Dermatology

Tuberculosis, Cutaneous

Are You Confident of the Diagnosis?

Cutaneous tuberculosis manifests in several forms. Primary cutaneous tuberculosis occurs in previously unsensitized individuals, and secondary tuberculosis occurs in individuals who are previously sensitized or infected with Mycobacterium tuberculosis.

The forms of cutaneous tuberculosis are summarized in Table I.

Table I.

Clinical forms of cutaneous tuberculosis.
Primary Tuberculosis
Tuberculous chancre
Miliary tuberculosis
Secondary Tuberculosis
Lupus vulgaris
Scrofuloderma
Tuberculosis verrucosa cutis
Tuberculous gumma
Tuberculosis cutis orificialis
Tuberculids
Lichen scrofulosorum
Papulonecrotic tuberculid

Lupus vulgaris and scrofuloderma are the two most common forms of cutaneous tuberculosis.

Lupus vulgaris

Lupus vulgaris is a chronic and progressive form of skin tuberculosis that affects the head and neck area, lower extremities, and gluteal region. Typically, the lesion is a solitary, well-demarcated, erythematous, indurated, and slowly enlarging plaque (Figure 1).

Figure 1.

Lupus vulgaris.

The surface shows epidermal changes in the form of scaling and crusting. Diascopy may demonstrate apple-jelly nodules, which represent the microscopic granulomas. Spontaneous healing occurs, with scarring and atrophy at the center.

The lesions characteristically reappear within the area of atrophy. The morphological variants include hypertrophic or verrucous, ulcerative, and atrophic forms. Fibrosis, contractures, and mutilation of the adjoining structures (such as the nasal cartilage) are the complications of long-standing lesions. Rarely, squamous cell carcinoma may develop in chronic lesions.

Skin biopsy reveals tuberculoid granulomas involving the upper and mid dermis, along with epidermal changes. The granulomas are noncaseating and consist of epitheloid cells, Langhans giant cells, and lymphocytes. Fibrosis may be present in areas of scarring. M.tuberculosis is usually not demonstrated in the smear or culture. The purified protein derivative (PPD) skin test is positive.

The differential diagnosis includes sarcoidosis, cutaneous leishmaniasis, borderline tuberculoid leprosy, chromoblastomycosis, and discoid lupus erythematosus.

Sarcoidosis can usually be differentiated by the lack of epidermal changes, although ulcerative and verrucous forms exist. The plaques are succulent and do not show scarring or mutilation.

In leishmaniasis, the plaques are severely inflammatory, with surrounding edema. Tissue smear may show Leishman-Donovan (LD) bodies. These cytoplasmic inclusion bodies represent amastigotes. Chronic lymphoplasmocytic infiltrate is seen in histology, in addition to the organisms themselves, especially with the aid of a Giemsa stain.

The lesions of chromoblastomycosis are verrucous papulonodules with marked psoriasiform epidermal changes. The lesions are usually located on the acral extremities. The bedside potassium hydroxide (KOH) test will demonstrate the typical sclerotic cells.

Discoid lupus erythematosus lesions are scarring plaques with follicular plugging, central depigmentation, and peripheral hyperpigmentation. The lesions are located on sun-exposed sites, including the ears.

Scrofuloderma

The lesion in scrofuloderma is unilateral, and is the result of direct invasion of M tuberculosis into the skin from an underlying tuberculous focus, which could be in the lymph nodes, bone/joints, and testes. The common sites are neck, axillae, and groin.

The cutaneous lesion in scrofuloderma is a discharging (thin serosanguinous) sinus/ulcer attached to the underlying structure. The ulcers are undermined and shallow, with bluish margins (Figure 2). Spontaneous resolution is possible, with characteristic puckered scars.

Figure 2.

Scrofuloderma.

Tuberculin skin test is strongly positive. Skin biopsy from the active margin shows tuberculoid granuloma with necrosis. The tubercle bacilli is demonstrable in both the smear and culture.

Scrofuloderma has to be differentiated from actinomycosis if it involves the neck or inguinal region. Actinomycosis can be differentiated from scrofuloderma by the presence of large indurated plaque or nodule, with multiple sinuses that discharge pus or sulfur granules. The Gram stain of these granules will demonstrate numerous bacterial filaments.

Scrofuloderma can mimic hidradenitis suppurativa, which is characterized by recurrent episodes of multiple deep-seated nodules and abscess formation, with intercommunicating sinus tracts, in the axillae or groin. In the later stage, there will be large bands of scars with bridging fibrosis.

Tuberculosis verrucosa cutis

Tuberculosis verrucosa cutis occurs on the acral extremities as a large hyperkeratotic verrucous indurated plaque. Sometimes, the verrucous plagues can involve the entire sole or foot (Figure 3). The surface may show fissures with pus discharge. Perilesional erythema is often seen.

Figure 3.

Tuberculosis verrucosa cutis.

Skin biopsy from the deep keratotic areas will reveal marked epidermal hyperplasia and noncaseating epitheloid cell granulomas with lymphocytes and plasma cells in the upper and mid dermis. Neutrophilic microabscess may be seen in the epidermis. Tuberculin skin test is strongly positive. The organisms are are not demonstrated or grown in the culture.

The differential diagnosis includes common warts, which present as hyperkeratotic verrucous papules or nodules on the dorsal surfaces of the hands, fingers, elbows, or knees. Paring of the lesion with a scalpel blade will demonstrate fine bleeding points, which is the hallmark of warts.

Tuberculous gumma or metastatic abscess

Tuberculous gumma or metastatic abscesses are cold abscesses that result from hematogenous spread of M tuberculosis. They present as multiple soft dermal or subcutaneous swellings that break down to produce necrotic ulcers. Clinically, the lesions resemble scrofuloderma, and hence, the term scrofulous gumma is often used (Figure 4, Figure 5). The tuberculin skin test is weakly positive. Skin biopsy shows suppurative granulomas with copious numbers of organisms.

Figure 4.

Scrofulous gumma.

Figure 5.

Tuberculous gumma (cold abscess).

Tuberculosis Cutis Orificialis

The typical tuberculosis cutis orificialis lesion is a painful shallow granulomatous ulcer, in and around the mucosal orifices, usually in perianal or perioral locations. It is seen in seriously ill patients with chest or abdominal tuberculosis, and is caused by autoinoculation.

Acute Miliary Tuberculosis

The skin lesions of acute miliary tuberculosis are nonspecific, and consist of erythematous papules, vesicles, or pustules. They are caused by the hematogenous spread of the organism. The involvement of the internal organs is widespread, and the constitutional symptoms are severe. The patients are severely ill. The tuberculin skin test is negative. Histology shows tuberculous granuloma with numerous microabscesses and organisms.

Tuberculous chancre

Tuberculous chancre is very rare, and occurs at the site of inoculation of the organisms in previously unsensitized individuals. The lesion starts as an asymptomatic papule at the site of injury, which later ulcerates. The ulcer mimics scrofuloderma, with shallow ulcers and undermined bluish margins. The ulcer may heal spontaneously or progress to develop lupus vulgaris. Regional lymphadenopathy develops 4 to 8 weeks after the infection.

Early skin biopsy reveals a neutrophilic infiltrate with numerous organisms. Later, typical necrotizing tuberculous granuloma is seen. The tuberculin skin test is usually negative in the early stage and becomes positive later.

Tuberculids

Tuberculids are skin lesions that occur as a result of delayed hypersensitivity reactions to M tuberculosis. The criteria for the diagnosis include strongly positive tuberculin skin test, absence of M tuberculosis in the smear and negative culture, typical tuberculoid histopathology in lesional skin biopsy, and resolution of skin lesions with antituberculous therapy.

Lichen scrofulosorum

Lichen scrofulosorum lesions consist of asymptomatic, skin-colored or lichenoid, follicular and parafollicular papules. The lesions are usually arranged in clusters on the trunk. Crops of lesions recur at variable intervals. The disease is commonly seen in children and young adults.

An underlying tuberculous focus is seen in 87% of the cases. Most commonly, the focus is seen in lymph nodes, followed by bones and lungs. It may also occur in association with other forms of cutaneous tuberculosis. Histology shows epitheloid cell granulomas around the hair follicles.

Lichen scrofulosorum may resemble other follicular disorders such as keratosis pilaris, lichen nitidus, lichen spinulosus, and pityriasis rubra pilaris.

Papulonecrotic tuberculid

Typically, papulonecrotic tuberculid lesions are symmetrical papules on the extensor aspect of the extremities and gluteal region. Individual lesions are necrotic and covered with crusts. Removal of the crusts will reveal a deep ulcer. Recurrence is common and the older lesions may heal with scars. The glans penis may sometimes be the only site of involvement. Histology reveals wedge-shaped necrosis of the epidermis, along with epitheloid cell granulomas in the upper dermis.

Who is at Risk for Developing this Disease?

Cutaneous tuberculosis accounts for about 1.5% of extrapulmonary tuberculosis cases. The prevalence of cutaneous tuberculosis varies, depending on the geographical region. Overall, the global incidence of cutaneous tuberculosis has declined considerably; however, it remains a major health problem in developing countries in Asia.

The occurrence of cutaneous tuberculosis has no significant male or female preponderance; however, scrofuoderma and lupus vulgaris tend to occur more commonly in women than in men, whereas tuberculosis verrucosa cutis is often seen in men.

Scrofuloderma and lupus vulgaris are the two most common forms of skin tuberculosis. In recent reports from Asia, tuberculids (lichen scrofulosorum) are the second most common form of cutaneous tuberculosis. Scrofuloderma is the most common form of cutaneous tuberculosis in children, while lupus vulgaris is the most frequent form in adults. Generalized miliary tuberculosis is seen in infants with immunosuppression.

The risk factors for development of skin tuberculosis are poor living conditions, overcrowding, malnutrition, poverty, illiteracy, and human immunodeficiency virus (HIV) infection.

What is the Cause of the Disease?

Etiology

Cutaneous tuberculosis is caused by Mycobacterium tuberculosis, and rarely, by M bovis.

Pathophysiology

The clinical manifestations of cutaneous tuberculosis primarily depend on the mode of infection, previous sensitization, and the immune status of the host. The mode of infection may be exogenous, autoinoculation, or endogenous.

Exogenous inoculation of M tuberculosis following minor wounds and injury leads to the development of tuberculous chancre or tuberculosis verrucosa cutis. Endogenous spread may occur in three ways:

  1. 1. By contiguous extension of the tuberculous process (e.g. scrofuloderma from an underlying lymph node or bone tuberculosis)

  2. 2. Via lymphatic vessels, as in lupus vulgaris

  3. 3. By hematogenous dissemination in cases of acute miliary tuberculosis, tuberculous gumma, and lupus vulgaris.

Systemic Implications and Complications

Patients with any form of cutaneous tuberculosis should be screened for associated systemic tuberculosis, which is more often seen in children.

Tuberculous lymphadenitis is the most common association, followed by pulmonary, bone, and abdominal tuberculosis. The work-up includes Mantoux tuberculin skin test, Quantiferon TB gold test (QFT G), chest screening (x-ray or computed tomography [CT] scan), abdominal ultrasound or CT scan, and bone scintigraphy. The other appropriate screening tests (including urine culture for acid-fast bacillus, cerebrospinal fluid analysis, CT/magnetic resonance imaging of the brain) should be done, depending on the clinical presentation.

The Mantoux tuberculin skin test is a good screening tool to detect the mycobacterial infection. It is performed by intradermal injection of five tuberculin units, which equals 0.0001mg of purified protein derivative (PPD) of M tuberculosis. The injection should be placed on the flexor side of the forearm, about 2-4 inches below the elbow, The patient must be educated to return within 48 to 72 hours for reading. Only the induration, which can be felt, should be measured and recorded. Induration of 10mm or more is considered significant, and indicates infection, but not necessarily disease.

QFT G quantifies the release of interferon gamma by blood monocytes on stimulation by highly specific M tuberculosis antigens (the early secretory antigen target 6 (ESAT- 6), culture filtrate protein 10, and TB 7.7). For the test, 5mL of whole blood is drawn directly into a Vacutainer tube, which is precoated with the antigens. These antigenic proteins are absent from most of the nontuberculous mycobacteria and bacillus Calmette-Guerin.

The sensitivity of QFT G is similar to the Mantoux test. Centers for Disease Control and Prevention recommend that QFT G be used in all circumstances in which the Mantoux test is recommended, which includes patient contact investigation, evaluation of recent immigrants, and surveillance programs.

Treatment Options

Treatment options are summarized in Table II.

Table II.

Treatment options for cutaneous tuberculosis.
First-line antituberculous drugs Dosage/day
Isoniazid (H) 3-5mg/kg
Rifampicin (R) 10-20mg/kg
Ethambutol (E) 15-20mg/kg
Pyrazinamide (Z) 20-30mg/kg
Second-line antituberculous drugs Dosage/day
Streptomycin 12-1mg/kg (1g/day)
Kanamycin 15-30mg/kg
Amikacin 15mg/kg
Capreomycin 15-30mg/kg
Ciprofloxacin 500-1000mg/day
Ofloxacin 400mg/day
Levofloxacin 500mg/day
Gatifloxacin 400mg/day

Optimal Therapeutic Approach for this Disease

The diagnosis is based on the typical clinical appearance. Mantoux tuberculin skin test, QFT G test, chest x-ray, hemogram, serum biochemistry, and skin biopsy for histology and culture are usually recommended.

The Mantoux test is of low Centers for Disease in immunosuppressed individuals, and also in the diagnosis of doubtful cases of cutaneous tuberculosis.

The utility of polymerase chain reaction (PCR) is controversial, and hence the treatment decision should not be based primarily on the PCR results. HIV testing is also recommended because patients with HIV may require a longer period of antitubercular therapy.

Other tests include lymph node biopsy/fine needle aspiration cytology and organ-specific radiologic imaging, depending on the clinical circumstances, to document the tuberculous infection elsewhere.

Once the diagnosis is established by clinical and laboratory testing, the patient should be prescribed antitubercular therapy (ATT). The standard regimen for cutaneous tuberculosis consists of an initial 2 months of intensive phase therapy with four drugs (ethambutol, rifampicin, isoniazid, and pyrazinamide [EHRZ]), followed by 4 months of maintenance therapy with two drugs (isoniazid and rifampicin [HR]). Prophylactic pyridoxine (10-25mg/day) should be added to the regimen, to prevent isonicotinic acid hydrazide (INH) related neuropathy.

Patients with an underlying systemic involvement, especially bone and central nervous system tuberculosis, and extensive skin involvement may need a longer period of antitubercular therapy. The World Health Organization has implemented Directly Observed Treatment Shortcourse (DOTS). The whole course of treatment is given under the direct supervision of assigned medical personnel. According to DOTS guidelines, the patient is treated with EHRZ thrice weekly for 2 months, followed by HR daily for 4 months.

The treatment response is usually observed within 5 weeks of starting ATT. Patients who have not responded by this time are very unlikely to do so with further treatment and their diagnosis should be reviewed.

For patients with HIV/TB coinfection, start ATT first, followed by antiretroviral therapy (ART) within the first 8 weeks. Efavirenz (EFV) is the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI) in patients needing ART while on ATT. For those who are unable to tolerate EFV, a triple NNRTI is an alternative option.

Second-line drugs are reserved for multidrug-resistant tuberculosis. Factors predisposing to resistant tuberculosis include inadequate dosage, irregular therapy, poor compliance, poverty, associated HIV infection, and use of fewer drugs. Resistant tuberculosis is treated for a period of 18-24 months.

Patient Management

The patient and the family should be educated about the disease process and the need for taking regular treatment to promote drug compliance. Dosing schedule and timing of drug ingestion should be explained.

The family should be educated about the drug toxicity. The minor problems are nausea, loss of appetite, and red urine. The major problems are hepatitis, peripheral neuropathy, and ocular problems, especially with ethambutol.

To monitor patients, blood counts, urine analysis, and serum biochemistry should be done, preferably every month. In the case of altered liver function tests (elevation of liver enzymes three times that of normal), ATT should be stopped. Once the liver function becomes normal, restart ATT one by one.

Unusual Clinical Scenarios to Consider in Patient Management

  1. 1. Multifocal cutaneous tuberculosis: occurrence of scrofuloderma or lupus vulgaris in multiple and bilateral locations

  2. 2. Symmetrical occurence of lupus vulgaris on both knees, ankles, and gluteal region

  3. 3. Development of lupus vulgaris in the vicinity of scrofuloderma

  4. 4. Orofacial tuberculosis: involvement of lips, oral mucosa, tongue, and nasal cavity

  5. 5. Sporotrichoid pattern: occurence of cutaneous tuberculosis in a linear distribution due to lymphatic spread.

    Scrofuloderma, lupus vulgaris, and tuberculosis verrucosa cutis can occur in this sporotrichoid pattern. This has to be differentiated from sporotrichosis, in which lesions also occur in a linear distribution. It is usually featured by cord-like thickening of lymphatics in between the lesions. Regional lymphadenopathy is not present in sporotrichosis.

  6. 6. Tuberculous dactylitis: granulomatous swelling of the fingers, which is associated with an underlying bony tuberculosis.

All these unusual forms have been reported from Asia.

What is the Evidence?

Umapathy, KC, Begum, R, Ravichandran, G, Rahman, F, Paramasivan, CN, Ramanathan, VD. "Comprehensive findings on clinical, bacteriological, histopathological and therapeutic aspects of cutaneous tuberculosis". Trop Med Int Health. vol. 11. 2006. pp. 1521-28.

(The authors have studied the clinical, histological, bacteriological, and therapeutic aspects of cutaneous tuberculosis in 213 patients in Chennai, India. Among the 160 males, 77 (48%) had lupus vulgaris (LV), 68 (43%) had tuberculosis verrucosa cutis (TBVC), 15 (9%) had scrofuloderma (SFD). Among the 53 females, 33 (62%) had LV, 10 (19%) each had TBVC and SFD. Culture was positive in 112 (55%) cases. The positivity was similar for all three major forms of tuberculosis: 60 of 106 (57%) for LV, 40 of 73 (55%) for TBVC, and 12 of 24 (50%) for SFD.Ninety-six patients (87%) were susceptible to streptomycin, INH, and rifampicin. Fourteen (13%) showed resistance to one or more of the ATT medications. Nontuberculous mycobacteria were isolated in twenty patients. One hundred seventy-five patients (86%) had histopathology suggestive of tuberculosis; 108 (82%) of LV, 72 (90%) of TBVC, and 22 (95%) of SFD. The lesions resolved clinically within 3 months in 101 patients (47%), and by 6 months in an additional 95 patients.)

Ramesh, V, Misra, RS, Beena, KR, Mukherjee, A. "A study of cutaneous tuberculosis in children". Pediatr Dermatol. vol. 16. 1999. pp. 264-9.

(The authors have described their 7-year experience with pediatric skin tuberculosis. Of 199 skin tuberculosis patients, 63 were children. Forty had LV and twenty-three had SFD. M tuberculosis was isolated in four children (SFD-3: LV-1). All of them had histologic features suggestiuve of tuberculosis. Eight children had systemic involvement.)

Sethuraman, G, Kaur, J, Nag, HL, Khaitan, BK, Sharma, VK, Singh, MK. "Symmetrical scrofuloderma with tuberculosis verrucosa cutis". Clin Exp Dermatol. vol. 31. 2006. pp. 475-7.

(Many unusual forms of cutaneous tuberculosis have been reported. A 13-year-old child had a rare presentation of bilateral symmetrical scrofuloderma from an underlying bony focus on both ankles, along with tuberculosis verrucosa cutis.)

Kumar, U, Sethuraman, G, Verma, P, Das, P, Sharma, VK. "Psoriasiform type of lichen scrofulosorum: a clue to disseminated tuberculosis". Pediatr Dermatol. 2010.

(Lichen scrofulosorum is a tuberculid, characterized by erythematous to lichenoid follicular or parafollicular papules on the trunk and proximal extremities. The authors have reported a rare presentation of psoriasiform lichen scrofulosorum. A 16-year-old female child had extensive papulo-plaques with pustules on the trunk and extremities. She was admitted with a diagnosis of psoriasis and atypical pityriasis rubra pilaris. Skin biopsy showed perifollicular granulomas suggestive of lichen scrofulosorum. The child was found to have disseminated tuberculous focus in the lungs, liver, and several groups of lymph nodes. This kind of severe inflammatory and psoriasiform lichen scrofulosorum is extremely rare and it may be associated with disseminated tuberculosis.)
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