DR Mohammad HosseinSANEI
Department of pathology
Isfahan university of medical science
1
• . Gross tumor may be identified by
examination of the posterior and
posterolateral horseshoe-shaped
peripheral zone of the prostate looking for
asymmetry in size, color, and density of
tissue between right and left halves of the
prostate
2
• In more than 85% of prostates, gross
tumor will be identified
• Submission of the prostate in this manner
will allow detection of more than 90% of
positive margins, extraprostatic extension,
and seminal vesicle invasion with, on
average, a submission of only 12 to 13
cassettes (see later for description of
lymph node examination
3
• FIGURE 45-3. Gross photograph of benign
prostatic hyperplasia
4
adenocarcinoma
• FIGURE 45-66. Gross appearance of adenocarcinoma
of the prostate. Note more solid, homogeneous, gray–
white appearance to carcinoma (left) as compared
with contralateral benign prostate with a more spongy
5
appearance.
Gleason system
6
Gleason system
• is based on the glandular pattern of
the tumor as identified at relatively
low magnification
• cytologic features play no role in the
grade of the tumor
7
• Both the primary (predominant) and
the 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
8
• Because both the primary and
secondary patterns were considered
influential in predicting prognosis, a
combined Gleason grade resulted,
obtained by the addition of the
primary and secondary grades.
• If a tumor had only one histologic
pattern, then for uniformity, the
primary and secondary scores were
given the same grade
9
• The combined Gleason grades range
from 2 (1 + 1 = 2), which represents
tumors uniformly composed of
Gleason pattern 1 tumor, to 10 (5 + 5
= 10), which represents totally
undifferentiated tumors
10
The advantages of the Gleason
grading system are
• (a) it is easy to learn and apply
because it is based on lowmagnification pattern recognition
• and (b) it is less time consuming than
the grading systems that examine
cytologic features.
11
• Two older studies demonstrated good
interobserver and intraobserver
reproducibility with the Gleason
system with agreements to within one
combined Gleason grade of more
than 80% and 90%, respectively
• However, more recent studies
showed only moderate interobserver
reproducibility among academic and
private pathologists
12
• As shown on Gleason’s schematic
diagram (Fig. 15), there is a
continuum of differentiation between
the various Gleason patterns such
that the grade assigned at the
extremes of a particular Gleason
pattern may be somewhat subjective
13
• Another reason for grading
discrepancies is the presence of more
than two grades
• Gleason's system and most of the
other grading systems were
developed predominantly on needle
biopsy and TUR specimens, in which
it is uncommon for more than two
grades to be represented.
14
• In prostatectomy specimens, however,
tumors with multiple grades are not
infrequent
• If more than two grades exist in
Gleason's system, they should be
commented on in a note .
• The Gleason grade on biopsy material
has been shown to correlate fairly well
with that of the subsequent radical
prostatectomy
15
• Two large series comparing radical
prostatectomy specimens and their diagnostic
biopsies showed a correlation to within one
combined Gleason grade in approximately
73% of the cases
• The tendency to undergrade needle-biopsy
material results from the minimal amount of
tumor in the needle biopsy and the
consequent difficulty in appreciating either the
infiltrative nature of the tumor or the variability
in size and shape of the neoplastic glands,
features that are characteristic of Gleason
pattern 3
16
• An unavoidable cause of discrepant
grading between the biopsy and
subsequent prostatectomy specimen is
that due to sampling error by the needle
biopsy
• Because in TUR material there is greater
sampling of the prostate and more tissue,
the better to appreciate the overall
architecture of the tumor, the grades
assigned to TUR material tend to be more
accurate than those given on needle17
biopsy specimens .
• The major weakness of the Gleason
grading system is that, although at
both the low and high ends of the
Gleason system we have fairly
accurate predictive ability, the
prognosis of the remaining patients is
uncertain
18
The positive lymph node rate for various
Gleason scores is reported as follows:
•
•
•
•
2 to 4, less than 1%
5 to 6, 2% to 3%;
7, 10%;
8 to 10, 20% .
19
Extent of Cancer on Biopsy
• There are few data as to how the extent of
cancer on needle biopsy should be recorded
• . Our own results show that only the
number of involved cores and bilaterality
add to the prediction of pathologic stage,
beyond that provided by biopsy grade and
serum PSA values
20
Extent of Cancer on Biopsy
• Nevertheless, it is the convention to
provide additional quantification when
diagnosing cancer on needle biopsy
• We record the number of positive cores
and the percentage positivity of each
core
21
22
FIGURE 45-15. Gleason pattern 1 tumor composed of a
circumscribed nodule of uniform, single, separate, closely
23
packed glands
.
FIGURE 45-16. In Gleason pattern 2, although the tumor is still fairly
circumscribed, at the edge of the tumor nodule, there can be minimal extension
by neoplastic glands into the surrounding nonneoplastic prostate. The glands in
pattern 2 are still single and separate, yet they are more loosely arranged and
not quite so uniform as in pattern 1.
24
FIGURE 45-17. Pattern 3 tumor infiltrates in and among the
nonneoplastic prostate, with the glands having marked variation in size
and shape. Many of the glands are smaller than those seen in pattern 1
or 2 tumors. Smoothly circumscribed cribriform nodules of tumor also
are classified as pattern 3.
25
FIGURE 45-18. In Gleason pattern 4 tumor, the glands are no longer single and separate, as
seen in patterns 1 through 3, and are composed of fused glands with ragged infiltrating edges.
If one can mentally draw a circle around well-formed individual glands, then it is Gleason
pattern 3.
26
.
FIGURE 45-19. The Gleason pattern 5 tumor shows no glandular
differentiation with either solid masses of cells or individually infiltrating
cells.
27
.
FIGURE 45-21. Adenocarcinoma of the prostate, Gleason grade 3 + 3 = 6 on
needle biopsy. Note small glands infiltrating in and among larger benign glands.
28
FIGURE 45-22. Adenocarcinoma, Gleason grade 3 + 4 = 7. Note well-formed
glands consistent with Gleason pattern 3 (lower right) compared with fused
glands of Gleason pattern 4 (upper left).
29
FIGURE 45-24. Adenocarcinoma of the prostate, Gleason grade 3 + 3 = 6.
Infiltrative appearance among benign glands is diagnostic of cancer.
30
• FIGURE 45-20. Gleason pattern 5 with central
comedonecrosis.
31
Microscopic
Diagnosis
32
• The types of difficulty encountered in
diagnosing adenocarcinoma of the prostate
depend on whether we are evaluating
needle-biopsy material or TUR resection
specimens
• . In needle-biopsy material, there exists the
risk of overdiagnosing atrophic glands and
seminal vesicles as carcinoma, as well as
underdiagnosing adenocarcinoma because
of the limited amount of tumor present .
33
• Atrophic glands stand out at scanning
magnification because of their open
lumina lined by cells with a high
nuclear-to-cytoplasmic ratio, resulting
in a very basophilic appearance to the
glands
34
The most useful criteria to establish a
diagnosis of atrophic adenocarcinoma are
•
•
•
•
(a) an infiltrative pattern of growth,
(b) the presence of macronucleoli
(c) increased nuclear size
(d) the presence of adjacent, nonatrophic
cancer
An important feature, which may not
necessarily be readily identifiable in
atrophic glands, is the presence of a basal
cell layer
35
• FIGURE 45-30. Atrophic adenocarcinoma of the
prostate with very prominent nucleoli.
36
• FIGURE 45-31. Atrophic adenocarcinoma of the
prostate (left) merging with more typical
adenocarcinoma of the prostate (right).
37
• FIGURE 45-43. Needle biopsy showing glands
with partial atrophy.
38
• FIGURE 45-41. Needle biopsy showing sclerotic
atrophy with an infiltrative appearance.
39
The use of keratin antibodies specific
for prostatic basal cells is helpful in
identifying basal cells in atrophic
glands
Another potential source of
overdiagnosing prostatic
adenocarcinoma is the presence of
seminal vesicles or seminal vesicle–
type epithelium on needle biopsy
40
• The presence of prominent lipofuscin
granules within seminal vesicle
epithelium is an important diagnostic
aid
• Despite their marked enlargement
and often bizarre shapes, these cells
lack mitotic activity and commonly
appear degenerated in nature, similar
to what is seen with radiation atypia
41
• FIGURE 45-44. Needle biopsy of seminal
vesicles showing multiple small glands arranged
42
around central lumen.
• FIGURE 45-45. Scattered markedly atypical nuclei with a
degenerative appearance, characteristic of seminal vesicle
epithelium. Prominent lipofuscin pigment noted.
43
• Seminal vesicle-type epithelium is also
PSAP (not always PSA) negative and
high-molecular-weight cytokeratin can
distinguish between the two tissue types .
• A more common problem with the
evaluation of needle-biopsy material from
the prostate is not the overdiagnosis of
carcinoma, but rather the underdiagnosis
of carcinoma as a result of the limited
amount of tumor present
44
underdiagnosis of carcinoma
• An unusual pattern of adenocarcinoma
seen on needle biopsy that may be
underdiagnosed involves cancers with
voluminous xanthomatous cytoplasm in
which nuclei are small and often show no
or minimal atypia, termed foamy gland
carcinoma; intraluminal pink
homogeneous secretions are often
present
45
underdiagnosis of carcinoma
• The identification of this type of cancer
hinges on recognizing that the cytoplasm
is unique to malignant glands, and the
small, round nuclei are more uniformly
hyperchromatic and round without a hint of
a basal cell layer, as compared with
normal glands.
46
• FIGURE 45-32. Adenocarcinoma of the prostate with
abundant xanthomatous cytoplasm, small nuclei, and
pink homogeneous intraluminal secretions. Compare
47
cytoplasm with more typical adenocarcinoma (right).
• FIGURE 45-55. Xanthoma of the prostate.
48
recognition of prostatic cancer
• The recognition of prostatic cancer in these
cases rests on both the architectural
abnormalities resulting from the infiltrating
neoplastic glands and the cytologic features
of the neoplastic epithelium
• Although the finding of prominent nucleoli in
the small glands is reassuring, it is not
necessary to diagnose carcinoma. Often,
only significant nuclear enlargement
discriminates cancer from the surrounding
49
benign glands
FIGURE 45-25. Neoplastic glands composed of a
single layer of cells with enlarged nuclei, some with
prominent nucleoli.
50
• FIGURE 45-34. Low-grade adenocarcinoma showing
large back-to-back glands in which the luminal
surfaces have an even straight edge without papillary
infolding, and cells have abundant cytoplasm. Stains
51
for 34be12 were negative in these glands
• FIGURE 45-33.
Pseudohyperplastic
adenocarcinoma where
cancerous glands are
relatively large and have
papillary infolding
architecturally resembling
benign glands or high-grade
prostatic intraepithelial
neoplasia (PIN). The glands
show prominent nucleoli, yet
are too crowded to represent
high-grade PIN. Stains for
high molecular weight
cytokeratin were also
negative in the entire focus,
in support of the diagnosis of
cancer.
52
• ). Intraluminal pink acellular dense
secretions or blue-tinged mucinous
secretions seen in small suggestive glands
may be additional features that help to
differentiate malignant from benign glands,
given their greater frequency in
malignancy
• ). If the architectural or cytologic features
or both are diagnostic of cancer, searching
for a basal cell layer tends to confound
rather than to help.
53
.
FIGURE 45-27. Adenocarcinoma of the prostate with
blue-tinged mucinous secretions seen on hematoxylin and
eosin–stained section.
54
.
FIGURE 45-28. Adenocarcinoma with small glands with
enlarged nuclei, crystalloids, and mitotic figure. Adjacent
benign prostate glands contain lipofuscin pigment.
55
.
FIGURE 45-35. Adenocarcinoma of the prostate with
perineural invasion. Occasionally glands with perineural
invasion will show papillary infolding, mimicking a benign56
gland.
FIGURE 45-38. Perineural indentation by benign
prostate gland
57
.
FIGURE 45-37. Glomerulations with adenocarcinoma
showing cribriform formation that is not transluminal,
resembling glomeruli.
58
• FIGURE 45-49. Basal cell–specific cytokeratin
(34BE12) immunostaining demonstrates a patchy
basal cell layer surrounding some of the glands within
59
a nodule of adenosis.
FIGURE 45-49. Basal cell–specific cytokeratin
(34BE12) immunostaining demonstrates no basal cell in
60
small gland consist with adenocarcinom.
• Also, basal cells in benign glands tend to
stain uniformly and intensely, in contrast
to the patchy staining in adenosis
• Adenosis tends to be located centrally
within the gland, such that it is most
commonly seen in TUR resection
specimens
61
• In TUR resection specimens, we usually have
an entire nodule of adenosis to evaluate; it
would be highly unlikely for the entire focus to
show no immunoreactivity with basal cell–
specific cytokeratin
• . Consequently, the lack of basal cell–specific
cytokeratin staining in a nodule of glands in
which we are deciding between adenosis and
low-grade adenocarcinoma is highly
supportive of the diagnosis of
adenocarcinoma
62
• FIGURE 45-52. Sclerosing adenosis showing glands
of adenosis (left) merging with cytologically similar
63
cords and spindle cells (right).
• FIGURE 45-94. Basal cell hyperplasia characterized
by glandular structures with multiple cell layers. 64
• FIGURE 45-95. Basal cell hyperplasia with
prominent nucleoli and mitotic figures.
65
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Table 2. Helpful features in the needle-biopsy diagnosis of adenocarcinoma on H&Estained sections
Features diagnostic of adenocarcinoma
Perineural invasion
Mucinous fibroplasia (collagenous micronodules)
Glomerulations
Features favoring the diagnosis of cancer
(diagnosis based on a constellation of features)
Architecture
Small glands in between larger benign glands
Crowded glands that stand out from adjacent benign glands
Cytology
Prominent nucleoli
Nuclear enlargement
Hyperchromatic nuclei
Amphophilic cytoplasm
Mitotic figures
Luminal contents
Blue mucinous secretions
Pink amorphous secretions
Crystalloids in small infiltrating glands (i.e., not adenosis)
Adjacent findings
High grade PIN either away from small atypical glands or
in presence of numerous small atypical glands, such that
tangential sectioning or outpouching off of PIN not possible
PIN, prostatic intraepithelial neoplasia .
66
PROSTATIC INTRAEPITHELIAL
NEOPLASIA as
Roman bridge
• FIGURE 45-64. Central zone with Roman bridge and
cribriform formation. Note lack of nuclear atypia. 68
FIGURE 45-56. Low-grade prostatic intraepithelial neoplasia
with slight enlargement of nuclei and stratification, yet no
prominent nucleoli.
69
• FIGURE 45-61. High-grade prostatic intraepithelial
neoplasia (PIN) (left) with only a few atypical small glands. We
cannot distinguish between PIN and adjacent infiltrating
carcinoma versus outpouchings or tangential sections off of
70
high-grade PIN.
FIGURE 45-57. Low magnification of high-grade prostatic
intraepithelial neoplasia, showing glands with a normal
architectural pattern yet a basophilic appearance.
71
.
FIGURE 45-58. Basophilia of gland with high-grade prostatic intraepithelial neoplasia
(PIN) owing to nuclear stratification and high nuclear-to-cytoplasmic ratio with large
nuclei and prominent nucleoli. Note in left portion of field within a single gland, the
abrupt transition between benign-appearing nuclei and PIN nuclei.
72
FIGURE 45-59. Prominent tall papillary tufts within highgrade prostatic intraepithelial neoplasia (PIN). Nuclei appear
more benign toward the luminal surface of the papillary
projections. Note large nuclei with frequent nucleoli,
diagnostic of high-grade PIN, toward the edge of the gland 73
up against the basement membrane.
FIGURE 45-60. High-grade prostatic intraepithelial neoplasia
with cribriform pattern.
74
• FIGURE 45-71. Adenocarcinoma of the prostate
invading the seminal vesicles.
75
• FIGURE 45-80. Adenocarcinoma after hormone
therapy, showing tumor cells with pyknotic nuclei
76
and foamy cytoplasm resembling histiocytes.
• FIGURE 45-81. Benign prostate glands showing
77
radiation effect.
• FIGURE 45-82. Mucinous adenocarcinoma of the
prostate with glands of adenocarcinoma floating within
mucin.
78
• FIGURE 45-83. Adenocarcinoma of the prostate
with signet ring cell–like features.
79
• FIGURE 45-84. Adenocarcinoma of the prostate with
fine, eosinophilic cytoplasmic granules corresponding
to neuroendocrine differentiation. Immunostaining
revealed strong positivity with human chorionic
80
gonadotropin.
• FIGURE 45-85. Small cell carcinoma of the prostate
admixed with ordinary adenocarcinoma of the
81
prostate (right).
• FIGURE 45-86. Papillary prostatic duct
adenocarcinoma showing tall pseudostratified
columnar epithelium with dark cytoplasm.
82
• FIGURE 45-87. Cribriform pattern of prostatic duct
adenocarcinoma.
83
• FIGURE 45-88. Adenosquamous carcinoma.
84
• FIGURE 45-89. Infiltrating transitional cell carcinoma
in the prostate. Cells are more pleomorphic than is
poorly differentiated prostate adenocarcinoma.
85
• FIGURE 45-90. Intraductal transitional cell carcinoma
with rounded malignant urothelial nests. Associated
stromal invasion characterized by cords and single
cells of infiltrating transitional cell carcinoma.
86
• FIGURE 45-91.
Stromal sarcoma of
the prostate.
87
• FIGURE 45-92. Stromal proliferation of uncertain
malignant potential with appearance of benign
phyllodes tumor.
88
• FIGURE 45-96. Basaloid carcinoma of the prostate
89
with desmoplastic stromal reaction.