New Insights on Leishmaniasis in Domestic Animals

## Feline Leishmaniasis: What Do We Know So Far?

*Allana Barros Freitas, Sandra Alves Araújo, Fernando Almeida-Souza and Tatiane Aranha da Penha-Silva*

#### **Abstract**

Feline leishmaniasis has a nonspecific clinical condition, like the clinical signs presented by dogs, including anorexia, lymphadenomegaly, dermatitis, emaciation, hyperthermia and atrophy of the temporal muscle. Cats have been identified as an alternative reservoir; however, felines are increasingly sought after as companion animals, further exposing man. Diagnosis in these animals is still considered a challenge, since most cats are asymptomatic. Although infected cats are less often sick than dogs, likely due to natural feline resistance, clinical illness has been linked to immunosuppressive coinfections with feline immunodeficiency virus and feline leukemia virus. The feline immune response to *Leishmania* infection has been poorly investigated. In cats, the same drugs prescribed for dogs are used in the treatment, namely pentavalent antimonials, allopurinol and miltefosine. Felines play an important role in the epidemiology of leishmaniasis, acting mainly as alternative reservoirs and accelerating the spread of the disease. Thus, there is a need for standardization of diagnostic and treatment methods, including thorough clinical evaluation. It is important to alert to the definition of public policies and to awaken feline owners, as well as the population in general, about care and prevention.

**Keywords:** *Leishmania*, cats, diagnoses, treatment, immune response

#### **1. Introduction**

Leishmaniasis is still one of the most neglected diseases in the world, mainly affecting developing countries. Approximately 350 million people are at risk of contracting the disease, and about two million new cases are reported annually. Annually, approximately 0.2 to 0.4 million cases of visceral leishmaniasis and 0.7 to 1.2 million cases of cutaneous leishmaniasis occur worldwide [1].

The interaction between humans and reservoir animals is an important factor in maintaining disease transmission. Although dogs are the preferred target of sandflies, in comparison to humans, studies on the susceptibility of the disease in other hosts help to elucidate more consolidated data on this zoonosis. Other important risk factors to be highlighted are the lack of basic sanitation and the urbanization process in rural areas, leading to an adequate environment for the maintenance of the vector, making the animals in these areas increasingly susceptible to infection [2].

In domestic cats, clinical disease has been associated with immunosuppressive co-infections with feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) [3]. These species are less often sick than dogs, probably due to their natural resistance. Due to the increasing number of cases of feline leishmaniasis lately in several endemic countries, the role of the domestic cat as a host of *Leishmania* has been discussed [4, 5]. Many researchers suggest the role of this species as an additional domestic reservoir [6] and/or a secondary host [7], alternative or accidental [5]. Studies carried out in Italy and Brazil showed evidence on the ability of the cat to transmit the protozoan to the vector, characterizing its behavior as a reservoir of visceral leishmaniasis [6, 8].

The feline immune response to infection has been poorly investigated. The most accepted hypothesis is that cats have natural immune resistance to arthropods and the microorganisms they transmit and that this response is controlled by genetic factors. It is possible that cats are less susceptible to the various immunomodulatory proteins contained in arthropod saliva, and cats generate protective and/or sterilizing immune responses to arthropod-borne pathogens more competently than other animals [9].

Here, we will discuss the role of domestic cats as reservoirs of leishmaniasis, as well as the immunopathological characteristics that help in the maintenance of the disease.

#### **2. Epidemiological aspects**

The etiological agents of leishmaniasis are protozoa of the genus *Leishmania* [10] in which four subgenera *Leishmania*, *Viannia, Sauroleishmania and Mundinia* are identified [11–13]. Recognition of the subgenus is performed by identifying the developmental site of the parasite in the vectors gut and by molecular characterization. Thus, the parasite is classified as subgenus *Leishmania* when they develop in the midgut and foregut and as subgenus *Viannia* when they develop in the midgut, foregut, and hindgut of the vector [11]. The subgenus *Sauroleishmania* is related to all reptile-infecting species of *Leishmania*. The subgenus Mundinia is the most recently created, in 2018, grouping *Leishmania* species that infect humans and animals, in which there is still a need for clarification about the vectors and hosts involved in its transmission cycles.

The parasite presents two main evolutive forms during its life cycle: amastigote and promastigote. The promastigote form has an elongated shape, with an external flagellum and it is found in the digestive tract of the insect vector. The amastigote is oval, with no external flagellum, and its survival depends on cells of the mammalian mononuclear phagocytic system [14]. Its biological cycle is heteroxenic, which depends on an intermediate host (invertebrate) and a definitive host (vertebrate) [15].

The transmission of leishmaniasis in felines is still poorly understood due to the few studies, but the most accepted hypothesis by researchers is the transmission by insect vectors, popularly known as sand flies [3]. The disease has vector transmission through the bite of sandflies, which in the New World belongs to the genus *Lutzomyia* and in the Old World to the genus *Phlebotomus* [16].

Only female sandflies have the hematophagous behavior that serves for the maturation of eggs in the reproductive period and become infected by taking a blood meal in a vertebrate host that develops cutaneous lesions or active parasitemia in visceral leishmaniasis. When feeding, the vector ends up ingesting infective forms of the parasite that transform into promastigotes in the midgut and reproduce in large quantities. *Feline Leishmaniasis: What Do We Know So Far? DOI: http://dx.doi.org/10.5772/intechopen.112539*

After this process, they move to the salivary glands, where in the next feeding of the vector, they will be inoculated together with the saliva in another vertebrate host, continuing the cycle [16, 17].

Other forms of transmission already described in dogs, mice and humans, such as horizontal transmission, have not been proven in cats [18], but blood transfusion is considered a source of infection as it has already been proven in humans and in dogs [19].

The role of cats in the leishmaniasis cycle is still poorly defined, but it is known that cats are more resistant to manifesting the disease, and anti-leishmania treatments induce clinical but not parasitological cure. Once infected, the protozoan may be available to the vector, which can make them source of sandfly infection [20, 21].

It was reported that cats could be infected by at least seven species of the genus *Leishmania*: *L*. *mexicana*, *Laccophilus venezuelensis*, *L. braziliensis*, *L. amazonensis*, *L. infantum* [3], *L. major* and *L*. *tropica* [22]. Feline leishmaniasis is distributed in 13 countries (**Figure 1**).

The first case of natural infection in a domestic feline by *Leishmania* spp. was reported in 1912 in Algeria, in an animal residing with a dog and a child with visceral leishmaniasis. After his death, amastigote forms of *Leishmania* spp. in the bone marrow of the animal confirmed the diagnosis [23].

In Brazil, the first report of leishmaniasis in felines was in 1939, in the state of Pará. A cat with lesions on the nose and ears was diagnosed with *Leishmania* spp. confirmed with cytological examination, but it was not possible to identify the species [24].

In Europe, the disease has been reported in cats in Italy [25], Spain [26], Portugal [27] and Greece [28]. In the Middle East, reports have identified the occurrence of leishmaniasis in domestic and stray cats in Turkey [22, 29], in Egypt [30] and in stray cats in Iran [31]. In Asia, the disease has been reported in cats of southeastern Thailand, in Songkhla and Satun provinces [32], in Surathani and Phangnga [33]. In North America, there were reports in the United States [34] and Mexico [35]. In South America, cases occurred in Venezuela [36] and in Brazil [37], which is currently the country with the highest number of studies on feline leishmaniasis [38].

The atypical manifestation of the disease was reported in Africa [39] in a feline with an ocular manifestation, unilateral uveitis, which was initially classified as exudative panuveitis. After 6 months, the disease progressed and ophthalmic enucleation was required, which allowed the diagnosis by visualization of amastigote forms of *Leishmania* spp. on histopathological examination.

In Brazil, the incidence of diagnoses using molecular and serological techniques is around 7 and 8%, identifying the species *L*. *braziliensis*, *L*. *infantum* and *L*. *amazonensis* as the most frequent [40–42]. Studies observed the occurrence of feline leishmaniasis in 12 states [43] of the country: Mato Grosso do Sul [40, 44], Mato Grosso [44–46], Maranhão [47], Minas Gerais [48, 49], Pará [41], Paraná [50], Paraíba [51], Pernambuco [52, 53], Santa Catarina [54], São Paulo [55–57], Rio de Janeiro [58, 59], and Rio Grande do Norte [60]. The species already identified in Brazil were *L*. *braziliensis*, *L*. *amazonensis* and *L*. *infantum*, the latter being the one responsible for most cases that occurs in felines [43].

#### **3. Diagnosis**

The diagnosis for the detection of leishmaniasis is based on clinical findings and the epidemiology of the disease; however, laboratory analyzes are considered important tools in the diagnosis of infection [43, 61]. Currently, several methods are used (**Figure 2**), and these are applied to both dogs and cats, such as evaluation of clinical signs and parasitological, serological, and molecular tests [20, 21, 38].

Most cats are infected with *L. infantum* [51, 62]. In these cases, the predominant clinical signs are alopecia, crusts, nodules, ulcers and eye lesions, in addition to gingivostomatitis, hepatomegaly and lymphadenopathy [21]. The occurrence of signs such as fever, weight loss, stomatitis and enteritis, although rare, are also observed [55].

**Figure 2.** *Main methods of diagnosis to detect Leishmania in cats around the world.*

*Feline Leishmaniasis: What Do We Know So Far? DOI: http://dx.doi.org/10.5772/intechopen.112539*

The diagnosis of feline leishmaniasis through parasitological analysis is based on the direct observation of the amastigote forms of *Leishmania* spp. The test can be used to visualize the parasite in aspirates from lymph nodes, spleen, liver, and bone marrow [63, 64]. In animals with skin lesions, the material obtained can be used to make smears or imprints on slides, histopathological and immunohistochemical analysis and isolation in culture medium [65]. The main advantage of parasitological tests in the diagnosis of leishmaniasis is their high specificity and low cost.

Among the serological (also called immunological) methods most used in Brazil, and in the world, for the diagnosis of disease in animals are the Indirect Immunofluorescence Reaction (IFAT) and the Enzyme Immunoadsorption Assay (ELISA) [66, 67].

In Brazil, the IFAT is widely used in epidemiological studies of endemic areas. The technique uses the intact parasite as an antigen, but there is no standardized IFAT method for felines, much less a universally accepted antibody titer value that corresponds to the infection; therefore, validated titers in dogs are also used for felines [29, 68]. The ELISA is based on the reaction of antibodies present in the sera with soluble and purified *Leishmania* antigens obtained from in vitro culture [69]. In general, it is considered more sensitive and less specific than IFAT [62, 64]. Diagnosis in felines, it demonstrates greater sensitivity in clinically affected animals [70].

Although parasitological and serological methods are widely practiced, the use of molecular techniques for the detection of *Leishmania* spp. has been increasing, highlighting conventional and quantitative PCR (qPCR). These are the most used techniques for the confirmatory diagnosis of feline leishmaniasis due to the high sensitivity in the direct detection and characterization of the parasites, and especially in cases of asymptomatic animals [19, 71, 72]. PCR allows the identification of the parasite through different types of samples, such as spleen, bone marrow, lymph nodes and peripheral blood [73, 74]. In Brazil, there are reports of variations in molecular results depending on the type of tissue used for analysis [42].

The diagnosis of feline leishmaniasis is considered complex, since the number of cases of asymptomatic animals is alarming. In addition, the variety of *Leishmania* species as well as the different existing clinical manifestations have made it even more difficult, increasing the risks of human infection. In this sense, there is a great need for more specific and accurate molecular techniques.

#### **4. Immunopathology**

The immune response plays a crucial role in the control of *Leishmania* infection. T cells modulate and guide the reaction of macrophages to the parasite through the production of cytokines, although there are some differences according to the host species [75–77]. Cats are less frequently affected by arthropod-borne diseases than dogs [9].

Although these animals do not show important differences between their immune systems, the lower prevalence of *L. infantum* infection, as well as the clinical manifestations of the disease in cats, may be due to differences in the innate and adaptive immune responses of felines [3, 78]. Cats from endemic areas of canine leishmaniasis were able to activate a cell-mediated adaptative immune response against *L. infantum* through the production of IFN-γ, after stimulation with soluble parasite antigen. This response was variably associated with antibody or blood PCR positivity, providing a better estimate of cat exposure to *L. infantum* [79]. A cross-sectional comparative

study of the humoral and cell-mediated adaptive immune responses to *L. infantum* of naturally exposed dogs and cats was carried out in an endemic area (southern Spain) during the sand fly season. It was observed that all dogs and cats that produced IFN-γ had low negative or positive antibodies without parasitemia, whereas animals with high parasite loads and/or antibody levels did not produce IFN-γ after stimulation with soluble *L. infantum* antigens. It was concluded that there are similarities in dogs and cats for the immunopathogenesis of infection, and that cats can mount a specific Th1 immune response against *L. infantum.* However, these responses appear to have a lower level compared to dogs [80].

A comparative study on the activation of the complement system in different hosts after stimulation with *L. infantum* confirmed lower susceptibility of cats to infection due to lower activation of the classical and alternative pathways and higher activation of the lectin pathway due to lower deposition of C4b [81].

In two necropsied cats with multicentric, nodular and ulcerated skin lesions, the presence of *Leishmania* was observed in both cytological and histopathological analyses. In addition, the presence of Mott cells and multinucleated giant cells in the dermis, lymph node and spleen were described, suggesting the excessive production of immunoglobulins which is a finding in dogs with visceral leishmaniasis. In the same work, splenic, renal and hepatic amyloidosis was found, due to immunogenic amyloid, by the production of large amounts of antibody light chains and their fragments, which can be confirmed by the presence of Mott cells [51].

*L. infantum* infection in cats may also be associated with immunosuppressive diseases [82]. A study described the first case of disseminated viscerocutaneous feline leishmaniasis caused by *L infantum*, associated with an invasive squamous cell carcinoma (SCC), assuming that carcinogenesis is favored by the activation and function of macrophages and dendritic cells, which may allow clones of malignant cells to escape continuously from efficient immune destruction. In addition, they observed the development of a strong humoral response to the parasite, confirmed by the high titer found in the IFAT serology [26].

#### **5. Treatment and control**

A unique treatment for feline leishmaniasis is not yet reported, so the drugs currently available for dogs are the same as those prescribed for cats. The main drugs used in the treatment of this disease are pentavalent antimonials, allopurinol and miltefosine [83–85]. Currently, the use of allopurinol is the most common treatment against feline leishmaniasis [86, 87]. In addition, the use of drug association as a treatment for leishmaniasis has been proposed for some years.

For example, the combination of meglumine antimoniate with ketoconazole was successfully administered to a feline with skin lesions [88]. In addition, the association of allopurinol and N-methyl-glucamine antimoniate in the treatment of feline leishmaniasis showed satisfactory results; however, the appearance of adverse reactions was also reported [87, 89].

In general, the treatment of leishmaniasis is considered a great challenge due to its worldwide distribution, different species of parasites, wide variety of clinical forms and immune responses [90]. Although, in most cases, the available drugs promote the full clinical recovery of the animals, they do not cause the complete elimination of the parasite; therefore, proposing preventive measures against the disease is extremely necessary.

*Feline Leishmaniasis: What Do We Know So Far? DOI: http://dx.doi.org/10.5772/intechopen.112539*

Currently, prevention methods such as vaccines, use of a collar, spot-on and spray with repellent properties against sandflies have been used against leishmaniasis in dogs [91, 92]. However, a recent study showed that a collar initially produced for the prevention of fleas and ticks also held promise against infection in cats [93]. According to the authors, the product was 75% effective in preventing infection. Additionally, it was well tolerated by the animals, with no systemic adverse reactions and a decrease in local skin reactions. As for vaccines, some countries already use dogs; however, none are available for felines [94, 95].

#### **6. Conclusions**

The role of cats in the leishmaniasis cycle is still poorly defined, with this species being more resistant to manifesting the disease than other animals. Although there are similarities in the immunopathogenesis of the infection in dogs and cats, the response in felines seems to be at a lower level when compared to canines. However, both present treatments promote complete clinical recovery but do not cause complete elimination of the parasite. Therefore, preventive measures against the disease are still the most effective way of controlling the parasitic cycle.

#### **Acknowledgements**

The authors would like to thank FUNADESP (Agency for the Development of Private Higher Education) for the T.A. Penha-Silva scholarship. Dr. Fernando Almeida-Souza is a post-doctoral research fellow and scholarship holder of CAPES, grant number 88887.363006/2019-00.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Allana Barros Freitas1 , Sandra Alves Araújo2 , Fernando Almeida-Souza1,3 and Tatiane Aranha da Penha-Silva4 \*

1 Postgraduate Program of Animal Science – UEMA, São Luís, Brazil

2 Postgraduate Program of Biotechnology, RENORBIO – UFMA, São Luís, Brazil

3 Laboratory of Protozoology, IOC-Fiocruz, Rio de Janeiro, Brazil

4 Veterinary Medicine Course, Anhanguera College, São Luís, Brazil

\*Address all correspondence to: tatianearanha@hotmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Feline Leishmaniasis: What Do We Know So Far? DOI: http://dx.doi.org/10.5772/intechopen.112539*

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[66] Chatzis MK, Leontides L, Athanasiou LV, Papadopoulos E, Kasabalis D, Mylonakis M, et al. Evaluation of indirect immunofluorescence antibody test and enzyme-linked immunosorbent assay for the diagnosis of infection by Leishmania infantum in clinically normal and sick cats. Experimental Parasitology. 2014;**147**:54-59. DOI: 10.1016/j. exppara.2014.10.004

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#### **Chapter 9**

## Current Challenges in the Association between Canine Leishmaniasis and Malignant Disorders

*Helen Silva Ribeiro, Flávia de Oliveira Cardoso, Ana Lucia Abreu-Silva, Kátia da Silva Calabrese and Fernando Almeida-Souza*

#### **Abstract**

Neoplasms in dogs are estimated to account for up to 83% of all canine malignancies, while canine leishmaniasis is endemic and highly incident in areas like Brazil, east Africa, and India. The worldwide incidence of both diseases may indicate the presence of these two pathologies in the same tissue sample as eventual cases. However, a relationship between leishmaniasis and malignant disorders has been postulated in human and veterinary medicine. Depending on several direct or indirect factors, leishmaniasis can affect the clinical manifestation, diagnosis, therapeutic protocols, and the outcome of various malignant disorders. In addition, the similarity of the clinical presentation of cutaneous or visceral leishmaniasis with the clinical signs observed in many tumors may lead to misdiagnosis. Clinical cases of co-localization of *Leishmania* parasites and tumor cells in dogs were more associated with transmissible venereal tumors than histiocytic tumors, non-histiocytic lymphoma, or squamous cell carcinoma. This chapter reviews the circumstances involving canine leishmaniasis and malignant disorders, and the current challenge that the association between them represents to misdiagnosis or tumor-promoting potential of leishmaniasis, providing an overview of dog cases.

**Keywords:** *Leishmania*, neoplasm, dog, transmissible venereal tumor, diagnosis

#### **1. Introduction**

Neoplasms in dogs are estimated to account for up to 83% of all canine malignancies [1]. Its etiology is largely unknown and believed to be multifactorial [2], genetic [3, 4], auto-immune [5], hemoparasitic [6, 7], and viral diseases [8]. The exact mechanism by which chronic inflammatory processes induce oncogenesis is still

unclear, but persistent immunosuppression [9], epigenetic events [10], and relevant association with immunosenescence [11] have all been associated with neoplasm developments.

*Leishmania infantum*-infected macrophages parasitize tissues commonly causing granulomatous inflammatory reactions [12]. Infected dogs with poor body condition, or cachexia, mainly display skin signs including skin peeling, cutaneous lesions (nodular, ulcerative, and pustular), and exfoliative dermatitis. A wide variety of clinical signs and a number of unusual presentations make diagnosis a challenge to veterinarians [13–16].

*L. infantum* invades most of the dogs tissues and organs [16, 17] and it has also been sporadically reported in association with different types of tumors [7, 18, 19], including cutaneous large-cell lymphoma [20], cutaneous canine transmissible venereal tumor [21], splenic [20], hemangiosarcoma [22], soft tissue sarcoma, cutaneous small-cell lymphoma, adrenocortical adenoma [7], and perianal adenoma [23].

In transmissible venereal tumor (TVT), sarcoma, small-cell lymphoma, and adrenocortical adenoma, amastigotes were observed in the macrophage's cytoplasmic vacuoles and inside the neoplastic cells, probably in consequence of an atypical dissemination of *Leishmania* parasites [23]. These findings demonstrate the ability of *Leishmania* to parasitize neoplastic cells other than leucocytes [7, 19].

A relationship between leishmaniasis and malignant disorders has been postulated in human and veterinary medicine [22, 24]. Among the proposed theories, the chronic inflammation induced by *Leishmania* persistence, the interference with the local systemic immune system, and a direct implication of the parasite in the pathogenesis of cancer are considered most important. Etiopathogenic theories are based on the pathological observation that chronic inflammation can lead to development of dysplasia, abnormalities in cell division and activation of the p53 protein (an important tumor suppressor protein, whose loss of function leads the cell to genomic instabilities, i.e., the tumor sets in) [25]. However, definitive evidence of this association has not been proven to date. Depending on several direct or indirect factors, leishmaniasis can affect the clinical manifestation, diagnosis, therapeutic protocols, course, and outcome of various malignant disorders. The association between leishmaniasis and malignancy can be identified in four distinct situations: leishmaniasis mimicking malignancy, leishmaniasis associated with malignancy, malignancy developing in patients with leishmaniasis blemish, and leishmaniasis developing in patients with malignancy [24]. This chapter reviews these situations involving canine leishmaniasis and malignant disorders, and the current challenge that the association between them represents to misdiagnosis or tumor-promoting potential of leishmaniasis, providing an overview of dog case reports, and when possible, draws a comparison with case reports in humans.

#### **2. Histopathology, biochemical, and hematological parameters of canine leishmaniasis**

The liver, spleen, and lymph nodes are the organs most affected by the disease [26], as well as the kidney and skin. In humans with visceral leishmaniasis, liver function and morphology are modified by the presence of an inflammatory process in the portal and intralobular region, locally concentrated or diffusely localized. In dogs experimentally infected by intravenous and intraperitoneal injection of amastigotes of *L. infantum*, Gonzalez et al. [27] verified that, in both forms of inoculation, the

#### *Current Challenges in the Association between Canine Leishmaniasis and Malignant Disorders DOI: http://dx.doi.org/10.5772/intechopen.114275*

animals displayed alterations with multiple granulomas, with the visualization of the parasite, without predilection location. In addition to the *Kupffer* hypertrophy and hyperplasia are often seen in dogs naturally infected. Diffuse intralobular liver fibrosis was reported by Melo et al. [28], demonstrating that there are differences between infected and non-infected, with collagen deposition in symptomatic animals when compared to asymptomatic ones. When evaluated for the presence and size of granulomas, asymptomatic and symptomatic animals did not show differences between groups [29]. There is a granulomatous infection that only infiltrates *Kupffer* cells and hepatocytes. In chronic infections displaying different levels of severity, the granuloma was limited to the sinusoids and expanded to the portal region and the capsule, forming diffuse areas in resistant dogs. Hepatic granuloma in dogs affected with leishmaniasis is not organized [30].

Parasitism caused by *L. infantum* in the spleen can be verified, especially in the capsular and subcapsular regions and in the marginal zone, with mild intensity in asymptomatic animals, and intense parasitism in symptomatic ones [26, 31]. Studies demonstrated a reduction in regulatory T cells in the splenic tissue, indicating that they are capable of producing a greater amount of IL-10 when compared to non-infected dogs [32]. Santana et al. [29] found that susceptible dogs, that had a Montenegro intradermal reaction negative and splenic culture positive, showed smaller and fewer follicles, as well as changes in the splenic follicular organization, while severe form of leishmaniasis is associated with disorganization of white pulp [33].

In the kidney, the accumulation of immune complexes in the glomeruli can initiate glomerulonephritis and interstitial nephritis, which can lead to chronic renal failure in dogs, [34]. Santos et al. [35] evaluated histological alterations of dogs naturally infected with *Leishmania infantum* and observed amastigote form of the parasite in the kidneys and bladder of infected dogs, demonstrating that the clinical signs resulting from the urinary system alterations should be taken into account when diagnosing this disease. In fragments of the urinary bladder main alterations observed through the histopathological analysis were inflammatory reactions in the adventitial layer, characterized by moderate mononuclear infiltrate and focal perivascular infiltrate. The kidney showed glomerular degeneration and atrophy, granulomatous inflammation, apoptosis, and Bowman capsule lesions.

In general, skin lesions in dogs are focal ulcers, with raised edges, like human lesions. Other dermatological signs are alopecia, papular, and nodular dermatitis [36]. Boechat et al. [37] verified the presence of *L. (L.) infantum* amastigotes in the endometrium, ovaries, vaginal mucosa, skin, and mucosa of the vulva and mammary glands, and it was even possible to observe a greater parasite load and intense reaction inflammation in the vulva and breasts of naturally infected dogs. The number of foci and cellularity of the inflammatory infiltrates in symptomatic dogs is higher than in other groups conform seen by Verçosa et al. [38], as well as average area, perimeter, and extreme diameters of the inflammatory infiltrates were higher in symptomatic animals.

Canine leishmaniasis is also associated with alteration in hematological and biochemical parameters. Erythrogram of dogs seropositive for leishmaniasis shows moderate anemia, usually presented in the normocytic and normochromic form with non-regenerative character [39, 40]. This characteristic can be a consequent of the bone marrow invasion by the parasite, which induces inflammation and contributes to the reduction of erythrocyte production [41]. A thrombocytopenia is common and occurs due to vasculitis caused by immune complexes circulating blood, thrombocytopoiesis disorders, and platelet destruction [40].

Leukocyte response changes according to the stage of the disease [42]. Lymphopenia occurs due to the sequestration of cells in the spleen and lymph nodes, as well as by the destruction caused by *Leishmania* [43]. Other common changes such as eosinophilia and leukopenia are associated with clinical disease [44]. Lymphocytosis was observed in asymptomatic dogs [16, 45], biochemical parameters levels in serum may be higher than in dogs seronegative [43], and, in some cases, severe proteinuria may determine changes in normal serum protein values [46].

An unusual case of persistent pancytopenia caused by leishmaniasis in a human patient receiving immunomodulatory therapy for myeloma was recently described [47] and draws attention to possible similar cases in dogs. Pancytopenia in multiple myeloma is commonly caused by plasma cell infiltration and cytotoxic medications, however, fungal, bacterial, or viral infection, and treatment-associated myelodysplasia also warrant consideration. In regions where leishmaniasis occurs naturally, it should be also investigated, and in this case, the diagnosis of *Leishmania* infection and a proper therapeutic can reverse pancytopenia.

An usual alteration associated with leishmaniasis is hyperproteinemia, caused by the activation of B lymphocytes and high production of antibodies [40]. In fact, there is a decrease in the serum albumin level, in contrast to an expressive increase in the globulin levels, causing a significant increase in the levels of total plasmatic proteins during canine leishmaniasis [43, 48]. Liver function may also be normal or with changes suggestive of liver diseases [49]. It can be detected by increased activity of liver enzymes such as alkaline phosphatase (AP) and alanine aminotransferase (ALT) [49–51].

Alterations in biochemical parameters can also be associated with leishmaniasis treatment. A case report of a tumor lysis-like syndrome during therapy of visceral leishmaniasis consisting of hyperkalemia, hyperphosphatemia, hyperuricemia, and acute renal insufficiency, soon after the initiation of liposomal amphotericin B chemotherapy for severe visceral leishmaniasis, was observed in a human patient. Allopurinol therapy and intravenous fluid administration lead to a full recovery of the metabolic parameters. Awareness of this condition by veterinarians can lead to early recognition and preventive management of patients undergoing leishmaniasis treatment [52].

#### **3. Tumor and** *Leishmania* **infection association**

The worldwide incidence of cancer and the endemicity of leishmaniasis in areas like Brazil, east Africa, and India may indicate the presence of these two pathologies in the same tissue sample as eventual cases. Both diseases display an immunological bias in the pathology, course, and outcome of the disease progression associated with an impaired host Th1 response. Therefore, the Th2 cytokine microenvironment occurring in compartmentalized organs in progressive leishmaniasis [53] may potentially promote tumor cell proliferation as well as the other way around. In addition, the similarity of the clinical presentation of cutaneous, mucosal, or visceral leishmaniasis with lesions observed in many malignant disorders may lead to misdiagnosis [54]. Clinical cases of co-localization of *Leishmania* parasites and tumor cells in dogs were mainly associated with TVT or less frequently with histiocytic tumor, non-histiocytic lymphoma, or squamous cell carcinoma (**Figure 1**). First, we will discuss about the less frequent association of tumors with leishmaniasis, as well as misdiagnosis related to both diseases, and then the association of tumors with TVT will be reviewed.

*Current Challenges in the Association between Canine Leishmaniasis and Malignant Disorders DOI: http://dx.doi.org/10.5772/intechopen.114275*

*Organs affected by canine leishmaniasis, and most frequent neoplasms associated with leishmaniasis in dogs.*

The clinical identification of leishmaniasis is frequently related to skin lesions. However, most of the evidence about the association between cutaneous leishmaniasis and skin cancer is still based on case reports and other clinical observations rather than strong epidemiological observational studies [55]. An unlikely association of squamous cell carcinoma with an active cutaneous leishmaniasis was reported in an immunocompetent human patient [25], and a report of a case of basal cell carcinoma (Clark level IV) that had been developed on characteristic active lesion of mucocutaneous leishmaniasis, suggesting that carcinogenesis, in this case, was triggered by *Leishmania* parasites and induced by sun's ultraviolet (UV) radiation exposure [56]. Although causality is still to be proved, a biopsy may be essential to rule out associated skin malignancy in reluctant cutaneous leishmaniasis [25]. A report of a solitary cutaneous leiomyoma mimicking leishmaniasis demonstrates that neoplasms mimicking cutaneous leishmaniasis are an alert for an appropriate differential diagnosis [57].

Differential diagnosis of leishmaniasis and malignancy disorders due to similarities in clinical presentation, as well as its association, is perhaps reported for the three clinical forms of leishmaniasis: visceral, cutaneous, and mucosal. A chronic skin lesion histopathologically compatible with squamous cell carcinoma, and hence programmed for Mohs surgery, showed to be cutaneous leishmaniasis after review of the clinical and epidemiological history, and laboratory diagnosis. Treatment with miltefosine led to a complete resolution of the lesion [58]. Zambarbieri et al. [19] reported a case of *Leishmania* spp. infection in a cutaneous histiocytoma in a nodular lesion on the metacarpus of an old dog. In cytopathology examination, in some neoplastic cells, with moderate anisocytosis and anisokaryosis, *Leishmania* spp. amastigotes were observed in the cytoplasm.

A report of visceral leishmaniasis in a human patient with a lung tumor highlights leishmaniasis as a possibility to be considered in the diagnosis of causes of fever in patients undergoing chemotherapy in an endemic area [59]. In humans, visceral leishmaniasis was also reported in association with Hodgkin's lymphoma [60], melanoma

[61], and lymphoma, the last with cases of *Leishmania* infection or clinical manifestation after treatment for cancer [62]. The visceral leishmaniasis in association with multiple myeloma highlights the importance of histopathological correlation of positron emission tomography (PET) findings [63]. In this case, the liver, spleen, and bone marrow are the sites of infiltration most frequent in visceral leishmaniasis and should be observed as a differential diagnosis in PET scans.

A mucosal lesion with a tumor-like appearance by indirect laryngoscopy, but negative in indirect immunofluorescence assay test and bone marrow aspirate examination for *Leishmania*, revealed in biopsy a granulomatous inflammatory infiltrate and abundant *Leishmania* amastigotes, in addition to *Leishmania* parasites growth in culture, in a human patient. The lesions disappeared after treatment with meglumine antimoniate (850 mg/day) for 28 days [64]. Atypical cases of mucocutaneous leishmaniasis in human mimicking rectal cancer reported two different presentations: an erythematous nontender plaque measuring 5 cm by 5 cm was observed over the right perianal area of a 32-year-old male HIV patient; and two masses of different sizes and characteristics were observed around the anus and a fungating circumferential mass of 8 cm was seen above the proximal anal verge in a 40-year-old male. Atypical mucocutaneous leishmaniasis should be considered as a possible diagnosis in patients with chronic skin lesions resembling hemorrhoids and colorectal masses, especially in endemic areas for leishmaniasis [65]. A 50-year-old man mimicking multiple myeloma, presenting pancytopenia, hypergammaglobulinemia with concurrent hypoalbuminemia, showed normal cellularity, mild hemophagocytosis, increased plasma cells, and Mott cells in bone marrow aspirate. However, a thorough inspection of the bone marrow smears revealed the presence of *Leishmania* parasites. Mott cells are plasma cells with multiple cytoplasmic inclusions of immunoglobulin (Russell bodies) and it was associated with multiple myeloma cases. However, they have also been found in patients with infections such as *Leishmania* infection [66].

Other atypical report is the co-occurrence of mucosal leishmaniasis caused by *Leishmania infantum* and a retrospectively diagnosed concomitantly with a marginal zone lymphoma (MZL) in a 62-year-old man tongue. The patient was successfully treated first for MZL, but after six months, the tongue swelling returned with the identification of Leishman bodies (Giemsa stain) within the macrophages in the biopsy sample. Liposomal amphotericin B induced clinical improvement [67]. A human patient with metastatic non-small-cell lung carcinoma, after chemotherapy and a high dose of corticosteroids, showed a painful and swollen tongue. Biopsy showed an inflammation with histiocytes and *Leishmania* amastigotes indicating that the lowered immune status was important in developing mucosal leishmaniasis [68].

A gingival tumor-like lesion measuring 3 cm in the longest axis was reported to be an atypical presentation of visceral leishmaniasis in a six-year-old male mongrel dog. Upon histopathological analysis, a granulomatous inflammatory infiltrate, composed of plenty of plasma cells, lymphocytes, and histiocytes filled with amastigotes, was observed in the biopsy lesion. The diagnosis was confirmed by serological and immunohistochemistry assays. This case report reinforces that clinical and pathologist veterinarians should include leishmaniasis in the differential diagnosis of tumors and other chronic diseases of oral mucosa, especially in areas where the disease is endemic [69].

The relationship between parasites and immunotherapy is controversial, especially in leishmaniasis. It is well known that the increasing use of immunosuppressant medication by antitumor therapies makes patients susceptible to a new infection or turn symptomatic those asymptomatic *Leishmania* infected patients. On the other

*Current Challenges in the Association between Canine Leishmaniasis and Malignant Disorders DOI: http://dx.doi.org/10.5772/intechopen.114275*

hand, in an experimental breast cancer model *in vivo*, *Leishmania* spp. infection demonstrated an immunostimulatory effect in cancer treatment, triggering a strong cellular immune response, determined by an increase in the production of IFN-g and IL-2 and polarized toward Th1, as necessary in the defense against tumors [70].

#### **4. TVT and** *Leishmania* **infection association**

Canine TVT (CTVT) is a unique neoplastic entity, contagious and sexually transmitted especially those of street life and of reproductive age, and regarded as the oldest known mammalian somatic cell neoplasm in constant transmission. CTVT occurs worldwide with higher incidence in tropical areas, and has been mostly reported in dogs (*Canis familiaris*) and foxes (*Vulpes* sp.) [71, 72]. Due to the species' communication and licking habits, it may occur in different parts of the body as around the eyes, mouth, and nasal cavity, when it is called extragenital TVT [73]. When tumors and/ or their metastases occur in extragenital regions, other clinical signs may be present depending on the location of the affected organ [74–76], such as respiratory disorders, dyspnea, abdominal pain, and dysphagia [73, 77, 78].

Clinical signs often consist of genital lesions which, when present, may manifest as a single or multiple mass, friable on the foreskin or vulva [76, 77, 79], serosanguineous secretion, odor foul, and areas with or without necrosis [73]. In a case reported por Duzanski et al. [79] dog's tumor initially adhered to the adjacent tissues, and developed to a friable hyperemic mass of the cauliflower aspect. Metastasis may occur with lymphatic or visceral spread usually associated with underlying immunological impairment. In addition, TVT extragenital lesions, such as cutaneous, are common and have been reported even without primary genital lesions [71].

Atypical presentations of TVT are reported in association with *Leishmania* infection. Albanese et al. [21] reported an atypical primary cutaneous extragenital canine TVT with *Leishmania*-laden neoplastic cells in three subcutaneous round alopecic nodules, approximately 6–8 cm in diameter, located on the anterior and caudal dorsal region and in the ventral area of the neck. Intracytoplasmic *L. infantum* amastigotes were observed in the infiltrating macrophages. Intracellular amastigotes, 1–3 per cell, were present in vacuolated tumor cells. The patient received fluid therapy, erythropoietin 100 UI/kg, and intravenous injection of 0.075 mg/kg vincristine presenting regression of the nodules that decreased in size after one week, however, euthanasia was necessary due to a progressive worsening of the general condition of the dog.

A TVT was curiously reported associated with cutaneous metastasis in a female dog with leishmaniasis reactive left prescapular lymph node and subcutaneous nodular mass, not adhered to the musculature. Other visible signs were onychogryphosis, opaque, shineless, and brittle fur, with pruritic and lichenified exfoliative dermatitis in the left scapular region, ear tips and snout, and the presence of a few quantity of brownish-colored vulvar discharge with a putrid odor were the main clinical alterations. Cells with characteristics of TVT located in the genital mucosa, observed by cytology, demonstrated the presence of amastigote forms of the protozoan *Leishmania* sp. in the interior of the macrophages. TVT cells developed atypical metastasis in the cutaneous tissue in the region of the thirteenth rib. Due to the non-responsiveness of treatment and worsening of the clinical signs, the animal was euthanized [80].

Another atypical presentation of disseminated TVT associated with leishmaniasis occurred in an 8-year-old female dog that was pluriparous. There were no external

genital lesions, but TVT cells were present on the serous and endometrial surface in the histopathological examination of the uterine horns, in addition to cystic endometrial hyperplasia. The history of breeding with a stray dog indicates TVT sexual transmission, and then dissemination to the omentum, peritoneum, spleen, and liver, probably favored by immunosuppression [81].

Kegler et al. [82] made the first report describing infection of tumor cells by *L. infantum* in a genital TVT from an asymptomatic 2-year-old female boxer dog, with a vaginal serosanguineous discharge. Cytological and histological examinations were performed on a friable mass occupying the upper caudal part of the vagina revealing a monomorphic population of neoplastic round cells confirming to be canine TVT, with a presence of *L. infantum* amastigotes in tumor tissue. The authors highlight the transplantation of *Leishmania*-laden neoplastic as an alternative route of venereal transmission of leishmaniasis among dogs.

*Leishmania* sp. amastigotes were also detected in canine TVT of a 10-year-old, mixed breed, intact female dog, with no other clinical abnormalities otherwise. Tumor tissue imprint smears, cytological, and immunohistochemistry examination revealed *Leishmania* sp. amastigotes within infiltrating macrophages, confirmed by polymerase chain reaction (PCR). Histopathology of the lesion showed extensive infiltration of lymphocytes and plasma cells within the subepithelial vaginal stroma, with numerous neutrophils and macrophages with intracytoplasmic amastigote, and rare reminiscent canine TVT neoplastic cells within reactive area of fibrosis with newly formed collagen [71]. The authors discuss about the possibility of *Leishmania* infection may have started on or from the canine venereal tumor tissue, the latter option suggesting evidence of an alternative vector-independent route of transmission for canine visceral leishmaniasis in places where both diseases coexist.

Clinicopathological findings of canine TVT in leishmaniotic dogs can aid in the understanding of the biological behavior of TVT associated with leishmaniasis for future cases. In summary, TVT can harbor a large number of *Leishmania* parasites, and canine leishmaniasis may lower the immune defense against malignancy [83].

#### **5. Conclusions**

The cases of tumors that mimic leishmaniasis lesions indicate the need for an adequate cytological and histopathological diagnosis. Likewise, cases of clinical presentation of leishmaniasis that resemble tumors require special attention and may be related to atypical *Leishmania* species in a given region, as well as host-related conditions, such as immunosuppression. The association between leishmaniasis and tumors may mean that regular diagnostic methods are not sufficiently adequate. Therefore, the use of robust diagnostic tools, with greater precision and accuracy, such as molecular tests to identify the parasite DNA through PCR, can be used to avoid a misdiagnosis. In the same way, the association between leishmaniasis and tumors is a challenge as they can arise due to cases of immunosuppression induced or not by treatment, leading to hematological and biochemical changes that can compromise the effectiveness of the treatment. Atypical conditions related to the clinical presentation of tumors or leishmaniasis in dogs require special attention, especially in endemic areas, where the probability of association of both diseases becomes greater and should always be taken into consideration in the management and conduct of the patient in human and veterinary medicine.

*Current Challenges in the Association between Canine Leishmaniasis and Malignant Disorders DOI: http://dx.doi.org/10.5772/intechopen.114275*

#### **Acknowledgements**

This research was funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES (Finance Code 001), by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (26/211.680/2021) and Fundação de Amparo à Pesquisa e Desenvolvimento Científico e Tecnológico do Maranhão (APP-12233/22). HSR (CNPq 150336/2023-3) and FA-S (CAPES 88887.363006/2019-00) are postdoctoral research fellows. KC (315225/2021-1) and ALA-S (313348/2021-9) are research productivity fellows by Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq.

#### **Author details**

Helen Silva Ribeiro1 , Flávia de Oliveira Cardoso2 , Ana Lucia Abreu-Silva1 , Kátia da Silva Calabrese2 and Fernando Almeida-Souza1,2\*

1 Postgraduate Program of Animal Science—State University of Maranhão, São Luís, Brazil

2 Laboratory of Protozoology, Instituto Oswaldo Cruz-Fiocruz, Rio de Janeiro, Brazil

\*Address all correspondence to: fernandoalsouza@gmail.com

© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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*Edited by Fernando Almeida-Souza, Flávia de Oliveira Cardoso, Ana Lucia Abreu-Silva and Kátia da Silva Calabrese*

Leishmania parasites are a group of pathogens responsible for diseases known as leishmaniases. These pathologies affect predominantly the poorest people, mainly in tropical countries, exerting a high impact on mortality and morbidity rates. The absence of a vaccine and the reduced drug arsenal, associated with the diversity in the clinical presentation and hosts, highlight the complexity of the disease and its position as a worldwide public health problem. This book addresses different aspects related to leishmaniases, such as epidemiology, immunopathology, and the challenges of disease in humans and domestic animals. The information presented contributes to a better understanding of the Leishmania parasites and different clinical forms produced by infection, as well as their distribution around the world and their impacts on public health.

Published in London, UK © 2024 IntechOpen © andrewsafonov / iStock

Leishmania Parasites - Epidemiology, Immunopathology and Hosts

Leishmania Parasites

Epidemiology, Immunopathology and Hosts

*Edited by Fernando Almeida-Souza, Flávia de Oliveira Cardoso, Ana Lucia Abreu-Silva* 

*and Kátia da Silva Calabrese*