Lymph node-positive bladder cancer: surgical, pathologic, molecular and prognostic aspects

Abstract

The presence of lymphatic metastasis is associated with markedly worse prognosis in patients with bladder cancer, although surgical resection and chemotherapy can still provide long-term survival for selected patients. The prognostic stratification of patients with positive lymph nodes has been broadly discussed in the current literature and a more extensive pelvic lymph node dissection and thorough pathologic assessment has been advocated. It is clear that stratification using the tumor node metastasis staging system is insufficient to adequately discriminate prognosis between patients with different lymph node involvement. Lymph node density and extranodal extension have been extensively investigated and appear to influence the prognosis of these patients. Molecular markers have been developed to improve the diagnosis of micrometastatic disease, and new targeted therapies have shown promising preclinical results and are now being tested in different clinical scenarios.

Keywords::

• lymph node dissection/pelvic lymphadenectomy
• lymph node density
• lymph node-positive bladder cancer
• staging
• targeted therapy
• transitional cell (urothelial) carcinoma
• urinary bladder

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Around 25–30% of muscle invasive bladder cancer patients, who have undergone radical cystectomy, presented with positive lymph nodes at pathologic examination. The approximate disease-free survival rate for this group is approximately 25%.

• • However, adequate prognostic stratification for patients with lymph node metastasis is still missing and current data show that a subset of these patients is still potentially curable.

• • Prospective nonrandomized evidence demonstrated a survival benefit for extended pelvic lymph node dissection. Improvement on staging has also been suggested by the presence of skip metastatic lesions to more advanced lymphatic stations and increased lymph node accruals.

• • Pathologic assessment and patient characteristics have been proven to influence nodal counts. Theoretically, it can influence the detection of lymph node metastasis, although this has not yet been demonstrated in the literature.

Prognostic features

• • Studies comparing contemporary comparable population submitted to the same pelvic lymphadenectomy template have shown similar survival and metastatic detection, despite differences in nodal counts. However, the association of nodal count to survival suggests that it can be utilized as surrogate for quality of resection.

• • Intraoperative frozen biopsy and sentinel lymph nodes technique have not shown sufficient accuracy to avoid extended lymphadenectomy, due to the significant rates of skip lymphatic metastasis.

• • Lymph node density incorporates information about the quality of lymph node sample along with tumor burden. Although not uniformly accepted, this index is the most consistent across the literature.

• • The presence of extranodal extension and the aggregate lymph node metastasis diameter has also been associated with prognostic information, independently of node counts and gives important additional contribution for disease stratification.

Molecular markers & targeted therapy

• • Although not consistently shown, several publications have demonstrated a detrimental survival impact of micrometastatic detection in pathologic node-negative patients. Two markers were utilized on the positive studies, UPII and CK19. These studies had a small sample size and lack external validation.

• • Preoperative prediction of lymph node positivity is still preliminary, but the results of a pilot study are encouraging.

• • Detecting cancer cells in the bloodstream is expected to provide great information about metastatic potential and response to systemic therapy. To date, heterogeneous methodology has precluded high quality analysis; however, a meta-analysis has shown statistical association with stage III–IV disease.

• • Genetic evaluation and targeted therapies have produced incredible amounts of information regarding carcinogenesis, but clinical application is still under scrutiny.