The clinical, dermoscopic, and histopathologic differentiation of cutaneous leishmaniasis from cutaneous sarcoidosis and tuberculosis: A review article

INTRODUCTION

Leishmaniasis is a vector-borne disease that manifests as a cutaneous, mucosal and visceral disease.^[1] It is caused by Leishmania parasites and transmitted through the bite of sandflies belonging to Phlebotomus spp. and Lutzomyia spp.^[2]

Leishmania are classified into two types, according to the Eurocentric worldview, which is Old World species (Leishmania major, Leishmania tropica, Leishmania donovani, Leishmania infantum, and Leishmania aethiopica) and New World species (Leishmania amazonesis, Leishmania mexicana, Leishmania venezuelensis, Leishmania chagasi, Leishmania naiffi, and Leishmania viannia subgenus including Leishmania braziliensis, Leishmania panamensis, and Leishmania guyanesis).^[1,3]

The majority of countries in the Americas, the Middle East, the Mediterranean basin, and Central Asia are affected by leishmaniasis (approximately 95% of cases).^[1,4] The Old World leishmaniasis occurs in the Eastern Hemisphere, including Asia, the Middle East, Africa, and Southern Europe.^[1] On the other hand, New World leishmaniasis occurs in the Western Hemisphere, especially in Mexico, Central America, South America, and the United States.^[1] Poor hygiene, poverty, migration, malnutrition, poor housing conditions, and immunocompromised status are risk factors for leishmaniasis.^[1,5]

Cutaneous leishmaniasis (CL) can mimic many skin disorders, such as cutaneous sarcoidosis (CS) and cutaneous tuberculosis (CTB), which are considered “great imitators” due to the variety of their clinical presentations.^[5-7] These “great imitators” belong to cutaneous granulomatosis and have common clinical, dermoscopic, and histopathologic features, which make it difficult for physicians to differentiate these diseases from each other and can lead to inappropriate treatment and associated morbidities.^[5,6,8,9]

CLINICAL PRESENTATION

CL, mucosal leishmaniasis (ML), and visceral leishmaniasis (VL) are the three main phenotypic classifications of the disease. Leishmaniasis can present with an array of different clinical manifestations. The spectrum of clinical diseases can be classified to include CL of the Old World, CL of the New World, diffuse CL, disseminated CL, post-kala-azar CL, ML, VL, and leishmaniasis recidivans (LR).^[1]

It is usually typical to diagnose CL in endemic regions by specific clinical features.^[10] Depending on the type and stage of CL, papules, nodules, plaques, or ulcers can be the presenting manifestations.^[10] Acute, subacute, and chronic CL may all be present in some individuals, and it can also be asymptomatic or subclinical.^[1]

CS also has various manifestations ranging from more distinctive lesions (including papules, nodules, plaques, lupus pernio [LP], and infiltrative scars) to less distinctive lesions (including Darier-Roussy disease, scarring and nonscarring alopecia, erythroderma, annular, hypopigmented, angiolupoid, atrophic, ulcerative, psoriasiform, and ichthyosiform lesions).^[6] In addition, the clinical manifestations of CTB are varied and include papules, plaques, macules, patches, nodules, abscesses, erosions, and ulcers that mimic diverse skin disorders.^[7]

THE CLINICAL MANIFESTATIONS AND DIFFERENTIAL DIAGNOSIS OF CL

Typically, CL lesions are classified into two categories, Old World and New World, according to the geographic area.^[1,5] The lesions usually begin at the location of the sandfly bite as a small, single, and non-suppurative papule (typically on well-exposed locations of the face and limbs).^[1,5] However, numerous lesions may also occur.^[1] The papule slowly evolves over weeks or months into a nodule that can develop into a painless ulcer with a piled-up border.^[1,5] Depending on the respective species, these ulcers may spontaneously heal over months or years or can cause disfigurement and scars.^[1,5] It is estimated that progression, chronicity, and more severe clinical presentations occur in up to 10% of CL cases.^[5]

CL and CS have common clinical presentations.^[5] In CS, papules are the most common lesions, which are discrete and typically located on the face, eyelids, and nasolabial folds.^[6] These papular lesions are more frequent in acute sarcoidosis, and they heal without causing scars.^[6] The sarcoid lesions can be red, brownish-red, brown, or violet.^[6] Ulcerations can occur independently of other CS lesions or as a result of the worsening of other forms, such as papulonodular or atrophic lesions.^[6]

Tuberculosis can also resemble CL due to its varied manifestations, including scrofuloderma, tuberculosis verrucosa cutis (TVC), erythema induratum of Bazin, and tuberculosis chancre.^[7,9] Erythema induratum of Bazin manifests as erythematous-purple subcutaneous nodules, typically on the thighs and legs.^[9] The nodules progress a few centimeters, resulting in deep ulcers with caseous discharges and a pigmented scar, whether treatment is successful or not.^[9]

TVC lesions are presented as single and painless lesions that can range in appearance from erythematous papules to verrucous plaques that extend to the peripheral areas. Tuberculous chancre, an exogenous form of tuberculosis, results from direct skin infections caused by mycobacterium tuberculosis, which can occur from tattoos, body piercings, traumatic injuries, and surgical procedures performed with non-sterile materials. The tuberculous chancre present as firm, painless, slow-growing papules or nodules that are reddish-brown. The lesions develop into friable ulcers within 2 to 4 weeks, with a tendency to bleed.^[9] Scrofuloderma is a common form of CTB; caused by direct expansion from an underlying tuberculous focus in lymph nodes, bones, joints, or testicles. The common locations include neck, axillae and groin, with the cervical lymph nodes as a frequent infection source. Initial lesions present as red-brown, firm, painless, and subcutaneous nodules that develop into ulcers. There is a possibility of spontaneous healing, resulting in retractions, keloid scars, and the atrophic sequel.^[9]

DERMOSCOPY

Granulomatous disorders may have common dermoscopic features, but a detailed and accurate evaluation of each feature and its pattern may be helpful in distinguishing between them. The presence of structureless orange or orange-yellowish (focal or diffuse) areas and vessels, which can be linear or branching, represent the dermoscopic findings of granulomatous disorders. However, neither the presence nor the absence of orange to orangish-yellow structureless areas is adequate to confirm the diagnosis. Other dermoscopic findings of granulomatous disorders can be observed, including scaling, erythema, milia-like cysts, whitish areas, follicular plugs, and pigmentation structures.^[13]

HISTOPATHOLOGY

Histopathologic examination is an essential diagnostic tool that can assist in distinguishing between diseases that are mimickers of CL.^[5] The histopathology of CL shows granulomatous findings similar to those of cutaneous disorders with different etiologies, such as CTB and CS.^[9,20]

THE DIAGNOSTIC APPROACH

Although the diagnosis of CL can be made clinically with direct (microscopy, histopathology, and parasite culture) and/or indirect (serology, molecular, and immunologic tests) confirmations, the diagnosis of leishmaniasis is considered challenging.^[1,5] CL should be suspected based on the patient’s history, epidemiology, clinical symptoms, and physical examination findings.^[1] However, clinical diagnosis is not considered adequate and should always be supported with laboratory testing.^[27]

CS may have diverse presentations and can affect multiple systems.^[23] The diagnosis of CS is typically based on the clinical presentation and histopathologic confirmation of non-caseating granulomas with the support from history, physical examination, laboratory investigations, chest radiography, pulmonary function testing, fundoscopic and ophthalmologic evaluation, and electrocardiography to exclude the systemic involvement.^[6,23] The diagnosis of CS is confirmed only after excluding other suspected diseases.^[23]

It is difficult to distinguish sarcoidosis from tuberculosis, particularly in countries with a high tuberculosis prevalence.^[25,28] Systemic symptoms such as fever, weight loss, malaise, and fatigue can present in both sarcoidosis and tuberculosis.^[28] Therefore, the accurate diagnosis of tuberculosis requires a detailed evaluation of clinical, radiologic, and laboratory findings.^[25,28]

We created a schematic diagram for a stepwise approach for the diagnose CL [Figure 1].^{[1,5,8,20,23,25,26,28]}

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Figure 1:

A schematic diagram in approaching the diagnosis of cutaneous leishmaniasis by excluding cutaneous sarcoidosis and tuberculosis if they are considered differential diagnoses.

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CONCLUSION

CL may be difficult to diagnose because it imitates infectious, malignant, and granulomatous diseases. Among granulomatous diseases, CS and CTB should be differentiated from CL as they have common clinical, histopathologic, and dermoscopic characteristics.

In case the medical history of the patient suggests the diagnosis of CL but the performed diagnostic methods did not detect the parasite and the physical examination is similar to CS and CTB, a systematic diagnostic approach and further work-up should be done to exclude or confirm the diagnosis of the disease. Therefore, clinicians must be familiar with the clinical manifestations of these three diseases and should recognize the common and uncommon dermoscopic and histopathologic features of each. The misdiagnosis of these “the great imitators,” may lead to unfavorable outcomes.