To study the pathologic features of radical prostatectomy (RP) specimens of patients operated on the basis of a potentially “Insignificant” prostate cancer (Ca P) characterized by one single focus (less than 3
Patients and methods
PSA, biopsy features, and surgical specimens of a series of 56 patients submitted to RP for “insignificant Ca P” on TRUS prostate biopsies between 1988 and 2004 were compared regarding the number of tumor foci, Gleason grade and score, tumor volume determined by the cylinder method, as well as extraprostatic extension (EPE) and positive surgical margins (P.SM.).
70% of the patients had multifocal microfocal cancer apart from the index tumor. The presence of grade 4 was ignored by the biopsy in 50% of the cases, however the primary grade was correctly evaluated in more than 70% of the biopsy sets. 42% of the patients had a cancer volume less than 0.5
Patients diagnosed with prostate cancer on the basis of one single focus less than 3
Keywords: Micro focal, Prostate cancer, Radical prostatectomy.
The widespread use of prostate specific antigen (PSA) testing associated with increasingly extensive transrectal ultrasound (TRUS) prostate biopsy protocols triggered by ever lower PSA thresholds, have led over the recent years to a spectacular stage migration of prostate cancer, exemplified by 2 associated phenomenons:
- - a regular increase in the proportion of patients diagnosed with moderately differentiated, low volume (<0.2 to 0.5ml) potentially insignificant prostate cancers ,
- - a significant decrease of the volume of the cancers removed at surgery in the frame work of screening and early detection programs where the median tumor volume can be as low as 0.6 or 0.5ml .
These recent changes may explain the renewed interest in observation with delayed therapy at clinical/biological/pathological progression for highly selected patients, particularly those diagnosed with low volume, well differentiated tumors , , and . However, it has been known for a long time that the presence of a small volume of cancer on the biopsy may not translate into a small volume of tumor in the prostate, in a significant proportion of cases , , and .
In the absence of reliable imaging techniques documenting the actual tumor volume, the meticulous analysis of prostate biopsies remains the best tool to ascertain the extension of the cancer whithin and out of the prostate.
Therefore, it may be that a careful evaluation of the pathologic profile of the patients diagnosed with a potentially “insignificant” cancer may help to distinguish those with a truely “insignificant” well differentiated (Gleason
2. Patients and methods
From March 88 to March 04, 589 patients with clinically localized (T1 T2) prostate cancer were submitted to a radical retropubic prostatectomy (RRP). All biopsies were performed at our institution, the standard 6 core technique was replaced in 1996 by a 10 core protocol. All RP specimens were handled following the Stanford protocol. Biopsies and specimens were evaluated by 2 experienced uropathologists (L.A. B.G, M.T.) PSA assays were performed at the same laboratory using the Tosoh assay (normal level 3
From this data base, we extracted the patients operated on the basis of a potentially “insignificant” prostate cancer characterized by the presence of 1 single focus measuring 3
However, the volume of secondary cancer foci was not taken into account as their prognostic impact has been shown to be negligible .
Among the series of 589 consecutive patients submitted to RRP, 107 (18%) had a single positive biopsy. 56 of those met the criteria of potentially “insignificant” prostate cancer: one single focus measuring 3
|Age||Med: 63.8 (44–75)|
|PSA ng/ml||Med: 8.5 (11–35)|
|P.S.A.D.||Med: 0.13 (0.03–1.2)|
|T1 C||42 (75%)|
|Length of cancer||Med: 1
|Prior biopsy||13 (23%)|
|Prostate volume||Med: 53
The comparisons of biopsy and surgical specimen features allows to identify several salient points:
- 1. a significant discrepancy appeared between the biopsy and specimen Gleason scores which were identical in only 34% of the whole group and 42% of the 40 patients with a PSA<10ng/ml. However, a predominant grade 4 was missed in only 24% of the whole group and 15% when the PSA was below 10 (Table 2 and Table 3).
- 2. In 80% of the tumors, irrespective of serum PSA, a number of microscopic tumor foci (1–4, med 2) were associated with the index cancer measuring 1 to 3mm in diameter. The presence of bilateral tumor foci was observed in 78% but it is important to stress that a contralateral cancer focus of grade 4 overlooked at biopsy was detected only in 10% of the radical prostatectomy specimens.
- 3. The volume of the index cancer was less than 0.5ml in 42% of the patients of the whole group, and 54% if the PSA was below 10 (Table 4). There was no correlation between the length of the cancer on the biopsy and the volume of the tumor on the specimen.
- 4. In the whole group of patients, only 8% had EPE and none PSM. When the preoperative PSA was <10ng/ml, only 2 patients had EPE and none PSM.
- 5. Finally, in the end, 16 of 56 (29%) of the patients in this series met the criteria of “insignificant” prostate cancer: organ confined (Pt2) tumor moderately differentiated – (Gleason score≤6) of low volume (<0.5ml). Unfortunately, on the pre-operative criteria, they did not differ from the whole a group as far as prostate volume, PSA and PSA density as well as biopsy features were concerned (Table 5), no predictive criteria of truely “insignificant” prostate cancer could be identified from the analysis of these series.
|Biopsy Gleason score||Specimen Gleason score|
|Biopsy Gleason score||Specimen Gleason score|
|Tumor volume||Whole series||PSA
|56 pts||40 pts|
||24 (42%)||200 (50%)|
|Biopsy ≪ insignificant Ca ≫||Specimen ≪ insignificant ≫ Ca|
|Whole group (56)||PSA
|Med prostate volume||50
||50 (15–90)||57 (24–90)|
||5.6 (1.1–9.9)||5.9 (1.1–18.5)|
|Med PSAD||0.13 (0.03–1.2)||0.10 (0.10–0.13)||0.11 (0.003–0.65)|
These series may indeed give rise to several critics: it is retrospective; it spans over a 14 years period during which a significant stage migration has occured; the technique used to evaluate the tumor volume was at best simplistic but has been recommended by others  secondary foci were not taken into consideration in the measurement of the tumor volume because of the documented lack of their prognostic significance . Nevertheless, the issue of low volume well differentiated prostate cancer is becoming more and more important as the implementation of early diagnosis and screening programs for prostate cancer has led to an over extensive use of PSA testing associated with increasingly aggressive prostate biopsy protocols triggered by lower and lower PSA values from 4 to 3 or even 2.5
As a consequence, an expanding proportion of prostate cancers are detected on the basis of a small focus of well differentiated tumor present in one single core of the biopsy set . These cancers may indeed cause little harm to the patient during his lifetime hence the emerging issue of over diagnosis leading potentially to over treatment which is estimated to be around 40–50% in the European Screening Program 
Insignificant and unimportant prostate cancers in radical prostatectomy specimens have been defined as a low volume (0.2 to 0.5
Several authors have compared specimen and biopsy tumor caracteristics in order to determine the biological and pathological features that would predict with the best accuracy the presence of a low volume “indolent” prostate cancer:
- - J Epstein  considers that less than 3 positive biopsy cores containing each less than 50% of moderately differentiated prostate cancer (Gleason sum≤6) with a PSA density 0.15 is highly predictive oF insignificant prostate cancer.
- - TA Gardner  is more restrictive and considers that to be predictive of insignificant cancer in the specimens there are to be less than 5% of the total length of the biopsy cores invaded by moderately differentiated prostate cancer without any element of Gleason grade 4.
- - M. K. Terrris  opts for the following definition of biopsy insignificant prostate cancer: one single positive biopsy containing a focus of 3mm or less of moderately differentiated prostate cancer (Gleason score≤6), this is the definition we chose as this biopsy profile is increasingly prevalent and the most easy to define.
In this setting 30 to 55% of the patients operated on the basis of a “biopsy insignificant” prostate cancer will indeed harbour an “insignificant” tumor at pathological evaluation of their specimen. In a recent series, 5% of 1500 consecutive radical prostatectomy specimens contained only a minute focus of cancer sometimes extremely difficult to document , , and .
Therefore, it comes to no surprise that the issue of observation with delayed therapy in patients diagnosed on the basis of a potentially insignificant/unimportant prostate cancer has been revisited. On the other hand, it should be stressed that 45 to 70% of the patients with this profile will indeed have a “significant cancer” (Gleason score
Therefore awaiting potential future predictive biomarkers such as genetic biomarkers issued from micro-array technology, it may well be that observation over time, using among others, the PSA doubling time  will help the clinician to guide the patient's decision regarding treatment options.
However, it should be stressed that 92% of our patients (98% when the PSA was ≤10
-  M.R. Cooperberg, J.M. Broering, M.S. Litwin, D.P. Lubeck, S.S. Mehta, J.M. Henning, et al., and the CaPsure investigators. The contemporary management of prostate cancer in the United States: lessons from the cancer of the prostate strategic urologic research endeavor (CaPsure) a national disease registry. J Urol. 2004;171:1393-1401 Crossref.
-  R.F. Hoedemaeker, J.B.W. Rietbergen, R. Kranse, F.H. Schroder, T.H. van der Kwast. Histopathological prostate cancer characteristics at radical prostatectomy after population based screening. J Urol. 2000;164:411-415
-  C. Parker. Active surveillance: towards a new paradigm in the management of early prostate cancer. Lancet Oncol. 2004;5:101-106 Crossref.
-  Khan MA, Partin AW, Carter HB. Expectant management of localized prostate cancer. Urology 2003;62:793–799.
-  L. Klotz. Active surveillance with selective delayed intervention using PSA doubling time for good risk prostate cancer. Eur Urol. 2005;47:16-21 Crossref.
-  V. Ravery, J. Szabo, M. Toublanc, LA. Boccon Gibod, T. Billebaud, J.F. Hermieu, et al. A single positive biopsy in six does not predict a low volume prostate tumour. Br J Urol. 1996;77(5):724-728
-  A.K. Lee, T. Doytchinova, M.H. Chen, A.A. Renshax, M. Weinstein, J.P. Riou, et al. Can the core length involved with prostate cancer identify clinically insignificant disease in low risk patients diagnosed the basis of a single positive core?. Urol Oncol. 2003;21:123-127 Crossref.
-  J.W. Anast, G.L. Andriole, T.A. Bismar, Y. Yan, P.A. Humphrey. Relating biopsy and clinical variables to radical prostatectomy findings: can insignificant and advanced prostate cancer be predicted in a screening population?. Urology. 2004;64:544-550 Crossref.
-  M. Noguchi, T.A. Stamey, J.E. McNeal, R. Nolley. Prognostic factors for multifocal prostate cancer in radical prostatectomy specimens: lack of significance of secondary cancers. J Urol. 2003;170:459-463 Crossref.
-  J. Esptein. Pathological assessment of the surgical specimens. Urol Clin N Am. 2001;28:567-594
-  G. Draisma, R. Boer, S.J. Otto, I.W. Can Der Cruijsen, R.A.M. Damhuis, F.H. Scroder, et al. Lead times and overdection due to prostate-specific antigen screening: estimates from the european randomized study of screening for prostate cancer. J Nat Cancer Inst.. 2003;95:868-878 Crossref.
-  U.L. Brendler. Pathological and clinical findings to predict tumor extent of non palpable (T1C) prostate cancer. Jama. 1994;271:368-374
-  T.A. Gardner, M.L. Lemer, P.N. Schlegel, R.S. Waldbaum, E.D. Vaughan, J. Steckel. Microfocal prostate cancer: biopsy cancer volume does not predict actual tumour volume. Brit J Urol. 1998;81:839-843 Crossref.
-  M.K. Terris, J.F. McNeal, T.A. Stamey. Detection of clinically significant prostate cancer by transrectal ultrasound guided biopsies. J Urol. 1992;148:829-832
-  Y. Allory, Z. Merabet, L. Salomon, S. Swiebs, D. Vordos, A. Hoznek, et al. Risque de cancer non significatif chez les patients ayant eu un protocole de biopsies en saturation, traités par la prostatectomie radicale. Prog Urol. 2004;14(supl 1) abstract 06
-  R.F. Hoedemaeker, T.H. van der Kwast, F.H. Schroder. The clinical significance of a small focus of well-differentiated carcinoma at prostate biopsy. BJU international. 2003;92(2):92-96 Crossref.
-  A.M. Truskinovsky, H. Sanderson, J.I. Epstein. Characterization of minute adenocarcinomas of prostate at radical prostatectomy. Urology. 2004;64:733-737 Crossref.
-  K. Herkommer, R. Kuefer, J.E. Gshwend, R.E. Hautmann, B.G. Volkmer. Pathological to prostate cancer without neoadjuvant therapy: clinical presentation and follow up. Eur Urol. 2004;45:36-41 Crossref.
-  D.G. Bostwick, K.C. Bostwick. “Vanishing” prostate cancer in radical prostatectomy specimen incidence and long-term follow up in 38 cases. BJU Int. 2004;94(1):57-58 Crossref.
-  D. Klifa, L. Salomon, Y. Allory, A. de la Taille, D. Vordos, R. Yiou, et al. PT0 après prostatectomie radicale, présentation clinique et pronostique. Prog Urol. 2004;14(suppl 1) abstract 0152
-  Allan RW, Sanderson H, Epstein JI. Correlation of minute (0.5 mm of less) focus of prostate adenocarcinoma on needle biopsy with radical prostatectomy specimen: role of prostate specific antigen density. J Urol 2003;170:370–2.
-  M.W. Kattan, J.E. Estham, T.M. Wheeler, N. Maru, P.T. Scardino, A. Erbersdobler, et al. Counseling men with prostate cancer: a nomogram for predicting the presence of small, moderately differentiated, confined tumors. J Urol. 2003;170:1792-1797 Crossref.
-  P.J. Bastian, L.A. Mangolb, J.I. Epstein, A.W. Partin. Characteristics of insignificant clinical T1 C prostate tumors, a contemporary analysis. Cancer. 2004;101:2001-2005 Crossref.
-  E.A. Klein. What is “insignificant” prostate carcinoma?. Cancer. 2004;101:1923-1925 Crossref.
-  P.R. Caroll. Early stage prostate cancer: do we have problem with over detection, overtreatment or both?. J Urol. 2005;173:1061-1062
© 2005 Elsevier B.V., All rights reserved.