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.

1. Dr Malini

2. 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

3. Indications of prostate biopsy
 Symptoms - frequency
 Increased serum PSA
 Digital Rectal Examination – hard prostate

4. Biopsy Techniques for Prostate
Cancer Detection

5. Transrectal and Transperineal Biopsy Approaches
for Prostate Cancer Detection

6. 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

7. 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

8. 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)

9. 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

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 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.

12. 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.

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 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

15.  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

16. 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

17. Ganglia found in prostate needle biopsies should not be mistaken for high-grade carcinoma.
Note the intracellular pigment and satellite cells around neurons.

18. 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.

19. 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


20. ;y7

21. Histologic Variations of Normal
Prostate Tissue
 Atrophy
 Basal cell hyperplasia
 Urothelial metaplasia
 Perineural abutment
 Glands within skeletal muscle fibers
 Irregular prostate–periprostatic interface

22. Atrophic prostate
Glands retain lobulated architecture.
Cystic dilatation is common. Glands appear dark due to reduced cytoplasm.

23. 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

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). 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

26. 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

27. 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

28. 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

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 from the intraluminal proliferation of cancer cells that
forms balls or tufts within cancer glands, superficially resembling renal
glomeruli

31. 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.

32. 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

33. 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.

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 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

40. 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

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 (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

45. 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

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.
• 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.

48. 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

49. Mitosis and Apoptosis.
A mitotic figure (arrow, a) and
apoptotic bodies (arrows, b) are
found in cancer glands.

50. 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

51. 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)

52. 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

53. Simple atrophy.
(a) Glands have lobulated
architecture
(b) Nuclei are slightly enlarged
with small or inconspicuous
nucleoli

54. 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

55. 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.

56. 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

57. Histological
Features For and
Against Cancer
Diagnosis in
Biopsy

58. 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.

59. 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.

60. Limited prostate cancer.
There are only five cancer glands present in one needle core.
However, they display infiltrative growth pattern

61. Limited prostate
cancer.
• Significant nuclear enlargement
and hyperchromasia .
• These atypical glands are not
inflamed or atrophic.
• These glands are negative for p63

63. Benign mimics of prostatic carcinoma

64. Atypical
Morphological
Features Commonly
Encountered in
Various Benign
Mimics of Prostate
Cancer

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.
• 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

69. 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

70. 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 .

71. 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 .

72. • 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 .

73. • 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

74. 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

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 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

77. • 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

78. 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.

79. • 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 .

80. • (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

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 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).

83. 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

84. 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)

85. Diagnostic Approach to
Prostate Basal
Cell Lesions

86. 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

87. 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).

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, 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

90. 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

91. (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

92. 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

94. 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

95. 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

96. (c)Stroma surrounding the glands is cellular and hyalinized (arrows).
(d)Prominent nucleoli, crystalloids, and blue mucin are common

97. (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

98. 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.

99. 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)

100. • 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

101. Commonly Used
Immunohistochemical
Markers for Diagnosis
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 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.

106.  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.

107. 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

108. 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

109. Future Trends in Prostate Biopsy Sampling and
Its Clinical Applications

110. 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.

111. Thank you……..!