The Depth of Tumor Invasion is Superior to 8 th AJCC/UICC Staging System to Predict Patients Outcome in Radical Cystectomy.

30 th Congress of the European Society of Pathology Tuesday, September 11, 2018 The Depth of Tumor Invasion is Superior to 8 th AJCC/UICC Staging System to Predict Patients Outcome in Radical Cystectomy. A Proposal for a New Staging System. Toyonori Tsuzuki, Toshinori Nishikimi, Yota Murase, Hidehiro Iwata Aichi Medical University Hospital

The 30 th European Congress of Pathology Conflict of Interest (COI) Presenter: Toyonori Tsuzuki The author has no conflict of interest to disclose with respect to this presentation. Department of Surgical Pathology Aichi Medical University Hospital

Background The AJCC/UICC TNM classification is the gold standard to predict bladder cancer outcome. The paradigm of pathological stage (pt) categorization in bladder cancer remains the depth of tumor invasion into the different histologic layers of the bladder wall. However, the structure of these layers differs from their anatomic site.

AJCC/UICC pt staging 8 th edition TX T0 Ta Tis T1 T2 Primary tumor Primary tumor cannot be assessed No evidence of primary tumor Noninvasive papillary carcinoma Carcinoma in situ Tumor invades subepithelial connective tissue (lamina propria) Tumor invades musclularis propria T2a Tumor invades superficial muscularis propria (inner half) T2b Tumor invades deep muscularis propria (outer half) T3 T4 Tumor invades perivesical tissue T3a Microscopically T3b Macroscopically (extravesical mass) Tumor invades any of the following: prostatic stroma, uterus, vagina, pelvic wall, and abdominal wall T4a T4b Tumor invades prostatic stroma* or uterus or vagina Tumor invades pelvic wall or abdominal wall

Background The boundary of muscularis propria and perivesical tissue is commonly ill defined. The distinction on microscopic and macroscopic (pt3a vs pt3b) perivesical tissue is usually subjective. Therefore, the current TNM staging system demonstrates wide prognostic variability within each primary tumor stage.

Am J Surg Pathol. 2014;38 :167-75

Am J Surg Pathol. 2014;38 :167-75

Background The boundary of muscularis propria and perivesical tissue is commonly ill defined. The distinction on microscopic and macroscopic (pt3a vs pt3b) perivesical tissue is usually subjective. Therefore, the current TNM staging system demonstrates wide prognostic variability within each primary tumor stage.

Aim To develop a new pt staging system improving the objectivity and accuracy of prognosis in bladder cancer by integrating the depth of tumor invasion.

Methods We enrolled 117 muscle invasive urothelial carcinoma of the bladder patients between May 2004 to December 2013. No patients had distant metastasis. No patients received adjuvant and/or neoadjuvant chemotherapy. We reviewed the all slides and selected the slides showing deepest tumor invasion from the normal urothelium.

Methods pt2 (AJCC/UICC) (Tumor invades into the musclaris propria.) pt3(ajcc/uicc) (Tumor invades into the perivesicular tissue.) Normal urothelium The depth of tumor invasion was measured from the normal urothelium to the deepest tumor invasion.

Results Clinical characteristics No. patients 117 Male : female ratio 78:39 Patient s age (median) 35-87 (71) Follow-up duration (median) months 1-247 (32) No. developed recurrence 72 No. died of the disease 55 No. died of other causes 14

Analyzed prognostic valuables Depth of tumor invasion (mm) Pathological T stage (pt) 1973WHO grade (G1, G2, G3) Lymphovascular invasion Lymph node metastasis Concomitant CIS Age

Pathological characteristics Depth of tumor invasion(median) mm 2.57-37.14(10.80) pt2:pt3 38:79 1973 WHO grade G2 28 G3 89 Lympho-vascular invasion Present 59 Absent 58 Lymph node metastasis Present 14 Absent 103 Concomitant CIS Present 33 Absent 84

Cutoff value of depth of tumor invasion Harrell C-index in COX model Harrell C-index in Fine and Gray model

Univariate Multivariate Pathological factor Categori N Hazard Ratio 95% CI Pvalue* Hazard Univariate Ratio 95% CI Pvalue* Depth of tumor invasion <10 55 1 10<= 62 2.11 (1.27, 3.51) 0.0039 1.89 (1.11, 3.21) 0.0192 Lympho-vascular invasion V0 59 1 V1/V2 58 1.74 (1.06, 2.84) 0.0275 1.41 (0.84, 2.39) 0.1957 Lymph node metastasis yes 14 1 no 103 0.57 (0.29, 1.12) 0.1012 0.71 (0.35, 1.47) 0.3585 pt pt2 38 1 pt3 79 1.46 (0.85, 2.49) 0.171 1.08 (0.60, 1.95) 0.7859 Age <65 26 1 65<= 91 1.64 (0.87, 3.08) 0.1234 1.58 (0.83, 3.01) 0.1648 1973 WHO grade G2 28 1 G3 89 1.22 (0.68, 2.21) 0.5056 1.06 (0.58, 1.94) 0.8463 CIS yes 33 1 no 84 1.03 (0.60, 1.78) 0.9124 1.07 (0.61, 1.90) 0.805 Multivariate tor Categori N Hazard Ratio 95% CI Pvalue* Hazard Ratio 95% CI Pvalue* n <10 55 1 10<= 62 2.11 (1.27, 3.51) 0.0039 1.89 (1.11, 3.21) 0.0192 sion V0 59 1 V1/V2 58 1.74 (1.06, 2.84) 0.0275 1.41 (0.84, 2.39) 0.1957 is yes 14 1 no 103 0.57 (0.29, 1.12) 0.1012 0.71 (0.35, 1.47) 0.3585

Pathological factor Categori N Pr > ChiSq Hazard Ratio 95% CI Categori N Pr > ChiSq Hazard Ratio Depth of tumor invasion <10 55 1 10<= 62 0.011 2.136 1.19 3.835 Lympho-vascular invasion V0 59 1 V1/V2 58 0.246 1.425 0.783 2.594 Lymph node metastasis yes 14 1 no 103 0.0168 0.41 0.197 0.852 <10 55 1 pt pt2 38 1 pt3 79 0.8937 0.955 0.486 1.877 Age <65 26 1 65<= 91 0.125 1.912 0.835 4.376 1973 WHO V0 grade 59G2 28 1 1 G3 89 0.9285 0.97 0.502 1.875 CIS yes 33 1 no 84 0.6501 0.851 0.424 1.709 95% CI 10<= 62 0.011 2.136 1.19 3.835 V1/V2 58 0.246 1.425 0.783 2.594

Univariate Multivariate Categori N Hazard Ratio 95% CI Pvalue* Hazard Ratio 95% CI Pvalue* Univariate Multivariate Pathological factor Categori N Hazard Ratio 95% CI Pvalue* Hazard Ratio 95% CI Pvalue* Depth of tumor invasion <10 55 1 10<= 62 2.08 (1.23, 3.52) 0.0061 1.94 (1.12, 3.36) 0.0173 Lmpho-vascular invasion V0 59 1 <10 55 V1/V2 58 1 1.68 Lymph node metastasis yes 14 1 (1.01, 2.81) 0.0462 1.38 (0.80, 2.40) 0.2469 no 103 0.49 (0.25, 0.97) 0.0401 0.58 (0.28, 1.22) 0.1505 pt pt2 38 1 pt3 79 1.31 (0.76, 2.26) 0.3369 1 (0.55, 1.82) 0.9992 Age V0 59 <65 26 1 1 65<= 91 1.76 (0.91, 3.41) 0.0909 1.82 (0.93, 3.58) 0.0814 1973 WHO grade G2 28 1 G3 89 1.08 (0.59, 1.97) 0.8012 0.93 (0.50, 1.73) 0.8161 CIS yes 14 yes 33 1 1 no 84 1.28 (0.71, 2.30) 0.4061 1.29 (0.70, 2.38) 0.4131 10<= 62 2.08 (1.23, 3.52) 0.0061 1.94 (1.12, 3.36) 0.0173 V1/V2 58 1.68 (1.01, 2.81) 0.0462 1.38 (0.80, 2.40) 0.2469

Conclusions The depth of tumor invasion (<10 mm vs. >10 mm) was an independent prognostic factor in DFS, CSS, and OS. The depth of tumor invasion can be a novel staging system for bladder cancer, that is more objective and accurate than the current AJCC/UICC staging system in muscle invasive bladder cancer.

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