Lymph Node-positive Bladder Cancer

Surgical, Pathologic, Molecular and Prognostic Aspects

Jose A Pedrosa; Michael O Koch; Liang Cheng

Expert Rev Anticancer Ther. 2013;13(11):1281-1295.

Abstract and Introduction

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.

Introduction

Bladder cancer is expected to cause 15,210 deaths in 2013, making it the second most lethal urologic malignancy in the USA.^[1,2] Most of this mortality is related to muscle invasive disease, where the standard treatment is radical cystectomy with pelvic lymphadenectomy. It has been demonstrated that the presence of lymph node metastasis in patients with muscle invasive bladder cancer indicates a poorer prognosis compared with patients without lymphatic spread.^[3] Currently, imaging techniques are not reliable, leaving the pelvic lymphadenectomy as the only accurate way of obtaining information about lymphatic involvement.

In addition, the resection of metastatic lymph nodes has been associated with long-term survival.^[4–6] Moreover, pelvic lymphadenectomy has also been demonstrated to improve oncological outcomes in patients without lymph node metastasis, as outlined by the association between node counts and survival in patients with negative nodes,^[7] and provides opportunity for adjuvant therapy.^[8,9] These findings have helped consolidate the importance of the pelvic lymphadenectomy in the treatment of muscle invasive bladder cancer, but also outlined the necessity of standardization of surgical and pathological techniques. In this report, we are going to review the current literature on the therapeutic and prognostic implications of lymph node positivity in muscle invasive bladder cancer. Our aim was to address the impact of surgical and pathologic technique in the outcomes of this particular set of patients, and summarize the most important pathologic characteristics that influence on the prognosis of this disease.

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Next Section

Abstract and Introduction
Staging System
Surgical Aspects
Adjuvant Chemotherapy
Pathologic Aspects
Prognostic Interpretation of Positive Lymph Nodes
Molecular Markers
Target Therapy
Conclusion
Expert Commentary
Five-year View: The Future of Lymph Node-positive Bladder Cancer
References
Sidebar

Table 1. 2002 and 2010 tumor node metastasis classification of bladder cancer.
Pathologic TNM staging: 2002		Pathologic TNM staging: 2010
Primary tumor (pT)		Primary tumor (pT)
Tx	Primary tumor cannot be assessed	Tx	Primary tumor cannot be assessed
T0	No evidence of primary tumor	T0	No evidence of primary tumor
Ta	Noninvasive papillary carcinoma	Ta	Noninvasive papillary carcinoma
Tis	Carcinoma in situ	Tis	Carcinoma in situ
T1	Tumor invades subepithelial connective tissue (lamina propria)	T1	Tumor invades subepithelial connective tissue (lamina propria)
T2	Tumor invades muscularis propria	T2	Tumor invades muscularis propria
T2a	Tumor invades superficial muscularis propria (inner half)	T2a	Tumor invades superficial muscularis propria (inner half)
T2b	Tumor invades deep muscularis propria (outer half)	T2b	Tumor invades deep muscularis propria (outer half)
T3	Tumor invades perivesical tissue	T3	Tumor invades perivesical tissue
T3a	Microscopically	T3a	Microscopically
T3b	Macroscopically (extravesical mass)	T3b	Macroscopically (extravesical mass)
T4	Tumor invades any of the following: prostatic stroma, uterus, vagina, pelvic wall and abdominal wall	T4	Tumor invades any of the following: prostatic stroma, uterus, vagina, pelvic wall and abdominal wall
T4a	Tumor invades prostatic stroma or uterus or vagina	T4a	Tumor invades prostatic stroma or uterus or vagina
T4b	Tumor invades pelvic wall or abdominal wall	T4b	Tumor invades pelvic wall or abdominal wall
Regional lymph nodes (pN)		Regional lymph nodes (pN)
Nx	Regional lymph nodes cannot be assessed	Nx	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis	N0	No regional lymph node metastasis
N1	Single lymph node metastasis, 2 cm or less in greatest dimension	N1	Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac or presacral lymph node)
N2	Single lymph node metastasis, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension	N2	Multiple regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac or presacral lymph node)
N3	Lymph node metastasis, more than 5 cm in greatest dimension	N3	Lymph node metastasis to the common iliac lymph nodes
Distant metastasis (pM)		Distant metastasis (pM)
M0	No distant metastasis	M0	No distant metastasis
M1	Common iliac lymph nodes, retroperitoneal lymph nodes and distant metastasis	M1	Retroperitoneal lymph nodes and distant metastasis

TNM: Tumor node metastasis.

Table 2. Description of lymphadenectomy types and regions addressed by the dissection.
Lymphadenectomy types	Regions	Ref.
Limited	Obturator fossa	[15]
Standard	External iliac vessels, obturator fossa and internal iliac vessels	[27]
Modified standard	External iliac vessels, obturator fossa, internal iliac vessels and presacral region	[14]
Extended	External iliac vessels, obturator fossa, internal iliac vessels, presacral region and common iliac nodes	[26]
Super extended	External iliac vessels, obturator fossa, internal iliac vessels, presacral region, common iliac nodes, paracaval^†, periaortic^† and interaortocaval nodes^†	[26]

^†Caudal to the origin of the inferior mesenteric artery.

Table 3. Description of molecular markers used to detect lymph node metastasis and survival analysis in the setting of a positive marker with negative lymph node at pathologic examination.
Markers	Description	Technique	Detection rate	Survival analysis
p53	TP53 is a tumor suppressor gene, and its protein product function as a suppressor of cell proliferation and an apoptotic inductor triggered by DNA-damage	IHC/RT-PCR	76.3% [47]	No additional prognostic information for pN0 patients [47]
Cytokeratin	Cytokeratin is an epithelial marker which has widely utilized for detection of epithelial tumors due to the lacking of expression in lymphocytes. The subtypes investigated in bladder cancer were CK19, CK20 and CK7	IHC/RT-PCR	CK20: 56–46% [98,99]; CK7: 100% [99]; CK1: 93.1% [101]	Association of CK19 with UPII detected pN0 patients with worse prognosis (p < 0.05) [101]
MUC7	MUC7 is a high molecular weight glycoprotein normally detected at salivary gland. This protein was isolated in carcinoma in situ and invasive bladder carcinoma but no at normal urothelium	RT-PCR	83.3% ^[96]	–
UPII	Uroplakins are membrane protein that forms the membrane of human urothelium. The UPII is the most specific to the urothelium. Other ones are UPIa, UPIb and UPIII	IHC/RT-PCR	93.8–100% [98,101,98,102]	Recurrence rate pN0 UPII+ 91 vs 5% pN0 UPII- (p < 0.001) [102]
FXYD3	FXYD3 is a gene that is responsible for a membrane ion regulator protein that is linked to proliferative activity in pancreatic and breast cancer	RT-PCR	100% [103]	Association with CK20 did not show difference in prognosis of pN0 patients [103]

Sidebar

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.