Multifocal prostate cancer: biologic, prognostic, and therapeutic implications

Human Pathology (2010) 41, 781–793

www.elsevier.com/locate/humpath

Perspectives in pathology

Multifocal prostate cancer: biologic, prognostic, and therapeutic implications Matei Andreoiu MD a , Liang Cheng MD a,b,⁎ a

Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

b

Received 13 November 2009; revised 21 February 2010; accepted 25 February 2010

Keywords: Prostate; Prostatectomy; Multifocal; Tumor heterogeneity; Carcinogenesis; Precursor lesions; Prostatic intraepithelial neoplasia (PIN); Field effect; Tumor volume; Staging; Gleason grade; Molecular genetics; TMPRSS2-ERG gene fusion

Summary Prostatic adenocarcinoma is the most common cancer diagnosed in men and is often multifocal. Ongoing controversy exists about the most appropriate system of tumor classification and grading and the optimal curative treatment approaches. This review examines recent progress in the pathogenesis of multifocal prostatic adenocarcinoma and its biologic, pathologic, prognostic, and therapeutic implications. Prostatic cancer multifocality makes accurate clinical staging difficult, and repeated revisions have been undertaken in an effort to optimize prognostic accuracy. Although the 2010 revision represents an improvement over the previous systems, the clinical significance of the T2 substaging is questionable. Also discussed is the potential impact of tumor multifocality and clonal heterogeneity on the oncologic efficacy of novel focal ablative approaches. The clinical significance of smaller secondary tumors and the relationship between extent of chromosomal abnormalities and the metastatic potential of an individual tumor focus were reviewed. © 2010 Elsevier Inc. All rights reserved.

Prostate cancer is the leading malignancy among men in the United States [1]. It results in large health care expenditures every year, and both new and old modalities of treatment are continuously being introduced, reassessed, and modified on an ongoing basis. Despite the large volume of clinical activity and research, controversy still remains as to the most appropriate and clinically relevant staging and grading system. This is largely a result of the pathologically complex and uncertain clinical course of prostate cancer. Some tumors are undeniably aggressive, progress quickly, and can result in significant morbidity and premature death

⁎ Corresponding author. Departments of Pathology and Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. E-mail address: [email protected] (L. Cheng). 0046-8177/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2010.02.011

of the patient; however, a large proportion of these neoplasms display indolent course and progress slowly, obviating substantive impact on the long-term survival, and quality of life of patients. The complexity of prostate cancer, both in diagnosis and the optimal tailoring of management, is rooted in its multifocal origins within the prostate organ. Research for the past 2 decades has demonstrated the independent clonal nature of multiple tumor foci that can occur synchronously or metachronously. These disparate tumor foci can in turn progress at different rates depending on the nature of the genetic alterations present that impart differing degrees of biologic aggressiveness. The tendency of prostate cancer to develop multifocally has been demonstrated by many studies, with rates found to range anywhere from 60% to 90% [2-16] (Figs. 1-3). Greene

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M. Andreoiu, L. Cheng elements may reflect the evolution of poorly differentiated areas from more well-differentiated areas, likely owing to increased accumulation over time of chromosomal anomalies and progressively greater genetic instability. It is likely that the true representation of the pathogenesis of prostatic carcinoma is a combination of these 2 processes occurring concomitantly. A study by Cheng et al [11] used molecular analysis of microsatellite alterations in the DNA from separate tumors within the same prostate to demonstrate that the tumors had arisen independently. In studying the types of allelic loss at chromosome 8p12-21, the location of a tumor suppressor gene involved in early prostatic carcinogenesis, and at the BRCA1 locus on chromosome 17q21, the investigators found that the pattern was consistent with an independent tumor origin in 15 of 18 cases [11]. A random discordant pattern of allelic deletion was observed in distantly separate

Fig. 1 Gross pathology of a prostate with multifocal prostate cancer. Abbreviations: PCA, prostate cancer; BPH, benign prostatic hyperplasia.

et al [7] showed that more than 80% of prostates contained 2 or more widely separate tumors by the time of clinical diagnosis. Villers and his group [12] found a somewhat lower rate of multifocality in resected prostate specimens (50%), but noted that in those prostates that had more than one tumor focus, 80% of incidentally discovered tumors had volumes of less than 0.5 cm3, a similar proportion to that observed among incidentally diagnosed prostate tumors in the specimen group retrieved after radical cystectomy. These findings highlight the importance of understanding the pathogenesis and clinical implications of multifocality in prostate cancer.

1. Biologic consideration The biological basis for the multifocal and histologic heterogeneity attributes of prostate cancer has not been fully elucidated. Two main theories attempt to explain this process: (1) multiclonality of the initial disease and (2) clone evolution from the initial disease. The first is rooted in the knowledge that in most known biologic tumors, passage of time leads to a progressive growth in tumor volume. In the case of prostatic carcinoma, this eventually leads to the fusion and amalgamation of varying tumor lesions of varied size and grade. This in turn results in the eventual formation of larger, more histologically heterogeneous, coalesced tumors, and fewer small independent foci. Essentially, the initial disease is already rooted in independent multiclonal origins. Indirect evidence for this hypothesis is derived from studies showing decreased grade heterogeneity in small tumors compared to larger tumors in prostates with multifocal disease [17]. Alternatively, a second theory postulates a multiclonal evolution from the initial lesion. In this scenario, multifocal tumors displaying grade heterogeneity among their various

Fig. 2 Carcinogenesis of prostate cancer. Representation of multifactorial etiology leading to a field effect and progression from PIN to multifocal prostate carcinoma. The mechanism behind prostate carcinogenesis likely involves a combination of both acquired factors and inherited genetic predisposition. An underlying genetic predisposition could create a “field effect” upon which further environmental exposure to chemical and biologic carcinogens could lead to the formation of multiple precursor lesions. Through independent clonal expansion, these lesions would evolve into spatially separated and distinct cancers. High-grade PIN is the precursor lesion of prostate cancer in most cases, especially cancer arising in PZ, although that less relationship appears less certain for cancer originating in the transition and anterior zones.

Multifocal prostate cancer

Fig. 3 Prostate cancer multifocality. Diverse topographical distribution of different-sized tumor foci within a whole-mount prostate specimen. Tumor foci were circled.

tumors, whereas the same allele was consistently lost from different regions of the same tumor. Although the weight of evidence clearly points to an independent origin for many, if not most, prostatic tumors within an individual gland, the possibility that spatially separate tumors may arise through intraglandular dissemination has not been entirely ruled out. In the study by Cheng et al [11] investigating DNA alterations from different lesions within a prostate, the pattern of allelic loss seen in the specimens from 3 of the 18 patients was compatible with a mechanism of intraglandular dissemination. It is possible that some highly aggressive prostate cancers, from inception displaying rapid diffuse involvement of the gland, spread through satellite lesion formation and intraglandular dissemination [18]. It is not inconceivable that highly aggressive cancers actually arise through a monoclonal process rather than independent origin. In an analysis of 94 separate tumor samples from 30 patients who died of metastatic prostate cancer, Liu et al [19] demonstrated that multiple separate metastases may arise from a single precursor cancer cells. The mechanism behind prostate carcinogenesis likely involves a combination of both acquired factors and inherited genetic predisposition, a concept supported by extensive evidence [16,20-26] (Fig. 2). An underlying genetic predisposition could create a “field effect” upon which further environmental exposure to chemical and biologic carcinogens—such as xenotropic murine leukemia virusrelated virus [27,28] and inflammation [29]—could lead to the formation of multiple precursor lesions [11,30]. Through independent clonal expansion, these lesions would evolve into spatially separated and distinct cancers.

2. Morphological heterogeneity The morphological appearance of cancer cells reflecting differing degrees of dedifferentiation was elegantly analyzed

783 and classified by Gleason [31-33] into the currently used standard grading system, which is based on the degree of glandular differentiation and the interaction of the malignant glands with stroma. The presence of grade heterogeneity within multiple foci of prostatic adenocarcinoma in the same gland is a common finding [10]. A study of 115 embedded and serially sectioned, whole-mount prostatectomy specimens demonstrated an 87% prevalence of multifocality with extensive interfoci histologic heterogeneity within an individual specimen [10]. Furthermore, most foci contained at least one segment of tumor of a different Gleason grade than the overall grade assigned to the specimen. Among 100 specimens, there were 290 separate tumor foci and only 9 had the same Gleason grade in all foci. The Gleason grade of the index tumor was the same as the overall grade in only two-thirds of cases. Finally, the correlation between the primary grade of individual foci and the overall specimen was stronger than the same correlation applied to secondary grades. Given the heterogeneity of Gleason grade seen within most cancer foci in the prostate, questions arose whether any pattern could be discerned from the arrangement of individual elements of differing grade within the tumor. A study examined the potential spatial relationships among the various grades present within early stage, clinically detected prostate cancer [15]. The authors found absence of any predictable pattern among 101 tumors examined. More than 50% of prostates contained at least 3 different grades of cancer and the number of different grades increased with increasing tumor volume. The location within any given cancer of the high-grade elements appeared to be random. Small cancers were always well or moderately differentiated, whereas poorly differentiated elements were not seen in any peripheral zone (PZ) cancer smaller than 0.31 cm. These findings were in keeping with the observations by McNeal et al [34] that most prostate cancers tended to be at least well to moderately differentiated at inception and acquired poorly differentiated elements over time and with increasing tumor volume. These higher grade elements in turn would engage in more rapid division and lead to even greater, more invasive, and possibly metastatic tumor spread [35-37].

3. Anatomical zonal consideration The 2 most common zones of prostate cancer origin are the PZ and the transition zone (TZ) [34,38-41]. Initial studies showed that approximately 70% of tumors arose in the PZ, whereas 25% started in the TZ. Most cancers in the TZ showed distinctive morphologic traits, being composed of tall columnar cells lining glands of variable size and contour [41], though a more recent study suggests that typical TZ morphology was not specific and was observed in only 49% of TZ-predominant cancer [42]. The TZ boundary seemed to act as a barrier (at least for some time) to the further spread of

784 cancer beyond the TZs, in contrast to tumors in the PZ, which seemed to lack the clear cell histologic pattern, were more poorly differentiated and tended to be more infiltrative. In a study by Greene et al [43], PZ tumors were more likely to extend through the capsule and at a smaller volume. Although 20% of PZ tumors involved the seminal vesicles, hardly any TZ tumors did so. Furthermore, PZ tumors were almost always associated with high-grade intraepithelial neoplasia, whereas this association appeared missing when looking at TZ cancers. Given the multifocal origins of prostate cancer disease, clinicopathologic differences between tumors arising in the PZ and the TZ have been investigated. The most common site of origin is the PZ, making tumors arising in this part of the prostate more amenable to transrectal palpation and biopsy. In contrast, TZ tumors can frequently be missed on biopsy and are often discovered in TURP specimens [44]. Initial studies looking at the impact of zonal tumor origin indicated a much more indolent nature, with TZ tumors demonstrating an 81% 5-year cure rate, relative to 53% seen in PZ tumors [45]. In a series by Noguchi et al [46], TZ tumors demonstrated a biochemical recurrence-free rate of 71.5% versus 49.2% for PZ cancers. Accumulated evidence indicates that TZ tumors present with higher PSA levels and higher tumor volumes but more frequently shows organ-confined disease and lower Gleason scores [47,48]. A group examining pathologic characteristics in tumors arising in either zone found that PZ tumors displayed significantly higher Gleason scores (7 versus 5), proliferation rate, and microvessel density [49]. In addition, there was a lower expression of tumor markers related to tumor growth rate (p53 and bcl-2) present in tumors arising in the TZ. Similarly, Shannon et al [50] found that TZ tumors had significantly lower Gleason scores, less Gleason grade 4/ 5 elements, and lower rates of capsular penetration and positive surgical margins. They also found that a subset of TZ tumors tended to have features of high malignancy. Positive anterior and bladder neck margins were also more common in TZ than PZ carcinomas. However, recent data from the Memorial Sloan-Keterring Cancer Center (New York, NY) suggest anterior-predominant tumors are likely originating from anterior PZ rather than TZ origin [51]. In a study of 1262 consecutive patients undergoing radical prostatectomy, Chun et al [52] diagnosed TZ prostate cancers in 115 patients (9.1%). Multivariate analysis revealed no differences in the rate of biochemical recurrence between PZ and TZ cancers. Similarly, a study out of Japan looking at consecutive radical prostatectomy cases revealed greater PSA values and tumor volumes in TZ cancers compared with those of tumors located in the PZ [53]. Despite this, no significant difference in biochemical recurrence-free survival was seen between the 2 groups, suggesting that TZ cancers possess an intrinsically less aggressive phenotype than that of PZ cancers but will present with a greater volume and PSA level thereby resulting in a similar posttreatment course and recurrence rate. Augustin

M. Andreoiu, L. Cheng et al [47] found that TZ and pure PZ cancers with similar tumor stage, Gleason score, and surgical margin status showed no significant difference in biochemical cure after RP. Nevertheless, a clinical distinction between tumors arising from these 2 zones remains of significance as TZ tumors have been consistently shown to possess more favorable pathologic features despite higher PSA levels and tumor volume at diagnosis [45,54]. TZ cancers typically lack TMPRSS2-EGR gene fusion, commonly observed in PZ cancers [55].

4. Genetic basis of tumor multiclonality and aggressiveness High-grade prostatic intraepithelial neoplasia (PIN) is the precursor lesion of prostate cancer in most cases, especially cancer arising in PZ, although this relationship appears less certain for cancer originating in the transition and anterior zones [30,56-59]. Like prostatic carcinoma, it has also been commonly found to be multifocal [60]. Several molecular studies have examined the clonal origins of PIN and its corresponding transmission of these same genetic and morphologic differences to full-fledged prostatic carcinoma. Greene et al [61] used nuclear image analysis to determine the DNA ploidy value of each tumor focus in a series of 30 prostatectomy specimens in patients with early stage prostate cancer. The authors found that all cancers less than 0.02 cm3 were diploid, whereas 82% of foci greater than 2.0 cm3 were nondiploid. Furthermore, although most of the diploid tumors remained confined to the prostate (89%), 68% of the nondiploid tumors had invaded extraprostatically. These findings suggested that increased growth and aggressiveness of a tumor was linked to its ploidy. In addition, there were several small nondiploid tumors that displayed extraprostatic extension, whereas none of the diploid foci of similar small size did so. Although constrained from reaching any definitive conclusions due to a fairly small specimen sample, this study and the others discussed above suggest that increased malignancy is not a progressive process related to achieving a certain volume but rather an innate characteristic of the tumor imparted by the underlying genetic abnormality and extent of genetic aberrations. Bostwick et al [16] similarly showed the precursor nature of PIN lesions and their independent clonal origin. In examining the distribution and prevalence of allelic imbalance at 6 microsatellite markers from both PIN and adenocarcinoma foci, they demonstrated a similar pattern but lower overall proportion of allelic imbalance in the PIN regions (65% versus 82%). Significant genetic heterogeneity was observed in both PIN and prostate carcinoma, but no significant correlation between allelic imbalance and pathologic stage or tumor grade was seen. Their results indicated that although PIN foci could be genetically distinct from each other just as foci of prostatic carcinoma

Multifocal prostate cancer were distinct from each other, matched foci of PIN and carcinoma often appeared genetically related, suggesting a common origins. Furthermore, the multiple and apparently independent origins of PIN foci shown by this and other studies strongly suggests a field effect underlying the pathogenesis of prostatic neoplasia. The highest frequency of allelic imbalance has been found on chromosome arm 8p in 63% of foci of high-grade PIN and 91% of foci of prostate carcinoma [62]. Other studies have shown loss of portions of the 8p arm in both PIN and prostate carcinoma [63,64] indicating a potentially important role for alterations of this specific chromosomal region in the early progression of prostatic carcinoma. Specifically, deletions at the chromosomal regions 8p12-21 and 8p22 have been singled out studies of chromosome 8p. The results suggest that LOH changes in these regions occur early in the development of prostate cancer. The short arm of chromosome 8 has also been implicated in other human malignancies including bladder cancer, hepatocellular carcinoma, colorectal carcinoma, malignant fibrous histiocytoma, and nonsmall cell lung cancer [65-69]. Additional evidence for the important role of chromosomal alteration at 8p12-22, as well as 13q14-31, was provided by a group from Japan [70]. They examined 45 foci from multifocal prostate cancer in 22 prostatectomy specimens and found that tumors with losses in the above regions displayed larger volume and more features of heightened malignancy, such as a high Gleason score (≥4 + 3 and higher) or extracapsular invasion. Chromosomal alterations did not show the same pattern between any 2 tumor foci within the same prostate, once more pointing out the independent nature and differing clonal origin of prostate carcinoma. It is unclear which of the allelic loss events observed at various loci studied in metastatic disease, although clearly associated with more highly malignant tumors, truly represent early event in tumorigenesis prior to metastasis or late changes after invasion has already occurred. The importance of the heterogeneous nature of disparate foci possessing different malignant potentials within the same prostate was shown in a study by Sakr et al [63]. Eleven of 14 cases with multiple foci of PIN displayed differing allelic loss profiles among the PIN foci, suggesting these lesions arose independently and multifocally. The precursor nature of high-grade PIN was further supported by the finding that allelic loss patterns were similar, although less complex, than those of primary or metastatic tumors. Counterintuitively, the authors found that the pattern of allelic loss between metastatic deposits and that seen in the index tumor often differed, suggesting that the allelic loss occurred after metastasis or arose from an unsampled and smaller focus. Several other important findings regarding the origin and progression of prostatic carcinoma have been made [19,71-75]. The differences in metastases and primary prostate cancer by FISH and other techniques could be due

785 to sampling issues and remarkable tumor heterogeneity. Support for the possibility that some of the differences in types of allelic loss between the primary prostatic tumors and metastatic deposits in the study by Sakr et al [63] that may have been due to undersampling was provided by Jenkins et al [76]. That study investigated the role of c-myc oncogene amplification and other chromosomal changes in matched PIN, localized prostatic carcinoma, and lymph node metastases using FISH. They found that one or more primary tumors shared the same FISH anomalies as the matched ipsilateral metastatic foci, suggesting that multiple primary lesions had given rise to matched metastatic deposits. However, the frequencies of c-myc amplification and chromosomal aneusomy were higher in metastatic lesions, indicating that primary tumor cells with more genetic anomalies are the ones usually likely to metastasize due to their inherently greater genetic instability. Intraglandular differences in the number of extra c-myc copies and chromosomal anomalies not only both between PIN and prostatic carcinoma foci, which tended to have more, but also between geographically separate PIN lesions and between separated carcinoma lesions, clearly pointed to the genetically heterogeneous nature of prostatic cancer and the precursor nature of PIN [73]. Although, in general, the dominant focus of carcinoma showed more genetic changes than smaller foci, there were instances of small foci showing greater alterations than the dominant tumor focus, indicating that the size of a cancer focus and its degree of morphological aberration may not always reflect the extent of its genetic derangement. Although most circulating tumor cells never produce metastases and are present in a number of early cancers that are surgically curable, some such cells, even when released from small neoplastic foci, possess the capability for initiating metastatic colonies. Evidence for this process was provided by an elegant study from Schmidt et al [77], who identified PSA-positive circulating prostate tumor cells (CTCs) from the peripheral blood of patients with pathologically proven multifocal prostate cancer and subjected them to polymerase chain reaction-based microsatellite analysis. In 17 of 20 cases, the LOH pattern of the CTCs was identical to only one of the foci in the primary tumor. Moreover, even very small foci (as little as 0.2 cm3) were shown as seeders of CTCs in 6 cases. These results suggest that although CTCs are derived from distinct foci of a heterogeneous primary tumor, the size of the focus does not predict its potential for seeding. Several recent studies have pointed to observed fusions of the androgen-regulated gene TMPRSS2, and the ETS transcription factor family members, particularly ERG, as highly common and significant genomic alterations seen in prostate cancer [74,78-81]. Although being highly specific for prostate cancer [82,83], such fusions have also been found to be associated with advanced tumor stage and cancer-specific death or rate of metastasis [80,83,84]. Two separate groups assessed the fusion status of TMPRSS2-

786 ERG in spatially distinct tumor foci within the same prostate [80,85]. Both groups found a high incidence of TMPRSS2 gene rearrangement within at least one tumor focus, with rates of 70% and 53% in multifocal prostate cancer cases, respectively. Virtually all individual distinct lesions showed homogeneity for focal status, indicating that TMPRSS2-ERG fusion is an early event in prostate carcinogenesis. Heterogeneity for fusion status (interfocal clonal heterogeneity) was demonstrated in 41% and 70% of cases. Although neither group found a correlation between the Gleason score or size of the focus and its fusion status, other data have suggested that lesions showing TMPRSS2ERG fusion behave more aggressively than fusion-negative lesions [83,84,86], showing higher tumor stage and higher incidence of lymph node spread. These and other studies not only point to TMPRSS2-ERG gene fusion products as potentially valuable future biomarkers of independent smaller tumor lesions missed at biopsy but have once again revealed the heterogeneous nature of multifocal prostate carcinoma and its evolution through multiple, independent clonal expansions. Although an accumulating collection of studies seems to indicate TMPRSS2-ERG gene fusions as markers of poorly differentiated histology and increased malignancy, others have not found this association. Gopalan et al [87] evaluated the preponderance of this gene rearrangement in 521 cases of radically prostatectomy cases for clinically localized prostate cancer and in 40 unmatched metastases. The authors found that TMPRSS2-ERG gene rearrangements were not associated with increased stage, higher rate of recurrence, or worse outcome. Instead, a higher number of copies of this region was more likely to predict poor outcome and likely only reflected the significance of generalized aneuploidy as the true genetic factor of greatest impact. A study by Saramaki et al [88], investigating TMPRSS2-ERG rearrangement in prostate cancer xenografts and prostate cancer lines using reverse transcription polymerase chain reaction and FISH, revealed longer progression-free survival in prostatectomy patients whose dominant tumors contained rearrangements in this genetic region. Quite the opposite, gene fusion was not associated with any clinical variables predictive of outcome such as Gleason score, pathologic stage, or cell proliferation activity and quite unexpectedly was found to be an independent predictor of favorable outcome. Recent years have brought forth an increasing number of molecular and genetic analysis studies demonstrating an increasing array of genetic changes associated with the progressive transformation of normal prostatic tissue to PIN and eventually fully fledged carcinoma. Henrique et al [89] documented the epigenetic heterogeneity of high-grade PIN lesions at 3 gene promoters commonly methylated during carcinogenesis. Although aberrant APC and RARB2 promoter hypermethylation appear to be early events in the transition from normal tissue to high-grade PIN, GSTP1 hypermethylation appeared to be associated with progression

M. Andreoiu, L. Cheng of carcinoma lesions from an in situ stage to invasive neoplasia and thus may serve as a marker of clinically important high-grade PIN lesions. This confirmed their hypothesis that the increasing frequency of highly methylated alleles was consistent with clonal progression of increasing malignancy and added to their previous finding that prostate carcinomas displaying low methylation levels usually correspond to organ-confined and low- or intermediate-grade disease [90,91]. More recently, True et al [75] demonstrated that the differing metastatic potential and degree of tumor aggressiveness can be traced to diverging underlying genetic profiles with direct impact on functional tumor properties. Microdissection was used to obtain cohorts of cancer cells of Gleason patterns 3, 4, and 5 from prostatectomy samples. A multigene model capable of distinguishing low-grade from high-grade (4 or 5) cancer was generated. Several proteins such as monoamine oxidase A and DAD1 had significantly altered levels in poorly differentiated tumors. Beside generating potential future targets of growth inhibition in more lethal cancers, such studies are shedding further light on the differing genetic profiles underlying the Gleason grade of cancer tissue and its potential for invasiveness [71,75,92].

5. Tumor staging and prognostic challenges Given the abundantly demonstrated multifocal, multiclonal nature of prostatic carcinogenesis, an ongoing struggle to arrive at an accurate staging system that correlates well with pathologic staging and long-term prognosis continues. As of yet, a definitive answer has not been reached. The TNM staging system for prostate carcinoma was first introduced in 1992, when the American Joint Committee on Cancer and the International Union Against Cancer adopted a unified TNM staging system [93]. pT2 disease was defined as palpable but organ-confined disease, with pT2a representing involvement of less than 50% of one lobe, pT2b greater than 50%, and pT2c palpable involvement of both lobes. Under that system, tumor assessment was dependent on digital rectal examination and histologic confirmation of carcinoma. The prognostic strength of this staging system in predicting the actuarial risk of biochemical failure after prostatectomy represented a significant advance in allowing a more accurate and focused discussion with the patient regarding posttreatment outcome [94-97]. However, in the pursuit of simplification, the American Joint Committee on Cancer revised the TNM staging system in 1997 [98]. It resulted in the merging of the pT2a and pT2b categories into a single pT2a group designating unilateral palpable disease. Almost from the time of its introduction, the new system had a host of detractors who felt that the revised classification focused more on grouping patients with similar intragroup homogeneity in outcome

Multifocal prostate cancer than in maximizing prognostic accuracy [99]. Unfortunately, the recently released 2010 TNM staging manual [100] has not accounted for accumulated evidence that current pT2 classification was not optimal [9]. The current (2010) pT2 classification [100] was identical to the previous 2002 version [101]. Questions have even arisen about the true validity of clinical T2b stage tumors. In the first study to investigate the pathologic prevalence of clinically staged pT2 tumors through examination of 369 totally embedded and serially sectioned whole-mount radical prostatectomy specimens, not a single unilateral tumor occupying greater than one-half of single lobe (pT2b) could be identified in the large whole mount prostate cohort from the Indiana University (Indianapolis, IN) [9]. They found that 15% of the tumors were pT2a, 60% were pT2c, 20% were pT3a, and 5% pT3b. As the authors speculated, a palpable tumor involving greater than 25% of the prostate would make its confinement to a single lobe most unlikely, particularly given the multifocal distribution of carcinomatous foci. The strongly suggested conclusion, based on the results of both the clinical and pathologic studies discussed above, is that the optimal classification system should group pT2b tumors with those of pT2c stage. As currently classified, a pT2b tumor likely represents pathologically bilateral disease, either through contiguous but not clinically evident involvement by the primary tumor, de novo lesions of independent origin, or satellite lesions perhaps derived from intraglandular dissemination. Hence, pretreatment discussion with patients should reflect the similar outcome rates of pT2b and pT2c tumors and their grouping as a unified entity, that of bilateral multifocal disease. A group from Johns Hopkins University (Baltimore, MD) analyzed the 1314 cases of T2 disease that underwent prostatectomy and calculated the biochemical progressionfree survival [102]. Using the 1992 classification grouping, they in fact found a statistically significant difference in the outcome of men with pT2a versus pT2b disease but not between pT2b and pT2c groups. When the revised 1997 system was used, they found an inferior predictive ability and an underestimation of the ability of definitive therapy to cure men with pT2a disease. Another analysis by Iyer et al [103] also analyzed biochemical recurrence-free probability in a large cohort of patients and found that the 1992 classification of pT2 tumors resulted in a more accurate predictive ability in patients after external beam radiation therapy, as no significant difference in recurrence-free rates existed between 1992-classified pT2b and pT2c groups, and 5-year recurrence rates were similar [103]. The growing body of evidence demonstrating the diminished predictive power of the 1997 revised system led to yet another revision in 2002, essentially a rebuttal of the 2-tiered classification and reversion to the 3-tiered system for pT2 tumors. Despite improved outcome predictive value, there remains clear discordance between clinical staging and

787 pathologic staging of postprostatectomy under the current classification system. Clinical tumor understaging has consistently been shown to range in the 40% to 60% range [17,104,105]. This is clearly due to the multifocal, histologically heterogenous nature of prostate carcinoma. Controversy has also touched the concept of Gleason grading, as the recurrent and documented findings of multiple small foci with higher Gleason grade than that of the index tumor has cast some doubt on whether the established Gleason grading system and associated prognostic conclusions may fully predict the metastatic potential of all carcinoma foci in a prostatic gland. In a series of 61 completely sectioned whole-mount prostatectomy specimen with pT2 prostate cancer [17], a single histologic grade was present in only 16% of specimens. The findings also showed a clear trend suggesting that the frequency and extent of grade heterogeneity increase as tumors attain larger volumes. In 18% of cases, satellite tumors had a higher Gleason sum. Although a correlation between tumor volume or grade and frequency of capsular penetration was present, 11% of small volume (b1.0 cm3) tumors nonetheless displayed extraprostatic extension. The results raise doubts as to whether a singular focus on the index tumor as the primary determinant of clinical outcome may truly reflect or predict the true malignant potential of multifocal disease. Rather, a complete picture of the clinical and biologic potential of prostatic carcinoma in a gland can only be achieved by evaluating all tumors within a gland, something that current biopsy techniques, in the absence of detailed imaging guidance, are simply unable to reliably do. As a few small volume and low-grade tumors were also seen to penetrate the capsule, a tumor's ability to become locally invasive is defined not just by its degree of dedifferentiation but also its topographical location within the gland. Arora et al [10] also showed the weakness of focusing only on the Gleason profile of the primary index tumor as 290 separate tumor foci were seen in 100 prostatectomy specimens, and only 9 of these specimens had the same Gleason grade in all foci. In many cases, the overall Gleason score did not correlate with the score of the index tumor. In taking a closer look at index tumors, Pan et al [106] found a disproportionately adverse influence by high-grade elements on the biologic behavior of a tumor and its tendency to become locally invasive, even when those elements accounted for a minimal percentage of the overall tumor volume (b5%). Typical Gleason 5 or 6 tumors with smaller volume pattern 4/5 elements had a pathologic stage intermediate between Gleason 5/6 tumors without those high-grade elements and typical Gleason 7 tumors. They also showed a nearly identical progression rate to Gleason 7 tumors. Similarly, Gleason 7 tumors with tertiary pattern 5 behaved nearly identical to Gleason 8 tumors. Interestingly, the existence of pattern 5 elements did not impact the behavior of typical Gleason 8 tumors, likely reflecting the already inherently aggressive nature of Gleason 8 tumors.

788 These findings helped to partly reverse the view that the behavior of a tumor was dictated only by the predominant and second most common patterns. Accumulative data suggest the worst histologic grade dictates the biologic behavior of prostate cancer [106-111]. Strong support for the important prognostic role of highgrade lesions, even when present in a proportion tertiary to the 2 main histologic forms used to generate the overall Gleason grade was provided by a recent study from Epstein's group at Johns Hopkins University [112]. Using data obtained from a large cohort of 3230 men who had underwent radical prostatectomy, this group showed that high-grade tertiary components imparted biochemical recurrence-free rates intermediate to those of the same overall Gleason grade but no high-grade components and those of patients with tumors with the next highest overall Gleason grade. Clearly, this implicitly suggests that more poorly differentiated and aggressive lesions will lead to overall higher rates of progression and worse prognosis, irrespective of the relatively smaller size of these lesions. Consequently, the authors suggested that a modification of the current Gleason grading system to further accentuate the importance of high-grade tertiary components would result in more accurate prognostic tools in the management of clinically localized prostate cancer [112]. These accumulative evidences helped to fashion a new consensus on the optimal grading of prostate cancer, particularly in the preprostatectomy setting. The recommendation for reporting the pathologic grade of prostatectomy samples not only continues to reflect a summing of the primary and secondary pattern grades but also includes a specification of any high-grade tertiary elements present in the specimen, regardless of volume. However, in recognition of the potentially significant clinical impact of higher grade but low-volume tumors as well as the imperfect accuracy of needle biopsy in gauging the full extent of such disparate lesions within a prostate, needle biopsy grading is currently based on the sum of the primary and worst grades observed, regardless of the volume of cancer with the tertiary grade. In studies by Stamey et al [113] as well as others [114,115], the combined percentage of Gleason patterns 4 and 5 is one of the most powerful predictors of patient outcome and appears superior to conventional Gleason score in identifying patients at increased risk of disease progression. The authors recommend that the amount of high-grade cancer in a prostatectomy specimen should be taken into account in therapeutic decision making and assessment of patient prognosis [114,115]. It should be mentioned that there have been some contradictory studies published suggesting lack of clinical significance of secondary cancers and the primacy of the index tumor in determining outcomes. Noguchi et al [48], in examining a total of 222 prostatectomy specimens from patients with cT1c cancer, found no correlation between tumor distribution pattern (unifocal versus multifocal) and

M. Andreoiu, L. Cheng adverse prognostic factors such as capsular penetration, seminal vesicle invasion, positive surgical margins, or lymph node metastasis. Their analysis identified the percentage of Gleason pattern 4 or 5 in the biopsy as the strongest predictor of biochemical failure. Their conclusion was that secondary cancers in the prostate lack clinical significance. However, this was actually not supported by the data, which only suggested that multifocal cancer was just as likely to be organ confined as a unifocal cancer and that a large volume tumor was more likely to contain high-grade elements. This had been shown previously. It is also certainly true, however, that high-grade elements in even small tumors display increased and proven metastatic potential that may lead to worse outcomes irrespective of the characteristics of the index tumor. It is very possible, and has been shown in multiple instances, that some of the grade 4/5 tumor retrieved by the investigators during the preliminary biopsy came from smaller tumors, something not verifiable in the Noguchi study. It is our belief that it is not the existence of multifocality itself but rather the presence of high-grade, genetically unstable elements, regardless of the tumor volume of origin, that are most likely to determine the clinical prognosis. In addition, it can be further theorized that although low-grade tumors have been shown to penetrate the capsule owing to their topographical site of origin, their less aggressive nature will lead to distal spread in only a few instances as well as a slower and more limited local invasion. Clearly, a substantial body of evidence points to the metastatic potential of smaller volume primary tumors within the prostate [63,76,77]. As addressed earlier in this article, the pattern of allelic loss seen in metastatic deposits in one study did not consistently match that of the index tumor, suggesting an alternate, likely smaller focus of origin [63]. Another study showed a pattern of chromosomal anomalies detected through FISH consistent with seeding from several foci from the same gland rather than only from the largest dominant lesion. Schmidt et al [77] showed that, based on the types of LOH changes seen in primary lesions and systemic circulating tumor cells, the size of a carcinoma focus did not always predict its seeding ability. Further evidence for genetic changes of metastatic nodal cancer inconsistently correlating to those seen in the index tumor was provided by a group out of the Mayo Clinic who, through the use of FISH analysis on prostatectomy specimens, demonstrated that the dominant focus only occasionally shared chromosomal changes with nodal metastases in locally advanced prostate cancer (41.7% of cases) [116]. This was in keeping with the findings of Qian et al [64], who used FISH to also show that chromosomal changes in lymph node metastases were frequently found in nondominant primary tumor foci. In contrast to the conclusions by Noguchi et al [48] that multifocal cancer did not portend a more advanced pathologic stage or worse prognosis, a study from Austria seemed to suggest the opposite [117]. A retrospective review of 308 radical prostatectomy cases revealed a

Multifocal prostate cancer prevalence of disease multifocality in 66.9% of cases. The data indicated that multifocal cancer was associated with higher grade, stage, and recurrence rate than unifocal variants. Preoperative PSA and PSA density were not able to predict multifocality, whereas free-to-total serum PSA could. These results were in keeping with the finding that a significant proportion of smaller tumors displaying extracapsular invasion tended to have a higher composition of poorly differentiated high-grade elements, whereas large volume tumors confined to the prostate were mostly composed of low- and intermediate-grade lesions. What this highlights is the imperfect association between tumor volume, grade, and invasiveness, thereby emphasizing the importance of multifocality and the determination of the pathologic characteristics of all the independent foci in the prostate in accurately assessing prognosis. What also must be kept in consideration is that the presence of heterogeneity in medium to large prostate cancers leading to selective sampling of the primary lesion could also account for some of the above noted differences between the larger index tumors and smaller secondary tumors. Taken together, a reasonable interpretation of the data available at this time would be that although the dominant index tumor is more likely to have high-grade elements present and will be the driver of prognosis in most cases, nondominant foci, while not always delineated either clinically or pathologically, can show the potential for metastatic seeding and rapid, focal extraprostatic spread in a minor but still substantial proportion of cases, thereby, helping determine the true stage and the likelihood of progression and recurrence.

6. Multifocality and the challenge of focal ablative treatments Increasingly, the past decade has seen attempts to apply an array of novel techniques to the selective ablation of perceived clinically significant prostate cancer [118,119]. This has been driven by the rationale of trying to minimize the complications associated with radical resection of the entire prostate while achieving eradication of localized lesions with good oncologic outcome. Procedures such as cryosurgery, brachytherapy, high-intensity focused ultrasound, radiofrequency interstitial ablation, and others, have mostly been used in the initial management of patients with apparent locally confined, small volume and unilateral disease at initial diagnosis or in the setting of recurrence after failed primary therapy. There is a preponderance of evidence for the multifocal nature of most prostate carcinomas and concomitant difficulty in the preoperative delineation of all clinically significant tumors, sometimes including ones of small volume but containing high-grade elements. Accurate preoperative mapping of all tumor lesions in the prostate is

789 essential in determining optimal surgical management, but understaging clearly occurs even in the setting of extended saturation biopsy. Although experimental use of 3-dimensional computed tomographic (CT) prostate reconstruction has shown some potential in increasing the reliability of biopsies [120], accuracy remains a clear and present concern. A recent meta-analysis reported a pooled sensitivity of 0.42 and 0.39, respectively, of CT and magnetic resonance imaging in predicting lymph node metastasis [121]. It is hoped that further innovation and experimentation, either using CT or other imaging modalities, will increasingly allow us to more accurately establish the topographical extent of all cancer foci within a prostate, leading to more precise clinical staging. Estimating the location and extent of all potentially significant lesions is vital in appropriately selecting patients for focal treatment. However, the amount of tumor on transrectal needle biopsy has not been shown to be a good predictor of tumor volume [122]. In addition, a substantial proportion of tumors are in close vicinity to the urethra and may be undertreated in an effort to spare the urethra during focal ablation. A study of 350 prostatectomy specimens revealed that 84% of cases had tumor reaching within 5 mm of the urethra and the urethra was involved in 17% [123]. A further consideration is the knowledge that carcinoma lesions arising in the TZ tend to be less aggressive than those arising in the PZ [54,124,125], suggesting that mapping accuracy is most crucial when assessing for lesions in the latter region. To limit the impact of these pitfalls in preoperative diagnosis and staging as well as the most appropriate selection of cases for focal therapy, highly accurate intraprostatic imaging models [120] will be crucial for undertaking this management approach to prostate cancer. Although the absence of well-designed studies for long-term functional or oncologic outcome is lacking and prevents such approaches from being considered equivalent to standard treatments, when used in well-selected cases, focal therapy may offer a cost-effective way of achieving satisfactory oncologic control with low morbidity, shorter hospital stay, and improved quality of life, at least in the short-term. On the other hand, the current imperfect nature of biopsy and tumor mapping techniques in use can result in failure to reliably ablate all pathologically significant lesions in a prostate. This in turn carries worrisome implications for long-term oncologic control and progression. Further highlevel evidence is needed to allow for a more confident recommendation of such treatments. By using as-of-yet not fully proven therapeutic approaches, there is a risk of missing a potentially significant tumor while at an early locally confined stage. In such cases, only further largevolume prospective studies will help us to decide whether subsequent serial monitoring through imaging and/or repeat biopsy can make up for this deficiency by improving early detection of further progression and institution of successful salvage treatment.

790

7. Conclusion Most prostates with adenocarcinoma contain multiple, spatially separate and clonally distinct foci of disease. Intrafocal genetic homogeneity and interfocal genetic heterogeneity demonstrate the clonal development and evolution of morphologically distinct tumors. Although evidence exists for intraglandular dissemination in some cases, most of these distinct foci seem to arise independently. The index primary tumor tends to possess more highgrade foci and will drive the prognosis in most cases but the presence of poorly differentiated elements in smaller secondary tumors and their potential for metastatic seeding has clearly been proven through molecular studies. Similarly, genetic studies have demonstrated the multifocal and precursor nature of PIN and its independent clonal origins. The extent of chromosomal aberration strongly correlates with aggressiveness and metastatic potential. Although the revised 2010 staging system holds greater promise compared with previous editions, the true significance of the pT2 subclassification is questionable and further revision of the current staging system may be needed. Accurate anatomical and histologic delineation of the full extent of disease is crucial in accurately predicting outcome but is not always reliably achieved by current biopsy techniques. Finally, although they offer a more cost-effective and less morbid approach to treatment, the above noted limitations in staging may in turn impact the therapeutic reliability of focal ablative treatments.

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