Abstract: The only tumour known to be transmitted in nature by cell transplantation is the canine transmissible venereal tumour (TVT). The transmissible venereal tumour is transferred naturally by coitus and the tumour can be generated experimentally by inoculating living tumour cells into immunocompetent allogeneic dogs. Cytogenetic and immunological studies provide evidence that the tumour is transmitted by cells. Transmissible venereal tumour from various geographical origins is shown to have widespread and distinct chromosomal abnormalities, according to cytogenetic research. The basic material for comparative banding pattern analysis of transmissible venereal tumour chromosomes is now available, thanks to the definition of normal dog chromosomal banding patterns. These studies may help researchers figure out whether this rare tumour has a common cause or if it has recurred in household dogs. Immunological research also suggests that the transmissible venereal tumour is transmitted by cell transplantation. The immune response to the transmissible venereal tumour in dogs has proven that the tumour is antigenic and that immunological processes are involved in the generation of spontaneous regressions of this neoplasm.
INTRODUCTION
The tumour is a hereditary condition. Even though neoplasms occur in a wide range of tissues and are induced by a variety of agents including change in environment1, viruses, mutagenic chemicals and radiation, damage to the cellular genome is a common trait of practically all neoplasms. Decreased immunity may also predispose to neoplasms so proper diet is important to maintain the body's immune system2. Carcinogen-induced genetic damage is thought to be random and many changes may be insignificant3. A Canine Transmissible Venereal Tumour (CTVT) has various synonyms like infectious granuloma, sticker tumour, sticker's sarcoma, canine condyloma, Transmissible Venereal Tumour (TVT), venereal granuloma, transmissible lymphosarcoma, contagious venereal tumour, transmissible venereal sarcoma, contagious lymphosarcoma and infectious sarcoma4. A horizontally spread venereal round cell tumour in dogs is known as a transmissible venereal tumour. It is a naturally occurring tumour that is passed from animal to animal during copulation by living tumour cells. It typically affects the external genitalia and, in some circumstances, the internal genitalia, however, it has been seen in extra-genital locations5. The tumour cell itself is assumed to be the transmissible factor that causes this disease6. It iscontagious cancer that spreads with living cells and does notcross the major histocompatibility complex between dogs and other Canidae family members like wolves, jackals,foxes orcoyotes. These tumours are still a severe problem in areas where dog breeding is unregulated and they are easily transmitted from one dog to the next through damaged skin and mucosa5. In tropical and subtropical locations, this disease is most commonly observed in roaming, sexually active dogs7. One of the side effects of tumoral malignancy is thegradual weight loss in animals, which might escalate to cachexia8. This condition causes serosanguineous discharge throughthe external genitalia,pain andhaemorrhages in dogs. Except in puppies and immune-compromised dogs, the tumour rarely progresses. Some invasive substances that suppress the host's immune response may cause the lesions to persist. The tentative diagnosis is made based on the animal's history and clinical observations. The cytological and histological data are used to make a definitive diagnosis9. This condition has been treated with a variety of treatments, including surgery, radiation and chemotherapy10.
Etiopathology: Novinsky first identified canine transmissible venereal tumour in 1876, demonstrating that it could be transplanted from one susceptible host to another by inoculating it with tumour cells11. Some scientists linked this neoplasia to a viral agent due to cytoplasmatic inclusions identified in tumoral cells, despite the tumour not being reliably transmitted by cell-free extracts12. The current agreement is that transmissible venereal tumour is caused by allogeneic cellular transplants and that the aberrant cells of the neoplasm serve as transmission vectors. During mating or licking of afflicted genitalia, the exfoliation and transplantation of neoplastic cells during physical contact offer the main method of transmission into vaginal mucosa, as well as onto nasal or oral mucosa13. The presence of any mucosal lesion or loss of mucosal integrity facilitates implantation of the tumour14. The tumour begins to spread 15 to 60 days after implantation. Transmissible venereal tumours can grow slowly and inexorably for years, or they can be invasive and eventually become malignant and spread15. Transmissible venereal tumours are immunogenic and it has been seen that the host's immune system plays a key role in preventing tumour growth and spread16. This tumour may have a higher proclivity to metastasis in young dogs or dogs with a weakened immune system. Males are more likely than females to develop metastases. In less than 5-17 percent of cases, metastasis has been documented. Extragenital lesions have been observed in isolation as well as in conjunction with genital lesions13. Neoplastic foci on the genitalia could be seen in cases where extra-genital lesions are present, implying that most, if not all, cases are secondary to genital lesions13. Although spontaneous remission has been reported in experimental transplantation, it has yet to be proven in real-life situations.
Mode of transmission: The transmissible venereal tumour is a histiocytic tumour that can be spread from dog to dog through coitus, biting, licking, or sniffing the tumour affected areas5. It spreads by implanting live tumour cells in the mucosal membrane, especially if the surface is brokenor has lost its integrity. The conclusion that the tumour is spontaneously transmissible as an allograft was established after three crucial discoveries. For starters, it can only be created in the lab by transplanting live tumour cells rather than killed or filtered cells. Second, tumour karyotins are aneuploid, but all tumours from various geographic locations contain distinct marker chromosomes. Third, a LINE insertion near c-myc has been reported in all of the tumours analyzed till now and it can actas a diagnostic marker to confirm CTVT17.
It is primarily conveyed to the vaginal organs during sexual intercourse, but it can also impact the skin through direct tumour cell implantation during skin-tumour mass contact. Transplantation occurs when intact host tumour cells lose their production of MHC class I and II molecules, allowing the tissue to be transferred to a healthy animal via skin-to-mucosa contact18. Tumour cells generate an immunological response in healthy receivers, hence they could only be transferred between healthy animals who had the same MHC or into immunocompromised recipients. Cells can be produced from lymphohistiocytic cells that have been mutated by viruses, chemicals, or radiation and these clones of tumour cells can subsequently be propagated through allogeneic transplantation6. Clonal transmission is predicated on the fact that dogs have 78 chromosomes, with 76 being acrocentric. The number of chromosomes in cells separated from animals from various geographic regions ranges from 57 to 59, with 15 to 17 chromosomes metacentric or sub-metacentric. In addition to this distinguishing trait, most samples obtained from around the world show consistent and specific chromosomal abnormalities, such as the insertion of a LINE-1 near the c-myc oncogene in the Canine Transmissible Venereal Tumour (CTVT) genome. This genomic rearrangement has not been found in any other normal dog tissue and can be utilised to diagnose this condition19,20.
Treatment: The transmissible venereal tumour has been treated with a variety of procedures, including surgery, radiotherapy, immunotherapy, biotherapy and chemotherapy. Surgery has been widely used to treat small, localised transmissible venereal tumours, while the recurrence rate in cases of large invasive tumours might be as high as 50-68 percent. Laser surgery may be conducted at the same hand speed as that performed with a scalpel blade, with the added benefits of no haemorrhage21. Recurrence can potentially be caused by contamination of the surgical site with transmissible venereal tumour cells. Steroids can be used as analgesic adjuncts post-operatively22. Radiosensitivity has been demonstrated in transmissible venereal cancers using orthovoltage and cobalt23. There have also been reports of biotherapy studies. Calmette-bacillus guérin's (BCG) was administered intramuscularly for three weeks with occasional success24. Combined BCG and vincristine therapy is more effective than vincristine in treating CTVT, suggesting that the clinical course of this disease may be altered by immunochemotherapy25. ‘Phonophoresis’ using low frequency (18 to 100 KHz) or power ultrasound can also be helpful26.
Chemotherapy has proven to be the most successful and practical treatment, with vincristine sulphate being the most commonly prescribed medication. Vincristine is given intravenously (IV) once a week at a dose of 0.5 to 0.7 mg m–2 of body surface area27 or 0.025 mg kg–1. The progression of the lesions is gradual, but it is especially evident and significant at the start of treatment. In 5 to 7% of patients, cytostatic drugs like vincristine can produce myelosuppression and gastrointestinal symptoms, resulting in leukopenia and vomiting. They may cause both peripheral neurotoxicity, consisting mainly of peripheral neuropathy and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia or even coma28. As a result, a complete white blood cell count is recommended before each dosage. Ifthe white blood cell count falls below 4,000 mm3, the next vincristine treatment should be delayed for 3 to 4 days and the amount can be reduced to 25% of the dosage29.
Numerous different chemotherapeutic agents often used totreat transmissible venereal tumourinclude cyclophosphamide (at 5 mg kg–1PO, for 10 days as a one-drug therapy or as a combination therapy with prednisolone at 3 mg kg–1, for 5 days), vinblastine weekly(at 0.1 mg kg–1IV, for 4 to 6 weeks) and methotrexate (at 0.1 mg kg–1PO, every other day) or a combination of all three. Treatment with vincristine alone, on the other hand, does not appear to be beneficial5. To treat resistant cases, doxorubicin2 (at 30 mg m–1 IV, 3 doses every 21 days) can be administered9. When chemotherapy fails to completely eradicate the tumour, electro-cauterization or cryocauterization may be used. Small residual lesions can go away on their own after 1 or 2 weeks after therapy. Radiotherapy can be used where chemotherapy fails to resolve the problem. Radiotherapy directly interferes with the primary tumour and possibly reverses some immunosuppressive barriers within the tumour microenvironment-ideally, recovering the role of the primary tumour as an immunogenic hub30.
CONCLUSION
A transmissible venereal tumour is a naturally occurring tumour in dogs that is transmitted from animal to animal during copulation by live tumour cells and primarily affects the external genitalia, with the internal genitalia only rarely affected. In the vast majority of cases, treatment is effective and dogs who have spontaneous regression grow immune to future tumour challenges. It is the most prevalent neoplasia of the canineexternal genitalia in tropical and sub-tropical metropolitan areas. Due to its geographic frequency among tropic and sub-tropical stray dog populations, it has a highly transmissible nature among dogs and the ability to transfer to other wild animals such as foxes, jackals and coyotes. One factor for the high frequency appears to be a huge stray dog population and unregulated sexual behaviour. This sort of tumour is more common in sexually active male and female canines (2-8 years old) that are free to wander. In dogs, especially in underdeveloped countries, management has been difficult since most owners cannot afford the cost of surgical procedures and/or radiotherapy. Clinicians and owners must balance the possible advantages to the patient against the interestto breed the animal until sufficientinformation on reproductive effects becomes available.
SIGNIFICANCE STATEMENT
This review ascertains the nature of canine transmissible venereal tumour along with its etiopathology, mode of transmission and showcases the various treatment procedures that have proven successful as per the studies conducted.