Papillomavirus-associated neoplasms of dogs and cats

. Papillomavirus oncogenesis as a benign process, clinically diagnosed as papillomatosis, is common in small domestic animals, in particular among cats and dogs, but in the nosological structure of neoplasms has a different ratio depending on the species. Recent data indicate the provocation of precancerous and neoplastic lesions in domestic species by the papillomatosis virus. Clinically, oncogenesis is associated with lesions of the skin and mucous membranes, which is determined by the tropicity of the virus, since the papillomavirus replication cycle is closely related to the differentiation of cells of the multilayer squamous epithelium, and in accordance with the morphological classification provokes the development of epithelial tumors without specific localization. The following neoplasms were identified in the structure of tumors of epithelial origin in dogs and cats: papilloma, squamous cell carcinoma and basal cell carcinoma. In statistical studies during the study period, organ-specific tumors in dogs amounted to 23.85%, in cats 12.5%. The concept of infectious oncology is used, which includes and combines the basic principles of infectious and oncological processes. Bibliographic analysis revealed the associativity of papillomavirus infection with specific neoplasms, depending on the taxonomy of the virus and the type of animal.


Introduction
Viruses cause specific types of tumors, which is confirmed by data on the development of viral oncogenesis in many animal species, while specific types of neoplasms are clonal cell proliferation developing against the background of viral infection, including infection with papillomaviruses [1,2,3,4].Papillomaviruses of dogs and cats are DNA-containing viruses, the genome of which is represented by circular double-stranded DNA enclosed in a capsid [5,6].They infect epithelial cells, which leads to their uncontrolled reproduction, the appearance of papillomas and malignant tumors of various localization [7,8].Most dogs and cats are asymptomatically infected, which makes it impossible in some cases to associate viruses with any lesions and with oncogenesis in particular, while individual papillomas (warts) can be caused by several types of papillomavirus.Deep sequencing of virions extracted from animal papillomas revealed the presence of several types of papillomaviruses [9].
Diagnosis of skin neoplasms is important for the possible prediction of oncogenesis.Clinical diagnosis of papillomatosis in animals is not particularly difficult.Neoplasms are characterized by exophytic growth, different localization, the surface mimics the structure of the skin, which allows them to be attributed to tumors of epithelial origin during visual examination.The surgical method of therapy is one of the most frequently used and effective, which further allows the use of the obtained material for histological examination [10,11].Recent studies are focused on proving the etiological role of various types of virus in the development of skin neoplasms, in particular nevi and carcinomas localized on or in the skin, and having melanocytic and epithelial origin, respectively.Therefore, histological diagnostics is not always sufficient to study oncogenesis, with the exception of cyto-and histogenesis of these neoplasms [12,13,14].
Statistical data depend on the classification approach to the oncological problem of animals, while the research results do not make it possible to study the dependence of the development of the oncological process with viral oncogenesis.As a rule, the dependence of morbidity on age, animal species, environmental factors, the presence of chronic inflammation, changes in host immunity as a result of increased use of immunosuppressive drugs, changes in environmental factors, increased exposure to ultraviolet radiation, which can lead to an increase in viral oncogenic potential [15,16], is studied.The purpose of this study is to study the spread of epithelial tumors without specific localization in the structure of ocological diseases of small domestic animals, using a morphological classification approach when isolating nosological forms.To conduct a bibliographic analysis of oncological diseases diagnosed as tumors of viral genesis and viruses with proven oncogenicity.

Study object
Within the framework of scientific research, the nosological profile of oncological diseases of small domestic animals, in particular dogs and cats, was studied.For histological examination, 662 samples obtained from animals in the period from 2013 to 2021 as a result of surgical manipulations during animal examination and invasive therapy were used.When analyzing the results obtained, species differentiation was carried out, neoplasms of cats and dogs were taken into account separately, followed by morphological verification.In the nosological profile of oncological diseases of dogs, 390 neoplasms were considered, 272 tumors of various genesis of cats.

Histological method of diagnosis
After morphological evaluation, the obtained material was previously fixed with a 10% formalin solution to preserve the structure of the tissue.After the process of dehydration and degreasing, the material was impregnated with paraffin.Sections 4-5 microns thick were made for staining with hematoxylin and eosin.The study of histological sections included the method of light-optical microscopy on the microscope "Microvar-3".The neoplasms were verified using morphological classification, according to which several groups were distinguished, including both benign and malignant tumors, depending on histogenesis, cellular origin, tissue and cellular atypism.

Results
There is no exact information about the prevalence of papillomavirus infection in animals.Diagnostics is mainly focused on histological studies of neoplasms, including papillomas.There are data on epizootics or mass cases of clinical manifestations of tumor diseases in animal populations, but they are limited and their informativeness depends on the classification approach.It is believed that the tumor process is not characterized by mass spread, as in infectious, although there is the opposite data, but this was explained by the fact that humans and pets have the same environment and exposure to the same carcinogens.
During the study period, 662 neoplasms were subjected to statistical analysis, of which 58.92% were tumors of dogs and 41.08% were tumors of cats, which indicates the advantage of the spread of oncological diseases in dogs.The nosological profile also differs from the species of animals.The structure of oncological diseases of dogs is quite variable and a special place is occupied by mesenchymal tumors, which make up 36.67% of all diagnosed neoplasms.This group is represented by lipoma, fibroma, fibrolipoma, rhabdomyoma, chondrosarcoma, myosarcoma, liposarcoma and hemangiopericytoma with different localization (Fig. 1.).The spread of tumors of dogs and cats, % (where: ОSОepithelial tumors without specific localization (organ-nonspecific); ОNОtumors of exo-and endocrine glands, as well as of epithelial integument (organ-specific); МО -mesenchymal tumors; ОМtumors of melanin-forming tissue; ОСB -tumors of the blood system; Тteratoms).
Epithelial tumors without specific localization were diagnosed in 23.71% of cases, and it is this group that is associated with the etiological role of papillomaviruses, in particular with the provocation of papillomas that make up 79.56% of the neoplasms of the group under consideration and squamous cell carcinomas that make up 13.98%, respectively.In addition to these tumors, basal cell carcinomas were verified by histological examination, the indicators of which are insignificant in the group of epithelial tumors.
It is noted that the specificity of the lesion, the determining criterion for the similarity and unity of the etiological factor of many infectious diseases with oncological potential, and papillomatosis is no exception here.They are united by their dynamism and the development of pathological changes within the body, with the development of a characteristic clinical picture and specific lesions on the background of oncogenesis.Microscopically, squamous papillomas of dogs are of epithelial origin, also consisting of vascularized fibrous tissue as a stromal component.The parenchyma of the neoplasm is represented by various morphological types of cells that mimic the structure of the epidermis.The basement membrane is preserved, there are signs of acanthosis and coilocytosis (Fig. 2.).Squamous cell carcinoma is a malignant tumor consisting of squamous epithelial cells and is characterized by branching cell strands.Microscopically, there is also a violation of the integrity of the basement membrane, the invasiveness of tumor cells into the dermis, keratinization of individual cells, the presence of atypical mitoses.The layered differentiation of the epidermis is disrupted, layered structures are formed, extracellular clusters of horny masses in the form of complexes and layers of atypical cells of the squamous epithelium.Tumor cells in a state of dyskeratosis and parakeratosis, atypical epidermal cells are arranged concentrically, while maintaining the ability to keratinize (Fig. 3).Thus, squamous cell carcinoma and papilloma of dogs are the most common epithelial tumors, in the overall structure of cancer incidence are 3.33% and 18.97%, respectively.
The nosological profile of oncological diseases of cats is somewhat different, but there is also a variety of tumors taking into account morphological features and criteria for histological typing in diagnosis.The most common group is mesenchymal tumors, which make up 41.91% of all diagnosed.But unlike dogs, further in prevalence, tumors of the blood system should be distinguished -20.96% and tumors of the exo-and endocrine glands, amounting to 16.54%, due to the most frequently diagnosed breast carcinoma in this group.Epithelial tumors without specific localization, in particular papillomas, squamous cell carcinomas and basal cell carcinomas in cats account for 12.13%, which is lower than the indicator noted in dogs.When analyzing organ-specific neoplasms, it should be noted that papillomas are not widespread and account for only 0.37% in the structure of oncological diseases, squamous cell carcinoma occurs much more often, in 7.35% of cases.

Discussion
Many oncological diseases are not considered as an infectious problem, although recent data indicate a number of pathogens that provoke the clinical manifestation of infection in the form of local or disseminated oncogenesis, with the predominant localization of the pathogen in a certain group of cells that are subsequently the progenitors of the tumor.Studies of the role of viruses in oncogenesis in animals are limited and less accessible, although there is evidence of the etiology of viruses in various animal tumors.The study of oncogenic animal viruses is of particular importance in the study of oncogenesis.The taxonomic affiliation of viruses that cause oncological diseases of animals is similar to human viral oncogenesis and some of them are quite widespread in the population.According to the latest scientific data, papillomaviruses are associated with various lesions of the skin and mucous membranes, which somewhat changes the idea of the causes of neoplasms.It is noted that due to their tissue specificity, papillomaviruses can be grouped, i.e. which affect skin cells, as well as affecting mucosal cells [17].
Until 2002, papillomaviruses were part of the Rarovaviridae family, but then they were separated into an independent Papillomaviridae family.In 2019, instead of the five-rank structure of the viral classification, a new taxonomic structure containing 15 ranks and applicable to all viruses was proposed, although so far none of the viruses has been assigned to all ranks and papillomaviruses are no exception.In accordance with the new classification, the papillomaviruses of cats and dogs are differentiated into the following ranks and taxa: realm Monodnaviria, kingdom Shotokuvirae, phylum Cossaviricota, class Papovaviricetes, order Zurhausenvirales, family Papillomaviridae, subfamily Firstpapillomavirinae.Viral genera belonging to the Firstpapillomavirinae subfamily are named according to the Greek alphabet.Papillomavirus of cats and dogs belong to the genus Lambdapapillomavirus, the genus Chipapillomavirus, the genus Taupapillomavirus and the genus Dyothetapapillomavirus (Table 1).
The genus Lambdapapillomavirus is represented by 5 species (Lambdapapillomavirus 1, 2, 3, 4, 5).Representatives of this genus infect carnivorous animals and cause papillomas of the skin and mucous membranes.Papillomas are proliferative benign tumors with a complex pathogenesis, characterized by numerous thin fibrovascular outgrowths covered with hyperplastic epithelium.Exophytic growth of squamous cell papillomas, accompanied by the formation of finger-like protrusions above the skin surface.Epithelial cells of neoplasms retain their usual polarity and maturation sequence [18].Since papilloma viruses promote replication and provoke proliferation of epithelial cells, which leads to severe epithelial hyperplasia, the development of endophytic papilloma (inverted papilloma) is also possible.Papillomavirus replication in the lesion can be detected histologically by the presence of cell changes caused by the virus.In neoplasms with exophytic and endophytic growth, numerous enlarged keratinocytes are noted, less often cells with shrunken nuclei surrounded by a transparent cytoplasmic halo or coilocytes [19].
The genus Chipapillomavirus is represented by 3 species (Chipapillomavirus 1, 2, 3).Representatives of this genus are associated with skin plaques and malignant verruciform epidermodysplasia in carnivores.As a result of the studies, a complete sequencing of the genome of papillomaviruses was carried out, which were isolated from pigmented plaques [20].
The genus Dyothetapapillomavirus is represented by 1 species (Dyothetapapillomavirus 1).The virus included in this genus was isolated from bovenoid carcinomas of cats [23].Four types of Felis catus papillomavirus (FcaPV) virus have been completely sequenced from domestic cats.Of these, FcaPV -2 and FcaPV -3 cause pigmented plaques and bovenoid carcinomas in situ.The plaque containing FcaPV -5 showed unusual histological features, including hyperplasia and papillomavirus-induced cell changes in the sebaceous glands and inside the hair follicles.It was proposed to classify FcaPV -3, -4 and -5 within the same genus, but at the moment FcaPV-5 is not classified (Table 2).Recent studies have also shown that most cats are asymptomatically infected.Papillomaviruses spread all over the world and negatively affect the health and well-being of cats all over the world [19,24].

Conclusion
Papillomaviruses of dogs and cats have been detected in various benign and malignant neoplasms of the skin.Papillomas characterized by exophytic and endophytic growth are most often clinically diagnosed.The etiological role in the development of pigmented plaques, squamous and bovenoid carcinomas, as well as malignant verruciform epidermodysplasia has been proven using molecular genetic methods focused on the isolation of the virus genome.
The manifestation and development of papillomatous lesions in the body is accompanied by a number of characteristic morphological changes, while the study of tumors is limited to the study of tissue affiliation.An integrated approach, using methods focused on the isolation of the pathogen, is necessary for the formation of the fundamental principles of the development of infectious oncology as an independent science.Such comparisons of oncological and infectious processes for the study of the nosological profile are possible only with the use of morphological classification of animal tumors, which allows focusing on the specific features of the structure of neoplasms that determine the belonging of the tumor in accordance with generally accepted diagnostic criteria.
Infectious oncology is a concept that includes and combines the basic principles of infectious and oncological processes.Identification of the pathogen genome in a number of infections requires additional diagnostic methods focused on proving its etiological role in clinical manifestation, and infectious oncology is no exception in this.Thus, the oncological process is a continuation of the infectious process or one of its stages.How this transition takes place taking into account the immune response of the body, whether the manifestation of infection in the form of a tumor process is mandatory or this process can be stopped.When studying in the form of independent knowledge, it is very difficult to come to a unified thinking and theoretical reconstruction of such a problem.A comprehensive diagnostic approach is required, based on diagnostic methods that allow detecting the entire replication cycle of the virus in lesions.A tumor is a specific lesion characteristic of an infectious disease, where its genome is localized, in contrast to a specific lesion of an inflammatory nature, where the pathogen is localized.

Table 1 .
Features of neoplasms depending on the genus and type of the Canis familiaris papillomavirus (CPV)

Table 2 .
Features of neoplasms depending on the type of Felis catus papillomavirus (FcaPV)