Pathologic evaluation of radical cystectomy specimens
A cooperative group report
The authors evaluated the pathology of radical cystectomy and pelvic lymph node specimens from patients with bladder carcinoma who were enrolled in a cooperative group trial. Their objective was to determine whether current practices conform to suggested pathology practice guidelines for reporting on radical cystectomy and pelvic lymph node specimens.
Overall, 268 patients underwent radical cystectomy with pelvic lymph node dissection over 11 years in a total of 109 diverse geographic locations and types of institutions. Institutions included 50 community hospitals, 36 academic hospitals, and 23 Veterans Administration (VA)/military hospitals, which evaluated 84, 137, and 47 patients, respectively. The quality of pathology examination was assessed based on the original pathology reports of specimens that were submitted according to published practice guidelines.
Among all types of institutions, pathologic evaluation of radical cystectomy specimens generally was complete for tumor histology, grade, size, location, pathologic stage, lymph node status, prostate involvement, and associated mucosal abnormalities, including ureters and urethra. Perivesical fat (soft tissue) margins were not recorded in 10% of specimens, and 18% of patients did not mention either the presence or the number of lymph nodes. These deficiencies were observed primarily at community and VA hospitals.
The overall quality of pathologic examination of radical cystectomy specimens is high. Better reporting of soft tissue margin status and pelvic lymph node counts is needed to achieve compliance with the standards published by evolving practice protocols. Standardized pathologic evaluation and reporting of radical cystectomy specimens will optimize important prognostic information and foster better communication between the pathologist, surgeon, and interested oncologists to benefit patients. Cancer 2004. © 2004 American Cancer Society.
Over the last decade, a number of groups, such as the Association of Directors of Anatomic and Surgical Pathology and the College of American Pathologists Cancer Committee, have published guidelines for reporting common malignant tumors.1–3 The initial set of pathology practice guidelines, published in 1986, included guidelines for bladder carcinoma.4 Subsequent reports provided expanded guidelines for reporting radical cystectomy specimens5, 6 and for evaluating lymph nodes for metastatic disease.7 Recent studies suggest that implementation of such guidelines may improve the quality of histopathology reporting of specimens from patients with malignant disease.8, 9
Radical cystectomy with pelvic lymphadenectomy is the most effective treatment for invasive bladder carcinoma. Pathologic tumor stage, surgical margins, and lymph node status are the most important predictors of postcystectomy survival.10 The number of lymph nodes retrieved also is an important determinant of outcome for patients with bladder carcinoma, regardless of whether they have positive or negative lymph node status.11 Such pathologic features help to identify patients whose malignancies are likely to be cured by surgery and patients who have a high risk of developing tumor recurrences.
The Southwest Oncology Group (SWOG) conducted a multiinstitutional study of radical cystectomy, with or without neoadjuvant chemotherapy, for patients with muscle-invasive bladder carcinoma.12 The cooperative group mechanism assures a high level of participation by diverse community and academic hospitals, permitting analysis of possible variations in the pathologic examination of radical cystectomy specimens as practiced currently in the United States. In the current study, we assessed the quality of the pathologic evaluation of patients who were enrolled in the SWOG 8710 trial to determine whether current practices conform to suggested guidelines for reporting radical cystectomy specimens.
MATERIALS AND METHODS
The SWOG 8710 trial accrued a total of 307 eligible patients with muscle-invasive (clinical T2–T4a classification) bladder carcinoma during an 11-year period (1987–1998). Of these, 268 patients underwent radical cystectomy. Half of all patients (n = 135) received cisplatin-based chemotherapy before surgery. Pathologic information was abstracted from the original pathology reports (provided in either narrative or checklist form) and was reviewed by one of the investigators (H.W.H.). Analysis of the data was approved by SWOG and by the institutional review board at Memorial Sloan-Kettering Cancer Center (New York, NY).
Patients were treated at a total of 109 different institutions located in 42 states, as well as in Canada (12 centers in the South, 12 in the Midwest, 10 in the East, and 9 in the West). The contributing institutions included 50 community hospitals (n = 84), 36 academic medical centers (n = 137), and 23 Veterans Administration (VA)/military hospitals (n = 47). Half of all participating VA Medical Centers were affiliated with medical schools.
Radical cystectomy specimens were processed by methods used routinely at each institution. The bladder was opened on its anterior surface and inspected before tissue specimens were collected for histologic examination. Lymph nodes were retrieved from submitted specimens by visual inspection and by palpation. Clearing solutions or molecular techniques were not used. At least one microscopic section from each suspicious lymph node was prepared and stained for histologic evaluation.
The guidelines published for examining and reporting radical cystectomy specimens were used to evaluate diagnostic information detailed in the pathology reports from the various institutions.5, 6 The majority of pathology reports were narratives of the findings, and only 19% of reports (52 specimens) provided information in a synoptic format. Details of specimen assessment, grading schemes, tumor stage, and other variables were set by each contributing institution and pathologist.
We noted whether the pathologist reported the tumor type (histology), macroscopic tumor size, configuration and location, tumor grade, pathologic tumor (pT) classification, lymphatic/vascular invasion, associated carcinoma in situ, prostate involvement (urethral, ducts, stromal invasion), margin status (urethra, ureters, perivesical fat), lymph node status (positive or negative for metastasis), and the number of lymph nodes (total number of lymph nodes examined and number of positive lymph nodes). We also recorded the extent of pelvic lymph node dissection (PLND) documented on the operation report (none, limited, or standard) and the way in which the surgeon submitted lymph nodes for pathologic examination (as separate lymph node packets or en bloc with the cystectomy specimen). Of the 268 patients who underwent cystectomy, 244 (91%) were registered to the study by the end of 1995, before the expanded 1996 pathology practice guidelines were available.
Associations among variables were explored using the chi-square test. All P values < 0.05 were considered to indicate significance.
Table 1 summarizes patient characteristics. The 1997 version of the American Joint Committee on Cancer (AJCC) TNM staging system13 was used to classify tumors as organ confined (pT0–pT2) or extravesical (pT3–pT4) disease and lymph node–negative or lymph node–positive disease. Tumors were considered to have negative lymph node status if no lymph nodes were found in any of the specimens.14 The extent of PLND and the way in which the lymph nodes were submitted for pathologic examination (i.e., in separate packets or en bloc with the cystectomy specimen) were recorded, because these variables can affect how many lymph nodes are found by the pathologist.15 Of the 268 patients who underwent cystectomy, 9% did not undergo lymph node dissection. Of the 245 patients for whom the style of lymph node submission was recorded, 13% had pelvic lymph nodes submitted en bloc with the bladder specimen rather than as separate specimens.
Table 1. Patient Characteristics
| < 65 yrs||148 (55)|
| ≥ 65 yrs||120 (45)|
| Male||216 (81)|
| Female|| 52 (19)|
|Clinical tumor classification|| |
| cT2||109 (41)|
| cT3–cT4||159 (59)|
|Pathologic tumor classification|| |
| pT0–pT2||184 (69)|
| pT3–pT4|| 84 (31)|
|Lymph node statusa|| |
| Negative||213 (79)|
| Positive|| 55 (21)|
|Pelvic lymph node dissection|| |
| None|| 23 (9)|
| Limited|| 99 (37)|
| Standard||146 (54)|
|Lymph nodes submittedb||245|
| Lymph nodes submitted separately||213 (87)|
| Lymph nodes submitted en bloc|| 32 (13)|
Table 2 shows the collective results of pathologic evaluation of radical cystectomy specimens and lymph nodes according to institution type. Across all institutions, all pathologists (100%) reported histologic type, tumor size, configuration, location within the bladder, major pathologic stage, and associated mucosal abnormalities (including carcinoma in situ and prostatic involvement by transitional carcinoma). Lymphovascular invasion by the primary tumor was not reported by 10% of institutions. Urethral and ureteral margins of resection were reported for virtually all specimens. However, soft tissue surgical margins (perivesical fat) were not evaluated or reported for 10% of all specimens, and this discrepancy was most common among community hospitals (15%) and VA/military hospitals (21%). Regardless of whether lymph node dissection was performed, 7% of pathologists did not record lymph node status (almost all in community hospitals), presumably because no lymph nodes were examined. Seven percent of pathology reports did not report finding any lymph nodes (because no lymph nodes were submitted), and another 11% reported multiple lymph nodes sampled but did not record the exact number. Such departures occurred most often in community hospitals, which had a compliance rate of only 69% for reporting the total number of lymph nodes and the number of positive lymph nodes evaluated. The number of positive lymph nodes was reported for each patient who had lymph node–positive disease.
Table 2. Pathologic Assessment of Cystectomy Specimens and Pelvic Lymph Nodesa
|No. of specimens||268||137||84||47||—|
|Histologic type reported||268 (100)||137||84||47||—|
|Tumor size and location reported||268 (100)||137||84||47||—|
|Pathologic tumor classification||268||137||84||47|| |
| pT0–pT2||184 (69)||95||60||29||—|
| pT3–pT4|| 84 (31)||42 (31)||24 (29)||18 (38)||0.50|
|Grade reported||268 (100)||137||84||47||—|
|Lymph/vascular invasion|| || || || || |
| Reported||241 (90)||133||67||41||—|
| Not reported|| 27 (10)|| 4 (3)||17 (20)|| 6 (13)||0.01|
|Carcinoma in situ reported||268 (100)||137||84||47||—|
|Prostate involvement reported||216 (100)||98||71||47||—|
|Margins (urethra/ureters)|| || || || || |
| Positive/negative||266 (99)||137||83||46||—|
| Not reported|| 2 (1)||0||1||1||—|
|Margins (perivesical fat)|| || || || || |
| Positive/negative||242 (90)||134||71||37||—|
| Not reported|| 26 (10)|| 3 (2)||13 (15)||10 (21)||< 0.0001|
|Lymph node status|| || || || || |
| Not reported|| 18 (7)|| 2 (1)||16 (19)||0||< 0.0001|
|No. of lymph nodes|| || || || || |
| Exact no. stated||221 (82)||123 (90)||58 (69)||40 (85)||—|
| No. stated as ‘multiple’|| 29 (11)||12 (9)||10 (12)|| 7 (15)||—|
| Not reported|| 18 (7)|| 2 (1)||16 (19)|| 0 (0)||< 0.0001|
|PLND|| || || || || |
| None|| 23 (9)|| 2 (1)||18 (21)|| 3 (6)||—|
| Limited|| 99 (37)||41 (30)||37 (44)||21 (45)||—|
| Standard||146 (54)||94 (69)||29 (35)||23 (49)||< 0.0001|
|Lymph nodes submitted||245||135||66||44||—|
| Lymph nodes submitted separately||213 (87)||124 (92)||51 (77)||38 (86)||—|
| Lymph nodes submitted en bloc|| 32 (13)||11 (8)||15 (23)|| 6 (14)||0.02|
A lack of information on margins was not correlated with age, gender, or chemotherapy use (i.e., treatment arm of the study). Of the 84 patients who had microscopic extravesical disease (pT3–pT4), 11 (13%) had pathology reports that failed to report the margin status. Of the 23 patients who did not undergo lymph node dissection, 5 (22%) did not have surgical margins recorded, compared with 16 of 99 patients (16%) who underwent limited dissection and 5 of 146 patients (3%) who underwent standard lymph node dissection (P < 0.001). Of the 32 reports of cases in which lymph nodes were submitted en bloc, 6 reports (19%) failed to record margins, compared with 15 of 213 reports (7%) of cases in which pelvic lymph nodes were submitted separately (P = 0.03). Lymph nodes were found in 250 of 268 specimens overall (93%), despite the finding that only 245 of 268 specimens (91%) had some amount of PLND performed on them. Pathologists found lymph nodes in 6 of 23 patients (26%) for whom no PLND was recorded; in these 6 patients, 1, 2, 2, 3, 5, and 6 lymph nodes, respectively, were counted. There was one patient who underwent limited PLND and had en bloc submission of lymph nodes reported, but this patient had no lymph nodes discovered by the pathologist. The exact number of lymph nodes found was not specified in 44% of en bloc specimens and in 8% of separately submitted lymph node specimens (P < 0.0001).
For 31 of 84 pT3–pT4 tumors (37%), the pT3 classification was subdivided into the pT3a category (microscopic extravesical invasion) and the pT3b category (macroscopic extravesical invasion), whereas the pT3 classification was not subdivided in this way for the remaining 53 tumors (63%). Incidental adenocarcinoma of the prostate was noted in 27 of 216 patients (12.5%). Close margins (within 1–4 mm of the inked perivesical margin) were recorded in only 5 patients.
The major findings of the current study were that the overall quality of pathologic evaluation of radical cystectomy specimens and pelvic lymph nodes removed from patients with bladder carcinoma was high and that such pathologic evaluation conformed to evolving pathology practice guidelines. Deficiencies were noted in the reporting of soft tissue margin status and the number of lymph nodes evaluated. We focused on these two surgical variables, because a multivariable analysis of the SWOG 8710 trial showed that margin status and the total number of lymph nodes found strongly predicted outcomes for patients with bladder carcinoma (unpublished data).
Perivesical fat margins were not reported in 10% of 268 cystectomy specimens; virtually all cases in which these margins were not reported were handled by community or VA pathologists. Measurement of the margin of fat overlying palpable or macroscopic tumor to determine margin status and distance of tumor from the inked margin was mentioned for only five specimens. The number of lymph nodes was not reported in 7% of specimens, most of which were processed at community hospitals, and another 11% of lymph nodes were reported as being multiple, without enumeration of the exact number found. Among the 24 specimens (9%, most of which were processed at community or VA hospitals) in which no lymph node dissection was performed by the surgeon, perivesical lymph nodes were reported in only 6 specimens, whereas in the remaining 18 specimens, the pathologists either did not detect or did not attempt to detect perivesical lymph nodes. Perivesical lymph nodes commonly are embedded within the vascular pedicles to the bladder. Lack of adjacent lymph nodes provides information to the surgeon regarding radial margins around the bladder and completeness of dissection, and evidence of tumor involvement of such lymph nodes not only has prognostic significance but also may provide an indication for adjuvant chemotherapy.
In fairness to pathologists, the total number of lymph nodes retrieved has emerged only recently as a significant pathologic variable with an impact on the outcome of both patients with lymph node–negative bladder carcinoma and patients with lymph node–positive bladder carcinoma.11 Although it behooves the pathologist to diligently search for and sample as many lymph nodes as possible, the number found is highly dependent on the extent of the lymph node dissection performed by the surgeon and on the way in which the lymph nodes are submitted for evaluation. Lymph nodes are easier to dissect from separate lymph node packets (resulting in higher lymph node yields) than from en bloc lymph node specimens submitted with the bladder specimen.
Although the 1997 AJCC staging system divides the pT3 category into pT3a (microscopic extravesical spread) and pT3b (macroscopic extravesical spread) subcategories, only 37% of pT3 specimens were dichotomized according to this feature. A recent study has suggested that these subdivisions of the pT3 category are of questionable prognostic significance.16 Incidental adenocarcinoma of the prostate was noted in only 12.5% of cystoprostatectomy specimens. This figure is less than the conservative 27% incidence of prostate carcinoma reported in earlier studies17 and considerably less than the incidence reported in contemporary studies, which found that approximately 50% of male cystectomy specimens harbored incidental prostate carcinoma.18 Pathologists in the current study focused on the extent of bladder carcinoma involvement of the prostate and reported a low rate of associated prostate carcinoma. The significance of incidental prostate carcinoma on the long-term outcome of patients after radical cystoprostatectomy for bladder carcinoma is unknown.
Accurate assessment of the extent of tumor in cystectomy specimens results from a combination of aggressiveness on the part of the surgeon in resecting widely around the bladder and in removing lymph nodes and diligence on the part of the pathologist in examining the specimen for tumor mass in fat and lymph nodes. The current review of a multiinstitutional cooperative group study demonstrates wide variability in both of these characteristics, suggesting that more uniformity in terms of both surgical and pathologic techniques is needed. Our overall impression, however, is that the quality of pathologic evaluation of cystectomy specimens, as practiced currently in diverse hospitals in the United States, follows accepted guidelines; thus, such published practice protocols (using pathology checklist templates) appear to be achieving their goal of making all significant and relevant pathologic information available. Perhaps the most important message to be taken from the current review is that better communication between the surgeon (in providing and labeling cystectomy and lymph node specimens) and the pathologist (in evaluating extent of tumor, margins, and lymph nodes according to accepted guidelines) will optimize prognostic information and improve current pathology standards.19
Finally, the most recent updated protocol for evaluating specimens obtained from patients with bladder carcinoma is available from the College of American Pathologists.20 These guidelines for pathologists provide the most detailed checklist for examining and reporting cystectomy specimens. Although some of the suggested items have not been validated, all may be clinically relevant and warrant further study. Consistent pathologic evaluation is critical to the design of clinical trials involving patients with carcinoma of the urinary bladder and to the interpretation of the results of such trials.