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PATIENT AND UROLOGIST DRIVEN SECOND OPINION OF PROSTATE NEEDLE BIOPSIES
0022-5347/05/1744-1390/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 174, 1390 –1394, October 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000173633.56174.c4
PATIENT AND UROLOGIST DRIVEN SECOND OPINION OF PROSTATE NEEDLE BIOPSIES THERESA Y. CHAN
AND
JONATHAN I. EPSTEIN*
From the Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland
ABSTRACT
Purpose: We reviewed second opinion prostate needle biopsies that were patient and urologist driven to determine how often an expert opinion resulted in a different diagnosis. Materials and Methods: Of 3,155 prostate needle biopsy consultations received during a 6-month interval 684 were sent at the request of the patient or urologist. A significant change in outside diagnosis was one that could potentially result in a change in therapy or prognosis. Results: The second opinion was requested by patients (21.6%), urologist (63.9%) and patients plus urologists (14.5%). The distribution of the 684 outside diagnoses was benign in 6.1%, HGPIN in 7.6%, atypical (ATYP) in 29.8% and cancer in 56.5%. In 241 cases (35.2%) a change in diagnosis was rendered upon expert review. We agreed with the majority of outside cancer, benign and HGPIN diagnoses, in contrast to only 36.8% of outside ATYP cases (p ⬍0.0001). Uncommonly did a cancer diagnosis become a benign one or vice versa. Of changes affecting outside cancer diagnoses 73.5% were due to changes in Gleason score. The diagnosis was more likely to be changed when the consultation was requested by the urologist rather than by the patient (41.4% vs 25%, p ⬍0.0001). Conclusions: Cases diagnosed as ATYP have the highest likelihood of being changed upon expert review. Urologists should consider sending such cases for consultation to attempt to resolve the diagnosis as definitively benign or malignant before subjecting the patient to repeat biopsy. KEY WORDS: prostate, prostatic neoplasms, biopsy, referral and consultation
Several studies have addressed second opinion in surgical pathology.1⫺13 Some of these studies looked specifically at urological pathology diagnoses and the impact of changes in diagnosis.3, 5, 7, 8 However, to our knowledge patient or urologist driven second opinions of prostate needle biopsies have not been investigated. We reviewed prostate needle biopsies for which second opinions were requested by the patient and/or urologist to determine how often an expert review diagnosis differed from that made elsewhere.
HGPIN to cancer and vice versa, benign to ATYP or HGPIN and vice versa, and changes in Gleason score from 4 or less to 6 or greater, 5 or 6 to 7 or greater, 7 to 8 or greater and vice versa. A change in diagnosis from ATYP to HGPIN and vice versa was not considered significant since patients with these diagnoses are often treated and followed similarly. Statistical analysis using the Pearson chi-square test was performed with a commercial software program (StataCorp, College Station, Texas).
MATERIALS AND METHODS
RESULTS
Of 3,155 prostate needle biopsy consultations directed to one of us (JIE) from March to September 2001, 684 (21.7%) sent at the request of the patient and/or urologist were identified. Data recorded were outside diagnosis, urological pathology expert review diagnosis, if high molecular weight cytokeratin staining was performed, patient age and type of outside institution (academic/teaching hospital, community hospital or commercial laboratory). In cases in which there was a question of whether the slides with the representative lesion were sent to us for review, we contacted the outside institution and pathologist to ensure that we were diagnosing the same lesion. Also, we contacted the outside institution to obtain a block or unstained slides on which to perform high molecular weight cytokeratin staining if it had not already been done and we believed that the stain would aid in the diagnosis. A significant change in outside diagnosis was one that could potentially result in a change in therapy or prognosis. We considered significant changes to be benign, atypical (ATYP) or
The majority of cases submitted for review had an outside diagnosis of cancer (56.5%) or ATYP (29.8%). Overall 241 of 684 cases (35.2%) had a significant change in diagnosis (tables 1 and 2). In the 241 cases with a change in diagnosis the most common one was from an outside diagnosis of HGPIN or ATYP to cancer (13.9%). Upon expert review we agreed with only 36.8% of outside ATYP diagnoses (p ⬍0.0001, table 1). Of the 204 outside ATYP cases 92 (45.1%) were diagnosed as cancer and 33 (16.2%) were diagnosed as benign upon review (figs. 1 and 2). The majority of changes (73.6%) affecting outside ATYP diagnoses were due to the diagnosis being changed to a cancer diagnosis with the majority having a Gleason score of 6. Of the 386 outside cancer cases cancer was confirmed in 359 (93%). However, 102 cases (26.4%) had a change in diagnosis, of which 75 (19.4%) had a significant change in Gleason score, 21 (5.4%) were diagnosed as ATYP and 6 (1.6%) were diagnosed as benign upon review (fig. 3). The majority of changes (73.5%) affecting outside cancer diagnoses were due to changes in Gleason score. Of the 241 cases with a change in diagnosis the second most common one was a change in Gleason score (10.9%). Of the 75 cases with a significant change in Gleason score 40 (53.3%) were up graded and 35 (46.7%) were down graded (figs. 4 and 5). Of the 29 outside Gleason score 8 or
Submitted for publication January 4, 2005. * Correspondence and requests for reprints: Johns Hopkins Hospital, Weinberg Building, Room 2242, 401 North Broadway St., Baltimore, Maryland 21231 (telephone: 410-955-5043; FAX: 410-9550115; e-mail: [email protected]). 1390
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SECOND OPINION OF PROSTATE NEEDLE BIOPSIES TABLE 1. Diagnoses made elsewhere of 684 biopsies, and percent of each category confirmed by expert review
Benign HGPIN ATYP Ca Total
No. Outside (%)
No. Confirmed (%)
42 (6.1) 52 (7.6) 204 (29.8) 386 (56.5)
35 (83.3) 39 (75) 75 (36.8) 359 (93)
684
greater cases 37.9% were changed compared with 20% of the 240 outside Gleason score 5 to 6 cases (p ⫽ 0.03). Of cases sent in for review it was uncommon for a benign case to be changed to cancer. Mean patient age was 62.7 years and age did not correlate with the source of referral or likelihood of a changed diagnosis. Of the 684 cases sent for a second opinion 148 (21.6%) were requested by the patient, 437 (63.9%) were requested by the urologist and 99 (14.5%) were requested by the patient and the urologist. The diagnosis was more likely to be changed when the consultation was requested by the urologist, rather than by the patient (41.4% vs 25%, p ⬍0.0001). Of the cases 368 (53.8%) were from community hospitals, 262 (38.3%) were from commercial laboratories and 54 (7.9%) were from academic/teaching hospitals. Of the 241 cases with a significant change in diagnosis 20 (8.3%) were from academic/teaching hospitals, 148 (61.4%) were from community hospitals and 73 (30.3%) were from commercial laboratories. Of all cases sent by the patient or urologist the majority were from community hospitals (61.5% and 57.9%), followed by commercial laboratories (18.9% and 37.1%, respectively). A significant change in diagnosis was more likely when the case was from a community hospital compared with a commercial laboratory (40.2% vs 27.9%, p ⫽ 0.001). No significant difference was seen when academic/teaching hospitals were compared with community hospitals or commercial laboratories. Commercial laboratories performed high molecular weight cytokeratin staining more often than community hospitals (32.1% vs 19.3%, p ⬍0.0001). Molecular weight cytokeratin staining was performed elsewhere or by us in 166 of 684 cases (24.3%). DISCUSSION
Although there have been several studies of second opinions in prostate needle biopsy material,3⫺5, 8, 13 to our knowledge patient or urologist driven second opinions of prostate needle biopsies have not been investigated. We found that approximately a third of these cases had a significant change in diagnosis and the majority of changes were in consultations with an outside ATYP diagnosis. An ATYP diagnosis can be rendered on needle biopsy for several reasons.14 Most often there are relatively few atypical glands present that have insufficient cytological and/or architectural atypia for the pathologist to render a definitively malignant diagnosis. Cancer may not be diagnosable since the pathologist cannot
exclude mimickers of cancer, such as atrophy, adenosis, nonspecific granulomatous prostatitis and HGPIN. Associated inflammation can result in an atypical diagnosis because inflammation can cause benign glands to resemble cancer. Another reason for an ATYP diagnosis relates to glands or cells with crush artifact as a result of mechanical distortion from the needle biopsy procedure. In contrast to a HGPIN, benign and cancer diagnosis with which we agreed with the outside diagnosis in the majority of cases (75%, 83.3% and 93%, respectively), 61.3% of outside ATYP cases were changed to a cancer or benign diagnosis. A change in diagnosis from outside ATYP to cancer was the most common change in diagnosis, accounting for 38.1% of all cases with a significant change. The difference between an ATYP and a cancer diagnosis often reflects the experience and comfort level of the pathologist in making a diagnosis of a small focus of cancer. Compared with the diagnosis of cancer in many other organ systems the diagnosis of prostate cancer is often subtle, requiring a constellation of features. It is difficult to assess how commonly a benign diagnosis was changed to cancer. If one looked at the entire group, only 3 of 684 (0.4%) outside benign cases were diagnosed as cancer upon review. These values are similar to those in a previous study of missed lesions on prostate needle biopsy, in which only 6 cancers (0.2%) were missed when the referring pathologist did not identify carcinoma in other areas of the prostate biopsies.5 However, it was relatively uncommon for benign cases to be sent for review with the 3 cases in the current study representing 7.1% of the 42 benign cases sent for a second opinion. Given the small numbers of such cases studied, it is difficult to generalize from these data. There is scant information on the incidence of missed cancer diagnoses on needle biopsy. To do these studies one would have to be allowed to review prior benign cases for missed cancer at an institution, which would have patient care and medicolegal ramifications. There are more data on the likelihood of an outside cancer diagnosis being read as benign. In the current study 6 of 386 cases (1.6%) diagnosed elsewhere as cancer were considered benign after expert review. In 2 other studies of patients referred for radical prostatectomy at our institution with an outside diagnosis of prostate cancer 1.2% to 1.3% of malignant diagnoses were diagnosed as benign upon review.3, 4 In the current study it was more common for an outside cancer diagnosis to change to ATYP, as in 21 of the 386 outside cancer cases (5.4%), rather than change all the way to benign. Although many of these ATYP cases may show cancer on repeat biopsy,14 some will not. Patients are then spared the morbidity of unnecessary treatment. In addition to resolving discrepant diagnoses with repeat biopsy, cases can potentially be resolved using special studies,15, 16 such as high molecular weight cytokeratin and ␣-methylacyl-CoA racemase (AMACR) immunohistochemistry or by obtaining an additional consultation. However, for some atypical lesions a definitive diagnosis cannot be made regardless of staining results. At the time of this study AMACR was not available. Recent studies showed that neg-
TABLE 2. Of 684 biopsies 241 cases with significant change in outside diagnoses Outside/Second Opinion Benign/Ca Ca/benign Benign/HGPIN HGPIN or ATYP/benign HGPIN or ATYP/Ca Ca/ATYP Totals (significant changes): Grade diagnosis
No. Cases (% 684 biopsies)
Outside/Second Opinion (Gleason score)
3 (0.4) 6 (0.9) 4 (0.6) 37 (5.4) 95 (13.9) 21 (3.0)
4 or Less/6 or greater 5–6/7 5–6/8 7/5–6 7/8–9 8–9/7
166 (24.3)
No. Cases (% 684 biopsies) 10 23 3 24 4 11
(1.5) (3.4) (0.4) (3.5) (0.6) (1.6)
75 (10.9)
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SECOND OPINION OF PROSTATE NEEDLE BIOPSIES
FIG. 1. Sections show ATYP glands from elsewhere, which were diagnosed as Gleason score 3 ⫹ 3 ⫽ 6 adenocarcinoma in our second opinion review. A, H & E, reduced from ⫻200. B, H & E, reduced from ⫻400.
ative AMACR staining can be seen in approximately 18% of cases considered to be cancer based on hematoxylin and eosin staining combined with negative basal cell markers.16 However, positive AMACR staining may be seen in HGPIN as well as in other benign entities.16 Therefore, the interpretation and use of AMACR staining must be done with caution, although it may have helped make a definitive diagnosis in some of our ATYP cases. Similarly experience is required to interpret basal cell stains since benign glands and mimickers of prostate cancer may show patchy or even negative staining, potentially leading to a misdiagnosis of cancer or ATYP. The majority of changes (73.5%) affecting outside cancer diagnoses were due to changes in Gleason score. While the significance of a change in Gleason score may be argued, these changes may impact treatment in terms of whether a patient is a candidate for watchful waiting, surgery or radiation, or the type of surgery or radiation recommended.8 For example, the largest number of cases with a grade change involved Gleason score 5 to 6 vs Gleason score 7. Whereas watchful waiting may be an option in a man in the seventh decade of life with a small Gleason score 5 to 6 cancer on biopsy, definitive therapy would typically be recommended for a comparably sized Gleason score 7 tumor. The finding of extensive Gleason score 7 tumor on multiple cores might tip the balance toward radiotherapy over surgery, as opposed to extensive Gleason score 6 cancer. Nerve sparing surgery might be the preference for a T1c Gleason score 6 cancer of relatively limited quantity on biopsy, in contrast to a Gleason score 7 cancer on biopsy that is associated with a higher
FIG. 2. A, section shows crowded glands diagnosed elsewhere as ATYP glands. B, accompanying high molecular weight cytokeratin stain reveals patchy staining of basal cells in focus, which we diagnosed as crowded benign glands. H & E, reduced from ⫻400.
FIG. 3. Section shows glands diagnosed elsewhere as Gleason score 3 ⫹ 3 ⫽ 6 adenocarcinoma. Focus reveals glands with cytological atypia, and yet papillary infolding. In our second opinion review it was classified as ATYP glands suspicious for but not diagnostic of cancer. H & E, reduced from ⫻400.
likelihood of extraprostatic extension. For similar reasons brachytherapy as monotherapy is often performed for Gleason score 6 cancer on biopsy, and yet it is considered potentially insufficient for a Gleason score 7 tumor. One could argue that the disagreements seen in this study,
SECOND OPINION OF PROSTATE NEEDLE BIOPSIES
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FIG. 4. Section of adenocarcinoma graded elsewhere as Gleason score 2 ⫹ 3 ⫽ 5. In our second opinion review we classified it as Gleason score 4 ⫹ 3 ⫽ 7. A, H & E, reduced from ⫻200. B, H & E, reduced from ⫻400.
FIG. 5. Section shows adenocarcinoma diagnosed elsewhere as Gleason score 4 ⫹ 3 ⫽ 7. We diagnosed this cancer as Gleason score 3 ⫹ 3 ⫽ 6. A, H & E, reduced from ⫻200. B, H & E, reduced from ⫻400.
particularly those involving grade, have a degree of subjectivity. A limitation of our study is that there is no objective gold standard concerning which diagnoses are correct. Clinical followup would not have definitively proved the validity of lesions that we diagnosed as ATYP or cancer on needle biopsy. The basis of our study was the diagnoses rendered by one of the leading experts in prostate pathology, who routinely examines a high volume of prostate needle biopsies. Even among genitourinary experts there is not 100% concordance in assigning Gleason score.17 However, there is some objective evidence that the Gleason score assigned by those with greater experience is more accurate than the score diagnosed elsewhere. Gleason score assigned to needle biopsies at a center where the staff has with extensive prostate cancer experience correlated with radical prostatectomy Gleason score and pathological stage much more closely that scores assigned elsewhere.18 This study highlights that an ATYP diagnosis along with Gleason score have a high likelihood of being diagnosed differently if sent for consultation. Although cases from academic/teaching hospitals accounted for the least number of cases (8.3%) with a significant change in diagnosis, surprisingly a significant change in diagnosis was nonetheless made in 37% of all cases from academic/teaching hospitals. The diagnosis was more likely to be changed when the consultation was requested by the urologist, rather than by the patient. Some bias of which we are not aware may have been present in our study that prompted cases to be sent for a second opinion and may have affected the magnitude of our findings. In conclusion, cases diagnosed as ATYP
have the highest likelihood of being changed upon expert review and urologists should consider sending such cases for consultation in an attempt to resolve the diagnosis as definitively benign or malignant before subjecting the patient to repeat biopsy. REFERENCES
1. Bruner, J. M., Inouye, L., Fuller, G. N. and Langford, L. A.: Diagnostic discrepancies and their clinical impact in a neuropathology referral practice. Cancer, 79: 796, 1997 2. Coblentz, T. R., Mills, S. E. and Theodorescu, D.: Impact of second opinion pathology in the definitive management of patients with bladder carcinoma. Cancer, 91: 1284, 2001 3. Epstein, J. I., Walsh, P. C. and Sanfilippo, F.: Clinical and cost impact of second-opinion pathology. Review of prostate biopsies prior to radical prostatectomy. Am J Surg Pathol, 20: 851, 1996 4. Kronz, J. D., Westra, W. H. and Epstein, J. I.: Mandatory second opinion surgical pathology at a large referral hospital. Cancer, 86: 2426, 1999 5. Kronz, J. D., Milord, R., Wilentz, R., Weir, E. G., Schreiner, S. R. and Epstein, J. I.: Lesions missed on prostate biopsies in cases sent in for consultation. Prostate, 54: 310, 2003 6. Leslie, K. O., Fechner, R. E. and Kempson, R. L.: Second opinions in surgical pathology. Am J Clin Pathol, suppl., 106: S58, 1996 7. Murphy, W. M., Rivera-Ramirez, I., Luciani, L. G. and Wajsman, Z.: Second opinion of anatomical pathology: a complex issue not easily reduced to matters of right and wrong. J Urol, 165: 1957, 2001 8. Nguyen, P. L., Schultz, D., Renshaw, A. A., Vollmer, R. T., Welch, W. R. and Cote, K.: The impact of pathology review on
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9. 10. 11. 12.
13.
14. 15.
16.
17.
18.
SECOND OPINION OF PROSTATE NEEDLE BIOPSIES
treatment recommendations for patients with adenocarcinoma of the prostate. Urol Oncol, 22: 295, 2004 Selman, A. E., Niemann, T. H., Fowler, J. M. and Copeland, L. J.: Quality assurance of second opinion pathology in gynecologic oncology. Obstet Gynecol, 94: 302, 1999 Tsung, J. S.: Institutional pathology consultation. Am J Surg Pathol, 28: 399, 2004 Weir, M. M., Jan, E. and Colgan, T. J.: Interinstitutional pathology consultations. A reassessment. Am J Clin Pathol, 120: 405, 2003 Wetherington, R. W., Cooper, H. S., Al-Saleem, T., Ackerman, D. S., Adams-McDonnell, R., Davis, W. et al: Clinical significance of performing immunohistochemistry on cases with a previous diagnosis of cancer coming to a national comprehensive cancer center for treatment or second opinion. Am J Surg Pathol, 26: 1222, 2002 Wurzer, J. C., Al-Saleem, T. I., Hanlon, A. L., Freedman, G. M., Patchefsky, A. and Hanks, G. E.: Histopathologic review of prostate biopsies from patients referred to a comprehensive cancer center: correlation of pathologic findings, analysis of cost, and impact on treatment. Cancer, 83: 753, 1998 Chan, T. Y. and Epstein, J. I.: Follow-up of atypical prostate needle biopsies suspicious for cancer. Urology, 53: 351, 1999 Novis, D. A., Zarbo, R. J. and Valenstein, P. A.: Diagnostic uncertainty expressed in prostate needle biopsies. A College of American Pathologists Q-probes Study of 15,753 prostate needle biopsies in 332 institutions. Arch Pathol Lab Med, 123: 687, 1999 Zhou, M., Aydin, H., Kanane, H. and Epstein, J. I.: How often does alpha-methylacyl-CoA-racemase contribute to resolving an atypical diagnosis on prostate needle biopsy beyond that provided by basal cell markers? Am J Surg Pathol, 28: 239, 2004 Allsbrook, W. C., Jr., Mangold, K. A., Johnson, M. H., Lane, R. B., Lane, C. G., Amin, M. B. et al: Interobserver reproducibility of Gleason grading of prostatic carcinoma: urologic pathologists. Hum Pathol, 32: 74, 2001 Steinberg, D. M., Sauvageot, J., Piantadosi, S. and Epstein, J. I.: Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol, 21: 566, 1997 EDITORIAL COMMENT
These authors remind us that the Gleason scoring system lacks precision. They document that in as many as a third of cases review led to a change in diagnosis. Because the authors most likely received the most difficult cases, one must wonder what would happen if these slides were sent for a third, fourth or fifth review. The authors conclude that difficult slides, especially those read as ATYP, should be sent for consultation before subjecting a patient to repeat biopsy. Is this really the best strategy? Are we certain that a diagnosis of prostate cancer that is based on an extremely small quantity
of tissue will identify patients who are likely to have clinically significant disease within 20 years? For me, if the diagnosis is not unequivocal, I would want to get more tissue before subjecting a patient to surgery. Peter C. Albertsen Division of Urology University of Connecticut Health Center Farmington, Connecticut REPLY BY AUTHORS The cases sent for a second opinion of the Gleason score did not represent the most difficult as these were identified by patients or urologists. Only a pathologist reviewing the slides could determine whether the Gleason score was borderline or difficult to interpret. Cases sent for a second opinion in terms of Gleason score were routine cases assigned a Gleason score by the initial institution when there was no indication on the pathology report that the cases were difficult to grade. The second issue relates to cases diagnosed as “atypical, suspicious for carcinoma.” If a general practicing pathologist diagnoses a case as atypical, yet upon review by a urological pathology expert it is diagnosed as adenocarcinoma, can the clinician act on the diagnosis rendered by the expert? As with any consulting relationship, one should have confidence in the individual providing the second opinion. In terms of my own practice, I (JIE) never diagnose adenocarcinoma of the prostate unless I am 100% confident of the diagnosis. Even if I am 98% sure that a focus is cancer, yet there is something that argues against the diagnosis, I will diagnose the focus as atypical and ask for a repeat biopsy. Although I am considered aggressive in terms of diagnosing limited cancer on biopsy, I still will potentially under diagnose malignancy on a small percentage of cases rather than over diagnose even a single case. Finally, will cases diagnosed as atypical by general practicing pathologists, which upon review are diagnosed as cancer by experts in genitourinary pathology, likely develop clinically significant disease within 20 years? Even for cases with a minute focus of unequivocal adenocarcinoma of the prostate on needle biopsy that is Gleason score 3⫹3⫽6, I (JIE) routinely add a comment that these patients may be candidates for watchful waiting depending on serum PSA level, and patient and clinician preferences. Although repeat biopsy is 1 method that can help predict whether a small focus of cancer identified on needle biopsy is representative of the entire tumor or a sampling artifact, biopsies are not foolproof and one may underestimate the amount of cancer present within the prostate. Consequently, the potential danger in having a diagnosis of atypical glands which is then followed by a negative repeat biopsy is that it does not exclude the possibility that the first biopsy was cancer or that the cancer is “insignificant.” In contrast, if the initial biopsy is sent for consultation to an expert in urological pathology and diagnosed as unequivocally malignant, the patient and urologist can proceed on a treatment plan, whether it be watchful waiting or definitive therapy.
Vol. 174, 1390 –1394, October 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000173633.56174.c4
PATIENT AND UROLOGIST DRIVEN SECOND OPINION OF PROSTATE NEEDLE BIOPSIES THERESA Y. CHAN
AND
JONATHAN I. EPSTEIN*
From the Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland
ABSTRACT
Purpose: We reviewed second opinion prostate needle biopsies that were patient and urologist driven to determine how often an expert opinion resulted in a different diagnosis. Materials and Methods: Of 3,155 prostate needle biopsy consultations received during a 6-month interval 684 were sent at the request of the patient or urologist. A significant change in outside diagnosis was one that could potentially result in a change in therapy or prognosis. Results: The second opinion was requested by patients (21.6%), urologist (63.9%) and patients plus urologists (14.5%). The distribution of the 684 outside diagnoses was benign in 6.1%, HGPIN in 7.6%, atypical (ATYP) in 29.8% and cancer in 56.5%. In 241 cases (35.2%) a change in diagnosis was rendered upon expert review. We agreed with the majority of outside cancer, benign and HGPIN diagnoses, in contrast to only 36.8% of outside ATYP cases (p ⬍0.0001). Uncommonly did a cancer diagnosis become a benign one or vice versa. Of changes affecting outside cancer diagnoses 73.5% were due to changes in Gleason score. The diagnosis was more likely to be changed when the consultation was requested by the urologist rather than by the patient (41.4% vs 25%, p ⬍0.0001). Conclusions: Cases diagnosed as ATYP have the highest likelihood of being changed upon expert review. Urologists should consider sending such cases for consultation to attempt to resolve the diagnosis as definitively benign or malignant before subjecting the patient to repeat biopsy. KEY WORDS: prostate, prostatic neoplasms, biopsy, referral and consultation
Several studies have addressed second opinion in surgical pathology.1⫺13 Some of these studies looked specifically at urological pathology diagnoses and the impact of changes in diagnosis.3, 5, 7, 8 However, to our knowledge patient or urologist driven second opinions of prostate needle biopsies have not been investigated. We reviewed prostate needle biopsies for which second opinions were requested by the patient and/or urologist to determine how often an expert review diagnosis differed from that made elsewhere.
HGPIN to cancer and vice versa, benign to ATYP or HGPIN and vice versa, and changes in Gleason score from 4 or less to 6 or greater, 5 or 6 to 7 or greater, 7 to 8 or greater and vice versa. A change in diagnosis from ATYP to HGPIN and vice versa was not considered significant since patients with these diagnoses are often treated and followed similarly. Statistical analysis using the Pearson chi-square test was performed with a commercial software program (StataCorp, College Station, Texas).
MATERIALS AND METHODS
RESULTS
Of 3,155 prostate needle biopsy consultations directed to one of us (JIE) from March to September 2001, 684 (21.7%) sent at the request of the patient and/or urologist were identified. Data recorded were outside diagnosis, urological pathology expert review diagnosis, if high molecular weight cytokeratin staining was performed, patient age and type of outside institution (academic/teaching hospital, community hospital or commercial laboratory). In cases in which there was a question of whether the slides with the representative lesion were sent to us for review, we contacted the outside institution and pathologist to ensure that we were diagnosing the same lesion. Also, we contacted the outside institution to obtain a block or unstained slides on which to perform high molecular weight cytokeratin staining if it had not already been done and we believed that the stain would aid in the diagnosis. A significant change in outside diagnosis was one that could potentially result in a change in therapy or prognosis. We considered significant changes to be benign, atypical (ATYP) or
The majority of cases submitted for review had an outside diagnosis of cancer (56.5%) or ATYP (29.8%). Overall 241 of 684 cases (35.2%) had a significant change in diagnosis (tables 1 and 2). In the 241 cases with a change in diagnosis the most common one was from an outside diagnosis of HGPIN or ATYP to cancer (13.9%). Upon expert review we agreed with only 36.8% of outside ATYP diagnoses (p ⬍0.0001, table 1). Of the 204 outside ATYP cases 92 (45.1%) were diagnosed as cancer and 33 (16.2%) were diagnosed as benign upon review (figs. 1 and 2). The majority of changes (73.6%) affecting outside ATYP diagnoses were due to the diagnosis being changed to a cancer diagnosis with the majority having a Gleason score of 6. Of the 386 outside cancer cases cancer was confirmed in 359 (93%). However, 102 cases (26.4%) had a change in diagnosis, of which 75 (19.4%) had a significant change in Gleason score, 21 (5.4%) were diagnosed as ATYP and 6 (1.6%) were diagnosed as benign upon review (fig. 3). The majority of changes (73.5%) affecting outside cancer diagnoses were due to changes in Gleason score. Of the 241 cases with a change in diagnosis the second most common one was a change in Gleason score (10.9%). Of the 75 cases with a significant change in Gleason score 40 (53.3%) were up graded and 35 (46.7%) were down graded (figs. 4 and 5). Of the 29 outside Gleason score 8 or
Submitted for publication January 4, 2005. * Correspondence and requests for reprints: Johns Hopkins Hospital, Weinberg Building, Room 2242, 401 North Broadway St., Baltimore, Maryland 21231 (telephone: 410-955-5043; FAX: 410-9550115; e-mail: [email protected]). 1390
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SECOND OPINION OF PROSTATE NEEDLE BIOPSIES TABLE 1. Diagnoses made elsewhere of 684 biopsies, and percent of each category confirmed by expert review
Benign HGPIN ATYP Ca Total
No. Outside (%)
No. Confirmed (%)
42 (6.1) 52 (7.6) 204 (29.8) 386 (56.5)
35 (83.3) 39 (75) 75 (36.8) 359 (93)
684
greater cases 37.9% were changed compared with 20% of the 240 outside Gleason score 5 to 6 cases (p ⫽ 0.03). Of cases sent in for review it was uncommon for a benign case to be changed to cancer. Mean patient age was 62.7 years and age did not correlate with the source of referral or likelihood of a changed diagnosis. Of the 684 cases sent for a second opinion 148 (21.6%) were requested by the patient, 437 (63.9%) were requested by the urologist and 99 (14.5%) were requested by the patient and the urologist. The diagnosis was more likely to be changed when the consultation was requested by the urologist, rather than by the patient (41.4% vs 25%, p ⬍0.0001). Of the cases 368 (53.8%) were from community hospitals, 262 (38.3%) were from commercial laboratories and 54 (7.9%) were from academic/teaching hospitals. Of the 241 cases with a significant change in diagnosis 20 (8.3%) were from academic/teaching hospitals, 148 (61.4%) were from community hospitals and 73 (30.3%) were from commercial laboratories. Of all cases sent by the patient or urologist the majority were from community hospitals (61.5% and 57.9%), followed by commercial laboratories (18.9% and 37.1%, respectively). A significant change in diagnosis was more likely when the case was from a community hospital compared with a commercial laboratory (40.2% vs 27.9%, p ⫽ 0.001). No significant difference was seen when academic/teaching hospitals were compared with community hospitals or commercial laboratories. Commercial laboratories performed high molecular weight cytokeratin staining more often than community hospitals (32.1% vs 19.3%, p ⬍0.0001). Molecular weight cytokeratin staining was performed elsewhere or by us in 166 of 684 cases (24.3%). DISCUSSION
Although there have been several studies of second opinions in prostate needle biopsy material,3⫺5, 8, 13 to our knowledge patient or urologist driven second opinions of prostate needle biopsies have not been investigated. We found that approximately a third of these cases had a significant change in diagnosis and the majority of changes were in consultations with an outside ATYP diagnosis. An ATYP diagnosis can be rendered on needle biopsy for several reasons.14 Most often there are relatively few atypical glands present that have insufficient cytological and/or architectural atypia for the pathologist to render a definitively malignant diagnosis. Cancer may not be diagnosable since the pathologist cannot
exclude mimickers of cancer, such as atrophy, adenosis, nonspecific granulomatous prostatitis and HGPIN. Associated inflammation can result in an atypical diagnosis because inflammation can cause benign glands to resemble cancer. Another reason for an ATYP diagnosis relates to glands or cells with crush artifact as a result of mechanical distortion from the needle biopsy procedure. In contrast to a HGPIN, benign and cancer diagnosis with which we agreed with the outside diagnosis in the majority of cases (75%, 83.3% and 93%, respectively), 61.3% of outside ATYP cases were changed to a cancer or benign diagnosis. A change in diagnosis from outside ATYP to cancer was the most common change in diagnosis, accounting for 38.1% of all cases with a significant change. The difference between an ATYP and a cancer diagnosis often reflects the experience and comfort level of the pathologist in making a diagnosis of a small focus of cancer. Compared with the diagnosis of cancer in many other organ systems the diagnosis of prostate cancer is often subtle, requiring a constellation of features. It is difficult to assess how commonly a benign diagnosis was changed to cancer. If one looked at the entire group, only 3 of 684 (0.4%) outside benign cases were diagnosed as cancer upon review. These values are similar to those in a previous study of missed lesions on prostate needle biopsy, in which only 6 cancers (0.2%) were missed when the referring pathologist did not identify carcinoma in other areas of the prostate biopsies.5 However, it was relatively uncommon for benign cases to be sent for review with the 3 cases in the current study representing 7.1% of the 42 benign cases sent for a second opinion. Given the small numbers of such cases studied, it is difficult to generalize from these data. There is scant information on the incidence of missed cancer diagnoses on needle biopsy. To do these studies one would have to be allowed to review prior benign cases for missed cancer at an institution, which would have patient care and medicolegal ramifications. There are more data on the likelihood of an outside cancer diagnosis being read as benign. In the current study 6 of 386 cases (1.6%) diagnosed elsewhere as cancer were considered benign after expert review. In 2 other studies of patients referred for radical prostatectomy at our institution with an outside diagnosis of prostate cancer 1.2% to 1.3% of malignant diagnoses were diagnosed as benign upon review.3, 4 In the current study it was more common for an outside cancer diagnosis to change to ATYP, as in 21 of the 386 outside cancer cases (5.4%), rather than change all the way to benign. Although many of these ATYP cases may show cancer on repeat biopsy,14 some will not. Patients are then spared the morbidity of unnecessary treatment. In addition to resolving discrepant diagnoses with repeat biopsy, cases can potentially be resolved using special studies,15, 16 such as high molecular weight cytokeratin and ␣-methylacyl-CoA racemase (AMACR) immunohistochemistry or by obtaining an additional consultation. However, for some atypical lesions a definitive diagnosis cannot be made regardless of staining results. At the time of this study AMACR was not available. Recent studies showed that neg-
TABLE 2. Of 684 biopsies 241 cases with significant change in outside diagnoses Outside/Second Opinion Benign/Ca Ca/benign Benign/HGPIN HGPIN or ATYP/benign HGPIN or ATYP/Ca Ca/ATYP Totals (significant changes): Grade diagnosis
No. Cases (% 684 biopsies)
Outside/Second Opinion (Gleason score)
3 (0.4) 6 (0.9) 4 (0.6) 37 (5.4) 95 (13.9) 21 (3.0)
4 or Less/6 or greater 5–6/7 5–6/8 7/5–6 7/8–9 8–9/7
166 (24.3)
No. Cases (% 684 biopsies) 10 23 3 24 4 11
(1.5) (3.4) (0.4) (3.5) (0.6) (1.6)
75 (10.9)
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FIG. 1. Sections show ATYP glands from elsewhere, which were diagnosed as Gleason score 3 ⫹ 3 ⫽ 6 adenocarcinoma in our second opinion review. A, H & E, reduced from ⫻200. B, H & E, reduced from ⫻400.
ative AMACR staining can be seen in approximately 18% of cases considered to be cancer based on hematoxylin and eosin staining combined with negative basal cell markers.16 However, positive AMACR staining may be seen in HGPIN as well as in other benign entities.16 Therefore, the interpretation and use of AMACR staining must be done with caution, although it may have helped make a definitive diagnosis in some of our ATYP cases. Similarly experience is required to interpret basal cell stains since benign glands and mimickers of prostate cancer may show patchy or even negative staining, potentially leading to a misdiagnosis of cancer or ATYP. The majority of changes (73.5%) affecting outside cancer diagnoses were due to changes in Gleason score. While the significance of a change in Gleason score may be argued, these changes may impact treatment in terms of whether a patient is a candidate for watchful waiting, surgery or radiation, or the type of surgery or radiation recommended.8 For example, the largest number of cases with a grade change involved Gleason score 5 to 6 vs Gleason score 7. Whereas watchful waiting may be an option in a man in the seventh decade of life with a small Gleason score 5 to 6 cancer on biopsy, definitive therapy would typically be recommended for a comparably sized Gleason score 7 tumor. The finding of extensive Gleason score 7 tumor on multiple cores might tip the balance toward radiotherapy over surgery, as opposed to extensive Gleason score 6 cancer. Nerve sparing surgery might be the preference for a T1c Gleason score 6 cancer of relatively limited quantity on biopsy, in contrast to a Gleason score 7 cancer on biopsy that is associated with a higher
FIG. 2. A, section shows crowded glands diagnosed elsewhere as ATYP glands. B, accompanying high molecular weight cytokeratin stain reveals patchy staining of basal cells in focus, which we diagnosed as crowded benign glands. H & E, reduced from ⫻400.
FIG. 3. Section shows glands diagnosed elsewhere as Gleason score 3 ⫹ 3 ⫽ 6 adenocarcinoma. Focus reveals glands with cytological atypia, and yet papillary infolding. In our second opinion review it was classified as ATYP glands suspicious for but not diagnostic of cancer. H & E, reduced from ⫻400.
likelihood of extraprostatic extension. For similar reasons brachytherapy as monotherapy is often performed for Gleason score 6 cancer on biopsy, and yet it is considered potentially insufficient for a Gleason score 7 tumor. One could argue that the disagreements seen in this study,
SECOND OPINION OF PROSTATE NEEDLE BIOPSIES
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FIG. 4. Section of adenocarcinoma graded elsewhere as Gleason score 2 ⫹ 3 ⫽ 5. In our second opinion review we classified it as Gleason score 4 ⫹ 3 ⫽ 7. A, H & E, reduced from ⫻200. B, H & E, reduced from ⫻400.
FIG. 5. Section shows adenocarcinoma diagnosed elsewhere as Gleason score 4 ⫹ 3 ⫽ 7. We diagnosed this cancer as Gleason score 3 ⫹ 3 ⫽ 6. A, H & E, reduced from ⫻200. B, H & E, reduced from ⫻400.
particularly those involving grade, have a degree of subjectivity. A limitation of our study is that there is no objective gold standard concerning which diagnoses are correct. Clinical followup would not have definitively proved the validity of lesions that we diagnosed as ATYP or cancer on needle biopsy. The basis of our study was the diagnoses rendered by one of the leading experts in prostate pathology, who routinely examines a high volume of prostate needle biopsies. Even among genitourinary experts there is not 100% concordance in assigning Gleason score.17 However, there is some objective evidence that the Gleason score assigned by those with greater experience is more accurate than the score diagnosed elsewhere. Gleason score assigned to needle biopsies at a center where the staff has with extensive prostate cancer experience correlated with radical prostatectomy Gleason score and pathological stage much more closely that scores assigned elsewhere.18 This study highlights that an ATYP diagnosis along with Gleason score have a high likelihood of being diagnosed differently if sent for consultation. Although cases from academic/teaching hospitals accounted for the least number of cases (8.3%) with a significant change in diagnosis, surprisingly a significant change in diagnosis was nonetheless made in 37% of all cases from academic/teaching hospitals. The diagnosis was more likely to be changed when the consultation was requested by the urologist, rather than by the patient. Some bias of which we are not aware may have been present in our study that prompted cases to be sent for a second opinion and may have affected the magnitude of our findings. In conclusion, cases diagnosed as ATYP
have the highest likelihood of being changed upon expert review and urologists should consider sending such cases for consultation in an attempt to resolve the diagnosis as definitively benign or malignant before subjecting the patient to repeat biopsy. REFERENCES
1. Bruner, J. M., Inouye, L., Fuller, G. N. and Langford, L. A.: Diagnostic discrepancies and their clinical impact in a neuropathology referral practice. Cancer, 79: 796, 1997 2. Coblentz, T. R., Mills, S. E. and Theodorescu, D.: Impact of second opinion pathology in the definitive management of patients with bladder carcinoma. Cancer, 91: 1284, 2001 3. Epstein, J. I., Walsh, P. C. and Sanfilippo, F.: Clinical and cost impact of second-opinion pathology. Review of prostate biopsies prior to radical prostatectomy. Am J Surg Pathol, 20: 851, 1996 4. Kronz, J. D., Westra, W. H. and Epstein, J. I.: Mandatory second opinion surgical pathology at a large referral hospital. Cancer, 86: 2426, 1999 5. Kronz, J. D., Milord, R., Wilentz, R., Weir, E. G., Schreiner, S. R. and Epstein, J. I.: Lesions missed on prostate biopsies in cases sent in for consultation. Prostate, 54: 310, 2003 6. Leslie, K. O., Fechner, R. E. and Kempson, R. L.: Second opinions in surgical pathology. Am J Clin Pathol, suppl., 106: S58, 1996 7. Murphy, W. M., Rivera-Ramirez, I., Luciani, L. G. and Wajsman, Z.: Second opinion of anatomical pathology: a complex issue not easily reduced to matters of right and wrong. J Urol, 165: 1957, 2001 8. Nguyen, P. L., Schultz, D., Renshaw, A. A., Vollmer, R. T., Welch, W. R. and Cote, K.: The impact of pathology review on
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treatment recommendations for patients with adenocarcinoma of the prostate. Urol Oncol, 22: 295, 2004 Selman, A. E., Niemann, T. H., Fowler, J. M. and Copeland, L. J.: Quality assurance of second opinion pathology in gynecologic oncology. Obstet Gynecol, 94: 302, 1999 Tsung, J. S.: Institutional pathology consultation. Am J Surg Pathol, 28: 399, 2004 Weir, M. M., Jan, E. and Colgan, T. J.: Interinstitutional pathology consultations. A reassessment. Am J Clin Pathol, 120: 405, 2003 Wetherington, R. W., Cooper, H. S., Al-Saleem, T., Ackerman, D. S., Adams-McDonnell, R., Davis, W. et al: Clinical significance of performing immunohistochemistry on cases with a previous diagnosis of cancer coming to a national comprehensive cancer center for treatment or second opinion. Am J Surg Pathol, 26: 1222, 2002 Wurzer, J. C., Al-Saleem, T. I., Hanlon, A. L., Freedman, G. M., Patchefsky, A. and Hanks, G. E.: Histopathologic review of prostate biopsies from patients referred to a comprehensive cancer center: correlation of pathologic findings, analysis of cost, and impact on treatment. Cancer, 83: 753, 1998 Chan, T. Y. and Epstein, J. I.: Follow-up of atypical prostate needle biopsies suspicious for cancer. Urology, 53: 351, 1999 Novis, D. A., Zarbo, R. J. and Valenstein, P. A.: Diagnostic uncertainty expressed in prostate needle biopsies. A College of American Pathologists Q-probes Study of 15,753 prostate needle biopsies in 332 institutions. Arch Pathol Lab Med, 123: 687, 1999 Zhou, M., Aydin, H., Kanane, H. and Epstein, J. I.: How often does alpha-methylacyl-CoA-racemase contribute to resolving an atypical diagnosis on prostate needle biopsy beyond that provided by basal cell markers? Am J Surg Pathol, 28: 239, 2004 Allsbrook, W. C., Jr., Mangold, K. A., Johnson, M. H., Lane, R. B., Lane, C. G., Amin, M. B. et al: Interobserver reproducibility of Gleason grading of prostatic carcinoma: urologic pathologists. Hum Pathol, 32: 74, 2001 Steinberg, D. M., Sauvageot, J., Piantadosi, S. and Epstein, J. I.: Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol, 21: 566, 1997 EDITORIAL COMMENT
These authors remind us that the Gleason scoring system lacks precision. They document that in as many as a third of cases review led to a change in diagnosis. Because the authors most likely received the most difficult cases, one must wonder what would happen if these slides were sent for a third, fourth or fifth review. The authors conclude that difficult slides, especially those read as ATYP, should be sent for consultation before subjecting a patient to repeat biopsy. Is this really the best strategy? Are we certain that a diagnosis of prostate cancer that is based on an extremely small quantity
of tissue will identify patients who are likely to have clinically significant disease within 20 years? For me, if the diagnosis is not unequivocal, I would want to get more tissue before subjecting a patient to surgery. Peter C. Albertsen Division of Urology University of Connecticut Health Center Farmington, Connecticut REPLY BY AUTHORS The cases sent for a second opinion of the Gleason score did not represent the most difficult as these were identified by patients or urologists. Only a pathologist reviewing the slides could determine whether the Gleason score was borderline or difficult to interpret. Cases sent for a second opinion in terms of Gleason score were routine cases assigned a Gleason score by the initial institution when there was no indication on the pathology report that the cases were difficult to grade. The second issue relates to cases diagnosed as “atypical, suspicious for carcinoma.” If a general practicing pathologist diagnoses a case as atypical, yet upon review by a urological pathology expert it is diagnosed as adenocarcinoma, can the clinician act on the diagnosis rendered by the expert? As with any consulting relationship, one should have confidence in the individual providing the second opinion. In terms of my own practice, I (JIE) never diagnose adenocarcinoma of the prostate unless I am 100% confident of the diagnosis. Even if I am 98% sure that a focus is cancer, yet there is something that argues against the diagnosis, I will diagnose the focus as atypical and ask for a repeat biopsy. Although I am considered aggressive in terms of diagnosing limited cancer on biopsy, I still will potentially under diagnose malignancy on a small percentage of cases rather than over diagnose even a single case. Finally, will cases diagnosed as atypical by general practicing pathologists, which upon review are diagnosed as cancer by experts in genitourinary pathology, likely develop clinically significant disease within 20 years? Even for cases with a minute focus of unequivocal adenocarcinoma of the prostate on needle biopsy that is Gleason score 3⫹3⫽6, I (JIE) routinely add a comment that these patients may be candidates for watchful waiting depending on serum PSA level, and patient and clinician preferences. Although repeat biopsy is 1 method that can help predict whether a small focus of cancer identified on needle biopsy is representative of the entire tumor or a sampling artifact, biopsies are not foolproof and one may underestimate the amount of cancer present within the prostate. Consequently, the potential danger in having a diagnosis of atypical glands which is then followed by a negative repeat biopsy is that it does not exclude the possibility that the first biopsy was cancer or that the cancer is “insignificant.” In contrast, if the initial biopsy is sent for consultation to an expert in urological pathology and diagnosed as unequivocally malignant, the patient and urologist can proceed on a treatment plan, whether it be watchful waiting or definitive therapy.