Path. Res. Pract. 191, 868 - 872 (1995)
High Grade Prostatic Intraepithelial Neoplasia in Prostates Removed Following Irradiation Failure in the Treatment of Prostatic Adenocarcinoma 1 A. Arakawa, S. Song, P. T. Scardino and T. M. Wheeler Departments of Pathology, Scott Department of Urology, Baylor College of Medicine and The Methodist Hospital, Houston, Texas, U.S.A.
SUMMARY Prostatic Intraepithelial Neoplasia (PIN) is widely considered to be a precursor lesion for adenocarcinoma of the prostate. No information is available, however, on the sensitivity of PIN to irradiation or the distribution of residual PIN after radiotherapy. We studied a series of forty-six totally embedded, whole mounted, serially sectioned prostates removed by salvage radical retropubic prostatectomy following irradiation failure in which no hormonal therapy/ablation had been undertaken. The mean age of patients was 65 (56-74) years, the mean dose of radiotherapy was 7266 (6,000-9,000) cGy (15 external beam, 27 external beam plus iridium or gold seeds, 3 iodine, and 1 unknown) and the mean interval from irradiation therapy to prostatectomy was 60 (16-145) months. Thirty-two (70%) of the patients had high grade PIN within the prostatectomy specimen. The pattern of PIN was recorded as described by Bostwick and co workers5• The frequency of the different patterns per positive case paralleled in rank those in Bostwick's series of non-irradiated prostates, with the most common to least common per patient being: tufting (78.1 %), micropapillary (59.3%), cribriform (34.4%) and flat (15.6%). However, the mean number of foci of PIN per prostate was less than in Bostwick's series (7.1 foci vs. 17 foci). There was no statistically significant difference between groups with or without high grade PIN with regard to various clinical factors (last preoperative serum PSA, age, dose of radiotherapy, interval from irradiation therapy to prostatectomy, Kaplan-Meier survival), or pathologic factors (presence of confined tumor, extracapsular extension, positive surgical margins, seminal vesicle invasion, or positive lymph nodes on permanent sections). We conclude that high grade PIN is common in the prostates of patients who have failed irradiation therapy and that, theoretically, not all recurrent tumors derive from regrowth of the initial, incompletely eradicated tumor. However, because there was no significant difference between the two groups with regard to the clinical and pathologic parameters listed, we consider it likely that most recurrent tumors derive from the initial incompletely eradicated tumor. 1 Supported by SPORE grant 1 P50 CA 58204- 01 CF2, National Institute of Health
© 1995 by Gustav Fischer Verlag, Stuttgart
Intraepithelial Neoplasia in Prostate . 869
Introduction Prostate cancer is an increasing public health problem in the United States where it is now the most commonly diagnosed non-skin malignancy in men and the second leading cause of death in men, second only to cancer of the lung l . Efforts to control this cancer through chemoprevention should focus on preventing the progression of an identifiable premalignant lesion 3 • At present, the only generally accepted histologic precursor is prostatic intraepithelial neoplasia (PIN), and reproducible criteria for its identification and grading were originally described by McNeal and Bostwick under the term "intraductal dysplasia"9. This lesion has been described over the years by a number of other terms that were less precise and not as widely accepted. At a recent consensus conference on PIN, the grading of PIN lesions was lumped into two categories -low grade (previously PIN 1) and high grade (previously PIN 2 and PIN 3)6. The response of PIN to irradiation therapy has not been documented, although currently irradiation therapy is frequently employed as a primary treatment modality for carcinoma of the prostate in patients who are not considered operative candidates, and in the past has been used for nearly all patients with clinically localized tumor as well. The reappearance of tumor after apparently successful irradiation treatment may be due to regrowth of incompletely eradicated tumor or progression from incompletely eradicated PIN
to invasive carcinoma - a new tumor. Although the diagnosis of high grade PIN alone is not considered an indication for definitive treatment by surgery or irradiation, both treatment options are widely employed in treating in situ carcinoma of the breast lO , 11. Indeed, this is true even though a biopsy diagnosis of isolated high grade PIN is more often accompanied by invasive carcinoma on rebiopsy than is carcinoma in situ of the breast, either lobular or ductal, on either immediate rebiopsy or mastectomy2. The present study was undertaken to determine the alterations in high grade PIN which accompany curative doses of irradiation therapy and to compare these results to other published series of non-irradiated patients. Only high grade PIN was studied because low grade PIN may not always be reproducibly identified, may overlap with reactive atypia and may not be an immediate precursor lesion for invasive carcinoma? Results Overall 32 of 46 (70%) patients had identifiable high grade PIN within the salvage radical prostatectomy specimen. This number is similar to the number in the series of prostatectomies in which there was no history of radiation therapy4. A summary of comparisons of the clinical and pathological findings in the two groups of patients (those with and without high grade PIN) is given in Table 1, and comparison of the Kaplan-
Table 1. Clinical and Pathologic Features of Prostates Removed for Irradiation Failure
# Patients Age Dose of XRT (cGy) Interval XRT-RPx (mos.)
32 65.3 (56-74) 7224 (6000-8000) 58.3 (16-145)
14 65.2 (56-73) 7750 (7500-9000) 57.7 (24-120)
0.96* 0.22* 0.90*
3.2 (3-5) 3.6 (2-5) 6.8 (5-8) 12.7 (0.7-46.5) 4.4 (0.002-15.51) 4/32 (13%) 22/32 (69% ) 8/32 (25 %) 17/32 (53 %) 1/32 (3%)
3.7 (3-4) 3.5 (3-5) 7.2 (6-9) 24.7 (0.6-83.5) 4.9 (0.23-17.13) 2/14 (14%) 13/14 (93%) 6/14 (43 % ) 11/14 (79 % ) 1114 (7%)
Gleason grade Primary Secondary Sum PSA mean (range) Total Tumor Vol. (cc) Confined Tumor ECE(+):j: SM (+) §
by Students t test by Chi-square test ECE (+) denotes presence of extracapsular extension SM (+) denotes positive surgical margins SVI denotes presence of seminal vesicle invasion
0.10* 0.20* 0.75* 0.868t 0.078 t 0.226 t 0.103 t 0.538 t
870 . A. Arakawa et at.
Table 3. High Grade PIN in Irradiation Failure
Relationship to Cancer
ateral to the largest focus of cancer as within the borders of this cancer, as shown in table 3.
Years Fig.1. Kaplan-Meier survival curves of patients with (n = 32) and without (n = 14) high grade PIN.
Meier survival curves is shown in Figure 1. There were no significant differences between the two groups in any of the categories listed. Although it has been shown that large tumors are less likely than smaller tumors to be accompanied by high grade PIN, this was not a factor in our series since the volume of cancer did not differ significantly between the two groups8. The frequencies of the different patterns of PIN per positive case are listed in Table 2 and parallel in rank those in Bostwick's series of non-irradiated prostates, with the most common to least common pattern per patient as follows: tufting (78.1 %), micropapillary (59.3%), cribriform (34.4%) and flat (15.6%). These figures are compared to Bostwick's: tufting (86.6%), micropapillary (85%), cribriform (31.6%) and flat (28.3%)5. The difference in the numerical values of the percentages may reflect the effect of irradiation therapy or may reflect methodological differences, since Bostwick classified the PIN foci on the basis of the predominant type of pattern only. In our cases there were frequently two or more patterns present in the same focus without a clearly dominant pattern; in such instances these foci were classified in the hierarchical manner described in the materials and methods section. High grade PIN occurred with approximately the same frequency contralTable 2. Patterns of PIN in Irradiation Failure Flat
Tufting Micro- Cribriform papillary 25
# of foci showing 15 pattern (n = 199)
% of foci showing pattern
# prostates with pattern (n = 32) % prostates with pattern
Discussion At present, PIN represents the only widely accepted lesion that is thought to be an immediate precursor to invasive carcinoma of the prostate. Indeed, many investigators have recognized foci of PIN "budding" off a microacinus without an accompanying basal cell layer; this seems to be the strongest morphological evidence linking PIN to invasive carcinoma4 • Understanding the biology of PIN and its molecular relationship to carcinoma is critical in planning chemopreventative strategies to prevent clinical prostate cancer. Virtually no data have been published regarding the persistence of PIN following definitive irradiation therapy for carcinoma of the prostate. Our study attempted to address this point, albeit in a biased series of patients who had failed irradiation with regrowth or persistence of clinical prostate cancer. Although the distribution of the different patterns of high grade PIN and the total number of patients with high grade PIN in our irradiated series are similar to those in Bostwick's non-irradiated series, the actual number of foci of high grade PIN per prostate with high grade PIN may be less. The possibility that this may be the result of a decrease in the total number of ducts/acini following irradiation was not addressed in our study. In any event, high grade PIN is apparently no more sensitive to irradiation therapy than invasive carcinoma. Indeed it is possible that high grade PIN is less sensitive than invasive carcinoma to irradiation therapy. This possibility might be addressed, at least in part, by studying prostates at autopsy in patients found to have no invasive prostatic carcinoma after definitive irradiation therapy. Failure to eradicate PIN may lead to evolution of new tumors with time, even after the initial invasive cancer has been eradicated. Data from the present series suggest that there were no significant clinical or pathologic differences between the patients with or without high grade PIN. Because the data show no differences, we consider it likely that the persistence of PIN had no effect on the evolution of the cancer in these cases, and, therefore, that the recurrent cancer derived from the initial, incompletely eradicated tumor. Circumstantial evidence is all that is available until evi-
Fig. 2. High magnification photomicrograph of high grade PIN showing a rim of basal cells around border of a gland. Note that the lumenal cells show nuclear enlargement and focally prominent nucleoli (H&E x 420).
Fig. 3. High magnification photomicrograph of irradiation effect in a prostatic gland. There are scattered mononuclear inflammatory cells, prominent basal cells, marked nuclear pleomorphism, and enlargement of lumenal cells (H&E x 420).
872 . A. Arakawa et al.
dence is gathered to show a molecular identity shared by the initial and recurrent tumors. Material and Methods ~rom 1984 to 1994, all patients who ~adlc~l prost~tectomy at The Methodist
underwent salvage Hospital following lffadlatlOn failure but who had not received hormonal therapy .were included in this study. All prostates were entirely sectIOned by the whole-mount technique as previously described 12 • Briefly, all prostates were fixed overnight in 10% neutral buffered formalin and marked on the external surface with a':l indelible ink prior to sectioning. With the exception of t~e apI~al and bladder neck margins, the prostate was sectioned m a plane perpendicular to the rectal surface at 5 mm intervals for whole-mount sections up to the lower th!rd of the s~minal vesicles. The areas of cancer were mapped with a markmg pen, and from this the volume of tumor was calculated by multiplying the area of cancer foci on each section by the section thickness of 5 mm. A correction factor of 1:33 was use~ to correct for tissue shrinkage caused by the tissue processmg. ~nly areas of high grade PIN were mapped, using the cri~ena of McNeal and Bostwick for recognizing the lesions origm~lly described as "intraductal dysplasia," grades 2 or 39 (Fig. 2). A~chit~ct~rally benign ducts and acini with atypia due to the IrradiatIOn therapy were not considered to be related to PIN and were separated from PIN using the criteria of B<;>stwick6 (~ig. 3). Each area of high grade PIN was mapped With a markmg pen and the pattern of PIN was recorded for each focus according to the four patterns described by Bostwlck"and c?w<;>rk.ers, n!mely "flat," "tufting," "micropapillary, and cnbnform 5. If more than one pattern of high grade PIN were present per focus, the lesion was classified according to the overwhelmingly predominant pattern. However, if there was no predominant pattern the lesion was classified according to the architecturally m~st advanced pattern (reverse order of the listing above). The number of foci of PIN and the relationship of the PIN focus to the dominant cancer (within, adjacent to, or contralateral to the cancer) were recorded.
References I American Cancer Society (1994) Selected Cancers. Cancer Facts & Figures 1994: 9-17 2 AzzopardiJG (1979) Problems in breast pathology. W. B. Saunders, London-Philadelphia-Toronto 3 Boone CW, Kelloff GJ (1994) Development of surrogate endpo!nt biomarkers for cl!nical trials of cancer chemopreventatlv~ ag~nts: re~atlo~shlps to fundamental properties of premvaslve (mtraeplthehal) neoplasia. J Cell Biochem suppl ' 19: 10-22 4 Bostwick DG (1992) Prostatic intraepithelial neoplasia (PI~): current concepts. J Cell Biochem, suppl16H: 10-19 Bostwick D.G, Amin MB, Dundore P, Marsh W, Schultz OS (1993) Architectural patterns of high grade prostatic intraepithelial neoplasia. Hum Pathol 24: 298-310 6 Drago JR, Mostofi FK, Lee F (1989) Introductory remarks and workshop summary. Urology 34(suppl): 2-3 7 Epstein JI, Grignon OJ, Humphrey PA, McNeal JE, Sesterhenn lA, Troncoso P, Wheeler TM (in press) Interobserver reproducibility in the diagnosis of prostatic intraepithelial neoplasia. Am J Surg Pathol 8 Kastendiec~ H (1980), Correlation between atypical primary hyperplaSia and carcmoma of the prostate: a histological study of 180 total prostatectomies. Path Res Pract 169: 366-387 9 McNeal JE, Bostwick DG (1986) Intraductal dysplasia: a premalignant lesion of the prostate. Hum Pathol 17: 64-71 10 Solin LJ, Fowble BL, Schultz OJ, Yeh IT, Kowalyshyn MJ, Goodman RL (1990) Definitive irradiation for intraductal carcinoma of the breast. I J Rad Oncol 19: 843-850 11 Solin LJ, Recht A, Fourquet A' Kurtz J , Kuske R , McNee,se M, McCo~mick B, Cross MA, Schultz OJ, Bornstein BA, Spltaher JM, Vilcoq JR, Frowble BL, Harris JR, Goodman RL, (~~91). Ten-'ye~rs results of breast-conserving surgery and defImtive madlatlOn for intraductal carcinoma (ductal carcinoma in situ) of the breast. Cancer 68: 2337-2344 12 Wheeler TM (1989) Anatomic considerations in prostate cancer. Urol Clin N Am 16: 623-634
Key words: Prostate cancer - Prostatic intraepithelial neoplasia - Irradiation therapy Dr. T. Wheeler, Dept. of Pathology, MS 205, The Methodist Hospital, 6565 Fannin Street, Houston, TX 77030-2707, U.S.A.