Accepted Manuscript

Diagnostic difficulties with atrophy, atypical adenomatous hyperplasia (AAH) and

atypical small acinar proliferation (ASAP). A Systematic Review of Current Literature

Adam Kowalewski, Łukasz Szylberg, Anna Skórczewska, Andrzej Marszałek

PII: S1558-7673(16)30031-3
DOI: 10.1016/j.clgc.2016.02.003
Reference: CLGC 555

To appear in: Clinical Genitourinary Cancer

Received Date: 16 December 2015

Revised Date: 29 January 2016
Accepted Date: 14 February 2016

Please cite this article as: Kowalewski A, Szylberg Ł, Skórczewska A, Marszałek A, Diagnostic
difficulties with atrophy, atypical adenomatous hyperplasia (AAH) and atypical small acinar proliferation
(ASAP). A Systematic Review of Current Literature, Clinical Genitourinary Cancer (2016), doi: 10.1016/
j.clgc.2016.02.003.

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 ACCEPTED MANUSCRIPT
Diagnostic difficulties with atrophy, atypical adenomatous hyperplasia (AAH) and

atypical small acinar proliferation (ASAP). A Systematic Review of Current Literature

Authors:

Adam Kowalewski1*, Łukasz Szylberg1*, Anna Skórczewska1 and Andrzej

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Marszałek1,2

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Corresponding Author:

Adam Kowalewski

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Department of Clinical Pathomorphology CM UMK,
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ul. Sklodowskiej-Curie Str. 9

85-094 Bydgoszcz, POLAND

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Phone: +48 52 5854200

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Fax: +48 52 5854049

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e-mail: kowalewskiresearch@gmail.com

Affiliations:
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1. Chair and Department of Clinical Pathomorphology Collegium Medicum in

Bydgoszcz, Nicolaus Copernicus University in Torun

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2. Chair and Department of Oncologic Pathology and Prophylactics, Poznan

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University of Medical Sciences and Department of Oncologic Pathology, Greater

Poland Cancer Center

Acknowledgements: *equal contribution of both authors

Conflict of Interest: The authors declare that they have no conflict of interest.
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Key words:

AAH; ASAP; Prostate; Cancer; Mimickers

Running title: AAH, ASAP and Cancer

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Abstract

Prostate cancer is the second leading cause of cancer death in man, behind only

lung cancer. In some cases proper diagnosis of prostate neoplasia can be

challenging and the differential diagnosis needs to be made with atypical non-

malignant lesions such as atrophy, atypical adenomatous hyperplasia (AAH) and

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atypical small acinar proliferation (ASAP). Atrophy and AAH have a benign clinical

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outcome and if detected on needle biopsy or transurethral resection of the prostate,

clinical follow-up seems appropriate. On the other hand, ASAP cannot be determined

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to be benign or malignant lesion. In clinical practice diagnosis of ASAP is an

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indication for re-biopsy because the chance of finding prostate adenocarcinoma is
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even higher than if there was earlier diagnosed high-grade prostatic intraepithelial

neoplasia (HGPIN). Malignant lesions require more restrictive treatment and

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therefore differentiation between atrophy, AAH, ASAP and adenocarcinoma is

essential. A systematic review of current literature allow to present diagnostic

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algorithm for atrophy, AAH, ASAP and adenocarcinoma. We proposed an algorithm

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that covers the practical issues related to the interpretation and further procedure.
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Introduction

Prostate cancer is the second leading cause of cancer death in man, behind only

lung cancer.1 Over 95% of all diagnosed malignant prostatic cases are represented

by acinar adenocarcinoma.2,3 In some cases, proper diagnosis of prostate neoplasia

can be challenging and the differential diagnosis needs to be made with atypical non-

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malignant lesions.4 Atrophy (especially partial) is definitely the most frequent

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mimicker of the prostate cancer. Two other examples of non-malignant lesions

include atypical adenomatous hyperplasia (AAH) and atypical small acinar

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proliferation (ASAP). Some key features of those three lesions are summarized in

Table 1. Both atrophy and AAH have a benign outcome. AAH occurs especially in the

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transition zone of the prostate. Recently, pathologists face it more frequently because
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the sampling of the transition zone has become more prevalent in biopsies in last
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years. If detected on needle biopsy or transurethral resection of the prostate tissue,

clinical follow-up seems appropriate.5 Atypical small acinar proliferation is found

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mostly in the peripheral zone of the prostate and cannot be determined to

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be benign or malignant lesion. ASAP is an indication for re-biopsy because the

chance of finding prostate adenocarcinoma in the further material is even higher than
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if in previous attempt there was diagnosed high-grade prostatic intraepithelial

neoplasia (HGPIN). Isolated ASAP is an important clinical dilemma as it frequently

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occurrs in needle biopsies in men with long life expectancy.6 Malignant lesions
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require more aggressive treatment and therefore differentiation between the atrophy,

AAH, ASAP and adenocarcinoma (especially low grade) is crucial for further clinical

steps. Possible survival time benefit must be balanced according to the potential

harms of overdiagnosis and with complications of treatment, including urinary,

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sexual, and bowel dysfunctions.7 In such cases additional techniques used for

diagnosis such as immunohistochemistry may be very useful.8,9

Atrophy

Prostatic atrophy is a common age-related process that may represent a pitfall

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in the diagnosis of adenocarcinoma.10 It is found in 83.7% of prostate needle biopsies

mostly in the peripheral zone.11 Atrophy is divided morphologically into diffuse and

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focal form. Among the latter, the most essential are areas of partial and simple

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atrophy which often coexist. In the diffuse form all acini of the gland are atrophic.

Such pattern could be usually observed as a consequence of radiotherapy and/or

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hormonal therapy.
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Simple atrophy is composed of darkly basophilic glands with crowded

hyperchromatic and bland-appearing nuclei. It often involves an entire lobule,

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although only isolated acini may be affected. The acini are small and lined by the
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smaller epithelial cells.12 Additionally, in contrast to partial atrophy, in simple atrophy

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cytoplasmic cell volume is significantly reduced with increased fibrous stroma and

periacinar collagen deposition.13,14

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Partial atrophy is the most common entity that causes difficulties in the
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differential diagnosis of adenocarcinoma on needle biopsies.10,15 It may be mistaken

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for cancer because of expression of α-methylacyl coenzyme A racemase (AMACR)

which is found in 69.1% of such cases. In addition, basal cells may be scattered and

in some acini completely absent. It is reflected by staining with 34βE12/p63 which is

negative in 31.4%. This is why recognition of the classic morphology of partial

atrophy on routine H&E-stained sections is critical to avoid misdiagnosis.15 Partial

atrophy consists of crowded and small glands often with disorganized growth pattern.

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Irregularly placed nuclei are elongated perpendicular to the gland circumference.

Nucleoli are prominent in up to 25% of cases.13,16 An intriguing finding in partial

atrophy foci is the complete absence of chronic unspecific inflammation which is seen

in simple atrophy in 56.2% of cases.

Features that favour atrophy in differentiation with adenocarcinoma include

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lack of infiltrative pattern of atrophic glands between larger benign glands, lack of

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coexisting typical adenocarcinoma, and lack of significant cytologic atypia.13

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Atrophy does not elevate PSA levels and is not associated with increased risk

of cancer.12

Atypical adenomatous hyperplasia

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AAH of the prostate is a pathologic lesion that can mimic prostate cancer. It is a
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benign condition that initially was assumed to be a precursor of adenocarcinoma.

AAH is a proliferation of architecturally abnormal prostatic glands with no significant

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cytologic atypia.5 AAH foci are observed predominantly in the transition zone. The
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mean age at diagnosis ranges from 64 to 70 years.17 Overall, AAH is rare finding,

reaching only 2% of TURPs, and below 1% of core biopsies.18

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AAH is localized and circumscribed lesion consisting of crowded small acini

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that merge with larger glands.17 Glands vary in size and shape. Typically they are
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lined by cuboidal to short columnar cells. Although glands are densely packed, stay

well separated and show no evidence of fusion. Luminal borders are serrated and

irregular. The lumens of glands/acini are often empty, but may contain corpora

amylacea and crystalloids in up to 24% of biopsies.5,18,19 Nuclei are slightly enlarged,

round to oval with uniform fine chromatin with small or inconspicuous nucleoli.5 AAH

is frequently multifocal and in 84% of cases associated with nodular hyperplasia.18

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There is even a tendency to diagnose all small acinar proliferations with

accompanying nodular hyperplasia as AAH.20 Focally a few basal cells with dense

amphophilic cytoplasm can be found. AAH does not increase PSA level or form

palpable tumor on digital rectal examination.17

It may be difficult to distinguish AAH from low-grade prostatic adenocarcinoma

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because both are observed in transition zone and may show intraluminal crystalloids

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and mitotic figures. The crucial feature of all AAH cases is fragmented basal cell layer

which can be demonstrated by patchy immunostaining for high molecular weight

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cytokeratin (CK 34βE12) or p63 (Figure 1). In contrast to adenocarcinoma, AAH

show no significant atypia. Furthermore, fluorescent in situ hybridization (FISH)

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demonstrate chromosomal abnormalities in 9% of AAH cases versus 55% of
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adenocarcinoma cases.5 In addition, adenocarcinoma show high expression of
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alpha-methylacyl-CoA racemase (AMACR) which is weak or absent in 68% of AAH.

However, more than 50% of AAH cases demonstrate stronger AMACR expression
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when associated with prostatic adenocarcinoma.21

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Nowadays, there is no evidence of progression of AAH into prostatic

intraepithelial neoplasia (PIN). Follow-up suggests a benign outcome. In the case of

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diagnosed AAH, a clinical follow-up is advised but rapid re-biopsies are not

necessary.5 It is also important to distinguish AAH from ASAP because clinical

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procedure in the latter is different.22

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Atypical small acinar proliferation

ASAP is a proliferation of small acini with features strongly suggestive but not

diagnostic for the cancer6 (Figure 2). ASAP is a minute lesion often associated with

prostatic intraepithelial neoplasia or cancer.23 Isolated ASAP is found in 1-5% of

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prostate biopsies.22,23,24 ASAP is located predominantly in the peripheral zone of the

prostate. The etiology of ASAP reflects that of prostatic adenocarcinoma.25

Although atypia is characteristic for ASAP, it is not always significant. Acini

vary in size and shape (some contain luminal crystalloids). Inflammatory infiltrate

(chronic in 64% of cases and acute in 21% of cases) usually accompany the lesion.

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In adjacent area, atrophy is found in 59% and HGPIN in 42% of cases.

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Proteinaceous secretions in acinar lumen are observed in 33% and stromal fibrosis in

21% of ASAPs. ASAP is characterized by nuclear (88%) and nucleolar (55%)

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enlargement. Amphophilic cytoplasm is noted in 18% of cases. Moreover, ASAP

demonstrate no basal cells, which is also characteristic for adenocarcinoma.25

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ASAP represents pathologist’s inability to render an incontrovertible diagnosis

of adenocarcinoma for one of two reasons. First is qualitative difference – ASAP

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shows low degree of atypia. Second is quantitative difference (too few atypical
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glands). Average ASAP focus diameter is 0.4 mm, versus 0.8 mm for minimal cancer.

In ASAP average number of acini is 11, versus 17 for minimal cancer.25

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83% of patients with ASAP have increased serum PSA levels. Abnormalities
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on digital rectal examination are found in 49% of cases.26 Risk of subsequent

detection of cancer22 ranges from 17 to 60% of cases.6,23,27,28,29,30 Current guidelines

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recommend repeat biopsy within 3-6 months after initial diagnosis of isolated ASAP.
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If the biopsy result is negative, next biopsy should be done within a year.31,32 Prostate

cancer diagnosed after initial biopsy with ASAP is similar to cancer found on initial

biopsy.33 77% of patients with cancer diagnosed after initial biopsy with ASAP have

Gleason grade 3+3 and 23% have Gleason grade 3+4. It is worthly to mention that

according current clinical protocol, men with life expectancy < 10 years may not need

curative therapy and do not need rebiopsy.

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In general it is recommended to repeat biopsy at the site of ASAP because the

foci are often accompanied by the cancer. On the other hand, in 39% of cases,

cancer is found in a different site from the initial ASAP diagnosis suggesting that

rebiopsy should include multiple samples from different parts of the gland.34

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Final remarks

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Atrophy, AAH and ASAP can mimic prostate carcinoma and might cause substantial

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troubles with proper diagnosis. A systematic review of current literature allow to

present diagnostic algorithm for atrophy, AAH, ASAP and adenocarcinoma. Algorithm

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covers the practical issues related to the interpretation and further proceeding (Fig.
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3).
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Figures legends
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Figure 1.
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Immunohistochemical study of cytokeratin 34βE12 expression. Please note,

presence of discontinuous expression of the basal cells. Primary objective

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magnification 10x.
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Figure 2.
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Micrograph of area of atypical small acinar proliferation (ASAP). Hematoxylin and

eosin staining. Primary objective magnification 10x.

Figure 3.

Diagnostic algorithm for atrophy, atypical small acinar proliferation (ASAP), atypical

adenomatous hyperplasia (AAH) and adenocarcinoma.

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Table 1. Comparison between partial atrophy, AAH and ASAP

Features Partial atrophy AAH ASAP

6th -7th decade 6th -7th decade 6th -7th decade

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Age (years)
Type of lesion Benign Benign Unspecified

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Main localization Peripheral zone Transition zone Peripheral zone
Significant atypia none none Usually

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Accompanied by Atrophy 91% Nodular hyperplasia 84% Inflammatory infiltrations 85%,

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Atrophy 59%,

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HGPIN 42%
Proteinaceous none none present (33% cases)

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secretions
Stromal fibrosis none none present (21% cases)

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Immunohistochemistry:
34βE12/p63 in basal Positive / positive discontinuous (68.7%) Positive (discontinuous) Negative
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cells
Symptoms None None Increased PSA levels (83%)
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Abnormalities on DRE (49%)

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AAH, atypical adenomatous hyperplasia; ASAP, atypical small acinar proliferation; HGPIN, high grade prostatic intraepithelial neoplasia;
PSA, prostate specific antigen; DRE, digital rectal examination.
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