Indian Journal of Animal Research

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Indian Journal of Animal Research, volume 58 issue 1 (january 2024) : 141-145

Tumour Node Metastasis Staging as Prognostic Indicator for Surgical Decision-making Tool in Canine Mammary and Superficial Neoplasms: A Survival Analysis Study

Sudheesh S. Nair1,*, M.K. Narayanan1, Sainulabdeen Anoop1, B. Dhanush Krishna1, Usha Narayanapillai1, K.D. John Martin1
1Department of Veterinary Surgery and Radiology, College of Veterinary and Animal Sciences, Kerala Veterinary and Animal Sciences University, Thrissur-680 651, Kerala, India.
Cite article:- Nair S. Sudheesh, Narayanan M.K., Anoop Sainulabdeen, Krishna Dhanush B., Narayanapillai Usha, Martin John K.D. (2024). Tumour Node Metastasis Staging as Prognostic Indicator for Surgical Decision-making Tool in Canine Mammary and Superficial Neoplasms: A Survival Analysis Study. Indian Journal of Animal Research. 58(1): 141-145. doi: 10.18805/IJAR.B-4808.
Background: Streamlining surgical approaches for various neoplasms in dogs utilising tumour node metastasis (TNM) staging and assessment of quality of life (QOL) of a cancer patient has always been a challenge in veterinary surgical oncology. The study was intended to assess TNM staging as a prognostic indicator and basis of surgical decision in canine mammary and superficial neoplasms.

Methods: Thirty six cases of canine neoplasms were studied in three groups  based on TNM staging of neoplasms. The histopathology of the excisional biopsy samples were correlated with TNM stages and the response to treatment was assessed using Modified Karnofsky performance scales in dogs and response evaluation criteria in solid tumours (RECIST). The survival status of the animals was compared by Kaplan Meier analysis and results were interpreted using the log rank test. 

Result: The TNM staging formed the basis for surgical decision making and direct correlation was detected between TNM staging and histopathological grading of neoplasms. The mean survival time was found more in alone surgical group with TNM stages TA N0-1 M0, compared to neoadjuvant therapy (TA N1 M0-1) and adjuvant therapy groups (TA N1 M1).
In the past few decades, upraise in the canine cancer incidence were recorded  with more than 50 per cent older dog population developing cancer and one-fourth of the reported populations eventually dying from it (Lewis et al., 2018). The mainstay treatment option of surgery for cancer got fortified by adopting multimodal approaches like neoadjuvant and adjuvant chemotherapy to combat the deadly disease effectively at an earlier stage. Streamlining surgical approaches to various neoplasms in dogs utilising TNM staging and assessment of quality of life (QOL) of a cancer patient had always been a challenge in veterinary surgical oncology (Kudnig and Seguin, 2012). The present study was aimed to explore the Tumour Node Metastasis (TNM) staging as a prognostic indicator and basis of surgical decision making. The study also envisaged correlation of the TNM staging with the histopathological findings and the survival status of the tumours. Our hypothesis was that there existed significant difference in the overall survival distribution between the different severity of neoplasms treated with surgery alone, neoadjuvant chemotherapy followed by surgery and then surgery followed by adjuvant chemotherapy protocols.
Thirty six cases of neoplasms in dogs presented to University Veterinary Hospitals of Kerala Veterinary and Animal Sciences University, including 18 mammary and 18 superficial neoplasms during a period of three years from 2018-2020 were selected based on the TNM staging of mammary neoplasms (Sorenmo et al., 2019) and TNM staging of skin and subcutaneous neoplasms (Hauck, 2013). The selected animals were studied in three groups of twelve animals, with each group consisting of six cases of mammary neoplasms and six cases of superficial neoplasms.

Group I-(Surgery alone). These animals serially numbered as I1, I2, I3, I4, I5, I6, I7, I8, I9, I10, I11 and I12 had localized tumour with well-defined surgical margin and TNM stages-TA N0-1 M0, which were subjected to curative-intent surgery alone with minimum two cm wide margin radical resections including deep fascial planes. 

Group II-(Neo- adjuvant chemotherapy followed by surgery) consisted of twelve animals serially numbered as II1, II2, II3, II4, II5, II6, II7, II8, II9, II10, II11 and II12 with tumours having ill-defined surgical margins with inflammatory changes  and TNM stages-TA N1 M0-1.

Group III-(Surgery followed by adjuvant chemotherapy) consisted of twelve animals serially numbered as III1, III2, III3, III4, III5, III6, III7, III8, III9, III10, III11 and III12 with presence of malignant features as evident in TNM stages-TAN1M 1 (viz., neoplasms of any size with poorly differentiated margins, metastatic changes in lymph node and confirmed pulmonary metastasis).

The neoadjuvant and adjuvant chemotherapies in group II and III were carried out using vinblastine-prednisolone (VBL-P) protocol (vinblastine at 2 mg/ m intravenously and prednisolone at 1 mg/kg body weight intramuscularly) and doxorubicin prednisolone (DOX-P) protocol (doxorubicin at 18 mg/m2 and prednisolone at 1 mg/kg bodyweight intramuscularly) in biweekly intervals for two cycles.

Suitable surgical options of lumpectomy, a single mastectomy, radical mastectomy, regional mastectomy, unilateral or bilateral mastectomy, radical en-bloc curative-intent surgery, wide margin excision along with the normal tissue, marginal excision just outside pseudocapsule and intralesional debulking excision were performed on case to case basis as per Thomson and Britt (2012) and Withrow (2007). Histopathological analysis and grading of all neoplasms were done as per Goldschmidt and Goldschmidt (2017) and Dennis et al., (2011).

Response evaluation was assessed by modified karnofsky performance scales (MKP) adapted for dogs (Morrison, 2002) and response evaluation criteria in solid tumours (RECIST) guidelines (Eisenhauer et al., 2009) on third month and sixth month observations. The observations in all three groups were compared and results were statistically analysed using SPSS version 24. The survival status of the animals after treatment was compared by plotting survival curve using Kaplan Meier analysis and results were interpreted using the log rank test.
TNM staging

The details of the mammary and superficial neoplasms studied in three groups and the TNM staging are depicted in Fig 1, Fig 2 and Table 1. Animals of group I had normal sentinel lymph nodes with very less reactive changes and group II and III animals had reactive to metastatic changes in the lymph node. The physical examination findings of lymph nodes were in accordance with Tuohy et al., (2009) who reported the importance of routine sentinel lymph node evaluation as the most important step in TNM staging and clinical assessment aiding in surgical decision making in veterinary oncology. In the present study, early pulmonary metastasis signs were characterized based on the size in ascending order form by fine dots of miliary nodules, pulmonary micronodules, pulmonary nodule, pulmonary mass, multiple solid nodules, single solid mass, cavitary nodules and single cavity mass. Similar classifications were followed by Spasov et al., (2018) and Weerakkody (2019). The animals of group II had early metastatic changes and were subjected to neoadjuvant chemotherapy. This was in accordance with Gustafson and Bailey (2019) who recommended neoadjuvant chemotherapy for down staging cancer. The neoadjuvant chemotherapy was also intended for preventing the tumour spread and defining the surgical margin for resection. Similar recommendations were given by Chun et al., (2007). The animals selected in the group III had advanced pulmonary metastasis and warranted adjuvant chemotherapy after marginal excision of the neoplasms. Similar recommendations were given by Farese et al., (2019).

Fig 1: Showing details of the mammary neoplasms studied in three groups.



Fig 2: Showing details of superficial neoplasms studied in three groups.



Table 1: TNM staging and Surgical decision making along with correlation by histopathological analysis and response evaluation.


 
Histopathological findings
 
The details of histopathological analysis and grading of neoplasm are depicted in Table 1. In group I animals, TNM staging (TA N 0-1 M0) were correlated with benign neoplasms like adenoma, lipoma and benign mixed tumour. Group II  (TA N 0-1 M0-1) and group III animals (TA N 0-1 M1) were identified as having neoplasms with aggressive histopathological features of inflammatory carcinoma, intraductal papillary carcinoma, comedocarcinoma, ductal carcinoma, malignant mixed tumour neoplasms,  anaplastic carcinoma, osteogenic melanoma, carcinosarcoma, synoviosarcoma and fibrosarcoma.
 
Response evaluation
 
Response Evaluation Criteria In Solid Tumours (RECIST) and Modified Karnofsky performance status used to study  response evaluation assessment in third and sixth month are enlisted in Table 1. All the cases of group I showed RECIST parameter of CR (complete response) characterized by the disappearance of all target lesions and 100 per cent resolution of neoplasm as observed in the third and sixth-month review  with  Modified Karnofsky performance status scale 0. Recurrence with advanced pulmonary metastasis despite multimodal therapy of adjuvant chemotherapy was noticed in high grade malignant neoplasms.  In Group II and III malignant neoplasms showed invaluable response (IR) to treatment and animals with advanced pulmonary metastasis died on eighth and tenth month respectively. Progressive disease with increase in pulmonary metastasis were reported in invasive carcinoma mammary gland, Anaplastic carcinoma and Trichoblastic  carcinoma among Group III animals. These observations were found in accordance with Parachini et al., 2019 who reported that pulmonary metastasis of cutaneous and subcutaneous malignant neoplasms could be considered as a terminal event in dogs. The Kaplan Meier survival curve and log-rank test were used to interpret the results and assess the QOL of the patients after the treatment. The details are depicted in Fig 3. The log-rank test tested the null hypothesis that there existed non significant difference in the overall survival distribution between the groups. In the present study c2 value was 9.061, p<0.05, therefore, the null hypothesis was rejected indicating that there existed a significant difference between survival distributions for the three groups. The severity of the cases on presentation and the malignancy were more in group III and was correlated with a lower mean survival time of 9.38±0.92 months in group III (TAN1M1), compared to 12.194±0.65 months in group II (TA N1 M0-1) and 17.12±0.82 months in Group-I. Previous studies by Karayannopoulou et al., (2001) and Yamagami et al., (1996) also reported lower survival rates in dogs with regional lymph node metastasis than those without lymph node involvement and worst prognosis with distant metastasis. Neoadjuvant chemotherapy or primary chemotherapy selected based on the TNM staging served to downstage a chemo sensitive neoplasm (cytoreduction) before performing a definitive surgical therapy. Similar findings were reported by (Chun et al., 2007), Gustafson and Bailey (2019). The adjuvant chemotherapy acted as an adjunct treatment modality in case of extensive neoplasms with stages TA N1 M0-1 delaying the recurrence after incomplete surgical excision and also to slow down the distant metastasis. Brunnberg et al., (2016) also reported similar findings. Recurrence with advanced pulmonary metastasis despite multimodal therapy of adjuvant chemotherapy was noticed in animals with invasive ductal carcinoma, soft tissue sarcoma (STS) and other malignant superficial neoplasms like osteogenic melanoma, carcinosarcoma, synoviosarcoma and fibro sarcoma. These findings were in accordance with Tran et al., (2016) and Bray, (2016).

Fig 3: Showing survival function plot comparing three groups.

From the present study, it can be concluded that TNM staging of neoplasm can form the basis of surgical planning and act as valid prognostic indicator in canine mammary and superficial neoplasms. Also the survival status of animals directly depended on the TNM staging and severity detected by histopathological findings.
 
Present study followed standard therapeutic and surgical procedures on clinical cases of neoplasms in dogs in accordance with relevant guidelines and regulations. Ethics approval was taken from the university institutional animal ethics committee and as per academic and technical sanction vide Kerala Veterinary and Animal Sciences University order No. KVASU/DAR/Acad/ A2/14528 /2017 dated 06-02-2019.
The authors declare that they have no conflicts of interest.

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