The Pathologic Assessment For Predicting Outcomes In Patients With Cervical Carcinoma And Osteosarcoma Underwent Neoadjuvant Therapies

【Background】 The concept of neoadjuvant therapy(chemotherapy) was first brought into clinical practice by Rosen in 1979. So far, the neoadjuvant therapy has been the major treatment in malignant tumors. With the effects of these treatments, such as, controlling of the accompanying symptoms of malignant tumors; releasing the discomfort of the patients’ psychological reaction, lowering the clinical staging of TNM, shrinking the primary lesions, limiting the scope of nodal metastasis, lots of patients who could not endure the surgical treatments, might have also got the chance to receive surgical treatments with much higher achievement ratio of operation and effectively dealing with tumor metastasis and post-operative complications. With so many benefits from neoadjuvant therapy, more and more doctors recommended these treatments as one of the most effective treatment to malignant tumors.As for cervical squamous cell carcinoma patients, both neoadjuvant radiotherapy(RT) and concurrent chemoradiotherapy(CCRT) has been the major treatments. The neoadjuvant chemotherapy have significantly improved long-term survival in patients with osteosarcoma of the extremity. Currently, the neoadjuvant chemotherapy has been the standard treatment of osteosarcoma.However, to date, no clear assessment criteria have been confirmed for cervical carcinoma patients who undergo neoadjuvant RT or CCRT and osteosarcoma patients undergo the neoadjuvant chemotherapy that can predict the prognosis well. And especially for those cervical carcinoma patients, there are almost no clear pathologic assessment criteria at all. As neoadjuvant therapies are applied in more and more cervical carcinoma and osteosarcoma patients, the need for a reliable and easily applied assessment, especially pathologic assessment becomes increasingly critical.【Objectives】 1. To analyze the clinical and pathological information about cervical squamous cell carcinoma patients who have received neoadjuvant radiotherapy(RT) or concurrent chemoradiotherapy(CCRT), and test the existing tumor curative effect evaluation standards or methods, confirm its results; 2. Retrospective analysis cervical squamous cell carcinoma patients who received neoadjuvant RT or CCRT with the objective of identifying a pathologic parameter that can be objectively, reproducibly, and quantitatively measured and can be used to predict patient outcomes; 3. To directly study the prognostic factors for disease progression in osteosarcoma, and test the accuracy of the existing prognostic criterion used for the treatment of osteosarcoma; 4. To identify the relationship between residual tumor cells calculated by tumor necrosis rate(TNR) after neoadjuvant chemotherapy and the outcomes among osteosarcoma patients.【Methods】 1. Retrospective analysis of 173 cervical squamous cell carcinoma patients who received neoadjuvant RT or CCRT with the objective of identifying risk factors and test the existing tumor evaluation standards or methods to predict patient outcomes; 2. Retrospective analysis of 846 patients with osteosarcoma underwent the neoadjuvant chemotherapy, and match with 197 follow-up information, to identify the risk factors and test the existing tumor evaluation standards or methods to predict patient outcomes; 3. With the microscope magnified scale measurement, find out the invasion depth of all the cervical squamous cell carcinoma and the expression of all these invasion depth; 4. By using the AE1/AE3 immunohistochemical staining, the invisable residue tumor cells was identified to analyze the cytokeratin immunostaining corrected invasion depth; 5. Chi-square test and Spearman test were used to analyze the relationship of existing tumor evaluation standards or methods and the outcomes of patients; 6. Kaplan–Meier method and Cox hazard regression model were employed to analyze the relationship of the existing tumor evaluation standards or methods and survival in cervical squamous cell carcinoma or osteosarcoma patients.【Results】 1. Both the pre-operative clinical and post-operative pathologic FIGO stage can predict survival-related outcomes of cervical squamous cell carcinoma patients who received neoadjuvant RT or CCRT; 2. The existing tumor evaluation standards the WHO double diameter measurement evaluation and the RECIST 1.1 were correlated with the outcomes of cervical squamous cell carcinoma patients who received neoadjuvant RT or CCRT; and both tumor lesions situated in a previously irradiated area and the ultrasound examinations could be useful in these two evaluation standards; 3. The tumor necrosis rate(TNR) and tumor regression grade(TRG) failed to be prognostic indicators for cervical squamous cell carcinoma patients who received neoadjuvant RT or CCRT; 4. The tumor invasion depth(TID) with a cut-off point of “3.75 mm” or the tumor invasion depth with cytokeratin immunostaining correction(TIDC) with a cut-off point of “4.75 mm” measured at the cervical internal surface is a new and easily applied pathologic prognostic factor for distant metastasis and survival outcomes in patients with cervical squamous cell carcinoma treated with neoadjuvant RT or CCRT; 5. The lymph node involvement was found to be an independent prognostic factor for recurrence and distant metastasis for patients with cervical squamous cell carcinoma treated with neoadjuvant RT or CCRT; 6. As for osteosarcoma patients underwent neoadjuvant chemotherapy, the biological characteristics of the tumor itself highly correlate with the outcomes of these patients, such as tumor length with a cut-off point of “18.5 cm”, tumor width with a cut-off point of “7.5 cm”, tumor depth with a cut-off point of “7.5 cm” and tumor volume with a cut-off point of “43.99 cm3”; 7. The existing tumor evaluation standards: the WHO double diameter measurement evaluation and the RECIST 1.1 were not correlated with the outcomes of osteosarcoma patients underwent neoadjuvant chemotherapy; 8. The tumor regression grade(TRG) failed to be prognostic indicators for osteosarcoma patients underwent neoadjuvant chemotherapy; 9. Tumor necrosis rate(TNR) showed significant impact on prognosis prediction of osteosarcoma patients underwent neoadjuvant chemotherapy.【Conclusions】 1. For the first time, the tumor invasion depth(TID) with a cut-off point of “3.75 mm” or the tumor invasion depth with cytokeratin immunostaining correction(TIDC) with a cut-off point of “4.75 mm”measured at the cervical internal surface is proved to be a new and easily applied pathologic prognostic factor for distant metastasis and survival outcomes in patients with cervical squamous cell carcinoma treated with neoadjuvant RT or CCRT; 2. Based on measurements of tumor lesions situated in a previously irradiated area taken via transvaginal ultrasound, the WHO double diameter measurement evaluation and RECIST 1.1 criteria were predictive of distant metastasis and survival-related outcomes of patients with cervical squamous cell carcinoma treated with neoadjuvant RT or CCRT; 3. As for patients with cervical squamous cell carcinoma treated with neoadjuvant RT or CCRT, both the pre-operative clinical and post-operative pathologic FIGO staging were predictive of distant metastasis and survival-related outcomes; 4. The lymph node involvement was found to be an independent prognostic factor for recurrence and distant metastasis for patients with cervical squamous cell carcinoma treated with neoadjuvant RT or CCRT; 5. The tumor regression grade(TRG) and tumor necrosis rate(TNR) failed to be prognostic indicators for cervical squamous cell carcinoma patients underwent neoadjuvant therapy; 6. As for osteosarcoma patients underwent neoadjuvant chemotherapy, the biological characteristics of the tumor itself highly correlate with the outcomes of these patients, such as tumor length with a cut-off point of “18.5 cm”, tumor width with a cut-off point of “7.5 cm”, tumor depth with a cut-off point of “7.5 cm” and tumor volume with a cut-off point of “43.99 cm3”; 7. The residual tumor cells confirmed by tumor necrosis rate(TNR) proved to be an independent variable with respect to progression-free and overall survival and may thus be regarded as a new promising prognostic factor for osteosarcoma patients underwent neoadjuvant chemotherapy.