Francisco G. Bravo, MD*, Eduardo Gotuzzo, MD

Clinics in Dermatology (2007) 25, 173 – 180

Cutaneous tuberculosis Francisco G. Bravo, MD*, Eduardo Gotuzzo, MD Instituto de Medicina Tropical Alexander von Humboldt, Facultad de Medicina Alberto Hurtado, Universidad Peruana Cayetano Heredia, Hospital Nacional Cayetano Heredia, Lima 31, Peru

Abstract Cutaneous tuberculosis continues to be one of the most elusive and more difficult diagnoses to make for dermatologists practicing in developing countries. Not only because they have to consider a wider differential diagnosis (leishmaniasis, leprosy, actinomycosis, deep fungal infections, etc) but also because of the difficulty in obtaining a microbiological confirmation. Despite all the advances in microbiology, including sophisticated techniques such as polymerase chain reaction, the sensitivity of new methods are no better than the gold standard, that is, the isolation of Mycobacterium tuberculosum in culture. Even now, in the 21st century, we rely on methods as old as the intradermal reaction purified protein derivative (PPD) standard test and therapeutic trials, as diagnostic tools. In this situation, it is important to recognize the many clinical faces of cutaneous tuberculosis to prevent missed or delayed diagnoses. D 2007 Elsevier Inc. All rights reserved.

Historical aspects

Epidemiology

Scrofuloderma and lupus vulgaris are the oldest forms of cutaneous tuberculosis (TB) described in the medical literature and were known as the king’s evil.1 Lupus, meaning wolflike, initially referred to any ulcerative lesion, reminiscent of a wolf bite. In 1803, Robert Willand used the word lupus as a reference to the latter stages of facial cutaneous TB. This clinical description of facial lupus was the origin of similar terms such as lupus erythematosus and lupus pernio (a variant of sarcoidosis). The term tuberculosis verrucosa cutis (TVC) was coined in 1869. Kaposi was the first to define the mucocutaneous involvement seen in TB. Darier introduced the concept of tuberculide in 1896. Later, Pautrier modified this notion to define papulonecrotic tuberculide.

Worldwide, there are more cases of TB now than at any other time in the history of humankind. The World Health Organization estimates that between 1.5 and 2 million people die each year from TB. Indeed, estimates are that there is a TB-related death every minute. In 1999, the World Health Organization estimated that there were a staggering 8,417,000 new cases of TB globally, representing a reverse of the steady decline in incidence that had been seen during the latter half of the 20th century. Cutaneous TB comprises only a small proportion (b1%2%) of all cases of TB2; nevertheless, bearing in mind the high prevalence of TB in many developing countries, these numbers become significant. If one assumes that 1% of all TB cases will have cutaneous involvement, dermatologists from countries such as India, where 1,847,000 new cases of TB were reported in 1999, and Peru, where 58,000 new cases were reported in the same year,2 then one could expect to see an annual incidence of some 18,000 and 580 cases of cutaneous TB, respectively.

* Corresponding author. Instituto de Medicina Tropical Alexander von Humboldt. Fax: +51 1 482 3404. E-mail address: [email protected] (F.G. Bravo). 0738-081X/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2006.05.005

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It is interesting to contrast these figures with the different case series that have been reported around the world: Farina (Spain), 11 cases in 14 years; Visser (South Africa), 92 cases in 12 years; Chong (Hong Kong), 176 cases in 10 years; Jerajani, Mumbai (India), 291 cases in 10 years; Kumar in Chandigarh (India), 402 cases in 25 years; Buttho (Pakistan), 153 cases in 4 years3; and Tincopa (Peru), 32 cases over 2 years.4 Scrofuloderma and lupus vulgaris appear to be the most common forms with an increasing incidence of tuberculides being reported from Japan and the Far East.5 The numbers in these series may express a true incidence or reflect serious underreporting—a well-known problem in resource-poor countries dealing with a high burden of disease. The high prevalence of ganglionar TB and the uncertainty of its inclusion or exclusion in cutaneous TB notifications, furthermore, may partly explain the gross discrepancy between the predicted and actual incidence rates. Factors, such as HIV coinfection and migration, will ensure that cutaneous TB will remain a diagnosis that the dermatologist should always consider.

Classification The most widely accepted classification system for cutaneous TB is based of the mechanism of propagation by (i) direct inoculation (ii) through contiguous infection, or (iii) hematogenous dissemination.6 One useful additional concept that has been introduced is the bacterial load,3 analogous to that described by Ridley and Jopling in reference to M leprae in Hanson’s disease. Thus, cutaneous TB is classified into multibacillary and paucibacillary forms (Table 1). The multibacillary forms include primary-inoculation TB or tuberculous chancre (by direct inoculation), scrofuloderma, TB periorificialis (by continuity), and acute miliary TB and gumma (by hematogenous dissemination). These forms of the disease show abundant mycobacteria in the skin that can readily be seen by direct visualization of ZiehlNielson stained material and can be easily isolated by culture of biopsy material. Table 1

Cutaneous tuberculosis

! By direct inoculation Primary inoculation TB ! By continuity Scrofuloderma Tuberculosis Multibacillary Periorificialis forms ! By hematogenous Acute Miliary spreading Tuberculosis Gumma (cold abscess) ! By direct inoculation Tuberculosis (re-exposure) Verrucosa Cutis Lupus Vulgaris Paucibacillary (occasionally) forms ! By hematogenous Lupus Vulgaris spreading

The paucibacillary forms are those where there are sparse bacilli seen on histology and the microorganisms are difficult to isolate. Paucibacillary disease includes those forms of cutaneous TB that occur either by direct inoculation or through reexposure such as TVC and some cases with the morphology of lupus vulgaris, notably isolated lesions in acral locations. Hematogenous dissemination is implicated in cases of facial lupus vulgaris or disease involving multiple sites. From this point of view, it is useful to think of tuberculid as the extreme form of the paucibacillary spectrum. Those universally accepted as true tuberculid include papulonecrotic tuberculid, erythema induratum of Bazin, and lichen scrofulosorum. Added to this are those exceptional cases presenting with the clinical picture of lupus miliaris disseminatum fasciei and granulomatous mastitis, where, either by direct visualization of the bacillus or the success of a therapeutic trial, a presumptive diagnosis of TB can be confirmed.

Clinical forms When considering cutaneous TB, one must be mindful that although the morphology of the lesions may vary greatly, certain findings may be very indicative of cutaneous TB: the scrofuloform picture, the annular plaque with verrucose border of lupus vulgaris, or the frankly hypertrophic plaque on acral locations of TVC. A positive contact history with persons having old or active TB would support the diagnosis. The following is a description of the clinical forms common in developing countries:

Multibacillary forms Primary-inoculation TB (tuberculous chancre) In cases of primary-inoculation TB, the social history is often helpful because the patient is usually a health care or laboratory worker that has acquired TB through accidental inoculation of contaminated material. Another common presentation is seen in children (often with no previous bacillus of Calmette-Gue´rin (BCG) immunization) that are exposed to Mycobacterium tuberculosis through a household member of caregiver with pulmonary TB. Lesions are usually located on the face, hands, and feet. Variants of this form include acute primary gingivitis (as an expression of oral primary TB), granulomatous paronychia, and penile chancre. The patient will develop a papule or a nodule that will eventually ulcerate 2 or 3 weeks after the exposure. Nontender lymphadenopathy may ensue producing a clinical picture of a lymphocutaneous complex analogous to the Ghon complex seen in the pulmonary infection (Fig. 1). Early biopsy shows a neutrophilic infiltrate that evolves to produce a necrotizing tuberculous granuloma

Cutaneous tuberculosis

Fig. 1

175

Primary cutaneous tuberculosis with lymphadenopathy.

with multiple acid-fast bacilli present. Typically, the diagnosis is easily established based on the history, clinical picture, histology, and microbiologic findings. Lesions may resolve spontaneously or progress into a lupus vulgarislike picture. Rarely, primary-inoculation TB will lead to disseminated disease. Differential diagnosis includes any etiology with sporotricoid patterns, for example, sporotrichosis, cat scratch disease, and tularemia. The tuberculin or PPD standard test is usually negative at the beginning of the course although, later, may become positive.

Scrofuloderma Scrofuloderma is the most common form of cutaneous TB seen in many developing countries4,7 and in some European series.3 It is caused by the continuous propagation of infection from an underlying structure, most commonly lymph node or bone. Children, young adults, and elderly patients are usually affected. An abscess will form by continuity or fistula formation from an underlying nidus

Fig. 2

Scrofuloderma.

Fig. 3

Scrofuloderma.

with subsequent induration of surrounding areas resulting in an ulcer surrounded by keloid tissue (Figs. 2-4). The most commonly affected areas are the neck, axillae, chest wall, and groin. The patient may have active pulmonary or pleural disease with systemic symptoms. Histology shows tuberculous granulomata surrounding areas of wedge-shaped necrosis. Acid-fast bacilli are readily seen on biopsy material or on direct examination of the secretions. The PPD is strongly positive. The differential diagnosis includes actynomicosis, granuloma inguinale, lymphogranuloma venerum, and hydradenitis supurativa.

Tuberculosis periorificialis Periorificial TB is also produced by propagation of disease from an active focus from deep tissue. This form of cutaneous TB is rare and usually affects middle-aged men. In the case of oral TB (Fig. 5) it is usually secondary to active TB, affecting the upper airway or the

Fig. 4 This lesion on the chest represents scrofuloderma from mediastinal disease.

176

F.G. Bravo, E. Gotuzzo underlying tissue (Fig. 6). They are a product of metastatic, hematogenous spread of mycobacteria that remain latent until, for whatever reason (eg, lack of an effective immune system or malnutrition) the infection manifests itself. Histology shows suppurative granulomata with nonspecific infiltrates. Direct examination of the pus will usually demonstrate the presence of the mycobacteria. The tuberculin test is usually positive but may be negative if associated with poor general condition of the patient.

Paucibacillary forms Tuberculosis verrucosa cutis Fig. 5

Oral secondary TB as expression of periorificial disease.

lungs. Conversely, perineal TB is normally secondary to intestinal or genitourinary disease. The most common lesion is a painful ulcer with a pseudomembranous fibrinous base. Occasionally, instead of an ulcer, a plaque reminiscent of lupus vulgaris or hypertrophic tissue as in TVC may be seen. The lesions can be located anywhere in the buccal mucosa, around the anus, the vulva, or the penis. The histology demonstrates tuberculous granulomata and the presence of multiple acid-fast bacilli. Cultures are usually positive even with a negative tuberculin (PPD) response. Any anal lesion must be differentiated from malignancy. Painful anal ulcerations may also be seen in cutaneous amoebiasis due to Entamoeba histolytica and in anal paracoccidiomycosis. Oral paracoccidiomycosis is also painful, unlike other infections such as mucocutaneous leishmaniasis (Espundia) and rhinoscleroma that are typically nonpainful.

Acute miliary tuberculosis

Tuberculosis verrucosa cutis is characterized by the presence of a solitary, verrucose plaque, usually on an extremity such as the hand or the foot (Fig. 7). It is usually painless and occurs as a consequence of reexposure (reinoculation) to the mycobacterium in an individual with previous exposure. It affects adults and children. In children, lesions are usually seen on the feet. It has been reported as a common form of presentation in Asia, although a recent series from Japan showed a decreasing prevalence.5 The so-called prosecutor wart of Laennec is a typical example. Lesions have also been described in other anatomical sites such as the face and around the anus but always with the same verrucose appearance. An identical appearance is seen among ranchers and cattle workers, although in these, cases the species involved is most commonly M bovis. The PPD test is strongly positive. The biopsy demonstrates pseudocarcinomatous hyperplasia with poorly defined noncaseating, tuberculous granulomata. The visualization of the mycobacterium and/or their isolation from culture is the exception rather than the rule. Lesions tend to be chronic but remain sensitive to specific anti-TB treatment, which itself can act as a diagnostic tool.11

Acute miliary TB variant is usually seen in the context of advanced pulmonary or disseminated TB, usually seen in children and adolescents. The trunk is the most common location. The macroscopic appearance of the cutaneous lesion is of small erythematous macules or papules that become necrotic. Histology will demonstrate necrotizing tuberculous granuloma with multiple acid-fast bacilli. The diagnosis is not difficult if one takes into account the whole clinical picture, although the tuberculin (PPD) test may be negative. It is interesting to make a morphological analogy between this form of disease and papulonecrotic tuberculid, where the latter may be considered to represent the paucibacillary pole of the clinical spectrum.

Gumma Gummas are cold abscesses that will develop at extremities or on the trunk of patients with no involvement of

Fig. 6

Gumma.

Cutaneous tuberculosis

177 The macroscopic appearance is the most characteristic: a slowly enlarging plaque with a slightly elevated verrucose border and central atrophy. The plaque is the result of an enlarging papule representing multiple coalescent micropapules known as blupomes.Q The consistency is soft, and the color is reddish brown, having a classic bapple jellyQ appearance of on diascopy. Lupus vulgaris of the face produces scarring and facial deformity. Lesions may ulcerate at the center and cause exophytic growth, especially on the nose. Lesions affecting the earlobe may have a pseudotumoral appearance. Multiple lesions may appear simultaneously after a temporal inmunosuppression, as described in postexanthematous forms, such as after measles. The histology will show multiple noncaseating granulomas with sparce or absent acid-fast bacilli. Mycobacterial culture is frequently negative. PPD testing, however, should be positive.

Tuberculids

Fig. 7

Tuberculosis verrucosa cutis.

The differential diagnosis should include verrucose forms of leishmaniasis, chromoblastomycosis, sporotrichosis, lobomycosis, and mycobacterial infection other than TB, for example, M marinum. Hypertrophic lichen planus, rupioid psoriasis, and squamous cell carcinoma should also be considered in the differential.

Tuberculids are found in the paucibacillary pole of the cutaneous TB spectrum. They include papulonecrotic tuberculid, erythema induratum of Bazin (EIB), and lichen scrofulosorum. They were once regarded as a purely autoimmune systemic reaction to the presence of mycobacteria in the host with an acquired immunity against TB. There is increasing evidence, however, of the presence of bacilli in the lesions themselves as demonstrated by polymerase chain reaction techniques in EIB and in papulonecrotic tuberculid. Papulonecrotic tuberculid

Lupus vulgaris This is the most common form of cutaneous TB in India, Pakistan, and Tunisia7-10 and used to be the predominant form seen in Europe. Females seem to be more commonly affected. Lesions due to hematogenous spread are found on the face (Fig. 8). Those located on extremities usually occur by reinnoculation, as in TVC (Fig. 9).

Fig. 8

Lupus vulgaris on the face.

Papular necrotic tuberculid can be considered to represent the paucibacillary pole of blood-borne disseminated TB, as opposed to the multibacillary picture of acute miliary TB. The elementary lesion consists of multiple symmetric papules, 1 to 5 mm in diameter, with an umbilicated, necrotic center. The lesions are usually found on the extensor areas of extremities but may occur on the lower abdomen, trunk,

Fig. 9 Lupus vulgaris on the hand (most likely result of a reinoculation).

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Fig. 11 Fig. 10

Tuberculous mastitis.

Erythema induratum of Bazin.

buttocks and earlobes, eventually forming variceliform scars. They are most often seen in young adults and children with active tuberculous disease elsewhere. In children, phlyctenular conjunctivitis seems to be an associated finding.12 Tissue biopsy reveals a palisading granuloma with intradermal coagulative necrosis and adjacent follicular necrosis. The lesions of papulonecrotic tuberculid may coexist with those of erythema induratum of Bazin.13 Bacilli are absent, but the PPD should be positive. Polymerase chain reaction techniques have demonstrated the presence of mycobacteria within the lesions.14 Erythema induratum of Bazin Erythema induratum of Bazin is the most commonly reported form of tuberculid nowadays.3-5,15 It represents a TB-associated panniculitis. The classic clinical picture is of ulcerated nodules on the posterior aspects of the legs (Fig. 10). Typically, the patient is female. Patients illicit a strongly positive PPD test. Associated active pulmonary disease is frequently present. The classic histology should have 3 of 4 of the following elements: a septal panniculitis, necrosis of fat tissue, vasculitis (either small or large vessel involvement),16 and granuloma formation. Acid-fast bacilli are seldom found, even on culture, but mycobacterial DNA has been demonstrated within lesions using polymerase chain reaction methods.16 The same histologic characteristics may occasionally be seen in erythema nodosum occurring on the anterior aspect of the shins. This overlap of EIB and erythema nodosum in the context of TB is well recognized. The main differential diagnosis for EIB is the so-called nodular vasculitis, a disease most likely related to venous insufficiency. The similarities between nodular vasculitis and EIB include clinical and histologic findings. A distinction can usually be made, however, based on a previous history of (or contact with) TB, a positive PPD reaction, an elevated erythrocyte sedimentation rate (ESR), and abnormal chest

X ray.17 Thus, in an area of high TB endemicity, EIB will be much more likely than nodular vasculitis. Lichen scrofulosorum A prospective study of patients with cutaneous TB in India in 2005 found that as many as 7% had lichen scrofulosorum.18 This disease usually presents as an eruption of multiple miniature follicular or parafolicullar lichenoid papules.18-21 These are commonly arranged in clusters and almost always affect the trunk. The disease occurs mostly in children, with 80% of patients younger than 16 years. It is usually associated with TB of the lung, bone, or lymph nodes, although up to 30% of patients may have no obvious focus of TB.

Fig. 12 This acneiform lesion in a child showed tuberculoid granulomas and acid fast bacilli, becoming a real Lupus Miliaris on the face.

Cutaneous tuberculosis Patients demonstrate a strong positive reaction to PPD, often measuring 18 mm or larger. A history of BCG vaccination is found in up to 70% of patients. The histopathology shows a superficial perifolicular epithelioid granuloma with occasional giant cells. Tubercle bacilli are seldom found in the lesions. The differential diagnosis may include lichen spinulosus, lichen nitidus, keratosis pilaris, pityriasis rubra pilaris, and lichenoid sarcoidosis. Lichen scrofulosorum has been recently described after BCG vaccination and M avium infections.18 The lesions will start to regress after 4 weeks of therapy, although they may take up to a year to disappear completely. Granulomatous mastitis and lupus miliaris disseminatus faciei: true or false tuberculids? Occasionally, in our practice, we have encountered cases of the so-called granulomatous mastitis,22 an entity that many authors do not consider to be related to TB at all. The clinical picture is mostly of unilateral, ulcerated plaques or nodules on the breast (Fig. 11) of a female patient with a positive contact history of TB. The lesions usually follow a chronic course and show a poor response to non-TB antibiotic therapies. Many of the women affected may have had multiple biopsies to rule out breast carcinoma. On histology, tuberculoid granulomas with fat necrosis are seen. Despite a strongly positive PPD test, acid-fast bacilli are not found. Lesions, however, respond to specific antituberculous antibiotic therapies. This diagnosis should be considered in areas of high TB prevalence. Although a difficult diagnosis to make, one may consider TB-related granulomatous mastitis as a form of EIB affecting the breast. In other matters, we concur with the general assumption that lupus miliaris diseminatus faciei is most likely a form of rosacea. Even so, papulonecrotic lesions that may lead to varicelliform disfigurement affecting the faces of children and adults are encountered in regions with extremely high levels of TB prevalence.23 (Fig. 12) Skin biopsy shows tuberculoid granulomas with caseating necrosis. Acid-fast bacilli are present, and PPD testing is positive in such cases. Regardless of the name given to such cases (lupus miliaris diseminatus faciei, acnitis or variants of papulonecrotic tuberculides), these conditions should be considered a clinical expression of the paucibacillary pole of cutaneous TB and should alert the dermatologist to keep an open mind in such circumstances.

Diagnosis and therapy A clinical diagnosis is dependant upon a careful evaluation of the clinical presentation. Does the patient fit any of the clinical categories described above? Supporting evidence includes epidemiological data, contact history or previous tuberculous disease, and the result of the tuberculin reaction.

179 A skin biopsy should be performed in all cases and specimens stained and cultured for acid-fast bacilli. Too strict diagnostic microbiological criteria, however, may result in missed diagnosis. If available, polymerase chain reaction testing using the appropriate probe should de carried out. A negative result does not exclude the diagnosis.24,25 A strongly positive PPD reaction of N15 mm in diameter should be considered of diagnostic value.26 In areas of high TB prevalence, a therapeutic trial of antiTB chemotherapy should be considered.27-30

Treatment Because most cases of TB of the skin are related to tuberculous disease of other organs and the bacillary load in the skin is usually less than elsewhere, treatment regimens, such as used to treat pulmonary TB, should be sufficient. This will include schemes of directly observed therapy short course. Standard therapy regimes involving 2 months of quadruple therapy (isoniazid, rifampicin, pyrazinamide, and ethambutol) followed by a further 4 months of isoniazid plus rifampicin) are adopted in most centers. Longer treatment courses are usually indicated only in cases where there is associated extrapulmonary disease involving the central nervous system or bone. A clinical response should by expected by between weeks 4 and 6 of the therapeutic trial,29 with lupus vulgaris showing a faster response than scrofuloderma. Patients with cutaneous TB should be incorporated into any state-funded cutaneous TB program to ensure proper case-contact tracing and better compliance monitoring. Failure to respond to therapy raises the possibility of drug resistance.31 Such cases should be referred to specialists with experience in managing patients with multi–drugresistant TB.

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F.G. Bravo, E. Gotuzzo 20. Thami GP, Kaur S, Kanwar AJ, Mohan H. Lichen scrofulosorum: a rare manifestation of a common disease. Pediatr Dermatol 2002; 19:122 - 6. 21. Torrelo A, Valverde E, Mediero IG, Zambrano A. Lichen scrofulosorum. Pediatr Dermatol 2000;17:373 - 6. 22. Tse GM, Poon CS, Ramachandram K, et al. Granulomatous mastitis: a clinicopathological review of 26 cases. Pathology 2004; 36:254 - 7. 23. Navarrete G. Tubercu´lides de la cara: una expression diferente de la tuberculosis. Gac Med Mex 2003;139:36 - 7. 24. Hsiao PF, Tzen CY, Chen HC, Su HY. Polymerase chain reaction based detection of Mycobacterium tuberculosis in tissues showing granulomatous inflammation without demonstrable acid-fast bacilli. Int J Dermatol 2003;42:281 - 6. 25. Tan SH, Tan BH, Goh CL, et al. Detection of Mycobacterium tuberculosis DNA using polymerase chain reaction in cutaneous tuberculosis and tuberculids. Int J Dermatol 1999;38:122 - 7. 26. Desai AM, Hsu S. Medical pearl: interpretation of tuberculin skin tests in patients who have received the BCG vaccine. J Am Acad Dermatol 2005;53:868 - 9. 27. Akoglu G, Karaduman A, Boztepe G, et al. A case of lupus vulgaris successfully treated with antituberculous therapy despite negative PCR and culture. Dermatology 2005;211:290 - 2. 28. Lipsker D, Grosshans E. What is lupus vulgaris in 2005? Dermatology 2005;211:189 - 90. 29. Ramam M, Mittal R, Ramesh V. How soon does cutaneous tuberculosis respond to treatment? Implications for a therapeutic test of diagnosis. Int J Dermatol 2005;44:121 - 4. 30. Sehgal VN, Sardana K, Bajaj P, Bhattacharya SN. Tuberculosis verrucosa cutis: antitubercular therapy, a well-conceived diagnostic criterion. Int J Dermatol 2005;44:230 - 2. 31. Hay RJ. Cutaneous infection with Mycobacterium tuberculosis: how has this altered with the changing epidemiology of tuberculosis? Curr Opin Infect Dis 2005;18:93 - 5.