The Hunt for Lymph Nodes: Is Total Submission of Standard-Template and Extended-Template Pelvic Lymph Node Dissections Necessary for Detecting Metastatic Prostate Cancer?

Following approval from the institutional review board, the pathology information system was used to retrieve cases of RP with PLND performed at our institution from May 1, 2012, to June 28, 2019. A total of 733 cases were included in the study. All cases were grossed by pathology residents and it has been standard practice at our institution for PLND to be entirely submitted for histologic evaluation. Residents first isolate and document the number of grossly identifiable LNs in their cassette key and then submit the entire remaining fat in additional cassettes. LN yield from submission of remaining fat was estimated by subtracting the final total LN yield from the total that was grossly identified.

Pathology reports were reviewed, and the following data were collected for each case: LN status, final LN count, number of grossly identified LNs, number of cassettes submitted for grossly identified LNs and remaining fat, and RP features such as Gleason score (GS) (converted to Grade Groups for analysis), extraprostatic extension, margin status, tumor volume, bladder neck involvement, and seminal vesicle invasion. Operative notes in the electronic medical record were reviewed and the type of PLND that was performed (ST versus EXT) was recorded. Slides, if available, of all positive LN (+LN) cases were reviewed, and the size of the +LN and size of metastatic focus were documented. Extranodal extension was not recorded. Differences between categorical values were assessed by Pearson χ² test or Fisher exact test and continuous values by student t test or Wilcoxon test depending on whether the distribution of the data was parametric or nonparametric. R² values were also obtained between 2 continuous values. JMP Pro 14.2.0 software was used for statistical analysis. A P value of <.05 was considered as statistically significant.

Of 733 cases, 715 had thorough gross descriptions suitable for analysis of LN counts. Most of these cases involved submission of additional cassettes for the remaining fat after grossly identifiable LNs were dissected (697 of 715, 97.5%), with a mean of 6 (SD = 5; range, 1–44) extra cassettes per case. Among these cases, more than half involved submission of an additional 5 or fewer cassettes (437 of 697, 63%).

Of the 733 RP cases, 31% (n = 227) had EXT PLND and 69% (n = 505) had ST PLND. One case had missing clinical information. Based on RP pathologic features, EXT PLND cases were associated with more adverse features such as positive margins, extraprostatic extension, and seminal vesicle invasion (Table 1), likely due to preoperative selection criteria such as higher GS.

EXT PLND yielded a significantly higher mean number of total and +LNs than ST PLND. However, EXT PLND specimens required significantly more tissue blocks for grossly identifiable LNs and remaining fat, even as many as 44 additional cassettes for the remaining fat for 1 case (Table 2). There was poor correlation between number of cassettes submitted for PLND and total LN and +LN yield (R² = 0.247 and 0.29, respectively). The added value of submitting remaining fat after dissection of all grossly identifiable LNs meant identifying an average of 5.7 more LNs (5.5 = SD; range, 0–44) across both PLND types. Submission of remaining fat for EXT PLND yielded an average of about 7 more LNs as compared to 5 for ST PLND. However, there was also a poor correlation between number of cassettes submitted for remaining fat and additional LN yield (R² = 0.175).

There were 77 positive PLND specimens (22 ST, 54 EXT, and 1 unknown) (10.5%, n = 77 of 733), with a range of +LNs from 1 to 17, and mean of 2.4. Positive PLND showed adverse pathologic features as compared to negative PLND, including extraprostatic extension, seminal vesicle invasion, bladder neck involvement, higher GS, higher tumor volume, and positive margin status. There was also a significant difference in the total number of LNs and the number of cassettes submitted for positive PLND versus negative PLND. However, there was no significant difference in LN yield from submission of remaining fat (Table 3).

Of these 77 PLND specimens, 70 had slides available for review. The total number of +LNs was 157 and most were grossly identified (n = 139 of 157, 88.5%). Mean size of these grossly identifiable +LNs was significantly higher as compared to those that were not (0.93 cm versus 0.32 cm; P < .001). Of the 18 (11.5%) not grossly identified +LNs (corresponding to 15 cases), just 4 of 15 cases would have been understaged as pN0 if all the remaining fat were not submitted. Table 4 summarizes additional details for these 4 cases. These 4 +LNs were present in the first, second, and eighth block of remaining fat. In 3 cases, the LNs were microscopic (0.2 cm) and the other was 1.6 cm. The remaining 11 of 15 cases had +LNs in blocks with grossly identifiable LNs, and hence, submission of remaining fat did not change pathologic staging and yielded only an additional 1 or 2 more +LNs.

Available follow-up information was available for 3 of the potentially understaged cases. Patient A received radiation to the prostatic bed owing to adverse RP features such as tertiary pattern 5 and multifocal positive margins. Patient B did not receive any additional therapy as prostate-specific antigen (PSA) levels remained undetectable on long-term follow-up. Patient C was lost to follow-up, and on review of the operative note, the PLND was noted to have suspicious findings. Finally, patient D was given salvage radiation because of rising PSA levels. Hence, +LNs alone did not alter management. Considering the total of 697 cases wherein extra cassettes were submitted for remaining fat, complete submission of PLND only changed staging in a small minority of cases (0.6%, n = 4 of 697).

A total of 4062 blocks were submitted for the remaining fat after LN dissection. We used an estimated cost of $12.20 per block, which includes cost of material, technical labor, and trainee/faculty preview time as based on a study by Bsirini et al⁹  on submission of extra cassettes for intestinal resections, which has a similar current procedural terminal (CPT) code of 88307 to PLND. If this extra tissue were not submitted for histologic examination, then a savings of at least $49,556.40 is expected. Screening time per slide of an LN dissection is hard to measure as it is dependent on many variables. If we use an estimate of 136 seconds, as based on a study by Steiner et al¹⁰  of pathologists viewing images of negative LNs, then the average wasted time based on our mean of 6 extra cassettes per case (range, 1–44) would be 13.6 min/case (range, 2.3–99.7).

Lymphadenectomy and subsequent pathologic examination remain the gold standard for detecting LN metastases in RP for prostate cancer, which is an uncommon event found in 3.7% of cases in the United States between 2004 and 2013.¹¹  This trend appears to be increasing owing to the more frequent use of extended dissections.¹²  Studies have shown that there is no correlation between LN size and possibility of harboring metastasis, and hence, it is critical to examine all LNs resected.¹³  Currently, there are no standardized guidelines for processing RP PLND specimens. Total submission for histologic examination appears to not be a common practice and left to the discretion of individual laboratories.^8,14  We have been following this practice at our institution for at least 9 years wherein residents submit the entire remaining fatty tissue after dissection of grossly identifiable LNs. This study aimed to analyze the utility of this practice and impact on the laboratory.

Our study shows that although entire submission of EXT and ST PLND yielded more LNs, in 99.4% of cases there would be no impact on pathologic N staging if only grossly identified LNs were submitted. Only 4 cases would have been understaged as N0 if remaining fat had not been submitted. All 4 cases had adverse RP pathologic features including GS 7 or greater, extraprostatic extension, and/or positive surgical margins. In 1 case, the +LN was 1.6 cm and likely would not have been missed if meticulous grossing techniques were followed and/or grossed by an experienced resident. Of the 3 patients with follow-up information, having a +LN alone did not seem to impact patient management as it was driven by a combination of rising postoperative PSA levels and other adverse pathologic features.

Like other studies, we found that EXT PLND yielded significantly more LNs and +LNs than ST PLND.^15,16  However, this came at the cost of submitting, processing, and examining significantly more cassettes, even as high as 44 more cassettes per slides for a single case. Submission of more cassettes did not correlate well with LN yield. This extra cost is ultimately absorbed by the laboratory, as both dissection types have similar CPT codes and thus reimbursements. Although complete submission of either EXT or ST PLND meant reviewing only an additional 5 or so slides in 63% of our cases, when scrutinizing a total of 4062 blocks, this number can equate to significant cost and time savings that can be reallocated to other resources.

A few studies have examined complete submission of PLND for prostate cancer,^17–20  with our study including the largest sample size. In a study by Rais-Bahrami et al,²⁰  complete submission did not impact N staging, although their cohort only included 59 cases. Yoon et al¹⁷  and Perry-Keene et al¹⁹  showed similar findings to our study, with a very small percentage (<1%) of cases being upstaged. The largest impact on staging was in the study by Ni Mhaolcatha et al,¹⁸  wherein 4 of 141 cases (3%) were upstaged. This group¹⁸  and Yoon et al¹⁷  recommended selectively submitting the entire specimen for only higher-risk cases such as those with a Grade Group 3 biopsy and/or pT3 on RP. While this is cost-effective, a disadvantage would be the 2-step procedure and subsequent delay of the pathology report. If this were applied to our cohort, then we would detect 100% of +LNs in our study. However, this would still involve complete submission of a significant number of cases (n = 242) only to benefit a tiny fraction of patients (<1%).

Complete submission of PLND is costly and labor-intensive, and in order to relieve the burden on the laboratory, different approaches for specimen handling have been studied. Montironi et al²¹  used a whole mount technique for PLND and reported less time needed to sample the tissue, fewer blocks to be cut, and fewer slides to be reviewed. However, the disadvantages include the requirement of manual processing and storage difficulties. Some groups reported higher LN yield when using fat-clearing agents such as xylene to enhance LN counts without the need for submitting the entire fatty tissue,²²  yet the use of fat-clearing agents is also rarely used by laboratories.¹⁴  Complete submission of PLND still does not guarantee that all +LNs will be detected. Serial sectioning, immunohistochemistry, and reverse transcription–polymerase chain reaction can detect additional occult metastatic foci of prostate cancer^23,24 ; however, these practices also drive up overall costs.

Unlike other organ systems, there is no set national quality standard for the minimum number of LNs for RP. In addition, staging is N1 regardless of the number of +LNs identified. Several studies have investigated how many LNs need to be examined for optimal staging in prostate cancer, with wide ranges from 10 to 20.^15,25–28  Briganti et al²⁷  found that examining 10 LNs or fewer was associated with almost a 0% chance of identifying nodal metastasis. Maccio et al¹⁵  arrived at similar conclusions but noted that N-positive status alone was not an independent prognostic factor on multivariate analysis, but rather pT stage, GS, and age at diagnosis. In our study, 61% (448 of 733) of cases had more than 10 LNs. Without complete submission, only 30% (217 of 733) would have more than 10 LNs. Notably, a study by Kluth et al²⁹  found that the number of LNs harvested did not show any prognostic significance in pN0, clinically localized prostate cancer. However, the number of +LNs harvested and presence of even minimal tumor in LNs may have a prognostic impact on oncologic outcomes.^30,31  If we discount our 1 case (patient D) with the 1.6-cm LN present only in the remaining fat, then our 3 cases that would have been understaged all had microscopic LNs (0.2 cm) identified only in the remaining fat. Additional studies can be pursued to investigate whether long-term outcomes vary between patients with positive microscopic or macroscopic LNs. Once quality standards are enacted with regard to a minimum number of +LNs that need to be examined for RP and/or if N-positive staging for prostate cancer is dependent on the number of +LN, then complete submission of PLND can be considered. At this time, this practice is not recommended owing to increased cost and burden on the laboratory with little impact on patient management.

Limitations of our study include a retrospective study design, lack of follow-up information on all patients, and the fact that we only reviewed slides of positive PLND cases. Although we know that finding the +LNs for the 4 potentially understaged cases would likely not have changed patient management on its own, we do not have information on whether the number of +LNs or total number harvested had any impact on management. Knowing this information from our clinical colleagues may provide support for a more extensive submission of PLND. A slide review of all 733 study cases and correlating gross assessment of LNs with histologic findings would not have been feasible. In our abbreviated review of 70 cases, the number of LNs in the gross description reflected histologic findings in most cases.

To conclude, meticulous grossing techniques should be followed to identify all possible LNs in EXT and ST PLND specimens for prostate cancer. Complete submission of PLND is costly and requires intensive labor with no significant impact on pathologic N staging for most cases. Hence, we recommend that the remaining fat of PLND specimens not be submitted after meticulous dissection of LNs. In the current environment of staffing shortages, rising costs, declining reimbursements, and increasing workload demands, this recommended practice is cost-effective, assists in balancing workload, and does not adversely affect patient management.