Diagnostic Accuracy of Ga-68-HBED-CC-PSMA-Ligand-PET/CT before Salvage Lymph Node Dissection for Recurrent Prostate Cancer

Abstract

Background: By targeting the prostate-specific membrane antigen (PSMA) on prostate cancer (PCa) cells PSMA-PET/CT shows great potential in locating the site of biochemical recurrence even at low PSA (Prostate-specific antigen)-levels. Accurate imaging of PCa recurrent lymph node metastases (LNM) is crucial for metastases directed therapies such as salvage-lymph node dissection (salvage-LND). Objective: To evaluate the diagnostic accuracy of PSMA-PET/CT for detection of affected lymph-node regions at salvage-LND for nodal recurrence of PCa. Design, setting and participants: 30 patients with the suspicion of exclusively nodal PCa-relapse after primary therapy underwent a template pelvic and/or retroperitoneal salvage-LND after whole body 68-Ga-PSMA-PET/CT. The diagnostic accuracy of PET/CT was evaluated in comparison to the histopathology of 965 resected lymph nodes (LN) dissected from 68 main regions (pelvic left/right, retroperitoneal) and 289 subregions (common iliac, external iliac, obturator, internal iliac, presacral, aortic-bifurcation, aortal, caval). LNM and tumor deposits in LNM were measured bidimensionally in the histopathology. PSMA-expression was analyzed by immunohistochemistry in LNM. Results: LNM were present in 11.4% of the resected LN (110/965) resulting in 45 positive main regions and 85 positive subregions. PET/CT was true positive in 41 main regions and 69 subregions. Three PET-negative main regions and 16 PET-negative subregions finally contained LNM, the majority of these false negative subregions (13/16) were in neighboring regions of true-positive subregions. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were: main region-based 93.2%, 100%, 100%, 88.9% and 95.6%, subregion-based 81.2%, 99.5%, 98.6%, 92.7 and 94.1%. Median short diameters of tumor deposits in LNM resected from false-negative subregions (1.3 mm) were significantly smaller than in LNM removed from true-positive subregions (5.5 mm, p<0.0001). Based on anatomical subregions containing just one LNM, the necessary short diameter of tumor deposits in LNM required to reach a detection rate of 50% and 90% was estimated to be ≥ 2.3 mm and ≥ 4.5 mm, respectively. Conclusion: In men with biochemical PCa-relapse and positive PSMA-PET/CT, PET/CT detects metastatic affected anatomical regions with high accuracy at a main region and at a subregion-level. If the decision for salvage-LND is prompted by a positive PSMA-PET/CT, the size of metastases is crucial for accurate detection of affected regions. All LNM showed a clear PSMA-expression in the immunohistochemistry. Further studies need to investigate how to translate the high anatomical correlation observed between PET/CT and surgical findings into optimal approaches for target salvage-LND.

Keywords: PSMA-PET/CT; prostate cancer, lymph node metastases; salvage lymph node dissection; salvage lymphadenectomy..

Figure 1

(A, B) Maximum intensity projections (MIP) of PSMA-PET/CT and the transversal PET (E, F) with the corresponding CT (C, D) images from patient N°1 with a single lymph node metastasis (initial PSA 7.43 ng/ml, Gleason-score 3+4 at radical prostatectomy in history, PSA 1.72 ng/ml at salvage-lymphadenectomy) and patient N°2 with multiple lymph node metastases (initial PSA 4.11 ng/ml, Gleason-score 4+5 at radical prostatectomy in history, PSA 1.78 ng/ml at salvage-lymphadenectomy). Red arrows indicate lymph node metastases.

Figure 2

Boxplots showing the sizes of whole lymph node metastases (A) and tumor deposits in lymph nodes (B) either removed from true-positive or false-negative subregions at surgery. Sizes are shown in two dimensions: median longitudinal and short-axis diameters (mm) of (A) lymph node metastases and (B) tumor deposits in lymph node metastases. Thick horizontal lines represent medians, crosses represent means, boxes show the 25^th and 75^th percentiles, whiskers represent the minimum and maximum values. n.s. p > 0.05, ** p ≤ 0.01, *** p ≤ 0.001. (C) Detection rates of LNMs in dependence on the longitudinal diameter of tumor deposits in lymph node metastases (LNM). The estimated threshold to reach a detection rate of 90% (d90) is 6.0 mm. (D) Detection rates of LNMs in dependence on the short axis diameters of tumor deposits in lymph node metastases (LNM). The estimated threshold to reach a detection rate of 90% (d90) is 4.5 mm.

Figure 2

Boxplots showing the sizes of whole lymph node metastases (A) and tumor deposits in lymph nodes (B) either removed from true-positive or false-negative subregions at surgery. Sizes are shown in two dimensions: median longitudinal and short-axis diameters (mm) of (A) lymph node metastases and (B) tumor deposits in lymph node metastases. Thick horizontal lines represent medians, crosses represent means, boxes show the 25^th and 75^th percentiles, whiskers represent the minimum and maximum values. n.s. p > 0.05, ** p ≤ 0.01, *** p ≤ 0.001. (C) Detection rates of LNMs in dependence on the longitudinal diameter of tumor deposits in lymph node metastases (LNM). The estimated threshold to reach a detection rate of 90% (d90) is 6.0 mm. (D) Detection rates of LNMs in dependence on the short axis diameters of tumor deposits in lymph node metastases (LNM). The estimated threshold to reach a detection rate of 90% (d90) is 4.5 mm.

Figure 2

Boxplots showing the sizes of whole lymph node metastases (A) and tumor deposits in lymph nodes (B) either removed from true-positive or false-negative subregions at surgery. Sizes are shown in two dimensions: median longitudinal and short-axis diameters (mm) of (A) lymph node metastases and (B) tumor deposits in lymph node metastases. Thick horizontal lines represent medians, crosses represent means, boxes show the 25^th and 75^th percentiles, whiskers represent the minimum and maximum values. n.s. p > 0.05, ** p ≤ 0.01, *** p ≤ 0.001. (C) Detection rates of LNMs in dependence on the longitudinal diameter of tumor deposits in lymph node metastases (LNM). The estimated threshold to reach a detection rate of 90% (d90) is 6.0 mm. (D) Detection rates of LNMs in dependence on the short axis diameters of tumor deposits in lymph node metastases (LNM). The estimated threshold to reach a detection rate of 90% (d90) is 4.5 mm.

Figure 3

(A) Representative immunohistochemistry (IHC) for prostate-specific membrane antigen (PSMA) in lymph node metastases removed from a true-positive subregions (dark brown). (B) IHC for PSMA in small tumor deposits in lymph node metastases removed from false-negative subregions.