—  SHORT COURSE #13  —

Interpretation of Prostate Needle Biopsies

Case 4A, 4B, 5, 6, 7 - Benign Mimics of Prostate Cancer and Unusual Cancer Morphologies which Mimic Benign Conditions

Rajal Shah and Ming Zhou


Case 4A :
A 65 year-old white American male with serum PSA of 4 ng/ml, underwent extended 12 core biopsies.

Diagnosis:
Multifocal post atrophic hyperplasia with chronic inflammation.

Case 4B :
Same patient as from case 2A, Biopsy from right apex.

Diagnosis:
Partial atrophy of the prostate.

Case 5:
A 62 year-old male with an elevated serum PSA 12 ng/ml, underwent sextant biopsy to rule out prostate cancer.

Diagnosis:
Basal cell hyperplasia.

Case 6:
A 78 year-old African American male with a preoperative diagnosis of elevated PSA (8 ng/ml) and urinary retention. Patient underwent sextant biopsy.

Diagnosis:
Adenosis (Atypical adenomatous hyperplasia)

Case 7:
A 67-year-old-male patient with a past history of prostate cancer and radiation treatment, now presenting with rising PSA. Patient underwent sextant biopsy. asfd Diagnosis: Benign prostate tissue with marked radiation induced cytological atypia. No evidence of malignancy.

Benign Mimickers of Prostate Adenocarcinoma

Various benign patterns and processes can mimic prostate adenocarcinoma, especially in the context of presence of limited carcinoma [1]. These mimics include various anatomic structures, inflammatory and reactive conditions and pathophysiological conditions including atrophy, hyperplasia and metaplasia. Benign mimics are encountered in increasing frequency due to large number of prostate needle biopsies performed in PSA screening era and especially with extended biopsy approach where transition zone may be sampled. Many of these lesions are readily recognized and separated from malignancy but some may cause potential diagnostic difficulties.

A useful approach of classifying benign mimickers is in relation to major growth patterns similar to applied for Gleason grading of prostate adenocarcinoma. This approach also provides a conceptual framework for discussing differential diagnosis. Using this approach one may deal with:

1) Small gland pattern mimicking low Gleason score 4-6 carcinomas (A)

2) Large gland/cribriform pattern mimicking Gleason score 7-8 carcinomas (B)

3) Fused gland/solid pattern mimicking Gleason score 8-10 carcinomas (C).

Most benign mimickers enter the differential diagnosis of small gland (acinar) adenocarcinoma.

A) Mimics with Small Gland Pattern resembling Gleason score 4-6 carcinomas

Normal Anatomic structures:

1) Seminal vesicle/ejaculatory ducts

Seminal vesicle tissue is usually sampled in needle biopsies unexpectedly, but sometimes as a result of specific sampling. Ejaculatory duct epithelium has similar morphology to that of the seminal vesicle and usually is not separable from it in needle biopsy specimens. The sampling incidence of seminal vesicle/ejaculatory duct in needle biopsies range approximately 4-5% [2].

Key histological features useful to separate from adenocarcinoma:
1) Presence of scattered pleomorphic nuclei ("monster nuclei") and nuclear pseudo inclusions are distinctive features. A well-differentiated adenocarcinoma demonstrates uniform cytological atypia, and rarely would demonstrate scattered cytological pleomorphism.

2) A useful feature appreciated at low power is presence of central lumen with peripheral small branching glands surrounded by smooth muscle.

3) Golden-brown cytoplasmic lipofuscin pigment, which is at times very prominent.

Lipofuscin pigment may be present in normal, hyperplastic, PIN glands and carcinomatous glands [3]. However pigment in cancer glands is rare and usually not prominent. Therefore presence of pigment must be correlated with other features.

Seminal vesicle epithelium also frequently demonstrate intraluminal crystalloids and amorphous secretions [2].

4) In rare problematic cases, negative immunohistochemistry for PSA and PAP (prostate acid phosphatase) along with basal cell staining of 34bE12 are helpful.

2) Verumontenum mucosal gland hyperplasia

Verumontenum mucosal gland hyperplasia (VMGH) is a benign small acinar proliferation that occurs exclusively in the region of the verumontenum and adjacent posterior urethra where the ejaculatory ducts and utricle empty into the urethra. In the needle biopsies VMGH is an infrequent finding but frequently appreciated in radical prostatectomy specimens.

Key histological features useful to separate from adenocarcinoma [4, 5]:
1) Circumscribed collection of small, closely packed acini, frequently in proximity to urethral lining

2) Characteristic brown/orange amorphous corpora/crystalloids in the lumen are characteristic of these glands

3) Glands lined by bland cytology with conspicuous presence of basal cells

4) PSA and HMWCK basal cell reaction pattern in VMGH are similar to benign prostate glands.

3) Cowper's glands
Cowper's glands are paired bulbourethral (periurethral) glands located below the prostatic apex. They are rarely sampled in prostatic specimens. Majority of lesions mimicking Cowper's gland are examples of mucinous metaplasia of prostatic acini associated with atrophy.

Key histological features useful to separate from adenocarcinoma [6, 7]:
1) Dimorphic population of a central duct surrounded by tightly packed round acini composed of cells with abundant mucinous cytoplasm, arranged in a lobular pattern of distribution is characteristic feature.

2) Uniform basally located bland nuclei.

3) Skeletal muscle typical of apical region is frequently present in the periglandular stroma

4) Mucicarmine, PAS-diastase stains demonstrate mucin positivity, HMWCK 34betaE12 positive in ducts and attenuated in acini, PSA variably positive, PAP negative

Cowper's glands may get confused with small acinar adenocarcinoma particularly foamy gland cancer. Awareness of ductal-acinar architecture, cytoplasmic mucin and lack of cellular atypia distinguishes from adenocarcinoma.

Pathophysiological conditions

4) Atrophy

Background and significance
Focal atrophy of prostate is a frequent lesion and accounts for one of the most commonly encountered mimics of prostate cancer in consultation practice [8].

There is renewed interest in understanding the significance of focal atrophy, particularly when it is associated with inflammation. Studies have demonstrated that focal atrophy, particularly when associated with inflammation contain an elevated proliferative fraction in the epithelial cells than benign glands, demonstrate some of the early genetic changes seen in HGPIN and prostate cancer and also demonstrate increased staining of stress related oxidative enzyme II-glutathione s-transferase (GSTP1) [9, 10, 11]. To highlight the fact that these atrophic foci generally harbor associated inflammation and show increased proliferation, DeMarzo et al have proposed an alternative name "proliferative inflammatory atrophy" for these lesions [11]. These lesions are recently proposed as one possible mechanism through which early prostate carcinogenesis develops [11, 12, 13].

Histological subtypes:
There are several morphologic variants of focal prostate atrophy. Franks in 1954 originally described 5 patterns: 1) simple atrophy, which was later sub-classified into a) with and without cyst formation (b); 2) sclerotic atrophy; 3) post atrophic hyperplasia, which was later sub-classified into lobular hyperplasia and sclerotic atrophy with hyperplasia [14, 15]. Franks suggested that this later lesion was more proliferative than benign glands [15]. In more contemporary literature, several descriptions of various morphological patterns of focal prostate atrophy have been presented. In an attempt to provide a standardized description of various terminology DeMarzo et al have recently attempted to provide a working group classification of focal atrophy of the prostate into four types [49]:

1) Simple atrophy (SA); 2) Simple atrophy with cyst formation; 3) Post atrophic hyperplasia (PAH); and 4) Partial atrophy

In addition, a number of other pathological processes such as type of inflammation, fibrosis (sclerosis) may be apparent.

In routine practice, PAH and partial atrophy may cause considerable difficulty in separating from adenocarcinoma and will be discussed here.

Post atrophic hyperplasia: (Lobular hyperplasia, Sclerotic atrophy with lobular hyperplasia) [10, 16, 17]

Key histological features useful to separate from adenocarcinoma:
1) Low power appearance is a key in recognition. They appear as a lobulated collection of basophilic appearing small and mostly round acini frequently arranged surrounding central dilated "feeder" duct, resembling to breast lobule.

2) Acini contain low cuboidal cells with very scant cytoplasm, both lateral and apical to the nucleus of the atrophic cells

3) Sometimes, basal cells within PAH may show mild to moderate nucleolar enlargement, concerning for cancer at high power.

4) Basal cell markers demonstrate fragmented or discontinuous staining pattern with frequent loss of staining in part of lesion, which should not be over interpreted as cancer.

5) PAH lesions are frequently accompanied by inflammation.

Partial Atrophy:
This subtype was first coined by Epstein et al and others have used the term PAH to describe similar lesions [18]. We believe partial atrophy has differing histological, immunohistochemical, and cellular kinetics than post atrophic hyperplasia [10, 51]. This is the only subtype of atrophy that does not solely depend on the architectural arrangement of the involved acini, but requires distinct cytological features [49, 51]. This benign mimic accounts for one of the most common reasons for which an expert consultation is sought in contemporary practice.

Key histological features useful to separate from adenocarcinoma [51]:
1) Luminal cells with less than normal, but relatively abundant cytoplasm compared to other types of atrophy, which is placed lateral to the nucleus giving it a distinctly pale or clear appearance at low magnification (does not appear basophilic like PAH or SA)

2) Architectural arrangement can be lobulated or sometimes in disorganized patch form.

3) The glandular lumen range from straight borders to undulated or stallete shaped.

3) Presence of few glands within the focus demonstrating "fully developed atrophy"

4) Nuclei are rarely enlarged. Micronucleoli can be seen but the presence of macronucleoli is very unusual feature and should argue against the diagnosis.

4) Basal cell markers frequently demonstrate patchy or fragmented staining pattern. Small proportion of these lesions can be entirely negative for basal cell markers. AMACR is usually not expressed in these lesions but a very small proportion can demonstrate weak to moderate expression [50, 51].

5) Basal cell hyperplasia
Basal cell hyperplasia is typically seen as part of the spectrum of benign prostatic hyperplasia in transition zone specimens [19, 20]. Recently, it has been recognized that basal cell hyperplasia may also affect the peripheral zone and may be encountered in needle biopsies [21]. Basal cell hyperplasia also occurs in association with atrophy, in the setting of antiandrogen therapy.

Key histological features useful to separate from adenocarcinoma:
1)Nodular expansion of uniform round glands with stratified nuclei associated with a cellular stroma. Other growth pattern of basal cell hyperplasia include cribriform and pseudo cribriform architecture and therefore may also get confused with cribriform carcinomas.

2) There is lack of secretory cell differentiation in complete form in which solid nests of dark-blue cells are present. In the incomplete form, there are residual small lumina lined by secretory cells with clear cytoplasm and are surrounded by multiple layers of basal cells.

3) The basal cells display oval, round or somewhat spindled nuclei with homogeneous glassy or vesicular chromatin. Cytoplasm is scant. Nucleoli are usually indistinct but sometimes are prominent and may raise concern for adenocarcinoma. [22, 23]

4) Microcalcifications are common. Rarely one may encounter intracytoplasmic hyaline globules, which is considered to be specific feature of basal cell hyperplasia.

5) The adjacent stroma is very cellular and consists of proliferating fibroblasts and smooth muscle cells similar to seen in benign prostate hyperplasia.

6) Immunohistochemical staining for basal cell markers is strongly positive.

In needle biopsies, sometimes basal cell hyperplasia may be seen with unusual atypical presentation, which may give significant diagnostic difficulties [23]. Particularly, infiltrative growth pattern, prominent nucleoli, blue intraluminal mucin may be seen frequently, so careful analysis of various features should be made before arriving at the diagnosis [23].

6) Adenosis (Atypical adenomatous hyperplasia)
Adenosis, also referred to as atypical adenomatous hyperplasia, is a proliferative lesion found more frequently in the transition zone than in needle biopsies. One of the most common lesion that may be confused with carcinoma is adenosis [24, 25]. Because of the overlapping features with low-grade adenocarcinoma, it has been considered a precursor for low-grade cancer, however overall significance of the lesion remains uncertain [23, 26, 27, 28]. Many of the so-called Gleason grade 1+1=2 adenocarcinoma in modern day practice represents examples of adenosis.

Key histological features useful to separate from adenocarcinoma:
The distinction of adenosis from low-grade adenocarcinoma is based on combination of architectural and cytological features:

1) At low power well-circumscribed or lobulated lesion comprising of a mixture of complex glands typical of hyperplasia are admixed with uniform small round glands is characteristic feature. Small glands have similar cytoplasmic and cytological features like large benign glands and essentially merge with them rather than appear distinctly different as seen in adenocarcinoma.

2) Another important feature in separating adenosis from low-grade adenocarcinoma is based on nuclear features. The lining cells have small nuclei with fine chromatin. Nucleoli are occasionally present but are generally small (<1 um). Huge nucleoli (>3 um) seen in adenocarcinoma are absent.

3) Stroma is usually cellular.

3) Crystalloids and basophilic mucin can occasionally be present [29]

4) Basal cell markers typically demonstrate fragmented staining with loss of staining in some glands, which should not be confused with cancer. As long as atypical glands not staining are part of the atypical focus and appear similar in cytoplasmic and cytological characteristics like atypical glands staining, it should be regarded as benign glands. AMACR has significant limitations in resolving this condition as it is expressed either focally or diffusely in almost 20% of cases [30, 31].

7) Nephrogenic adenoma
Nephrogenic metaplasia (adenoma) is a benign metaplastic lesion involving the urothelial mucosa. It commonly involves the urinary bladder but may occur in any part of the urinary tract including the prostatic urethra (10%), where it may create diagnostic difficulty with prostate adenocarcinoma or clear cell adenocarcinoma.

In most cases there is history of prior treatment, trauma, stones or other long standing problems.

Key histological features useful to separate from adenocarcinoma [34, 35, 36, 37]:
1) Presence of both exophytic papillary and infiltrative tubulocystic components. However, both may not be present in same lesion. In lesions involving the prostatic urethra the papillary portion is often absent making diagnosis difficult.

2) The tubulocystic portion consists of small tubules ranging up to dilated cystic structures

3) Lining epithelium ranges from flat to cuboidal to hobnail in appearance. Nuclear atypia when present is usually of degenerative in nature. The cytoplasm is usually eosinophilic with uniform nuclei and frequent prominent nucleoli.

4) The tubules are frequently surrounded by thick basement membrane, which may be enhanced with PAS stain. Inflammation is frequent with the lesions.

5) PSA and PAP are usually negative. Cytoplasmic staining of 34bE12 found in > 50% of nephrogenic adenoma cases. AMACR is positive in significant proportion of cases, a significant diagnostic pitfall [38, 39] . PSA, PAP and 34 bE12 are most useful panel.

8) Post radiation atypia
Evaluation of prostate needle biopsies following radiation therapy is one of the challenging areas in surgical pathology. Radiation treatment is a frequent choice for patients with clinically localized or locally advanced adenocarcinoma of the prostate. Many of these patients will be biopsied starting usually at 12-18 months following completion of treatment to monitor their response or to confirm or rule out the presence of recurrent/persistent tumor in case of rising PSA.

Radiation can induce a number of changes within non-neoplastic prostatic acini that mimic adenocarcinoma including nuclear enlargement and prominent nucleoli. These changes are usually pronounced when it occur in small atrophic glands. The distinction is critical for prognosis and treatment, as residual adenocarcinoma in post-radiation setting may become an indication for salvage radical prostatectomy.

Key histological features useful to separate from adenocarcinoma [40, 41]:
1) The diagnosis is best made at low power. Presence of atrophic lobular or randomly placed small to medium sized glands within the abundant stroma is a useful feature (Adenocarcinomas typically have an infiltrative appearance and look more typical of adenocarcinoma).

2) Presence of scattered marked cytological cytological atypia within well formed glands. Prostate carcinoma that are sufficiently differentiated to form glands rarely manifest the degree of cytological atypia seen with radiation, and if present would be more uniformly present in all cells. Nuclear chromatin appears degenerative with frequent prominent nucleoli and cytoplasmic vacuolization.

3) Basal cell markers are typically positive in atypical glands and very helpful in difficult cases [42].

Radiation atypia typically last for prolonged period of time after radiation treatment.

Histological features of residual carcinoma in post-radiation setting
Residual carcinoma in post-radiation setting may demonstrate radiation therapy effect or present without any evidence of radiation changes. In the first setting diagnosis can be particularly challenging, while in later instance adenocarcinoma look more typical as conventional or dedifferentiated adenocarcinoma.

Residual carcinoma demonstrating radiation changes:

1) Small clusters or haphazard glands with clear cells and "balloon" cytoplasm. The lack of immunoreactivity with basal cell markers very helpful in confirming the positive diagnosis.

2) Nuclei may appear pyknotic or there may be significant nuclear enlargement with prominent nucleoli. Nuclear atypia is usually uniform rather than scattered atypia seen in benign glands treated with radiation.

3) Paneth cell change in malignant epithelium

4) Stromal changes of fibrosis and atrophy similar to non-neoplastic prostate.

The Gleason grading in this setting of residual carcinoma demonstrating radiation changes is not applicable.

B) Mimics with Large Gland/Cribriform pattern resembling Gleason score 7-8 carcinoma:

Table 1 Spectrum of Cribriform Proliferations in Prostate

Benign
Central zone glands
Reactive glands 		Precursor Lesions
Cribriform HGPIN
Proliferative Lesions
Clear cell cribriform hyperplasia
Adenoid cystic-like basal cell hyperplasia 		Malignant Lesions
Cribriform carcinoma (Most [>95%] Gleason pattern 4 and rare Gleason pattern 3)
Adenoid cystic-like basaloid carcinoma

1) Central zone glands
Anatomically, prostate is divided into three zones: 1) central zone; 2) transition zone; and 3) peripheral zone. The central zone forms a cone-shaped volume surrounding the ejaculatory ducts with its apex at the verumontenum and its base at the bladder neck. The central zone glands may mimic HGPIN or rarely cribriform carcinoma. They are commonly encountered in needle biopsies particularly from the base biopsies.

Key histological features useful to separate from PIN and cancer [43, 44]:
1) Large, complex glands with numerous papillary infoldings which may demonstrate roman bridges and cribriform pattern

2) Cytologically, the glands are lined by tall-pseudostratified epithelium with dense eosinophilic cytoplasm. In contrast to HGPIN, nuclei stream parallel to glandular bridges. The cytological atypia seen is often of basal cell nature.

2) Reactive atypia in large glands
Medium to large glands in the setting of associated inflammation, ischemia or therapy may display reactive cytological atypia, distortion and metaplastic changes, which may simulate HGPIN or carcinoma.

Key histological features include:
1) The recognition of associated inflammation, infarction or therapy

2) Low power architecture of the glands with maintenance of basal cell compartment at higher power. In difficult cases basal cell IHC very helpful.

3) Adenoid cystic-like basal cell hyperplasia
While most form of basal cell hyperplasia is characterized by relatively small gland nest proliferation, the incomplete form of basal cell hyperplasia may be composed of medium to large glands with a complex cribriform pattern. The presence of typical areas of basal cell hyperplasia, lack of significant infiltration and absence of cytological atypia favor diagnosis of adenoid-cystic like basal cell hyperplasia over cribriform carcinoma.

4) Clear cell cribriform hyperplasia
Benign nodular hyperplasia occasionally displays area of prominent cribriform glands, which may dominate the histological picture. It is exclusively seen in TURP specimens representing the transition zone of the prostate gland. Cribriform hyperplasia enters the differential diagnosis of both HGPIN and cribriform carcinoma.

Key histological features useful to separate from carcinoma [46]:
1) Crowded proliferation of complex glands without cytological atypia. In most instances the cribriform glands have clear cytoplasm and uniform round lumina.

2) The cells comprising the central lumina are cuboidal to low columnar secretory-type cells with uniform round nuclei and clear cytoplasm.

3) Basal cells are prominently displayed around the periphery.

5) Cribriform HGPIN
HGPIN is discussed in detail in its section. In some cases there are atypical cribriform glands in which the differential is between cribriform PIN and cribriform Gleason pattern 3 cancer, where small glands of acinar adenocarcinoma are absent. Glands diagnostic of cribriform PIN occur in the setting of more ordinary high grade PIN. Cribriform glands tend to be few in number, or may only focally involve a gland. In difficult cases, when basal cells are identified, infiltrating cancer is ruled out. However, when only few glands are present PIN may completely lack basal cells and distinction may be impossible [45].

C) Mimics with fused glands/solid pattern resembling Gleason score 8-10 carcinoma:

1) Sclerosing adenosis
Sclerosing adenosis is a unique, rare proliferative lesion, which may get confused for high grade cancer. It is largely restricted to the transition zone of the prostate and generally is seen as an incidental finding in TURP or radical prostatectomy specimens [32, 33].

Key histological features useful to separate from adenocarcinoma:
1) Poorly circumscribed proliferation of variably sized and shaped glands in a dense spindle cellular stroma. The glands range from small and round to large and complex. They may be compressed with slit like lumens, and therefore at high magnification may be confused with high-grade Gleason pattern 4 or 5. The finding of only one or several small foci of a cellular lesion suspicious for high-grade carcinoma should prompt a consideration for sclerosing adenosis.

2) Basal cell layer usually present but frequently difficult to appreciate

3) Nucleoli are often prominent

4) Presence of unique hyaline sheath-like stroma surrounding some glands.

5) HMWCK 34bE12 positive in basal cell pattern, Basal cells undergo myoepithelial metaplasia and will stain positively for S-100 and muscle-specific actin.

2) Granulomatous prostatitis
Granulomatous prostatitis may simulate carcinoma both clinically as well as microscopically. Clinically prostate often feels firm to hard. Serum PSA is often elevated in range of 30-40 ng/ml with PSA > 4 ng/ml are seen in 84% of nonspecific granulomatous prostatitis [47]. When granulomatous and chronic inflammation is florid and diffuse, prostate ducts may not be appreciated and therefore it may raise the suspicion of high-grade Gleason pattern 5 carcinoma. The problem is often amplified if poor preservation or mechanical artifacts are present.

Key histological features useful to separate from carcinoma:
1) The recognition of inflammatory nature of infiltrate along with the association of epithelioid giant cells and fibrosis are very helpful features.

2) In difficult cases IHC for cytokeratins, PSA and lymphohistiocytic markers may be helpful.

Granulomatous prostatitis is usually non-specific but may be associated with BCG-therapy related changes or fungus and tuberculosis associated infections. In cases without history of BCG therapy special stains for microbial organisms may be helpful.

3) Paraganglion
Paraganglionic tissue is usually encountered within posterolateral periprostatic tissue in needle biopsy or radical prostatectomy specimens. They may simulate Gleason pattern 4 carcinoma.

Key histological features useful to separate from adenocarcinoma [48]:
1) Small, solid nests of cells with clear or amphophilic cytoplasm often with a "zellaballen" arrangement. An organoid type delicate vasculature is very helpful feature.

2) The cytoplasm is clear to amphophilic mimicking hypernephroid Gleason pattern 4.

3) PSA and PAP negative and neuroendocrine markers are positive.

Benign mimickers of adenocarcinoma of the prostate: helpful features to differentiate from cancer

Table 2 Benign Mimics of Prostate Cancer: General helpful hints to distinguish from prostate cancer

1) Hesitate to make diagnosis of prostate cancer when nuclei occupy almost full cell height and/or cytoplasm has same appearance as surrounding benign glands.
2) Presence of very cellular spindle stroma favor benign proliferative lesion.
3) Rarely prostate cancer may contain stratified nuclei like basal cell hyperplasia, but usually will have relatively abundant granular or amphophilic cytoplasm.
4) Prostate Cancer is typically characterized by more uniform cytological atypia. Random or scattered cytological atypia favor benign process.
5) Adenosis, atrophy and HGPIN lesions are typically characterized by fragmented and patchy basal cell staining pattern.
6) Majority of HGPIN, nephrogenic adenoma and some adenosis lesions express AMACR.

Table 3 Immunohistochemical Staining Pattern of Common Benign Mimics

Benign Mimic PSA/PAP 34βE12/p63 AMACR Other
Seminal vesicle - + - -
VMH + + - -
Cowper's glands -/+ (- PAP) Attenuated + - Mucicarmine +
Basal cell hyperplasia - + - -
Adenosis + Attenuated + -/+ -
Sclerosing adenosis + Attenuated + - S-100 +
MSE +
Nephrogenic adenoma - Cytoplasmic staining for 34βE12 in >50% +/- -
Radiation atypia + + - -
Atrophy + Attenuated + -/+ -
Cribriform HGPIN + Attenuated + +

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