Current Status of Lymph Node Imaging in Bladder and Prostate Cancer

doi:10.1016/j.urology.2016.02.014

Urology

Volume 96, October 2016, Pages 1-7

https://doi.org/10.1016/j.urology.2016.02.014 Get rights and content

The bladder and the prostate have a multitude of primary lymphatic landing sites, making the sentinel node concept inapplicable in patients with bladder or prostate cancer. However, some imaging techniques may be helpful in guiding surgeons for the removal of suspicious nodes that would not have been resected in a standardized template. Despite the multitude of new imaging techniques available today, a meticulous histologic workup of lymph nodes retrieved by an extended pelvic lymph node dissection still has the highest accuracy for detection of lymph node metastases in bladder or prostate cancer.

Section snippets

Localization of LNs

The lymphatic drainage pattern of a specific cancer and the localization of LN metastases determine the template for LN dissection. Thus, the primary lymphatic landing sites of the bladder and the prostate have to be known. In the past, several large pathoanatomical LN mapping studies were performed.8, 9 Surgical mapping studies, however, have limited value in assessing lymphatic drainage as it is only possible to assess what is exposed and removed. If a specific anatomical area is never

Fluorescent Dyes

Fluorescent dyes can be injected into the organ of interest at the start of surgery and allow real-time visual identification of sentinel LNs without radioactivity. The most commonly used fluorescent dye is indocyanine green (ICG).

The data on the use of fluorescent dyes for LN imaging in BC are limited. In 12 patients who underwent open RC and PLND (median of 17 LNs removed per patient) for BC, ICG lymphangiography was performed.¹⁶ Five patients had LN metastases in histopathology but none had

Pelvic Nodal Imaging Using MRI or CT

CT and conventional MRI are widely used for preoperative detection of LN metastases in patients with BC or PC. Their diagnostic accuracy, however, is less than optimal. In BC and PC, CT may miss 30% to 40% of LN metastases.21, 22 Thus, upstaging of clinical N0 to pathological N+ is frequently found despite negative preoperative imaging.23, 24 These imaging techniques rely mainly on morphologic criteria (LN size, shape, and internal architecture), although the major shortcomings of these

Positron Emission Tomography (PET)

The diagnostic efficiency of PET does not depend, like CT or MRI, on traditional parameters such as size or shape, but on the increased metabolic rate of specific tissues and their volume.

BC is one of the various malignant tumors and metastases that show an enhanced glucose utilization. Fluorodeoxyglucose (FDG) is a marker of increased glucose uptake. In BC, predominantly ^18FFDG PET was used for detection of LN metastases.

In a prospective study, 51 BC patients received a FDG-PET/CT scan before

Molecular Staging and Imaging

Retz et al⁴⁶ investigated MUC7 (a high molecular weight glycoprotein expressed in carcinoma in situ and invasive BC, but not in normal urothelium) as a possible marker for small numbers of tumor cells in histologically normal LNs using reverse transcriptase polymerase chain reaction (RT-PCR). Twenty-nine percent (46/160) of histologically classified normal LNs (pN0) from 17 BC patients were positive for MUC7 and thus contained cancer cells despite negative conventional histopathological workup.

Conclusion

All of the imaging studies presented above may facilitate the detection of some, but not all, LN metastases. Some of the imaging studies may be helpful in guiding the surgeon in the removal of suspicious nodes in remote pelvic areas that would not have been resected in a standardized template. They cannot, however, replace a meticulous histologic workup of LNs retrieved by an extended PLND that has, so far, the highest sensitivity for detection of LN metastases. However, even histologic

Ethical Standards

Ethical committee review was not required as the manuscript is a review of the published literature.

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Conventional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) has limitations in the clinical evaluation of invasive bladder cancer (BC) for the assessment of not only local extension but also metastatic spread. The sensitivity and specificity of CT and MRI for the detection of lymph node (LN) metastases is low [1,2], often leaving small metastases undetected preoperatively, while their use may lead to misinterpretation of reactively enlarged LNs as metastatic. Patients with LN metastases have a chance for cure if radical cystectomy (RC) with accurate pelvic lymph node dissection (PLND) is performed [3].
According to current guidelines, bone scintigraphy is not routinely indicated in patients with invasive bladder cancer prior to radical cystectomy unless specific symptoms are present. These guidelines, however, are based on sparse data of low quality.
To assess the clinical impact of routine staging bone scintigraphy on further patient management.
A retrospective, single-center study of 1287 consecutive patients, who were scheduled to undergo radical cystectomy due to invasive bladder cancer between January 2000 and December 2017, was conducted. All patients were prospectively followed up according to our institutional protocol.
Bone scintigraphy as staging imaging prior to radical cystectomy.
The primary endpoint was the change in intended patient management. Secondary endpoints were the need for additional imaging, the diagnostic performance of baseline bone scintigraphy, and the association between clinical and radiological findings on bone metastases and survival. Logistic and Cox regression models were used for univariate and multivariate analyses.
Of 1287 patients scheduled for radical cystectomy, 1148 (89%) underwent bone scintigraphy as staging imaging. Overall, baseline bone scintigraphy led to a change in the intended management in 19/1148 (1.7%) patients. Additional imaging was performed in 44/1148 (4%) patients. Although positive bone scintigraphy findings were associated with the occurrence/development of bone metastases, the diagnostic performance of baseline bone scintigraphy was generally poor (positive predictive value, negative predictive value, sensitivity, and specificity were 56%, 89%, 27%, and 96%, respectively). Higher clinical tumor stage and the nonperformance of cystectomy had negative impacts on cancer-specific survival and overall survival, while positive bone scintigraphy was associated with worse cancer-specific survival. This study was limited by its retrospective nature and the lack of follow-up bone scintigraphy in all patients.
These results demonstrate the limited value of bone scintigraphy in the staging of invasive bladder cancer and do not support its routine use.
In this study, we looked at the clinical impact of bone scintigraphy on the diagnostics of patients with invasive bladder cancer. We found that routine staging bone scintigraphy had limited impact on further patient management. We conclude that bone scintigraphy should not be part of routine staging in patients with invasive bladder cancer.
Lymphatic metastasis of bladder cancer: Molecular mechanisms, diagnosis and targeted therapy
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The diffusion weighted imaging (DWI) of MRI can distinguish malignant nodes with limited diffusion, improving the detection rate together with T2-weighted imaging (T2WI) [65,66]. However, DWI had a relatively high false negative rate, so it is not applicable for excluding LN metastasis [64]. Novel superparamagnetic iron oxide contrast agents for MRI, including ferumoxtran-10 [67] and ferumoxytol [68], improved the resolution to detect LNs with a size of 3.0 mm [69].
Bladder cancer is the most common and lethal cancer of the urinary system. Lymphatic metastasis is the primary and main metastatic type of bladder cancer, leading to an extremely poor prognosis in patients. Therefore, a better understanding of molecular mechanisms may provide potential targets for the diagnosis and treatment of lymphatic metastasis in bladder cancer. Herein, we summarize the current knowledge of molecular mechanisms of the lymphatic metastasis in bladder cancer, including lymphangiogenesis and its regulators, noncoding RNAs, and microenvironment-associated molecules. Novel radiomics and genomics approaches have substantially improved the preoperative diagnostic accuracy of lymph node metastasis in patients with bladder cancer. Newly discovered targets may lead to promising therapeutic strategies for clinical intervention in lymphatic metastasis of bladder cancer. More basic and translational studies need to be conducted to further clarify the molecular mechanisms, and identify predictive markers and therapeutic targets of lymphatic metastasis for bladder cancer patients.
Preoperative Staging With <sup>11</sup>C-Choline PET/CT Is Adequately Accurate in Patients With Very High-Risk Prostate Cancer
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All patients underwent abdominal–pelvic CECT examinations that were separately evaluated as morphologic imaging by a dedicated uroradiologist. Abdominal–pelvic LNs > 10 mm in the short axis or any LN > 15 mm in the large axis were considered suspicious for LNM at morphologic imaging.18 All PET/CT and CECT images were reviewed by 2 dedicated nuclear physicians and a radiologist, respectively, who reached consensus when necessary.
To evaluate the accuracy of ¹¹C-choline positron emission tomography (PET)/computed tomography (CT) for nodal staging of prostate cancer (PCa) in different populations of high-risk patients.
We evaluated 262 individuals with intermediate- or high-risk PCa submitted to radical prostatectomy and extended pelvic lymph node dissection. Within men with high-risk disease, we identified a subgroup of individuals harboring very high-risk (VHR, n = 28) disease: clinical stage ≥ T2c and more than 5 cores with Gleason score 8-10; primary biopsy Gleason score of 5; 3 high-risk features; or prostate-specific antigen ≥ 30 ng/mL. The diagnostic accuracy of PET/CT and contrast-enhanced CT (CECT) was assessed after stratifying patients according to risk group classification on a patient- and anatomic region–based analysis.
On patient-based analysis, considering high-risk patients (n = 155), ¹¹C-choline PET/CT versus CECT had sensitivity and specificity of 50% and 76% versus 21% and 92%, respectively. Considering VHR men as separate subgroups (n = 28), ¹¹C-choline PET/CT versus CECT had sensitivity and specificity of 71% and 93% versus 25% and 79%, respectively. Accordingly, in the VHR category, the area under the curve of ¹¹C-choline PET/CT versus CECT was 0.86 (95% confidence interval, 0.71-1.0) versus 0.69 (95% confidence interval, 0.52-0.86), respectively. On anatomic region–based analysis, considering the VHR group, ¹¹C-choline PET/CT versus CECT had sensitivity and specificity of 70.6% and 95.5% versus 35.3% and 98.5%, respectively.
Patients with VHR characteristics could represent the ideal candidate to undergo disease staging with PET/CT before surgery with the highest cost efficacy.
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However, the heterogeneity of study designs and a general lack of consensus over protocols and reporting standards make such evidence challenging to interpret. Contemporary overview of SLND literature in PCa has highlighted its feasibility and sensitivity but does not provide conclusive evidence to validate the benefit of SLND [15–18]. Against this backdrop, we aim to provide a comprehensive review of the current literature to summarise the evidence for the use of SLND in PCa management.
The sentinel lymph node dissection (SLND) concept relies on the accurate detection of primary nodal landing sites and could represent a major advancement towards accurate, non-invasive pelvic staging in prostate cancer (PCa). Different iterations of the technique have now been validated and reproduced mostly in large-volume centres. The existing evidence denotes the feasibility and sensitivity of SLND, with encouraging pre- and intraoperative detection rates of 98% and 96%. Yet, current surgical practice mandates a backup template dissection due to a false negative rate, up to 7.1%, of tracer-guided surgery. In practice, SLND failed to achieve nodal detection in up to 20% of pelvic sidewalls. Despite scarce validated evidence, current consensus mainly attributes these false negative cases to altered prostatic drainage secondary to malignant obliteration of lymphovascular structures. In parallel, multiple SLND studies have highlighted the complex and variable drainage pathways from the prostate, furthering the established anatomical atlases. The most promising approach may therefore rely in magnetic nanoparticles and PCa-targeting ligands. However, in the absence of a clear sentinel node or region for the prostate, formal SLND is difficult to integrate in routine surgical practice for now. As such, tracer-guided dissection is only used as a complementary intervention to highlight first- echelon nodes and aberrant lymphatic pathways found beyond the commonly adopted pelvic lymphadenectomy templates.
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: Financial Disclosure: The authors declare that they have no relevant financial interests.

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Review ArticleCurrent Status of Lymph Node Imaging in Bladder and Prostate Cancer

Section snippets

Localization of LNs

Fluorescent Dyes

Pelvic Nodal Imaging Using MRI or CT

Positron Emission Tomography (PET)

Molecular Staging and Imaging

Conclusion

Ethical Standards

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Current Status of Lymph Node Imaging in Bladder and Prostate Cancer