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Benign mimickers and potential precursors of prostatic adenocarcinoma
MINI-SYMPOSIUM: PATHOLOGY OF PROSTATE CANCER
Benign mimickers and potential precursors of prostatic adenocarcinoma
PCa but they may present problems, especially in thin core needle biopsies. A recent study confirmed that small glandular patterns, including benign crowded glands, atrophy including partial atrophy, radiation atypia, adenosis and basal cell hyperplasia, still frequently cause diagnostic difficulty among pathologists.3 Several lesions have been postulated to represent precursors to PCa based on clinical, epidemiological, pathological and molecular evidence.4 The best-studied precursor lesion is prostatic intraepithelial neoplasia.5 Other potential lesions include atypical adenomatous hyperplasia and proliferative inflammatory atrophy. From the standpoint of clinical practice, identification of these precursor lesions in biopsy samples may imply a risk of finding cancer subsequently and therefore may impact patient management. Pathologists should therefore be attuned to recognition of these precursor lesions. In this review, the differential diagnosis of PCa will be discussed with emphasis on benign mimickers as outlined in Table 1. The clinical significance and morphological features of putative precursor lesions of PCa will also be highlighted.
Ming Zhou John R Srigley
Abstract The diagnosis of prostatic adenocarcinoma (PCa) in needle biopsy, especially when present in small amounts, is often challenging. Before making a malignant diagnosis, it is imperative to consider and rule out various benign processes that can simulate cancer. A useful method of classifying benign mimickers is in relationship to the major architectural patterns depicted in the Gleason diagram. The four major patterns are small gland, large gland, fused gland and solid nests and single cells. Most mimickers have small gland architecture and include atrophy, post-atrophic hyperplasia and atypical adenomatous hyperplasia. Normal anatomical and vestigial structures such as seminal vesicle/ejaculatory duct tissue, Cowper’s gland, verumontanum mucosal glands, mesonephric glands and paraganglionic tissue may be confused with PCa. Additionally, metaplastic and hyperplastic processes may be mistaken for PCa. Furthermore, inflammatory processes including non-specific granulomatous prostatitis, xanthoma and malakoplakia may simulate highgrade PCa. In addition to mimickers there are a number of putative precursors of PCa. High-grade prostatic intraepithelial neoplasia has been expensively studied and is thought to be a precursor of at least a subset of PCa. The pathologist’s awareness of the vast array of benign mimickers coupled with prudent use of immunohistochemistry is a critical step in the systematic approach to the diagnosis of PCa. Recognition of PCa precursors in pathological specimens may significantly impact patient management.
A pattern-based approach to differential diagnosis The Gleason diagram, most recently modified in 2011,6 is not only important in grading PCa, but also provides a conceptual framework
Benign mimickers in relation to major growth patterns of prostatic adenocarcinoma Small gland pattern Seminal vesicle Cowper’s gland Atrophy Partial atrophy Post-atrophic hyperplasia Reactive atypia Mucinous metaplasia Nephrogenic metaplasia (adenoma) Basal cell hyperplasia Benign nodular hyperplasia Sclerosing adenosis Verumontanum mucosal gland hyperplasia Mesonephric gland hyperplasia Atypical adenomatous hyperplasia
Keywords adenocarcinoma; benign mimickers; prostate gland; prostatic intraepithelial neoplasia
Prostatic adenocarcinoma (PCa) has a constellation of architectural and cytological features that pathologists rely on to make confident malignant diagnosis.1,2 Most histological features in isolation are not specific and can be found in a wide range of benign prostatic lesions and normal histoanatomical structures. Only three histological features, namely intraglandular glomerulation, mucinous fibroplasia (collagenous micronodules) and perineural invasion, are purportedly specific for and therefore diagnostic of PCa.1,2 Most mimickers of PCa are readily recognized and easily separated from
Large gland pattern Clear cell cribriform hyperplasia Adenoid cystic-like basal cell hyperplasia Reactive atypia Fused gland pattern Paraganglioma Xanthoma Malakoplakia
Ming Zhou MD PhD is at the Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA. Conflicts of interest: none declared.
Solid and single-cell pattern Usual prostatitis with crush artifacts Non-specific granulomatous prostatitis Signet-ring-like change in lymphocytes and stromal cells
John R Srigley MD is at the Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. Conflicts of interest: none declared.
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Table 1
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for discussing differential diagnosis.7 In the Gleason diagram, there are four major architectural patterns for the purpose of discussion of differential diagnosis (Figure 1). The predominant pattern is the small glandular one and consists of small to medium discrete acini which correspond to Gleason patterns 1e3. Most benign mimickers enter the differential diagnosis of small acinar adenocarcinoma. Poorly formed small glands are now considered to be part of Gleason pattern 4. The second pattern is large gland pattern comprising large acini and/or papillary and cribriform structures. Several proliferative and metaplastic processes exhibit this growth pattern. The third pattern is fused gland pattern. A few normal anatomic structures and benign processes simulate this pattern. Both large and fusion gland patterns generally correspond to Gleason pattern 4. The final pattern of adenocarcinoma is the solid nests and single infiltrating cells that correspond to Gleason pattern 5. Certain inflammatory lesions may be mistaken for solid or single-cell adenocarcinoma. The benign mimickers and the corresponding patterns of adenocarcinoma that may be simulated are shown in Table 1. Most but not all of these patterns and processes will be discussed below. It is important to note that there is a range of normal glandular histology in the prostate. Some crowed small gland lesions (benign small glands, not further specified) as well as some intraglandular complexities in medium to large glands may be part of the normal histological spectrum and do not necessarily represent any pathological process.
targeted sampling. SV is morphologically similar to the ejaculatory duct (ED); however, the latter is surrounded by a band of loose fibrovascular connective tissue and lacks the well-formed muscular wall of the former. These two structures are not always distinguishable on prostate biopsies and if so are designated as “benign seminal vesicle/ejaculatory duct (SV/ED) tissue”. SV consists of a central lumen with branching glands that give rise to numerous small glands (Figure 2a). Scattered or random nuclear atypia is often present in the luminal cells but mitoses are not identified. Small nuclear pseudoinclusions are often seen. Cytoplasmic golden-brown lipofuscin pigment is a constant feature although the amount varies from case to case. SV epithelium stains positively for PAX-2,8 PAX-89 and MUC6 and negatively for prostatic-specific antigen (PSA) and prostatic acid phosphatase (PAP). 34bE12 stains the basal layer of SV glands. Well-formed glands containing random atypical nuclei and golden-brown pigment are the most reliable features to separate SV/ED from its mimickers, including benign prostatic tissue with radiation atypia, high-grade prostatic intraepithelial neoplasia, intraductal carcinoma of the prostate and urothelial carcinoma involving the prostate. Cowper’s gland Cowper’s glands, also known as the bulbourethral glands, are paired periurethral structures located near the prostatic apex. They are rarely sampled in resection specimens or biopsies from the apex. Cowper’s glands have central ducts surrounded by tightly packed mucinous acini (Figure 2b). Skeletal muscle fibres are sometimes present in the stroma. The mucinous cells stain for mucin (mucicarmine, PAS-D), variably for PSA and are negative for PAP. The ductal cells stain for 34bE12 and in some cases attenuated cells around the periphery of the acini are also positive. Cowper’s glands can be distinguished from foamy gland adenocarcinoma by its lobular configuration and ductal-acinar architecture, cytoplasmic mucin, and lack of cellular atypia.
Seminal vesicle (SV) SV tissue may be present in transurethral resectates or needle biopsies, usually incidentally, but sometimes as a result of
Gleason grading scheme of prostatic adenocarcinoma I 1
Verumontanum mucosal gland hyperplasia (VMGH) VMGH is a frequent finding in radical prostatectomy specimens but rarely seen in needle biopsy due to its suburethral location. It is composed of relatively uniform, closely packed round glands containing numerous orange-brown amorphous concretion and corpora amylacea (Figure 2c). Adjacent prostatic urethral epithelium may be present. Lipofuscin pigment may be present within the cytoplasm of glandular cells. These features differentiate VMGH from low-grade adenocarcinoma with small glandular architecture and crowded growth.
2
3
II
III
4
5
Reactive atypia in benign glands Inflammation and sometimes ischaemia (infarction) may cause significant architectural and cytological atypia in benign glands thus raise suspicion for adenocarcinoma. The glands in most cases of reactive atypia are small and atrophic (Figure 3a). Occasionally, large cribriform glands are found (see Figure 6a). There may be basal cell or urothelial cell hyperplasia. In some cases, especially in ischaemia, the epithelium undergoes squamous metaplasia. Mild to moderate nuclear enlargement is seen and sometimes nucleoli are prominent. Importantly adenocarcinoma may also be found in areas of inflammation and ischaemia. One should be very cautious
IV
Figure 1 The four major architectural patterns for the discussion of differential diagnosis of benign mimickers are: I e small gland (Gleason patterns 1e3); II e large gland glands with cribriform and papillary architecture (Gleason pattern 4); III e fused gland (Gleason pattern 4) and IV e solid nests, cords and single cells (Gleason pattern 5).
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making a cancer diagnosis when there is intense inflammation or ischaemic change in the background. Postradiation atypia Radiation therapy can cause profound morphological changes in benign prostate glands (Figure 3b). Glands are markedly atrophic but still maintain their lobular architecture. Individual glands can have a highly irregular contour and are lined with multiple layers of predominantly basal cells. The cytoplasm is usually dense and eosinophilic rather than being clear. Scattered markedly atypical nuclei are present. Basal cell hyperplasia, urothelial and squamous metaplasia, stromal fibrosis and oedema are also seen. Benign glands with radiation atypia may be mistaken for prostate adenocarcinoma with treatment effect, which demonstrates relatively small uniform pyknotic nuclei and abundant vacuolated cytoplasm. Basal cell markers may be helpful in identifying irradiated benign glands. Basal cell hyperplasia (BCH) BCH is typically seen as part of benign prostatic hyperplasia in the transition zone, but may also affect the peripheral zone and encountered in needle biopsies. BCH may also occur in association with atrophy, often in the setting of antiandrogen and radiation therapy. BCH manifests as nodular expansion of uniform round glands with stratified nuclei (Figure 3c, d). Cells have scant cytoplasm and oval or somewhat elongated nuclei with homogeneous vesicular chromatin and indistinct nucleoli. Several patterns may be appreciated in BCH. In complete BCH, basal cells form solid nests without luminal formation. In incomplete BCH, residual small lumina are lined by secretory cells with clear or eosinophilic cytoplasm that are surrounded by multiple layers of basal cells. Adenoid cystic-like BCH is an uncommon form composed of medium to large glands with a complex cribriform pattern, sometimes with cyst formation and squamous metaplasia (see Figure 6c). Microcalcifications are common. Rarely intracytoplasmic hyaline globules are found and are considered to be a specific feature of BCH. The stroma is cellular. The basal cells are positive for basal cell markers 34bE12 and p63, negative for AMACR, but may be weakly and focally positive for PSA and PSAP. BCH may be confused with PCa, but the presence of dense cellular stroma, multiple layers of oval and vesicular nuclei, microcalcifications and cytoplasmic hyaline globules are features that distinguish BCH from PCa. PCa with p63 positivity is a rare lesion that may be mistaken for BCH.10 The carcinomatous glands exhibit infiltrative growth and are uniformly positive for p63 but negative for 34bE12. BCH may superficially resemble high-grade PIN. However, basal cells proliferate into the surrounding stroma and nuclei are uniform and have smooth chromatin in BCH. Finally, florid BCH should be distinguished from basal cell carcinoma. Identification of infiltrative features including extraprostatic extension and perineural invasion is the key. Tumour necrosis, frank cytological atypia and mitoses support the diagnosis. Nephrogenic metaplasia/adenoma (NA) NA is usually encountered in the prostatic urethra and subjacent prostatic tissue, and is distinctively uncommon in needle biopsies. In most instances, there has been a previous history of trauma, instrumentation or transurethral resection.
Figure 2 Normal or developmental vestigial structures with small gland architecture mimicking cancer. (a): Seminal vesicle. (b): Cowper’s glands. (c): Verumontanum mucosal glands hyperplasia.
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Figure 3 Reactive and metaplastic lesions with small gland architecture mimicking cancer. (a): Inflamed benign glands with small gland architecture, nuclear enlargement and conspicuous nucleoli. (b): Benign glands with radiation atypia. (c, d): Basal cell hyperplasia comprises basophilic glands at low power (c). The glands are lined with small, uniform, dark basal cells (d). (e, f ): Nephrogenic metaplasia consists of small tubules and occasional cysts resembling ecstatic vessels (e) which are positive for PAX-2 (f ).
NA commonly exhibits an exophytic tubulocystic growth pattern. Small poorly formed glands, small tubules resembling renal tubules and dilated cysts resembling ectatic vessels are seen (Figure 3e). The tubules are frequently surrounded by thick basement membrane. The lining epithelial cells are flat, cuboidal and hobnail with uniform nuclei. Clear and signet-ring cells may be seen. Nuclear atypia, if, present, appears degenerative. Mitoses are rare or absent. Background inflammation is frequent. Most NA express PAX-2 (Figure 3f) and PAX-8 and AMACR.11 PSA and PAP are negative. Cytoplasmic 34bE12 staining is found in >50% of cases.
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A panel using PAX-2 or PAX-8, PSA, PAP, and 34bE12 is useful in separating NA from PCa. Atrophy Atrophy is a common process typically found in older patients, but also present in young adult prostates. While idiopathic in many cases, atrophy is commonly associated with chronic inflammation and may be a manifestation of local chronic ischaemia. Atrophy can also be the result of radiation and antiandrogen therapy.
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The hallmark of atrophy is reduced amount of cytoplasm in secretory cells which imparts a basophilic appearance at low magnification except in partial atrophy (see discussion below). There are four distinct morphological patterns of atrophy, simple atrophy, cystic atrophy, post-atrophic hyperplasia (PAH) and partial atrophy (PA).12 These patterns often coexist. In simple atrophy, the overall glandular architecture is preserved but the glands appear shrunken (Figure 4a). The stroma is frequently sclerotic and contains inflammation. Cystic changes are often present. The term cystic atrophy is applied when the atrophic glands are significantly dilated and rounded and cyst-like (Figure 4b). PA usually has a lobular, or sometimes more diffuse and disorganized architecture, at low magnification (Figure 4c). The glands vary in size and the large glands typically have highly irregular contour. The glands appear pale rather than basophilic due to abundant cytoplasm lateral to the nuclei even though the cell height
is drastically reduced with scant apical cytoplasm. Nuclei may be slightly enlarged with small or inconspicuous nuclei. Granular eosinophilic luminal secretions and occasionally mucin may be seen. Immunostains for basal cell markers are often patchy in most glands, and may be entirely negative in some glands (Figure 4d). The stain for AMACR is positive in many examples of PA although the staining intensity is generally less than that seen in PCa. PAH consists of lobular collection of small, round and basophilic acini frequently arranged around central dilated “feeder” ducts (Figure 4e). The stroma is sclerotic and contains inflammation. Secretory cells are low cuboidal with scant cytoplasm. Basal cells may proliferate and show mild to moderate nucleolar enlargement. Basal cell markers usually demonstrate continuous but sometime patchy positivity. PAH generally lacks AMACR expression. Simple and cystic atrophy does not pose diagnostic challenges. However, PA and PAH are the most common mimickers
Figure 4 Atrophy. (a): Simple atrophy. (b): Cystic atrophy. (c, d): Partial atrophy (c). Basal cell marker p63 is focal or even absent in some glands in partial atrophy (d). (e): Post-atrophic hyperplasia.
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Figure 5 Benign lesions with small gland architecture mimicking cancer. (a): Benign prostatic hyperplasia, small gland pattern. (b, c): Atypical adenomatous hyperplasia (b). Basal cell marker p63 is focally positive or even negative in some glands (c).
Figure 6 Large glands with papillary and cribriform architecture. (a): A large inflamed benign gland. (b): Clear cell cribriform hyperplasia. (c): Adenoid cystic-like basal cell hyperplasia.
of PCa in contemporary practice.3 The low power small glandular proliferation and frequently patchy and negative basal cell stains may lead to an overdiagnosis of cancer. However, most cancers have straight luminal borders. It should be emphasized that carcinoma may have an atrophic appearance and as such may be misdiagnosed as atrophy. Atrophic
adenocarcinomas are composed of small dark acini usually with an infiltrative growth pattern. Nuclear atypia and nucleoli are usually recognized at least focally. In contrast, there should not be significant nuclear enlargement and nucleoli in PA and PAH. One should always be cautious about making a cancer diagnosis when the glands in question are atrophic and have
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Paraganglion Paraganglionic tissue may be encountered within prostatic and periprostatic tissue, usually the latter, and is often associated with a nerve. Paraganglia are characterized by small, solid nests of cells with clear or amphophilic cytoplasm and a delicate
the same cytoplasmic quality as adjacent more obvious benign glands. Benign prostatic hyperplasia (BPH), small gland pattern BPH occasionally has areas composed of mainly small to medium-sized, closely packed acini with rounded lumens, and may be mistaken for low-grade, Gleason pattern 1 or 2 adenocarcinoma (Figure 5a). The nodular circumscription, uniform architecture, presence of basal cells and intervening cellular stroma serve to separate this proliferative lesion from cancer. Atypical adenomatous hyperplasia (AAH) AAH, also known as adenosis, affects mainly the transition zone and is found mainly in transurethral resections and radical prostatectomy specimens, and is uncommon in needle biopsies. AAH consists of well-circumscribed nodule of relatively uniform small round glands intermixed with large complex glands typical of hyperplasia (Figure 5b). Small and large glands have similar cytological features. Nuclei may be slightly enlarged and have small but not prominent nucleoli. Stroma is usually cellular. Crystalloids and blue mucin are occasionally present. Basal cell markers typically demonstrate fragmented or occasionally absent staining around some glands (Figure 5c). AMACR is either focally or diffusely positive in up to 70% of lesions (Figure 5c). AAH must be differentiated from low-grade PCa of the anterior and transition zones, in which glands are more uniform in size and shape and lack basal cells completely. Clear cell cribriform hyperplasia (CCCH) CCCH represents a spectrum of BPH and can occasionally dominate the histological picture. It consists of nodular proliferation of crowded cribriform glands with cellular stroma (Figure 6b). The cribriform glands have uniform, round lumina and lack complex/confluent architecture. The cells comprising the central cribriform areas are cuboidal to low columnar secretory-type cells with uniform round nuclei and clear cytoplasm and lack nuclear atypia. There are prominent basal cells around the periphery. CCCH may be mistaken for cribriform HGPIN, but lacks significant nuclear atypia seen in the latter. Cribriform adenocarcinoma may also enter the differential diagnosis, but has nuclear atypia and lacks basal cell lining. Sclerosing adenosis (SA) SA is an uncommon lesion largely restricted to the transition zone and is therefore an incidental finding in transurethral resectations or radical prostatectomy specimens, and rare in needle biopsies. It consists of circumscribed proliferation of variably sized and shaped glands, often microacini, and individual cells embedded in a cellular and often oedematous stroma (Figure 7a). Prominent nucleoli and blue mucin are commonly present. Thick hyaline basement membrane surrounds at least some glands. Basal cells undergo myoepithelial metaplasia and show coexpression of both basal cell (34bE12 and p63) (Figure 7b) and myoepithelial markers (muscle-specific actin and S100) (Figure 7c). SA may be mistaken for a high-grade PCa. The key features distinguishing the two include the variation in glandular size and shape, thickened basement membranes, cellular stroma and positive immunohistochemistry for basal cell markers and actin in SA.
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Figure 7 Sclerosing adenosis (a). Stains for basal cell marker p63 (b) and myoepithelial marker (c) are positive. Photo courtesy of Dr. Rajal Shah, Dallas, TX.
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inflammation is usually diffuse and has mixed inflammatory cells including neutrophils, eosinophils, lymphocytes and histiocytes (Figure 8c). The inflammation is centred around and may obscure ducts and acini. Therefore it may be mistaken for a highgrade carcinoma. The inflammatory nature of the lesion along with the association of giant cells and fibrosis are helpful diagnostic clue. In difficult cases, immunohistochemistry for cytokeratins, prostatic-specific markers and lymphohistiocytic markers may be used. Well-formed granulomas may be inconspicuous in non-specific granulomatous prostatitis and when present in significant numbers should raise the possibility of an infectious aetiology such as tuberculosis or fungal disease.
network of capillaries. Paraganglionic tissue can simulate the fused gland pattern of adenocarcinoma. Another potential issue is mistaking extraprostatic paraganglionic tissue in radical prostatectomy as extraprostatic extension of cancer. Xanthoma Collections of lipid-laden macrophages in the prostate may be mistaken for the hypernephroid pattern or foamy gland type of adenocarcinoma (Figure 8a). Xanthomatous histiocytes have small uniform nuclei within inconspicuous nucleoli and are commonly admixed with inflammatory cells. Some hypernephroid or foamy gland carcinomas predominantly have small dark nuclei without prominent nucleoli. But careful examination invariably identifies typical carcinoma component with prominent nucleoli. In rare cases, immunohistochemistry for epithelial and prostatic cells (cytokeratin, PSA, PAP) and histiocytes (CD68) is required to resolve the diagnostic ambiguity.
Degenerative changes in lymphocytes and stromal cells Lymphocytes and sometimes stromal cells may undergo degenerative changes which result in a signet-ring-like morphology and can resemble high-grade adenocarcinoma composed of individual signet-ring cells (Figure 8d) if the change is prominent.
Malakoplakia The early phase of malakoplakia when von Hansemann histiocytes predominate may simulate a high-grade carcinoma (Figure 8b). The lack of any acinar differentiation and admixed inflammatory infiltrate along with MichaeliseGutmann bodies will lead to a correct diagnosis.
Precursor lesions of prostate adenocarcinoma Several lesions have been postulated to represent the precursors to PCa based on clinical, epidemiological, pathological and molecular evidence.4 Atypical adenomatous hyperplasia (AAH or adenosis) is considered by some authorities as a precursor to some anterior/transition zone carcinoma, as it has a predilection for the transition zone and morphologically simulates carcinoma
Non-specific granulomatous prostatitis This condition clinically simulates carcinoma with firm to hard prostate gland and elevated PSA. In biopsy samples,
Figure 8 Inflammatory lesions mimicking high-grade cancer. (a): Xanthoma. (b): Malakoplakia with MichaeliseGutmann bodies (arrows). (c): Non-specific granulomatous prostatitis with diffuse mixed inflammatory infiltrates. (d): Degenerative changes in lymphocytes and stromal cells simulating signet-ring pattern of prostatic adenocarcinoma.
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arising in the anterior/transition zones. Additionally, patients with AAH are usually 5e10 years younger than those with carcinoma. However, a direct link between AAH and adenocarcinoma is lacking. Genetic alterations in AAH are infrequent and different from those seen in transition zone PCa.13 Examples of carcinoma arising in close relationship to AAH are rare. Most importantly, men with AAH are not at increased risk of developing adenocarcinoma during follow-up.14 Therefore, the relationship between AAH and carcinoma is at best circumstantial.
The major importance of AAH is its potential for being misdiagnosed as adenocarcinoma. Several forms of atrophy (simple atrophy and post-atrophic hyperplasia) are commonly associated with inflammation and when increased proliferative activity of epithelium is demonstrated by stains such as MIB-1, the term “proliferative inflammatory atrophy (PIA)” has been used. PIA has been proposed as another precursor lesion to PCa based on epidemiological and molecular studies.15,16 However, a morphological link between
Figure 9 Prostatic intraepithelial neoplasia (PIN). Low-grade PIN glands (arrows, a) have no prominent nucleoli at high magnification (b). HGPIN glands (arrows, c) exhibit prominent nucleoli at 20 magnification (d). The HGPIN glands are positive for basal cell marker, often discontinuous (p63, e). A subset of HGPIN glands (arrows) is positive for ERG (red nuclear staining) and is invariably intermixed with ERG-positive cancer glands (arrowheads) (f ).
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Figure 10 Architectural patterns of HGPIN. Four major architectural patterns include tufting (a), micropapillary (b), flat (c) and cribriform (d). Other uncommon patterns include vacuolated/signet-ring-like (e), inverted (f ) and foamy gland (g).
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Figure 11 Mimickers of HGPIN. (a): Ductal carcinoma. (b, c): PIN-like prostate carcinoma with closely packed large glands (b) that are negative for basal cell marker p63 (c). (deg): Intraductal carcinoma of the prostate. Large cribriform glands with markedly irregular glandular contour (d). Comedo necrosis (arrows, e) and marked nuclear pleomorphism (f ) are characteristic. Basal cells are always retained in these glands (g).
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almost always associated with high-grade and large volume cancer. The number of IDC-P glands is always more than that of HGPIN in radical prostatectomy and biopsy specimens.23 IDC-P glands are often larger and more irregular than HGPIN glands and are much more likely to have dense cribriform or solid architecture and comedo necrosis. In addition, the constituent cells in IDC-P are more likely to exhibit marked nuclear pleomorphism. Basal cells are always retained in these glands. LGPIN is not associated with increased cancer detection in subsequent follow-up biopsies and its diagnosis is not readily reproducible even among urologic pathologists; therefore, it should not be diagnosed and reported in prostate biopsy.5 In contrast, isolated HGPIN diagnosed in contemporary needle biopsy practice carries a 22e27% risk of finding PCa in subsequent biopsy5,24,25 as opposed to an 18e20% cancer risk associated with a benign or LGPIN diagnosis. In certain clinical situations, HGPIN renders even higher cancer risk. For example, the cancer risk associated with multifocal HGPIN and atypical small acinar proliferation (ASAP) was 71% compared to the cancer risk of 43% and 42%, respectively, associated with ASAP alone and ASAP and unifocal HGPIN.26 Therefore a finding of unifocal (one core) HGPIN does not confer any adverse risk for PCa detection and the decision regarding re-biopsy is determined by other clinical factors including history, DRE finding and PSA parameters. If the initial sampling was limited (six or fewer cores) or when HGPIN is multifocal (involving two or more cores) a re-biopsy within 1 year is generally recommended. HGPIN on its own does not result in an abnormal digital rectal examination or elevated serum PSA level and can only be diagnosed by histological examination of the prostate tissue. No treatment is required for HGPIN as an isolated finding in prostate needle biopsy.
PIA and PCa is lacking and the finding of PIA in prostate biopsy is not associated with an increased PCa detection in repeat biopsy.17 Therefore, PIA is not considered to be a direct PCa precursor. Prostatic intraepithelial neoplasia (PIN) is the best-studied precursor lesion supported by clinical, epidemiological, pathological and molecular evidence. PIN was first described by McNeal et al. as a precursor to some PCa under the name “intraductal dysplasia” in 1960s,18 and the concept was more precisely defined by McNeal and Bostwick in 1986.19 PIN comprises of architecturally benign prostatic acini and ducts lined with cytologically atypical cells. Originally categorized into grades 1e3, PIN is now dichotomized into low (grade 1) and high-grade (grades 2 and 3). PIN manifests at low magnification (Figure 9) as basophilic glands with architecture similar to adjacent benign glands. The basophilic appearance is due to cytoplasmic amphophilia, nuclear stratification, enlargement and hyperchromasia. The histological criteria to separate low-grade PIN (LGPIN) and highgrade PIN (HGPIN) is arbitrary but one consistent and reasonable approach is to diagnose HGPIN when nucleoli are visible at 20 magnification. The presence of mitosis and pleomorphic nuclei can also be used to diagnose HGPIN in glands with other histological features of HGPIN but inconspicuous nucleoli. HGPIN glands have basal cell lining which may be patchy or even absent in small glands. AMACR is positive in majority of HGPIN glands. TMPRSS2eERG gene fusion, a chromosomal alteration highly specific for PCa, is present in approximately 20% of HGPIN which is always intermixed with cancer that harbours TMPRSS2eERG gene fusion.20,21 There are four major architectural patterns of high HGPIN, including tufting, flat, micropapillary and cribriform (Figure 10). Cribriform HGPIN is distinctively rare and the majority is now considered to represent intraductal carcinoma of the prostate. Other histological variations similar to adenocarcinoma variants including mucinous, foamy gland, neuroendocrine, squamous and small cell HGPIN are rarely encountered. In general, these histological variants do not have significant clinical difference and their mentioning is for differential diagnostic consideration. HGPIN may be mistaken for a number of benign and cancerous lesions (Figure 11). Central zone glands, seminal vesicle/ejaculatory duct epithelium, reactive atypia due to inflammation, infarction, or radiation, transitional cell metaplasia, squamous cell metaplasia, clear cell cribriform hyperplasia and basal cell hyperplasia were discussed previously. Cribriform carcinoma is differentiated from cribriform HGPIN by its crowded growth, concomitant typical small cancer glands and absent basal cell lining. Compared to HGPIN with moderate amount of intervening stroma, PIN-like PCa often has closely packed glands. Basal cell staining is required to establish a cancer diagnosis on needle biopsy. Ductal adenocarcinomas may consist of very large and/or confluent glands and often contains true papillary fronds with well-formed fibrovascular cores. Solid and necrosis can be seen. In contrast, HGPIN glands are similar to the adjacent benign glands in size and shape and possess micropapillary fronds without fibrovascular cores. Ductal adenocarcinoma may retain basal cells so the immunostains for basal cell markers is of little value in their distinction. Intraductal carcinoma of the prostate (IDC-P) is considered by some to represent the intraductal spread by PCa.22 It is
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Summary A wide variety of benign lesions and normal anatomic structures may be confused with PCa. In general, awareness of these PCa mimickers coupled with careful microscopic examination and prudent use of ancillary immunohistochemical studies aimed at identifying prostatic basal cells (34bE12, CK5/6, p63), prostatic secretory cells (PSA, PAP), newer PCa markers (AMACR, ERG) usually lead to a definitive diagnosis. Several lesions have been postulated to represent precursors to PCa. However, PIN remains the best-established one. Its recognition in pathological specimens may significantly impact patient management. A
REFERENCES 1 Epstein JI. Diagnosis and reporting of limited adenocarcinoma of the prostate on needle biopsy. Mod Pathol 2004; 17: 307e15. 2 Humphrey PA. Diagnosis of adenocarcinoma in prostate needle biopsy tissue. J Clin Pathol 2007; 60: 35e42. 3 Herawi M, Parwani AV, Irie J, Epstein JI. Small glandular proliferations on needle biopsies: most common benign mimickers of prostatic adenocarcinoma sent in for expert second opinion. Am J Surg Pathol 2005; 29: 874e80. 4 Epstein JI. Precursor lesions to prostatic adenocarcinoma. Virchows Arch 2009; 454: 1e16.
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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: 820e34. 6 Epstein JI, Cubilla AL, Humphrey PA. Tumors of the prostate gland, seminal vesicles, penis, and scrotum. Washington, DC: American Registry of Pathology, 2011. 7 Srigley JR. Benign mimickers of prostatic adenocarcinoma. Mod Pathol 2004; 17: 328e48. 8 Quick CM, Gokden N, Sangoi AR, Brooks JD, McKenney JK. The distribution of PAX-2 immunoreactivity in the prostate gland, seminal vesicle, and ejaculatory duct: comparison with prostatic adenocarcinoma and discussion of prostatic zonal embryogenesis. Hum Pathol 2010; 41: 1145e9. 9 Tacha D, Zhou D, Cheng L. Expression of PAX8 in normal and neoplastic tissues: a comprehensive immunohistochemical study. Appl Immunohistochem Mol Morphol 2011. 10 Osunkoya AO, Hansel DE, Sun X, Netto GJ, Epstein JI. Aberrant diffuse expression of p63 in adenocarcinoma of the prostate on needle biopsy and radical prostatectomy: report of 21 cases. Am J Surg Pathol 2008; 32: 461e7. 11 Fromont G, Barcat L, Gaudin J, Irani J. Revisiting the immunophenotype of nephrogenic adenoma. Am J Surg Pathol 2009; 33: 1654e8. 12 De Marzo AM, Platz EA, Epstein JI, et al. A working group classification of focal prostate atrophy lesions. Am J Surg Pathol 2006; 30: 1281e91. 13 Bettendorf O, Schmidt H, Eltze E, et al. Cytogenetic changes and loss of heterozygosity in atypical adenomatous hyperplasia, in carcinoma of the prostate and in non-neoplastic prostate tissue using comparative genomic hybridization and multiplex-PCR. Int J Oncol 2005; 26: 267e74. 14 Meyer F, Tetu B, Bairati I, Fradet Y. Prostatic intraepithelial neoplasia in TURP specimens and subsequent prostate cancer. Can J Urol 2006; 13: 3255e60. 15 De Marzo AM, Nakai Y, Nelson WG. Inflammation, atrophy, and prostate carcinogenesis. Urol Oncol 2007; 25: 398e400.
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16 Palapattu GS, Sutcliffe S, Bastian PJ, et al. Prostate carcinogenesis and inflammation: emerging insights. Carcinogenesis 2005; 26: 1170e81. 17 Postma R, Schroder FH, van der Kwast TH. Atrophy in prostate needle biopsy cores and its relationship to prostate cancer incidence in screened men. Urology 2005; 65: 745e9. 18 McNeal JE. Origin and development of carcinoma in the prostate. Cancer 1969; 23: 24e34. 19 McNeal JE, Bostwick DG. Intraductal dysplasia: a premalignant lesion of the prostate. Hum Pathol 1986; 17: 64e71. 20 Mosquera JM, Perner S, Genega EM, et al. Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res 2008; 14: 3380e5. 21 Perner S, Mosquera JM, Demichelis F, et al. TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. Am J Surg Pathol 2007; 31: 882e8. 22 McNeal JE, Yemoto CE. Spread of adenocarcinoma within prostatic ducts and acini. Morphologic and clinical correlations. Am J Surg Pathol 1996; 20: 802e14. 23 Shah RB, Magi-Galluzzi C, Han B, Zhou M. Atypical cribriform lesions of the prostate: relationship to prostatic carcinoma and implication for diagnosis in prostate biopsies. Am J Surg Pathol 2010; 34: 470e7. 24 Merrimen JL, Jones G, Srigley JR. Is high grade prostatic intraepithelial neoplasia still a risk factor for adenocarcinoma in the era of extended biopsy sampling? Pathology 2010; 42: 325e9. 25 Merrimen JL, Jones G, Walker D, Leung CS, Kapusta LR, Srigley JR. Multifocal high grade prostatic intraepithelial neoplasia is a significant risk factor for prostatic adenocarcinoma. J Urol 2009; 182: 485e90. discussion 90. 26 Merrimen JL, Jones G, Hussein SA, Leung CS, Kapusta LR, Srigley JR. A model to predict prostate cancer after atypical findings in initial prostate needle biopsy. J Urol 2011; 185: 1240e5.
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Benign mimickers and potential precursors of prostatic adenocarcinoma
PCa but they may present problems, especially in thin core needle biopsies. A recent study confirmed that small glandular patterns, including benign crowded glands, atrophy including partial atrophy, radiation atypia, adenosis and basal cell hyperplasia, still frequently cause diagnostic difficulty among pathologists.3 Several lesions have been postulated to represent precursors to PCa based on clinical, epidemiological, pathological and molecular evidence.4 The best-studied precursor lesion is prostatic intraepithelial neoplasia.5 Other potential lesions include atypical adenomatous hyperplasia and proliferative inflammatory atrophy. From the standpoint of clinical practice, identification of these precursor lesions in biopsy samples may imply a risk of finding cancer subsequently and therefore may impact patient management. Pathologists should therefore be attuned to recognition of these precursor lesions. In this review, the differential diagnosis of PCa will be discussed with emphasis on benign mimickers as outlined in Table 1. The clinical significance and morphological features of putative precursor lesions of PCa will also be highlighted.
Ming Zhou John R Srigley
Abstract The diagnosis of prostatic adenocarcinoma (PCa) in needle biopsy, especially when present in small amounts, is often challenging. Before making a malignant diagnosis, it is imperative to consider and rule out various benign processes that can simulate cancer. A useful method of classifying benign mimickers is in relationship to the major architectural patterns depicted in the Gleason diagram. The four major patterns are small gland, large gland, fused gland and solid nests and single cells. Most mimickers have small gland architecture and include atrophy, post-atrophic hyperplasia and atypical adenomatous hyperplasia. Normal anatomical and vestigial structures such as seminal vesicle/ejaculatory duct tissue, Cowper’s gland, verumontanum mucosal glands, mesonephric glands and paraganglionic tissue may be confused with PCa. Additionally, metaplastic and hyperplastic processes may be mistaken for PCa. Furthermore, inflammatory processes including non-specific granulomatous prostatitis, xanthoma and malakoplakia may simulate highgrade PCa. In addition to mimickers there are a number of putative precursors of PCa. High-grade prostatic intraepithelial neoplasia has been expensively studied and is thought to be a precursor of at least a subset of PCa. The pathologist’s awareness of the vast array of benign mimickers coupled with prudent use of immunohistochemistry is a critical step in the systematic approach to the diagnosis of PCa. Recognition of PCa precursors in pathological specimens may significantly impact patient management.
A pattern-based approach to differential diagnosis The Gleason diagram, most recently modified in 2011,6 is not only important in grading PCa, but also provides a conceptual framework
Benign mimickers in relation to major growth patterns of prostatic adenocarcinoma Small gland pattern Seminal vesicle Cowper’s gland Atrophy Partial atrophy Post-atrophic hyperplasia Reactive atypia Mucinous metaplasia Nephrogenic metaplasia (adenoma) Basal cell hyperplasia Benign nodular hyperplasia Sclerosing adenosis Verumontanum mucosal gland hyperplasia Mesonephric gland hyperplasia Atypical adenomatous hyperplasia
Keywords adenocarcinoma; benign mimickers; prostate gland; prostatic intraepithelial neoplasia
Prostatic adenocarcinoma (PCa) has a constellation of architectural and cytological features that pathologists rely on to make confident malignant diagnosis.1,2 Most histological features in isolation are not specific and can be found in a wide range of benign prostatic lesions and normal histoanatomical structures. Only three histological features, namely intraglandular glomerulation, mucinous fibroplasia (collagenous micronodules) and perineural invasion, are purportedly specific for and therefore diagnostic of PCa.1,2 Most mimickers of PCa are readily recognized and easily separated from
Large gland pattern Clear cell cribriform hyperplasia Adenoid cystic-like basal cell hyperplasia Reactive atypia Fused gland pattern Paraganglioma Xanthoma Malakoplakia
Ming Zhou MD PhD is at the Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA. Conflicts of interest: none declared.
Solid and single-cell pattern Usual prostatitis with crush artifacts Non-specific granulomatous prostatitis Signet-ring-like change in lymphocytes and stromal cells
John R Srigley MD is at the Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. Conflicts of interest: none declared.
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Table 1
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for discussing differential diagnosis.7 In the Gleason diagram, there are four major architectural patterns for the purpose of discussion of differential diagnosis (Figure 1). The predominant pattern is the small glandular one and consists of small to medium discrete acini which correspond to Gleason patterns 1e3. Most benign mimickers enter the differential diagnosis of small acinar adenocarcinoma. Poorly formed small glands are now considered to be part of Gleason pattern 4. The second pattern is large gland pattern comprising large acini and/or papillary and cribriform structures. Several proliferative and metaplastic processes exhibit this growth pattern. The third pattern is fused gland pattern. A few normal anatomic structures and benign processes simulate this pattern. Both large and fusion gland patterns generally correspond to Gleason pattern 4. The final pattern of adenocarcinoma is the solid nests and single infiltrating cells that correspond to Gleason pattern 5. Certain inflammatory lesions may be mistaken for solid or single-cell adenocarcinoma. The benign mimickers and the corresponding patterns of adenocarcinoma that may be simulated are shown in Table 1. Most but not all of these patterns and processes will be discussed below. It is important to note that there is a range of normal glandular histology in the prostate. Some crowed small gland lesions (benign small glands, not further specified) as well as some intraglandular complexities in medium to large glands may be part of the normal histological spectrum and do not necessarily represent any pathological process.
targeted sampling. SV is morphologically similar to the ejaculatory duct (ED); however, the latter is surrounded by a band of loose fibrovascular connective tissue and lacks the well-formed muscular wall of the former. These two structures are not always distinguishable on prostate biopsies and if so are designated as “benign seminal vesicle/ejaculatory duct (SV/ED) tissue”. SV consists of a central lumen with branching glands that give rise to numerous small glands (Figure 2a). Scattered or random nuclear atypia is often present in the luminal cells but mitoses are not identified. Small nuclear pseudoinclusions are often seen. Cytoplasmic golden-brown lipofuscin pigment is a constant feature although the amount varies from case to case. SV epithelium stains positively for PAX-2,8 PAX-89 and MUC6 and negatively for prostatic-specific antigen (PSA) and prostatic acid phosphatase (PAP). 34bE12 stains the basal layer of SV glands. Well-formed glands containing random atypical nuclei and golden-brown pigment are the most reliable features to separate SV/ED from its mimickers, including benign prostatic tissue with radiation atypia, high-grade prostatic intraepithelial neoplasia, intraductal carcinoma of the prostate and urothelial carcinoma involving the prostate. Cowper’s gland Cowper’s glands, also known as the bulbourethral glands, are paired periurethral structures located near the prostatic apex. They are rarely sampled in resection specimens or biopsies from the apex. Cowper’s glands have central ducts surrounded by tightly packed mucinous acini (Figure 2b). Skeletal muscle fibres are sometimes present in the stroma. The mucinous cells stain for mucin (mucicarmine, PAS-D), variably for PSA and are negative for PAP. The ductal cells stain for 34bE12 and in some cases attenuated cells around the periphery of the acini are also positive. Cowper’s glands can be distinguished from foamy gland adenocarcinoma by its lobular configuration and ductal-acinar architecture, cytoplasmic mucin, and lack of cellular atypia.
Seminal vesicle (SV) SV tissue may be present in transurethral resectates or needle biopsies, usually incidentally, but sometimes as a result of
Gleason grading scheme of prostatic adenocarcinoma I 1
Verumontanum mucosal gland hyperplasia (VMGH) VMGH is a frequent finding in radical prostatectomy specimens but rarely seen in needle biopsy due to its suburethral location. It is composed of relatively uniform, closely packed round glands containing numerous orange-brown amorphous concretion and corpora amylacea (Figure 2c). Adjacent prostatic urethral epithelium may be present. Lipofuscin pigment may be present within the cytoplasm of glandular cells. These features differentiate VMGH from low-grade adenocarcinoma with small glandular architecture and crowded growth.
2
3
II
III
4
5
Reactive atypia in benign glands Inflammation and sometimes ischaemia (infarction) may cause significant architectural and cytological atypia in benign glands thus raise suspicion for adenocarcinoma. The glands in most cases of reactive atypia are small and atrophic (Figure 3a). Occasionally, large cribriform glands are found (see Figure 6a). There may be basal cell or urothelial cell hyperplasia. In some cases, especially in ischaemia, the epithelium undergoes squamous metaplasia. Mild to moderate nuclear enlargement is seen and sometimes nucleoli are prominent. Importantly adenocarcinoma may also be found in areas of inflammation and ischaemia. One should be very cautious
IV
Figure 1 The four major architectural patterns for the discussion of differential diagnosis of benign mimickers are: I e small gland (Gleason patterns 1e3); II e large gland glands with cribriform and papillary architecture (Gleason pattern 4); III e fused gland (Gleason pattern 4) and IV e solid nests, cords and single cells (Gleason pattern 5).
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making a cancer diagnosis when there is intense inflammation or ischaemic change in the background. Postradiation atypia Radiation therapy can cause profound morphological changes in benign prostate glands (Figure 3b). Glands are markedly atrophic but still maintain their lobular architecture. Individual glands can have a highly irregular contour and are lined with multiple layers of predominantly basal cells. The cytoplasm is usually dense and eosinophilic rather than being clear. Scattered markedly atypical nuclei are present. Basal cell hyperplasia, urothelial and squamous metaplasia, stromal fibrosis and oedema are also seen. Benign glands with radiation atypia may be mistaken for prostate adenocarcinoma with treatment effect, which demonstrates relatively small uniform pyknotic nuclei and abundant vacuolated cytoplasm. Basal cell markers may be helpful in identifying irradiated benign glands. Basal cell hyperplasia (BCH) BCH is typically seen as part of benign prostatic hyperplasia in the transition zone, but may also affect the peripheral zone and encountered in needle biopsies. BCH may also occur in association with atrophy, often in the setting of antiandrogen and radiation therapy. BCH manifests as nodular expansion of uniform round glands with stratified nuclei (Figure 3c, d). Cells have scant cytoplasm and oval or somewhat elongated nuclei with homogeneous vesicular chromatin and indistinct nucleoli. Several patterns may be appreciated in BCH. In complete BCH, basal cells form solid nests without luminal formation. In incomplete BCH, residual small lumina are lined by secretory cells with clear or eosinophilic cytoplasm that are surrounded by multiple layers of basal cells. Adenoid cystic-like BCH is an uncommon form composed of medium to large glands with a complex cribriform pattern, sometimes with cyst formation and squamous metaplasia (see Figure 6c). Microcalcifications are common. Rarely intracytoplasmic hyaline globules are found and are considered to be a specific feature of BCH. The stroma is cellular. The basal cells are positive for basal cell markers 34bE12 and p63, negative for AMACR, but may be weakly and focally positive for PSA and PSAP. BCH may be confused with PCa, but the presence of dense cellular stroma, multiple layers of oval and vesicular nuclei, microcalcifications and cytoplasmic hyaline globules are features that distinguish BCH from PCa. PCa with p63 positivity is a rare lesion that may be mistaken for BCH.10 The carcinomatous glands exhibit infiltrative growth and are uniformly positive for p63 but negative for 34bE12. BCH may superficially resemble high-grade PIN. However, basal cells proliferate into the surrounding stroma and nuclei are uniform and have smooth chromatin in BCH. Finally, florid BCH should be distinguished from basal cell carcinoma. Identification of infiltrative features including extraprostatic extension and perineural invasion is the key. Tumour necrosis, frank cytological atypia and mitoses support the diagnosis. Nephrogenic metaplasia/adenoma (NA) NA is usually encountered in the prostatic urethra and subjacent prostatic tissue, and is distinctively uncommon in needle biopsies. In most instances, there has been a previous history of trauma, instrumentation or transurethral resection.
Figure 2 Normal or developmental vestigial structures with small gland architecture mimicking cancer. (a): Seminal vesicle. (b): Cowper’s glands. (c): Verumontanum mucosal glands hyperplasia.
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Figure 3 Reactive and metaplastic lesions with small gland architecture mimicking cancer. (a): Inflamed benign glands with small gland architecture, nuclear enlargement and conspicuous nucleoli. (b): Benign glands with radiation atypia. (c, d): Basal cell hyperplasia comprises basophilic glands at low power (c). The glands are lined with small, uniform, dark basal cells (d). (e, f ): Nephrogenic metaplasia consists of small tubules and occasional cysts resembling ecstatic vessels (e) which are positive for PAX-2 (f ).
NA commonly exhibits an exophytic tubulocystic growth pattern. Small poorly formed glands, small tubules resembling renal tubules and dilated cysts resembling ectatic vessels are seen (Figure 3e). The tubules are frequently surrounded by thick basement membrane. The lining epithelial cells are flat, cuboidal and hobnail with uniform nuclei. Clear and signet-ring cells may be seen. Nuclear atypia, if, present, appears degenerative. Mitoses are rare or absent. Background inflammation is frequent. Most NA express PAX-2 (Figure 3f) and PAX-8 and AMACR.11 PSA and PAP are negative. Cytoplasmic 34bE12 staining is found in >50% of cases.
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A panel using PAX-2 or PAX-8, PSA, PAP, and 34bE12 is useful in separating NA from PCa. Atrophy Atrophy is a common process typically found in older patients, but also present in young adult prostates. While idiopathic in many cases, atrophy is commonly associated with chronic inflammation and may be a manifestation of local chronic ischaemia. Atrophy can also be the result of radiation and antiandrogen therapy.
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The hallmark of atrophy is reduced amount of cytoplasm in secretory cells which imparts a basophilic appearance at low magnification except in partial atrophy (see discussion below). There are four distinct morphological patterns of atrophy, simple atrophy, cystic atrophy, post-atrophic hyperplasia (PAH) and partial atrophy (PA).12 These patterns often coexist. In simple atrophy, the overall glandular architecture is preserved but the glands appear shrunken (Figure 4a). The stroma is frequently sclerotic and contains inflammation. Cystic changes are often present. The term cystic atrophy is applied when the atrophic glands are significantly dilated and rounded and cyst-like (Figure 4b). PA usually has a lobular, or sometimes more diffuse and disorganized architecture, at low magnification (Figure 4c). The glands vary in size and the large glands typically have highly irregular contour. The glands appear pale rather than basophilic due to abundant cytoplasm lateral to the nuclei even though the cell height
is drastically reduced with scant apical cytoplasm. Nuclei may be slightly enlarged with small or inconspicuous nuclei. Granular eosinophilic luminal secretions and occasionally mucin may be seen. Immunostains for basal cell markers are often patchy in most glands, and may be entirely negative in some glands (Figure 4d). The stain for AMACR is positive in many examples of PA although the staining intensity is generally less than that seen in PCa. PAH consists of lobular collection of small, round and basophilic acini frequently arranged around central dilated “feeder” ducts (Figure 4e). The stroma is sclerotic and contains inflammation. Secretory cells are low cuboidal with scant cytoplasm. Basal cells may proliferate and show mild to moderate nucleolar enlargement. Basal cell markers usually demonstrate continuous but sometime patchy positivity. PAH generally lacks AMACR expression. Simple and cystic atrophy does not pose diagnostic challenges. However, PA and PAH are the most common mimickers
Figure 4 Atrophy. (a): Simple atrophy. (b): Cystic atrophy. (c, d): Partial atrophy (c). Basal cell marker p63 is focal or even absent in some glands in partial atrophy (d). (e): Post-atrophic hyperplasia.
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Figure 5 Benign lesions with small gland architecture mimicking cancer. (a): Benign prostatic hyperplasia, small gland pattern. (b, c): Atypical adenomatous hyperplasia (b). Basal cell marker p63 is focally positive or even negative in some glands (c).
Figure 6 Large glands with papillary and cribriform architecture. (a): A large inflamed benign gland. (b): Clear cell cribriform hyperplasia. (c): Adenoid cystic-like basal cell hyperplasia.
of PCa in contemporary practice.3 The low power small glandular proliferation and frequently patchy and negative basal cell stains may lead to an overdiagnosis of cancer. However, most cancers have straight luminal borders. It should be emphasized that carcinoma may have an atrophic appearance and as such may be misdiagnosed as atrophy. Atrophic
adenocarcinomas are composed of small dark acini usually with an infiltrative growth pattern. Nuclear atypia and nucleoli are usually recognized at least focally. In contrast, there should not be significant nuclear enlargement and nucleoli in PA and PAH. One should always be cautious about making a cancer diagnosis when the glands in question are atrophic and have
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Paraganglion Paraganglionic tissue may be encountered within prostatic and periprostatic tissue, usually the latter, and is often associated with a nerve. Paraganglia are characterized by small, solid nests of cells with clear or amphophilic cytoplasm and a delicate
the same cytoplasmic quality as adjacent more obvious benign glands. Benign prostatic hyperplasia (BPH), small gland pattern BPH occasionally has areas composed of mainly small to medium-sized, closely packed acini with rounded lumens, and may be mistaken for low-grade, Gleason pattern 1 or 2 adenocarcinoma (Figure 5a). The nodular circumscription, uniform architecture, presence of basal cells and intervening cellular stroma serve to separate this proliferative lesion from cancer. Atypical adenomatous hyperplasia (AAH) AAH, also known as adenosis, affects mainly the transition zone and is found mainly in transurethral resections and radical prostatectomy specimens, and is uncommon in needle biopsies. AAH consists of well-circumscribed nodule of relatively uniform small round glands intermixed with large complex glands typical of hyperplasia (Figure 5b). Small and large glands have similar cytological features. Nuclei may be slightly enlarged and have small but not prominent nucleoli. Stroma is usually cellular. Crystalloids and blue mucin are occasionally present. Basal cell markers typically demonstrate fragmented or occasionally absent staining around some glands (Figure 5c). AMACR is either focally or diffusely positive in up to 70% of lesions (Figure 5c). AAH must be differentiated from low-grade PCa of the anterior and transition zones, in which glands are more uniform in size and shape and lack basal cells completely. Clear cell cribriform hyperplasia (CCCH) CCCH represents a spectrum of BPH and can occasionally dominate the histological picture. It consists of nodular proliferation of crowded cribriform glands with cellular stroma (Figure 6b). The cribriform glands have uniform, round lumina and lack complex/confluent architecture. The cells comprising the central cribriform areas are cuboidal to low columnar secretory-type cells with uniform round nuclei and clear cytoplasm and lack nuclear atypia. There are prominent basal cells around the periphery. CCCH may be mistaken for cribriform HGPIN, but lacks significant nuclear atypia seen in the latter. Cribriform adenocarcinoma may also enter the differential diagnosis, but has nuclear atypia and lacks basal cell lining. Sclerosing adenosis (SA) SA is an uncommon lesion largely restricted to the transition zone and is therefore an incidental finding in transurethral resectations or radical prostatectomy specimens, and rare in needle biopsies. It consists of circumscribed proliferation of variably sized and shaped glands, often microacini, and individual cells embedded in a cellular and often oedematous stroma (Figure 7a). Prominent nucleoli and blue mucin are commonly present. Thick hyaline basement membrane surrounds at least some glands. Basal cells undergo myoepithelial metaplasia and show coexpression of both basal cell (34bE12 and p63) (Figure 7b) and myoepithelial markers (muscle-specific actin and S100) (Figure 7c). SA may be mistaken for a high-grade PCa. The key features distinguishing the two include the variation in glandular size and shape, thickened basement membranes, cellular stroma and positive immunohistochemistry for basal cell markers and actin in SA.
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Figure 7 Sclerosing adenosis (a). Stains for basal cell marker p63 (b) and myoepithelial marker (c) are positive. Photo courtesy of Dr. Rajal Shah, Dallas, TX.
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inflammation is usually diffuse and has mixed inflammatory cells including neutrophils, eosinophils, lymphocytes and histiocytes (Figure 8c). The inflammation is centred around and may obscure ducts and acini. Therefore it may be mistaken for a highgrade carcinoma. The inflammatory nature of the lesion along with the association of giant cells and fibrosis are helpful diagnostic clue. In difficult cases, immunohistochemistry for cytokeratins, prostatic-specific markers and lymphohistiocytic markers may be used. Well-formed granulomas may be inconspicuous in non-specific granulomatous prostatitis and when present in significant numbers should raise the possibility of an infectious aetiology such as tuberculosis or fungal disease.
network of capillaries. Paraganglionic tissue can simulate the fused gland pattern of adenocarcinoma. Another potential issue is mistaking extraprostatic paraganglionic tissue in radical prostatectomy as extraprostatic extension of cancer. Xanthoma Collections of lipid-laden macrophages in the prostate may be mistaken for the hypernephroid pattern or foamy gland type of adenocarcinoma (Figure 8a). Xanthomatous histiocytes have small uniform nuclei within inconspicuous nucleoli and are commonly admixed with inflammatory cells. Some hypernephroid or foamy gland carcinomas predominantly have small dark nuclei without prominent nucleoli. But careful examination invariably identifies typical carcinoma component with prominent nucleoli. In rare cases, immunohistochemistry for epithelial and prostatic cells (cytokeratin, PSA, PAP) and histiocytes (CD68) is required to resolve the diagnostic ambiguity.
Degenerative changes in lymphocytes and stromal cells Lymphocytes and sometimes stromal cells may undergo degenerative changes which result in a signet-ring-like morphology and can resemble high-grade adenocarcinoma composed of individual signet-ring cells (Figure 8d) if the change is prominent.
Malakoplakia The early phase of malakoplakia when von Hansemann histiocytes predominate may simulate a high-grade carcinoma (Figure 8b). The lack of any acinar differentiation and admixed inflammatory infiltrate along with MichaeliseGutmann bodies will lead to a correct diagnosis.
Precursor lesions of prostate adenocarcinoma Several lesions have been postulated to represent the precursors to PCa based on clinical, epidemiological, pathological and molecular evidence.4 Atypical adenomatous hyperplasia (AAH or adenosis) is considered by some authorities as a precursor to some anterior/transition zone carcinoma, as it has a predilection for the transition zone and morphologically simulates carcinoma
Non-specific granulomatous prostatitis This condition clinically simulates carcinoma with firm to hard prostate gland and elevated PSA. In biopsy samples,
Figure 8 Inflammatory lesions mimicking high-grade cancer. (a): Xanthoma. (b): Malakoplakia with MichaeliseGutmann bodies (arrows). (c): Non-specific granulomatous prostatitis with diffuse mixed inflammatory infiltrates. (d): Degenerative changes in lymphocytes and stromal cells simulating signet-ring pattern of prostatic adenocarcinoma.
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arising in the anterior/transition zones. Additionally, patients with AAH are usually 5e10 years younger than those with carcinoma. However, a direct link between AAH and adenocarcinoma is lacking. Genetic alterations in AAH are infrequent and different from those seen in transition zone PCa.13 Examples of carcinoma arising in close relationship to AAH are rare. Most importantly, men with AAH are not at increased risk of developing adenocarcinoma during follow-up.14 Therefore, the relationship between AAH and carcinoma is at best circumstantial.
The major importance of AAH is its potential for being misdiagnosed as adenocarcinoma. Several forms of atrophy (simple atrophy and post-atrophic hyperplasia) are commonly associated with inflammation and when increased proliferative activity of epithelium is demonstrated by stains such as MIB-1, the term “proliferative inflammatory atrophy (PIA)” has been used. PIA has been proposed as another precursor lesion to PCa based on epidemiological and molecular studies.15,16 However, a morphological link between
Figure 9 Prostatic intraepithelial neoplasia (PIN). Low-grade PIN glands (arrows, a) have no prominent nucleoli at high magnification (b). HGPIN glands (arrows, c) exhibit prominent nucleoli at 20 magnification (d). The HGPIN glands are positive for basal cell marker, often discontinuous (p63, e). A subset of HGPIN glands (arrows) is positive for ERG (red nuclear staining) and is invariably intermixed with ERG-positive cancer glands (arrowheads) (f ).
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Figure 10 Architectural patterns of HGPIN. Four major architectural patterns include tufting (a), micropapillary (b), flat (c) and cribriform (d). Other uncommon patterns include vacuolated/signet-ring-like (e), inverted (f ) and foamy gland (g).
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Figure 11 Mimickers of HGPIN. (a): Ductal carcinoma. (b, c): PIN-like prostate carcinoma with closely packed large glands (b) that are negative for basal cell marker p63 (c). (deg): Intraductal carcinoma of the prostate. Large cribriform glands with markedly irregular glandular contour (d). Comedo necrosis (arrows, e) and marked nuclear pleomorphism (f ) are characteristic. Basal cells are always retained in these glands (g).
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almost always associated with high-grade and large volume cancer. The number of IDC-P glands is always more than that of HGPIN in radical prostatectomy and biopsy specimens.23 IDC-P glands are often larger and more irregular than HGPIN glands and are much more likely to have dense cribriform or solid architecture and comedo necrosis. In addition, the constituent cells in IDC-P are more likely to exhibit marked nuclear pleomorphism. Basal cells are always retained in these glands. LGPIN is not associated with increased cancer detection in subsequent follow-up biopsies and its diagnosis is not readily reproducible even among urologic pathologists; therefore, it should not be diagnosed and reported in prostate biopsy.5 In contrast, isolated HGPIN diagnosed in contemporary needle biopsy practice carries a 22e27% risk of finding PCa in subsequent biopsy5,24,25 as opposed to an 18e20% cancer risk associated with a benign or LGPIN diagnosis. In certain clinical situations, HGPIN renders even higher cancer risk. For example, the cancer risk associated with multifocal HGPIN and atypical small acinar proliferation (ASAP) was 71% compared to the cancer risk of 43% and 42%, respectively, associated with ASAP alone and ASAP and unifocal HGPIN.26 Therefore a finding of unifocal (one core) HGPIN does not confer any adverse risk for PCa detection and the decision regarding re-biopsy is determined by other clinical factors including history, DRE finding and PSA parameters. If the initial sampling was limited (six or fewer cores) or when HGPIN is multifocal (involving two or more cores) a re-biopsy within 1 year is generally recommended. HGPIN on its own does not result in an abnormal digital rectal examination or elevated serum PSA level and can only be diagnosed by histological examination of the prostate tissue. No treatment is required for HGPIN as an isolated finding in prostate needle biopsy.
PIA and PCa is lacking and the finding of PIA in prostate biopsy is not associated with an increased PCa detection in repeat biopsy.17 Therefore, PIA is not considered to be a direct PCa precursor. Prostatic intraepithelial neoplasia (PIN) is the best-studied precursor lesion supported by clinical, epidemiological, pathological and molecular evidence. PIN was first described by McNeal et al. as a precursor to some PCa under the name “intraductal dysplasia” in 1960s,18 and the concept was more precisely defined by McNeal and Bostwick in 1986.19 PIN comprises of architecturally benign prostatic acini and ducts lined with cytologically atypical cells. Originally categorized into grades 1e3, PIN is now dichotomized into low (grade 1) and high-grade (grades 2 and 3). PIN manifests at low magnification (Figure 9) as basophilic glands with architecture similar to adjacent benign glands. The basophilic appearance is due to cytoplasmic amphophilia, nuclear stratification, enlargement and hyperchromasia. The histological criteria to separate low-grade PIN (LGPIN) and highgrade PIN (HGPIN) is arbitrary but one consistent and reasonable approach is to diagnose HGPIN when nucleoli are visible at 20 magnification. The presence of mitosis and pleomorphic nuclei can also be used to diagnose HGPIN in glands with other histological features of HGPIN but inconspicuous nucleoli. HGPIN glands have basal cell lining which may be patchy or even absent in small glands. AMACR is positive in majority of HGPIN glands. TMPRSS2eERG gene fusion, a chromosomal alteration highly specific for PCa, is present in approximately 20% of HGPIN which is always intermixed with cancer that harbours TMPRSS2eERG gene fusion.20,21 There are four major architectural patterns of high HGPIN, including tufting, flat, micropapillary and cribriform (Figure 10). Cribriform HGPIN is distinctively rare and the majority is now considered to represent intraductal carcinoma of the prostate. Other histological variations similar to adenocarcinoma variants including mucinous, foamy gland, neuroendocrine, squamous and small cell HGPIN are rarely encountered. In general, these histological variants do not have significant clinical difference and their mentioning is for differential diagnostic consideration. HGPIN may be mistaken for a number of benign and cancerous lesions (Figure 11). Central zone glands, seminal vesicle/ejaculatory duct epithelium, reactive atypia due to inflammation, infarction, or radiation, transitional cell metaplasia, squamous cell metaplasia, clear cell cribriform hyperplasia and basal cell hyperplasia were discussed previously. Cribriform carcinoma is differentiated from cribriform HGPIN by its crowded growth, concomitant typical small cancer glands and absent basal cell lining. Compared to HGPIN with moderate amount of intervening stroma, PIN-like PCa often has closely packed glands. Basal cell staining is required to establish a cancer diagnosis on needle biopsy. Ductal adenocarcinomas may consist of very large and/or confluent glands and often contains true papillary fronds with well-formed fibrovascular cores. Solid and necrosis can be seen. In contrast, HGPIN glands are similar to the adjacent benign glands in size and shape and possess micropapillary fronds without fibrovascular cores. Ductal adenocarcinoma may retain basal cells so the immunostains for basal cell markers is of little value in their distinction. Intraductal carcinoma of the prostate (IDC-P) is considered by some to represent the intraductal spread by PCa.22 It is
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Summary A wide variety of benign lesions and normal anatomic structures may be confused with PCa. In general, awareness of these PCa mimickers coupled with careful microscopic examination and prudent use of ancillary immunohistochemical studies aimed at identifying prostatic basal cells (34bE12, CK5/6, p63), prostatic secretory cells (PSA, PAP), newer PCa markers (AMACR, ERG) usually lead to a definitive diagnosis. Several lesions have been postulated to represent precursors to PCa. However, PIN remains the best-established one. Its recognition in pathological specimens may significantly impact patient management. A
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