Leishmaniasis

Background

This parasitic infection is caused the protozoan Leishmania. In North America, this disease is very uncommon. However, the Gulf War brought several servicemen back to the United States, suffering from this infection. There may be cutaneous, mucocutaneous, or visceral involvement depending upon the species and host immune response. There is also species variation depending upon the geography. Occasionally, the disease has been divided into Old World and New World disease.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

INCIDENCE About 400,000 new cases each year, worldwide

GEOGRAPHY

Central Italy L. infantum zymodemes Montpellier-1 is the only agent responsble for cutaneous disease

ISRAEL

Leishmania tropica in northern Israel: a clinical overview of an emerging focus.

Shani-Adir A, Kamil S, Rozenman D, Schwartz E, Ramon M, Zalman L, Nasereddin A, Jaffe CL, Ephros M.

Department of Dermatology, Emek Medical Center, Afula, Israel.

J Am Acad Dermatol. 2005 Nov;53(5):810-5. Epub 2005 Sep 15. Abstract quote

BACKGROUND: In Israel, most cutaneous leishmaniasis (CL) is caused by Leishmania major. Recently a new focus of CL caused by Leishmania tropica has been described in Tiberias and the surrounding area of northern Israel.

OBJECTIVE: The aim of this study was to evaluate clinical (size, number, location, and type of lesion) and laboratory (culture and polymerase chain reaction [PCR] analysis) parameters at diagnosis, response to treatment, and outcome of patients with CL due to L tropica.

METHODS: Between September 2002 and March 2004, patients with direct smear-confirmed CL were evaluated; clinical records were reviewed and a telephone survey was performed.

RESULTS: Forty nine patients, 34 (69%) male and 15 (31%) female, were studied. Mean age was 31.1 years (median 26 years, range 1-70); 76% of patients live in Tiberias and the surrounding area. The mean number of lesions was 2.6 (median 2, range 1-10). Lesions were commonly located on the face (61%) and upper limbs (57%). PCR analysis was performed in 27 patients and was positive for L tropica in 26. Fifty percent of patients studied received multiple therapeutic regimens because of incomplete response or treatment failure. Topical paromomycin was used in 44 patients (90%), with a complete response reported in only 17 (39%); of the 9 patients treated with intralesional sodium stibogluconate, a complete response was reported in 6 (67%); of the 5 patients treated with intravenous sodium stibogluconate, 4 (80%) were cured.

LIMITATIONS: The relatively small number of patients studied combined with the fact that some were assessed retrospectively limit our conclusions. In addition, 50% of the patients studied received multiple therapeutic regimens because of failure of, or incomplete responses to, their initial therapy, thereby making comparisons difficult.

CONCLUSIONS: The cure rate in those completing a course of antimony therapy, either 10 or more days of intravenous therapy or therapy administered intralesionally, was 75% (95% confidence interval [CI], 50.5-99.5%) as compared with 45% (95% CI, 28.9-60.5%) among those completing at least 10 days of topical paromomycin. To date, no standardized, simple, safe, and highly effective regimen for treating L tropica exists. Large, controlled clinical trials to evaluate current treatment regimens as well as new medications for CL, and especially CL attributed to L tropica, are urgently needed.

Mediterranean basin L. major and L. tropica have been isolated from skin lesions rather than L. infantum

DISEASE ASSOCIATIONS CHARACTERIZATION

TRANSPLANT,
ORGAN

Reactivation of dormant cutaneous Leishmania infection in a kidney transplant patient.

Mirzabeigi M,

Farooq U,

Baraniak S,

Dowdy L,

Ciancio G,

Vincek V.

Department of Pathology, School of Medicine, University of Miami, Miami, FL, USA.

J Cutan Pathol. 2006 Oct;33(10):701-4. Abstract quote

Background: Leishmaniasis is an infection caused by a protozoan parasite belonging to genus Leishmania and transmitted by the Phlebotomus sandfly. Clinical presentations of infection include visceral, cutaneous, and mucocutaneous forms. Leishmaniasis is endemic in Africa, Asia, Europe, South America, and southern part of North America. This infection is extremely rare in the US and is mostly found among travelers coming from endemic areas. Cases of cutaneous and visceral leishmaniasis have been reported in organ transplant recipients in endemic areas.

Case report: We describe a case of cutaneous leishmaniasis in a kidney transplant patient, originally from Bolivia, who resides in the area known to be non-endemic for leishmaniasis and who is known not to travel within or outside of the US after the transplantation.

Results: Histologic examination of cutaneous lesion revealed extensive subcutaneous lymphohistiocytic inflammation with clusters of amastigote within histiocytes.

Conclusion: To our knowledge, this is the first case of cutaneous leishmaniasis in a kidney transplant patient residing in the US in an area known to be non-endemic for leishmaniasis, probably after reactivation of a previously dormant infection acquired outside of the US at least 9 months prior to developing clinical symptoms.

PATHOGENESIS CHARACTERIZATION

Hemoflagellate protozoan Leishmania L. major
L. tropica
L. aethiopica
L. infantum

Vector is Female sand fly (Phlebotomus)
Infected sand fly bites and cutaneous disease develops at bite site

Incubation period of 1 week to 3 months leads to erythematous papule at site which progresses to a nodule then ulcer

Spontaneously regresses over 6-12 months and leaves a scar

CHEMOKINE RECEPTOR 5 DELTA32 POLYMORPHISM

Analysis of the CC chemokine receptor 5 delta32 polymorphism in a Brazilian population with cutaneous leishmaniasis.

Brajao de Oliveira K,

Vissoci Reiche EM,

Kaminami Morimoto H,

Pelegrinelli Fungaro MH,

Estevao D,

Pontello R,

Franco Nasser T,

Watanabe MA.

Department of Pathological Sciences, Biological Sciences Center, Londrina State University, Londrina, Parana, Brazil.

J Cutan Pathol. 2007 Jan;34(1):27-32. Abstract quote

Patients with mucocutaneous leishmaniasis (MCL) show a vigorous T-cell immune response against Leishmania braziliensis. Because the Th response is associated with inflammation, the non-functional CC chemokine receptor 5 (CCR5) may rely in a less severe inflammatory state.

The aim of this study was to investigate the CCR5 gene in a Brazilian population with leishmaniasis compared with healthy control subjects and to determine the progression from cutaneous to MCL in the Delta32 allele carriers. Among 100 patients with Montenegro skin test and indirect immunofluorescence assay (IIF) values positive for leishmaniasis, there were 32% women and 68% men. The patients were 89% CCR5/CCR5, 10% CCR5/Delta32, and 1% Delta32/Delta32, while healthy subjects showed a 91% incidence of CCR5/CCR5, 8% of CCR5/Delta32, and 1% of Delta32/Delta32. The CCR5/CCR5 patients (89%) showed a large spectrum of clinical manifestations, where 22.47% had active mucous lesions and 77.53% had cutaneous lesions.

In this work, the Delta32 allele carriers (10%) showed only cutaneous manifestations when compared with wild-type individuals. Finally, with regard to the Delta32 allele carriers, a less severe spectrum of clinical manifestations was observed in comparison with wild-type individuals. Although a lack of mucocutaneous lesions was evident among Delta32 allele carriers, the number of individuals studied was small.

Therefore, further investigations are needed to elucidate the role of CCR5 in the clinical aspects of leishmaniasis.

LABORATORY/
RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

LABORATORY MARKERS

GENERAL

Old world cutaneous leishmaniasis in los angeles: a case report, overview of the current literature, and guide for the treating dermatopathologist.

Sarantopoulos GP, Binder S, Wortmann G, Hochberg L, Healey P.
Am J Dermatopathol. 2003 Aug;25(4):321-6 Abstract quote
We describe a case of cutaneous leishmaniasis in a Spanish patient visiting Los Angeles. Leishmania species cause both cutaneous and visceral disease; the majority of infections with Leishmania are of the cutaneous form.

Although leishmaniasis is a relatively rare occurrence in the United States, travel by United States' citizens to endemic regions and increased United States military operations in the Middle East raise the chances of encountering cutaneous leishmaniasis.

The following case report and overview of the current literature outlines the major morphologic findings and current diagnostic modalities available to diagnose cutaneous leishmaniasis.

POLYMERASE CHAIN REACTION

Experience with New World cutaneous leishmaniasis in travelers.

Scope A, Trau H, Anders G, Barzilai A, Confino Y, Schwartz E.

Department of Dermatology, Chim Sheba Medical Center, Tel Hashomer, Israel.

J Am Acad Dermatol. 2003 Oct;49(4):672-8. Abstract quote

In recent years, New World cutaneous leishmaniasis has been seen at a higher incidence among returning Israeli travelers. Leishmania braziliensis and related species cause unsightly cutaneous lesions possibly complicated with a mucosal disease.

A total of 12 patients with New World cutaneous leishmaniasis were treated in our clinic, 11 of whom (92%) acquired the disease in the Bolivian Amazon Basin. Five (42%) had regional lymphadenopathy in addition to cutaneous lesions. Polymerase chain reaction was performed for 8 patients to identify the causative Leishmania species. In all, 9 patients (75%) were cured by a single course, and 3 (25%) after an additional course of intravenous sodium stibogluconate. The treatment was well tolerated clinically. Laboratory abnormalities, mainly elevation of liver enzymes (58%), were reversible.

We concluded that polymerase chain reaction is a useful tool in establishing the species diagnosis of leishmaniasis and that sodium stibogluconate appears to be a safe and effective treatment for L braziliensis infection.

Value of diagnostic techniques for cutaneous leishmaniasis.

Faber WR, Oskam L, van Gool T, Kroon NC, Knegt-Junk KJ, Hofwegen H, van der Wal AC, Kager PA.

Department of Tropical Dermatology, Academic Medical Center, The Netherlands.
J Am Acad Dermatol. 2003 Jul;49(1):70-4. Abstract quote
BACKGROUND: Traditional diagnostic tests, ie, smear, culture, and histopathology of a skin biopsy specimen, are not always conclusive in patients with a clinical diagnosis of cutaneous leishmaniasis (CL).

OBJECTIVE: Our purpose was to find out if a polymerase chain reaction (PCR) specific for Leishmania organisms might be more sensitive than the traditional diagnostic techniques, thereby decreasing the number of false-negative diagnoses.

METHODS: In a prospective study, smear, culture, and histopathology of skin biopsy specimens from 46 patients with a possible diagnosis of CL were compared with PCR specific for Leishmania. In addition, the Montenegro test as a measure of cellular immunity against the Leishmania parasite was performed. Proven CL was defined as a case in which at least 1 of the 3 traditional tests showed the presence of Leishmania parasites.

RESULTS: Of our 46 patients, 22 had leishmaniasis. Of the traditional tests, culture was the most sensitive but there were no statistically significant differences between the sensitivities of the various tests. PCR results were positive in all cases of proven leishmaniasis. Moreover, 3 patients with the clinical diagnosis of CL and negative findings on traditional tests had positive PCR results. Only 1 patient with a strong clinical suggestion of CL and positive Montenegro test results had negative PCR findings; this patient also had negative smear, culture, and histopathology results.

CONCLUSION: PCR appears to be the most sensitive single diagnostic test for CL.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

SKIN Caused by L. tropica in Asia and Africa
L. Mexicana in Central and South America

Localized

Diffuse
Anergic individuals
Widespread nodules and macules without ulceration or visceral involvement

Recidivans (Lupoid)

Dermal Post-Kala Azar

Pathology of post-kala-azar dermal leishmaniasis: a light microscopical, immunohistochemical, and ultrastructural study of skin lesions and draining lymph nodes.

Ismail A,

Gadir AF,

Theander TG,

Kharazmi A,

El Hassan AM.

Department of Clinical Pathology and Immunology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.

J Cutan Pathol. 2006 Dec;33(12):778-87. Abstract quote

Background: Whereas the clinical manifestations and treatment of post-kala-azar dermal leishmaniasis (PKDL) have been adequately described before, the pathology received little attention, particularly the African form of PKDL which shows some clinical differences from the disease in India. Therefore, our aim was to characterize the pathology and the immunohistopathology in PKDL lesions and correlate the histopathological findings with the clinical features of the disease.

Methods: Biopsies of skin lesions were examined for histopathological changes in formalin-fixed tissues and for cell phenotypes and adhesion molecules by immunohistochemistry.

Results: The epidermis showed various changes in different combinations. The dermis was infiltrated by lymphocytes and macrophages, but plasma cells were scanty or absent. The majority of cells were CD3 T cells, with a preponderance of CD4 over CD8 cells. Degenerating basal keratinocytes expressed HLA-DR, ICAM-1 and Leishmania antigen and closely interacted with CD4 T cells. Regional lymph nodes showed hyperplasia of the B- and T-cell zones.

Conclusions: The inflammatory reaction in PKDL lesions is in response to Leishmania parasites and/or antigen. The majority of cells are CD4 T cells. Degeneration of the basal keratinocytes is probably due to the action of cytotoxic CD4 T cells interacting with leishmania-expressing epidermal cells.

Cutaneous leishmaniasis in soldiers from Fort Campbell, Kentucky returning from Operation Iraqi Freedom highlights diagnostic and therapeutic options.

Willard RJ, Jeffcoat AM, Benson PM, Walsh DS.

Dermatology Services, Blanchfield Army Community Hospital, Fort Campbell, Kentucky, USA.

J Am Acad Dermatol. 2005 Jun;52(6):977-87. Abstract quote

BACKGROUND: Cutaneous leishmaniasis (CL), rare in the first Gulf War, is common in American troops serving in Operation Iraqi Freedom. Awareness of the clinical features and treatment options of CL would benefit clinicians who may encounter soldiers, as well as civilians, returning from the Middle East with skin lesions.

OBJECTIVE: Our purpose was to describe our clinical experience in treating soldiers with CL.

METHODS: From December 2003 through June 2004, approximately 360 of an estimated 20,000 soldiers returning from a yearlong deployment in Iraq with skin lesions suspected of being CL were examined by dermatologists. We summarized CL diagnoses, laboratory evaluations, and treatments, including localized heat therapy (ThermoMed model 1.8; ThermoSurgery Technologies, Inc, Phoenix, Ariz), oral fluconazole, cryotherapy, and itraconazole.

RESULTS: Among 237 soldiers diagnosed with CL, 181 had one or more laboratory confirmations, most by Giemsa-stained lesion smears and polymerase chain reaction (PCR). PCR was positive for all 122 smear-positive and 26 biopsy-positive lesions and all 34 smear negative and all 3 biopsy-negative cases. Primary outpatient treatments, including ThermoMed (n = 26), oral fluconazole (n = 15), cryotherapy (n = 4), and itraconazole (n = 2), were safe and tolerable. Treatment failure occurred in 2 fluconazole recipients and was suspected in 1 ThermoMed and 2 fluconazole recipients. Seventy-two soldiers elected no treatment.

LIMITATION: This was a retrospective study.

CONCLUSION: Approximately 1% of Ft Campbell troops returning from Iraq were diagnosed with CL, most by laboratory confirmation. PCR appeared to be the most useful diagnostic technique. Among outpatient treatments, ThermoMed and cryotherapy had favorable safety and efficacy profiles.

MUCOCUTANEOUS Caused by L. brasiliensis
Resemble cutaneous lesions
Vegetating, verrucous, and sporotrichoid lesions may occur

Espundia-large destructive ulcerative lesions of the mucous membranes around tounge, nasopharynx, and body orifices
May develop up to 25 years after initial infection

VISCERAL (KALA-AZAR) Caused by L. donovani
Fever, anemia, hepatosplenomegaly
Cutaneous involvement in 5%, usually 1-5 years after initial infection
Skin lesion may be erythematous macules and nodules, resembling leprosy

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL
Nodular infiltate characterized by lymphocytes, small granulomas, and giant cells
Numerous parisitized macrophages
Organisms localize at the periphery of macrophages-the marquee sign

DONOVAN BODIES Round to oval basophilic structures about 2-4 um in diameter are present within the cytoplasm corresponding to the intracellular amastigotes
Lack of capsule distinguishes from Histoplasma

SKIN Presence of necrosis with a reactive response is considered a favorable prognostic feature in mucocutaneous variant

VARIANTS

GRANULOMATOUS

Interferon-gamma Treatment Induces Granulomatous Tissue Reaction in a Case of Localized Cutaneous Leishmaniasis.

Haas N, Hauptmann S, Paralikoudi D, Muche M, Kolde G.

Departments of Dermatology and Allergy (N.H., M.M., G.K.) and Pathology (S.H., D.P.), Charite, Humboldt-University Berlin, Berlin, Germany.
Am J Dermatopathol 2002 Aug;24(4):319-23 Abstract quote
Leishmania spp. suppress macrophage activity as part of their interaction with the immune system. Interferon-gamma (IFNgamma), a cytokine that participates in the activation of macrophages and the killing of intercellular parasites, induces healing of leishmaniasis.

We investigated a sequence of local and systemic inflammatory cell parameters after IFNgamma therapy in a patient with chronic, localized, cutaneous leishmaniasis caused by Leishmania donovani. Histology, immunohistochemistry, polymerase chain reaction (PCR) for L. donovani, and analysis of T-cell receptor gene fragments from skin lesions as well as peripheral blood phenotyping were performed before, during, and after IFNgamma therapy. During therapy, epithelioid cell granulomas developed with a high number of lesional human leukocyte antigen (HLA) DR+ macrophages, and HLA-DR expression on monocytes increased to high counts, indicating macrophage activation. Simultaneously, T-cell receptor-beta gene-specific PCR showed a peak at 243 base pairs, indicating clonal expansion of Leishmania-reactive T lymphocytes.

After therapy, PCR detected minimal residual leishmanial DNA in healing lesions, suggesting the destruction of the parasites. In conclusion, IFNgamma therapy compensates for the parasite-dependent major histocompatibility complex class II downregulation and induces healing of chronic cutaneous leishmaniasis.

SPECIAL STAINS/
IMMUNO-
HISTOCHEMISTRY CHARACTERIZATION

IMMUNO-HISTOCHEMISTRY

Identification of parasite antigen, correlation of parasite density and inflammation in skin lesions of post kala-azar dermal leishmaniasis

K R Beena1, V Ramesh and Ashok Mukherjee

J Cutan Pathol 2003;30:616-620 Abstract quote

Background: Post kala-azar dermal leishmaniasis (PKDL) is an unusual dermatosis following kala-azar (KA). Demonstration of the amastigotes in lesions plays an important role in the diagnosis of PKDL. It was aimed to evaluate the utility of an antibody G2D10 in detecting leishmania parasite antigen, to correlate the parasite number/percentage of parasites with the inflammation, and to assess the epidemiological significance associated with the location of the parasites.
Material and methods: The study was conducted on 50 cases. Hematoxylin and eosin (H & E) stains and immunohistochemical (IHC) stains, using G2D10 antibody, was performed on the skin biopsies. The number of parasites and density of inflammation were semiquantitatively assessed.

Results: Leishmania donovan bodies (LDBs) were identified in 50% of cases with the H & E compared to 80% positivity with the IHC. All 50 cases showed inflammation in the superficial dermis (SD). About 44% showed dense inflammation compared to 16% sparse and 40% moderate inflammation. Parasite percentage was maximum in the SD (100%) compared to 75 and 42% in the mid and deep dermis, respectively.

Conclusions: The IHC showed a higher percentage of LDB localization (80 vs. 50%). Density of inflammation was maximum in the SD. The parasite percentage was correlated with the inflammation. Location of parasites could have an epidemiological significance.

ELECTRON MICROSCOPY

Cutaneous leishmaniasis: Texas case diagnosed by electron microscopy.

Maloney DM, Maloney JE, Dotson D, Popov VL, Sanchez RL.

University of Texas-Houston Medical School, USA.
J Am Acad Dermatol 2002 Oct;47(4):614-6 Abstract quote
A 78-year-old woman from south-central Texas without a history of travel outside the state presented with an erythematous papule on her right forearm. A biopsy specimen showed non-necrotizing granulomatous inflammation with negative stains for organisms.

The lesion was recalcitrant to treatment with topical steroids, and a second biopsy specimen, obtained 3 months later, showed a histiocytic infiltrate in the upper dermis. Numerous, round, 1- to 30-microm bodies were seen within vacuoles in the histiocyte's cytoplasm. Giemsa, Grocott-Gomori methenamine-silver nitrate, and periodic acid-Schiff stains were negative. Electron microscopic examination of the paraffin-embedded tissue showed parasites diagnostic of leishmaniasis.

On review of the literature, we found that 29 other cases of autochthonous cutaneous leishmaniasis have been reported in Texas. We emphasize the endemic nature of this condition in Texas.

PROGNOSIS AND TREATMENT CHARACTERIZATION

TREATMENT

PHOTODYNAMIC THERAPY

Treatment of cutaneous leishmaniasis by photodynamic therapy.

Gardlo K, Horska Z, Enk CD, Rauch L, Megahed M, Ruzicka T, Fritsch C.

Departments of Dermatology at Heinrich-Heine-University and Hadassah-Germany Skin Center, Hadassah Medical Organization.
J Am Acad Dermatol. 2003 Jun;48(6):893-6. Abstract quote
BACKGROUND: Cutaneous leishmaniasis represents a common health problem and standard treatments are often ineffective or yield poor cosmetic results.

OBJECTIVE: We compared the efficacy of photodynamic therapy (PDT) with paromomycin sulfate in 10 lesions of cutaneous leishmaniasis.

METHODS: Five lesions were treated by PDT with Metvix (Photocure, Oslo, Norway) and 75 J/cm(2) red light. PDT was performed twice weekly and, after 12 weeks, once weekly. The other 5 lesions were treated with paromomycin sulfate once daily. All nonresponding lesions of the paromomycin-treated plaques finally also underwent PDT.

RESULTS: All 5 lesions treated by PDT and 2 of the paromomycin sulfate-treated plaques were clinically and histologically Leishmania free. Three lesions with poor response to paromomycin sulfate finally responded to subsequent PDT. Ten months after therapy there was no recurrence, and cosmetic outcome after PDT was excellent.

CONCLUSION: PDT may be an effective therapeutic alternative in cutaneous leishmaniasis.

VACCINATION

Vaccination against cutaneous leishmaniasis: current status.

Melby PC.

Department of Veterans Affairs Medical Center, Medical Service, South Texas Veterans Health Care System, San Antonio, Texas, USA.
Am J Clin Dermatol 2002;3(8):557-70 Abstract quote
The different cutaneous leishmaniases are distinct in their etiology, epidemiology, transmission, and geographical distribution. In most instances cutaneous leishmaniasis is limited to one or a few skin ulcers that develop at the site where the parasites were deposited during the bite of the sandfly vector. Lesions typically heal spontaneously after several months but some lesions can be large and follow a chronic, more severe course. Protective immunity is usually acquired following cutaneous infection with Leishmania spp., so prevention of disease through prophylactic immunization appears to be feasible. Since vaccination with live, virulent parasites is associated with an unacceptable rate of adverse events, attention has turned to the use of killed or attenuated parasite vaccines and defined subunit vaccines.

Whole parasite vaccines have the advantage of delivering multiple antigenic epitopes that may be necessary for initiation of a broad-based immune response. Persistent or repeated immune-stimulation by parasite antigens and/or sustained expression of interleukin-12 appear to be critical elements in the development of durable immunity. A number of purified or recombinant antigens, when co-administered with a vaccine adjuvant, appear promising as vaccine candidates against cutaneous leishmaniasis. The sustained expression of recombinant Leishmania antigens by vaccination with DNA is an attractive approach because it mimics the persistent antigenic stimulation of subclinical infection. Effective vaccine-induced immunity must generate an antigen-specific memory T cell population that, upon exposure to the infecting parasite, rapidly produces a type 1 effector T cell response that leads to interferon-gamma-mediated activation of infected macrophages to kill the intracellular parasites.

This parasite-directed recall response must be prompt and of sufficient magnitude to overcome the subversive effect that the intracellular infection has on macrophage effector function. It is unlikely that vaccination against cutaneous leishmaniasis would induce sterile immunity, but a small number of parasites are likely to persist subclinically.

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Clin Infect Dis 1996;22:1-3
Arch Dermatol 1998;134:193-198
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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SPECIAL STAINS/ IMMUNO- HISTOCHEMISTRY	CHARACTERIZATION
IMMUNO-HISTOCHEMISTRY
Identification of parasite antigen, correlation of parasite density and inflammation in skin lesions of post kala-azar dermal leishmaniasis K R Beena1, V Ramesh and Ashok Mukherjee	J Cutan Pathol 2003;30:616-620 Abstract quote Background: Post kala-azar dermal leishmaniasis (PKDL) is an unusual dermatosis following kala-azar (KA). Demonstration of the amastigotes in lesions plays an important role in the diagnosis of PKDL. It was aimed to evaluate the utility of an antibody G2D10 in detecting leishmania parasite antigen, to correlate the parasite number/percentage of parasites with the inflammation, and to assess the epidemiological significance associated with the location of the parasites. Material and methods: The study was conducted on 50 cases. Hematoxylin and eosin (H & E) stains and immunohistochemical (IHC) stains, using G2D10 antibody, was performed on the skin biopsies. The number of parasites and density of inflammation were semiquantitatively assessed. Results: Leishmania donovan bodies (LDBs) were identified in 50% of cases with the H & E compared to 80% positivity with the IHC. All 50 cases showed inflammation in the superficial dermis (SD). About 44% showed dense inflammation compared to 16% sparse and 40% moderate inflammation. Parasite percentage was maximum in the SD (100%) compared to 75 and 42% in the mid and deep dermis, respectively. Conclusions: The IHC showed a higher percentage of LDB localization (80 vs. 50%). Density of inflammation was maximum in the SD. The parasite percentage was correlated with the inflammation. Location of parasites could have an epidemiological significance.
ELECTRON MICROSCOPY
Cutaneous leishmaniasis: Texas case diagnosed by electron microscopy. Maloney DM, Maloney JE, Dotson D, Popov VL, Sanchez RL. University of Texas-Houston Medical School, USA.	J Am Acad Dermatol 2002 Oct;47(4):614-6 Abstract quote A 78-year-old woman from south-central Texas without a history of travel outside the state presented with an erythematous papule on her right forearm. A biopsy specimen showed non-necrotizing granulomatous inflammation with negative stains for organisms. The lesion was recalcitrant to treatment with topical steroids, and a second biopsy specimen, obtained 3 months later, showed a histiocytic infiltrate in the upper dermis. Numerous, round, 1- to 30-microm bodies were seen within vacuoles in the histiocyte's cytoplasm. Giemsa, Grocott-Gomori methenamine-silver nitrate, and periodic acid-Schiff stains were negative. Electron microscopic examination of the paraffin-embedded tissue showed parasites diagnostic of leishmaniasis. On review of the literature, we found that 29 other cases of autochthonous cutaneous leishmaniasis have been reported in Texas. We emphasize the endemic nature of this condition in Texas.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

PATHOGENESIS	CHARACTERIZATION
Hemoflagellate protozoan Leishmania	L. major L. tropica L. aethiopica L. infantum
Vector is Female sand fly (Phlebotomus)	Infected sand fly bites and cutaneous disease develops at bite site Incubation period of 1 week to 3 months leads to erythematous papule at site which progresses to a nodule then ulcer Spontaneously regresses over 6-12 months and leaves a scar
CHEMOKINE RECEPTOR 5 DELTA32 POLYMORPHISM
Analysis of the CC chemokine receptor 5 delta32 polymorphism in a Brazilian population with cutaneous leishmaniasis. Brajao de Oliveira K, Vissoci Reiche EM, Kaminami Morimoto H, Pelegrinelli Fungaro MH, Estevao D, Pontello R, Franco Nasser T, Watanabe MA. Department of Pathological Sciences, Biological Sciences Center, Londrina State University, Londrina, Parana, Brazil.	J Cutan Pathol. 2007 Jan;34(1):27-32. Abstract quote Patients with mucocutaneous leishmaniasis (MCL) show a vigorous T-cell immune response against Leishmania braziliensis. Because the Th response is associated with inflammation, the non-functional CC chemokine receptor 5 (CCR5) may rely in a less severe inflammatory state. The aim of this study was to investigate the CCR5 gene in a Brazilian population with leishmaniasis compared with healthy control subjects and to determine the progression from cutaneous to MCL in the Delta32 allele carriers. Among 100 patients with Montenegro skin test and indirect immunofluorescence assay (IIF) values positive for leishmaniasis, there were 32% women and 68% men. The patients were 89% CCR5/CCR5, 10% CCR5/Delta32, and 1% Delta32/Delta32, while healthy subjects showed a 91% incidence of CCR5/CCR5, 8% of CCR5/Delta32, and 1% of Delta32/Delta32. The CCR5/CCR5 patients (89%) showed a large spectrum of clinical manifestations, where 22.47% had active mucous lesions and 77.53% had cutaneous lesions. In this work, the Delta32 allele carriers (10%) showed only cutaneous manifestations when compared with wild-type individuals. Finally, with regard to the Delta32 allele carriers, a less severe spectrum of clinical manifestations was observed in comparison with wild-type individuals. Although a lack of mucocutaneous lesions was evident among Delta32 allele carriers, the number of individuals studied was small. Therefore, further investigations are needed to elucidate the role of CCR5 in the clinical aspects of leishmaniasis.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL	Nodular infiltate characterized by lymphocytes, small granulomas, and giant cells Numerous parisitized macrophages Organisms localize at the periphery of macrophages-the marquee sign
DONOVAN BODIES	Round to oval basophilic structures about 2-4 um in diameter are present within the cytoplasm corresponding to the intracellular amastigotes Lack of capsule distinguishes from Histoplasma
SKIN	Presence of necrosis with a reactive response is considered a favorable prognostic feature in mucocutaneous variant
VARIANTS
GRANULOMATOUS
Interferon-gamma Treatment Induces Granulomatous Tissue Reaction in a Case of Localized Cutaneous Leishmaniasis. Haas N, Hauptmann S, Paralikoudi D, Muche M, Kolde G. Departments of Dermatology and Allergy (N.H., M.M., G.K.) and Pathology (S.H., D.P.), Charite, Humboldt-University Berlin, Berlin, Germany.	Am J Dermatopathol 2002 Aug;24(4):319-23 Abstract quote Leishmania spp. suppress macrophage activity as part of their interaction with the immune system. Interferon-gamma (IFNgamma), a cytokine that participates in the activation of macrophages and the killing of intercellular parasites, induces healing of leishmaniasis. We investigated a sequence of local and systemic inflammatory cell parameters after IFNgamma therapy in a patient with chronic, localized, cutaneous leishmaniasis caused by Leishmania donovani. Histology, immunohistochemistry, polymerase chain reaction (PCR) for L. donovani, and analysis of T-cell receptor gene fragments from skin lesions as well as peripheral blood phenotyping were performed before, during, and after IFNgamma therapy. During therapy, epithelioid cell granulomas developed with a high number of lesional human leukocyte antigen (HLA) DR+ macrophages, and HLA-DR expression on monocytes increased to high counts, indicating macrophage activation. Simultaneously, T-cell receptor-beta gene-specific PCR showed a peak at 243 base pairs, indicating clonal expansion of Leishmania-reactive T lymphocytes. After therapy, PCR detected minimal residual leishmanial DNA in healing lesions, suggesting the destruction of the parasites. In conclusion, IFNgamma therapy compensates for the parasite-dependent major histocompatibility complex class II downregulation and induces healing of chronic cutaneous leishmaniasis.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
TREATMENT
PHOTODYNAMIC THERAPY
Treatment of cutaneous leishmaniasis by photodynamic therapy. Gardlo K, Horska Z, Enk CD, Rauch L, Megahed M, Ruzicka T, Fritsch C. Departments of Dermatology at Heinrich-Heine-University and Hadassah-Germany Skin Center, Hadassah Medical Organization.	J Am Acad Dermatol. 2003 Jun;48(6):893-6. Abstract quote BACKGROUND: Cutaneous leishmaniasis represents a common health problem and standard treatments are often ineffective or yield poor cosmetic results. OBJECTIVE: We compared the efficacy of photodynamic therapy (PDT) with paromomycin sulfate in 10 lesions of cutaneous leishmaniasis. METHODS: Five lesions were treated by PDT with Metvix (Photocure, Oslo, Norway) and 75 J/cm(2) red light. PDT was performed twice weekly and, after 12 weeks, once weekly. The other 5 lesions were treated with paromomycin sulfate once daily. All nonresponding lesions of the paromomycin-treated plaques finally also underwent PDT. RESULTS: All 5 lesions treated by PDT and 2 of the paromomycin sulfate-treated plaques were clinically and histologically Leishmania free. Three lesions with poor response to paromomycin sulfate finally responded to subsequent PDT. Ten months after therapy there was no recurrence, and cosmetic outcome after PDT was excellent. CONCLUSION: PDT may be an effective therapeutic alternative in cutaneous leishmaniasis.
VACCINATION
Vaccination against cutaneous leishmaniasis: current status. Melby PC. Department of Veterans Affairs Medical Center, Medical Service, South Texas Veterans Health Care System, San Antonio, Texas, USA.	Am J Clin Dermatol 2002;3(8):557-70 Abstract quote The different cutaneous leishmaniases are distinct in their etiology, epidemiology, transmission, and geographical distribution. In most instances cutaneous leishmaniasis is limited to one or a few skin ulcers that develop at the site where the parasites were deposited during the bite of the sandfly vector. Lesions typically heal spontaneously after several months but some lesions can be large and follow a chronic, more severe course. Protective immunity is usually acquired following cutaneous infection with Leishmania spp., so prevention of disease through prophylactic immunization appears to be feasible. Since vaccination with live, virulent parasites is associated with an unacceptable rate of adverse events, attention has turned to the use of killed or attenuated parasite vaccines and defined subunit vaccines. Whole parasite vaccines have the advantage of delivering multiple antigenic epitopes that may be necessary for initiation of a broad-based immune response. Persistent or repeated immune-stimulation by parasite antigens and/or sustained expression of interleukin-12 appear to be critical elements in the development of durable immunity. A number of purified or recombinant antigens, when co-administered with a vaccine adjuvant, appear promising as vaccine candidates against cutaneous leishmaniasis. The sustained expression of recombinant Leishmania antigens by vaccination with DNA is an attractive approach because it mimics the persistent antigenic stimulation of subclinical infection. Effective vaccine-induced immunity must generate an antigen-specific memory T cell population that, upon exposure to the infecting parasite, rapidly produces a type 1 effector T cell response that leads to interferon-gamma-mediated activation of infected macrophages to kill the intracellular parasites. This parasite-directed recall response must be prompt and of sufficient magnitude to overcome the subversive effect that the intracellular infection has on macrophage effector function. It is unlikely that vaccination against cutaneous leishmaniasis would induce sterile immunity, but a small number of parasites are likely to persist subclinically.