Accuracy of Combined Computerized Tomography and Fine Needle Aspiration Cytology in Lymph Node Staging of Localized Prostatic Carcinoma

0022-5347/94/1515-1310$03.00/0 THE JOURNAL OF UROLOGY Copyright © 1994 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Vol. 151, 1310-1314, May 1994

Printed in U.S.A.

ACCURACY OF COMBINED COMPUTERIZED TOMOGRAPHY AND FINE NEEDLE ASPIRATION CYTOLOGY IN LYMPH NODE STAGING OF LOCALIZED PROSTATIC CARCINOMA REIN VAN POPPEL, FILIP AMEYE, RAYMOND OYEN, WIM VAN DE VOORDE

AND

LUC BAERT

From the Departments of Urology, Radiology and Pathology I, University Hospitals Katholieke Universiteit Leuven, Leuven, Belgium

ABSTRACT

The sensitivity and accuracy rate of computerized tomography (CT) in lymph node staging of localized prostatic carcinoma is commonly considered to be low. Fine needle aspiration cytology of pathological lymph nodes seen on radiological staging can enhance this low accuracy rate. We prospectively investigated the accuracy of CT and fine needle aspiration cytology in lymph node evaluation of 285 patients with clinically locally confined prostatic carcinoma. The sensitivity, specificity and accuracy rates of this combined method were 77.8%, 100% and 96.5%, respectively. False-negative staging results were found in only 10 patients with minimal nodal disease. Although in contrast with previous reports, combined CT and fine needle aspiration cytology in our hands seems to be a highly efficient staging method for lymph node involvement. This method could be considered as an alternative to surgical lymphadenectomy in the preoperative evaluation of the nodal status of patients with localized prostatic carcinoma who are scheduled for radical prostatectomy or curative radiotherapy. KEY WORDS:

prostatic neoplasms; neoplasm staging; lymph nodes; tomography, x-ray computed; biopsy

Local-regional lymph node involvement is an important therapeutic determinant in the treatment of patients with apparently locally confined prostatic carcinoma. Only patients without nodal and/or metastatic disease are usually considered for radical prostatectomy or radiotherapy with curative intent. The accuracy of radio nuclide bone scans in evaluating the skeleton for metastatic disease is well documented. 1 More controversy exists about the most useful method for lymph node staging. 2 Surgical lymphadenectomy is undoubtedly the most accurate method. However, its efficacy must be weighed against the invasiveness and morbidity, with reported complication rates of 20 to 30%.3 Intraoperative analysis of pelvic lymph nodes with frozen sections is less invasive but characterized by high false-negative rates (29%) and high negative predictive values (81.4 to 96.1 %).4 Extraperitoneal pelvioscopy and transperitoneallaparoscopic lymphadenectomy are promising methods with high accuracy and low morbidity rates but they remain invasive. 5 ,6 Radiological lymph node staging has been repeatedly reported to be less accurate. Bipedal lymphangiography has been used less frequently because of the procedural difficulty, the related morbidity and the considerable false-negative and falsepositive rates. 7 Reports on the efficacy of computerized tomography (CT) in lymph node staging are conflicting. Sensitivity and specificity rates range from 27 to 75%, and from 66 to 100%, respectively.8,9 The results of magnetic resonance imaging are comparable to those of CT.lO The accuracy of these methods, however, can be greatly improved by the addition of percutaneous fine needle' aspiration of suspected or enlarged lymph nodes. l l We prospectively investigated the accuracy of CT and fine needle aspiration cytology for lymph node staging in 285 patients with clinically locally confined prostatic carcinoma without biochemical or scintigraphic arguments for bone metastasis. The accuracy of this combined method will be correlated with the definitive pathological examination of the lymph nodes at pelvic lymph node dissection, or radiological evaluation of the lymph node areas or lymphatic pathways at further CT followup. Accepted for publication October 8, 1993.

MATERIALS AND METHODS

From January 1987 to April 1993, 285 patients with pathologically confirmed, clinically localized prostatic carcinoma were considered to be suitable candidates for radical prostatectomy, considering the clinical tumor stage and general condition. The disease was clinically defined as stage Al in 13 patients, stage A2 in 27, stage B1 95, stage B2 in 104 and low volume stage C1 in 46,12 Initial staging consisted of prostatic acid phosphatase (PAP, enzymatic technique) and prostate specific antigen (PSA) determinations (Hybritech Tandem assay), transrectal sonography, chest x-ray, bone scan and skeletal x-rays of hot spots. No patient had any objective evidence of occult stage DO or systemic metastatic stage D2 disease as confirmed by normal PAP assays and negative bone surveys. Patient age ranged from 51 to 74 years (mean 64). PSA values (normal range 0.2 to 2.7 ,ug./l.) ranged from 3.5 to 54 ,ug./l. (median 8.1). All 285 patients were evaluated for pelvic nodal disease by CT (scan time 4.0 seconds, 125 kv., 310 mA.). After oral and intravenous contrast medium administration to distinguish vascular and intestinal structures from lymph nodes, CT was performed between the pubic arch and aortic bifurcation with a slice thickness of 8 mm. and a table incrementation of 10 mm. To perform cytological evaluation, the visualized nodes were punctured under CT guidance using a biopsy needle of different length (10 to 15 cm.) and diameter (18 and 19.5 gauge).2 One node per patient was punctured and 2 samples were taken in each case. The cost of CT, the material necessary for the puncture and the puncture itself is about $150. The material obtained was smeared on several slides, according to recommended principles. 13 At least half of the slides were immediately fixed in alcohol for Papanicolaou staining. Airdried smears were also prepared and stained with the MayGrunwald-Giemsa method. When a tissue core was obtained, it was fixed in Bouin's solution and processed for histological examination (hematoxylin and eosin, and PAP-PSA staining). For cytological interpretation the specimens were classified as class O-not representative, class I-negative, class II-benign changes, class III-suspicious, class IV-very suspicious and class V-certainly malignant. This procedure was repeated if the material obtained was not representative (class 0) or if

1310

LYMPH NODE STAGING OF LOCALIZED CARCINOMA

cytological analysis was equivocal (class III or IV). All CT scans and punctures as well as the pathological examinations were done by the same radiologist (R. 0.) and pathologist (W. V. d. V.). Patients with enlarged lymph nodes on CT and unequivocally positive fine needle aspiration cytology results were immediately offered hormonal therapy. Patients with equivocal fine needle aspiration cytology findings underwent another puncture. Patients with class V cytology results at the second fine needle aspiration were offered hormonal therapy. The regression of pathological lymph nodes, as diagnosed by fine needle aspiration cytology, was evaluated after hormonal therapy by periodic CT in all patients. Although inflammatory nodes also may regress, the disappearance of an enlarged lymph node (with class V cytology results) after hormonal therapy was considered a tumor response. Patients with negative CT scans or unequivocally negative cytology results at initial or repeat fine needle aspiration of enlarged nodes on CT underwent staging lymphadenectomy, followed immediately by radical prostatectomy as described previously.2, 14, 15 No frozen sections were performed. A modified pelvic lymph node dissection was performed as described by Paulson, limiting the dissection to the medial margin of the external iliac vein, pelvic floor and hypogastric vessels with removal of the lymphatic tissues of the obturator fossa. 16 The lymphadenectomy specimen, fixed in Bouin's solution for 24 hours, was examined in a standardized fashion following generally accepted instructions. 17 All detectable lymph nodes were included for routine microscopic examination of hematoxylin and eosin stained sections. Pathological lymph node staging criteria as mentioned in the 1987 tumor, nodes and metastasis classification were applied. IS For the purpose of this study, further ramification according to the size and site of lymph node involvement was made as initially proposed by Rutishauser and Hering,19 and later by Schroder et a1. 20 Minimal nodal disease (so-called microscopic metastases, stage pNla) was defined either as metastases smaller than 0.2 cm. or as microscopic infiltration of the intranodallymphatic sinus. All other lymph node metastases (stages pNlb, pN2a, pN2b and pN2c) were designated as major nodal involvement. Sensitivity, specificity, and accuracy of CT alone and combined with fine needle aspiration cytology were determined by correlating the preoperative findings to the definitive pathological examination of the lymphadenectomy specimen or to the lymph node status at CT after hormonal treatment when no pelvic lymph node dissection was performed. The staging result was considered true positive when an enlarged lymph node on CT was confirmed by positive fine needle aspiration cytology or was regressing at followup CT after hormonal therapy. The staging result was considered true negative when, in the absence of lymph nodes on preoperative CT or in the presence of enlarged lymph nodes but with unequivocally negative fine needle aspiration cytology results, pathological examination confirmed the negativity of the pelvic lymph node dissection specimen.

1311

istics, preoperative clinical stage, postoperative pathological stage, Gleason score, details on pathological examination of the pelvic lymph node dissection specimen and followup data of this latter group are presented in table 1. The mean number of lymph nodes removed in this group was 13 (range 9 to 16). No clinically objective signs of progression were noted in this group at a mean followup of 26 months (range 12 to 51). In summary, there were 232 true negative (95.9%) and 10 false-negative (4.1%) cases in the group with negative preoperative CT evaluation. Of the 43 patients (2 with stage AI, 4 with stage A2, 8 with stage Bl, 11 with stage B2 and 18 with stage Cl disease) with CT scans positive for lymph node involvement 30 (1 with stage AI, 5 with stage Bl, 10 with stage B2 and 14 with stage Cl cancer) had positive fine needle aspiration cytology results with unequivocal class V disease. After starting hormonal therapy, patients underwent followup CT according to the protocol. All patients had regression of lymph nodes at 3 to 6 months, suggesting true positivity in these 30 patients. An equivocal (class III to IV) fine needle aspiration cytology result was initially found in 5 patients (1 with stage B2 and 4 with stage Cl disease). At repeat fine needle aspiration cytology all 5 patients had unequivocal class V cytology findings. Distant CT followup in these patients again showed regression of enlarged lymph nodes after hormonal therapy. Eight patients (2 with stage AI, 3 with stage A2 and 3 with stage Bl cancer) with suspicious CT but negative fine needle aspiration cytology (class I to II) findings underwent staging pelvic lymph node dissection and proved to have no metastatic nodal disease (mean number of lymph nodes removed was 12.3, range 10 to 14). However, inflammatory changes and enlargement of the obturator nodes were noted in 4 of the 5 patients with stage A tumor. Of these 43 patients 35 had true positive and 8 true negative staging evaluations. Among the total group of 285 patients evaluated, analysis of the data showed 240 true and 10 false-negative, and 35 true and 0 false-positive results. The calculated sensitivity, specificity and accuracy rates of the combined staging method with CT and fine needle aspiration cytology were 77.8%, 100% and 96.5%, respectively. If only CT without fine needle aspiration cytology were performed as a staging method, analysis of the data showed 232 true negative, 10 false-negative, 35 true positive and 8 false-positive results. The calculated sensitivity, specificity and accuracy rates of CT alone would be 77.8%, 96.6% and 93.7%, respectively. The incidence of positive lymph nodes according to clinical stage is summarized in table 2. Intraoperative or postoperative complications directly related to the pelvic lymph node dissection were minor. Prolonged lymphorrhea (greater than 5 days) was noted in 5 patients and resolved spontaneously with time in all. Paresthesia in the buttock regions due to manipulation of the obturator nerve was noted in 4 patients and resolved spontaneously. One patient had transient paresis of the adductor muscles. The fine needle aspiration procedure took 15 to 30 minutes and was always well tolerated. No patient had any hemorrhagic, infectious or inflammatory complication.

RESULTS

The overall patient characteristics, strategy and results of the staging procedure are summarized in the figure. Of the 285 patients 242 (11 with stage AI, 23 with stage A2, 87 with stage Bl, 93 with stage B2 and 28 with stage Cl disease) showed no evidence of pathological lymph nodes on staging CT and, consequently, underwent staging pelvic lymph node dissection and radical prostatectomy. Node-free disease was confirmed in 232 patients at definitive pathological examination of the pelvic lymph node dissection specimen. The numbers of lymph nodes removed ranged from 8 to 19 (mean 12.9). However, 10 patients (1 with stage A2, 2 with stage B2 and 7 with stage Cl cancer) had unexpected nodal involvement with minimal nodal disease confined to 1 lymph node (stage pNla). The patient character-

DISCUSSION

The presence of positive lymph nodes is an important finding in the treatment planning and prognosis of patients with clinically localized prostatic carcinoma. Patients with node positive disease are generally believed to have systemic cancer and are at increased risk for early failure after presumed curative therapy. Several reports suggest that patients with lymphatic extension have relapse much earlier and more frequently than those without nodal disease regardless of the treatment modality used for the primary tumor.21 However, there are no randomized trials comparing failure rates in a statistically significant number of patients with either positive or negative nodal disease treated by the same modality, such as radical surgery

1312

<

LYMPH NODE STAGING OF LOCALIZED CARCINOMA 242 ptsCT NO (11 A1, 23 A2, 87 81, 9382,28 (1)

Rad Prost

+ LND

Rad Prost

8 pts d. I-II (2 A1, 3 A2, 3 B1)

43 pts CT N+ (2A1,4A2,8B1,

232 pts pNo (11 A1,22A2,87B1,91 82,21 (1)

- - - - - - (

NAC

~

I

I

..

30 pts d. V

11 B2, 18 (1)

+ LND

8 pts pNo 2nd FNAC

5 pts c . III-IV (1 B2,4(1)

10 pts pN1a (1 A2, 2 B2, 7 (1)

5 ptsc . V

HT

+ f.u.

HT + f.u.CT )I

5 pts N+

CT

30 pts N+

(1 A2, 5 81, 1082,14(1)

Patient (pts) characteristics are shown according to preoperative clinical stage and lymph node status on CT. Definitive pathological examination of removed lymph nodes is indicated. CT-No, no detectable lymph nodes on preoperative CT. CT-N+, pathological lymph nodes on CT. FNAC, fine needle aspiration cytology. LND, lymph node dissection. cl., cytology class. HT, hormonal therapy. f.u.CT,followup CT after hormonal therapy. Rad Prost, radical prostatectomy. TABLE

1. Preoperative and postoperative clinical data of 10 patients with unexpected stage pN1a disease on definitive pathological examination of

removed lymph node Pt. VI HK SA DL HM RL GF VA LW DP

Clinical Stage C1 A2 C1 C1 B2 C1 C1 C1 C1 B2

PSA (I'g./l.)

Lymph Node Pathology (No./total)

12 8 9.3 8.9 2.3 8.9 7.3 10.1 8.9 6.3

pN1a pN1a pN1a pN1a pN1a pN1a pN1a pN1a pN1a pN1a

(1/9) (1/10) (1/16) (1/15) (1/16) (1/10) (1/12) (1/14) (1/16) (1/12)

Pathological Stage' pT3N1aMO pT2N1aMO pT3N1aMO pT3N1aMO pT3N1aMO pT2N1aMO pT3N1aMO pT3N1aMO pT2N1aMO pT3N1aMO

Gleason Score

Followup (mos.)t

6 6 9 7 7 6 7 8 7 8

51 48 46 37 24 22 20 18 17 12

* Pathological stage of the radical prostatectomy specimen; 1987 tumor, nodes and metastasis classification. t No patient had progression on followup.

Number of patients with positive lymph nodes and incidence of pathological lymph nodes according to initial clinical stage

TABLE 2.

Clinical Stage

Total No. Pts.

A1 A2 B1 B2 C1

13 27 95 104 46

No. Pts. With Pos. Lymph Nodes (%)

o

(0) 2 (7.4)

5 (5.3) 13 (12.5) 25 (54.0)

or radiation therapy without adjuvant hormonal therapy if node positive disease is confirmed. Several reports indicate that the cancer related prognosis is better in patients with lower stage nodal disease, although some differences exist in the terminology applied to the volume of the disease. Rutishauser and Hering have proposed a staging classification depending on the histological and macroscopic degree of involvement: stage pN1.1-a single microscopic focus, stage pN1.2-macroscopically detectable unilateral invasion of 1 lymph node and stage pN2-macroscopic invasion of 2 or more lymph nodes. 19 Analysis of disease-free survival demonstrates no significant difference between stages pNO and pNl (both stages pN1.1 and pN1.2), whereas all stage pN2 tumors progress more rapidly. Others reported no survival difference in patients with involvement of a single node compared to those with negative nodes,22 or they stressed the favorable outcome of treatment in patients with minimal or low volume nodal disease. 23 -27 Still, the presence of nodal disease is considered an indicator of systemic cancer and most urologists will exclude these patients from curative treatments, such as radical prostatectomy and radiotherapy. Although still debatable and empirical, one might assume that a subgroup of patients with minimal or low nodal disease and favorable prognostic factors may nonetheless benefit from treatment with curative intent. Standard staging pelvic lymph node dissection is currently the most accurate technique to assess the pelvic lymph node status in clinically localized prostatic carcinoma. However, a

certain complication rate with this technique is reported. Paul et al observed a mean morbidity rate of 27%, varying from 4 to even 53%.28 The extent ofthe dissection has an important role in the variability of these results. With a modified technique, however, limiting the dissection to the medial margin of the external iliac vein and including the nodes surrounding the obturator nerve,16 lower morbidity rates were observed. 29 , 30 Although some physicians suggest that less extended pelvic lymph node dissection might overlook microscopic metastasis in the common and external iliac and presacral nodes, current belief is that modified pelvic lymph node dissection can provide accurate staging with minimal risk to the patient.31 Despite this low toxicity, surgical pelvic lymph node dissection for staging purposes remains a rather invasive procedure. Laparoscopic pelvic lymph node dissection and extraperitoneal pelvioscopy are promising operative staging procedures compared with surgical pelvic lymph node dissection. In experienced hands, laparoscopic pelvic lymph node dissection proved to be equally efficient compared with open pelvic lymph node dissection. 6, 32 A complication rate of 15 % was reported in a large retrospective multicenter study.33 Overall accuracy, specificity and sensitivity rates of 95%,100% and 84%, respectively, were obtained with extraperitoneal pelvioscopy in patients with prostate or bladder cancer. Morbidity consisted of transient lymphorrhea in 5 patients, and injury to the external iliac vein and obturator nerve in 1. 5 Although characterized by high accuracy and lower morbidity rates, these methods remain invasive. Analysis of intraoperative frozen sections of pelvic lymph nodes could obviate the need for a supplementary surgical staging procedure. In a retrospective analysis of 310 patients Epstein et al reported high accuracy rates of intraoperative frozen section assessment of lymph Ilode involvement, classifying correctly 96.5% of the patients. 34 They identified by random frozen sections 67.6% of the patients with microscopic metastases in preoperatively grossly uninvolved pelvic lymph node dissection specimens. These findings were not confirmed

LYMPH NODE STAGJ:NG OF LOCALIZED CARCINOMA

others. Hermansen et al reviewed 6 studies on frozen section analysis of pelvic lymph nodes of prostatic carcinoma patients, indicating a false-negative rate of approximately 29% with a predictive value of a negative test ranging from 81.4 to 96.1 %.4 The high false-negative rate can be due to several factors. If only enlarged or suspicious lymph nodes are selected for analysis, a major intraoperative sampling error can occur. In preparing the tissue sample for frozen section analysis error can occur in the selection of the block or blocks of tissues to be frozen. Although the technical quality of frozen sections is sufficiently close to that of paraffin sections, slide interpretation can be a final source of error, especially if minimal microscopic invasion is present. The possibility of false-negative or positive findings together with the time-consuming nature of this procedure may discredit this method. A final disadvantage of this approach with frozen sections is that the patient must be fully informed about the disease, since some urologists will cancel the radical prostatectomy and perform hormonal therapy when frozen sections are positive. Relating to the invasiveness of surgical staging procedures and possible low accuracy of frozen section analysis, there is an obvious need for noninvasive preoperative staging modalities. Bipedal lymphangiography has been omitted as a staging method due to the low sensitivity and specificity rates, and the possible morbidity in patients with severe pulmonary disease or allergy to iodinated contrast material. Loening et al reported a false-positive and false-negative rate of 59% and 36%, respectively, with lymphangiography followed by pelvic lymph node dissection,35 although these results can be improved by aspiration cytology of radiographically suspicious areas. l l Reports on accuracy rates of CT in demonstrating nodal metastases have been controversial. The reported series were relatively small with variable sensitivity, specificity and accuracy rates. 5. 8. 9 The possible explanation for false-negative results observed with CT is multifactorial. Sampling error in the detection of small lymph nodes, alterations in nodal architecture, and various degrees of microscopic and macroscopic invasion are the most important factors. The technical variability of performing CT, such as the method of scanning, slice thickness and use of intravenous or oral contrast medium to opacify vessels and intestinal structures, all influence the diagnostic accuracy. Finally, observer variability in data interpretation cannot be overlooked. Percutaneous fine needle aspiration cytology is able to enhance dramatically the accuracy rates for lymph node staging of prostatic carcinoma by lymphangiography and CT. 36 ,3? Most experience has been reported in the staging of different pelvic and retroperitoneal malignancies, correlating fine needle aspiration cytology of positive nodes on lymphangiography with definitive pathological results of pelvic lymph node dissection. Accuracy rates of CT guided fine needle aspiration cytology are actually based on studies with a limited number of patients. 3? Various reports on biopsy results in the former group show discordant results, with reported accuracy rates varying between 68% and 91 %.11,38 False-positive results are extremely rare, since it is relatively easy to identify malignant cells in the aspirates of suspicious lymph nodes. Negative or equivocal results of fine needle aspiration cytology are not conclusive, necessitating a new puncture or a surgical staging procedure. The complication rate with this technique was reportedly low, varying from 0.05 to 2.5% of the patients. 36 No complications occurred in our patients, which is undoubtedly related to the expertise of the radiologist, and the complication rate might be higher in the general medical community. We prospectively evaluated the efficacy of CT and fine needle aspiration cytology as staging procedures for locally confined or low stage C1 prostate cancer. In our hands, this proved to be a highly efficient staging method, with high sensitivity, specificity and accuracy rates of 77.8%, 100% and 96.5%, respectively. The false-negative results were seen only in patients

1313

with micl'Oscopic invasion of 1 lymph node (stage pNla), found mainly in patients with Clinical stage Cl tumors. However, no lymph node involvement more than stage pNla was missed by this method. These findings are in discordance with previous results on the efficacy of CT in detecting pelvic lymph nodes. Several factors can be responsible for this discrepancy. By adherence to a strict protocol of performing CT (slice thickness, table incrementation, oral and intravenous contrast medium, and so forth) and considering every enlarged lymph node as a pathological finding (even those smaller than 5 mm.) the sampling error can be limited. All CT scans were interpreted by the same radiologist, considerably limiting inter-observer variability. The specificity and accuracy rates of this method are undoubtedly increased by combining fine needle aspiration cytology of suspected or pathological lymph nodes with CT imaging. The presumed specificity and accuracy rates of CT alone as a staging modality are lower compared to those of CT combined with fine needle aspiration cytology. These results confirm the findings of others and prove the important diagnostic value of this method. 38 One could criticize the low incidence of positive lymph nodes in our patient group, questioning the completeness in performing the modified lymphadenectomy. The high mean number of lymph nodes removed is an indirect indicator of the surgical quality. Moreover, analysis of our data shows an incidence of positive lymph nodes in clinical stages AI, A2, B1, B2 and C1 tumors of 0%,7.4%,5.3%,12.5% and 54%, respectively. These incidence rates correspond well with the recent data of Petros and Catalona. 39 We confirm their statement that this lower incidence of nodal involvement relative to previous reports reflects a true change in the stage at which prostate cancer currently is diagnosed. One could criticize our method not to perform intraoperative frozen sections during radical prostatectomy. Analysis of our data, however, indicates that only microscopic node disease was missed. In view of the known low accuracy rates of frozen section analysis, one can assume that these lesions probably could have been missed by an intraoperative assessment. Furthermore, the aforementioned literature data suggest that this subgroup of patients may benefit from major curative therapies. In our patients with stage pN1a disease no progression was noted at a mean followup of 26 months. However, we must await further followup before definitive conclusions can be drawn. In regard to the reported false-negative rates, the timeconsuming procedure and the need for preoperative patient information as opposed to the high accuracy rate of our method, one may consider omitting intraoperative frozen section analysis. In conclusion, the proposed staging procedure by CT of the pelvis is an efficient method to evaluate the nodal status of patients who are scheduled for radical prostatectomy or curative radiotherapy. Its combination with fine needle aspiration cytology when enlarged nodes are found significantly improves the accuracy over CT alone. Surgical staging procedures may still be considered in patients with equivocal CT and fine needle aspiration cytology staging results, or in those with unfavorable prognostic indicators, such as advanced clinical stage, high PSA level or PSA index and tumor aneuploidy. REFERENCES

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