PhD in Veterinary Sciences for Animal Health and Food Safety

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Supervisor

Phd thesis

Re-evaluation of the clinical tumor-nodes-metastasis (TNM) staging system for canine oral tumors

● Scientific background/state of the art

Oral cancers are common in dogs and represent about 6% of all tumors in this species.1 The most frequent malignancies in the oral cavity are malignant melanoma (MM), squamous cell carcinoma, fibrosarcoma and osteosarcoma. Peripheral odontogenic fibroma and acanthomatous ameloblastoma are the more frequent benign tumors in this site.2,3 Oral tumors, in both human and veterinary medicine, are classified according to a TNM staging system. This model provides indications on prognosis, helps the clinician in planning the treatment and in standardizing the tumors classification.4 Survival rate varies according to the stage of the cancer, with longer survivals in dogs with a localized tumor without systemic involvement.a Tumor stages are based on evaluation of three parameters: the size of the primary tumor (T), the regional lymph nodes status (N) and the presence of distant metastasis (M).5 The clinical TNM staging system is obtained with data collected through physical examination, imaging techniques, and biopsies.6 The veterinary TNM staging system presents some limitations. The “T” factor refers only to the tumor size without considering its localization into the oral cavity and the different anatomical skull dimensions among dog breeds. The “N” parameter refers to the regional lymph nodes, but it does not specify which or how many nodes should be considered and removed. “M” indicates only the presence of distant metastasis without considering their number and localization.5,7

● Aims

The first aim of this research project is to develop a new TNM classification more specific than the current one and able to provide a more accurate prognosis in dogs with oral tumors.The “T” parameter will be replaced by an index (I) that will refer to both tumor and oral cavity size, while “N” factor will include more information such as number, size and distribution of the regional lymph nodes. Moreover, such as in human medicine,8 a new classification for MM will be developed including different histological data such as bone invasion, mitotic and Ki67 index in addition to the clinical features.9
A second aim of the PhD project is to evaluate the role of the new “I” index as predictor for recurrence after surgical removal for each oral tumor. Additionally, an algorithm will be created to help the clinician in the therapeutic decision-making process for the best treatment.

● Materials and methods

In this project, all the dogs affected by oral tumors presented to Veterinary Teaching Hospital of Grugliasco, since January 1st, 2010, will be retrospectively considered. Only patients without distant metastasis treated with surgery and/or radiotherapy that underwent computed tomography (CT) will be enrolled. We aim to include a minimum of seventy dogs. The “I” index will be calculated on CT images. The tumor size (maximum diameter, volume, surface) will be measured and then related to patient’s oral cavity size (e.g. mandible or maxilla length or volume).10 As a first step, in non-metastatic dogs with oral tumors, the Time to Recurrence (TTR), considered as the time from treatment to the first local recurrence, will be evaluated and then correlated with “I” and “T” parameters. Considering the malignant tumors only, the “I” index will be divided into groups based on the survival rate, similarly to what has been done for “T” in the current TNM classification.
In a second phase, the “I” index in dogs affected by MM will be improved also considering the tumor histological features. Accordingly, we will develop a function, with the DSV statisticians’ support to better define the “I” groups and to provide a more accurate range of time representative of the survival rate for each “I” group.
Once the new parameters will be defined, dogs with oral tumors will be classified with both staging systems (the standard TNM vs the modified one).

● Expected results

We expect to provide a new method to stage oral tumors in dogs. This system should be easy to apply and reliable.
The new clinical staging system, based on “I” parameter, should provide, both to the clinician and the owner, a more accurate prognosis for each single patient and it should support the clinician to select the best medical or surgical approach. Considering the tumor and the oral cavity ratio, it should be possible to better predict the achievement of local tumor control. When compared to the TNM staging system, the new one is expected to be more precise in defining tumor outcome, and in providing a more accurate prediction of the survival time and the disease-free interval.

• References

1. Verstraete FJ. Mandibulectomy and maxillectomy. Vet Clin North Am Small Anim Pract. 35(4):1009-39, 2005
2. Liptak JM. Oral tumors. In: Vail DM, Thamm DH, Liptak JM, eds. Withrow and MacEwen's Small Animal Clinical Oncology. 6th ed. St. Louis: Elsevier:432-448, 2020.
3. Mikiewicz M, Paździor-Czapula K, Gesek M, et al. Canine and Feline Oral Cavity Tumours and Tumour-like Lesions: A Retrospective Study of 486 Cases (2015-2017). J Comp Pathol.172:80-87, 2019.
4. Brierley J, O'Sullivan B, Asamura H, et al. Global Consultation on Cancer Staging: promoting consistent understanding and use. Nat Rev Clin Oncol.16(12):763-771, 2019.Mupparapu M, Shanti RM. Evaluation and Staging of Oral Cancer. Dent Clin North Am.62(1):47-58, 2018.
5. Owen LN: TNM classification of tumors in domestic animals, ed 1, Geneva, WHO, 1980.
6. Huang SH, O'Sullivan B. Overview of the 8th Edition TNM Classification for Head and Neck Cancer. Curr Treat Options Oncol.18:40, 2017.
7. Hahn KA, DeNicola DB, Richardson RC, Hahn EA. Canine oral malignant melanoma: prognostic utility of an alternative staging system. J Small Anim Pract. 1994;35(5):251-256.
8. Sobin LH. TNM: evolution and relation to other prognostic factors. Semin Surg Oncol.21(1):3-7 2003.
9. Smedley RC, Sebastian K, Kiupel M. Diagnosis and Prognosis of Canine Melanocytic Neoplasms. Vet Sci.9(4):175, 2022. https://doi.org/10.3390/vetsci9040175
10. Gioso MA, Carvalho VG. Oral anatomy of the dog and cat in veterinary dentistry practice. Vet Clin North Am Small Anim Pract.35(4):763-80, 2005.

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