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Prostate biopsy

This document discusses the histopathological evaluation of prostate needle biopsies. It begins by covering normal prostate histology, including the components and cell types present. Variations of normal tissue are then reviewed. Key features that indicate prostate cancer are described, such as mucinous fibroplasia, glomerulation, and perineural invasion. Architectural patterns commonly seen in cancer, like infiltrative growth and cribriform structures, are also outlined. The document provides guidance on distinguishing between benign and malignant findings in prostate biopsies.

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Dr Malini
Topics to be covered 1. Indications 2. Technique of biopsy 3. General approach to prostate needle biopsy 4. Normal histology 5. Histologic variations of normal prostatic tissue 6. Histologic features specific for prostate cancer 7. Limited cancer on needle biopsy 8. Benign mimics of prostate cancer 9. IHC 10. Current concepts in gleason score
Indications of prostate biopsy  Symptoms - frequency  Increased serum PSA  Digital Rectal Examination – hard prostate
Biopsy Techniques for Prostate Cancer Detection
Transrectal and Transperineal Biopsy Approaches for Prostate Cancer Detection
Biopsy Parameters That Impact Prostate Cancer Detection Rate in Prostate Needle Biopsy  Factors related to biopsy procedure and operator 1. Number of cores obtained 2. Laterality of the biopsy procedure (paramedian versus laterally directed biopsy approach) 3. Transrectal versus transperineal (anterior-based) approach 4. Operator experience and skill  Factors related to pathology laboratory practice 1. Number of needle cores embedded in cassette (ideal 1–2 core/cassette) 2. Tissue-sectioning protocol and number of levels examined 3. Histotechnologist’s skill 4. Pathologist’s skill and experience
General Approach to Prostate Needle Biopsy Evaluation 1. Use benign glands as reference and study their low-power architectural features and high-power cytological features (cytoplasmic characteristics, nuclear size and morphology, and nucleolar prominence in secretory and basal cells) 2. Scan biopsy cores to look for glands that appear different from and do not fit in with benign glands 3. Evaluate the architectural features at low power and cytological features at high power of atypical glands 4. Cancer diagnosis is made based on hematoxylin–eosin stain (H&E) examination; use ancillary immunohistochemistry prudently to support H&E impression
Normal histology of prostate  Glandular component is composed of acini and ducts, which is subdivided into large (primary, major, excretory) and peripheral (secondary, minor)  Acini & ducts contain secretory cells, basal cells & scattered neuroendocrine cells  Secretory cells  located in the luminal side, contribute to products of seminal fluid, like Prostatic acid phosphatase (PAP) and Prostate-specific antigen (PSA)  Secretory cells also co-express various keratins & vimentin  Normal secretion is a neutral mucosubstance ( most adenocarcinomas secrete acidic & neutral mucin)
In this benign gland, the luminal contour shows tufts and papillary infoldings. The tall secretory epithelial cells have pale clear cytoplasm and uniform round or oval nuclei. Prominent nucleoli are not seen. Many basal cells can be identified
 Basal cells  Form a thin continuous layer that separates secretory cells from basement membrane  Cell nuclei are cigar-shaped or resembles fibroblasts & are oriented parallel to BM  Inconspicuous in benign glands  Characteristically contains keratin 34Eβ12, CK8.2, 312 C8-1  Normally, these cells do not have phenotype of myo- epithelial cells as they are negative for S-100 or SMA  Do not express PSA or PAP
This benign gland contains corpora amylacea. Even at low magnification, basal cells can be clearly seen. Compare this with next slide which highlights the basal cell layer with the immunostain for high molecular weight cytokeratin 34bE12.
Basal cells are present in a continuous layer in most benign glands. The antibodies to high molecular weight cytokeratin 34bE12 stain basal cells but not secretory or stromal cells in the prostate. Besides cancer, the basal cell layer may be disrupted in atrophy, inflammation, atypical adenomatous hyperplasia (adenosis), and high-grade PIN.
 Neuroendocrine cells  express chromogranin A & B, secretogranin II, and hormones like somatostatin & calcitonin  Co-express PSA suggesting common origin with secretory cells
Neuroendocrine cells are seen in benign prostate, high-grade PIN, and cancer. They are most abundant near verumontanum. In this image, many neuroendocrine cells with large eosinophilic granules (Paneth cell-like change) are seen in atrophic prostate glands
 Large prostatic ducts  lined by transitional epithelium which is continuous with & indistinguishable from lining of prostatic urethra  Do not display umbrella cells, but a single layer of columnar cells that are PSA & PAP positive  Prostatic stroma  Mainly composed of smooth muscle fibres, which functions to squeeze out prostatic secretions  Peripheral nerves are evenly distributed in the apex, mid gland & base
Skeletal muscle fibers of the urogenital diaphragm extend into the apical and anterior peripheral regions of the prostate. Not infrequently, skeletal muscle fibers are seen in needle biopsies from those regions
Ganglia found in prostate needle biopsies should not be mistaken for high-grade carcinoma. Note the intracellular pigment and satellite cells around neurons.
Benign prostatic glands may abut nerves. Occasionally, they may even partially or completely wrap around a nerve. This should not reflexly lead to the diagnosis of adenocarcinoma with perineural invasion. The gland in question in this image lacks enlarged nuclei or nucleoli and shows scattered basal cells.
A. Corpora amylacea are inspissated secretions that may have a lamellated appearance. Usually they are pink or purple in appearance. Sometimes they may be golden-brown. B. This image shows a round eosinophilic corpus amylaceum in an atrophic gland. Corpora amylacea are more commonly seen in benign glands and are rare in carcinomas. Over time, they may calcify and form prostatic calculi. A B +-o 
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Histologic Variations of Normal Prostate Tissue  Atrophy  Basal cell hyperplasia  Urothelial metaplasia  Perineural abutment  Glands within skeletal muscle fibers  Irregular prostate–periprostatic interface
Atrophic prostate Glands retain lobulated architecture. Cystic dilatation is common. Glands appear dark due to reduced cytoplasm.
Urothelial metaplasia. A form of basal cell hyperplasia, urothelial metaplasia consists of stratified basal cells with longitudinal nuclear grooves arranged perpendicular to the basement membrane
Basal cell hyperplasia. (a). Prostate glands are rimmed with one or several layers of basal cells (b). Basal cells have scant cytoplasm and round-to-oval hyperchromatic nuclei. They are positive for basal cell markers such as p63. Some basal cells are stratified and have prominent nucleoli and may be mistaken for HGPIN. Calcification can also be seen.
Perineural abutment. (a). A benign prostate gland abuts and loosely encircles a nerve fiber (b) Has to be distinguished from perineural invasion by prostate cancer. In difficult cases, immunostains for basal cells, such as p63, can be used to confirm the benign nature of the glands
Prostate glands within skeletal muscle fibers. Skeletal muscle can be found intraprostatically, usually in the apex and anterior fibromuscular layer. Prostate glands can be found within the skeletal muscle fibers; therefore, finding cancer glands within the skeletal muscle fibers should not be interpreted as extraprostatic extension
Irregular prostate–periprostatic interface. The prostate does not have a true capsule. Cancer glands intermixed with fat in needle biopsy can be interpreted as extraprostatic extension by cancer
Histological Features Considered Specific for and Diagnostic of Cancer  Three features have not been reported in benign glands and are considered specific for prostate cancer:  Mucinous fibroplasia (collagenous micronodules)  Glomerulation  Perineural invasion  Cancer diagnosis can be rendered when one of the three features is present in biopsy
 Mucinous fibroplasia  It is acellular or hypocellular hyalinized stroma within or outside cancer glands (arrows), and results from hyalinization of extravasated mucin
Glomerulation: It results from the intraluminal proliferation of cancer cells that forms balls or tufts within cancer glands, superficially resembling renal glomeruli
l Perineural invasion: It is defined as tight circumferential or near circumferential encircling of a nerve fiber by cancer glands. It should be distinguished from perineural abutment by benign glands.
Major features (strongly associated with cancer and rarely seen in noncancer lesions) 1. Abnormal architectural pattern  Infiltrative growth pattern  Large cribriform glands with irregular contour  Single or cords of atypical cells  Solid nests with or without comedo necrosis 2. Absence of basal cells  Can be confirmed by basal cell marker immunohistochemistry 3. Nuclear atypia  Nuclear enlargement  Prominent nucleoli  Hyperchromasia
1: abnormal architectural pattern –infiltrative growth. •Most characteristic growth pattern for prostate cancer, with cancer glands situated between and on both sides of the larger and paler benign glands. •This growth pattern is indicative of invasion. The cancer glands are typically small with rigid round lumens as opposed to large benign glands with undulating luminal borders.
Abnormal architectural pattern – crowded glands. •Cancer glands are closely packed and more crowded than the adjacent benign glands, and are often circumscribed without infiltrative pattern. •This should raise a suspicion for cancer. •However, such growth pattern may also be seen in adenosis (atypical adenomatous hyperplasia), which should always be considered and ruled out before a cancer diagnosis is rendered
Abnormal architectural pattern – haphazardly arranged glands without accompanying benign glands. The cancer glands grow in a haphazard fashion and dissect stroma and muscle bundles without accompanying benign glands
Abnormal architectural pattern – single or cords of atypical cells. Single cancer cells infiltrate in the stroma. They also form short cords
Abnormal architectural pattern – irregular cribriform structure. Cancer glands demonstrate large cribriform architecture with irregular and infiltrative borders
Abnormal architectural pattern –solid nests. Cancer cells form solid nests without discernible lumens
2: absence of basal cells. a. Cancer glands are devoid of basal cells on H&E examination b. Confirmed by immunostain for basal cell marker p63 which is negative
Partial atrophy with patchy basal cells. (a). Basal cells can be absent in few benign glands also, such as partial atrophy (b). Basal cell immunostain for p63 demonstrates focal staining in some glands and complete absence of staining in other glands However, glands with and without basal cell lining have identical cytological features. Other noncancerous lesions that often demonstrate patchy or absent basal cells include adenosis and HGPIN
3: Nuclear atypia – nuclear enlargement. Using the adjacent benign glands (right lower of the image) as reference, the cancer cells have significantly enlarged nuclei
3: Nuclear atypia – prominent nucleoli. (a) Cancer cells have prominent nucleoli (b) Nucleolar prominence depends on the several tissue processing factors, including fixation, tissue section thickness, and staining protocols. Alcohol-based fixatives often obscure the nuclear detail with blurred chromatin and inconspicuous nucleoli (c) Whereas Hollandes fixative enhances nucleoli with visible nucleoli even in basal cells of benign glands
3: nuclear atypia – hyperchromasia. Compared to the adjacent benign glands, cancer cells can have larger hyperchromatic and pleomorphic nuclei (arrows)
Minor features (less strongly associated with cancer, may also be seen in non cancer lesions)  Cytoplasm  Cytoplasmic amphophilia (dark cytoplasm)  Intraluminal contents  Amorphous secretion  Blue mucin  Crystalloids  Mitosis and apoptosis  More common in prostate cancer  Adjacent high-grade prostatic intraepithelial neoplasia (HGPIN)  Cancer often associated with HGPIN
Amphophilic cytoplasm. • Compared with benign glands with clear cytoplasm, cancer glands often have amphophilic, or dark, cytoplasm. • This feature can be appreciated at low scanning power and, together with the infiltrative growth Pattern • Often provides the first clue to the presence of cancer in the biopsy. • The atypical glands with these minor features usually appear significantly different and therefore stand out from the benign glands
Amorphous intraluminal secretion. • Cancer glands have eosinophilic amorphous material within their lumens. • They are more common in cancer, but can also be found in some benign lesions
Blue mucin. • Cancer glands have blue-tinged wisps of mucin, often together with dense pink secretion, within their lumens. • They are more common in cancer, but can also be found in some benign lesions.
Crystalloids. • Dense eosinophilic crystalloid structures that assume various shapes such as rhomboid and needle are in the lumens of the cancer glands. • They are more common in cancer, but can also be found in some benign lesions
Mitosis and Apoptosis. A mitotic figure (arrow, a) and apoptotic bodies (arrows, b) are found in cancer glands.
Cancer associated with HGPIN. 1. Cancer glands (arrowheads) often intermingle with HGPIN glands (arrows). 2. The presence of HGPIN should alert pathologists to look for cancer in the biopsy
Benign Conditions That Cause Architectural and Cytological Atypia Benign process Atypical histological features Inflammation Small, crowded or cribriform glands Significant nucleoli Atrophy Haphazard and disorganized pattern, poorly formed glands, mild nuclear enlargement, and small nucleoli Adenosis (atypical adenomatous hyperplasia) Crowded glands HGPIN with adjacent small focus of atypical glands A few atypical glands immediately adjacent to larger HGPIN glands (uncertain whether atypical glands represent micro invasive cancer or tangential sectioning and/or outpouching of HGPIN glands)
Benign prostate glands with exuberant inflammation. • The epithelial cells exhibit significant cytological atypia, including nuclear enlargement and small nucleoli. • Cancer glands, however, can also be associated with inflammation
Simple atrophy. (a) Glands have lobulated architecture (b) Nuclei are slightly enlarged with small or inconspicuous nucleoli
Adenosis. • Circumscribed, lobular collection of glands with variable sizes. • Some glands are clearly benign with large irregular contour and undulating luminal borders. • Smaller glands with rigid lumens are identical to larger benign glands cytologically
HGPIN with adjacent small focus of atypical glands (PINATYP). • A few atypical glands (arrowhead) lie immediately adjacent to larger HGPIN glands (arrows) and are negative for basal cell marker p63 and positive for a methylacyl-CoA racemase (AMACR) • Note the HGPIN glands are also positive for AMACR and are scarcely positive for p63.
Prostate cancer with subtle architectural and cytological atypia. (a) In this case, the cancer glands display crowded growth pattern (b) The cancer cells have minimum nuclear enlargement and inconspicuous nucleoli (c)This focus is negative for basal cell marker p63 .The cancer diagnosis in such cases requires a substantial number of cancer glands and IHC
Histological Features For and Against Cancer Diagnosis in Biopsy
Quantitative Threshold for Diagnosing Limited Cancer in Biopsy  Depending on the architectural and cytological atypia- more atypia, fewer glands are required to make a cancer diagnosis.  At least three glands are required to make a cancer diagnosis, if there is no full-blown cancer associated architectural and cytological features.
A Practical Approach to Diagnosis of Limited Cancer in Needle Biopsy  Use benign glands as reference and evaluate the architectural and cytological features of atypical glands  A definitive cancer diagnosis can be established only when all three criteria are met: 1. Atypical glands exhibiting major and/or minor architectural atypia 2. Atypical glands exhibiting cytological atypia 3. Benign processes that may cause architectural and cytological atypia are carefully considered and ruled out.
Limited prostate cancer. There are only five cancer glands present in one needle core. However, they display infiltrative growth pattern
Limited prostate cancer. • Significant nuclear enlargement and hyperchromasia . • These atypical glands are not inflamed or atrophic. • These glands are negative for p63
Benign mimics of prostatic carcinoma
Atypical Morphological Features Commonly Encountered in Various Benign Mimics of Prostate Cancer
Seminal vesicle/ejaculatory duct epithelium. • At low power peripherally located well-formed small branching glands with cytoplasmic amphophilia, budding from central dilated lumina is a common feature. Well-formed muscular layer surrounding glands favors seminal vesicle tissue. • At higher magnification, the epithelium lining the lumina and small glands show nuclear hyperchromasia and random pleomorphism (arrows), also referred to as “monster nuclei.” • Nuclear pseudoinclusions are commonly seen. • Prominent golden-brown lipofuscin granules (arrowhead) are typical.
Verumontanum mucosal gland hyperplasia. • At low power lobulated collection of relatively uniform, closely packed, round, small acini, frequently accompanied by adjacent urothelial epithelium (arrow) is a common presentation. • Intraluminal brown orange concretions (arrow) are a frequent and distinctive feature. • At high magnification The luminal cells have small uniform nuclei and inconspicuous nucleoli. An intact basal cell layer is present
• Cowper’s glands. • Composed of tightly circumscribed or lobulated proliferation of small, uniform acini lined by mucus-containing cells with a central duct. • This dimorphic population of ducts (arrow) surrounded by acini is characteristic . Cytological features are bland, including small nuclei and inconspicuous nucleoli. • Mucin is present in the intracellular compartment in contrast to intraluminal mucin in prostate cancer • Skeletal muscle is frequently present in stroma
Mesonephric remnant hyperplasia. • Glands appear atrophic with attenuated bland epithelium and grow in a lobulated or sometimes infiltrative pattern. • Intraluminal dense eosinophilic secretions (arrows) and papillary infoldings and tufts are common useful features to distinguish from adenocarcinoma of the prostate
Mucinous metaplasia typically involves part of a lobule. 1. Transition to benign atrophic glands in the background is seen. 2. Glands are lined by tall columnar cells with abundant intracytoplasmic mucin. 3. In contrast to Cowper’s glands, dimorphic duct/acini architecture is not seen
Simple atrophy, cystic atrophy a) In simple atrophy, overall architecture of the glands is maintained with marked reduction of cytoplasm, creating a basophilic appearance at low power b) In cystic atrophy, an undulated glandular architecture of the normal gland is lost; glands are round and cystically dilated with attenuated cytoplasm . c) Accompanied by inflammation and sclerotic stroma .
Morphological spectrum of partial atrophy. The majority of partial atrophy lesions are composed of a lobular arrangement of crowded glands with stellate/undulating gland lumina, and scant pale clear cytoplasm, imparting a distinct pale appearance at low power .
• Partial atrophy composed of a disorganized proliferation of predominantly small, round to occasionally poorly formed glands (arrows). • In addition to partially atrophic glands, there are several completely atrophic glands (arrowheads), a very useful diagnostic clue. • The pale cytoplasm of the lesion is similar to the adjacent benign gland • At high power, frequent micronucleoli (arrow) are visible. Note pale, clear cytoplasm placed laterally to the nuclei, lack of nuclear enlargement and macronucleoli, as well as the presence of few completely atrophic glands within the focus .
• Partial atrophy showing disorganized growth pattern and predominant poorly formed glands mimicking cancer. • Note relatively benign cytology, pale cytoplasm, and few completely atrophic glands within the focus. • Immunohistochemistry for basal cell markers demonstrates very patchy staining with the lack of staining in the majority of glands
Partial atrophy with atypical features, suspicious for cancer. 1. At low power, several disorganized glands with partially atrophic cytoplasm are present. A few completely atrophic glands are also present. These features are suggestive of partial atrophy. 2. At higher magnification, these glands demonstrated bland cytology. However,the edge of this lesion appears infiltrative (arrow, a) 3. IHC identical to cancer 4. Despite the presence of several features of partial atrophy, one cannot rule out cancer. Therefore, it is best to diagnose this case as atypical suspicious for cancer
• Postatrophic hyperplasia. • At low power, circumscribed /lobulated collection of small dark atrophic acini with round-to-distorted contours arranged around a larger dilated duct (arrow; a b). • The dark appearance of the lesion at low power may arouse a suspicion for cancer but is due to scant cytoplasm rather than abundant amphophilic/granular cytoplasm seen in cancer.
 At high magnification, the acini are lined by cuboidal secretory cells with minimal nuclear enlargement, increased nucleus-to- cytoplasmic ratio, and small but visible nucleoli. The stroma is usually sclerotic
• Pseudoinfiltrative growth patterns in focal atrophy. (a–b) • Benign atrophic glands with haphazard or pseudoinfiltrative growth pattern may raise concern at low-power examination (a and b). • However, the pattern of infiltration is like a “patch” different than the true infiltration pattern with cancer glands situated between or on both sides of the benign glands
Adenosis (atypical adenomatous hyperplasia). • a. At low power, adenosis is characterized by a circumscribed collection of variably sized glands • b. Within the nodule, small round acini are admixed with larger benign-appearing glands with papillary infolding (arrows). There are no obvious cytoplasmic or cytological differences between them. Essentially, small and large glands merge with each other imperceptibly.
• c. At high power, the columnar cells have abundant pale to clear cytoplasm and bland-appearing nuclei with inconspicuous to small nucleoli . • d. The stroma between the glands is cellular, a feature to suggest a benign reactive nature .
• (e)Basal cell markers typically demonstrate a discontinuous/patchy- staining pattern, with some glands lacking the staining . • (f)A small percentage (~30%) of adenosis lesions may demonstrate mild-to-moderate AMACR expression
Basal cell hyperplasia. (a). A well-circumscribed nodule of basal cell hyperplasia, also referred to as basal cell adenoma is a form of epithelial hyperplasia in which glands have markedly stratified lining cells with high N:C ratio, and appears basophilic at low magnification (b).In incomplete basal cell hyperplasia, a luminal differentiation is Seen.
(c) In complete basal cell hyperplasia, dark-staining nests are seen in a cellular stroma. • Note the lack of lumen formation. The presence of cellular spindly stroma is a feature suggestive of the benign proliferative nature • In basal cell hyperplasia, nuclei are stratified, arranged like a pack of cigar without visible cytoplasm and are coffee bean–like with frequent grooves and vesicular glassy chromatin. (d).Prominent nucleoli are frequently seen (arrows in d).
Basal cell hyperplasia (e)can also present with adenoid cystic carcinoma-like cribriform architecture simulating cribriform carcinoma. • Also note cellular spindly stroma (f)Intraluminal calcifications and cytoplasmic hyaline globules can be seen in basal cell hyperplasia
Basal cell hyperplasia in prostate needle biopsy. a) Dark-staining nests with stratified epithelium are seen in a haphazard pattern b) Nuclei are stratified with frequent prominent nucleoli c) Immunohistochemical markers for basal cell detection are helpful in difficult cases (c, p63)
Diagnostic Approach to Prostate Basal Cell Lesions
Nephrogenic adenoma. A classical nephrogenic adenoma with both papillary and underlying tubular components. (a) Polypoid or papillary component has edematous stroma without well- defined fibrovascular cores and lining epithelium is cuboidal and lacks stratification. • Underlying tubules are variably sized and mimic renal tubules. Note thickened eosinophilic basement membrane surrounding tubules (arrow), one of the characteristic features of nephrogenic adenoma (b) Prostatic urethra biopsy exhibits exclusively a tubular component, mimicking a prostate adenocarcinoma
Nephrogenic adenoma • The tubules are lined by cuboidal hobnail epithelium. • Degenerative cytological atypia and features such as intraluminal blue mucin can be encountered. • Background inflammation and calcifications are common (c and d).
• Nephrogenic adenoma (e) presenting predominantly with nested (f) signet ring cell like pattern. • These patterns may be mistaken for nested urothelial carcinoma and poorly differentiated prostate adenocarcinoma. • Hyalinized basement membrane surrounding glands (f) and superficial nature of the lesion (e) are useful features to suggest the diagnosis
(g). Rarely, nephrogenic adenoma may present with prominent fibrous and myxoid component (h). Cytoplasmic AMACR expression is present in the vast majority of nephrogenic adenoma, (i)Nuclear transcription factors PAX- 2 or PAX-8 are expressed in nephrogenic adenoma and are helpful markers to support the diagnosis in difficult cases
Central zone histology mimicking HGPIN. (a) Central zone histology is typically a mimicker of HGPIN; however, prominent cribriform architecture in some cases may mimic cancer. • In the central zone, glands are complex with frequent papillation and undulating architecture with pseudostratified lining epithelium • At low magnification, glands demonstrate distinct cytoplasmic eosinophilia (b). Roman bridges and cribriform architecture are common • In contrast to HGPIN, nuclei stream parallel to bridges in comparison to perpendicular orientation in HGPIN
(c). The cytological atypia is seen in basal cells (arrow), a feature helpful to differentiate from HGPIN or cancer Before making a diagnosis of HGPIN or atypia in biopsies from the base area of the prostate, central zone histology should be ruled out
Clear cell cribriform hyperplasia. • Clear cell cribriform hyperplasia represents a spectrum of benign prostate hyperplasia and therefore is typically encountered in the transition zone of the prostate. (a)There is a nodular proliferation of nonconfluent cribriform glands with clear to eosinophilic cytoplasm (b)The cells forming the central lumina are cuboidal to low columnar secretory-type cells, with uniform round nuclei and clear cytoplasm. • The glands (arrows) are rimmed with a prominent basal cell layer
Malakoplakia. • There is a diffuse sheet-like proliferation of pink epithelioid histiocytes, accompanied by other inflammatory cells, similar to nonspecific xanthogranulomatous prostatitis. • The histiocytic nature of epithelioid cells and the presence of Michaelis-Gutmann bodies (arrow) suggest the diagnosis of malakoplakia
Sclerosing adenosis mimicking high-grade prostate carcinoma. • This specimen demonstrates a proliferation of poorly formed and complex glands mimicking high-grade prostate carcinoma. • Lowpower recognition is a key. (a). It typically forms a well-circumscribed nodule of tightly packed glands (b). At high magnification, glands demonstrate complex proliferation, poorly formed glands with slit-like lumina, fused glands, and even single cells with signet ring cell-like features, mimicking high-grade cancer
(c)Stroma surrounding the glands is cellular and hyalinized (arrows). (d)Prominent nucleoli, crystalloids, and blue mucin are common
(e)Basal cells are highlighted with basal cell marker p63. (f) Basal cells undergo myoepithelial metaplasia and show coexpression of basal cell markers and S-100 and muscle-specific actin. • When one or more well-circumscribed cellular lesions mimicking high-grade prostate cancer are encountered in TURP or biopsies from the transition zone of the prostate, sclerosing adenosis should be ruled out
Paraganglia mimicking high-grade prostate carcinoma and extraprostatic extension. (a)At low power, paraganglia consist of small, solid nests of cells with clear cytoplasm separated by a delicate vascular network, mimicking high-grade Gleason pattern 4 or 5 prostate carcinoma. • Its presence in adipose tissue , impart an impression of extraprostatic tumor extension. (b)At high power, the cells have clear to amphophilic, finely granular cytoplasm. Random cytological atypia may be seen and nuclei are often hyperchromatic, but nucleoli are inconspicuous.
Recognition of the delicate vascular network pattern referred to as the “Zellballen” arrangement is an important clue. In difficult cases, positive neuroendocrine markers support the diagnosis (synaptophysin)
• Xanthomatous infiltrate in prostate needle biopsy. (a) Xanthoma cells grow in a diffuse infiltrative pattern, mimicking poorly differentiated prostate carcinoma with foamy features . (b)Lack of any glandular differentiation and relatively bland nuclear features suggests the diagnosis of xanthomatous infiltrate • In small needle biopsysamples, a panel of immunohistochemical markers of histiocytic lineage (CD- 68) and pancytokeratin may be necessary to rule out carcinoma. • Presence of other inflammatory cells would support the diagnosis of xanthomatous infiltrate
Commonly Used Immunohistochemical Markers for Diagnosis of Prostate Cancer in Biopsy
Basal Cell Markers  Types of basal cell markers 1. HMWCK: cytoplasmic intermediate filaments detected by several antibody preparations (34bE12, CK5/6, CK14) 2. p63: nuclear antigen 3. Basal cell cocktail (34bE12+ p63)  Staining pattern in prostate cancer 1. Prostate carcinoma lacks staining for basal cell markers 2. HMWCK may rarely be positive in cancer cells, but not in basal cell distribution, due to excessive antigen retrieval and staining 3. p63 can rarely be found in cancer cells with uniform and non-basal cell distribution  Diagnostic utility  A negative basal cell marker staining in atypical glands morphologically suspicious for cancer supports a cancer diagnosis  Pitfalls  Adenosis, partial atrophy, high-grade prostatic intraepithelial neoplasia (HGPIN) may have discontinuous or even absent basal cell lining
a-Methylacyl CoA Racemase (AMACR, P504S)  Types of antibodies  Monoclonal (P504S) and polyclonal, both with comparable sensitivity and specificity  Staining pattern in prostate cancer  Apical cytoplasmic granular staining  Diagnostic utility 1. Positive AMACR staining in atypical glands morphologically suspicious for cancer supports a cancer diagnosis 2. Positive AMACR may convert an ATYP to cancer diagnosis where morphology is suspicious for but not diagnostic of cancer and basal cell markers are negative
Points to remember in Gleason Grading on needle biopsy  Gleason grade is solely based on architectural pattern, cytologic features are not factored in.  Both the primary (predominant) and secondary (second most prevalent) architectural patterns are identified and assigned a grade from 1 to 5, with 1 being the most differentiated and 5 being undifferentiated.  If a tumor has only one histologic pattern, then for uniformity, the primary and secondary patterns are given the same grade.  Full Gleason score is assigned to even to small foci of cancer on needle biopsy, because it has been demonstrated that the grade assigned to these minimal cancers is just as accurate compared with cases with more extensive cancer on biopsy.
 In setting of three grades on biopsy where the highest grade is the least common, the highest grade is taken as the secondary pattern.  One should assign a separate Gleason score to each involved core, especially when one of the cores is high grade (Gleason score 4 + 4 = 8) and other cores have lower-grade cancer.
Current Concepts of Gleason Grading 1. Gleason pattern 1 or 2 should be rarely if ever applied in the biopsy setting 2. Gleason grade in the biopsy setting essentially starts with Gleason pattern 3 3. A few malignant glands located between benign glands indicate pattern 3 (small focus of cancer does not necessarily mean low-grade cancer) 4. Virtually all cribriform carcinomas represent pattern 4 or 5 if associated with necrosis 5. Clusters of glands with poorly formed glandular lumina where tangential sectioning is ruled out represent Gleason pattern 4
6. Percentage of pattern 4 in the setting of Gleason score 7 (3 + 4 versus 4 + 3) bears prognostic importance 7. Multiple cores with cancer of different Gleason grades, grade information of individual core(s) better correlates with Gleason grade of radical prostatectomy 8. Any amount of higher pattern in the needle biopsy should be reported 9. In the setting of high-grade tumor of large volume, a small amount (< 5%) of lower-grade pattern can be ignored and need not be reported 10. Tertiary pattern 5 in the biopsy should be reported as the secondary pattern in the needle biopsy due to its prognostic significance 11. Many “special” types of prostate cancers are considered examples of Gleason pattern 4 or 5
Future Trends in Prostate Biopsy Sampling and Its Clinical Applications
References  Springers Prostate Biopsy Interpretation: An Illustrated Guide by Shah and Zhou.  Lippincotts Williams and Wilkins Prostate biopsy interpretation series by Epstein and Yang.  Robbins and Cotran pathologic basis of disease 9e.  Sternberg’s Diagnostic surgical pathology.
Thank you……..!

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Prostate biopsy

  • 1.
  • 2.
    Topics to becovered 1. Indications 2. Technique of biopsy 3. General approach to prostate needle biopsy 4. Normal histology 5. Histologic variations of normal prostatic tissue 6. Histologic features specific for prostate cancer 7. Limited cancer on needle biopsy 8. Benign mimics of prostate cancer 9. IHC 10. Current concepts in gleason score
  • 3.
    Indications of prostatebiopsy  Symptoms - frequency  Increased serum PSA  Digital Rectal Examination – hard prostate
  • 4.
    Biopsy Techniques forProstate Cancer Detection
  • 5.
    Transrectal and TransperinealBiopsy Approaches for Prostate Cancer Detection
  • 6.
    Biopsy Parameters ThatImpact Prostate Cancer Detection Rate in Prostate Needle Biopsy  Factors related to biopsy procedure and operator 1. Number of cores obtained 2. Laterality of the biopsy procedure (paramedian versus laterally directed biopsy approach) 3. Transrectal versus transperineal (anterior-based) approach 4. Operator experience and skill  Factors related to pathology laboratory practice 1. Number of needle cores embedded in cassette (ideal 1–2 core/cassette) 2. Tissue-sectioning protocol and number of levels examined 3. Histotechnologist’s skill 4. Pathologist’s skill and experience
  • 7.
    General Approach toProstate Needle Biopsy Evaluation 1. Use benign glands as reference and study their low-power architectural features and high-power cytological features (cytoplasmic characteristics, nuclear size and morphology, and nucleolar prominence in secretory and basal cells) 2. Scan biopsy cores to look for glands that appear different from and do not fit in with benign glands 3. Evaluate the architectural features at low power and cytological features at high power of atypical glands 4. Cancer diagnosis is made based on hematoxylin–eosin stain (H&E) examination; use ancillary immunohistochemistry prudently to support H&E impression
  • 8.
    Normal histology ofprostate  Glandular component is composed of acini and ducts, which is subdivided into large (primary, major, excretory) and peripheral (secondary, minor)  Acini & ducts contain secretory cells, basal cells & scattered neuroendocrine cells  Secretory cells  located in the luminal side, contribute to products of seminal fluid, like Prostatic acid phosphatase (PAP) and Prostate-specific antigen (PSA)  Secretory cells also co-express various keratins & vimentin  Normal secretion is a neutral mucosubstance ( most adenocarcinomas secrete acidic & neutral mucin)
  • 9.
    In this benigngland, the luminal contour shows tufts and papillary infoldings. The tall secretory epithelial cells have pale clear cytoplasm and uniform round or oval nuclei. Prominent nucleoli are not seen. Many basal cells can be identified
  • 10.
     Basal cells Form a thin continuous layer that separates secretory cells from basement membrane  Cell nuclei are cigar-shaped or resembles fibroblasts & are oriented parallel to BM  Inconspicuous in benign glands  Characteristically contains keratin 34Eβ12, CK8.2, 312 C8-1  Normally, these cells do not have phenotype of myo- epithelial cells as they are negative for S-100 or SMA  Do not express PSA or PAP
  • 11.
    This benign glandcontains corpora amylacea. Even at low magnification, basal cells can be clearly seen. Compare this with next slide which highlights the basal cell layer with the immunostain for high molecular weight cytokeratin 34bE12.
  • 12.
    Basal cells arepresent in a continuous layer in most benign glands. The antibodies to high molecular weight cytokeratin 34bE12 stain basal cells but not secretory or stromal cells in the prostate. Besides cancer, the basal cell layer may be disrupted in atrophy, inflammation, atypical adenomatous hyperplasia (adenosis), and high-grade PIN.
  • 13.
     Neuroendocrine cells express chromogranin A & B, secretogranin II, and hormones like somatostatin & calcitonin  Co-express PSA suggesting common origin with secretory cells
  • 14.
    Neuroendocrine cells areseen in benign prostate, high-grade PIN, and cancer. They are most abundant near verumontanum. In this image, many neuroendocrine cells with large eosinophilic granules (Paneth cell-like change) are seen in atrophic prostate glands
  • 15.
     Large prostaticducts  lined by transitional epithelium which is continuous with & indistinguishable from lining of prostatic urethra  Do not display umbrella cells, but a single layer of columnar cells that are PSA & PAP positive  Prostatic stroma  Mainly composed of smooth muscle fibres, which functions to squeeze out prostatic secretions  Peripheral nerves are evenly distributed in the apex, mid gland & base
  • 16.
    Skeletal muscle fibersof the urogenital diaphragm extend into the apical and anterior peripheral regions of the prostate. Not infrequently, skeletal muscle fibers are seen in needle biopsies from those regions
  • 17.
    Ganglia found inprostate needle biopsies should not be mistaken for high-grade carcinoma. Note the intracellular pigment and satellite cells around neurons.
  • 18.
    Benign prostatic glandsmay abut nerves. Occasionally, they may even partially or completely wrap around a nerve. This should not reflexly lead to the diagnosis of adenocarcinoma with perineural invasion. The gland in question in this image lacks enlarged nuclei or nucleoli and shows scattered basal cells.
  • 19.
    A. Corpora amylaceaare inspissated secretions that may have a lamellated appearance. Usually they are pink or purple in appearance. Sometimes they may be golden-brown. B. This image shows a round eosinophilic corpus amylaceum in an atrophic gland. Corpora amylacea are more commonly seen in benign glands and are rare in carcinomas. Over time, they may calcify and form prostatic calculi. A B +-o 
  • 20.
  • 21.
    Histologic Variations ofNormal Prostate Tissue  Atrophy  Basal cell hyperplasia  Urothelial metaplasia  Perineural abutment  Glands within skeletal muscle fibers  Irregular prostate–periprostatic interface
  • 22.
    Atrophic prostate Glands retainlobulated architecture. Cystic dilatation is common. Glands appear dark due to reduced cytoplasm.
  • 23.
    Urothelial metaplasia. A formof basal cell hyperplasia, urothelial metaplasia consists of stratified basal cells with longitudinal nuclear grooves arranged perpendicular to the basement membrane
  • 24.
    Basal cell hyperplasia. (a).Prostate glands are rimmed with one or several layers of basal cells (b). Basal cells have scant cytoplasm and round-to-oval hyperchromatic nuclei. They are positive for basal cell markers such as p63. Some basal cells are stratified and have prominent nucleoli and may be mistaken for HGPIN. Calcification can also be seen.
  • 25.
    Perineural abutment. (a). Abenign prostate gland abuts and loosely encircles a nerve fiber (b) Has to be distinguished from perineural invasion by prostate cancer. In difficult cases, immunostains for basal cells, such as p63, can be used to confirm the benign nature of the glands
  • 26.
    Prostate glands withinskeletal muscle fibers. Skeletal muscle can be found intraprostatically, usually in the apex and anterior fibromuscular layer. Prostate glands can be found within the skeletal muscle fibers; therefore, finding cancer glands within the skeletal muscle fibers should not be interpreted as extraprostatic extension
  • 27.
    Irregular prostate–periprostatic interface. Theprostate does not have a true capsule. Cancer glands intermixed with fat in needle biopsy can be interpreted as extraprostatic extension by cancer
  • 28.
    Histological Features ConsideredSpecific for and Diagnostic of Cancer  Three features have not been reported in benign glands and are considered specific for prostate cancer:  Mucinous fibroplasia (collagenous micronodules)  Glomerulation  Perineural invasion  Cancer diagnosis can be rendered when one of the three features is present in biopsy
  • 29.
     Mucinous fibroplasia It is acellular or hypocellular hyalinized stroma within or outside cancer glands (arrows), and results from hyalinization of extravasated mucin
  • 30.
    Glomerulation: It results fromthe intraluminal proliferation of cancer cells that forms balls or tufts within cancer glands, superficially resembling renal glomeruli
  • 31.
    l Perineural invasion: It isdefined as tight circumferential or near circumferential encircling of a nerve fiber by cancer glands. It should be distinguished from perineural abutment by benign glands.
  • 32.
    Major features (stronglyassociated with cancer and rarely seen in noncancer lesions) 1. Abnormal architectural pattern  Infiltrative growth pattern  Large cribriform glands with irregular contour  Single or cords of atypical cells  Solid nests with or without comedo necrosis 2. Absence of basal cells  Can be confirmed by basal cell marker immunohistochemistry 3. Nuclear atypia  Nuclear enlargement  Prominent nucleoli  Hyperchromasia
  • 33.
    1: abnormal architecturalpattern –infiltrative growth. •Most characteristic growth pattern for prostate cancer, with cancer glands situated between and on both sides of the larger and paler benign glands. •This growth pattern is indicative of invasion. The cancer glands are typically small with rigid round lumens as opposed to large benign glands with undulating luminal borders.
  • 34.
    Abnormal architectural pattern– crowded glands. •Cancer glands are closely packed and more crowded than the adjacent benign glands, and are often circumscribed without infiltrative pattern. •This should raise a suspicion for cancer. •However, such growth pattern may also be seen in adenosis (atypical adenomatous hyperplasia), which should always be considered and ruled out before a cancer diagnosis is rendered
  • 35.
    Abnormal architectural pattern– haphazardly arranged glands without accompanying benign glands. The cancer glands grow in a haphazard fashion and dissect stroma and muscle bundles without accompanying benign glands
  • 36.
    Abnormal architectural pattern –single or cords of atypical cells. Single cancer cells infiltrate in the stroma. They also form short cords
  • 37.
    Abnormal architectural pattern –irregular cribriform structure. Cancer glands demonstrate large cribriform architecture with irregular and infiltrative borders
  • 38.
    Abnormal architectural pattern–solid nests. Cancer cells form solid nests without discernible lumens
  • 39.
    2: absence ofbasal cells. a. Cancer glands are devoid of basal cells on H&E examination b. Confirmed by immunostain for basal cell marker p63 which is negative
  • 40.
    Partial atrophy withpatchy basal cells. (a). Basal cells can be absent in few benign glands also, such as partial atrophy (b). Basal cell immunostain for p63 demonstrates focal staining in some glands and complete absence of staining in other glands However, glands with and without basal cell lining have identical cytological features. Other noncancerous lesions that often demonstrate patchy or absent basal cells include adenosis and HGPIN
  • 41.
    3: Nuclear atypia– nuclear enlargement. Using the adjacent benign glands (right lower of the image) as reference, the cancer cells have significantly enlarged nuclei
  • 42.
    3: Nuclear atypia– prominent nucleoli. (a) Cancer cells have prominent nucleoli (b) Nucleolar prominence depends on the several tissue processing factors, including fixation, tissue section thickness, and staining protocols. Alcohol-based fixatives often obscure the nuclear detail with blurred chromatin and inconspicuous nucleoli (c) Whereas Hollandes fixative enhances nucleoli with visible nucleoli even in basal cells of benign glands
  • 43.
    3: nuclear atypia– hyperchromasia. Compared to the adjacent benign glands, cancer cells can have larger hyperchromatic and pleomorphic nuclei (arrows)
  • 44.
    Minor features (lessstrongly associated with cancer, may also be seen in non cancer lesions)  Cytoplasm  Cytoplasmic amphophilia (dark cytoplasm)  Intraluminal contents  Amorphous secretion  Blue mucin  Crystalloids  Mitosis and apoptosis  More common in prostate cancer  Adjacent high-grade prostatic intraepithelial neoplasia (HGPIN)  Cancer often associated with HGPIN
  • 45.
    Amphophilic cytoplasm. • Comparedwith benign glands with clear cytoplasm, cancer glands often have amphophilic, or dark, cytoplasm. • This feature can be appreciated at low scanning power and, together with the infiltrative growth Pattern • Often provides the first clue to the presence of cancer in the biopsy. • The atypical glands with these minor features usually appear significantly different and therefore stand out from the benign glands
  • 46.
    Amorphous intraluminal secretion. •Cancer glands have eosinophilic amorphous material within their lumens. • They are more common in cancer, but can also be found in some benign lesions
  • 47.
    Blue mucin. • Cancerglands have blue-tinged wisps of mucin, often together with dense pink secretion, within their lumens. • They are more common in cancer, but can also be found in some benign lesions.
  • 48.
    Crystalloids. • Dense eosinophiliccrystalloid structures that assume various shapes such as rhomboid and needle are in the lumens of the cancer glands. • They are more common in cancer, but can also be found in some benign lesions
  • 49.
    Mitosis and Apoptosis. Amitotic figure (arrow, a) and apoptotic bodies (arrows, b) are found in cancer glands.
  • 50.
    Cancer associated withHGPIN. 1. Cancer glands (arrowheads) often intermingle with HGPIN glands (arrows). 2. The presence of HGPIN should alert pathologists to look for cancer in the biopsy
  • 51.
    Benign Conditions ThatCause Architectural and Cytological Atypia Benign process Atypical histological features Inflammation Small, crowded or cribriform glands Significant nucleoli Atrophy Haphazard and disorganized pattern, poorly formed glands, mild nuclear enlargement, and small nucleoli Adenosis (atypical adenomatous hyperplasia) Crowded glands HGPIN with adjacent small focus of atypical glands A few atypical glands immediately adjacent to larger HGPIN glands (uncertain whether atypical glands represent micro invasive cancer or tangential sectioning and/or outpouching of HGPIN glands)
  • 52.
    Benign prostate glandswith exuberant inflammation. • The epithelial cells exhibit significant cytological atypia, including nuclear enlargement and small nucleoli. • Cancer glands, however, can also be associated with inflammation
  • 53.
    Simple atrophy. (a) Glandshave lobulated architecture (b) Nuclei are slightly enlarged with small or inconspicuous nucleoli
  • 54.
    Adenosis. • Circumscribed, lobularcollection of glands with variable sizes. • Some glands are clearly benign with large irregular contour and undulating luminal borders. • Smaller glands with rigid lumens are identical to larger benign glands cytologically
  • 55.
    HGPIN with adjacentsmall focus of atypical glands (PINATYP). • A few atypical glands (arrowhead) lie immediately adjacent to larger HGPIN glands (arrows) and are negative for basal cell marker p63 and positive for a methylacyl-CoA racemase (AMACR) • Note the HGPIN glands are also positive for AMACR and are scarcely positive for p63.
  • 56.
    Prostate cancer withsubtle architectural and cytological atypia. (a) In this case, the cancer glands display crowded growth pattern (b) The cancer cells have minimum nuclear enlargement and inconspicuous nucleoli (c)This focus is negative for basal cell marker p63 .The cancer diagnosis in such cases requires a substantial number of cancer glands and IHC
  • 57.
    Histological Features For and AgainstCancer Diagnosis in Biopsy
  • 58.
    Quantitative Threshold forDiagnosing Limited Cancer in Biopsy  Depending on the architectural and cytological atypia- more atypia, fewer glands are required to make a cancer diagnosis.  At least three glands are required to make a cancer diagnosis, if there is no full-blown cancer associated architectural and cytological features.
  • 59.
    A Practical Approachto Diagnosis of Limited Cancer in Needle Biopsy  Use benign glands as reference and evaluate the architectural and cytological features of atypical glands  A definitive cancer diagnosis can be established only when all three criteria are met: 1. Atypical glands exhibiting major and/or minor architectural atypia 2. Atypical glands exhibiting cytological atypia 3. Benign processes that may cause architectural and cytological atypia are carefully considered and ruled out.
  • 60.
    Limited prostate cancer. Thereare only five cancer glands present in one needle core. However, they display infiltrative growth pattern
  • 61.
    Limited prostate cancer. • Significantnuclear enlargement and hyperchromasia . • These atypical glands are not inflamed or atrophic. • These glands are negative for p63
  • 63.
    Benign mimics ofprostatic carcinoma
  • 64.
  • 65.
    Seminal vesicle/ejaculatory duct epithelium. •At low power peripherally located well-formed small branching glands with cytoplasmic amphophilia, budding from central dilated lumina is a common feature. Well-formed muscular layer surrounding glands favors seminal vesicle tissue. • At higher magnification, the epithelium lining the lumina and small glands show nuclear hyperchromasia and random pleomorphism (arrows), also referred to as “monster nuclei.” • Nuclear pseudoinclusions are commonly seen. • Prominent golden-brown lipofuscin granules (arrowhead) are typical.
  • 66.
    Verumontanum mucosal gland hyperplasia. •At low power lobulated collection of relatively uniform, closely packed, round, small acini, frequently accompanied by adjacent urothelial epithelium (arrow) is a common presentation. • Intraluminal brown orange concretions (arrow) are a frequent and distinctive feature. • At high magnification The luminal cells have small uniform nuclei and inconspicuous nucleoli. An intact basal cell layer is present
  • 67.
    • Cowper’s glands. •Composed of tightly circumscribed or lobulated proliferation of small, uniform acini lined by mucus-containing cells with a central duct. • This dimorphic population of ducts (arrow) surrounded by acini is characteristic . Cytological features are bland, including small nuclei and inconspicuous nucleoli. • Mucin is present in the intracellular compartment in contrast to intraluminal mucin in prostate cancer • Skeletal muscle is frequently present in stroma
  • 68.
    Mesonephric remnant hyperplasia. • Glandsappear atrophic with attenuated bland epithelium and grow in a lobulated or sometimes infiltrative pattern. • Intraluminal dense eosinophilic secretions (arrows) and papillary infoldings and tufts are common useful features to distinguish from adenocarcinoma of the prostate
  • 69.
    Mucinous metaplasia typicallyinvolves part of a lobule. 1. Transition to benign atrophic glands in the background is seen. 2. Glands are lined by tall columnar cells with abundant intracytoplasmic mucin. 3. In contrast to Cowper’s glands, dimorphic duct/acini architecture is not seen
  • 70.
    Simple atrophy, cysticatrophy a) In simple atrophy, overall architecture of the glands is maintained with marked reduction of cytoplasm, creating a basophilic appearance at low power b) In cystic atrophy, an undulated glandular architecture of the normal gland is lost; glands are round and cystically dilated with attenuated cytoplasm . c) Accompanied by inflammation and sclerotic stroma .
  • 71.
    Morphological spectrum ofpartial atrophy. The majority of partial atrophy lesions are composed of a lobular arrangement of crowded glands with stellate/undulating gland lumina, and scant pale clear cytoplasm, imparting a distinct pale appearance at low power .
  • 72.
    • Partial atrophycomposed of a disorganized proliferation of predominantly small, round to occasionally poorly formed glands (arrows). • In addition to partially atrophic glands, there are several completely atrophic glands (arrowheads), a very useful diagnostic clue. • The pale cytoplasm of the lesion is similar to the adjacent benign gland • At high power, frequent micronucleoli (arrow) are visible. Note pale, clear cytoplasm placed laterally to the nuclei, lack of nuclear enlargement and macronucleoli, as well as the presence of few completely atrophic glands within the focus .
  • 73.
    • Partial atrophyshowing disorganized growth pattern and predominant poorly formed glands mimicking cancer. • Note relatively benign cytology, pale cytoplasm, and few completely atrophic glands within the focus. • Immunohistochemistry for basal cell markers demonstrates very patchy staining with the lack of staining in the majority of glands
  • 74.
    Partial atrophy withatypical features, suspicious for cancer. 1. At low power, several disorganized glands with partially atrophic cytoplasm are present. A few completely atrophic glands are also present. These features are suggestive of partial atrophy. 2. At higher magnification, these glands demonstrated bland cytology. However,the edge of this lesion appears infiltrative (arrow, a) 3. IHC identical to cancer 4. Despite the presence of several features of partial atrophy, one cannot rule out cancer. Therefore, it is best to diagnose this case as atypical suspicious for cancer
  • 75.
    • Postatrophic hyperplasia. •At low power, circumscribed /lobulated collection of small dark atrophic acini with round-to-distorted contours arranged around a larger dilated duct (arrow; a b). • The dark appearance of the lesion at low power may arouse a suspicion for cancer but is due to scant cytoplasm rather than abundant amphophilic/granular cytoplasm seen in cancer.
  • 76.
     At highmagnification, the acini are lined by cuboidal secretory cells with minimal nuclear enlargement, increased nucleus-to- cytoplasmic ratio, and small but visible nucleoli. The stroma is usually sclerotic
  • 77.
    • Pseudoinfiltrative growthpatterns in focal atrophy. (a–b) • Benign atrophic glands with haphazard or pseudoinfiltrative growth pattern may raise concern at low-power examination (a and b). • However, the pattern of infiltration is like a “patch” different than the true infiltration pattern with cancer glands situated between or on both sides of the benign glands
  • 78.
    Adenosis (atypical adenomatoushyperplasia). • a. At low power, adenosis is characterized by a circumscribed collection of variably sized glands • b. Within the nodule, small round acini are admixed with larger benign-appearing glands with papillary infolding (arrows). There are no obvious cytoplasmic or cytological differences between them. Essentially, small and large glands merge with each other imperceptibly.
  • 79.
    • c. Athigh power, the columnar cells have abundant pale to clear cytoplasm and bland-appearing nuclei with inconspicuous to small nucleoli . • d. The stroma between the glands is cellular, a feature to suggest a benign reactive nature .
  • 80.
    • (e)Basal cellmarkers typically demonstrate a discontinuous/patchy- staining pattern, with some glands lacking the staining . • (f)A small percentage (~30%) of adenosis lesions may demonstrate mild-to-moderate AMACR expression
  • 81.
    Basal cell hyperplasia. (a).A well-circumscribed nodule of basal cell hyperplasia, also referred to as basal cell adenoma is a form of epithelial hyperplasia in which glands have markedly stratified lining cells with high N:C ratio, and appears basophilic at low magnification (b).In incomplete basal cell hyperplasia, a luminal differentiation is Seen.
  • 82.
    (c) In completebasal cell hyperplasia, dark-staining nests are seen in a cellular stroma. • Note the lack of lumen formation. The presence of cellular spindly stroma is a feature suggestive of the benign proliferative nature • In basal cell hyperplasia, nuclei are stratified, arranged like a pack of cigar without visible cytoplasm and are coffee bean–like with frequent grooves and vesicular glassy chromatin. (d).Prominent nucleoli are frequently seen (arrows in d).
  • 83.
    Basal cell hyperplasia (e)canalso present with adenoid cystic carcinoma-like cribriform architecture simulating cribriform carcinoma. • Also note cellular spindly stroma (f)Intraluminal calcifications and cytoplasmic hyaline globules can be seen in basal cell hyperplasia
  • 84.
    Basal cell hyperplasiain prostate needle biopsy. a) Dark-staining nests with stratified epithelium are seen in a haphazard pattern b) Nuclei are stratified with frequent prominent nucleoli c) Immunohistochemical markers for basal cell detection are helpful in difficult cases (c, p63)
  • 85.
  • 86.
    Nephrogenic adenoma. A classicalnephrogenic adenoma with both papillary and underlying tubular components. (a) Polypoid or papillary component has edematous stroma without well- defined fibrovascular cores and lining epithelium is cuboidal and lacks stratification. • Underlying tubules are variably sized and mimic renal tubules. Note thickened eosinophilic basement membrane surrounding tubules (arrow), one of the characteristic features of nephrogenic adenoma (b) Prostatic urethra biopsy exhibits exclusively a tubular component, mimicking a prostate adenocarcinoma
  • 87.
    Nephrogenic adenoma • Thetubules are lined by cuboidal hobnail epithelium. • Degenerative cytological atypia and features such as intraluminal blue mucin can be encountered. • Background inflammation and calcifications are common (c and d).
  • 88.
    • Nephrogenic adenoma (e)presenting predominantly with nested (f) signet ring cell like pattern. • These patterns may be mistaken for nested urothelial carcinoma and poorly differentiated prostate adenocarcinoma. • Hyalinized basement membrane surrounding glands (f) and superficial nature of the lesion (e) are useful features to suggest the diagnosis
  • 89.
    (g). Rarely, nephrogenicadenoma may present with prominent fibrous and myxoid component (h). Cytoplasmic AMACR expression is present in the vast majority of nephrogenic adenoma, (i)Nuclear transcription factors PAX- 2 or PAX-8 are expressed in nephrogenic adenoma and are helpful markers to support the diagnosis in difficult cases
  • 90.
    Central zone histologymimicking HGPIN. (a) Central zone histology is typically a mimicker of HGPIN; however, prominent cribriform architecture in some cases may mimic cancer. • In the central zone, glands are complex with frequent papillation and undulating architecture with pseudostratified lining epithelium • At low magnification, glands demonstrate distinct cytoplasmic eosinophilia (b). Roman bridges and cribriform architecture are common • In contrast to HGPIN, nuclei stream parallel to bridges in comparison to perpendicular orientation in HGPIN
  • 91.
    (c). The cytologicalatypia is seen in basal cells (arrow), a feature helpful to differentiate from HGPIN or cancer Before making a diagnosis of HGPIN or atypia in biopsies from the base area of the prostate, central zone histology should be ruled out
  • 92.
    Clear cell cribriformhyperplasia. • Clear cell cribriform hyperplasia represents a spectrum of benign prostate hyperplasia and therefore is typically encountered in the transition zone of the prostate. (a)There is a nodular proliferation of nonconfluent cribriform glands with clear to eosinophilic cytoplasm (b)The cells forming the central lumina are cuboidal to low columnar secretory-type cells, with uniform round nuclei and clear cytoplasm. • The glands (arrows) are rimmed with a prominent basal cell layer
  • 94.
    Malakoplakia. • There isa diffuse sheet-like proliferation of pink epithelioid histiocytes, accompanied by other inflammatory cells, similar to nonspecific xanthogranulomatous prostatitis. • The histiocytic nature of epithelioid cells and the presence of Michaelis-Gutmann bodies (arrow) suggest the diagnosis of malakoplakia
  • 95.
    Sclerosing adenosis mimickinghigh-grade prostate carcinoma. • This specimen demonstrates a proliferation of poorly formed and complex glands mimicking high-grade prostate carcinoma. • Lowpower recognition is a key. (a). It typically forms a well-circumscribed nodule of tightly packed glands (b). At high magnification, glands demonstrate complex proliferation, poorly formed glands with slit-like lumina, fused glands, and even single cells with signet ring cell-like features, mimicking high-grade cancer
  • 96.
    (c)Stroma surrounding theglands is cellular and hyalinized (arrows). (d)Prominent nucleoli, crystalloids, and blue mucin are common
  • 97.
    (e)Basal cells arehighlighted with basal cell marker p63. (f) Basal cells undergo myoepithelial metaplasia and show coexpression of basal cell markers and S-100 and muscle-specific actin. • When one or more well-circumscribed cellular lesions mimicking high-grade prostate cancer are encountered in TURP or biopsies from the transition zone of the prostate, sclerosing adenosis should be ruled out
  • 98.
    Paraganglia mimicking high-grade prostatecarcinoma and extraprostatic extension. (a)At low power, paraganglia consist of small, solid nests of cells with clear cytoplasm separated by a delicate vascular network, mimicking high-grade Gleason pattern 4 or 5 prostate carcinoma. • Its presence in adipose tissue , impart an impression of extraprostatic tumor extension. (b)At high power, the cells have clear to amphophilic, finely granular cytoplasm. Random cytological atypia may be seen and nuclei are often hyperchromatic, but nucleoli are inconspicuous.
  • 99.
    Recognition of thedelicate vascular network pattern referred to as the “Zellballen” arrangement is an important clue. In difficult cases, positive neuroendocrine markers support the diagnosis (synaptophysin)
  • 100.
    • Xanthomatous infiltratein prostate needle biopsy. (a) Xanthoma cells grow in a diffuse infiltrative pattern, mimicking poorly differentiated prostate carcinoma with foamy features . (b)Lack of any glandular differentiation and relatively bland nuclear features suggests the diagnosis of xanthomatous infiltrate • In small needle biopsysamples, a panel of immunohistochemical markers of histiocytic lineage (CD- 68) and pancytokeratin may be necessary to rule out carcinoma. • Presence of other inflammatory cells would support the diagnosis of xanthomatous infiltrate
  • 101.
    Commonly Used Immunohistochemical Markers forDiagnosis of Prostate Cancer in Biopsy
  • 102.
    Basal Cell Markers Types of basal cell markers 1. HMWCK: cytoplasmic intermediate filaments detected by several antibody preparations (34bE12, CK5/6, CK14) 2. p63: nuclear antigen 3. Basal cell cocktail (34bE12+ p63)  Staining pattern in prostate cancer 1. Prostate carcinoma lacks staining for basal cell markers 2. HMWCK may rarely be positive in cancer cells, but not in basal cell distribution, due to excessive antigen retrieval and staining 3. p63 can rarely be found in cancer cells with uniform and non-basal cell distribution  Diagnostic utility  A negative basal cell marker staining in atypical glands morphologically suspicious for cancer supports a cancer diagnosis  Pitfalls  Adenosis, partial atrophy, high-grade prostatic intraepithelial neoplasia (HGPIN) may have discontinuous or even absent basal cell lining
  • 103.
    a-Methylacyl CoA Racemase(AMACR, P504S)  Types of antibodies  Monoclonal (P504S) and polyclonal, both with comparable sensitivity and specificity  Staining pattern in prostate cancer  Apical cytoplasmic granular staining  Diagnostic utility 1. Positive AMACR staining in atypical glands morphologically suspicious for cancer supports a cancer diagnosis 2. Positive AMACR may convert an ATYP to cancer diagnosis where morphology is suspicious for but not diagnostic of cancer and basal cell markers are negative
  • 105.
    Points to rememberin Gleason Grading on needle biopsy  Gleason grade is solely based on architectural pattern, cytologic features are not factored in.  Both the primary (predominant) and secondary (second most prevalent) architectural patterns are identified and assigned a grade from 1 to 5, with 1 being the most differentiated and 5 being undifferentiated.  If a tumor has only one histologic pattern, then for uniformity, the primary and secondary patterns are given the same grade.  Full Gleason score is assigned to even to small foci of cancer on needle biopsy, because it has been demonstrated that the grade assigned to these minimal cancers is just as accurate compared with cases with more extensive cancer on biopsy.
  • 106.
     In settingof three grades on biopsy where the highest grade is the least common, the highest grade is taken as the secondary pattern.  One should assign a separate Gleason score to each involved core, especially when one of the cores is high grade (Gleason score 4 + 4 = 8) and other cores have lower-grade cancer.
  • 107.
    Current Concepts ofGleason Grading 1. Gleason pattern 1 or 2 should be rarely if ever applied in the biopsy setting 2. Gleason grade in the biopsy setting essentially starts with Gleason pattern 3 3. A few malignant glands located between benign glands indicate pattern 3 (small focus of cancer does not necessarily mean low-grade cancer) 4. Virtually all cribriform carcinomas represent pattern 4 or 5 if associated with necrosis 5. Clusters of glands with poorly formed glandular lumina where tangential sectioning is ruled out represent Gleason pattern 4
  • 108.
    6. Percentage ofpattern 4 in the setting of Gleason score 7 (3 + 4 versus 4 + 3) bears prognostic importance 7. Multiple cores with cancer of different Gleason grades, grade information of individual core(s) better correlates with Gleason grade of radical prostatectomy 8. Any amount of higher pattern in the needle biopsy should be reported 9. In the setting of high-grade tumor of large volume, a small amount (< 5%) of lower-grade pattern can be ignored and need not be reported 10. Tertiary pattern 5 in the biopsy should be reported as the secondary pattern in the needle biopsy due to its prognostic significance 11. Many “special” types of prostate cancers are considered examples of Gleason pattern 4 or 5
  • 109.
    Future Trends inProstate Biopsy Sampling and Its Clinical Applications
  • 110.
    References  Springers ProstateBiopsy Interpretation: An Illustrated Guide by Shah and Zhou.  Lippincotts Williams and Wilkins Prostate biopsy interpretation series by Epstein and Yang.  Robbins and Cotran pathologic basis of disease 9e.  Sternberg’s Diagnostic surgical pathology.
  • 111.

Editor's Notes

  • #72 In small biopsy samples, seminal vesicle and ejaculatory duct structures are usually not distinguishable unless biopsy targeting seminal vesicle is performed.