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PATHOLOGY OF PROSTATE
Lawrence True and Funda Vakar-Lopez
INTRODUCTION
As with all specialty areas in medicine, our knowledge of the prostate
gland and of diseases of the prostate continues to advance.
Furthermore, a number of detailed books and monographs that focus
on the prostate gland have been published within the past ten years.
Accordingly, rather than provide readily available and potentially
redundant information for the reader, we shall assume readers have a
basic knowledge of prostate anatomy and histopathology and shall
focus our discussion on pathologic findings of both current and
potential clinical relevance that have been made in recent years.
PROSTATE ANATOMY
Prostate “Capsule”
A distinctive and clinically important feature of prostate gland
anatomy that poses challenges to the surgical pathologist examining the prostatectomy for extracapsular extension is the prostatic
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“capsule.” In a prostate gland the band of fibrous tissue separating
the glandular prostate parenchyma from the periprostatic connective tissue is not a single structure, nor is it of uniform thickness.
Although a fibrous capsule is a more clearly defined structure anteriorly and laterally, in the region of the neurovascular bundle
toward the base of the prostate thin fibromuscular bundles and
fibrous tissue extend from this band into the periprostatic adipose
tissue. These strands of fibrous and fibromuscular tissue are histologically identical to the capsule.1 One of the histologic landmarks
used for pathologic staging of prostate cancer is the prostate “capsule.” “Extraprostatic extension” (EPE) or breach of the prostatic
“capsule” is a criterion of higher stage. The most clear cut form of
EPE is exemplified by carcinoma cells contacting, or “touching,”
periprostatic adipose tissue, since no fat cells are found in prostatic
parenchyma. Based on this criterion, a potential dilemma for the
pathologist occurs when a carcinoma extends into the fibrous tissue strands that radiate from the prostatic stroma into the fat, but
does not contact adipocytes. Variance among generalist pathologists as to the precise histological definition of EPE is high. A
multi-institutional study has provided guidelines for such a situation. Carcinoma that is in fibrous tissue that is beyond the
projected border of histologically normal prostate parenchyma
should be regarded as EPE. Validation of these histological criteria
is based on the finding that this definition minimizes variance
among urologic pathologists.2
Zones of the Prostate
Since descriptions of normal prostate zonal histology by McNeal,
updates on the histological zones of the prostate are few.
Nonetheless, it is worth mentioning some aspects of normal prostate
anatomy and histology and their clinical correlations. As has been
well documented, the majority of prostatic adenocarcinomas occur in
the peripheral zone (PZ). Carcinoma of the transition zone (TZ) has
a couple of distinctive features. TZ cancers, in general, have features
associated with a good prognosis — a low Gleason grade and low
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rates of capsule penetration and of margin positivity. Furthermore,
most TZ cancers have a distinctive histology, being composed of
large glands with abundant pale cytoplasm and basally located, small
nuclei that have inconspicuous nucleoli.3 A third observation concerns prostate cancer in African Americans — TZ-only tumors may
be more frequent and the cancers frequently involve the surgical
margins.
Another anatomic consideration is the absence of extraprostatic
soft tissue in the anterior apical region which makes surgical
approaches in this area more limited and surgically challenging,
thereby resulting more often in cancer being at these surgical margins.
Whether the specific location of positive margins is of biological or
clinical relevance merits attention.4
Cell Types of the Prostate
Progress has been made in the identification of different prostate cell
types based on immunohistochemical profiles. Prostate parenchymal
cells have distinctive profiles of cell membrane gene products. Those
that are unique to the predominant parenchymal cell types can serve
as tools to sort specific cell types for determining cell-specific transcriptomes. For example, luminal epithelial cells express CD’s 10, 24,
26, and 57, basal epithelial cells express CD’s 44, 49f, 95, and
133, and the fibromuscular stromal cells express CD’s 49a, 49e,
and 61. Expression of prostate luminal cell membrane proteins by
prostate cancer enables us to isolate cancer cells for transcriptome
characterization.
Epithelial cells can also be subcategorized by expression patterns
of keratins and of other molecules. Luminal cells express keratins
8 and 18. basal cells express cytokeratins 5, 10, and 14, transcription
factor p63, and membrane pump protein ABCG2. An amplifying progenitor/stem cell expresses CD44, alpha(2)beta(1), and CD133.5
Finally, there is evidence of a specific prostate epithelial cell that has
functional stem cell properties, i.e. this cell can generate a prostate,
at least in the rodent. This cell is identified by coexpression of
CD133, CD44, and CD117, and in the rodent, of sca-1.6
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BENIGN PROSTATIC HYPERTROPHY (BPH)
BPH, defined as an enlarged prostate gland resulting from an
increased number of parenchymal cells, is a morphological manifestation of some cases of lower urinary tract obstruction/syndrome
(LUTS). However, an enlarged prostate is not invariably associated
with obstructive uropathy. Conversely LUTS may occur without
BPH.7 BPH, which is characterized by the formation of nodules that
most frequently have an increased stromal: epithelial cell ratio, occurs
almost exclusively in the transition zone. Why these hypertrophic
nodules occur only in the transition zone is unknown.
The diagnosis of BPH in needle biopsies is limited because biopsies target the peripheral zone and biopsies are so small that the only
distinct histological feature of nodules — their spherical architecture —
cannot be visualized. Only in prostates enlarged by extensive BPH do
the nodules compress the peripheral zone to such an extent that
nodules can be sampled in peripherally directed needle biopsies. In
extended biopsy schemes, where the transition zone is intentionally
sampled, the frequency of encountering a BPH nodule is higher. Still
the diagnosis is limited by the fact that the borders of the nodules
cannot be seen clearly in the cores. Clues to the presumptive diagnosis of BPH in needle cores are the typically more cellular stroma of
the nodule compared with the adjacent peripheral zone stroma and
the rounded conformation of the nodules. Little is known of the
pathogenesis of BPH.
Observations implicate different processes in the pathogenesis
of BPH — inflammatory cells (CD4 and CD8 T cells),8 stromal
cells, which secrete cytokines that induce growth, mediated by basic
fibroblast growth factor and/or TGF beta 1, under stimulation by
interleukin 8, and extracellular matrix proteins.9 Recent studies highlight the role of the extracellular matrix proteoglycans in initiation and
progression of these nodules.10 Versican, an extracellular matrix proteoglycan, is overexpressed in the stromal cells of BPH nodules
compared to the surrounding stroma, presumably contributing to the
expansion of stroma in the BPH nodules. There is cell line-based evidence that versican can activate macrophages to express growth factor
interleukin 6.
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INFLAMMATION
Inflammatory processes that manifest as inflammatory cell infiltrates in
tissue can, conventionally, be classified as acute (neutrophilic cell-rich)
and chronic (mononuclear cell-rich). Rare is the situation where
inflammation in the prostate is sufficiently dense that there is a definite
clinical correlation. However, there are a couple of situations that merit
some discussion — granulomatous prostatitis and chronic prostatitis.
Granulomatous Prostatitis
Granulomatous prostatitis, histologically characterized by sheets or
nodules of macrophages, which are predominantly mononuclear with
rare multi-nucleated Langhans type cells, and lymphocytes, only rarely
presents as a clinical problem. Microorganisms that often evoke granulomatous inflammation in tissue — mycobacteria and fungi — are
extremely rare causes of granulomatous prostatitis in North America.
More frequent are granulomas resulting from BCG, when instilled
intravesically to treat superficial urothelial cell carcinoma. BCG can
produce granulomatous infiltrates in prostate that, rarely, form sufficiently large foci of necrosis as to be clinically detectable.
The most frequent type of granulomatous prostatitis that can pose
a clinical challenge is idiopathic granulomatous prostatitis that forms
a palpable nodule by digital rectal examination and that clinically
mimics a focus of cancer. Pathologically these nodules are composed
of a densely cellular infiltrate of granulomatous inflammation.
Distinction of these self-limited lesions from high-grade prostate carcinoma is readily provided by immunostains. Carcinomas express
immunoreactive keratin and PSA. The cells of granulomatous prostatitis express CD45 (a marker of lymphocytes) and CD68 (a marker of
histiocytes/macrophages).11
Chronic Prostatitis
The term “chronic prostatitis” poses problems since, historically,
urologists and pathologists have used the term differently. To the urologist, chronic prostatitis is the combination of a clinical syndrome that
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is characterized by lower genitourinary tract and/or genital pain or
discomfort and inflammatory cells in expressed prostatic secretions.12
Following recognition that many of these patients do not have an
infection, this clinical syndrome of uncertain pathogenesis has been
termed chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).
CP/CPPS appears not to be an inflammatory process.13 Nor does the
prostate appear to be the primary organ of this disease.14 Conversely,
the finding of mononuclear inflammatory cells in the prostate does not
warrant a pathologic diagnosis of chronic prostatitis since (1) the number of mononuclear inflammatory cells that represents a “normal”
complement for the prostate has never been defined, and (2) there is
no compelling evidence that the presence of mononuclear inflammatory cells in prostate parenchyma is associated with a clinical
consequence, with the exception of granulomatous prostatitis.
Nonetheless, there is evidence that inflammatory cells of different
lineages may have a role in prostate disease. For example, antigen processing cells isolated from the prostate have been used to produce a
prostate cancer vaccine that is apparently reactive to the cancer from
which they were isolated.15 And, since inflammatory cells, particularly T
cells, are reportedly more numerous in nodules of BPH, these cells may
play a role in the pathogenesis of BPH.8 As a final example, androgen
ablative therapy reportedly induces a T cell infiltrate into benign prostate
glands and prostate carcinoma.16 However, these inflammatory cell infiltrates may not be readily distinguished from “normal” inflammatory cell
populations of the prostate. In addition to there being no definition of
what the “normal” inflammatory cell complement of the prostate is, the
residence of inflammatory cells in tissue is transient and may be too brief
to be sampled in sections of prostate tissue. Furthermore, many reports
of increased numbers of inflammatory cells have not used rigorous
sampling strategies to count cells in an unbiased manner.17
PRE-NEOPLASTIC LESIONS
Prostatic Intraepithelial Neoplasia (PIN)
PIN is regarded as the preinvasive stage of prostate neoplasia due to
the cytological, immunohistochemical, and genetic similarity between
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the cells of PIN and the cells of the typical prostate adenocarcinoma.
Historically PIN was divided into three grades, based primarily upon
the extent and frequency of nuclear histological abnormalities.18 This
publication provided both illustrations and detailed histological criteria for the grades of PIN. Of multiple histological features listed in
this paper, the features that best distinguish high- from low-grade
PIN are nuclear changes in the majority of epithelial cells — increase
in nuclear size, variation in nuclear size, large, prominent nucleoli,
and increased heterochromatin. Subsequent studies have categorized
PIN into low-grade PIN (generally recognized as PIN grade 1) and
high-grade PIN (generally recognized as PIN grades 2 and 3).
Current practice is to only report high-grade PIN. In one study
observer variability was only moderate for diagnosing PIN grade 1
(kappa = 0.3) but far better for distinguishing PIN grade 2 or 3 from
PIN grade 1 or normal (kappa = 0.6).19
There are histologic variants of PIN.20 The most common variants are the tufted (59% of PIN) and micropapillary (34% of PIN)
patterns. Less frequent are the cribriform (6% of PIN), and, as <1% of
cases of PIN, flat, inverted (hobnail), comedocarcinoma-like and neuroendocrine-type variants of PIN. However, there is no clinical
significance in subtyping PIN.21 Distinction of all forms of PIN from
carcinoma is best provided by immunostains for basal cell markers,
i.e. p63, keratins 5/6, 10, and 14. Retention of a basal cell layer distinguishes PIN from invasive carcinoma. However, a caveat is that
basal cell marker stains may be partially absent in glands with PIN.
PIN came to the attention of pathologists when it was recognized
that a set of biopsies that contained only high-grade PIN came from
prostates that had a greater likelihood of having carcinoma in subsequent biopsies than prostates from which biopsies lacked cancer or
high-grade PIN.22 Subsequent large multi-institutional studies have
shown that the rate of discovery of cancer in the prostates from which
biopsies initially contained high-grade PIN is less than was originally
reported.23 Nevertheless, there are correlation studies that also support the interpretation that PIN is a preinvasive state of prostate
neoplasia, namely, codistribution with prostate carcinoma and
increasing frequency with which PIN is diagnosed in needle biopsies
in patients who subsequently are found to have prostate carcinoma.22
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These observations have been challenged more recently by studies
that reported that the median frequency of cancer detected following
a diagnosis of PIN is 24%, which is not significantly higher than the
frequency of a repeat biopsy retrieving cancer following a benign
biopsy set.24 In earlier studies, the initial diagnosis of PIN was based
on sextant biopsies and subsequent more extended biopsies that
detected invasive carcinoma. With the current practice of initial
extended biopsies, when high-grade PIN (HGPIN) without invasive
cancer was found in the first set of biopsies, the second set of
extended biopsies did not increase the probability of finding invasive
cancer foci not detected in the first set of biopsies. Therefore, the
current recommendation is not to necessarily re-biopsy men with only
a diagnosis of HGPIN in the first set of biopsies.
The three-dimensional relationship between foci of PIN and of
carcinoma in prostate glands has not been characterized. One recent,
detailed study showed that small foci of carcinoma in prostates with
dominant tumors occur as multiple outpouchings of ducts, have a tortuous 3-D architecture and are spatially associated with HGPIN in a
multifocal manner.25 This finding raises a couple of questions, including (1) where is the invasive/proliferative front of a cancer, and (2) is
there any strategy that would enable a pathologist to determine if a
biopsy is sampling the most biologically and clinically relevant part of
the cancer?
A final point to make is that PIN is not associated with an
increased serum PSA, as was initially reported.26 This finding should
not be surprising since (1) by being confined by the basement membrane of prostate glands the PSA of PIN cells lack a ready path to the
interstitium, and (2) since the glands with PIN represent a relatively
tiny fraction of glandular parenchyma in prostate glands, the contribution to total serum PSA from glands with PIN is miniscule.
Other Candidate Pre-Neoplastic Lesions
A number of histopathological entities of the prostate have been
proposed as pre-neoplastic lesions — atrophy, adenosis, and postatrophic hyperplasia. However, subsequent molecular and clinical
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studies failed to establish a link between these lesions and carcinoma.
Another lesion that was recently proposed as a precursor lesion is proliferative inflammatory atrophy (PIA).27 Several epidemiological and
molecular studies suggest a causal relationship between inflammation
with consequent release of mutagenic free radicals and cancer.28 A
study assessing the ability of pathologists to reliably identify atrophy
and to categorize atrophy lesions into discrete categories (simple atrophy, simple atrophy with cyst formation, postatrophic hyperplasia, and
partial atrophy) showed good inter- and intraobserver variability, raising the prospect that PIA might be reliably diagnosed.29 However, the
frequency of atrophy of any type without concomitant carcinoma and
the lack of increase in carcinoma diagnosis in repeat biopsies following
a diagnosis of PIA argue against PIA being a direct precursor of prostatic adenocarcinoma.30
PROSTATE CARCINOMA
Diagnosis of Prostate Cancer
With the availability of immunohistochemical tools to aid in diagnosing carcinoma, the features to make a histopathologic diagnosis of
prostate cancer have been well defined.31 Furthermore, publications
have documented the variety of histologic patterns of prostate carcinoma. These include foamy gland, mucinous (or, colloid),
adenosquamous, signet ring cell-like, transition zone-like, ductal (previously termed “endometrioid”), atrophic, neuroendocrine (or, small
cell) carcinoma, and sarcomatoid carcinoma. Some of these variants
have clinical relevance. For example, the transition zone-like adenocarcinomas, which are composed of tall columnar cells with generally
clear cytoplasm and small, basally oriented nuclei, tend to be both centered in the transition zone of the prostate and to have a somewhat
better outcome. TZ based cancer, diagnosed in TURP specimens,
appear to have a lower frequency of TMPRSS2-erg fusion cancers, and
a lower frequency of progression, than PZ-localized cancers.3
Conversely, sarcomatoid, neuroendocrine and ductal carcinoma have a
poorer outcome than the typical acinar prostate adenocarcinoma.32–34
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Furthermore, sarcomatoid and neuroendocrine carcinomas of the
prostate are, in general, resistant to androgen deprivation therapy. The
Gleason score assigned to these histological variants conforms to the
criteria for grading “conventional” adenocarcinomas of the prostate.
An exception is ductal carcinoma, which is regarded as a discrete entity
having a prognosis similar to Gleason score 8 (patterns 4 + 4) carcinomas. There are reports that foamy gland carcinoma has a slightly
worse outcome than other histological variants.35 The most important
aspects of these histologic variants is for practicing pathologists to
be aware that carcinoma can manifest histologically in different
histological patterns and that some patterns are usually associated
with a markedly more malignant course — ductal, sarcomatoid and
neuroendocrine.
Differential Diagnostic Considerations
Histopathologic entities considered in the differential diagnosis of
prostate carcinoma include atrophy, normal seminal vesicle/vas deferens, PIN, and benign glands affected by therapy, i.e. radiation,
androgen deprivation or chemotherapy. Since a definitive diagnosis
can be challenging to establish, particularly for very small foci of atypical glands, a widely used convention is to report glands for which the
pathologist cannot make a definitive diagnosis as “Atypical Small
Acinar Proliferation (ASAP).” Although ASAP is not a specific entity,
being more a description of a lesion of uncertain morphologic/
biologic nature, a survey has shown that many clinicians regard a
diagnosis of ASAP as equivalent to high-grade PIN. Both lesions
provide a rationale for re-biopsying the patient.36
Grading Prostate Carcinoma
There have been at least three recent advances in grading carcinoma —
(1) international adoption of the Gleason scheme for grading prostate
carcinoma, characterized in detail by the WHO/ISUP (International
Society of Urological Pathology);37 (2) general recognition that
many prostate carcinomas have been overgraded in the past based
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upon current WHO/ISUP criteria;38 (3) and demonstration of the
reproducibility of Gleason grading by pathologists.39 In 2005 at an
ISUP meeting of more than 50 genitourinary pathologists, cases were
reviewed for grading and consensus was reached with respect to architectural patterns of prostate carcinoma that met current criteria for
the different Gleason patterns. The meeting resulted in a publication
with a schematic that can, in general, be regarded as an update and
simplification of Gleason’s original schematic (Fig. 1). Some clinically
important conclusions of the consensus meeting are: (1) recognition
that Gleason patterns 1 and 2 are quite rare and, in general, are
confined to transition zone lesions found in TURP (transurethral
resection of prostate) specimens; (2) recognition that any prostate carcinoma that infiltrates between benign glands is at least a Gleason
pattern 3, since infiltration excludes the carcinoma from consideration
as Gleason pattern 1 or 2; (3) acknowledgement that, in general, any
cribriform pattern of carcinoma is best categorized as Gleason pattern 4;
and (4) categorization of ill-defined glands with poorly formed glandular lumina as Gleason pattern 4. These changes resulted in
upgrading of prostate carcinomas. When the biopsies scored according to the original classification were re-reviewed and scored with the
modified system, the frequency of Gleason score 6 cancers decreased
from 50% to 20%, and the frequency of Gleason score 7 cancers
increased from 25% to 70%.38 This migration of grade (an example of
the Will Rogers phenomenon) has had an impact on how Gleason 6
organ-confined cancer is clinically regarded, i.e. “Based on the
updated Gleason system organ confined, Gleason 6, margin negative
cancer is virtually 100% curable.”40
A controversial topic was distinguishing cribriform pattern 3 from
cribriform pattern 4. Making this distinction evoked much discussion
at the consensus conference, where cribriform pattern 3 was defined
a cribriform cancer glands with a smooth round contour and round
lumina and cribriform pattern 4 glands were defined as more irregular and angulated cribriform cancer glands. Since most cribriform cancers in needle biopsies are associated with cribriform pattern 4 cancers
elsewhere in needle biopsies, most genitourinary pathologists interpret cribriform cancers as Gleason pattern 4.41
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Fig. 1
Schematic of current WHO/ISUP Gleason patterns of prostate carcinoma.
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Verification that the 2005 WHO/ISUP Gleason grading scheme
has been of value is reflected in the fact that interobserver variability
studies have shown good reproducibility by pathologists in Gleason
grading.41 A caveat is that the smaller the focus of cancer, the greater
the interobserver variance. What appears now to be the most frequent
source of variability in grading is distinguishing tangential sections of
Gleason pattern 3 glands (Fig. 2) from the poorly formed variant of
Gleason pattern 4 glands (Fig. 3). More readily graded is the cribriform variant of Gleason pattern 4 (Fig. 4).
Ter tiary Gleason pattern
The Gleason scoring system relies on reporting the two most common
histological patterns, in both biopsies and prostatectomies.
Identification of a tertiary, or third most common, pattern required an
Fig. 2 Gleason pattern 3 carcinoma gland. Note that each cancer gland has a lumen
and is circumscribed by stroma.
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Fig. 3 Gleason pattern 4 carcinoma gland, poorly-formed gland variant. Note that
each cancer gland is a nest of cells without a lumen.
adjustment to the existing system. The implication and purpose of
reporting tertiary patterns in needle biopsies or prostatectomies differ.
The significance of a tertiary pattern in needle biopsies in which the
tertiary component is of higher category than the primary and secondary patterns comes from the fact that even a small amount of
high-grade component identifies the tumor as having the biology of a
tumor of higher grade.42 In the classic scenario a prostate biopsy may
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Fig. 4 Gleason pattern 4 carcinoma gland, cribriform gland variant. This collection
of cells in the center of the figure is composed of cancer cells that form back-to-back
glands with lumina and without intervening stroma.
include a tumor with Gleason score 3 + 4 or 4 + 3 and a smaller
amount of Gleason pattern 5. The consensus was that the Gleason
grading system be modified in cases like this, grading such a case as
Gleason score 8 (3 + 5) rather than 3 + 4 with a tertiary pattern 5. The
rationale for adopting this approach was to emphasize the probability
that the tumor would behave as a higher grade tumor. Another rationale is that all prognostic models that correlate grade with clinical
outcome only allow entry of two Gleason patterns, thereby precluding
the ability to enter a tertiary pattern as a data element.
The main objective in identifying a tertiary pattern in prostatectomies, on the other hand, is to improve prognostic stratification of
the patient. Numerous studies have shown the prognostic importance
of the presence of a tertiary Gleason pattern in a prostate cancer for
which a prostatectomy was done.43 The widely used definition is the
presence of a third component that is of higher grade than the primary and secondary patterns and that comprises less than 5% of the
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tumor volume. If a tertiary higher grade component is more than 5%
of the tumor, then this grade is assigned as the secondary grade.
Another important issue regarding the significance of a tertiary
higher grade component with Gleason score 6 (3 + 3) or Gleason score
8 (4 + 4), where there are only two patterns. Studies point out that a
Gleason score 6 (3 + 3) tumor with a minor grade 4 component
behaves worse than Gleason score 6 (3 + 3) tumors but not as bad as
do Gleason score 7 (3 + 4) tumors. Although the reporting of tertiary
components has gained wide acceptance, the way to actually phrase the
reports in practice varies because of the lack of a way to incorporate the
grade of a tertiary component into the existing predictive nomograms/tables, studies or for clear patient counseling. One proposal is to
report the typical Gleason score with the tertiary pattern and a modified score, i.e. Gleason score 6 (3 + 3) with tertiary pattern 4 (Gleason
score 6.5).44 An issue raised by this proposal is whether clinicians and
biomedical investigators who are not familiar with the fact that the
numbers assigned to different Gleason patterns realize that the Gleason
grades are not continuous variables but are categorical variables. Stated
another way, there is no such entity as a Gleason score 6.5 cancer.
Percentage of Gleason patterns
Even in the absence of a tertiary component, the percentage of different Gleason patterns, i.e. pattern 3 vs. 4, plays a role in predicting
recurrence.45 And, the percentage of Gleason pattern 4 or 5 vs. patterns 3 or 4, correlates directly with tumor volume and probability of
metastases.46 Finally, there is further evidence that the relative proportions of patterns in cancers that have patterns 3, 4, and 5 are of
prognostic importance.42 Whether these findings can be confirmed
will depend upon interpathologist variance in identifying Gleason patterns being minimal.
In addition to assigning a Gleason grade, some outcome tables
and nomograms used by clinicians also attach importance to the location of the highest Gleason pattern. For example, a high Gleason
pattern in the prostate bladder neck/base is correlated with a higher
probability of adverse outcome and of a positive surgical margin.
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Grade progression
A final aspect of grading concerns grade progression. Defined as
tumor exhibiting a higher grade on a follow-up biopsy, grade progression is being used as a metric for non-responsiveness of tumor to
systemic or neoadjuvant therapy. The challenge with the concept is
that finding a higher grade on a subsequent biopsy may mean no
more than not having sampled that component of the tumor in earlier biopsies, for which there is indirect evidence.47
SPINDLE CELL LESIONS
Although rare, spindle cell tumors of the prostate have recently been
reviewed.48 Important observations include the following: (1) recognition that some spindle cell tumors identified by needle biopsies of
the prostate are in fact spindle cell neoplasms that are primary in
another organ; (2) more precise characterization, and, hence, categorization for therapy and prognosis, of spindle cell tumors can be done
by immunophenotyping and fluorescence in situ hybridization
(FISH); and (3) better characterization, both by phenotype and by
clinical outcome, is now done of sarcomatoid prostate carcinoma. We
shall discuss these respectively.
Non-Prostate Spindle Cell Lesions
Due to the proximity of other organs adjacent to the prostate, particularly the gastrointestinal tract, primary tumors of these organs, such
as GI stromal tumors (GIST’s) of the colorectum, may be sampled by
a needle biopsy that was directed to the prostate. Such a tumor, therefore, might be mistakenly interpreted as a primary tumor of the
prostate. Correct identification of these tumors relies on careful
review of pathologic findings, such as discontinuity of the spindle cell
tumor from prostate parenchyma in the needle core biopsy, immunohistochemical profiling, and review of the radiologic findings. For
example, GIST’s have an immunophenotype (muscle actin-negative,
CD133-positive) that is distinct from that of prostate stroma (muscle
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actin-positive, CD133(c-kit)-negative).49 By identifying a spindle cell
tumor as a GIST the patient can be treated with systemic therapy specific for most GIST’s — the tyrosine kinase inhibitor imitanib, which
induces remission or cure in most patients.
Prostate Spindle Cell Lesions
Historically, primary spindle cell tumors of the prostate, both benign
and malignant, have been categorized based on histological architecture and cytological atypia, supplemented with clinical and
immunohistochemical data. One of the more common clinically localized lesions of the prostate and bladder neck is one that has received
multiple names, including postoperative spindle cell nodule,
inflammatory pseudotumor, and pseudosarcomatous fibromyxoid
tumor, and inflammatory myofibroblastic tumor (IMT).50 Although
immuno- and histological phenotyping have enabled us to more
specifically categorize these lesions, there is molecular evidence that
these entities are identical, differing only in the clinical setting and
relative ratios of component cell types. In the majority (70%) of these
lesions, ALK gene translocation (anaplastic lymphoma kinase) has been
detected by FISH. This genetic abnormality suggests that at least some
of these tumors are neoplasms with limited growth potential.
There are other more rare spindle cell lesions of the prostate,
including the solitary fibrous tumor, nerve sheath tumors, and the
quite rare “smooth muscle tumor of unknown malignant potential”
(STUMP) of the prostate. The differential diagnosis of STUMP is a
nodular glandular-stromal hyperplasia with a particularly hypercellular
stroma and low-grade leiomyosarcoma. Some STUMP’s have a
prominent myxoid stroma; rarely, a phyllodes pattern has been
reported. Due to limitations of sampling in a needle core biopsy, distinction of STUMP from a low-grade leiomyosarcoma may not be
possible. This uncertainty may be the basis for the unpredictable outcome of a STUMP. In a series with follow-up, the majority of men
with STUMP of the prostate were either free of disease or suffered no
more than localized recurrence. A minority of men were subsequently
found to have a leiomyosarcoma.51
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Sarcoma of Prostate
The majority of primary sarcomas of the prostate are leiomyosarcomas. Less frequent are rhabdomyosarcoma and malignant fibrous
histiocytoma. The subtypes can be distinguished by immunophenotype. For example, leiomyosarcomas, which have a rather characteristic histological architecture of spindle cells, are smooth muscle
actin-positive, S100 protein-negative, in contrast with peripheral
nerve sheath tumors, which can also have a variably vesiculated histological appearance, but that are smooth muscle actin-negative, S100
protein-positive. To increasing degrees, there are systemic therapies
that are tailored to these phenotypes. The long-term clinical outcome
of prostate sarcomas is poor. Tumor size and grade, and the histological subtype of sarcoma do not affect actuarial survival.52
Carcinosarcoma (Sarcomatoid Carcinoma) of Prostate
Finally, immunophenotyping of histologically malignant sarcomatoid
neoplasms that in fact are the rare mixed carcinosarcoma of the prostate
have enabled us to distinguish this primary prostate tumor from primary
sarcomas of the prostate.53 This distinction is important to make since a
needle core biopsy of the prostate may retrieve only the sarcomatoid
component. The sarcomatoid component lacks the immunohistochemical profile characteristic of such primary prostate sarcomas as
leiomyosarcoma and rhabdomyosarcoma, and, furthermore, rarely
expresses prostate-specific biomarkers, such as prostate-specific antigen.
This distinction is also important to make since systemic therapy for sarcomatoid carcinoma and leiomyosarcoma are different.
PATHOLOGY OF NON-SURGICAL THERAPY
More and more men undergo non-surgical therapy, whether it be
various forms of hormonal deprivation, chemotherapy, radiotherapy or
a combination of these. The ongoing challenge for the pathologists is
to recognize the histologic changes that these therapies cause in
prostate tissue — in prostatectomies, needle biopsies or metastatic sites.
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Radiation Therapy
Radiation therapy, both by seed implants of radioemitters and by
external beam, and androgen deprivation therapy exert effects on the
morphology of both benign and malignant prostate tissue resulting in
distinctive histological patterns. The histological patterns resulting
from these two types of radiation therapy can be distinguished, more
so by their effects on benign than on malignant tissue. Specifically,
benign glands affected by radiation therapy are atrophic. Epithelial
cells that have a basal cell phenotype and that form a multi-layered
epithelium predominate. A subset of the epithelial cells of benign
glands affected by radiation is markedly atypical with enlarged nuclei
and prominent nucleoli. In contrast, androgen deprivation results in
atrophy with basal cell hyperplasia, but without the nuclear atypia or
the multi-cell layered change in the epithelium of the benign glands.54
In contrast to the prominence and atypia of benign glands, carcinoma
glands are relatively inconspicuous — shrunken with small nuclei and
nucleoli and abundant vacuolated cytoplasm. When in doubt, a set of
immunostains (for low and high molecular weight keratin and for
PSA) can help make a definitive diagnosis. Carcinoma cells express
low molecular weight keratin and PSA. Benign glands, being composed predominantly of cells with a basal cell phenotype, are high
molecular weight keratin positive and lack PSA-positive cells, but for
the rare residual non-neoplastic luminal cell. Recognized recently is
the finding that post-brachytherapy “spikes” (or, increases) in the
serum PSA value within two years of a patient receiving seed implants
does not always predict progression of the patient’s cancer. The
biopsy-confirmed cancer in some patients who had serum PSA values
as high as 10 ng/ml within two years of the brachytherapy did not
progress.55
Androgen Deprivation (Blockade) Therapy
The effect of androgen deprivation on the cancer cells is somewhat similar to the effect of radiation therapy. Cancer cells have
an enlarged, clear and/or vacuolated cytoplasm with shrunken
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hyperchromatic nuclei and inconspicuous nucleoli.56 In some
prostate cancers the changes are so marked that cancer cells might
be overlooked at low microscopic magnification. When in doubt, a
set of immunostains (for low molecular weight keratin and for PSA
and/or PSAP) can help identify carcinoma cells and, thus, make a
definitive diagnosis. Carcinoma cells express low molecular weight
keratin, PSAP and, variably, PSA. An important consideration for
pathologists looking at a biopsy of the prostate and evaluating it for
cancer is to make sure that attention is paid at high magnification,
particularly to cells that have those characteristic sets of histologic
changes.
Neoadjuvant Therapy
With the advent of neoadjuvant chemotherapy for prostate cancers at
high risk of progression have come reports of correlations between
histologic features of the cancer and clinical outcome. For example,
patients subjected to combination chemotherapy of docetaxel and
mitoxantrone had an increased frequency of several histological
features — intraductal carcinoma, cribriform architecture (identical to
Gleason pattern 4 carcinoma), tumor cell vacuolization, mucinous
change in carcinoma glands, and single cell infiltration of carcinoma
cells. Although none of these changes were pathogonomic of the
chemotherapy regimen, the changes were of clinical importance since
the intraductal and cribriform patterns correlated with higher likelihood of a patient’s cancer progressing.57 In one study, the cribriform
pattern and/or intraductal pattern of cancer spread were stronger
predictors of biochemical relapse than pathologic stage, tumor volume, PSA level at diagnosis and biopsy Gleason score. Stromal
changes, which were characteristic of prostate treated with this neoadjuvant regimen — increased vascularity, cellularity and presence of
mucin — had no predictive value. Nor did such cytologic features of
tumor cells as enlargement of nucleoli, apoptosis, cytoplasmic clearing and/or vacuolization of tumor cells.58
Novel androgen deprivation regimens that inhibit androgen synthesis at multiple points in the androgen signaling and metabolic
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pathway are being applied to patients at high risk of tumor progression. This strategy is based on observations that intra-prostate
androgen levels in patients on conventional androgen deprivation
therapy (one- or two-drug regimens) are at a level that is sufficient to
activate androgen receptors. Some intraprostatic androgens originate
from carcinoma cells, which have enzymes to synthesize androgens.59
The prostate cancer in patients on this multi-drug regimen exhibit
histologic changes that are similar to, though more marked (in
nuclear vacuolization, creation of tissue lacunae, and shrinkage of
tumor cells) than the changes seen in cancers treated with one- or
two-drug androgen deprivation regimens.60
RECOMMENDATIONS FOR PATHOLOGY
REPORTS
Needle Biopsy Reports
Although guidelines for reporting the findings of needle biopsies have
been published, recent publications emphasize the need to use standards for data and standard terminology to ensure correct
interpretation by clinicians and to use uniform criteria for current and
future clinical trials.61 Templates, many based on CAP guidelines, are
growing in acceptance and use.
Regardless of the different biopsy schemes practiced by urologists,
the basic information to be reported include the overall Gleason
score, the amount of cancer in the needle biopsies, the number of
needle biopsies with cancer, the location of high-grade cancer and
presence of extracapsular invasion.62 The determination of the
amount of cancer in the needle biops(ies) could be problematic since
cancer amount can be assessed in a variety of ways, i.e. visual estimate
of percent of biopsy tissue that is cancer, number of cores with cancer, linear measurement of cancer in the biopsy tissue. However, all
measurements correlate equally well with biochemical failure.63
Practicioners often enter this data into nomograms to estimate the
probability of cancer being organ-confined and of low stage.
Nomograms that are widely used are those developed by Partin,64
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Kattan,65 and D’Amico for patients following radical prostatectomy66
and by Shipley67 and D’Amico66 following radiation therapy.
However, these are limited in the precision with which they predict
clinical outcome.68 The most accurate of these, the Kattan nomogram, provided information content greater than 0.5 (scale of 0 to 1)
in only 50% of cases.
Knowing how urologists use the pathology data is relevant to the
scripting pathology reports. Based on a recent survey, parameters in
needle biopsy reports valued by urologists for patient management
are, in decreasing frequency, Gleason score of cancer, extent of cancer
involvement, and, for cancer-free sets of biopsies, the presence of
atypical small acinar proliferation (ASAP). Perineural invasion was
valued by only a minority of urologists.69 In another survey, the value
placed by urologists on different pathology parameters differed with
the clinical situation of the patient. When intent-to-cure surgery was
planned, information on the following parameters was sought —
extent of cancer (reported as number of positive biopsies), overall
Gleason score, highest Gleason score in any biopsy, location of the
positive biopsies, amount of cancer in the biopsies, and presence of
extraprostatic extension. When palliative care was planned, only overall Gleason score, highest Gleason score, and number of positive
biopsies were used for patient management. The presence of perineural invasion was not used for clinical decision marking by most
urologists.36
Radical Prostatectomy Reports
The parameters of a radical prostatectomy that are conventionally
reported include Gleason score of cancer, status of the surgical margin, and status of tissues that provide staging data (presence of
extraprostatic extension by cancer, extension into seminal vesicles,
and/or metastasis to regional lymph nodes).
Of debatable prognostic value is the volume of cancer in the
prostate.70,71 Differences in how much cancer volume contributes to
prognosis might, at least in part, be attributed to the many different
ways that volume is determined, i.e. evaluation of the tumor in three
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dimensions, percentage tumor estimates based on visual inspection or
grid morphometric analysis, measurement of the largest tumor focus
and computer-assisted image analysis.72 A study comparing different
methods of determining cancer volume in sections of prostatectomies
concluded that computer-assisted image analysis was the most accurate method, albeit so time consuming as to preclude its widespread
use.73
Additional challenges to obtaining accurate pathologic data are
posed when fresh tissue is obtained for research. Since prostate cancers are rarely grossly identifiable and since most cancers involve only
a small volume of the entire prostate, strategies have evolved that
include timely sampling of the unfixed tissue to not compromise the
quality of macromolecules (RNA, DNA, protein) while handling to
specimen to not compromise the quality of histologic data, i.e. status of surgical margins, of seminal vesicles, and of extra-prostatic
extension.
Surgical margin
The status of the surgical margin provides prognostic information. In
addition to margin status, the extent and location of cancer involving
the margin provides additional prognostic data.74 For example, the
prognostic power of a positive apical margin is weaker than is that of
a positive posterolateral margin.75 There are several aspects of the
margin that merit discussion — the influence of strategies for sampling the margin on margin positivity, interobserver consistency in
identifying a positive margin, and the significance of benign prostate
parenchyma at a margin. The method used to sample a prostatectomy
affects the probability of finding cancer at a margin. In a completely
sectioned prostatectomy specimen, the number of tissue blocks containing a positive margin section increases if the thousands of sections
from a completely sectioned prostatectomy are examined.76
Observer variability in characterizing the status of the margin is
“moderate/good” (kappa = 0.74).2 Variability appears to result
from thermal artifact and the sensitivity of the observer in recognizing a positive margin.2 Additional variance might be attributable
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to uncertainty as to the definition of “positive margin.” An early
publication that reported that prostate cancer cells that were virtually at the margin, but not literally at the margin, i.e. cut across or
inked, were not associated with an increased probability of failure
post-prostatectomy.77 Subsequent studies support these criteria for
margin-positivity.78 The fact that 20% to 30% of patients with cancer confined to the prostate and with negative margins fail provides
impetus for identifying additional margin-associated prognostic
factors. Tumor that is “very close” to a margin in a single section
raises the possibility that deeper in the block from which the section was taken the margin might be involved, as was demonstrated
in a study of the completely sectioned prostate.76 This finding is
not unexpected since the sampling frequency of tissue blocks is
only about one in 500 (or, one 6 µm thick section from a 3 mm
thick block of tissue).
The presence of benign prostate glands at a surgical margin of a
radical prostatectomy, attributable to incision of the prostate capsule
by the surgeon, is an infrequent event. In one series, benign prostate
glands were found at the surgical margin, most frequently at the apical margin, in 8% of cases. In these cases no cancer was identified at
the margin. At follow-up, none of these patients had biochemical
evidence of recurrence. To summarize, capsular incision is not associated with an increased likelihood of post-prostatectomy elevated
serum PSA.79
Extraprostatic extension
Determination of whether a cancer extends outside the prostate
(EPE) can also be problematic. This uncertainty and variance in
reporting EPE results, in part, from the lack of a discrete and microscopically well-defined prostate capsule.1 By convention, EPE
includes not only “tumor cells touching extraprostatic fat cells” but
also tumor in a fibromuscular band that is outside the fibromuscular
or gland-rich prostate parenchyma. In an interobserver study using
these criteria for EPE, specificity, sensitivity, and accuracy values for
EPE were quite good (88%, 95%, and 91%).2
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L ymph node dissection
The number of nodes found in pelvic lymph node dissections is being
used as a metric for adequacy of surgery and for prognostic information. This effort is based on the prognostic value of lymph node
counts in cystectomies done for urothelial cell carcinoma. Bladder
cancers that are pathologically localized to the bladder can be stratified for survival based on the total number of nodes that are
histologically analyzed in the pelvic node dissection.80 This approach
is being used for pelvic node dissections in prostatectomies. Several
parameters affecting node retrieval and count have not been established at a sufficiently rigorous level to minimize observer variability.
Sources of variability include the following: (1) many nodes are so
small that they can only be identified by microscopically analyzing all
pelvic fibroadipose tissue; (2) some nodes consist of so much adipose
tissue that they may not be recognized as lymph nodes at either gross
or microscopic levels; and (3) the number of lymph nodes that are
“normally” within the pelvis is unknown. Consequently, using a minimal number of nodes in a pelvic node dissection as a metric for
adequacy of surgery and of pathologic exam is likely to be erroneous.
As a corollary, the number of nodes retrieved by the urologist varies
markedly. The number of lymph nodes found in node dissections by
a urology group that does extended node dissections ranged from
nine to 68.81
TISSUE BIOMARKERS
Novel biomarkers are both based on genomic and proteomic findings.
A recent discovery is that 50% to 70% of prostate cancers have a
rearrangement of the TMPRSS2 promoter and an ets gene.82 Some
of these rearrangements may have prognostic significance. For example, TMPRSS2-ERG fusions are associated, at least in some studies,
with a more adverse outcome.83 TMPRSS2-ERG fusions are also
more frequent in tumors of higher grade and higher stage. An interesting correlation has been made between such genetic changes and
tumor histology. Prostate carcinomas with TMPRSS2-ERG fusions
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have larger nucleoli than carcinomas without that genetic change.84
Rarely, promoters of genes other than TMPRSS2 have been associated with an ets gene.
The number of tissue biomarkers that can be assessed by
immunostains continually grows. The use of high-throughput, highdensity mRNA expression microarrays has led to the discovery of
gene products that distinguish cancer cells from benign epithelial cells
and, furthermore, that are distinctive for cancers of different Gleason
grade.85 One of the first applications of these technologies has been
the use of antibodies to alpha-methyl-CoA racemase (AMACR,
p504s) in immunostains to help confirm the histological impression
that a set of atypical cells, which are most often problematic in a very
small sample, is carcinoma.86 To elaborate, carcinoma cells of the
prostate, and of other organs, express AMACR at sufficiently higher
levels than do normal cells that immunostains help distinguish cancer
cells from normal cells. A caveat with using AMACR immunostains is
that some benign cells express AMACR. Conversely, some prostate
carcinomas lack AMACR immunoreactivity.87 Therefore, the
AMACR stain should not be used as a cancer-specific diagnostic tool,
but as an immunostain to supplement other markers, such as those
used to identify basal cells, i.e. high molecular weight keratin and/or
p63. A more recent observation is that a set of 52 genes distinguishes Gleason pattern 3 from Gleason patterns 4 and 5.85 Whether
immunostains for a set of these genes identified at the mRNA level
distinguish these Gleason patterns pends confirmation by other investigations. However, the prospect is that there will be molecular
biomarkers that distinguish carcinomas that have identical histology
and that can enable the pathologist to supplement a histological diagnosis with information that predicts the aggressiveness and/or
responsiveness to therapy of individual tumors. As one of many examples of the clinical importance of molecular tissue biomarkers, the
pattern of expression of CD10 (neutral endopeptidase) is prognostic.
Survival was, respectively, worse for CD10 negative cancer based on
membranous and cytoplasmic patterns of expression.88
Predictive molecular tissue biomarkers have also been identified. For
example, overexpression of growth differentiation factor 15 (GDF15)
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by cancer cells is associated with a decreased likelihood of neoadjuvant
chemotherapy (docetaxel and mitoxantrone) being effective in decreasing the probability of the cancer progressing.89
Imaging can provide useful information for the initial diagnosis,
for staging, and for clinical parameters — probability of disease
recurrence and of response to therapy. Conventional imaging
techniques — ultrasound (US), computerized tomography (CT),
and magnetic resonance imaging (MRI) — lack sensitivity and
specificity in detecting low volume carcinoma in the primary site.
New modalities being evaluated include magnetic resonance spectroscopic imaging (MRSI), dynamic contrast-enhanced MRI and
positron emission tomography (PET). MRSI takes advantage of the
differences in the concentration of specific molecules in normal prostatic tissue and cancer. For example levels of choline, a cell
membrane component, are higher in prostate cancer cells than in
non-neoplastic prostate tissue. Conversely, citrate and creatine are
more abundant in normal prostatic tissue. MRSI data can be
obtained within the same examination as the endorectal MRI using
the same endocoil. When added to MRI findings, MRSI improves
estimation of tumor volume and localization of the tumor within
the prostate gland. However, in a recent multi-center study where
sextant localization of the PZ tumors was the focus, MR imaging
alone and combined with MRSI had a similar and rather modest
degree of accuracy.90
FUTURE TRENDS
Quantitative analysis of histopathologic features has been undertaken
for decades. Some of these have yielded findings of apparent durable
significance. For example the lack of roundness of prostate cancer
nuclei correlates with a poor prognosis.91 And one set of parameters
used in a multiplex commercial assay are those of nuclear shape and
size.92 There are concerns about all morphometric analyses, (1) there
are sources of error that are often not taken into account,93 and
(2) sampling is often not done at a level sufficient to be confident that
the samples analyzed are representative. There are a set of rigorous
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sampling strategies designed to increase accuracy.17,94 However, all of
these are time-intensive. A relatively straightforward strategy for sampling is to sample the specimen for the object of interest to an extent
so that variance is within a predetermined standard deviation,
i.e. 0.05. The variance of a running mean can be used as a metric for
adequate sampling.95
There are numerous steps in the quantification of tissue-based
biomarkers using immunohistochemical techniques that are sources
of variance.96 Better assays for both assessing quality of tissue and for
quantifying analytes in tissue are needed. As one important source of
error, the validation of antibodies used in immunohistochemical biomarker studies is often not done with a level of specificity, sensitivity
and reproducibility sufficient for the immunostain to produce a reliable product. Explicit guidelines for antibody validation are
available.97
Currently, most tissue-based biomarker stains are immunoperoxidase stains. Fluorescent signals have a wider dynamic range and are
more quantitative than are enzyme-based immunohistochemical
assays. Fluorescent compounds include organic fluorophores and
quantum dots. In principle, quantum dots offer a number of advantages over organic fluorophores — a wider dynamic range and more
durable signals.98
The use of image analysis for quantifying immunohistochemical
signals potentially provides a more objective assessment of stains.
However, the appeal of image analysis being a “more objective” way
to analyze tissue should be tempered with the recognition that there
are observer or operator-dependent steps in image analysis, including
the setting of thresholds or cut-points and the selection of fields to
analyze.99
As the importance of quantifying molecular biomarkers has
increased, concern about the influence of preanalytic variables on
macromolecules has increased. For example, warm ischemia and cold
ischemia time influence the RNA expression profiles of prostate tissue.100,101 And, the quality of protein in formalin-fixed tissue can be
affected by post-immobilization events, such as duration of formalin
fixation.102
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2. Evans AJ, Henry PC, Van der Kwast TH, et al. (2008). Interobserver
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