Cutaneous leishmaniasis mimicking inflammatory and neoplastic processes: a clinical, histopathological and molecular study of 57 cases

Background: Cutaneous leishmaniasis displays considerable variation in its histopathological and clinical presentation. Clinically, it progresses from a papule into a painless ulcerated and crusted nodule/papule. Microscopically, it progresses from sheets of amastigote‐filled histiocytes to granulomatous inflammation. Methods: The study was conducted on 145 skin biopsies from untreated patients with histopathological and/or clinical suspicion of cutaneous leishmaniasis in Lebanon, Syria and Saudi Arabia (1992–2010). The pre‐biopsy clinical diagnosis and demographic data were collected. Biopsies were evaluated for the major microscopic pattern, and the parasitic index (PI) was also determined. Diagnosis was confirmed by polymerase chain reaction (PCR) followed by molecular sub‐speciation. Results: Of the 145 patients, 125 were confirmed as cutaneous leishmaniasis by PCR. Eighteen cases presented with a pre‐biopsy clinical diagnosis other than cutaneous leishmaniasis that ranged from dermatitis to neoplasm. Of the 125 cases, 57 showed a major histopathological pattern other than cutaneous leishmaniasis. Identification of amastigotes was equivocal (PI ≤1) in 38 of the 57 cases. Of interest, all the 18 cases with a pre‐biopsy clinical diagnosis other than cutaneous leishmaniasis also showed atypical histopathology for cutaneous leishmaniasis. Conclusions: The manifestations of cutaneous leishmaniasis are broad and may mimic other inflammatory and neoplastic diseases. Pathologists and dermatologists should be aware of such pitfalls and can utilize PCR to confirm the diagnosis of leishmaniasis. Saab J, Fedda F, Khattab R, Yahya L, Loya A, Satti M, A‐G Kibbi, Houreih MA, Raslan W, El‐Sabban M, Khalifeh I. Cutaneous leishmaniasis mimicking inflammatory and neoplastic processes: a clinical, histopathological and molecular study of 57 cases.     

Leishmaniasis

Leishmaniasis is a clinically heterogeneous group of diseases, caused by infection with protozoa of the genus Leishmania. The aggressiveness of the individual species, their organ preference and the host immune status determine disease course. This can range from a solitary, spontaneous healing ulcer (cutaneous leishmaniasis), to often destructive mucocutaneous disease to generalized involvement with visceral leishmaniasis which may be lethal if not treated. The protozoa are transmitted by small (2–4 mm) phle‐botomine sand flies. Protection with non‐impregnated mosquito nets is almost impossible. An estimated 12 million people are affected; 60,000 die annually. Every non‐healing ulcer associated with travel to between the 40th parallels should be suspected as possible leishmaniasis. The diagnostic approach should be standardized; one should attempt to directly demonstrate the organism in the edge of the ulcer and then subspeciate it. Both are basis requirements for initiating appropriate therapy. Pentavalent antimony preparations, amphotericin B and miltefosine are licensed in Germany. A number of other off‐label approaches are also commonly employed. Insect repellents, eradication of vectors and control of the animal reservoir are useful to prevent infection.     

Sporotrichoid cutaneous leishmaniasis in Tunisia: a clinical and histological study

BACKGROUND: The sporotrichoid variety of cutaneous leishmaniasis is defined by the presence of dermal and hypodermal nodules along the lymphatic stream, and remote from the primary inoculation lesions. This clinical form is usually considered rare. The aim of our study was to investigate the epidemiological, clinical, histological and evolutionary particularities of sporotrichoid cutaneous leishmaniasis in the south of Tunisia. PATIENTS AND METHODS: During a systematic study of all cases of cutaneous leishmaniasis from the south of Tunisia diagnosed in our hospital in 2002, sporotrichoid forms were diagnosed on the basis of clinical criteria. In all cases of sporotrichoid cutaneous leishmaniasis, the principal clinical characters were systematically specified. Cutaneous biopsies of subcutaneous nodules were performed in six cases. RESULTS: Of 102 patients with cutaneous leishmaniasis, 19 presented sporotrichoid cutaneous leishmaniasis, that is, a frequency of 19%. Between two and 20 painless subcutaneous nodules were arranged in linear strings on the upper leg in 79% of cases. Time to appearance varied between 12 days and one year after the primary lesions. Fourteen appeared without any preliminary treatment for cutaneous leishmaniasis and five appeared after Glucantime infiltration in the primary lesions. Biopsies of the nodules showed an inflammatory infiltrate composed of lymphocytes and histiocytes. This infiltrate was particularly dense and rich in plasmocytes at the level of the deep dermis. The biopsies were deep enough to involve the hypoderm in one case and the same type of infiltrate was noted at the level of interlobular septa. A small number amastigotes was seen in one deep biopsy sample. Outcome was favourable in all cases under treatment. CONCLUSION: Sporotrichoid cutaneous leishmaniasis appears to be common in the south of Tunisia, were cutaneous leishmaniasis is dominant because of Leishmania major. It is not associated with a poor prognosis.     

Periungual leishmaniasis

The vast majority of cases of cutaneous leishmaniasis are represented by limb injuries. A female patient, white, presented an ulcer with infiltrated borders located on the fourth finger of the left hand following occupational exposure in an area of native forest. Diagnosis of cutaneous leishmaniasis caused by Leishmania of the subgenus Viannia was confirmed. The patient failed to respond to treatment with antimony, but achieved clinical cure after this was associated with pentoxifylline. The case highlights the rarity of the periungual location of the leishmanial lesion and the difficulties encountered in therapy.     

Clinical aspects of cutaneous leishmaniasis acquired in Texas

Five patients with cutaneous leishmaniasis are described. Four of these patients acquired leishmaniasis in Texas. Four cases represent acute cutaneous leishmaniasis, and one case probably represents chronic cutaneous leishmaniasis. The classification and treatment of cutaneous leishmaniasis are reviewed. One patient in this report was successfully treated with topical antimony cream. Cutaneous leishmaniasis must be considered in the differential diagnosis of nonhealing ulcerated papules and nodules even in patients who do not have a foreign travel history.     

Treatment of cutaneous leishmaniasis with intralesional sodium stibogluconate

Background Cutaneous leishmaniasis is endemic in Israel. Leishmania major is the most prevalent species that cause cutaneous leishmaniasis. Current treatment options are limited and there are few investigations in search of alternative ones. Objective This study aims to assess our experience with intralesional sodium stibogluconate (SSG) in the treatment of cutaneous leishmaniasis. Methods A retrospective evaluation for all adult cases of cutaneous leishmaniasis treated by intralesional and intravenous SSG (Pentostam^®, GlaxoSmithKline) between 2004 and 2006 was performed, for cases referred to a tertiary care university‐affiliated medical centre in Israel. Intralesional SSG was injected at 0.5 mL per lesion (50 mg). Treatment was repeated every 2–3 weeks for a total of 12 weeks. Intravenous SSG was administered at a dose of 20 mg/kg for 10–20 days. Results Thirty‐three cases of cutaneous leishmaniasis were treated with intralesional SSG during the study period. The patients consist of 26 males and 7 females, mostly Israeli military personnel, and there were a total of 93 lesions. Within 3 months from treatment onset, 91% (30/33) had completed healing of the cutaneous lesions after an average of 3 treatments (range 1–6). Side‐effects were mild and were mostly pain during injection, with two patients developing mild local site reaction after the injection. Conclusions Intralesional SSG treatment is safe, effective and well tolerated with minimal side‐effects.     

Erfahrungen mit der kutanen Leishmaniasis

Background

The German S1 guidelines from 2009 contain a variety of recommendations for the treatment of cutaneous leishmaniasis.

Patients and methods

We report the results of our diagnostic procedures and treatment of 32 international patients in autumn 2010 in northern Afghanistan.

Results

Giemsa stain confirmed the clinical diagnosis within 24 hours. Eleven simple lesions and one larger ulcer responded well to cryotherapy and intralesional sodium stibogluconate. More complex lesions in 19 patients responded well to oral miltefosine. One patient refused outpatient therapy.

Conclusions

Cryotherapy and intralesional antimony compounds showed good results in early lesions of cutaneous leishmaniasis in northern Afghanistan. Outpatient treatment of complex lesions with miltefosine was successful in all cases.     

Cutaneous leishmaniasis in Pakistan

Leishmaniasis is a major health problem worldwide. It is also a particular problem in the rural areas of Pakistan. The disease occurs in varying presentations, from the self-limited and even self-healing cutaneous forms to fatal systemic disease. Lesions of cutaneous leishmaniasis may occur anywhere on the body but the most likely sites are the exposed parts. The initial papule rapidly gives rise to an ulcer. Systemic leishmaniasis is rarer in Pakistan and invariably fatal if not treated promptly. It affects the internal body organs, particularly the spleen and the liver. Leishmaniasis is transmitted by an infected female sandfly. Cutaneous lesions are usually single and often self-healing, but a presentation with multiple ulcers resulting from multiple bites from the sandfly is not rare in Pakistan. The disease has a very long history and lesions like leishmaniasis have been described dating back to the ninth century (Balkan sore). Cutaneous leishmaniasis has been given various names in different civilizations such as "Delhi boil" in India, "Baghdad boil" in Iraq, and "saldana" in Afghanistan. The organism responsible for leishmaniasis was discovered 100 years ago but the disease has not been eradicated; rather it is on rise in many parts of the world. If control measures are not taken, it might emerge as a major health problem. Pakistan has a burden of cutaneous and visceral leishmaniasis, the mucocutaneous form being almost nonexistent. The physicians need to know the diagnostic criteria as well as the treatment of the disease. Because of a scarcity of dermatologists in the rural areas, most of these cases present to general practitioners. Control of this disease is further complicated by an inadequate supply of appropriate drugs.     

Comparative study of cutaneous leishmaniasis in human immunodeficiency virus (HIV)-infected patients and non-HIV-infected patients in French Guiana

BACKGROUND: Few data are available on cutaneous leishmaniasis caused by dermotropic species in human immunodeficiency virus (HIV)-infected patients. OBJECTIVES: To describe nine cases of cutaneous leishmaniasis in HIV+ patients and to compare their clinical features and their response to treatment with those of HIV- patients with the forms of leishmaniasis commonly found in French Guiana. METHODS: A case-control study was carried out between July 1994 and December 2000 in French Guiana. We compared the following variables in nine HIV-infected patients with leishmaniasis and 27 matched controls: clinical type of leishmaniasis, number of lesions, presence of lymphangitis and adenopathy, the rate of recovery after treatment, and recurrence or reinfection. RESULTS: Eight of the HIV-infected patients had localized cutaneous leishmaniasis and one had mucocutaneous leishmaniasis. All of the controls had localized cutaneous leishmaniasis. Leishmania guyanensis was the only species isolated from HIV-infected subjects. HIV-Leishmania coinfected patients had a higher rate of recurrence or reinfection (P < 0.02) and a lower rate of recovery after one treatment cycle with pentamidine (P < 0.02) than did HIV- subjects. The CD4+ lymphocyte counts exceeded 200 mm(-3) in all HIV+ patients at the time of the diagnosis with leishmaniasis. CONCLUSIONS: In French Guiana, cutaneous leishmaniasis in moderately immunosuppressed HIV-infected subjects (> 200 CD4+ T cells mm(-3)) is characterized by a higher rate of recurrence or reinfection and is more difficult to treat than that in HIV- subjects.     

Cutaneous leishmaniasis in a child treated with oral fluconazole

We report a case of cutaneous leishmaniasis in a 3‐year‐old West African girl with a 3‐month history of multiple disfiguring, infiltrated, ulcerating and variably necrotic granulomatous plaques on the limbs and face that occurred after swimming in a river approximately 6 weeks before arriving in Australia. A diagnosis of cutaneous leishmaniasis, a protozoal zoonosis usually transmitted by the Phlebotomus species of sandfly, was considered. The clinico‐pathological features were consistent with Leishmania major infection, known to be the major endemic species causing cutaneous leishmaniasis in the country of origin. Because of the presence of lesions on the face, active treatment was instituted. Continuing resolution of all lesions over 6 weeks was noted to occur with cribiform scarring with the use of oral fluconazole 150 mg daily. Oral fluconazole appears to be emerging as a therapy for uncomplicated cutaneous leishmaniasis, with advantages particularly important in paediatrics.     

Can a simple outpatient‐based treatment be used to treat cutaneous leishmaniasis in young children? A Critically Appraised Topic

A 5‐year‐old boy from rural Afghanistan presented with a 1‐year history of a skin lesion on his left knee, confirmed by polymerase chain reaction to be cutaneous leishmaniasis (Leishmania tropica). Conventional treatment of cutaneous leishmaniasis involves intravenous or intralesional pentavalent antimonials. The aim of this Critically Appraised Topic (CAT) is therefore to determine what alternative effective but less painful treatments (such as oral or topical therapies) can be used to treat cutaneous leishmaniasis in children. Embase and PubMed were searched for ‘cutaneous leishmania*’ AND ‘treatment’ AND ‘children’ in August 2014. All abstracts from April 2008 to August 2014 were reviewed. This search period was chosen to follow on from the Cochrane reviews on Old World and American leishmaniasis. Five randomized controlled trials met our inclusion criteria and have been included in this CAT. The study design and reporting quality in most of the trials included in both Cochrane reviews was found to be poor, and neither Cochrane review investigated the effect of patient age on response to treatment. This CAT identified two nonpainful treatments, topical paromomycin and oral miltefosine, whose effective use in children is supported in the literature. However, both of these treatments are currently unlicensed in the U.K. Our patient was successfully treated with miltefosine 20 mg twice daily for 4 weeks, leading to good resolution of the leishmaniasis plaque but with residual scarring.     

A pilot study comparing low‐dose liposomal amphotericin B with N‐methyl glucamine for the treatment of American cutaneous leishmaniasis

Background Cutaneous leishmaniasis is an infectious re‐emerging disease that has increased in incidence worldwide. Antimony, a highly toxic drug, remains the first choice therapy to treat it. Liposomal amphotericin B is active against Leishmania and is less toxic than antimony. Objective To compare low‐dose liposomal amphotericin B with N‐methyl glucamine for the treatment of American cutaneous leishmaniasis. Patients/Methods In a controlled open‐label trial 35 patients with a localized form of American cutaneous leishmaniasis were included. They were allocated to a first group treated with 1.5 mg/kg/day of liposomal amphotericin B for 5 days, or to a second one treated with 20 mgSbV/kg/day of N‐methyl glucamine for 20 days. Results In the first group, 50% and 81% of patients experienced a clinical cure and clinical improvement respectively. There was a 100% clinical cure in the second group. Conclusion Liposomal amphotericin B seems to be promising and safe for the treatment of American cutaneous leishmaniasis.     

Comparison of tuberculosis cutis luposa and cutaneous leishmaniasis

We present a comparative study concerning two cases of tuberculosis cutis luposa and cutaneous leishmaniasis, respectively. These two Turkish female patients had suffered from changes of the facial skin since 20 years (tuberculosis cutis luposa) and for 5 months (cutaneous leishmaniasis). The tuberculosis cutis luposa had been misdiagnosed as cutaneous leishmaniasis and surgically treated. Both cases showed an apple jelly-like color at the edges of the lesions with soft tissue. With tuberculosis cutis luposa, the lesions had a larger extension and a more hyperkeratotic picture. We discuss the different histopathologic changes of both cases. As bacteriologic culture revealed mycobacterium tuberculosis, on one hand, and histopathology leishmania species intrahistiocytically, on the other, we could finally make the corresponding diagnoses.     

Childhood leishmaniasis: report of 106 cases

In Tunisia there are three epidemic clinical forms of cutaneous leishmaniasis. They are associated with three different species of Leishmania and are observed in different geographical areas. We undertook a single-center retrospective analysis of childhood leishmaniasis in order to describe epidemio-clinical profile, therapeutic characteristics and clinical outcomes of affected patients. The study comprises 166 children with 132 lesions of cutaneous leishmaniasis. The subjects ages range from 5 months to 15 years (average 8.75 years). The F:M sex ratio is 1.3. Leishmaniasis affects grown-up children in 74.5 percent of the cases. All of our patients live in an endemic area. The face is affected in 76.5 percent of cases. Mucosal leishmaniasis is present in 9 children (6.8 %). Clinical diagnosis confirmed by the parasitologic smear or histopathological examination in 89.6 percent of the cases. Treatment with intralesional meglumine antimoniate is done for 67 patients; the treatment regimen is one local injection (1 ml/cm(2)) per week until recovery. Systemic meglumine antimoniate is the initial therapy for 25 patients. Meglumine antimoniate treatment is well tolerated with no side-effects. All leishmaniasis lesions heal within an average period of 2.18 months. Childhood cutaneous leishmaniais is common in Tunisia. It has the characteristics of sporadic leishmaniasis. Mucosal leishmaniasis has a favorable outcome with no destruction, nor scaring deformity. The standard treatment remains intralesional meglumine antimoniate.     

Co‐infection of mucosal leishmaniasis and extra pulmonary tuberculosis in a patient with inherent immune deficiency

Background In Sri Lanka, cutaneous leishmaniasis is a well‐established disease caused by Leishmania donovani. Only a few cases of visceral disease and mucosal localization have been reported to date. Case report A 52‐year‐old man presented with severe local destruction of his upper and lower lip and total destruction of the anterior nasal septum and was diagnosed with mucosal leishmaniasis. The causative organism was confirmed to be Leishmania donovani. In addition he had tuberculous lymphadenitis and inherent immune deficiency. His previous medical history was unremarkable. The patient was successfully treated with intramuscular sodium stibogluconate. Conclusion The clinical picture and satisfactory treatment response to antimony are similar to mucosal leishmaniasis caused by L. donovani reported in India and Sudan and with the absence of primary skin lesions make it different from new world mucosal leishmaniasis. Even though leishmania and tuberculous co‐infection has been reported in association with HIV this has not been reported in inherent immune deficiency.     

Cutaneous leishmaniasis as travelers' disease. Clinical presentation, diagnostics and therapy

Leishmaniasis is a disease with worldwide increasing incidence, which in Germany is almost exclusively observed in patients who have travelled to classical endemic regions such as the Mediterranean basin. Cause of the disease is an infection with protozoan parasites of the genus Leishmania, which are transmitted by sand flies and replicate intracellularly within mammalian hosts. Depending on the inoculated parasite (sub-) species and the immune status of the host, a local cutaneous, diffuse cutaneous, mucocutaneous or visceral form of leishmaniasis will develop. Cutaneous leishmaniasis, which frequently appears only weeks after the bite of a sand fly, starts with the formation of a papule, which subsequently can turn into a skin ulcer. The latter may heal spontaneously after months leaving behind a scar or persist as chronic, non-healing cutaneous leishmaniasis. If cutaneous leishmaniasis is suspected, a sterile skin biopsy followed by appropriate diagnostic measures in a specialized laboratory to identify the pathogen should be performed. For the decision on the type of therapy, several clinical parameters (e.g. number and localization of lesions, immune status) and, most importantly, the underlying parasite (sub-) species need to be considered. Therapy can consist of a variety of topical measures or systemic drug treatment. A modern and safe vaccine does not yet exist.     

Unusual clinical variants of cutaneous leishmaniasis in Sicily

Background  The term "leishmaniasis" defines a group of vector-borne diseases caused by species of the genus Leishmania and characterized by a spectrum of clinical manifestations. Parasite properties (infectivity, pathogenicity, virulence), host factors, and host responses regulate heterogeneous disease expression. Sicily is one of the major islands of the Mediterranean Basin and is considered to be a hypo-endemic area for cutaneous leishmaniasis. Leishmania infantum is the most common species on the island.
Methods  Fifty patients (both sexes and different ages) with lesions clinically suggestive of cutaneous leishmaniasis were recorded over a 1-year period. The diagnosis was based on positive slit-skin smear and histopathologic studies when needed. Polymerase chain reaction (PCR) was performed as test confirmation.
Results  Twenty-five patients had typical solitary lesions of cutaneous leishmaniasis. Multiple lesions were present in five patients. In 20 patients, the lesions were very unusual, including erysipeloid, zosteriform, and lupoid leishmaniasis. The results of Leishmania isoenzyme characterization identified Leishmania infantum as the species responsible for the 20 atypical cases.
Conclusion  The global number of cases of cutaneous leishmaniasis in Sicily has increased in recent years, and such increases can be explained, in part, by the fact that, in this region, sandflies are present during a large part of the year. This is a result of the climatic variation in recent years (increasing temperature and humidity). There has also been an increase in the number of new and rare variants of cutaneous leishmaniasis. A knowledge of the unusual clinical variants of cutaneous leishmaniasis, as well as classical forms, allows early detection.     

Molecular diagnosis of cutaneous leishmaniasis and species identification: analysis of 122 biopsies with varied parasite index

Background: Cutaneous leishmaniasis is endemic in the Middle East and North Africa. Confirming the diagnosis histologically depends on amastigote identification, which varies significantly depending on the inoculum, strain type, host response and disease stage. Accurate histological diagnosis is mandatory for appropriate therapy. Methods: Skin biopsies from 122 patients from Lebanon, Syria and Saudi Arabia with clinical diagnosis of untreated leishmaniasis were reviewed and clinical data extracted. Cases were classified according to the modified Ridley's parasitic index. DNA was extracted from formalin‐fixed paraffin‐embedded blocks. Polymerase chain reaction (PCR) was performed using Leishmania‐specific ribosomal internal transcribed spacer 1 (ITS1‐PCR). Nested ITS1‐PCR was performed on cases negative for conventional ITS1‐PCR. ITS1‐PCR amplicons were digested with HaeIII for subsequent restriction fragment length polymorphism (RFLP) subspeciation. Results: Of 122 cases, 54 (44.3%) showed a parasitic index of 0–1+ (no unequivocal amastigotes). ITS1‐PCR (conventional and nested) was positive for all cases as compared with negative control tissue. RFLP identified Leishmania tropica in all cases. Patients with clinically suspected leishmaniasis, whose skin biopsies failed to detect amastigotes represented 44.3% of our cases. Conclusions: In this study, we describe a rapid and optimized protocol from DNA extraction to leishmaniasis subspeciation. ITS1‐PCR showed high sensitivity and specificity in confirming clinically suspected cases. Yehia L, Adib‐Houreih M, Raslan WF, Kibbi A‐G, Loya A, Firooz A, Satti M, El‐Sabban M, Khalifeh I. Molecular diagnosis of cutaneous leishmaniasis and species identification: analysis of 122 biopsies with varied parasite index.     

Außergewöhnliche klinische Manifestationen der kutanen Leishmaniasis

Cutaneous leishmaniasis is one of the most common dermatoses of the tropics. A major focus of this disease is the Syrian city of Aleppo, after which it was named in many textbooks (“Aleppo boil”). The first cases of cutaneous leishmaniasis were reported from Aleppo particularly more than 100 years ago. Syria is one of the most affected countries worldwide. This disease used to be well documented until the onset of the war in Syria in 2012, which is also supported by the numbers of the World Health Organisation (WHO), and Aleppo used to be the most affected Syrian city. Since 2012, the documentation of cutaneous leishmaniasis in Syria is no longer possible. An outbreak of cutaneous leishmaniasis has been detected especially in the besieged regions due to missing prevention measures against the sandflies and a lack of medical care. A short summary of the epidemiologic situation in Syria as well as outstanding and uncommon clinical manifestations of cutaneous leishmaniasis in Aleppo are presented.     

Leishmaniasis

Infections with Leishmania spp. rank among the top three most common travel‐associated dermatoses. Depending on the country where the infection was acquired and the patient's immune status, different disease manifestations may be observed. Ninety percent of cases present as cutaneous leishmaniasis, but the infection may also affect internal organs (visceral leishmaniasis). Without treatment, the latter is often fatal. Intermediate types include recurrent, diffuse, or mucocutaneous forms. Nodular lesions on exposed skin with a tendency to ulcerate over time in combination with a travel history should therefore prompt workup for leishmaniasis. The diagnosis is made through histology, parasite culture, and PCR using biopsy material. Therapeutic options range from local therapies in cases with singular lesions to systemic therapy in patients with more severe forms. The present review discusses the most important clinical features, details about diagnostic measures, and current therapeutic approaches.