Atypical Small Acinar Proliferation and High-grade Prostatic Intraepithelial Neoplasia in the Era of Multiparametric Magnetic Resonance Imaging: A Contemporary Review

Atypical Small Acinar Proliferation and High-grade Prostatic Intraepithelial Neoplasia in the Era of Multiparametric Magnetic Resonance Imaging: A Contemporary Review

Accepted Manuscript Title: Atypical Small Acinar Proliferation and High Grade Prostatic Intraepithelial Neoplasia in the Era of Multi-Parametric MRI: ...

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Accepted Manuscript Title: Atypical Small Acinar Proliferation and High Grade Prostatic Intraepithelial Neoplasia in the Era of Multi-Parametric MRI: a Contemporary Review Author: Todd G Manning, Ernest Cheung, Marlon Perera, Daniel Christidis, Jonathan S O'Brien, Catherine Mitchell, Damien M Bolton, Nathan Lawrentschuk PII: DOI: Reference:

S0090-4295(17)30388-6 10.1016/j.urology.2017.04.021 URL 20406

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Received date: Accepted date:

23-2-2017 14-4-2017

Please cite this article as: Todd G Manning, Ernest Cheung, Marlon Perera, Daniel Christidis, Jonathan S O'Brien, Catherine Mitchell, Damien M Bolton, Nathan Lawrentschuk, Atypical Small Acinar Proliferation and High Grade Prostatic Intraepithelial Neoplasia in the Era of MultiParametric MRI: a Contemporary Review, Urology (2017), 10.1016/j.urology.2017.04.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Atypical small acinar proliferation and high grade prostatic intraepithelial neoplasia in the era of Multi-Parametric MRI: A Contemporary Review Todd G Manning1,2, Ernest Cheung1,2, Marlon Perera1,2, Daniel Christidis1,2, Jonathan S O’Brien1,2, Catherine Mitchell3, Damien M Bolton1, Nathan Lawrentschuk1,4,5 1. University of Melbourne, Department of Surgery, Austin Health, Melbourne, Australia 2. The Young Urology Researchers Organisation (YURO), Melbourne, Australia 3. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia 4. Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia 5. Olivia Newton-John Cancer Research Institute, Melbourne, Australia Corresponding Author: Dr. Todd G Manning Austin Health, Department of Urology 145 Studley Rd Heidelberg, Victoria, Australia, 3084 Email: [email protected] TEL: +61 419 596 262 FAX: (03) 9496 2541 Conflicts of Interest: None The Authors Todd G Manning, Ernest Cheung, Marlon Perera, Daniel Christidis, Jonathan S O’Brien, Catherine Mitchell, Damien M Bolton and Nathan Lawrentschuk declare no conflicts of interest for this manuscript Word Count: 3255 Key Words: Atypical small acinar proliferation, ASAP, High-grade prostatic intraepithelial neoplasia, HGPIN, premalignant lesions, Multiparametric Magnetic Resonance Imaging


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Abstract Multiparametric Magnetic Resonance Imaging (mpMRI) has added to the armamentarium for the diagnosis and surveillance for organ confined prostate cancer. Atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) are premalignant prostatic lesions. The management of such lesions remains contentious, and the addition of mpMRI introduces further uncertainty given its ability to pick up indolent lesions and its use in targeted biopsy. We aimed to perform a comprehensive review of current evidence regarding ASAP, HGPIN and mpMRI to ascertain a consensus for a current management algorithm.

Introduction Prostate cancer (PCa) is the among the most common malignancies diagnosed in men (1). PCa differs from many other cancers as the clinical course is highly variable: frequently indolent and not significantly affecting overall survival. Frequently, premalignant lesions are diagnosed upon prostatic biopsy, including: atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN). The management of ASAP and HGPIN has remained contentious over the past decade, given the inherent risks of progression in premalignant disease. Contemporary surveillance protocols are lacking for these lesions as are recommendations regarding the overall requirement and time course for re-biopsy. Additionally, recommendations for re-biopsy in prostate cancer have recently undergone scrutiny with the adaptation of new technologies and techniques


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including transperineal biopsy (TPB) and Multiparametric magnetic resonance imaging (mpMRI). MpMRI has added to the armamentarium of the clinicians managing prostatic diseases. It provides the ability to identify prostatic lesions that may represent indolent or clinically significant disease. Additionally, the utility of serial mpMRI provides the ability to accurately monitor local disease progression. The technology has also been adopted for use in accurate targeting of suspicious lesions, once identified. Given the wide utility mpMRI offers in both diagnosis and surveillance, previous recommendations pertaining to the management of ASAP and HGPIN are potentially dated. We aimed to summarize the contemporary literature regarding ASAP and HGPIN in light of such technological advances with an aim to ascertain whether current guidelines should be reconsidered.

Methods and Results A comprehensive review was performed in-line with the PRISMA recommendations(2). MEDLINE, Web of Science and Google Scholar databases were searched using the keywords (“Acinar small atypical proliferation” OR “ASAP”) or (“High Grade Prostatic intraepithelial neoplasia” or “HGPIN”) and (“multiparametric magnetic resonance imaging” or “mpMRI” or “MRI”). Articles pertaining to the management of ASAP and HGPIN were included for assessment. Literature search was performed by two investigators (TM, EC) and discrepancies were resolved. Fulltext results in English were included for analysis in this review.



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HGPIN is defined as a pre-invasive, neoplastic proliferation of secretory cells within pre-existing ducts and acini, and is commonly seen in association with prostate cancer (Figure 1) (3). When analysed, the histology of patients with diagnosed prostate cancer regularly involves a higher total volume of HGPIN on biopsy than those with isolated HGPIN and no prostate cancer. This suggests a correlation of progression and subsequently indicates HGPIN as a possible prostate cancer precursor(4). The incidence of HGPIN on prostatic biopsy varies from 0.6 to 24% (5), with some attributing this to variation in population trends (older men had higher incidence than those who were younger or had early detection tests) (6). While HGPIN is said to be linked to prostate cancer, its malignant potential has been heavily debated. Studies published between 2000 and 2005 have identified that the risk of prostate cancer after re-biopsy within a year of initial biopsy of HGPIN was only 18.1% and not dissimilar to the risk after a negative initial biopsy (23%) (5). Others have attributed this to the extended nature (saturation) of initial biopsies that are now performed (7) which commonly include more than ten cores (8). As a result, many have suggested that re-biopsy should only be performed after one year in a patients diagnosed with HGPIN when additional clinical signs of prostate cancer are exhibited (9) (10). This recommendation has been further supported by Gallo et al, who reported that the risk of prostate cancer after HGPIN diagnosis was 21.5% and was lower than the malignant risk of normal prostatic tissue of 23%(11). Accordingly, contemporary recommendations for re-biopsy of HGPIN have reflected the current recommendations for those with normal prostatic tissue on initial biopsy(12). Conversely, in contrast to these recommendations, others have argued that although HGPIN may not be predictive of prostate cancer, its presence still indicates


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potential for malignant transformation and therefore repeat biopsy is indeed warranted (13) (14). Weighting this evidence, contemporary recommendations advise against early re-biopsy following diagnosis of HGPIN (7). However, the representative groups purporting these recommendations do acknowledge that the evidence base regarding the strict definition of what this early period is, and when it ends, is limited. Consequently, re-biopsy after one year remains a controversial topic. This is highlighted well by Roscigno M et al. who found that if re-biopsy was performed within six months of initial diagnosis of HGPIN, there was as expected a prostate cancer detection rate of 25%(15). However, if re-biopsy was delayed and performed within 11.4 months, there was a significantly higher detection rate of 44.6%. Although this data supports the recommendation of re-biopsy at exactly one year, it is worth noting that decision making regarding the timing of re-biopsy should account for all factors and be tailored to the patient (7) (9). Updated National Comprehensive Cancer Network (NCCN) guidelines state that the diagnosis of HGPIN should be split and considered as two separate subcategories. The group argues that patients with multifocal HGPIN undergo repeat biopsy in 6 months with focused sampling of identified areas and adjacent sites. Conversely they suggest that men with focal HGPIN should undergo follow-up as if diagnosed with a benign lesion (repeat PSA and DRE in 6 to 24 month periods and repeat biopsy if clinically indicated)(16).

Acinar small atypical proliferation Similar to HGPIN, ASAP reflects histological findings on biopsy that may be associated with subsequent diagnosis of adenocarcinoma of the prostate. It is defined histologically on biopsy by a collection of small acini that are suspicious but


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not diagnostic of prostatic adenocarcinoma (Figure 2) (17). Overall, ASAP is detected in approximately 5% - 10% of prostate biopsies and often presents diagnostic dilemma given the lack of evidence surrounding its proposed management pathway (5). Importantly, Borboroglu et al. found that adenocarcinoma of the prostate was detected in 47 of the 100 patients who underwent repeat biopsy(18). This group subsequently concluded that patients with isolated HGPIN and/or ASAP on prostate biopsy should proceed for follow up biopsy. Others have reported similar results and suggest ASAP as a strong predictor for prostate cancer progression. Progression rates varied but still remained relatively high (34-60%) after an initial ASAP positive biopsy(13, 19, 20)with a median gleason score of 7 in those that did progress (19).

The definition of ‘premalignant’ ‘Premalignant’ conditions lie on a spectrum between the classification of benign and malignant. Those that first described this concept over a century ago recognized that histologically these lesions comprise of morphologically abnormal cells which do not meet the strict requirements for the diagnosis of malignancy(21). These lesions often have a propensity with time to develop into malignant lesions and some may be appropriately ‘screened’ and dealt with before this change occurs(22). Although both HGPIN and ASAP have both been described by many as ‘premalignant’ lesions with malignant potential, others have argued that this may not entirely be accurate. Montironi et al. states that HGPIN is almost certainly a precursor to prostatic adenocarcinoma, pointing out that although similar cellular morphological changes to prostate cancer are present, that retention of a basal-cell layer precludes it from


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being defined as such(23). Similarly, Adamczyk et al. argues that HGPIN is the only recognized premalignant cancer of the prostate. They suggest that although ASAP lies within the same spectrum it is rather its lack of diagnostic features of PCa that is the underlying reason for the diagnosis of ASAP. They state that ASAP may instead be an “under-diagnosed cancer” rather than one which requires further cellular change for malignancy(24). Although argument over strict definitions is somewhat academic and often clinically irrelevant, this is not the case for these two lesions. As stated previously, ASAP’s progression to prostate cancer is relatively high, but its propensity for development of clinically significant cancer on re-biopsy (19, 25-27) is most concerning. This has prompted some to argue that it should be treated radically (radical prostatectomy) as a cancer rather than a premalignant lesion that can be safely observed(25). The definition is also important in delineating whether MRI is a suitable and safe surveillance tool especially given its contentious use in current prostate cancer regimens. Ultimately, contemporary evidence regarding both HGPIN and ASAP and their likelihood to develop malignancy is limited, and institutions report varied results. The formal distinction between premalignant and malignant lesions in the prostate as such remains somewhat unclear.

ASAP and repeat biopsy Taking the notion that ASAP is a strong predictor of prostate cancer on subsequent biopsy, some groups who do not advocate for radical treatment have suggested that the presence of ASAP necessitates repeat biopsy within three to six months (7) (28), although justification for this time interval remains relatively unclear. Some have suggested that given the high rate of progression that there is no


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permissible reason to delay biopsy longer than three months(29) with others advocating for a more patient centred approach, allowing for a delay in biopsy with councilling(19). Despite general disagreement and debate over the timing of rebiopsy most of these groups agree that repeat biopsy is indeed indicated. Leone et al. found that in a group of 264 patients that were re-biopsied, 34% were subsequently diagnosed with prostate cancer. Importantly, 22% of those who had a positive biopsy revealed clinically significant Gleason 7 or greater disease and of the 36 patients that proceeded to radicial prostatectomy 11 had Gleason 8 or greater disease. Despite these findings and given the relatively low overall risk of high grade disease (8% of the total cohort of rebiopsy) they recommended that the current recommendations of rebiopsy after 3-6 months (30) (31), were perhaps overzealous most of the time and that a less condensed rebiopsy regime may not result negatively for patients. They further support this claim by affirming the risks involved with biopsy (bleeding, infection, pain and urinary difficulty) (32) culminated with an increasing incidence of antimicrobial resistance (33). Leone et al. futher argued that earlier studies from which current guidelines were drawn (34) (5) did not take into account Gleason score and overall risk of aggressive disease may have been overcalled. They summise that “immediate repeat biopsy may be omitted in the majority of men with ASAP”. It is worth noting that evidence regarding the incidence of high grade cancer on re-biopsy has been variable with Warlick et. al. (27) suggesting that Gleason score ≥7 prostate cancer was present in 17.3% of men with ASAP on re-biopsy. Further, Raskolnikov et al identified prostate cancer of Gleason score ≥7 in only 5% of ASAP patients diagnosed with MRI/transrectal ultrasound fusion guided


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biopsy(35). In contrast, Dorin et al. found that 51% of patients had high grade disease on re-biopsy(26). NCCN guidelines support extended template re-biopsy within 6 months, with additional cores taken from the area previously identified with atypia. They do however acknowledge the paucity of evidence surrounding adjunctive tests. This currently includes adjunct imaging such as mpMRI. In addition to serum based tests such as the 4K Score; a series of kallikrein assays combined with clinical findings to algorithmically create a percentage risk of prostate cancer. As well as tissue based tests including ConfirmMDx; an assay based analysis of DNA, which identifies oncogenic changes in methylisation(16).

Concurrent ASAP and HGPIN Perhaps the best representation of the natural history of both HGPIN and ASAP concurrently is offered by Borboroglu et al. who found that of 1,391 men who underwent standard systematic sextant biopsy of the prostate, 137 had either HGPIN and/or ASAP(18). Subsequently, 100 men in this group underwent repeat prostate biopsy within 12 months of their initial biopsy and adenocarcinoma was detected in 47 of these patients. Adamczyk et al. despite a smaller sample size suggests that patients with both histological entities should be subject to an urgent repeat second biopsy. In their group of 98 patients subjected to second biopsy five had concurrent ASAP and HGPIN. Two of those re-biopsied (40%) were subsequently diagnosed with prostate cancer, although results regarding grade of these patients was not discussed. They


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conclude that urgent re-biopsy should be performed after 4-6 weeks, although reasoning for this exact time period is not clarified by the authors(24).

The role of multiparametric magnetic resonance imaging (mpMRI) The introduction of mpMRI has provided further contention regarding biopsy of premalignant prostatic lesions(10). Many have proported the use of mpMRI as an emerging adjunct or alternative in the diagnosis of prostate cancer (36). Additionally, the diagnostic pathway in prostatic malignancies has evolved, with several regions preferencing transperineal biopsy over transrectal biopsy of the prostate due to improved detection rates and fewer infective complications(37, 38). Moreover, the use of mpMRI has provided the possibility of targeted biopsy strategies by means of MRI fusion (39). In light of these newer technologies, the contemporary guidelines for the diagnosis of prostate cancer have changed drastically over the past decade, with many groups encouraging the use of mpMRI(12). Given the improving detection ability of mpMRI for prostate cancer, in addition to an increased overall awareness of the morbidity of biopsy, non-invasive investigations and surveillance of prostate cancer have become vastly more popular (40). Oberlin et al. identified that 261 men who had prior biopsy avoided futher biopsy by undergoing mpMRI, and also noted its role in follow up cognitive or image fusion techniques once a suspicious lesion was identified(41). They did however concede that some remaining uncertainty exists in its use as a primary surveillance tool given 47 % (237 patients) in their cohort went on to undergo needle biopsy post MRI. Tsivian et al. reported that mpMRI was highly sensitive and specific in excluding clinically significant and high grade prostate cancer with a negative predictive value of 90%(42). These findings were corroborated by Abd-Alazeez et al.


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who analysed the sensitivity of identification of prostate cancer in patients who had previous negative TRUS biopsy and found that there was a high negative predictive value for prostate cancer in mpMRI(43). Tsivian et al. also found that there was a 9697% specificity to prostate cancer lesions that were found to be highly suspicious in mpMRI with a positive predictive value of 60-79% in these lesions(42). Despite some self-stated shortcomings in their study (interobserver agreement, lack of blinding by surgeons mpMRI results etc), the group suggested that mpMRI is a highly effective tool for detection and characterisation of potential prostate lesions especially given its minmally invasive properties and possibilty for targeted biopsy. Similarly Girometti et al. found that due to the high negative predictive value of mpMRI, its use would be able to prevent unecessary biopsy in approximately 1/3 of the people who present with the dilemna of negative examination but where uncertainty remains for various reasons(44). The most up to date evaluation of the utility of mpMRI is ‘PROMIS’, a well designed multicentre paired cohort study evaluating mpMRI as a ‘triage tool’ to attempt to reduce unneccessary TRUS biospy of the prostate. The group’s analysis suggested a sensitivity of mpMRI for clinically significant cancer of 93% and a negative predictive value of 89% which was superior to TRUS biopsy. However, TRUS biopsy showed improved specificity and positive predictive value(45). The results also fell within quoted ranges in all categories of diagnostic accuracy from a well performed systematic review. This review also proported the usefulness of mpMRI in preventing unnessisary biopsies given the especially strong negative predictive value of the technology(46). However, despite the promising results of PROMIS, limitations regarding selection bias, differences in diagnostic power in transperineal biopsy and a lack of cost-effective analysis, have limited conclusive


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changes to current management pathways. This may change in the not too distant future, especially given the promising results were achieved with a 1.5 rather than 3 Tesla magnetic field strength.

MpMRI in identification and management of ASAP and HGPIN The use of mpMRI in the management and surveillance of diagnosed ASAP and HGPIN lesions remains unclear. At the time of writing this review no study to our knowledge has formally adressed detection rates in either condition on mpMRI. More comparative studies with subsequent histopathological data and patient follow up are required. Perhaps the most comprehensive analysis to date was performed by Raskolnikov et al. who suggested that isolated ASAP on MRI fusion biopsy was an uncommon event (2% within their series)(35). Additionaly, one year follow up yielded low detection of clinically significant prostate cancer and they summise that delay of subsequent rebiopsy may be justified. Despite this, the group does aknowledge that further validation is required, as mpMRI and fusion biopsy becomes increasingly popular. The key for mpMRI utility in premalignant lesions may lie in interval change on serial mpMRI. Regarding low grade prostate cancer lesions, Walton et al. points out that stable appearance on mpMRI correlates with stable Gleason score with men on active surveillance protocol (AS)(47). Moreover Perera et al. argues that although the detection of Prostate Imaging and Reporting System (PIRADS) 4 and 5 lesions on AS warrants concern, that the ability for mpMRI to accurately predict prostate cancer upstaging supports its use in AS. Additionally, the notion that a normal mpMRI has a low risk in representing progression to intermediate or high risk prostate cancer support the technology’s role for use in AS (48). It would not be


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unreasonable then, to theoretically extrapolate this to include premalignant lesions, given the underlying pathologic processes involved in their malignant tranformations, although this has yet to be definitively shown in prospective series. Perhaps there is a more pronounced role for surveillance with mpMRI in premalignant lesions for anteriorly located changes in the so called “prostatic evasive anterior tumour syndrome” (PEATS)(49). It has been recognised that anterior prostatic lesions show improved rates of detection with targeted mpMRI when compared to TRUS (50) and once again it would not be unreasonable to extrapolate this to include premalignant changes also. Yet, despite these positive directions, initial diagnosis and active surveillance of prostate cancer and subsequently premalignant lesions with mpMRI still remains contentious. Many have shown that patients who receive a negative result on initial mpMRI can still go on to develop clinically significant prostate cancer and argue that patients and clinicians may be lulled into a false sense of security by the initial negative result. (51). Perera et al. strongly argues that if used in initial biopsy setting, targeted biopsy should still be performed in conjunction with formal tempate biopsy given a lack in current evidence(12). Additionally in the setting of negative biopsy, mpMRI should be considered (if not previously completed) given the value of targeted biopsy if the resulting mpMRI is positive. It is not unreasonable to suggest then that given ASAP and HGPIN are premalignant lesions with aggressive potential that this noninvasive approach may be the best contemporaty algorithm to adopt. Although, given the relative propensity of ASAP and HGPIN to progress to prostate cancer on re-biopsy and given the reduced sensitivity of mpMRI in lower grade prostate cancer, councilling patients on their management plans is still paramount.


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Conclusion Contemporary evidence regarding the aetiology, natural history, suiveillance and management of ASAP and HGPIN is limited. The addition of powerful imaging adjunts including mpMRI introduce further uncertainty. Despite this, the addition of this new technology has shown some promise for patients and potentially has a future role as a non-invasive tool both diagnosing and monitoring progression of premalignant disease. However, due to the paucity of literature regarding mpMRI and these premalignant changes, formal recommendations may not be conclusively drawn. In light of this, and given the propensity for progression of ASAP and HGPIN, presently we recommend adopting the safest approach possible. This includes embracing the same recommendations regarding mpMRI in the current diagnosis and surveillance of low-grade prostate cancer as highlighted by Perera et al (12). References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. (1542-4863 (Electronic)). 2. Liberati A, Altman Dg Fau - Tetzlaff J, Tetzlaff J Fau - Mulrow C, Mulrow C Fau - Gotzsche PC, Gotzsche Pc Fau - Ioannidis JPA, Ioannidis Jp Fau - Clarke M, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. (17561833 (Electronic)). 3. Bostwick DG, Montironi R. Prostatic intraepithelial neoplasia and the origins of prostatic carcinoma. Pathol Res Pract. 1995;191(9):828-32. 4. Haggman MJ, Macoska JA, Wojno KJ, Oesterling JE. The relationship between prostatic intraepithelial neoplasia and prostate cancer: critical issues. J Urol. 1997;158(1):12-22. 5. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol. 2006;175(3 Pt 1):820-34. 6. Joniau S, Goeman L, Pennings J, Van Poppel H. Prostatic intraepithelial neoplasia (PIN): importance and clinical management. Eur Urol. 2005;48(3):379-85. 7. Oderda M, Gontero P. HIGH-GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA AND ATYPICAL SMALL ACINAR PROLIFERATION: IS REPEAT BIOPSY STILL NECESSARY? BJU International. 2009;104(11):1554-6. 8. Amin MM, Jeyaganth S, Fahmy N, Begin L, Aronson S, Jacobson S, et al. Subsequent prostate cancer detection in patients with prostatic intraepithelial neoplasia or atypical small acinar proliferation. Can Urol Assoc J. 2007;1(3):245-9.


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Figure 1: HGPIN (red arrow) displayed on Hematoxylin and Eosin staining at 100 x magnification Figure 2: ASAP (red arrow) displayed on Hematoxylin and Eosin staining at 100 x magnification


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