Atypical sclerosing adenosis of the prostate: a rare mimic of adenocarcinoma

Authors


L Cheng, MD, Director of Urologic Pathology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th Street, Clarian Pathology Laboratory Room 4010, Indianapolis, IN 46202, USA. e-mail: liang_cheng@yahoo.com

Abstract

Cheng L & Bostwick D G
(2010) Histopathology56, 627–631

Atypical sclerosing adenosis of the prostate: a rare mimic of adenocarcinoma

Aims:  Sclerosing adenosis of the prostate is a benign, small, acinar proliferation in dense spindle cell stroma, with a distinct immunohistochemical profiles. It is incidentally found in about 2% of transurethral resection specimens. The aim was to describe cases with significant cytological atypia mimicking cancer, which have not been previously reported.

Methods and results:  We describe five cases of sclerosing adenosis with significant cytological atypia, referred to as atypical sclerosing adenosis (ASA), which were initially considered suspicious or diagnostic of adenocarcinoma. Seven other cases of typical sclerosing adenosis were used as controls. All cases of typical and atypical sclerosing adenosis displayed an intact basal cell layer, which was immunoreactive for high-molecular-weight keratin, S100 protein, smooth muscle actin, and prostate-specific antigen, with no differences between ASA and the control group. Alpha-methylacyl-coenzyme A racemase was negative. Three of four cases of ASA had aneuploid DNA content by digital image analysis. All cases of typical sclerosing adenosis were diploid. During a mean follow-up of 33 months (range 5–73 months), none developed recurrence or prostatic cancer.

Conclusions:  ASA is an unusual small, acinar proliferation of the prostate that may be mistaken for adenocarcinoma, and should be distinguished from other mimics, including atypical adenomatous hyperplasia, mesonephric remnant hyperplasia, and post-atrophic hyperplasia. ASA is a benign lesion and aggressive treatment is unwarranted.

Abbreviations:
AMACR

α-methylacyl-CoA racemase

ASA

atypical sclerosing adenosis

PSA

prostate-specific antigen

SMA

smooth muscle actin

TUR

transurethral resection

Introduction

Sclerosing adenosis of the prostate is a benign small, acinar proliferation with a distinctive dense sclerotic stroma. It is usually an incidental finding in about 2% of transurethral resection (TUR) or radical prostatectomy specimens,1–3 and rarely is present in needle biopsy specimens. Sclerosing adenosis may simulate adenocarcinoma and accounts for up to 10% of cases overdiagnosed as adenocarcinoma.4,5 Multiple light microscopic and immunohistochemical features separate typical sclerosing adenosis from adenocarcinoma, including: (i) intact basal cell layer, a finding that can be confirmed immunohistochemically with antibodies directed against high-molecular-weight cytokeratin 34βE12; (ii) unique immunophenotype of the basal cells, including abundant S100 protein and smooth muscle actin (SMA) reactivity; (iii) cellular spindle cell stroma; (iv) variably thickened basement membrane; and (v) absence of significant cytological atypia.2,3,6–9 In this study, we compared five cases of atypical sclerosing adenosis (ASA), defined as sclerosing adenosis with cytological atypia, with seven other cases of typical sclerosing adenosis. To our knowledge, sclerosing adenosis with significant cytological changes has not been previously reported.

Materials and methods

Five cases of ASA were obtained from the consultation files of the authors. Seven other cases of typical sclerosing adenosis without atypia obtained from the surgical pathology files served as controls. ASA was defined by the presence of significant cytological atypia, which we define as at least two fold nuclear enlargement, nuclear hyperchromasia, pleomorphism, and the presence of one or more prominent nucleoli in the majority of acinar epithelial cells compared with those in uninvolved acini.

Immunohistochemical stains were performed for prostate-specific antigen (PSA; dilution 1:2000; Dako Corp., Carpinteria, CA, USA), basal cell-specific antikeratin antibody 34βE12 (dilution 1:10; Dako), S100 protein (dilution 1:2000; Dako), SMA (dilution 1:150; Dako) and α-methylacyl-CoA racemase (AMACR; dilution 1:100; Dako) on 5-μm sections from formalin-fixed paraffin-embedded tissue. Positive and negative controls were run in parallel and gave appropriate results. Nuclear DNA ploidy was evaluated by digital image analysis (CAS 200; Becton Dickinson, San Jose, CA, USA), as previously described.10–12

Results

The clinical and pathological findings are summarized in Table 1. Patients ranged in age from 63 to 76 years (mean 71 years). Four cases were diagnosed in TUR specimens; one case was detected in a needle biopsy specimen. The lesions ranged from 1.5 to 18 mm, with a mean of 5 mm. During a mean follow-up of 33 months (range 5–73 months), none developed recurrence or prostatic cancer.

Table 1.   Atypical sclerosing adenosis of the prostate
CasePatient age (years)Specimen typeNo. of fociDiameter (mm)DNA ploidyFollow-up (months)Clinical outcome
  1. TUR, transurethral resection; ANED, alive with no evidence of disease; DO, died of other cause; ND, not done.

  2. *This patient developed adenocarcinoma of prostate 28 months after initial diagnosis and underwent brachytherapy with seed implants. He was alive with no evidence of disease at last follow-up and had a prostate-specific antigen of 1.0 ng/ml.

171TUR218Aneuploid30ANED
276TUR11.5Diploid5ANED
371TUR15Aneuploid73DO
463Needle Bx13Aneuploid32ANED*
572TUR27ND24ANED

ASA consisted of well-circumscribed nodules of small to large acini proliferating in a typical cellular stroma (Figure 1). The acini showed considerable heterogeneity in size, shape, and spacing. A condensed rim of thickened hyalinized basement membrane was apparent around most acini. In some areas, the acini were closely packed with little intervening stroma. These acini were small with compressed or abortive lumina (Figure 1). There was a significant cytological atypia in all the cases of ASA (Figure 1). Most of the acini showed a partial or complete layer of basal cells by routine light microscopy, and this impression was confirmed by intense staining with basal cell-specific antikeratin 34βE12. In many acini, the basal cells at the periphery were compressed or flattened.

Figure 1.

 Atypical sclerosing adenosis of the prostate. A, Proliferation of small glands in a cellular sclerotic stroma. Many acini have a condensed rim of hyalinized connective tissue around their periphery. The acini vary considerably in size and shape. B–D, The acini are lined by atypical epithelial cells demonstrating enlarged, hyperchromatic nuclei with more prominent nucleoli. Many acini are compressed by stroma and have small lumina or appear as small solid clusters of cells. E, Basal-cell specific monoclonal antibody 34βE12 confirms the presence of a basal cell layer around most acini. F, Basal cells are strongly positive for S100 protein.

Both typical and atypical sclerosing adenosis showed similar immunoreactivity profiles. Immunoreactivity for S100 protein and SMA in these cells confirmed the presence of myoepithelial differentiation. The luminal aspect of the acinar epithelial cells was reactive with PSA. AMACR staining was negative.

DNA ploidy analysis was performed in four cases of ASA; three were aneuploid, one was diploid. In contrast, all cases of typical sclerosing adenosis had diploid DNA content.

Discussion

Sclerosing adenosis of the prostate is one of many small acinar proliferations that may be confused with adenocarcinoma. A variety of terms have been used by different authors to describe this entity, including adenomatoid tumour, pseudoadenomatoid tumour, sclerosing adenosis, and fibroepithelial nodule of the prostate.8,9,13–15 The terms adenomatoid and pseudoadenomatoid, initially used to convey the resemblance of this lesion to adenomatoid tumour of the testis, have been abandoned since the realization that the lesion is of prostatic origin based on immunoreactivity for PSA in the acinar cells. The term sclerosing adenosis was adopted in 1987 by Young and Clement and is now the accepted term to describe this entity.8 It has been well characterized immunohistochemically and ultrastructurally, and numerous case reports and small series on the subject have appeared in the English literature.2,3,6–9,13–16

Sclerosing adenosis typically lacks cytological atypia, and this is one of the criteria for distinguishing it from adenocarcinoma.1,3,4,8 A summary of salient features distinguishing typical and atypical sclerosing adenosis of the prostate from adenocarcinoma is given in Table 2. Mild atypia in acinar epithelial cells has been described by some authors,6–8,16 but moderate atypia has been described in only one case.7 This case exhibited enlarged vesicular nuclei, occasional prominent nucleoli, and a single mitotic figure, similar to our two cases with moderate cytological atypia. Nuclear pleomorphism, hyperchromasia, and the presence of multiple prominent nucleoli led to the consideration of adenocarcinoma by the referring pathologists. However, the presence of characteristic cellular myxoid stroma and the immunohistochemical profile led to the correct diagnosis. There was immunoreactivity for S100 protein and SMA in the basal cells indicating myoepithelial differentiation, a feature diagnostic of sclerosing adenosis. Occasionally, one may see S100 protein immunoreactivity in basal cell proliferations of the prostate such as basal cell hyperplasia, atypical basal cell hyperplasia, and adenoid cystic carcinoma.17 However, sclerosing adenosis is distinguished from these entities by the presence of immunoreactivity for SMA or ultrastructural evidence of cytoplasmic myofilaments in the basal cells. In contrast to prostatic adenocarcinoma, sclerosing adenosis is negative for AMACR.

Table 2.   Comparison of typical and atypical sclerosing adenosis with adenocarcinoma
 Typical sclerosing adenosisAtypical sclerosing adenosisAdenocarcinoma
  1. AMACR, α-methylacyl-coenzyme A racemase.

ArchitectureLobular small acinar proliferation; may form cell nests or clusters; prominent cellular stromaLobular small acinar proliferation; may occasionally have focally infiltrative marginsSmall acinar proliferation infiltrating the stroma; may be well circumscribed
AciniRound and smooth; appear to merge with stroma due to pale stainingRound and smooth; may have compressed or abortive luminaMay be rounded and smooth
Basement membraneProminent thickeningProminent thickeningInconspicuous
Basal cell layer
 Light microscopyUsually intactUsually intactAbsent
 34βE12 reactivityIntact or discontinuousIntact or discontinuousAbsent
Stromal changesProminent myxoid cellular stromaProminent myxoid cellular stromaWith or without stromal sclerosis
NucleiMay show mild enlargementProminent enlargementProminent enlargement
NucleoliUsually inconspicuousUsually prominentUsually prominent
Immunoreactivity
 S100 proteinPresent (basal cells)Present (basal cells)Absent
 ActinPresent (basal cells)Present (basal cells)Absent
 AMACRNegativeNegativePresent
DNA ploidyUsually diploidDiploid or aneuploidDiploid or aneuploid

Sclerosing adenosis is a benign lesion that requires no further treatment. However, the significant cytological atypia in our four cases of otherwise typical sclerosing adenosis raises issues regarding the pathogenesis and biological behaviour of this unusual lesion. Could sclerosing adenosis be one of the precursors of prostatic adenocarcinoma? This is unlikely given its rarity and lack of other evidence linking it clinically or pathologically with cancer. Could our cases of ASA actually represent a previously unrecognized pattern of adenocarcinoma (‘sclerosing adenosis-like pattern’) or, alternatively, ‘cancerization’ or pagetoid involvement of sclerosing adenosis from an adjacent focus of cancer? These possibilities are unlikely due to the absence of cancer elsewhere in the specimen and the benign clinical follow-up in three of our cases, although one patient (case 4) developed adenocarcinoma 28 months after the diagnosis of ASA on needle biopsies. Our observations indicate that the morphological spectrum of sclerosing adenosis includes varying degrees of cytological abnormalities, which, at the extreme, can be mistaken for cancer. Additional studies of ASA with long-term follow-up should resolve this issue. We should emphasize that the use of the terminology ‘atypical sclerosing adenosis’ does not imply that these lesions are premalignant. We speculate whether this type of abnormality is analogous to other longstanding lesions which may show cytological abnormalities such as ancient schwannomas. It is interesting that we found DNA aneuploidy in three of four cases of ASA, but all cases of typical sclerosing adenosis were DNA diploid. The significance of DNA ploidy status in these lesions is uncertain.

In summary, we have described ASA of the prostate, which differs from typical sclerosing adenosis by the presence of enlarged nuclei, prominent nucleoli, and aneuploid DNA content in the majority of cases. They share a common immunohistochemical profile that includes immunoreactivity for high-molecular-weight cytokeratin 34βE12, S100 protein, and actin in the basal cells that allows for their distinction from adenocarcinoma. Sclerosing adenosis should always be included in the differential diagnosis of small acinar proliferations in the prostate in order to prevent overdiagnosis of adenocarcinoma. This issue is particularly important in needle biopsy specimens with small suspicious foci or limited samples. We consider ASA as a benign lesion that does not require treatment.

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