PROSTATIC ADENOCARCINOMA, PROSTATIC INTRAEPITHELIAL NEOPL ASIA, AND INTRADUC TAL CARCINOMA Ming Zhou, MD, PhDa,b,c,d,e,*, Cristina Magi-Galluzzi, MD, PhDa,b,c,d,e KEYWORDS  Prostatic adenocarcinoma  Prostatic intraepithelial neoplasia  Intraductal carcinoma of the prostate

ABSTRACT

PROSTATIC ADENOCARCINOMA

P

Prostatic Adenocarcinoma: Overview

rostate carcinoma (PCa) exhibits a wide range of architectural and cytological features. Gleason grading remains as one of the most powerful histological prognostic parameters. However, it has evolved considerably. High-grade prostatic intraepithelial neoplasia (high-grade PIN) is accepted as a precursor lesion to PCa. Its detection in prostate biopsy is also considered as a risk factor for detecting cancer in subsequent biopsies. Such risk, however, has significantly decreased in recent studies. Intraductal carcinoma of the prostate (IDC-P) represents the intraductal spread of invasive cancer and constitutes a poor histologic parameter. This article reviews the key histological features of PCa, high-grade PIN and IDC-P, as well as the Gleason grading system that was most recently updated in 2005.

PCa is the most common noncutaneous malignancy in American men and is the third most common cancer in men worldwide.1 In 2008 there were an estimated 186,320 newly diagnosed cases and 28,860 deaths, which account for approximately 10% of all cancer deaths in men in United States.2 The prevalence rises dramatically with age. The disease is exceedingly rare before the age of 45 years and is uncommon before age 50 years. The prevalence is more than 45 times greater in men over 65 years than in those under 65 years.3 Multiple genetic and environmental factors have been implicated in the prostate carcinogenesis.4 Most PCa cases are asymptomatic and currently are detected by serum prostate-specific antigen (PSA) screening and digital rectal examination. About three

Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA c Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA d Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA e Department of Anatomic Pathology, Cleveland Clinic, L25, 9500 Euclid Avenue, Cleveland, OH 44195, USA * Corresponding author. Department of Anatomic Pathology, Cleveland Clinic, L25, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: [email protected] (M. Zhou). b

Surgical Pathology 1 (2008) 43–75 doi:10.1016/j.path.2008.08.001 1875-9181/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

surgpath.theclinics.com

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Zhou & Magi-Galluzzi fourths of cases arise in the peripheral zone, and some can result in abnormal digital rectal examinations. Rarely, PCa can lead to urinary obstruction when large tumor arises in the transition zone, extends into the transition zone from the peripheral zone, or invades the bladder neck. Locally aggressive PCa that involves the bladder and rectum can cause hematuria, rectal bleeding, or obstruction. Rarely, patients present with symptoms and signs that are related to PCa metastatic to other body sites, most commonly bone, regional lymph nodes, lung, and brain.

Key Pathologic Features PROSTATIC ADENOCARCINOMA Gross appearance PCa appears firm, solid, white-gray to yelloworange, in contrast to tan, spongy benign prostatic tissue. Cancer detected by PSA screening often is not grossly visible. Architectural features Haphazard glandular arrangement Infiltrative growth

Prostatic Adenocarcinoma: Gross Features

Less-differentiated glands with cribriform or fused glands, cords, sheets, or single tumor cells

In contrast to benign prostate tissue that appears tan and spongy, grossly evident PCa is firm, solid, and ranges in color from white-gray to yellow-orange.5 With PSA screening, small tumors of low stage are being detected more often, and PCa becomes less visible grossly.

Typically small glands with straight luminal borders Cytologic features Relatively uniform cytologic features Pale to amphophilic cytoplasm No lipofuscin pigment

Prostatic Adenocarcinoma: Microscopic Features

Nuclear features

PCa has a constellation of architectural, cytoplasmic, nuclear, and intraluminal features.6,7

Nuclear enlargement Hyperchromasia Variably prominent nucleoli

Architecture

Mitosis and apoptotic bodies rarely seen

PCa can exhibit one or several architectural patterns that are significantly different from those of benign glands. The most characteristic pattern is the infiltrative pattern with cancer glands situated between or on both sides of benign glands (Fig. 1A). This pattern indicates the invasive nature of PCa, because PCa in general does not induce the desmoplastic stromal response characteristic of other types of cancer. In contrast, a benign process usually maintains a lobular architecture. Cancer glands can also form a focus with closely packed, pale, small glands (Fig. 1B). The focus often is well circumscribed without an infiltrative pattern. In such cases, the differential diagnosis always should include a PCa that arises in the anterior or transition zone and adenosis (atypical adenomatous hyperplasia). The cancer glands also can display a haphazard growth and dissect stroma and smooth muscle bundles without accompanying benign glands (Fig. 1C). They also can form large cribriform structures with irregular and infiltrative borders (Fig. 1D). Finally, they can grow in single cells or cords of cells (Fig. 1E).

Intraluminal features

Absence of Basal Cells

Crystalloids Blue mucin Pink amorphous secretion Cancer-specific features Mucinous fibroplasia (collagenous micronodules) Glomeruloid formation Perineural invasion

PCa, typically in high-grade cancer and following treatment, PCa in general lacks basal cells. The lack of a basal cell layer is not always reliably observed on hematoxylin and eosin slides but can be confirmed with immunostaining for basal cells, including high-molecular-weight cytokeratin and P639 (Fig. 2).

Cytoplasm 8

The absence of basal cells is the hallmark of PCa . Although basal cells may be detected rarely in

In contrast to benign glands that have irregular and undulating luminal borders, PCa glands are

Prostatic Adenocarcinoma Fig. 1. Architectural patterns of PCa. (A) Cancer glands display an infiltrative growth pattern with malignant glands situated between or flanking benign glands. (B) They also can form a focus with closely packed, pale, and small glands.

smaller and have straight luminal borders. They may have amphophilic cytoplasm that is evident even at low magnification (Fig. 3). Low-grade PCa, however, often has pale, clear cytoplasm similar to that of benign glands. PCa typically lacks lipofuscin pigment that can be found in benign glands.

nucleoli (Fig. 4). Some PCas may lack prominent nucleoli but have enlarged and hyperchromatic nuclei. Mitoses and apoptotic bodies, which are found rarely in benign glands, are somewhat more common in PCa, although they still are not commonly seen in malignant glands. Cancer nuclei, even in poorly differentiated ones, show relative uniformity in size and shape.

Nuclei PCa invariably displays atypical nuclear features distinct from the surrounding benign glands, including nuclear enlargement and prominent

Intraluminal Contents Crystalloids, dense eosinophilic crystal-like structures found within the glandular lumens (Fig. 5A),

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Zhou & Magi-Galluzzi Fig. 1. (C) The cancer glands display haphazard growth and dissect stroma and smooth muscle bundles without accompanying benign glands. They also can form (D) large cribriform structures with irregular and infiltrative borders or, as shown on the following page, grow in single cells or cords of cells.

are more common in cancer than in benign glands, although they also are found frequently in adenosis. Intraluminal pink, amorphous, dense secretions (Fig. 5B) and blue-tinged mucin (Fig. 5C) are additional findings seen preferentially in PCa. In contrast, corpora amylacea are common in benign glands and are not seen in PCa.

Tumor Stroma Ordinary PCa does not elicit a stromal inflammatory or desmoplastic response. Ductal prostate

adenocarcinoma, however, may induce such stromal reactions with fibrosis and hemosiderin-laden macrophages.

Cancer-Specific Histologic Features Three histologic features are considered specific for PCa, because they have not been described in benign glands. Mucinous fibroplasia, or collagenous micronodules, occurs as delicate fibrous tissue with ingrowth of fibroblasts within or adjacent to cancer glands (Fig. 6A). Glomeruloid formation

Prostatic Adenocarcinoma Fig. 1. (E) The cancer glands can grow in single cells or cords of cells.

is created by intraluminal proliferation of cancer cells and often is surrounded by a crescentic space, superficially resembling a renal glomerulus (Fig. 6B). Perineural invasion represents tight circumferential or nearly circumferential encircling of a nerve by cancer cells (Fig. 6C). Occasionally, intraneural invasion of cancer cells can be seen

Fig. 2. Lack of basal cells in prostate carcinoma confirmed by the immunostain for a basal cell marker P63.

also. The cancer cells in perineural or intraneural invasion may have paradoxically bland nuclear features and may mimic benign glands. Benign prostatic glands occasionally can lie adjacent to and press on a nerve, a finding termed ‘‘perineural indentation by benign prostatic glands,’’ but benign glands do not encircle a nerve tightly.

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Zhou & Magi-Galluzzi Prostatic Adenocarcinoma: Differential Diagnosis PCa should be differentiated from many other benign and malignant prostate lesions (Table 1) that may cause architectural and/or cytologic atypia and therefore may be mistaken for cancer by unwary eyes. In many instances the differential is with normal prostatic and nonprostatic structures, including seminal vesicles/ejaculatory duct epithelium, Cowper’s gland, paraganglia, and mesonephric duct remnants. Benign prostatic lesions such as inflammation, atrophy (simple atrophy, partial atrophy, and postatrophic hyperplasia), metaplasia (urothelial, squamous, and mucinous), basal cell hyperplasia, benign prostatic hyperplasia, and benign prostatic glands with radiation and hormonal treatment effects can simulate PCa to varying degrees. On the other hand, PCa may exhibit only mild architectural or cytologic atypia, making it difficult to distinguish between malignant and benign prostate conditions. For example, a well-differentiated Gleason score 2 to 4 PCa, although rarely encountered, always should be differentiated from adenosis. Cribriform PCa should be distinguished from benign cribriform hyperplasia or cribriform high-grade PIN. Atrophic and foamy gland PCa may be confused with benign atrophy and xanthoma, respectively. Pseudohyperplastic PCa shares some architectural features with benign prostatic hyperplasia, although the former invariably has significant nuclear atypia. Careful evaluation of the architectural and

Differential Diagnosis PROSTATIC ADENOCARCINOMA 1. Normal prostatic/nonprostatic tissue (seminal vesicle/ejaculatory duct, verumontanum glands, Cowper’s glands, paraganglia, mesonephric remnants) 2. Benign lesions (atrophy, partial atrophy, postatrophic hyperplasia, urothelial/squamous metaplasia, basal cell hyperplasia, adenosis, sclerosing adenosis, inflammation, nonspecific granulomatous prostatitis, benign prostatic hypertrophy) 3. Benign prostatic tissue with treatment effect (radiation atypia) 4. High-grade PIN 5. Other malignant lesions of non-acinar type (urothelial, small cell, basal cell, and squamous cell carcinoma)

cytologic features and prudent use of basal cell markers and a-methylacyl coenzyme A racemase (AMACR) should lead to a correct diagnosis. PCa also should be differentiated from other non-acinar adenocarcinoma. Rarely, the prostate gland can be involved by primary urothelial carcinoma, small cell carcinoma, mucinous carcinoma, and signet-ring cell carcinoma. Such a diagnosis should be made only after a metastasis from other

Fig. 3. PCa glands with amphophilic cytoplasm.

Prostatic Adenocarcinoma

Fig. 4. PCa cells with enlarged nuclei and prominent nucleoli.

sites has been diligently excluded, however, because metastasis is far more common than non-acinar adenocarcinoma. Small cell carcinoma, urothelial carcinoma, and lymphoma should always be considered and ruled out for a highgrade PCa with a solid growth pattern and little or no glandular differentiation.

Prostatic Adenocarcinoma: Diagnosis Many histologic features are important for the diagnosis of PCa, but only three—collagenous micronodules (mucinous fibroplasia), glomerulation, and perineural invasion—are diagnostic of PCa. Furthermore, these three features are present only infrequently in PCa diagnosed by prostate biopsy. Therefore in most cases the diagnosis of cancer relies on other histologic features. These histologic features are categorized as major diagnostic criteria, which are present in most cases of PCa, and minor diagnostic criteria, which are present in only a minority of cases (Box 1).7,10,11 None of these features, however, is specific and diagnostic for PCa. Therefore, a definitive cancer diagnosis requires a constellation of major and minor criteria. Before a definitive cancer diagnosis is established, one must rule out any noncancerous

conditions that may cause architectural and cytologic atypia (Box 2).12–16 Benign glands with intense inflammation, especially acute inflammation, can cause both architectural and cytologic atypia resembling that seen in cancer. Benign glands with atrophic cytoplasm, including partial atrophy and postatrophic hyperplasia, can present as small crowded glands with nuclear atypia, although the degree of the nuclear atypia often is mild and prominent nucleoli should be absent. When the atypical glands form a relatively well-circumscribed focus, adenosis always should be ruled out before the diagnosis of well-differentiated, Gleason grade 5 or less cancer is rendered. Last, a small focus of atypical glands immediately adjacent to high-grade PIN may represent a focus of microinvasive cancer17 or tangential/out-pouching from the high-grade PIN glands (Fig. 7). The diagnostic criteria do not include the quantitative threshold for the number of glands required to make a cancer diagnosis. Most urologic pathologists require at least three glands to make a cancer diagnosis with confidence,10 although a cancer diagnosis can be made in the presence of fewer than three neoplastic glands if other characteristic architectural and cytologic features of PCa are present.

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Fig. 5. (A) PCa with crystalloids found within the glandular lumina. (B) Intraluminal pink, acellular, dense secretions are common findings.

A practical approach for diagnosis of PCa is shown in Fig. 8. A cancer diagnosis requires that all three criteria be satisfied, including the presence of architectural atypia, the presence of cytologic atypia, and the exclusion of benign conditions that may cause such architectural and cytologic atypia. If any one of these three criteria is not met, a cancer diagnosis cannot be made, and additional studies, including immunohistochemistry and deeper sections, should be

performed to try to arrive at a more definitive diagnosis.

Prostatic Adenocarcinoma: Prognosis The clinical outcomes for patients who have PCa are highly variable and depend on many host and tumor parameters and on response to therapy. Several clinicopathologic parameters, including preoperative serum PSA, Gleason grade, TNM stage, and surgical margin status, have been

Prostatic Adenocarcinoma Fig. 5. (C) PCa with bluetinged mucin also are common findings.

proven to have prognostic significance and to be useful in clinical management. Other factors, including DNA ploidy, tumor volume, and histologic subtypes, have been studied extensively. Their importance, however, remains to be validated in large multicenter trials. Some other factors, including perineural invasion, neuroendocrine differentiation, microvessel density, nuclear features other than ploidy, proliferation markers, and a variety of molecular markers, have not been studied sufficiently to demonstrate their prognostic value.

Pitfalls PROSTATIC ADENOCARCINOMA ! Cancer-specific histologic features (mucinous fibroplasia, glomerulation, and perineural invasion) infrequently are present in prostate biopsies; therefore in most cases a cancer diagnosis requires a constellation of architectural and cytologic features and the exclusion of benign conditions that may cause architectural and cytologic atypia.

PROSTATIC ADENOCARCINOMA: GLEASON GRADING SYSTEM Based on the architectural features of PCa, the Gleason grading system was proposed first by Dr. Donald Gleason in 1960s.18,19 In this system, PCa is categorized into one of five patterns (Gleason patterns 1–5) representing a morphologic continuum of decreasing glandular differentiation (Fig. 9A). Another unique feature of this system is that instead of assigning a single worst grade, the most prevalent and second most prevalent patterns are summed to obtain the final Gleason grade. The Gleason grading system currently is the most widely used system and has been endorsed by the World Heath Organization. Numerous reports have confirmed the significance of Gleason grade in predicting outcome in patients undergoing various treatment modalities, including surveillance, radical prostatectomy, and radiation therapy.20–24 In patients receiving neoadjuvant or adjuvant hormonal therapy, the Gleason grade also has been found to be an independent predictor of biochemical failure.20 The Gleason grading system has evolved significantly since its inception 40 years ago. It was modified most recently in 2005 following the recommendations of the International Society of Urological Pathology.25 There are several arguments for a contemporary approach to the Gleason grading system, including changed clinical

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Fig. 6. PCa-specific features. (A) Mucinous fibroplasias consists of delicate fibrous tissue with ingrowth of fibroblasts within or adjacent to cancer glands. (B) Glomeruloid formation is formed by intraluminal proliferation of malignant cells and often is surrounded by a crescentic space.

characteristics of PCa resulting from wide-spread PSA screening and transrectal ultrasound-guided needle biopsies, improved pathologic diagnosis resulting from the use of immunohistochemical markers, and the recognition of new histologic variants and tertiary Gleason patterns. The new Gleason grading scheme is summarized in Fig. 9B. The significant changes include a more stringent definition of Gleason pattern 3 cribriform glands and the grading of poorly formed glands as pattern 4.

PCa Gleason Pattern 1 Gleason pattern 1 consists of well-circumscribed nodules of closely packed but separate, uniform, round to oval, medium-sized acini (Fig. 10A). With the use of basal cell immunohistochemistry, however, most cases that once would have been diagnosed as Gleason score 1 1 1 5 2 now are identified as adenosis. Therefore, except for extremely rare exceptions, Gleason pattern 1 is a grade that should not be diagnosed regardless of the types of the specimen.

Prostatic Adenocarcinoma Fig. 6. (C) In perineural invasion, cancer glands entirely or partially encircle a nerve.

PCa Gleason Pattern 2

PCa Gleason Pattern 4

In Gleason pattern 2 the cancer glands form fairly circumscribed nodules, but there may be minimal infiltration at the periphery (Fig. 10B). The cancer glands demonstrate moderate variation in size and shape, with a looser arrangement and more atypia in cancer cells than seen in Gleason pattern 1. Cribriform glands are not permitted in Gleason pattern 2. Gleason pattern 2 is found occasionally in transurethral resection of the prostate and in multifocal low-grade cancer within the radical prostatectomy specimens. With needle biopsy, a diagnosis of Gleason grade 2 1 2 5 4 is rarely possible, because one must visualize the entire cancer nodule that often is sampled only partially by prostate biopsy. Because of poor reproducibility, lack of correlation between biopsy and prostatectomy Gleason grade, sampling error, and potential misunderstanding of the clinical implications, a Gleason grade of 3 or 4 should be stated rarely, if ever, in needle biopsy.

Fused glands, large or irregular cribriform glands, and ill-defined glands with poorly formed glandular lumina are graded as Gleason pattern 4 (Fig. 10E and F). Hypernephroid morphology in which fused glands have clear or very pale cytoplasm and superficially resemble clear cell renal cell carcinoma is encountered rarely. Gleason pattern 4 constitutes an important clinical decision-making point, because the presence of any Gleason pattern 4 signals clinically significant disease, and a different therapeutic modality may be indicated.

PCa Gleason Pattern 3

PROSTATIC INTRAEPITHELIAL NEOPLASIA

In Gleason pattern 3, there are discrete glandular units, typically smaller glands than in Gleason pattern 1 or 2, with infiltrates in and among benign glands (Fig. 10C). The cancer glands typically vary markedly in size and shape. Only cribriform glands similar in size to normal glands and with smooth noninfiltrative contours are considered as Gleason pattern 3 (Fig. 10D). Gleason pattern 3 is the most common grade encountered in needle biopsy specimens.

PCa Gleason Pattern 5 Gleason pattern 5 is graded when there is essentially no glandular differentiation, and tumor is composed of solid sheets, cords, or single cells (Fig. 10G and H). Comedocarcinoma with central necrosis surrounded by papillary, cribriform, or solid masses also is graded as pattern 5 (Fig. 10I).

Prostatic Intraepithelial Neoplasia: Overview ‘‘Prostatic intraepithelial neoplasia’’ is the preferred diagnostic term for a putative premalignant proliferation of atypical epithelial cells within the pre-existing prostatic ducts and acini.26 It can be diagnosed only by histology, because there are no specific clinical or radiologic findings, and serum PSA is not elevated.

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Box 1 Histologic criteria for diagnosis of prostate carcinoma

Key Pathologic Features PROSTATIC INTRAEPITHELIAL NEOPLASIA

Major criteria Architectural: infiltrative growth, small crowded glands, confluent/irregular cribriform glands, single/cords of cells Loss of basal cells Nuclear atypia: nuclear and nucleolar enlargement, hyperchromasia Minor criteria Intraluminal blue mucin Pink amorphous secretions Mitotic figures and apoptotic bodies Crystalloids

1. Appearance: high-grade PIN with luminal cell crowding, irregular spacing, and ‘‘piling-up’’ with chromatin hyperchromasia and clumping, and prominent nucleoli 2. Architectural patterns: flat, tufting, micropapillary, and cribriform 3. Histologic variants: signet-ring, mucinous, inverted, and small cell neuroendocrine carcinoma 4. Staining for basal cells may be complete, discontinuous, or occasionally absent. AMACR is detected in majority of high-grade PIN.

Adjacent high-grade PIN Amphophilic cytoplasm

PIN can be categorized as low grade and high grade based on the severity of architectural and cytologic atypia. The prevalence of high-grade PIN increases with age. The incidence of highgrade PIN in prostate needle biopsies varies from 0% to 24.6% with a mean of 7.7% (median, 5.2%), although it is present in almost all radical prostatectomies.

Prostatic Intraepithelial Neoplasia: Microscopic Features PIN glands have architecture similar to that of the adjacent benign glands but appear darker because of their higher nuclear density and increased cytoplasmic eosinophilia or amphophilia (Fig. 11A). Low-grade PIN shows crowding of luminal secretory cells and irregular nuclear spacing and stratification. Nuclei are enlarged and vary in size, although the chromatin appears normal and nucleolar prominence is rare or absent. The basal cell layer is intact. It is difficult to distinguish

Box 2 Histologic features suggesting a diagnosis other than prostate carcinoma Atypia associated with inflammation Atrophic cytoplasm Small glands merging with benign glands with indistinct cytoplasm and cytology Presence or mixture of adjacent PIN

reproducibly low-grade PIN from normal or hyperplastic epithelium; therefore, a diagnosis of lowgrade PIN is not recommended. Cytologically individual cells in high-grade PIN are enlarged more uniformly with less nuclear variation than seen in low-grade PIN. Many cells show large and prominent nucleoli and hyperchromatic and clumpy chromatin (Fig. 11B), similar to that seen in PCa. The basal cell layer often is discontinuous and occasionally can be absent. There are four major structural patterns (Fig. 12A–D),27 and several minor variations for high-grade PIN, including tufting (56%), micropapillary (29%), flat (15%), and cribriform (0%–5%). Uncommon to rare variants include inverted PIN, in which nuclei are aligned along the luminal surface rather than the basal aspect. The cells lining the high-grade PIN glands have nucleomegaly, coarse and hyperchromatic chromatin, and prominent nucleoli. Occasionally, they may exhibit neuroendocrine, signet-ring cell, and other features.28,29 These structural patterns are mentioned for diagnostic consideration and in general do not have any clinical significance.

Prostatic Intraepithelial Neoplasia: Differential Diagnosis Several histologic variations of normal prostatic glands and structures, including central zone glands and seminal vesicle or ejaculatory duct epithelium, should be recognized and distinguished from high-grade PIN. Prominent nucleoli are not present in these structures. High-grade PIN may involve central zone glands, however. Benign, non-neoplastic conditions, including prostate glands and ducts adjacent to inflammation

Prostatic Adenocarcinoma

Differential Diagnosis PROSTATIC INTRAEPITHELIAL NEOPLASIA  Prostatic central zone glands  Seminal vesicle/ejaculatory duct epithelium  Reactive atypia caused by inflammation, infarction, or radiation  Metaplasia (transitional cell, squamous cell)  Hyperplasia (clear cell cribriform hyperplasia, basal cell hyperplasia)  PCa with cribriform pattern  Ductal adenocarcinoma  Urothelial carcinoma

or infarction, squamous and transitional cell metaplasia, and benign glands after irradiation, also may cause architectural and cytologic atypia that may be mistaken for high-grade PIN. Basal cell hyperplasia often appears as small and solid nests, although some may retain lumens, in contrast to medium- to large-caliber glands affected by high-grade PIN. When prominent nucleoli are present, but the nucleoli are in the basal cells rather than in secretory cells, the term ‘‘atypical basal cell hyperplasia’’ is used. Fig. 7. High-grade PIN with adjacent small focus of atypical glands. Adjacent to a high-grade PIN gland are several small glands suspicious for cancer. They may represent a minute focus of invasive prostate carcinoma or tangential sectioning/ outpouching from the high-grade PIN gland.

One often can find secretory cells on top of the hyperplastic basal cells. Immunohistochemically, basal cell hyperplasia is positive for basal cell markers; the apical secretory cells are not, and only residual basal cells are highlighted by such stains in high-grade PIN. Although exhibiting cribriform architecture at low magnification, clear cell cribriform hyperplasia does not display cytologic atypia and frequently has a prominent basal cell layer that forms a collarette around the gland. Differentiating high-grade PIN from invasive cribriform PCa and IDC-P is more problematic. Invasive cribriform PCa lacks basal cell lining. The most salient histologic feature that distinguishes IDC-P from high-grade PIN is the presence of multiple cribriform glands with prominent nuclear atypia and comedonecrosis. Occasionally, ductal adenocarcinoma may arise in peripheral zone, or ordinary acinar PCa may have focal features resembling ductal adenocarcinoma. In addition, ductal adenocarcinoma usually retains basal cell layers. The papillae in ductal adenocarcinoma have true fibrovascular cores, however, and cells may show significant nuclear atypia with a high mitotic rate and extensive necrosis, features uncommon in high-grade PIN. When involving prostatic ducts and acini, urothelial carcinoma replaces the ductal–acinar epithelium with predominantly solid, highly atypical, and mitotically active neoplastic cells. The cytoplasm of these cells is dense or

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Fig. 8. A practical approach for diagnosis of prostate carcinoma in prostate biopsy. ATYP, atypical glands suspicious for PCa; IHC, immunohistochemistry.

Architectural Atypia

Cytological Atypia

Rule out benign conditions that may cause architectural/cytological atypia Any 1 absent

All 3 present

Atypical glands suspicious for PCa (ATYP)

PCa

Additional study (deeper sections, IHC)

PCa

Benign

ATYP

‘‘hard’’ and may show squamous differentiation, compared with the granular cytoplasm of PIN. Immunohistochemically, urothelial carcinoma cells are positive for cytokeratin K903 and P63 but are negative for prostate-specific markers such as PSA.

biopsy shows benign prostatic tissue. Therefore, the finding of low-grade PIN is not associated with an increased risk for detecting cancer in subsequent biopsies.30–33 Second, the diagnostic reproducibility for low-grade PIN is poor, even among expert uropathologists.6

Prostatic Intraepithelial Neoplasia: Diagnosis

Prostatic Intraepithelial Neoplasia: Immunohistochemistry

PIN glands retain benign architecture but appear basophilic at scanning power because of cytoplasmic amphophilia, nuclear crowding, and hyperchromasia. Several studies have shown that good distinction between low-grade and highgrade PIN can be achieved. The prominent nucleoli are the best discriminator between the two. There is no consensus as to what constitutes prominent nucleoli, but the presence of distinct nucleoli visualized at 20 magnification in even a few cells qualifies as prominent nucleoli, and therefore a diagnosis of high-grade PIN can be established. In contrast, low-grade PIN may have nuclear enlargement and stratification, but at higher magnification it has only inconspicuous or tiny nucleoli. In the absence of prominent nucleoli, the presence of mitosis and significant nuclear pleomorphism also can be used to diagnose high-grade PIN. There are two reasons that low-grade PIN should not be diagnosed in prostate biopsy. First, the finding of low-grade PIN in a needle biopsy is not associated with an increased risk for detecting cancer in subsequent biopsies. Cancer is found in approximately 18% of patients who undergo repeat biopsy after a first biopsy shows low-grade PIN. On the other hand, PCa is found in 20% of patients who undergo a repeat biopsy after a first

High-grade PIN is positive for pan-cytokeratins (AE1/3 and Cam5.2) and for the prostate-specific markers PSA and prostate-specific acid phosphatase. Stains for basal cells demonstrate complete, discontinuous, or even occasionally absent basal cell layers. Expression of AMACR is detected in most high-grade PIN.

Prostatic Intraepithelial Neoplasia: Prognosis The importance of recognizing high-grade PIN in needle biopsy lies in its association with PCa in

Pitfalls PROSTATIC INTRAEPITHELIAL NEOPLASIA ! The cancer risk associated with high-grade PIN has decreased to 25% in recent studies, similar to that associated with an initial benign diagnosis and lower than the previously reported cancer risk. Therefore, stringent diagnostic criteria for high-grade PIN should be employed. ! Basal cells occasionally may be absent in highgrade PIN, especially in small focus.

Prostatic Adenocarcinoma

Fig. 9. Gleason grading system for prostate carcinoma. (A) Original standardized drawing for grading prostate carcinoma. (From Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep 1966;50:125– 28.)

repeat biopsy.11,17,34,35 Therefore, patients who have a diagnosis of high-grade PIN in needle biopsy are advised to undergo repeat biopsies. The cancer risk in recently performed studies varies widely from that in studies that were performed in the early 1990s. In studies performed in the early 1990s, the average risk of cancer associated with high-grade PIN was 36%. In studies performed between 1995 and 1999, the risk dropped to 28%. In studies performed after 1999, the risk decreased further to 21%.36 In contemporary series, the cancer risk associated with high-grade

PIN is around 25%, only slightly higher than that associated with a benign diagnosis.11 Most studies comparing the cancer risk following a needle biopsy diagnosis of high-grade PIN and the cancer risk following a benign needle biopsy diagnosis show no difference between the two groups. Clinical variables, including PSA level, PSA velocity, findings on digital rectal examination or transurethral resection, and a family history of PCa, do not seem to predict the cancer risk associated with a diagnosis of high-grade PIN on prostate biopsy. Histologic variables, such as the number of

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Zhou & Magi-Galluzzi Fig. 9. (B). Modified Gleason grading system. (From Epstein JI, Allsbrook WC Jr, Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference of Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005; 29(9):1228–42; with permission.)

Prostatic Adenocarcinoma

Fig. 10. Gleason grading of PCa. (A) Pattern 1: cancer glands, which are closely packed but are separated and are of intermediate size and are similar in size and shape, form a well-circumscribed nodule. (B) Pattern 2: cancer glands are medium sized with some degree of variation in size and shape, have a looser arrangement, and form a circumscribed nodule with occasional peripheral infiltration.

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Zhou & Magi-Galluzzi Fig. 10. (C) Pattern 3: the cancer glands infiltrate between the adjacent benign glands. Cribriform glands are small and have smooth, round contours. (D) Pattern 4: cribriform glands are large and have irregular contours and jagged edges.

Prostatic Adenocarcinoma Fig. 10. (E) Poorly formed glands still have glandular configuration but have ill-formed glandular lumens. (F) Pattern 5: cancer cells form

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Zhou & Magi-Galluzzi Fig. 10. (G) solid sheets, (H) strands, or single cells invading the stroma.

Prostatic Adenocarcinoma Fig. 10. (I) Comedonecrosis is present.

cores involved by high-grade PIN and the extent of the involved cores and the type of high-grade PIN, as well as molecular and genetic attributes, do not influence the cancer risk in most studies. In a recent review article, the authors recommend that patients do not need a routine biopsy within a year following the diagnosis of high-grade PIN,11 and the patient and the treating physician should decide whether repeat biopsies should be performed beyond 1 year from the diagnosis of high-grade PIN. Several recent studies, however, suggest that in certain clinical scenarios highgrade PIN confers a much higher cancer risk than that reported in the literature. For example, one study found a 39% risk of finding PCa on repeat biopsies obtained after an initial diagnosis of widespread high-grade PIN that involved four or more biopsy cores and supported the need for repeat biopsy in this subset of patients.37 Another example is a prostate biopsy with a diagnosis of atypical glands suspicious for cancer (ATYP); repeat biopsies will detect cancer in 45% to 60% of patients with such a diagnosis. In a recent study by Ramirez and colleagues,38 however, the risk of cancer in patients who had both ATYP and highgrade PIN was 57%, compared with 40% in patients who had only ATYP.

INTRADUCTAL CARCINOMA OF THE PROSTATE Intraductal Carcinoma, Prostate: Overview It has been recognized that some ‘‘invasive,’’ Gleason pattern 3 to 5 prostatic adenocarcinomas actually have basal cell layers seen on light microscopic examination or, more commonly, on immunostains for basal cells. In the past, these lesions were diagnosed variably as high-grade PIN or as ductal-type prostatic adenocarcinoma. McNeal and colleagues39 first suggested that the finding may represent an aggressive form of prostatic adenocarcinoma, because it almost never is seen in the absence of an invasive component. If present, the invasive component almost always is high grade and has large tumor volume. The term ‘‘intraductal prostatic carcinoma’’ was proposed.

Intraductal Carcinoma, Prostate: Microscopic Features The enlarged prostate acini and ducts are filled with cytologically malignant cells. The basal cell layers are present or at least are partially preserved and can be confirmed by immunostains

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Key Pathologic Features INTRADUCTAL CARCINOMA OF THE PROSTATE 1 The prostate acini are enlarged, and the ducts are filled with cytologically malignant cells with complete or partial preservation of basal cell layers. 2 There are three major histologic patterns: trabecular, cribriform, and solid, with or without comedonecrosis. 3 ICD-P invariably is associated with high-grade and large-volume PCa seen in radical prostatectomy.

for basal cells (Fig. 13E). In radical prostatectomies, the IDC-P glands are intermingled with or are in the immediate vicinity of high-grade (Gleason pattern 4/5) and high-volume PCa. Several architectural patterns can be observed,40 including the trabecular, in which cellular columns two cells thick span the lumen and create elongated elliptic and crescent-shaped spaces between them (Fig. 13A); the classic cribriform type, with thick cell cords separated by uniform, punched-out round spaces (Fig. 13B); and the solid pattern with a solid mass of cells (Fig. 13C). Central comedonecrosis is present occasionally (Fig. 13D). Cytologically, IDC-P frequently has two cell populations: peripheral cells that are tall, pleomorphic, and mitotically active, and central cells with abundant cytoplasm that are cuboidal, monomorphic, and quiescent.

Differential Diagnosis INTRADUCTAL CARCINOMA OF THE PROSTATE  Central zone morphology  Cribriform clear cell hyperplasia  Cribriform high-grade PIN  Cribriform PCa  Urothelial carcinoma involving prostate ducts and acini  Metastatic carcinoma (eg, colorectal carcinoma) to the prostate

Intraductal Carcinoma, Prostate: Differential Diagnosis Normal histologic variations, such as central zone prostate glands, and benign glandular proliferation, such as cribriform clear cell hyperplasia, can present as cribriform structures. Nuclear atypia, mitosis, and comedonecrosis are absent, however. Cribriform high-grade PIN is rare. The glands are small with round contour. The cells are relatively uniform without marked nuclear pleomorphism or necrosis. Unlike IDC-P, invasive cribriform cancer lacks basal cell lining. Intraductal spread of urothelial carcinoma, either from the bladder primary or, exceedingly rarely, from the prostate primary, may mimic IDC-P. Cytologically, urothelial carcinoma typically is more pleomorphic than IDC-P. A panel of immunostains often can resolve the diagnostic ambiguity. IDC-P stains positive for prostate-specific markers, including PSA, PAP, prostate-specific membrane antigen, and P501S, whereas stains for basal cells, such as CK5/6, 34bE12, and P63, are positive only in the basal cells at the periphery of the cancer glands. In contrast, urothelial carcinoma is negative for prostatespecific markers and often is positive for the markers that recognize the prostate basal cells. Metastatic adenocarcinoma from other sites, colorectal adenocarcinoma in particular, may have extensive necrosis and mimic IDC-P. Clinical history and prudent use of immunostains (CDX-2 for colorectal adenocarcinoma) can lead to a correct diagnosis.

Intraductal Carcinoma, Prostate: Diagnosis Cohen and colleagues40 proposed five major criteria that are critical to the diagnosis of IDC-P and several minor criteria that are helpful and support this diagnosis. The major criteria that always are present in IDC-P include (1) large-caliber glands that are more than twice the size of normal peripheral zone gland structures and (2) are lined by basal cells as identified with basal cell markers. These glands are filled with cytologically malignant cells (3) that always span the entire glandular lumen (4). The fifth major criterion, central comedonecrosis, although not always present, is a common finding in IDC-P but is exceedingly rare in high-grade PIN. Minor criteria include frequent right-angle branching and rounded contours in IDC-P glands in contrast to the undulating outlines of benign glands and high-grade PIN. Guo and colleagues41 also proposed a set of morphologic criteria in prostate biopsy that define IDC-P as malignant epithelial cells filling large acini and prostatic ducts with at least partial

Prostatic Adenocarcinoma

Fig. 11. High-grade PIN. (A) At low magnification, high-grade PIN glands (left) have architecture similar to but appear darker than the adjacent normal glands (right). (B) Secretory cells show nuclear crowding and stratification. Nuclei are enlarged with coarse and hyperchromatic chromatin and prominent nucleoli.

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Fig. 12. Architectural patterns of high-grade PIN. Secretory cells form (A) undulating mounds (tufted pattern) or (B) cellular columns without fibrovascular cores (micropapillary pattern).

Prostatic Adenocarcinoma Fig. 12. (C) The flat pattern has no significant architectural changes. (D) The cribriform pattern has complex architecture with Roman bridges and cribriform formations.

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Fig. 13. Intraductal carcinoma of the prostate. Several architectural patterns can be observed, including (A) the trabecular pattern, in which two-cell-thick cellular columns span the lumen and create elongated elliptic and crescent-shaped spaces between them; (B) the classical cribriform type, with thick cell cords separated by uniform punched-out round spaces; and (C) the solid pattern with a solid mass of cells.

Prostatic Adenocarcinoma Fig. 13. (D) Central comedonecrosis occasionally can be present.

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Zhou & Magi-Galluzzi Fig. 13. (E) The basal cell layers are present or at least are partially preserved and can be confirmed by P63 immunostain.

preservation of basal cells forming either solid or dense cribriform patterns or loose cribriform or micropapillary patterns with either marked nuclear atypia (nuclear size six times normal or larger) or comedonecrosis.

Pitfalls INTRADUCTAL CARCINOMA OF THE PROSTATE ! IDC-P is difficult to diagnose and differentiate from cribriform high-grade PIN on prostate biopsy with limited material. ! Any atypical cribriform lesions with significant cytologic atypia or comedonecrosis should be regarded as IDC-P.

Intraductal Carcinoma, Prostate: Prognosis The importance of recognizing IDC-P lies in its association with a poorer prognosis than otherwise would be attributed to either high-grade PIN or Gleason pattern 3 cancer (for review, see40). IDC-P is associated with high-grade and high-volume cancer39,42,43,44 and has been found to have prognostic significance independent of Gleason grade, pathologic stage, and tumor volume.43,44 Therefore, the presence of IDC-P should be sought and reported in radical prostatectomy. IDC-P deserves special mention in reports of prostate biopsy. If a high-grade (Gleason pattern 4 or 5) invasive component is present with IDC-P, the diagnosis of IDC-P seems to be of academic interest. When associated with a Gleason pattern 3 component, however, IDC-P should be documented, and its poor prognostic significance should be mentioned. One solution could be grading the IDC-P component as pattern 4 or 5. If IDC-P is not associated with an invasive component in prostate biopsy, however, it is more difficult to distinguish from cribriform high-grade PIN, and it is prudent to diagnose it as IDC-P with a comment that IDC-P is often associated with high-grade

Table 1 Differential diagnosis of prostate carcinoma Differential Diagnosis Normal prostatic/ non-prostatic structures

Seminal vesicle/ ejaculatory ducts

Architectural Features

Cytologic Features

Immunohistochemistry

Central lumen with surrounding clusters of smaller glands

Scattered cells with prominent degenerative nuclear atypia Nuclear pseudoinclusion Golden brown pigments Prominent nucleoli negative Lipofuscin pigment positive Basal cells positive

Basal cell markers positive Secretory cell positive for PSA and MUC 6

Verumontanum Closely packed small acini beneath mucosal gland urethral mucosa hyperplasia Orange-brown dense luminal secretion Cowper’s glands Lobular collection of dimorphic

population of ducts and mucinous acini Intermixed with skeletal muscle fibers

Acini with voluminous, pale cytoplasm

PAP negative PSA negative or positive in heterogeneous clumpy fashion in a minority of cases Clear or amphophilic, granular Neuroendocrine markers positive cytoplasm PSA, PAP negative Inconspicuous nucleoli

Paraganglia

Most common in periprostatic tissue Small nest of clear cells with prominent vascular pattern Often associated with nerve

Mesonephric remnants

Lobular arrangement of small tubules with dense, eosinophilic intraluminal secretion

Tubules lined with single layer of cuboidal or flat epithelium

PSA, PAP negative HMWCK positive

Partial atrophy

Lobular configuration often maintained Pale glands with irregular or angulated contour Atrophy involving some glands or part of a gland Centrally dilated atrophic gland surrounded by clustered smaller atrophic glands Stroma may be sclerotic

May have mild nuclear atypia

Basal cells markers positive but often patchy or even absent in some glands AMACR weakly positive in some glands

Atrophic cytoplasm Inconspicuous nucleoli

Basal cell markers positive

Postatrophic hyperplasia

Prostatic Adenocarcinoma

Benign prostatic lesions

Basal cells positive

(continued on next page)

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Differential Diagnosis

Architectural Features

Cytologic Features

Stratification of elongated cells underneath the secretory cells Cells perpendicular to basement membrane Associated with inflammation, infarction, or androgen ablation therapy Small, solid nests with admixed inflammation Acinar, cribriform and solid growth patterns Squamous metaplasia, intraluminal calcifications, or intracytoplasmic eosinophilic globules may be present

Elongated nuclei with nuclear Basal cell markers positive grooves Perinuclear clearing

Adenosis

Lobular collection of small and large glands that are intermixed together

Small and large glands exhibit Basal cells immunostain may be patchy or absent in some similar cytologic features small glands Prominent nucleoli absent

Sclerosing adenosis

Mixture of well-formed glands, cords, or single cells and spindle cells

Thickened basement membrane around glands

Basal cells positive for P63, HMWCK, S-100, and actin

Containing lymphocytes, histiocytes, neutrophils, eosinophils, plasma cells Multinucleated giant cells rarely seen No cytologic atypia Basal cells positive

PSA, PAP and pan-cytokeratin negative, CD68 positive

Urothelial metaplasia

Squamous metaplasia

Basal cell hyperplasia

Nonspecific Mixed inflammatory process centered granulomatous around acini or duct prostatitis

Benign prostatic hypertrophy

Nodular arrangement of small and large glands

Immunohistochemistry

Basal cell markers positive Intercellular bridge Abundant squamoid cytoplasm Immature form may have prominent nucleoli

Bland oval or elongated cells Occasionally have prominent nucleoli

PSA, PAP negative Basel cell markers positive

Basal cell markers positive

High-grade PIN

Architecture similar to, but glands darker than, adjacent benign glands

Amphophilic cytoplasm Nuclear enlargement with prominent nucleoli, coarse chromatin

Basal cell markers highlight basal cell layers which may be discontinuous or even absent in smaller glands

Radiation effect in benign glands

Lobular configuration Individual glands with marked irregular contour Multilayered cells

Scattered cells with marked degenerative nuclear atypia

Basal cell markers positive, AMACR positive but may be reduced

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Table 1 Differential diagnosis of prostate carcinoma

Other malignant lesions

Urothelial carcinoma

Rounded, solid nests of pleomorphic cells in an intensely inflamed background

Small cell carcinoma

Diffuse sheets of small blue cells May intermix with acinar PCa component

Basal cell carcinoma

Infiltrating nests, cords, trabeculae, and sheets Adenoid cystic carcinoma pattern with extensive luminal formation with cribriform architecture Malignant features: infiltrative growth pattern, extraprostatic extension, perineural invasion, necrosis and stromal desmoplasia

Squamous cell carcinoma

Squamous cell carcinoma occurs as pure Identical to squamous cell squamous cell carcinoma of the prostate, carcinoma of other anatomic PCa with squamous component, urothelial sites and contains tumor cells carcinoma of the prostate with squamous with abundant eosinophilic differentiation, and urothelial carcinoma and ‘‘glassy’’ cytoplasm of the urinary bladder with squamous cell differentiation growing into the prostate

Greater nuclear pleomorphism CK7, CK20, K903, and P63 positive and mitotic activity Prostate-specific markers negative Dense eosinophilic cytoplasm More prominent squamous differentiation Tumor cells uniform with dense Positive for at least one neuroendocrine round or oval nuclei, diffuse marker chromatin, inconspicuous Prostate-specific markers and AMACR nucleoli, and very scant positive in a minority of cases cytoplasm TTF-1 positive in about 50% of the cases Uniform cell with scant amount Bcl-2 diffusely positive of cytoplasm Basal cell markers highlight multiple layers of cells

Squamous component of PCa may be weakly and focally positive for prostate-specific markers

Abbreviation: HMWCK, high-molecular-weight cytokeratin.

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Prostatic Adenocarcinoma, Prostatic Intraepithelial Neoplasia, and Intraductal Carcinoma.

Prostate carcinoma (PCa) exhibits a wide range of architectural and cytological features. Gleason grading remains as one of the most powerful histolog...
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