Vol. 135, February Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1986 by The Williams & Wilkins Co.
FINE NEEDLE ASPIRATION OF THE ABNORMAL PROSTATE: A CYTOHISTOLOGICAL CORRELATION H. BALLENTINE CARTER, ROBERT A. RIEHLE, JR.,* JUNE H. KOIZUMI, JAMES AMBERSON AND E. DARRACOTT VAUGHAN, JR. From the Department of Surgery (Urology), James Buchanan Brady Foundation and Department of Pathology, The Papanicolaou Cytology Laboratory, New York, New York
Cytological diagnosis by fine needle aspiration of the prostate was compared to histological diagnosis by either perineal needle biopsy or transurethral prostatic resection in 110 patients suspected to have prostatic cancer by rectal examination. Of the 94 prostatic aspirations that could be given a definite cytological diagnosis there was histological correlation in 85 (90.4 per cent). The false negative rate was 2. 7 per cent for fine needle aspiration and 5.3 per cent for perineal needle biopsy. Inadequate cytological samples occurred mainly at the beginning of the study. There was a 69 per cent correlation in 36 cases in which cytological grading was compared to histological grading. Our results indicate that fine needle aspiration is an easily performed, diagnostically reliable outpatient procedure with minimal complications that also can be used for grading purposes. The diagnosis of prostatic carcinoma traditionally has been established histologically in the United States by core needle biopsy of a suspicious prostate detected on rectal examination. Cytological diagnosis by transrectal aspiration has been used successfully in Europe for many years yet this skinny needle technique only recently has gained acceptance in this country. The simplicity, safety and accuracy of fine needle aspiration of the prostate have been documented, and its advantages over perinea! needle biopsy have been described. 1-s In this prospective study fine needle aspiration of the prostate was compared to perineal needle biopsy to determine the diagnostic accuracy and safety, as well as the correlation between histological and cytological grading from prostates suspicious for carcinoma. MATERIALS AND METHODS
From July 1983 to June 1984, 110 patients with an abnormal rectal examination suggestive of prostatic cancer were selected for fine needle aspiration under our protocol. Fine needle aspirations of the prostate were performed in all cases with a flexible 22 gauge disposable, prostatic aspiration needle, needle guide and aspiration syringe as described by Franzen and associates. 9 The metal steering ring was secured on a gloved index finger by a finger cot and the finger then was inserted into the rectum. The suspicious area of the prostate was palpated. The fine needle then was introduced through the steering ring to the prostatic lesion and, after removal of the stylet, suction was applied by pulling on the plunger of the syringe. While maintaining negative pressure suction, the needle was moved back and forth within the nodule. The suction was released before the needle was withdrawn from the prostate to avoid loss of the cell sample into the syringe and also to avoid contamination of the sample with rectal mucosa or rectal contents. The needle then was disconnected and attached to an air-filled syringe, and a droplet was expressed onto a glass slide. With a second slide the material was spread quickly and gently between the slides, then immersed immediately into 95 per cent ethanol to avoid drying artifact. The smearing and fixation procedure was performed in the endoscopy suite by a cytotechnologist. The slides were stained with the Papanicolaou technique. Four Accepted for publication August 7, 1985. * Requests for reprints: 525 East 68th St., New York, New York 10021. 294
separate passes of the needle were made in each patient, yielding 4 slides per patient for cytological inspection. In all cases the fine needle aspiration was performed by the same person (H.B. C.). Fine needle aspiration was followed by perineal needle biopsy with a Travenol needle in 108 of the 110 patients. Fine needle aspiration and perineal needle biopsy were performed with the patient under general anesthesia in the lithotomy position except for 3 aspirations that were performed with local anesthesia. In the remaining 2 cases the fine needle aspiration was followed by transurethral prostatic sampling. None of the patients received mechanical or antibiotic bowel preparation. However, 46 patients received perioperative parenteral antibiotics. Patients were monitored for 24 hours after the procedure for fever, perineal hematoma, pain and hematuria. The cytological results were reported the same day without knowledge of the histological report. Cytological specimens were classified by the cytopathologist into 5 categories: 1) material inadequate for diagnosis, 2) negative for malignant cells, 3) atypical, 4) suspicious for malignancy and 5) positive for malignant cells. Cases classified as atypical ranged from those containing mildly atypical prostatic epithelial cells usually associated with inflammation to a few cases exhibiting marked atypia that could not be classified further. Inadequate specimens were defined as those that contained either no prostatic epithelium or too scanty an amount for reliable diagnosis. The cytological appearance of benign and malignant prostatic lesions has been described previously. 3 •7• 10• 11 In summary, the characteristic features of benign prostatic epithelium are cohesive, orderly arrangement in sheets or groups, with cells having well defined cytoplasmic borders giving the sheet a honeycomb appearance (fig. 1, A and B). The cells are uniform with small, round, regular nuclei, fine granular chromatin and inconspicuous nucleoli. In contrast, malignant cells are larger with an increased nuclear-cytoplasmic ratio, moderate to marked variation in nuclear size and shape, and disorderly arrangement (fig. 1, C and D). In most cases there is a significant lack of cohesion among the cells. The nuclei are hyperchromatic with irregularity of the nuclear membrane, irregularly granular chromatin and prominent nucleoli. Of the 36 cases available for comparison tumors were classified as being of well, moderate or poor differentiation depending on cellular patterns, nuclear polymorphism and enlargement of
FINE NEEDLE ASPIRATION OF ABNORMAL PROSTATE
FIG. 1. A, sheet of benign prostatic epithelium demonstrates honeycomb appearance. Reduced from X40. B, high power view of benign prost atic epithelium. Reduced from XlOO. C, malignant prostatic epithelium demonstrates disorderly arrangement of cells. Reduced from X40. D, high power view of malignant epithelium. Reduced from XlOO.
nucleoli as described by Esposti.10 Well differentiated prostatic epithelium is characterized on aspiration by few free cells, moderate nuclear pleomorphism and no nucleolar enlargement (fig. 2, A) . Moderately differentiated adenocarcinoma has a similar pattern cytologically as described previously for well differentiated tumors with less cellular cohesiveness and more pronounced pleomorphism (fig. 2, B) . Bizarre-appearing nuclei and nucleolar enlargement characterize poorly differentiated prostatic epithelium (fig. 2, D) . Pathologically, all tumors were assigned a Gleason sum. The Gleason grading system is based on growth patterns rather than cytological details. With 5 morphological patterns, the most prevalent glandular configuration is added to the next most prevalent to yield a Gleason score ranging from 2 to 10. These growth patterns range from a well differentiated pattern of uniform, distinct, oval-shaped glands to more poorly differentiated patterns in which t here is marked variat ion in glan dular size and shape, as well as glandular coalescence and st romal invasion (fig. 2, C and E) . Cancer was diagnosed histologically and cytologically in 49 cases. However, for purposes of comparison only core needle biopsies and aspirations were graded. Of t he 47 malignant needle biopsies 3 initially were reported as benign and, therefo re, were not graded. In 44 cases t he needle biopsy result initially was reported as malignant , and in 8 of these either the cytology or histology specimens were not available for grading.
A total of 110 patients underwent fine needle aspiration of the prostate (see table) . Of these samples 4 (3.6 per cent) were inadequate and 5 patients (4.5 per cent) had cytologically suspicious aspirations. One of the inadequate samples contained no prostatic epithelium, 2 contained a few benign epithelial cells of prostatic origin and 1 contained malignant urothelial cells. Bladder biopsy in the latter patient revealed urothelial cell carcinoma in situ and the prostatic needle core biopsy was benign. Subsequent transurethral sampling of the prostate was interpreted as marked urothelial cell atypia of the prostatic duct epithelium. Of the 5 cytologically suspicious aspirations 2 were malignant and 3 benign by needle core biopsy. There were 7 atypical aspirations, 4 of which had documented prostatic malignancy eit her by needle biopsy or transurethral prostatic resection. Of the remaining 3 atypical aspirations 1 was benign, 1 atypical and 1 inadequate by perinea! needle biopsy. Of 110 aspirations 57 (52 per cent) were read as malignant. There was histological confirmation of malignancy in 45 of these 57 aspirations initially: 44 by perinea! needle biopsy and 1 by transurethral prostatic resection (see table) . Ten patients with the cytological diagnosis of malignancy had benign needle biopsies, 3 of whom subsequently had repeat prostat ic biopsies
CARTER AND ASSOCIATES
FIG. 2. A, example of well differentiated malignant prostatic cells obtained by fine needle aspiration. Reduced from X40. B, moderately differentiated prostatic epithelial cells on fine needle aspiration. Reduced from X40. C, prostatic needle biopsy shows moderately differentiated tumor from same patient. Reduced from XlOO. D, cells obtained by fine needle aspiration show poorly differentiated prostatic adenocarcinoma. Reduced from xlOO. E, needle biopsy from same patient demonstrates poorly differentiated tumor. Reduced from XlOO.
Fine needle aspiration versus perinea/ needle biopsy Cytology Studies Fine Needle Aspiration Results Malignant Benign Suspicious Atypical Inadequate Totals
Histology Studies Perinea! Needle Biopsy No. 57 37 5 7 4
44 (47)* 1 2 3
10 (7)* 36 3 1 4
Transurethral Prostatic Resection Malignant 1 (2)*
llO 50 54 2 2 2 * Subsequent repeat biopsies of initial benign histology specimens were malignant in 3 cases; 1 atypical perinea! needle biopsy was confirmed to be malignant on transurethral resection.
that were malignant. One patient with an atypical needle biopsy and one with an inadequate needle biopsy had malignant prostatic aspirations. A later transurethral prostatic resection on the patient with the atypical needle biopsy confirmed the diagnosis of prostatic malignancy histologically. Therefore, 49 of 57 malignant aspirations eventually were confirmed histologically to be malignant (see table). Of the 110 aspirations 37 were read as benign (33.6 per cent): 36 of these patients had benign and 1 had malignant needle biopsies. A total of 36 prostatic aspirates was classified as to the degree of differentiation and compared to the Gleason sum on the perinea! biopsy specimen. The Gleason sum ranged between 6 and 10. All prostatic aspirates were classified cytologically as either moderately or poorly differentiated except for 1 that was read as well differentiated and corresponded to a Gleason sum
of 7 histologically. If an aspirate had features of moderate and poor differentiation it was classified as being poorly differentiated for purposes of comparison. In addition, Gleason sums were divided into 3 groups corresponding to well (Gleason sum 2 to 4), moderate (Gleason sum 5 to 7) and poor (Gleason sum 8 to 10) differentiation. 12 There was accurate correlation between cytological and histological grading in 25 of 36 cases: 13 moderately and 12 poorly differentiated lesions on fine needle aspiration were given Gleason sums of 5 to 7 and 8 to 10, respectively. Of the remaining aspirates 1 classified as well and 2 as poorly differentiated cytologically had Gleason sums of 5 to 7 (moderately differentiated), while 8 classified cytologically as moderately differentiated had a Gleason sum of 8 to 10 (poorly differentiated) . In no case was a poorly differentiated tumor read as well differentiated by the other method.
FINE NEEDLE ASPIRATION OF ABNORMAL PROSTATE
There were 3 complications in the 110 patients (2.7 per cent). Twenty-four hours after the procedure 1 patient suffered an ileus and a decrease in hematocrit was documented. The ileus resolved in 72 hours with conservative management. Presumably, this represented a retroperitoneal pelvic hematoma secondary to perineal biopsy. A second patient required rehospitalization for clot retention 36 hours after the biopsies. He was discharged from the hospital the following day after overnight catheter drainage. A febrile episode occurred in 1 patient who underwent transrectal and perineal core prostatic biopsies, as well as fine needle aspiration for a firm nodule surrounded by normal tissue. Of interest, the area disappeared after aspiration. The cytology study was read as granulomatous prostatitis and the histology result was benign. These 3 patients had received antibiotics before and after the procedure. There were no complications in the patients who did not receive parenteral antibiotics. DISCUSSION
Fine needle aspiration of the prostate has been used extensively and successfully in the Scandinavian countries for many years. In the United States, however, it is only now beginning to gain acceptance. Several studies have compared conventional core biopsy and fine needle aspiration in the diagnosis of prostatic cancer. Zattoni and associates compared cytological findings to histological findings in 195 cases of suspected prostatic cancer and found agreement in 96.4 per cent. I False negative reports amounted to 2 of 195 (1 per cent) and 5 malignant aspirations in this series were unconfirmed histologically. Hosking and associates reported a correlation of 81.1 per cent between fine needle aspiration and needle biopsy in a series of 74 cases, with a false negative rate of 25 per cent for aspiration cytology. 2 Six cases that were positive for cancer cytologically could not be confirmed histologically. In a study of 56 patients Melograna and associates showed a 91 per cent correlation between aspiration cytology and needle biopsy, with a 23 per cent false negative rate for cytology and no false positives.3 Esposti and Franzen reported a correlation of 96 per cent, with 4 per cent false negative cytological findings in a large series of 350 patients. 4 Five patients in that series had malignant aspirations not confirmed histologically. Of the 94 prostatic aspirations in this study that could be given a definite cytological diagnosis there was eventual histological correlation in 85 (90.4 per cent). One patient with a fine needle aspiration read as benign had a positive perineal needle biopsy, giving a false negative rate of 2.7 per cent. A true false positive rate for fine needle aspiration cannot be evaluated in the current study, since in no case was the prostate gland removed and examined histologically. As stated previously, 49 of 57 malignant aspirations were confirmed histologically, 4 of these on repeat prostatic biopsy. Of the 8 patients with no histological confirmation of malignancy 1 had rapid clinical progression of obvious prostatic cancer and was treated with external radiation for outlet obstruction, 1 had carcinoma in situ of the bladder and metaplastic prostatic epithelium on subsequent transurethral prostatic resection, 2 were believed to have clinically localized disease missed by perinea! needle biopsy and underwent I25iodine implantation based on the fine needle aspiration and clinical examination, and the remaining 4 are under observation to have repeat biopsies at a later date. None of these 8 cases was considered concordant even though strong clinical suspicion of prostatic cancer existed, and no implication of histologically documented prostatic cancer is intended by giving the clinical outcome of these patients. A false negative rate for perineal needle biopsy of 5.3 per cent was obtained in this study. However, the true false negative rate could be higher with longer followup of the aforementioned 8 patients.
The rate of inadequate sampling by fine needle aspiration in previous reports ranged between 2 and 16 per cent as reported by Esposti, 6 and Melograna and associates,3 respectively. A similar incidence of 12 per cent inadequate needle biopsy results in 220 cases was reported by Alfthan and associates. 5 Our rate of inadequate sampling by fine needle aspiration was 3.6 per cent. In this study the inadequate category encompassed not only acellular specimens but also those containing minimal amounts of benign prostatic epithelium that were judged by the cytopathologist to be too scanty to permit reliable interpretation. Two of the inadequate specimens were of this type. Inadequate fine needle aspiration specimens were obtained mainly at the beginning of the study and rarely represented a problem once experience was gained in the use of the aspiration needle. Our experience with prostatic fine needle aspirations read as cytologically suspicious for malignancy is limited, having occurred in only 5 of 110 cases (4.5 per cent). Core biopsies revealed benign histological findings in 3 and adenocarcinoma in 2. Interestingly, 1 of the patients who had a suspicious aspiration and a negative perinea! needle biopsy clinically had a rock hard prostate with a primary lung cancer metastatic to the skin and eye. The fine needle aspiration specimen of another patient initially read as suspicious was one of the earliest obtained for this study. The perinea! needle biopsy was malignant and the fine needle aspiration contained several clusters of abnormal prostatic cells interpreted as strongly suspicious, intermixed with a fair amount of rectal epithelium. At a later date the cytopathologist reviewed the smears and, with the benefit of greater experience, assessed the specimen as positive for malignancy. It can be expected that as the urologist and cytopathologist gain experience in their respective roles, the reliability and accuracy of prostatic fine needle aspiration will increase. Of the 7 fine needle aspirations read as atypical 4 were malignant histologically, 1 was atypical and 1 was benign on perinea! needle biopsy. There was 1 inadequate biopsy in this group. Of interest, 1 of the atypical aspirations was read as infiltrating transitional cell cancer on perinea! needle biopsy. It seems reasonable to repeat the fine needle aspiration and/or the perineal needle biopsy in cases with suspicious or atypical cytological diagnoses. Air-drying artifact, and contamination of the aspirated material with rectal mucosa and/or rectal contents are potential problems of fine needle aspiration. If the Papanicolaou staining method is used rapid fixation in 95 per cent ethanol is of utmost importance to avoid air-dry distortion, which leads to difficulty in cytological interpretation. Additionally, suction must be released before withdrawal of the needle from the prostate gland to avoid contamination of the specimen and to avoid loss of the material into the barrel of the syringe. The Papanicolaou staining method was used in this study and is believed by our cytopathologist to give greater morphological correlation between tissue sections and cytological material as opposed to other methods. One of the disadvantages frequently attributed to fine needle aspiration compared to perinea! needle biopsy is loss of ability to grade prostatic cancer accurately. However, little has been written about the relationship between cytological and histological grading. Esposti demonstrated the prognostic significance of cytological grading in a 5-year followup of 469 patients who received hormonal therapy.Io In that study tumor aggressiveness and the cytological response to hormonal therapy correlated with the degree of differentiation. Of his 36 cases in which cytological and histological differentiation was compared 32 were graded identically, with high, moderate or poor as categories of differentiation. Ekman and associates found good correlation between transrectal aspiration biopsies and perinea! biopsies when grading was based on the degree of differentiation.13 Of 33 tumors 24
CARTER AND ASSOCIATES
were graded equally using well, intermediate or poor differentiation, and no tumors graded as poorly differentiated were read as well differentiated by the other biopsy method. When perineal biopsies were graded by the Gleason method Chodak and associates found inconsistent correlation between the Gleason sum and cellular differentiation of prostatic aspirates.14 In their study only 18 biopsies were compared and Gleason sums of 6 or 7 were found when the aspirates were well, moderate or poorly differentiated. In our study good correlation existed between cytological and histological grading, with concordance in 69 per cent of the cases. Cytologically, tumors were undergraded in 22 per cent of the cases and overgraded in only 5.5 per cent compared to the Gleason sum. Complications of needle core biopsy, most commonly fever, hematuria, perineal hematoma and clot retention, occurred in 159 of more than 4,300 cases in the world literature reviewed by Wendel and Evans. 11 In their own series of 250 cases a 7.2 per cent complication rate was reported. In our series the individual complication rate for each procedure cannot be estimated, since biopsy, aspiration and cystoscopy were performed during the same session. Complications occurred in 3 of our 110 patients (2.7 per cent). The 2 bleeding complications, hematoma and clot retention, are well recognized sequelae of needle core biopsy and have not been reported previously with fine needle aspiration. The third complication, presumed to be transient bacteremia, occurred in a patient who underwent perineal biopsy, transrectal biopsy and fine needle aspiration while on antibiotic prophylaxis. The incidence of complications associated with fine needle aspiration appears to be less than with needle core biopsy, which probably is secondary to the smaller gauge of the needle used in fine needle aspiration. Esposti and associates found the incidence of febrile reactions after fine needle aspiration to be about 1 per cent and sepsis occurred in 4 of 14,000 aspirations. 15 Bleeding complications were not noted. Based on our results and the findings of previous investigators, fine needle aspiration of the abnormal prostate is an easily performed, diagnostically reliable procedure with minimal complications. A larger volume of the prostate is available for sampling with the fine needle and the procedure can be repeated readily. We believe that cytological grading accurately reflects histological grading and has prognostic significance in terms of response to therapy. Of particular importance is the fact that fine needle aspiration can be performed in the office or outpatient setting on ambulatory patients as the initial procedure on
which to base the need for further evaluation in the diagnosis of prostatic cancer. REFERENCES
1. Zattoni, F., Pagano, F., Rebuffi, A. and Constantin, G.: Transrectal thin-needle aspiration biopsy of prostate: four years' experience. Urology, 22: 69, 1983. 2. Hosking, D. H., Paraskevas, M., Hellstein, 0. R. and Ramsey, E. W.: The cytological diagnosis of prostatic carcinoma by transrectal fine needle aspiration. J. Urol., 129: 998, 1983. 3. Melograna, F., Oertel, Y. C. and Kwart, A. M.: Prospective controlled assessment of fine-needle prostatic aspiration. Urology, 19: 47, 1982. 4. Esposti, P. L. and Franzen, S.: Transrectal aspiration biopsy of the prostate. A re-evaluation of the method in the diagnosis of prostatic carcinoma. Scand. J. Urol. Nephrol., suppl., 55: 49, 1980. 5. Alfthan, 0., Klintrup, H.-E., Koivuniemi, A. and Taskinen, E.: Cytological aspiration biopsy and Vim-Silverman biopsy in the diagnosis of prostatic carcinoma. Ann. Chir. Gynaec. Fenn., 59: 226, 1970. 6. Esposti, P. L.: Cytologic diagnosis of prostatic tumors with the aid of transrectal aspiration biopsy. A critical review of 1,110 cases and a report of morphologic and cytochemical studies. Acta Cytol., 10: 182, 1966. 7. Kaufman, J. J., Ljung, B. M., Walther, P. and Waisman, J.: Aspiration biopsy of prostate. Urology, 19: 587, 1982. 8. Linsk, J. A., Axilrod, H. D., Solyn, R. and Delaverdac, C.: Transrectal cytologic aspiration in the diagnosis of prostatic carcinoma. J. Urol., 108: 455, 1972. 9. Franzen, S., Giertz, G. and Zajicek, J.: Cytological diagnosis of prostatic tumours by transrectal aspiration biopsy: a preliminary report. Brit. J. Urol., 32: 193, 1960. 10. Esposti, P. L.: Cytologic malignancy grading ofprostatic carcinoma by transrectal aspiration biopsy. A five-year follow-up study of 496 hormone-treated patients. Scand. J. Urol. Nephrol., 5: 199, 1971. 11. Wendel, R. G. and Evans, A. T.: Complications of punch biopsy of the prostate gland. J. Urol., 97: 122, 1967. 12. Middleton, R. G.: Radical prostatectomy for localized prostate cancer. Sem. Urol., 1: 229, 1983. 13. Ekman, H., Hedberg, K. and Perrson, P. S.: Cytological versus histological examination of needle biopsy specimens in the diagnosis of prostatic cancer. Brit. J. Urol., 39: 544, 1967. 14. Chodak, G. W., Bibbo, M., Straus, F. H., II and Wied, G. L.: Transrectal aspiration biopsy versus transperineal core biopsy for the diagnosis of carcinoma of the prostate. J. Urol., 132: 480, 1984. 15. Esposti, P. L., Elman, A. and Norlen, H.: Complications of transrectal aspiration biopsy of the prostate. Scand. J. Urol. Nephrol., 9: 208, 1975.