Revista Cienfica, FCV-LUZ / Vol. XXXV Recibido: 04/04/2025 Aceptado:19/05/2025 Publicado: 29/05/2025 hps://doi.org/10.52973/rcfcv-e35673 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico 1 of 6 Clinic, macroscopic, cytomorphologic and histopathologic features of canine transmissible venereal tumor in two bitches: First report from Kyrgyzstan. Clinical case Caracteríscas clínicas, macroscópicas, citomorfológicas e histopatológicas del tumor venéreo transmisible canino en dos perras: Primer informe de Kirguistán. Caso clinico. Fatih Hatipoglu 1,2,* , Ali Risvanli 3,4 , Nariste Kadiraliyeva 5 , Iskhak Zhumagulov 4 ¹ Selcuk University, Faculty of Veterinary Medicine, Department of Pathology, 42250, Konya, Türkiye ² Kyrgyz-Turkish Manas University, Faculty of Veterinary Medicine, Department of Pathology, 720038, Bishkek, Kyrgyzistan ³ Firat University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynaecology, 23119, Elazıg, Türkiye ⁴ Kyrgyz-Turkish Manas University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynaecology, 720038, Bishkek, Kyrgyzistan ⁵ Kyrgyz-Turkish Manas University, Faculty of Veterinary Medicine, Department Histology, 720038, Bishkek, Kyrgyzistan * Corresponding author: ap@selcuk.edu.tr ABSTRACT Canine transmissible venereal tumour (CTVT) is a spontaneously arising, contagious neoplasm in dogs that propagates via the direct implantaon of viable tumour cells between animals. Transmission predominantly occurs during mang, leading to the development of growths chiefly on the external genitalia of both males and females. In this case report, it is aimed to describe the clinical, cytological, macroscopic and histopathological findings of two bitches with CTVT. In the clinical examinaon of both bitches, an 8-month-old Husky and 2-years-old Alabai crossbred, protruding, irregular, ulcerated and bleeding structures were observed in the vulva. In cytological examinaons, round to polyhedral-shaped cells with an eccentrically located nucleus, mulple mitosis and the characterisc disnct, cytoplasmic vacuolaons with clear outlines were observed. Histopathological examinaons of both cases revealed round or polyhedral neoplasc cells arranged in solid sheets or rows supported by fibrovascular connecve ssue septa. Numerous mitoc figures were also observed together with tumor cells. Tumor cells with indisnct cell borders had eosinophilic and finely granular cytoplasmic structures. Necroc changes in tumor cells and hemorrhage foci were also observed. A tumor cell embolism consisng of tumor cells adherent to the vessel wall was observed in the vessel lumen. It is think that these cases are important because they are being reported for the first me in Kyrgyzstan. Key words: Canine transmissible venereal tumor; clinic; cytomorphologic; macroscopic, histopathologic. RESUMEN El tumor venéreo transmisible canino (TVTC) es un cáncer transmisible de origen natural que se propaga entre perros mediante la transferencia alogénica de células cancerosas vivas. La enfermedad suele transmirse durante el coito y da lugar a la aparición de tumores asociados con mayor frecuencia a los genitales externos de perros machos y hembras. En este informe de caso, se pretende describir los hallazgos clínicos, citológicos, macroscópicos e histopatológicos de dos perras con CTVT. En el examen clínico de ambas perras, una cruza de Husky de 8 meses y una Alabai de 2 años, se observaron estructuras protuberantes, irregulares, ulceradas y sangrantes en la vulva. En los exámenes citológicos, se observaron células de forma redonda a poliédrica con un núcleo situado excéntricamente, mitosis múlples y las caracteríscas vacuolaciones citoplasmácas con contornos claros. Los exámenes histopatológicos de ambos casos revelaron células neoplásicas redondas o poliédricas dispuestas en sábanas o hileras sólidas sostenidas por septos de tejido conecvo fibrovascular. También se observaron numerosas figuras mitócas junto con las células tumorales. Las células tumorales con bordes celulares indisntos presentaban estructuras citoplasmácas eosinolicas y finamente granulares. También se observaron cambios necrócos en las células tumorales y focos de hemorragia. En la luz del vaso se observó una embolia de células tumorales adheridas a la pared del vaso. Se cree que estos casos son importantes porque se nofican por primera vez en Kirguistán. Palabras clave: Tumor venéreo transmisible canino; clínica; citomorfológico; macroscópico, histopatológico

Revista Cienfica, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico INTRODUCTION Canine transmissible venereal tumour (CTVT) is the oldest documented contagious cancer in dogs, with the first descripons dang back to the nineteenth century. It has been variously termed canine infecous sarcoma, venereal granuloma, transmissible lymphosarcoma, round-cell sarcoma, and Scker’s sarcoma [1 , 2 , 3]. Clinically, CTVT most oſten manifests on the mucosal surfaces of the external genitalia in both male and female dogs. As transmission typically occurs during coitus, the disease predominantly affects young, sexually mature animals. Although venereal spread is the primary route of infecon, CTVT cells can also be transplanted experimentally to other body sites and may disseminate between dogs via licking, bing, or direct contact with exisng tumours [4 , 5 , 6] This tumor has also been observed in other canid species such as coyotes (Canis latrans), jackals (Canis aureus), wolves (Canis lupus), and foxes (Vulpes vulpes) [7]. It is prevalent worldwide and considered endemic in over 90 countries [8]. Both male and female dogs (Canis lupus familiaris) can be infected, with an incidence rate of 35.5% in males and 64.5% in females. The occurrence is typically highest during the peak sexual acvity, especially in female dogs during their estrus period. Dogs of any breed, age, or sex can be suscepble to this tumor [9 , 10]. Genomic invesgaons indicate that CTVT originated from the somac ssues of a single canine ancestor approximately 11 000 years ago [11 , 12]. Despite its ancient emergence, me- resolved phylogenies demonstrate that global CTVT populaons only diverged within the past few hundred years [8 , 11 , 12]. Cytogenec analyses consistently demonstrate that CTVT cells carry an anomalous chromosomal complement—typically 57 to 64 chromosomes, averaging 59—whereas normal canine somac cells maintain 78 chromosomes [13]. The clinical presentaon of CTVT can vary among dogs depending on the locaon of the tumors. Infected dogs exhibit symptoms such as bloody prepual and vaginal discharges, genital swelling, reduced penile exposure, skin with ulcerave nodules, and a tendency to sniff the infected lesions [9 , 14]. Metastases have been reported in organs such as tonsils, liver, kidney, spleen, brain, eye, skin, peritoneum, skeletal muscle, tongue, mesenteric lymph nodes and maxillary bone [5 , 10 , 15 , 16 , 17 , 18]. When studies on CTVT are examined, it is seen that this study is the first report presenng an evaluaon of the occurrence of CTVT in Kyrgyzstan. The aim of this case report was to describe the clinical, cytological, macroscopic and histopathological findings of two dogs with CTVT in Kyrgyzstan. MATERIALS AND METHODS Cases descripons No experimental animals were used in this study. The cases studied were part of roune clinical pracce and surgical resecon of tumors were performed at the Faculty of Veterinary Medicine of Kyrgyz-Turkish Manas University, December 2023 and April 2024, where they were brought for treatment by treang veterinarians at the request of their owners and not for reasons related to the study. The animal owners were informed before the operaon and a consent form was obtained. In conducng this study, it is important to note that ethical clearance was not sought or required. This arcle represents a case report, not a formal research study involving experimentaon or clinical trials on animals. Two bitches were brought for examinaon to the clinics of the Kyrgyz-Turkish Manas University Faculty of Veterinary Medicine in Bishkek, Kyrgyzstan. The first case was an 8-month-old, bitch, Husky, the second one was (2-years-old), bitch, Alabai crossbred. In the first case, the owner reported that the bitch had a good appete and had difficulty urinaon. The dog in the first case was adopted 6 days ago and was brought to the clinic because it was thought to be in heat. Therefore, there is no informaon about it before. In the second case, it was reported that despite anbioc treatment for the wounds on the bitch’s vulva in another clinic, there was no improvement and it was brought to the Veterinary Faculty clinics for treatment. In the second case, as part of a project within the scope of the rehabilitaon of stray dogs, it was learned that one week ago anbioc treatment was applied to wounds on the vulva in another clinic. For this reason, no informaon about the animal’s previous life was obtained. As the result of this treatment was not obtained, the bitch was brought to the clinic of the Veterinary Faculty for treatment. Inially, imprint cytology preparaons were made from the cut surfaces of the excised masses by gently touching or scraping the ssue. These smears were air dried, stained using a Diff Quick kit (Fast Color Kit, DDK Italia, Italy), and examined under a light microscope (Euromex IS.1153.EPL, The Netherlands) for cytological assessment. Thereaſter, representave ssue samples were fixed in 10 % neutral buffered formalin for 24 hours, processed rounely, and embedded in paraffin. Secons 5 µm thick were cut on a microtome (Leica RM2255, Germany) and stained with hematoxylin and eosin following standard protocols [19]. RESULTS AND DISCUSSION The CTVT is a contagious malignancy in dogs that propagates via the transfer of living tumor cells between animals. Spread most frequently during mang, it gives rise to mass lesions predominantly on the external genitalia of both males and females. CTVT has now been documented on every connent where dogs are present [8 , 15 , 20 , 21 , 22]. This disease poses a significant global canine health burden and is especially common in regions with large stray dog populaons and unregulated breeding behaviors [15 , 22]. Infecon occurs chiefly in young, sexually acve dogs and shows no clear preference for any parcular breed or sex [8 , 20 , 23]. However, no reports have been found regarding the occurrence of CTVT in Alabai or Alabai crossbreed dogs. When the studies on the subject are evaluated, it is noteworthy that this diagnosed CTVT case was reported for the first me in an Alabai crossbreed. CTVT is disnguished by its ability to spread through the direct implantaon of viable tumor cells into previously unaffected ssues—most oſten during coitus but also via close social interacons such as sniffing, licking, or bing [15 , 23]. When located on the genital mucosa, these tumors exhibit a characterisc clinical presentaon. These are usually localized, hemorrhagic, possess a cauliflower-like growth paern, and a friable texture. Tumors may be single or mulple, ranging from a small nodule to a large mass [8 , 15 , 22 , 23]. 2 of 6

Canine Transmissible Venereal Tumor in Two Bitches / Hapoglu et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico In the clinical examinaon of both dogs, protruding, irregular, ulcerated and bleeding structures were observed in the vulva (FIG. 1 A-B). Aſter general checks, the masses along with other surrounding structures in the vulva of both dogs were surgically removed and sent to the pathology laboratory for diagnosis. In the first case (Husky), the mass removed by surgery was 4.5x2.5x2 cm in size, had a friable consistency, grayish-white in color, and occasional bleeding and ulcerated areas were noted. In the second case (Alabai crossbred), the mass was protruding from the vulva, cauliflower-like and had an ulcerated appearance. Nodular structures protruding from the vaginal mucosa were also noted. The mass was 19x12x10 cm in size, hard in consistency and the cut surface was yellowish-gray in color, and lobular and occasionally oval-round structures were also seen (FIG. 2 A-B). On thorax radiography (Poskom PXP-40HF, Korea), a small number of structures of different sizes in the lung that may be related to metastasis were observed (FIG. 3). FIGURE 1. A. Clinical appearance of protruding, irregular, ulcerated and bleeding structu- res in the vulva, B. Preoperave appearance of the vulvar mass, (Alabai crossbred bitch). FIGURE 2. A. Cauliflower-like mass in the vaginal lumen with a hard consistency and a yel- lowish-gray color on the cut secon, (second case), B. Lobular and occasionally oval-round nodular structures in the vaginal lumen, (second case). In both cases, similar clinical signs were reported by the owners and the extragenital appearance and macroscopic structures of the masses were consistent with those reported previously [4 , 5 , 6 , 8 , 23]. FIGURE 3. Thorax radiography. Foci of different sizes (arrows) in the lung that may be associated with metastasis (second case). Similarly, to other neoplasms, CTVT requires meculous anamnesis and clinical examinaon as the first steps in the diagnosc procedure. Addionally, this tumor exhibits characterisc cytological features; hence, cytology is oſten used to provide a prompt diagnosis of CTVT [15 , 22 , 23]. Although histopathology remains the gold standard for diagnosing CTVTs, cytological evaluaon—a fast, low cost, and field applicable method—has oſten been overlooked [13]. In comparison to roune histopathological analysis, cytology provides equally accurate, if not superior, confirmaon of CTVT [24]. This diagnosc benefit is parcularly important given that the microscopic appearance of TVT can closely resemble other roundcell neoplasms—such as hisocytoma, lymphosarcoma, or mast cell tumor—especially when lesions occur at extragenital sites [15]. In the cytological examinaons of the presented cases, round to polyhedral-shaped cells (FIG. 4 A-B-C) , with an eccentrically located nucleus, mulple mitosis (FIG. 4 A-C) and the characterisc disnct, cytoplasmic vacuolaons with clear outlines (FIG. 4 A-B-C) were observed. A marked difference in shape and size was observed in the nuclei of some tumor cells (anisonucleosis) (FIG. 4 B). 3 of 6

Revista Cienfica, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico FIGURE 4. Cytologic findings of first case (A) and second case (B,C). Round to polyhedral-shaped tumor cells, with an eccentrically located nucleus, mulple mitosis (black arrows), the characterisc disnct, cytoplasmic vacuolaons with clear outlines (red arrows), marked difference in shape and size in the nuclei of some tumor cells (anisonucleosis) (white arrows), Diff-Quick, 40x Disnct, sharply demarcated cytoplasmic vacuoles are the most characterisc finding in TVT cytology, with their size and number varying according to the individual tumor cell’s morphology. In cases where these vacuoles are absent, TVT cells can closely resemble other round cell neoplasms, although the overall cellular shape and the tumor’s anatomical locaon oſten provide crical diagnosc clues [13]. Addionally, TVT cells typically exhibit a relavely low nuclear to cytoplasmic rao alongside the disnct punctate vacuoles—features that together help to disnguish this neoplasm on cytological smears [25]. These changes reported in the cytological examinaon of CTVT, which is recommended by the researchers as a rapid and reliable diagnosc method, were observed in both cases. Histopathological examinaons of both cases revealed round or polyhedral neoplasc cells arranged in solid sheets or rows supported by fibrovascular connecve ssue septa. Numerous mitoc figures were also observed together with tumor cells (FIGS. 5 A-B and 6 A). Tumor cells with indisnct cell borders had eosinophilic and finely granular cytoplasmic structures. The nuclei of tumor cells were usually large and round, and size variaons were noceable (FIGS 5 A-B and 6 A). Tumor cell nuclei had centrally located nucleoli and some nuclei showed marginal hyperchromasia (FIG. 5 B). FIGURE 5. A-B. Round or polyhedral neoplasc cells arranged in solid sheets or rows supported by fibrovascular connecve ssue septa. Numerous mitoc figures (black arrows), together with tumor cells, H&EX40, B. Marginal hyperchromasia (white arrow), H&E, 40x, (First Case). Neutrophil granulocytes were also found along with tumor cells in ulcerated areas resulng from degeneraon and desquamaon of vaginal epithelium. Mononuclear cell infiltraon was observed in some areas along with tumor cells. In some secons, necroc changes in tumor cells (FIG. 6 B) and hemorrhage foci (FIG. 7 B) were observed. In one secon, a tumor cell embolism consisng of tumor cells adherent to the vessel wall was observed in the vessel lumen (FIG. 7 A-B). FIGURE 6. A. Round or polyhedral neoplasc cells with mitoc figures (black arrows) H&E, 40x, B. Necroc changes in tumor cells (red stars) and neoplasc cells, H&E, 10x, (Second Case) FIGURE 7. Tumor cell embolism consisng of tumor cells adherent to the vessel wall in the vessel lumen (red arrow) (A and B), fibrovascular connecve ssue septa (black arrow) (A), H&E, 10x, B. Perivascular hemorrhage foci (white arrows), H&E, 40x, (Second Case) Histopathological changes previously reported by the researchers [4 , 5 , 10 , 15] in tumor ssue and tumor cells in CTVT cases were observed in both cases. In addion, inflammatory changes were detected in ulcerated areas in these cases. In second case, necroc changes in tumor cells (FIG. 6 B) were noced in some areas. Hendrick [26] stated that these tumors are oſten infiltrated by varying quanes of lymphocytes— occasionally clustering into aggregates—along with plasma cells, eosinophils, and macrophages. In lesions undergoing 4 of 6

Canine Transmissible Venereal Tumor in Two Bitches / Hapoglu et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico regression, there is typically marked inflammaon accompanied by areas of necrosis and fibrous ssue formaon. Foster [27] further reported that CTVT can develop mulfocal necroc foci and may regress spontaneously through lymphocyte mediated cytotoxic mechanisms. In the presented cases, the observaon of lymphocyte infiltraon in some areas together with necroc tumor cells supports these views [26 , 27]. However, it is thought that necrosis may develop as a result of inadequate vascularizaon as a result of rapid growth of tumor ssue. Metastac disseminaon of CTVT has been reported in subcutaneous ssues, skin, regional lymph nodes, eyes, tonsils, liver, spleen, oral and nasal mucosa, brain, and bone marrow. Although fewer than 5 % of CTVT cases develop metastases, evidence indicates that such systemic spread markedly worsens clinical outcomes and is a documented cause of mortality. These rare but severe events highlight the crical need for prompt diagnosis and aggressive management when extragenital involvement is suspected [2 , 5 , 10 , 15 , 16 , 17 , 18]. In the second case (Alabai crossbred), structures related to lung metastasis were seen on thorax radiography (FIG. 3). In the same case, microscopic examinaons showed tumor cell embolism adhered to the vessel wall and in the vessel lumen in a secon (FIG. 7 A-B), which was evaluated as evidence that hematogenous metastasis had formed in this case. It should not be ignored that lung metastasis of CTVT, which has been reported by some invesgators [28 , 29], may lead to respiratory problems since it was also observed in this case. CTVT is amenable to mulple treatment strategies. Tradionally, management has centered on surgical excision of the lesion, which is frequently followed by single agent or combinaon chemotherapy protocols, and occasionally by radiotherapy. Surgical removal is reserved for solitary, welll ocalized masses and is generally avoided in cases with widespread or metastac involvement. Because convenonal excision carries a risk of tumor cell implantaon at the wound site, techniques such as electrosurgical resecon or cryosurgery are oſten employed as safer alternaves. Published recurrence rates aſter standard surgical excision vary widely, from approximately 12 % to 68 % [2 , 7 , 22 , 30]. Vincrisne is the most preferred and most reliable chemotheropeuc agent that can used even cases with metastase outside the genital organs. Vincrisne is an agent that inhibits the cell division during the metaphase stage. For this reason, it should be administered slowly and ensure that it does not inflitrate to subcutaneous ssue during the intravenous administraons [22 , 30]. Combinaon chemotherapy remains the cornerstone of CTVT treatment, with the classic regimen of vincrisne, cyclophosphamide, and methotrexate demonstrang high efficacy and remission rates. Several alternave protocols have been evaluated—including cyclophosphamide with prednisolone, vinblasne combined with cyclophosphamide or methotrexate, and adjuncve vincrisne–ivermecn therapy—to opmize outcomes and address drug resistance [2 , 7]. In parallel, immunotherapy has evolved from early passive techniques (convalescent serum or whole blood transfusion, tumor cell homogenate vaccines with bacterial adjuvants) to sophiscated acve strategies, such as cytokine gene delivery (interleukin 2, IL 6, IL 15 plasmids), dendric cell vaccines loaded with tumor exosomes, and exploraons of oncolyc viral vectors, all aimed at potenang host cellular immunity against CTVT [15]. CONCLUSIONS In the presented case report, CTVT was diagnosed to the cases due to the appearance of round-oval shaped tumor cells, mitoc figures and pronounced vacuoles in the cytoplasm in the cytological examinaons of both cases. Changes observed in tumor ssue and cells during histopathological examinaons support this diagnosis. When the studies conducted on the distribuon and prevalence of CTVT in dogs in the world and the literature that can be examined were evaluated, it was deemed appropriate to share these cases due to the lack of any reports in Kyrgyzstan related to CTVT. For this reason, these case reports are important because they are being reported for the first me in Kyrgyzstan. It was deemed appropriate to report the clinical, cytological, macroscopic and histopathological findings of CTVT that diagnosed in two different cases in order to contribute to the field of veterinary oncology and to be useful to clinicians. Conflict of interest There is no conflict of interest between the authors Funding This research received no external funding. Informed Consent Statement The animal owners were informed before the operaon and a consent form was obtained. In conducng this study, it is important to note that ethical clearance was not sought or required. 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