How do you differentiate between TIS (carcinoma in situ), stage one, and stage two in urothelial carcinoma (UTC) of the urinary tract?

From the Guidelines

To differentiate between TIS (carcinoma in situ), stage one, and stage two in urothelial carcinoma (UTC) of the urinary tract, a comprehensive approach including clinical evaluation, imaging, and histopathological examination is necessary, with CTU being the most used imaging modality for diagnosis and staging, as stated in the 2024 update of the ACR Appropriateness Criteria 1. The clinical evaluation should include a thorough history and physical examination, with particular attention to symptoms such as hematuria, which is present in approximately 85% of patients with bladder cancer 1.

• The diagnosis of TIS, stage one, and stage two UTC requires a combination of:
  • Cystoscopy to visualize the bladder and urethral lining
  • Biopsy to obtain tissue samples for histopathological examination
  • Imaging studies, such as CTU, to evaluate the extent of the disease and detect any metastases
• According to the NCCN clinical practice guidelines in oncology, version 3.2020, primary Tis is a high-grade lesion of the urothelium, and standard therapy for this lesion is resection followed by intravesical therapy with BCG 1.
• The 2024 update of the ACR Appropriateness Criteria suggests that CTU should be the initial examination for high-risk patients, and it can detect more bladder cancers than excretory urography 1.
• A recent retrospective analysis demonstrated the feasibility of using preoperative CTU features to predict the risk stratification of NMIBC, but further validation in a larger population is needed 1.
• The American Cancer Society estimates that in 2023, there will be 82,290 new cases of bladder cancer and 16,710 deaths from the disease in the United States, highlighting the importance of early detection and accurate staging 1.
• The principal task of imaging is to characterize the site of known UC in addition to evaluating for additional secondary sites in the ureters or bladder, extravesical/ureteral spread, and nodal and distant metastases, as stated in the 2024 update of the ACR Appropriateness Criteria 1.

From the Research

Differentiation between TIS, Stage One, and Stage Two in Urothelial Carcinoma (UTC)

• The differentiation between TIS (carcinoma in situ), stage one, and stage two in urothelial carcinoma (UTC) of the urinary tract can be achieved through various methods, including imaging techniques and biopsy procedures 2, 3, 4, 5, 6.
• Computed tomography urography is a recommended first-line imaging procedure for clinical survey of upper urinary tract carcinoma, and it has been shown to have high diagnostic accuracy for T3 or higher stage tumors 2.
• However, the differentiation between TIS, stage one, and stage two requires more specific methods, such as ureteroscopic biopsy, which can provide tissue diagnosis and predict exact histopathological grade in 78% of cases 4.
• Immunoperoxidase stains, such as CD44, ProExC, Laminin, and Fascin, can also be applied to urinary cytology samples to diagnose and stage urothelial carcinoma with high accuracy 5.
• A systematic review and meta-analysis found that ureteroscopic biopsy has a positive predictive value of 94% for cT1+/muscle-invasive disease and a negative predictive value of 60% for cTa-Tis/non-muscle-invasive disease 6.

Staging of Urothelial Carcinoma

• The staging of urothelial carcinoma can be done using the TNM classification of malignant tumors, which takes into account the size and extent of the tumor, as well as the presence of lymph node metastasis and distant metastasis 2, 3.
• The AJCC2017TNM classification is used to stage surgical specimens, while urinary cytology samples can be staged using immunohistochemical profiles, such as CD44, ProExC, Laminin, and Fascin 5.
• The diagnosis of Ta-stage tumors can be done according to the immunohistochemical profile [positive (+ve) CD44, negative (-ve) proExC, -ve Laminin, and -ve Fascin] with 100% sensitivity and 100% specificity 5.
• The diagnosis of Tis stage tumors can be done according to the immunohistochemical profile [-ve CD44, +ve proExC, -ve Laminin, and -ve Fascin] with 100% sensitivity and 93% specificity 5.

Limitations and Challenges

• The staging of urothelial carcinoma can be challenging due to the limitations of imaging techniques and biopsy procedures, which can lead to undergrading and understaging 6.
• The identification of high-grade tumors and subepithelial connective tissue invasion in ureteroscopic biopsy can show a moderate and strong correlation with invasive UTUC, respectively 6.
• However, a certain risk of undergrading and understaging should be assumed, and further studies are needed to improve the accuracy of staging and diagnosis of urothelial carcinoma 6.