing and atrophy. We Accepted for publication February 27, 2006. Dr. Janjua is a specialist, Ayza Skin and Research Center, report a case of TVC in a 15-year-old girl that was Lalamusa, Pakistan. Dr. Khachemoune is Assistant Professor, undiagnosed for 10 years. The diagnosis was Ronald O. Perelman Department of Dermatology, New York confirmed by a positive mycobacterial culture University School of Medicine, New York. Dr. Guillen is an intern, and characteristic histopathologic findings of the University of Illinois, Chicago. specimens. The patient responded well Reprints: Amor Khachemoune, MD, CWS, Ronald O. Perelman Department of Dermatology, New York University School of to antituberculous therapy (ATT), and the lesion Medicine, 530 First Ave, Suite 7R, New York, NY 10016 resolved with residual scarring. (e-mail: [email protected]). Cutis. 2006;78:309-316.

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Figure 1. Well-defined, verrucous, thick, scaly, linear Figure 2. Pseudoepitheliomatous epidermal hyperplasia plaque on the right knee at presentation. and well-formed tuberculous in the papillary and reticular dermis (H&E, original magnification 3100).

Case Report The remainder of the A 15-year-old girl presented with a 10-year his- showed unremarkable findings. A tory of a slowly enlarging warty Calmette-Guérin scar could be identi- plaque over the right knee. The lesion started fied on the left deltoid. Routine blood and urinalyses as a small asymptomatic red papule following a results were within reference range. Purified protein trivial injury and slowly progressed over several derivative test results were strongly positive (.15 mm months to form a large warty plaque covered of induration after 72 hours). Findings from a chest with a thick scale. The patient and her mother x-ray revealed no evidence of pulmonary . reported that the lesion also would get tender, Histopathologic examination results of a biopsy intermittently discharging yellowish . specimen taken from the lesion revealed marked The lesion initially was treated with home rem- epidermal hyperkeratosis, acanthosis, pseudoepi- edies and later with topical steroids and oral theliomatous hyperplasia, and multiple well-formed prescribed by local physicians, but the tuberculous granulomas in the dermis (Figure 2). lesion continued expanding slowly to involve a Each of the granulomas consisted of large numbers of large area of the right knee and upper leg. There , neutrophils, histiocytes, and Langhans was neither a family history of nor any known giant cells (Figure 3). However, caseation contacts with tuberculosis. was not present, and acid-fast bacilli could not be Results of a physical examination revealed a found. Mycobacterium tuberculosis was cultured from 437-cm, large, well-defined, verrucous, thick, scaly, the biopsy specimen. linear plaque situated over the right knee with Daily oral antituberculous therapy (ATT) involvement of the lower aspect of the anterior (rifampicin 450 mg/d, isoniazid 300 mg, and thigh and the right anterior upper aspect of the pyrazinamide 1200 mg) was recommended for leg. Central clearing with atrophy gave the lesion 3 months (Figure 4). The patient responded well to the a somewhat annular shape (Figure 1). Diascopy treatment and there was perceptible regression results did not show an apple jelly–brown color. of the skin lesion. Treatment was continued with Regional nodes were not palpable. rifampicin 450 mg/d and isoniazid 300 mg/d for

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Figure 3. A well-formed noncaseating consisting of lymphocytes, neutrophils, histiocytes, and Langhans giant cells (H&E, original magnification 3400). another 6 months, resulting in complete regression of the lesion with residual scarring.

Comment Tuberculosis is a serious public concern in Figure 4. Regression of the lesion after 3 months of anti- developing countries due to lower socioeconomic tuberculous therapy. status, , and overcrowding; addition- ally, the morbidity and mortality rates of the disease are increasing rapidly in these countries. The inci- TVC is a form of cutaneous tuberculosis that dence of tuberculosis also is on the rise in developed results from accidental inoculation of M tuberculosis countries, including the United States and United into the skin through open wounds or abrasions in Kingdom, both of which were previously considered previously infected or sensitized individuals with a free of this disease.1,2 moderate to high degree of immunity,6 as opposed Systemic tuberculosis was well-documented in to tuberculosis , which occurs in uninfected ancient medical scriptures, but its first intelligent or unsensitized individuals. Individuals vaccinated description, phthisis (to waste away), was given with the bacillus Calmette-Guérin have by (circa 460–376 bc).3 Cutaneous been sensitized and carry a higher risk of developing tuberculosis makes up only a small proportion of the TVC.7 In low socioeconomic environments, chil- cases of extrapulmonary tuberculosis. Children and dren can be infected by playing on ground contami- immunocompromised adults are at increased risk of nated with tuberculous .8 Autoinoculation of developing this form of the disease.3 a wound with a patient’s own tuberculous sputum Cutaneous tuberculosis may present in a number of rarely causes TVC.7 The sites of predilection for diverse clinical forms (Table). The 4 major categories inoculation tuberculosis in children are the lower of cutaneous tuberculosis that have been described extremities (ie, knees, thighs, and buttocks) because inthe include: (1) inoculation from these areas are most likely to be traumatized. In an exogenous source (ie, tuberculous chancre, adults, fingers and hands frequently are involved. tuberculosis verrucosa cutis [TVC]); (2) endog- The historically well-known “’s wart” is enous cutaneous spread either contiguous or by considered a prototype of TVC and is caused by autoinoculation (ie, tuberculosis cutis orificialis, accidental inoculation during .4 ); (3) hematogenous spread (ie, The diagnosis of TVC should be based on vulgaris, , tuberculosis / history and evolution of the disease, cardinal /); and (4) tuberculids (ie, erythema morphologic features, histopathologic characteris- induratum [Bazin disease], papulonecrotic tubercu- tics, and mycobacterial culture of the biopsy speci- lids, ).4,5 men. The of TVC typically are asymptomatic

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hypertrophic, LP, iododerma, LP, hypertrophic, , Majocchi , Majocchi mycosis, cous epidermal nevus, nevus, epidermal cous Glossitis, aphthosis, deep deep aphthosis, Glossitis, , coccidioido- histoplasmosis, mycosis, , , nocardiosis, mycosis, leishmaniasis, , , yaws, leishmaniasis, atypical mycobacterial infec- mycobacterial atypical Atypical mycobacterial infec- mycobacterial Atypical chromoblastomycosis, verru- chromoblastomycosis, tion, pyogenic granuloma, granuloma, pyogenic tion, tion, North American blasto- American North tion, bromoderma, verruca vulgaris verruca bromoderma, cat scratch disease scratch cat fungal , blastomycosis, Sporotrichosis, Differential

resemble a wart), peripheral peripheral a wart), resemble secondary bacterial infection bacterial secondary out ulcers with undermined undermined with ulcers out with no tendency to heal to tendency no with central clearing; dorsa of fingers fingers of dorsa clearing; central Mucocutaneous border of the the of border Mucocutaneous present after inoculation; may progress progress may inoculation; after meatus, and vagina; mucous vagina; and meatus, tongue; lesions ulcerate from ulcerate lesions tongue; to nodule, plaque, or ulcerate; ulcerate; or plaque, nodule, to children typically affected; face face affected; typically children edges) and extend rapidly, rapidly, extend and edges) and extremities are commonly commonly are extremities and A small papule progressing to to progressing papule A small 3–8 wk after infection after wk 3–8 expanding, with or without without or with expanding, only if only lymphadenopathy involved, may follow BCG vac- BCG follow may involved, hyperkeratotic plaque (can (can plaque hyperkeratotic buttocks in children; regional regional children; in buttocks cination; regional lymphadenopathy lymphadenopathy regional cination; nose, mouth, anus, urinary urinary anus, mouth, nose, or hands in adults, ankles and and ankles adults, in hands or membrane of the mouth or mouth the of membrane Painless brown papule 2–4 wk 2–4 papule brown Painless Clinical Presentation the beginning (soft punched (soft beginning the

(larynx, , lungs, (larynx,

variable TB test TB variable

Variable sensitivity; sensitivity; Variable

negative TB test TB negative visceral tuberculosis tuberculosis visceral intestines, and and intestines,

Sensitized; strongly Sensitized;

positive TB test TB positive

active underlying genitourinary tract); tract); genitourinary Status of Sensitivity/

Infection Previous Nonsensitized; Nonsensitized;

Tuberculosis

Type of Cutaneous Type

Tuberculous chancre Tuberculous Tuberculosis

verrucosa cutis verrucosa

orificialis cutis

Tuberculosis

Endogenous—

Clinical Presentations of Cutaneous Tuberculosis* Mode of Infection Exogenous

contiguous

Transmission or

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TABLE CONTINUED ON PAGE 314 CONTINUED ON PAGE TABLE Differential Diagnosis Differential leishmaniasis cosis, , cosis, Atypical mycobacterial infec- mycobacterial Atypical Colloid milia, vulgaris, acne milia, Colloid tion, sporotrichosis, actinomy- sporotrichosis, tion, lymphogranuloma syphilis, chronic discoid LE, discoid chronic syphilis, , systemic mycoses, systemic leprosy, , rosacea, tertiary rosacea, sarcoidosis, Drug reactions Drug hidradenitis gumma; Syphilitic suppurativa

Clinical Presentation Typically single plaque composed plaque single Typically nodules, and purpuric lesions that lesions purpuric and nodules, form sinuses; may present as present may sinuses; form on head and neck; and and lymphangitis neck; and head on forming scars; 90% of lesions occur occur lesions of 90% scars; forming nodules with central suppuration; suppuration; central with nodules involved, also may occur over over occur may also involved, immuno- affect commonly most cervical lymph nodes commonly commonly nodes lymph cervical sinus formation sinus masses enlarge to form form to enlarge masses chronic mastitis with abscess and and abscess with mastitis chronic lymphadenitis; subcutaneous subcutaneous lymphadenitis; involved or joints; healing healing joints; or bones involved Direct extension from the from extension Direct with cordlike scars scars cordlike with adherent scale; ulceration frequently frequently ulceration scale; adherent underlying tuberculous tuberculous underlying occurs, and involution leaves de- leaves involution and occurs, lymphadenitis may be associated be may lymphadenitis compromised hosts; ulceration ulceration hosts; compromised of red-brown papules with overlying overlying with papules red-brown of may occur may Generalized erythematous macules erythematous Generalized erythematous nontender Firm nodules that soften, ulcerate, and and ulcerate, soften, that nodules or papules, pustules, subcutaneous pustules, papules, or

Status of Sensitivity/ Infection Previous Sensitized; positive positive Sensitized; meninges present; present; meninges usually present; present; usually

test TB negative

positive TB test TB positive

Previously infected infected Previously

and sensitized sensitized and

focus of infection infection of focus

TB test TB

of the lungs or or lungs the of Fulminant tuberculosis Fulminant primary Sensitized;

Type of Cutaneous Type Tuberculosis Lupus

abscess

tuberculosis

Scrofuloderma miliary Acute Tuberculosis

ulcer/gumma/

Mode of Infection or Hematogenous

Endogenous—

autoinoculation

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Lichen nitidus, LP, secondary LP, nitidus, Lichen Papulopustular secondary Papulopustular necrotizing vasculitis necrotizing , nodular nodosum, Erythema matoid papulosis, perforating papulosis, matoid nodosa, tertiary syphilis, tertiary nodosa, et varioliformis acuta, Churg- acuta, varioliformis et vasculitis, polyarteritis vasculitis, matory panniculitides matory collagenosis, perforating GA, other infectious and inflam- and infectious other Strauss granuloma, lympho- granuloma, Strauss syphilis, pityriasis lichenoides pityriasis syphilis, syphilis, sarcoidosis syphilis, Differential Diagnosis Differential

Groups of indolent, minute keratotic, minute indolent, of Groups Symmetrically distributed, 2–3-mm, 2–3-mm, distributed, Symmetrically the trunk trunk the Predominantly affects middle-aged affects Predominantly arranged in discoid groups over over groups discoid in arranged several months several 1–8-mm subcutaneous nodules on on nodules subcutaneous 1–8-mm pustular or necrotic and appearing and necrotic or pustular women; tender, erythematous, erythematous, tender, women; and scrofuloderma and with or without ulcerations over over ulcerations without or with association with erythema nodosum erythema with association lower posterior calves; lesions resolve resolve lesions calves; posterior lower in crops; lesions resolve slowly with slowly resolve lesions crops; in reddish-brown papules; lesions papules; reddish-brown varioliform scarring; may appear in in appear may scarring; varioliform firm, inflammatory papules, becoming papules, inflammatory firm, discrete 2–4-mm, yellowish-pink to yellowish-pink 2–4-mm, discrete Clinical Presentation

Sensitized and infected, and Sensitized Sensitized/Evidence Sensitized/Evidence one third to two thirds thirds two to third one lymph nodes; positive positive nodes; lymph

Sensitized; positive Sensitized; TB test TB

in especially cases, of disease present in in present disease TB test TB positive TB test TB positive

lymph nodes; strongly strongly nodes; lymph

of prior or active active or prior of involving bones or or bones involving Status of Sensitivity/ Infection Previous

Lichen Lichen Papulonecrotic Papulonecrotic

Erythema Erythema

tuberculids

(Bazin disease) disease) (Bazin

induratum induratum

scrofulosorum

Type of Cutaneous Type Tuberculosis

Tuberculids annulare. granuloma GA, erythematosus; lupus LE, planus; lichen LP, Calmette-Guérin; bacillus BCG, ; indicates *TB

(continued) Mode of Infection Transmission or

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and start as small papules that slowly progress to ethambutol may be added to the regimen.15 The verrucous or hyperkeratotic plaques over several intensive-phase treatment should result in percep- months to years.9 Superficial scaling and fissuring tible regression of the lesion, prompting the treating with subsequent intermittent purulent discharge physician to continue the treatment through the may occur. There may be central clearing with scar- continuation phase. Surgical excision of the isolated ring and atrophy, as seen in this case. The disease lesion also is useful.4 usually runs a prolonged course with persistent ver- Our case of cutaneous tuberculosis remained undi- rucous lesions, especially if left untreated.9 Regional agnosed for an unusually long period of 10 years. lymph nodes commonly are not enlarged unless Although cutaneous tuberculosis may be regarded as there is superadded bacterial infection.10 Other a rare finding in the United States and other devel- organs, including the lungs, , and kidneys, do oped countries, it is not uncommon in countries with not appear to be affected in TVC, which differs endemic tuberculosis. Delay in referral may lead to from other forms of cutaneous tuberculosis.11 TVC is long-standing extensive lesions, as in this case. Physi- only locally invasive and usually does not any cian awareness and education of early diagnosis and deformity or functional impairment of the affected management of cutaneous tuberculosis are key to extremity, but exceptions can occur.9 reducing the number of cases similar to ours. Differentiation from infection with atypical myco- may prove to be difficult and usually requires Acknowledgment—The authors wish to thank culture of the causative organism.4,12 Other unusual Elizabeth Davis, MFA, at the Wellman Center for infections such as North American blastomyco- Photomedicine, Boston, Massachusetts, for her sis, chromoblastomycosis, Majocchi granuloma, and editorial assistance. fixed sporotrichosis may need to be differentiated from TVC by histopathology. Inflammatory derma- References toses, including psoriasis, lichen simplex chronicus, 1. Mangtani P, Jolley DJ, Watson JM, et al. Socioeconomic hypertrophic discoid lupus erythematosus, and hyper- deprivation and notification rates for tuberculosis in trophic lichen planus, also may mimic TVC but are London during 1982-91. BMJ. 1995;310:963-966. differentiated on the basis of characteristic clinical 2. Steenland K, Levine AJ, Sieber K, et al. of findings and histopathology.4,12 tuberculosis infection among New York state prison The histopathologic features of TVC include a employees. Am J . 1997;87:2012-2014. pseudoepitheliomatous epidermal hyperplasia with 3. Bhutto AM, Solangi A, Khaskhely NM, et al. Clinical hyperkeratosis and a dense dermal infiltrate of neu- and epidemiological observations of cutaneous tuberculo- trophils, lymphocytes, and giant cells arranged in sis in Larkana, Pakistan. Int J Dermatol. 2002;41:159-165. multiple well-formed tuberculous granulomas.13,14 4. Odom RB, James WD, Berger TG. Tuberculosis. In: Acid-fast bacilli rarely are seen and typical tuber- Odom RB, James WD, Berger TG, eds. Andrews’ culous foci with caseation necrosis are uncommon. of the Skin: Clinical Dermatology. 9th ed. Philadelphia, Pa: Case reports in the literature indicate the usefulness WB Saunders, 2000:417-426. of polymerase chain reaction for the detection of 5. Beyt BE, Ortbals DW, Santa Cruz DJ, et al. Cutaneous M tuberculosis in cutaneous tuberculosis.13,14 Poly- mycobacteriosis: analysis of 34 cases with a new classifica- merase chain reaction has not been found to be tion of the disease. Medicine. 1981;60:95-109. very helpful in the paucibacillary forms of cutaneous 6. Prendiville J, Kaufman D, Esterly NB. Psoriasiform tuberculosis such as TVC.14 In cases for which the plaque on the buttock. tuberculosis verrucosa cutis. Arch clinician has strong suspicion but negative labora- Dermatol. 1989;125:115, 118. tory test results, it might be possible to use the dra- 7. Barbagallo J, Tager P, Ingleton R, et al. Cutaneous matic response to ATT as a diagnostic criterion.15,16 tuberculosis: diagnosis and treatment. Am J Clin Dermatol. A study of patients with equivocal laboratory results 2002;3:319-328. noted 100% clinical improvement in all patients tak- 8. Wong KO, Lee KP, Chiu SF. Tuberculosis of the skin in ing ATT for 20 days, and it has been proposed that Hong Kong. Br J Dermatol. 1968;80:424-429. response to treatment in 4 weeks can be used to sup- 9. Foo CC, Tan HH. A case of tuberculosis verrucosa port the diagnosis.11 cutis–undiagnosed for 44 years and resulting in fixed- Standard multidrug ATT is the treatment of flexion deformity of the arm. Clin Exp Dermatol. 2005;30: choice and most lesions resolve after 4 to 5 months.17 149-151. An intensive phase of ATT consists of rifampicin, 10. Sehgal VN, Srivastava G, Khurana VK, et al. An appraisal isoniazid, and pyrazinamide used for 2 months, with of epidemiologic, clinical, bacteriologic, histopathologic, rifampicin and isoniazid continued for an additional and immunologic parameters in cutaneous tuberculosis. 4 to 10 months. In cases of isoniazid resistance, Int J Dermatol. 1987;26:521-526.

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11. Pandhi D, Reddy BS, Chowdhary S, et al. Cutane- 14. Tan SH, Tan BH, Goh CL, et al. Detection of ous tuberculosis in Indian children: the importance of Mycobacterium tuberculosis DNA using polymerase chain for involvement of internal organs. J Eur Acad reaction in cutaneous tuberculosis and tuberculids. Dermatol Venereol. 2004;18:546-551. Int J Dermatol. 1999;38:122-127. 12. Gruber PC, Whittam LR, du Vivier A. Tuberculosis 15. Sehgal VN, Sardana K, Bajaj P, et al. Tuberculosis verrucosa cutis on the sole of the foot. Clin Exp Dermatol. verrucosa cutis: antitubercular therapy, a well-conceived 2002;27:188-191. diagnostic criterion. Int J Dermatol. 2005;44:230-232. 13. Hsiao PF, Tzen CY, Chen HC, et al. Polymerase chain 16. Sehgal VN. Cutaneous tuberculosis. Dermatol Clin. reaction based detection of Mycobacterium tuberculosis 1994;12:645-653. in tissues showing granulomatous without 17. Ramesh V, Misra RS, Saxena U, et al. Comparative demonstrable acid-fast bacilli. Int J Dermatol. 2003;42: efficacy of drug regimes in skin tuberculosis. Clin Exp 281-286. Dermatol. 1991;16:106-109.

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