Histopathology 2012, 60, 153–165. DOI: 10.1111/j.1365-2559.2011.04079.

REVIEW

Therapy-associated effects in the prostate gland

John R Srigley , Brett Delahunt1 & Andrew J Evans2
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada, 1Department of
Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington,
New Zealand, and 2Laboratory Medicine Program, Department of Pathology, University Health Network, Toronto General
Hospital, Toronto, ON, Canada

Srigley J R, Delahunt B & Evans A J

(2012) Histopathology 60, 153–165
Therapy-associated effects in the prostate gland

Diverse therapies are used to treat both benign pros- apy, and interstitial laser thermotherapy, may have
tatic hyperplasia and adenocarcinoma. Transurethral morphological effects on prostate tissue. It is important
resection, a common surgical procedure, may give rise for the pathologist to be aware of the spectrum of
to characteristic necrobiotic granulomas that manifest histological changes affecting the prostate gland post-
in subsequent pathology samples. Radiation and hor- therapy. The treatment effects may obscure residual
mone therapy have traditionally been used in prostatic carcinoma, and make measurements of tumour extent
adenocarcinoma. Morphological effects are often iden- and stage difficult. Furthermore, some therapies can
tified in needle biopsy specimens, transurethral resec- profoundly alter the neoplastic glands to such an extent
tates, and radical prostatectomy specimens. A range of that Gleason scoring is no longer valid. As new
histological changes are noted in the non-neoplastic therapies are developed for prostate cancer, it is
prostate tissue, as well as in the pre-neoplastic and important to document their effects on benign and
carcinomatous areas. Other ablative therapies, such as malignant prostate tissue and to understand possible
cryotherapy, and emerging focal therapies, including implications for traditional prognostic factors, espe-
high-intensity focused ultrasound, photodynamic ther- cially Gleason grade.
Keywords: ablative techniques, carcinoma, chemotherapy, hormones, prostate, radiation, treatment
Abbreviations: 5-ARI, 5a-reductase inhibitor; AMACR, a-methylacyl-CoA racemase; BPH, benign prostatic
hyperplasia; HGPIN, high-grade prostatic intraepithelial neoplasia; HIFU, high-intensity focused ultrasound; LHRH,
luteinizing hormone-releasing hormone; MAB, maximal androgen blockade; PCPT, Prostate Cancer Prevention
Trial; PDT, photodynamic therapy; PSA, prostate-specific antigen; RT, radiation therapy; TURP, transurethral
resection of the prostate

resectates, and radical prostatectomy specimens. The

Introduction
A wide variety of therapies are used to treat both
benign prostatic hyperplasia (BPH) and prostatic ade-
nocarcinoma (Table 1). Many of these modalities result
in morphological effects that may be identified in post-
treatment needle biopsy specimens, transurethral
Address for correspondence: Professor J R Srigley, Department of
Laboratory Medicine, Credit Valley Hospital, 2200 Eglinton Avenue
West, Mississauga, ON L5M 2N1, Canada. e-mail: jsrigley@cvh.on.ca
 2011 Blackwell Publishing Limited.
best-studied therapy-associated effects are those asso-
ciated with traditional surgery, radiation therapy (RT),
and hormones.1,2 It is important for the pathologist to
know the spectrum of morphological changes associ-
ated with these therapies, and to be able to identify
residual tumour when present. Ideally, the pathologist
should be provided with clinical information related to
prior therapies on requisitions accompanying pathol-
ogy samples. In some cases, even in the absence of
clinical information, the morphological effects are
154 J R Srigley et al.
Table 1. Therapies with potential effects on the prostate
gland
Traditional surgical procedures
Transurethral resection
Orchidectomy (castration)
Radiation
External beam
Brachytherapy
Novel radiation delivery devices (Gamma Knife;
Cyber Knife)
Hormone therapy
Oestrogen
Maximum androgen blockade
LHRH agonists, anti-androgens
5-a-Reductase inhibitors
Chemotherapy
Other ablative and focal therapies
Cryotherapy
Microwave therapy
High-intensity focused ultrasound
Photodynamic therapy
Interstitial laser
Nutritional and herbal supplements
characteristic of a particular therapy, and should be
noted in the pathology report. Furthermore, severe
treatment effects, especially those associated with
hormone therapy and RT, may interfere with the
assessment of histological tumour grade and extent of
disease. In this article, the morphological effects of
traditional therapies and those associated with the
novel and emerging treatments will be reviewed.
Traditional surgical procedures
transurethral r esection of the prostate
(turp)
TURP is commonly used as a treatment for BPH, and is
occasionally employed to relieve obstruction in patients
with established prostate cancer. This procedure may
result in a characteristic pattern of granulomatous
prostatitis.3 This pattern may also be seen rarely after
prostatic needle biopsy. The development of post-TURP
granulomas is thought to represent a response to
cauterized prostate tissue, secretions, and material from
the diathermy instruments.4
The histological pattern consists of granulomas
varying in shape from round and oval to elongated,
stellate, and irregular (Figure 1). They display a central
zone of fibrinoid necrosis surrounded by pallisaded
epithelioid histiocytes. A rim of lymphocytes and
fibrosis is often seen around the histiocytes. Occasion-
ally, giant cells are seen. Older granulomas may display
hyalinization, and localized vasculitis may be noted.
The differential diagnosis includes infective granulomas
and non-specific granulomatous prostatitis.5 The latter
tend to be centred on ductal acinar units, and do not
display the striking fibrinoid change associated with
post-TURP granulomas. Infectious granulomas usually
have caseous necrosis and frequent giant cells.
orchidectomy
Historically, bilateral orchidectomy (castration) has
been used as a androgen-ablative treatment for pros-
tate cancer. In recent years, with the advances in
chemical castration, orchidectomy is uncommonly
used. The therapeutic effects of bilateral orchidectomy
on prostate histology are profound, and essentially
similar to those seen with other forms of maximal
androgen blockade (MAB), and will be covered in a
subsequent section.
Radiation therapy
Radiation therapy (RT) is commonly used as a primary
treatment for prostate cancer. External beam RT, often
with conformal and intensity-modulated approaches, is
Figure 1. Characteristic post-transurethral resection granuloma.
Note central necrosis surrounded by palisaded histiocytes and a rim of
small lymphocytes.
 2011 Blackwell Publishing Ltd, Histopathology, 60, 153–165.
 Therapy-associated effects in the prostate gland 155

often employed for locally advanced disease.6,7 Brachy- A

therapy, which involves the implantation of radioactive
seeds in the prostate gland, is used to treat clinically
localized disease, particularly low-volume and low-
grade tumours.8 Neoadjuvant and adjuvant hormone
therapy may also be combined with RT.9 Novel
radiosurgery with Gamma Knife and Cyber Knife
technology is also being developed for the treatment
of prostate cancer.10
Pathologists usually encounter the effects of radia-
tion in needle biopsy specimens obtained to assess
residual disease post-RT.1 Radiation changes may also
be identified in transurethral resectates and salvage
radical prostatectomy specimens.11 The prostate biop-
B
sies are often associated with clinical trials, and are
usually performed 18–24 months after completion of
the RT. The morphological effects of RT are well
described in the literature, and may range from
minimal to pronounced.1,2 All RT modalities produce
similar findings at the histological level.
Non-neoplastic prostate tissue often displays a vari-
ety of histological effects after exposure to radia-
tion.1,2,12–16 The non-neoplastic glands are
commonly atrophic, resulting in an increased stromal
to glandular ratio (Figure 2). The secretory cells are
markedly shrunken, and there is a prominence of basal
cells. Spotty cellular atypia is commonly noted. These
findings are usually identified at low magnification. The Figure 2. Radiation effects on non-neoplastic glands. A, Note
degree of RT-associated changes may vary between glandular atrophy, basal cell prominence, and focal cytologic atypia.
cases, and within an individual case. At intermediate to B, Note focal nuclear enlargement and chromatin smudging.
high magnification, basal cells are often vacuolated and
show nuclear pleomorphism, hyperchromasia, and surethral resectates and salvage radical prostatectomy
smudged chromatin. Macronucleoli may also be iden- specimens, RT effects similar to those described for
tified. Squamous, mucinous and Paneth cell-like meta- needle biopsy specimens may be encountered.1
plasia may occur in patients treated with RT with or On scanning magnification, irregularly scattered
without hormonal therapy. In addition to the epithelial glands, nests and single cells showing cytoplasmic
changes, stromal fibrosis and vascular sclerosis may vacuolation and nuclear enlargement are noted (Fig-
occur, and the latter may be quite striking. ure 3).1,13,14,16 The low-power architecture is partic-
High-grade prostatic intraepithelial neoplasia ularly important in separating malignant glands from
(HGPIN) is often less prevalent and less extensive in the treatment effects induced in non-neoplastic glands.
post-RT biopsy specimens than in pretreatment speci- The latter show a more regular epithelial–stromal
mens.1,13,16 The typical architectural patterns of relationship, often maintaining some degree of lobular
HGPIN are maintained, but individual cells show organization. Perineural invasion may also be helpful
cytoplasmic shrinkage, resulting in a more crowded in identifying residual tumour cells, although non-
appearance, and nuclear smudging may be seen. The neoplastic glands may abut nerves (Figure 4). In many
effect of RT on adenocarcinoma is variable, and ranges cases, the residual tumour is readily identified with
from no to minimal effects to pronounced changes, routine microscopy; however, in some difficult cases,
making the identification of cancer cells challeng- immunohistochemistry may be required. The tumour
ing.1,13,14,16 In an individual case, the presence and cells showing treatment effects stain positively for low
degree of RT effects may vary between cores and even molecular weight cytokeratin, prostate-specific antigen
within one core. This pattern is seen especially in (PSA), and a-methylacyl-CoA racemase (AMACR)
brachytherapy cases, and may relate to the distribution (P504S) (Figure 3). They are negative for basal cell
of radiation dosage around individual seeds. In tran- markers such as high molecular weight cytokeratin
 2011 Blackwell Publishing Ltd, Histopathology, 60, 153–165.
156 J R Srigley et al.
A have received combined RT and androgen deprivation
B
Figure 3. Adenocarcinoma with radiation effects. A, Note small
clusters, poorly formed glands, and individual cells with small
smudged nuclei. B, Strong a-methylacyl-CoA racemase
(AMACR ⁄ P504S) positivity is seen in residual tumour cells.
Figure 4. Radiation effects on carcinomatous glands. Note small
clusters of vacuolated tumour cells and tiny, poorly formed glands.
Note the perineural distribution of some residual tumour cells. Non-
neoplastic prostate glands showing atrophy, inflammation and basal
cell prominence can be seen in the upper part of the field.
and p63. In contrast, atrophic non-neoplastic glands
show prominent basal cell markers, often with residual
PSA staining and AMACR negativity. In patients who
treatment, no treatment effects over and above those
attributed to the RT will be observed unless the patient
is receiving hormone therapy at the time of the post-RT
biopsy.16
It has been shown that 2-year post-RT biopsy results
can be predictive of long-term disease-free survival.15
The degree of treatment effect and the Gleason score
are important variables in this analysis.14,15 Radiation
effects can lead to spurious increases in Gleason score,
and when treatment effects are pronounced, a Gleason
score should not be rendered; however, a suitable
comment should be added to the report. There are a
few grading systems for treatment effects, based on the
detailed assessment of cytological and nuclear fea-
tures14,17 (Table 2). The grading systems are used in
part to decide on the application of Gleason scoring. In
the Crook modification of the Bocking and Aufferman
system, nuclear and cytoplasmic features are graded
separately, and individual grades are combined for a
score of 0–6. Biopsy specimens showing a combined
score of 0–1 have minimal treatment effects, and are
cases where Gleason scores can be applied. Local failure
rates associated with low treatment scores were about
55% in one study.15 Combined treatment scores of 3–4
had local failure rates in the range of 30%, and those
tumours showing dramatic treatment effects (scores of
5–6) had 5-year survival rates, similar to negative
biopsy specimens.15 From a practical perspective, one
can qualitatively categorize the radiation effects as
Table 2. Grading treatment effects in post-radiation prostate
biopsy specimens14,17
Cytoplasmic
0: no identifiable treatment effect
1: swelling and microvesicular change
2: more extensive vacuolization with voluminous
cytoplasm, ruptured cytoplasm, and lipofuscin
accumulation
3: only single cells
Nuclear
0: no identifiable treatment effect
1: some enlargement, with smudging and still visible
nucleoli
2: large bizarre nuclei with smudging and rare or
absent nucleoli
3: pyknotic, small nuclei
 2011 Blackwell Publishing Ltd, Histopathology, 60, 153–165.

minimal, moderate, or severe. Gleason scores are given
in those cases where there are minimal RT-associated
changes. The degree of RT-associated effects may be
used to predict which patients may benefit from salvage
radical prostatectomy in the setting of RT failure.
Hormone therapy
Androgen deprivation therapy is commonly used to
treat patients with locally advanced and metastatic
prostatic carcinoma. This approach exploits the andro-
gen-dependent nature of prostatic adenocarcinoma,
and can have profound morphological effects on benign
and neoplastic prostate tissue.1,2,12,13 Historically,
hormone therapy involved castration and ⁄ or oestro-
gens.18 The early studies on the effects of androgen
deprivation on prostate tissue led to the ground-
breaking discovery of Huggins and Hodges19,20 of the
androgen-dependent nature of prostate cancer. Oestro-
gen treatment leads to prominent squamous metapla-
sia of benign prostate glands and a reduction in the
number and size of prostatic adenocarcinoma cells.21,22
Prominent nuclear pyknosis is seen, and cytoplasmic
vacuolation with ballooning and signet ring cells is
commonly noted. Cell rupture may be identified, and
the stroma is often pale-staining and may be vacuo-
lated or fibrotic.
In more recent years, MAB with a combination of
luteinizing hormone-releasing hormone (LHRH) agon-
ists and anti-androgens has been used to produce
‘chemical castration’.18,23 Some hormonal agents used
for the treatment of prostatic disease are listed in
Table 3. Monotherapies with LHRH agonists or pure
anti-androgens such as cyproterone acetate have also
been used.24 Hormone therapy has an established role
Table 3. Hormone treatment modalities
Orchidectomy
Oestrogen (diethylstilbestrol)
Contemporary androgen blockade
LHRH agonists (leuprolide, goserelin)
Anti-androgens
Steroidal (cyproterone acetate)
Non-steroidal (flutamide, bicalutamide)
Others
Ketoconazole
5a-Reductase inhibitors (finasteride, dutasteride)
LHRH, luteinizing hormone-releasing hormone.
 2011 Blackwell Publishing Ltd, Histopathology, 60, 153–165.
Therapy-associated effects in the prostate gland 157
in locally advanced and metastatic disease, but it is also
used in neoadjuvant or adjuvant settings along with
RT or radical prostatectomy.25,26 5a-Reductase inhib-
itors (5-ARIs) have been used both for the treatment of
BPH and, more recently, as chemopreventive agents to
reduce the risk of prostate cancer development.27–29
Pathologists need to be familiar with the changes
associated with hormone therapy, as these may be
encountered in needle biopsy specimens, transurethral
sections, and radical prostatectomy specimens.
Several characteristic histological effects are associ-
ated with MAB.1,2,12,13,30,31 The changes vary with
the type of agent, dosage, and duration of therapy. The
more severe changes are generally associated with
higher dosages over a longer duration. In normal
prostate tissue, glandular atrophy, basal cell promi-
nence and hyperplasia, and cytoplasmic vacuolation
are commonly seen (Figure 5). Although global glan-
dular atrophy may be seen, it tends to be more
prominent in the peripheral zone. Occasionally, atro-
phic glands undergo rupture, with spillage of secretions
and corpora amylacea into adjacent stroma. Although
squamous metaplasia was commonly noted with oes-
trogen treatment, it is rarely associated with modern
MAB.
MAB has been shown to decrease the prevalence and
extent of HGPIN.31–37 Recognition of HGPIN may be
difficult, as high-tufted and micropapillary patterns
may be reduced to low-tufted and flat patterns
(Figure 6). Furthermore, cytoplasmic loss and a reduc-
tion in the prominence of nucleoli may be seen with
hormone therapy.
The effects of MAB on adenocarcinoma have been
well studied, and are often dramatic in patients who
have been treated for 2–3 months.1,2,12,13,30–34 There
Figure 5. Effects of maximal androgen blockade on non-neoplastic
glands. Note glandular atrophy and basal cell prominence. The
secretory cells are shrunken and show vacuolation.
158 J R Srigley et al.
Figure 6. Effects of maximal androgen blockade on high-grade
prostatic intraepithelial neoplasia (HGPIN). Note atrophic, non-
neoplastic glands on the left, and HGPIN on the right. HGPIN glands
show a low-tufted pattern. There is cytoplasmic loss. Marked nuclear
atypia and nucleoli prominence are still present.
is a decrease in the number of neoplastic glands, with a
relative increase in the amount of stromal tissue.
Neoplastic glands are often small and atrophic, with a
compressed or collapsed lumina (Figure 7). Small cords
and individual tumour cells, sometimes resembling
histiocytes, may be present. There is often nuclear
pyknosis and hyperchromasia with relatively incon-
spicuous nucleoli. Cytoplasmic clearing, vacuolation
and, sometimes, dissolution may be seen (Figure 8). In
addition, one may identify mucinous stromal pools
and ⁄ or unusual branched clefts within the stroma,
yielding a haemangiopericytoma-like pattern.30
Chronic inflammation may accompany the stromal
changes.
Figure 7. Effects of maximal androgen blockade on prostatic adeno-
carcinoma. Note the presence of shrunken and vacuolated tumour
cells between non-neoplastic glands. Some spaces contain mucoid
material, and lining cells are inconspicuous.
Figure 8. Effect of maximal androgen blockade on prostatic adeno-
carcinoma. High-power photomicrograph showing irregular small
vacuolated spaces containing mucin near the inked prostatic margin.
A few spaces are lined by shrunken tumour cells.
Immunohistochemistry may be used to identify
residual neoplastic cells.1,13 The hormone-treated cells
stain positively for low molecular weight cytokeratin
and often for PSA. AMACR (P504S) expression is
usually maintained, and there is an absence of basal
cell markers (high molecular weight cytokeratin and
p63). The severity of the hormone effects is related to
the duration of therapy, and is generally most pro-
nounced after 3 months of treatment.
The morphological effects associated with androgen
deprivation, in particular the glandular collapse and
arrangement of cells as cords and individually, can lead
to a spuriously high Gleason score (score of 9–10)
(Figure 9). While appearing to be high grade, the
neoplastic cells often have a low mitotic rate and show
Figure 9. Effects of maximal androgen blockade on prostatic adeno-
carcinoma. Note shrinkage of tumour cells resulting in poorly formed
glands and nests. This change would result in a spuriously high
Gleason score.
 2011 Blackwell Publishing Ltd, Histopathology, 60, 153–165.

a low Ki67 (MIB-1) score, indicating reduced prolifer-
ation.38,39 It is generally recommended that a Gleason
score should not be assigned when significant hor-
monal effects are identified.1,2,12,13,31 Some investiga-
tors have suggested that cribriform and intraductal
patterns are strong architectural predictors of PSA
failure; however, this has not been fully validated.40
When MAB has been used as neoadjuvant therapy
prior to radical prostatectomy, there has been a
significant down-staging of prostatic carcinoma in
about half of cases.41 This effect is related to tumour
shrinkage, with volume reductions in the range of 40–
60% being observed with prolonged MAB treat-
ment.32,38 There are also reductions in the rates of
extraprostatic extension and margin positivity.31,42,43 It
may be difficult to identify residual carcinoma in radical
prostatectomy specimens in the setting of neoadjuvant
hormone therapy. Careful examination at scanning
magnification can lead to the identification of subtle
areas of epithelial stromal disruption and the presence
of small foci of hormonally altered adenocarcinoma.
Apparent lymphohistiocytic infiltrates should be care-
fully examined, as tumour cells may resemble histio-
cytes. A pathologist encountering the so-called
‘vanishing cancer’ syndrome (pT0) should think about
the possibility of neoadjuvant hormone therapy as a
possible reason for the apparent lack of tumour
cells.30,41,44 Additionally, MAB may result in fewer
lymph nodes being found in pelvic lymph node dissec-
tions.45,46 Serial sections and immunohistochemistry
may be employed in some situations, as some histiocyte-
like cells may turn out to be altered tumour cells.
Although neoadjuvant hormones have a dramatic
effect on prostate cancer, several trials have failed to
identify a specific clinical benefit of neoadjuvant
hormone therapy prior to radical prostatectomy, and,
for the most part, this practice has been abandoned.47
Effects of 5-ARI therapy on prostate
morphology
5-ARIs such as finasteride and dutasteride block the
5a-reductase enzyme, which converts testosterone into
dihydotestosterone. These agents have been commonly
used to treat BPH and male pattern baldness. Recently,
there has been much interest in the use of 5-ARIs as
chemopreventive agents to reduce the risk of develop-
ment of prostate cancer.28,48,49 The Prostate Cancer
Prevention Trial (PCPT) reported a reduction in pros-
tate cancer in patients treated with finasteride as
compared with the placebo group over 7 years of
follow-up.27 There was a higher proportion of high-
grade tumours (Gleason 7–10) in the finasteride group,
 2011 Blackwell Publishing Ltd, Histopathology, 60, 153–165.
Therapy-associated effects in the prostate gland 159
raising the possibility that high-grade disease was
induced by this treatment.27 It was also suggested that
the Gleason scoring post-5-ARI therapy might be
unreliable, for reasons cited earlier in this article.50
However, the effects of 5-ARIs on prostate tissue are
generally mild or non-existent. A recently published
blinded histological review indicated that the morpho-
logical changes associated with 5-ARI treatment are
unlikely to result in a spurious increase in Gleason
scores.51 Most pathologists continue to provide Gleason
scores in prostate cancer specimens from patients
treated with 5-ARIs. The increased proportion of
high-grade tumours found in the PCPT is probably
the result of an ascertainment bias related to the pro-
nounced prostate shrinkage in the 5-ARI group.52–54
Neuroendocrine differentiation
There is an association between the use of MAB and
neuroendocrine differentiation in prostatic adenocarci-
nomas.55,56 Scattered neuroendocrine cells are com-
monly seen in prostatic carcinoma, and it has been
shown that there is an increased proportion of
neuroendocrine cells in patients treated with anti-
androgen therapy.57 Neuroendocrine tumours in the
form of small-cell or large-cell neuroendocrine carci-
noma may arise in the setting of hormonally treated
prostatic adenocarcinoma of the usual acinar type
(Figure 10).55,56,58 Patients with the emerging neuro-
endocrine tumours often have low or undetectable
PSA levels, but present with local-regional or meta-
static disease.56 Sometimes, the neuroendocrine carci-
nomas are identified in patients undergoing TURP for
malignant urinary obstruction.56 The neuroendocrine
carcinomas may be pure or combined with usual
acinar patterns (Figure 11).55,56,58 Neuroendocrine
markers such as CD56, synaptophysin and chromogr-
anin may be used to confirm a diagnosis. Prostatic
epithelial markers such as PSA and prostate-specific
acid phosphatase are often negative in the neuroen-
docrine areas.56 Gleason scoring is generally not
applicable in the setting of a neuroendocrine carci-
noma of the prostate gland.59 Neuroendocrine carci-
nomas occurring post-androgen treatment may be
treated with the standard therapy used for neuroen-
docrine carcinomas arising elsewhere, but generally
respond poorly.56,60
Chemotherapy
Chemotherapy has traditionally been used for patients
with metastatic hormone-resistant prostate cancer. A
variety of chemotherapeutic agents have been em-
160 J R Srigley et al.
Figure 10. Large-cell neuroendocrine carcinoma after hormonal
therapy. Note the presence of both large-cell neuroendocrine (A) and
small acinar (B) patterns of carcinoma. The acinar carcinoma shows
cytoplasmic vacuolation.
ployed, including, in recent years, drugs such as
mitoxantrone, etoposide, cistplatinum, vinblastine–est-
ramustine, taclitaxel, and docetaxel. In general, little or
no positive effect on survival has been demonstrated in
prospective randomized control trials. A number of new
chemotherapeutic agents are being developed.61,62
Relatively little is known about the histological effects
of chemotherapy on prostate cancer in metastatic
settings, as follow-up biopsies are rarely performed and
neoadjuvant studies are uncommon.26,63 More re-
cently, there have been clinical trials of neoadjuvant
chemotherapy for high-risk prostate cancer prior to
radical prostatectomy. Some trials have resulted in
interesting observations regarding the morphological
effects of chemotherapy.64 A recent study by O’Brien
et al.,65 investigating radical prostatectomies following
neoadjuvant treatment with docetaxel and mitoxan-
throne, documented significant morphological findings.
The carcinomas in the prostatectomy specimens
showed a variety of distinctive histological patterns,
including inconspicuous collapsed glands, small incon-
Figure 11. Post-chemotherapy treatment effects in radical prosta-
tectomy specimen after neoadjuvant treatment with docetaxel and
mitoxantrone. Note prominent tumour cell vacuolation. (Image
courtesy of L. True, Seattle, WA, USA.)
spicuous individual tumour cells, prominently vacuo-
lated tumour cells, and intraductal and cribriform
architectural growth patterns. Less frequent findings
included tumour-associated basophilic mucus, a nested
growth pattern, and large pleomorphic eosinophilic
tumour cells. In that study, the presence of intraductal
and cribriform histological features post-chemotherapy
were associated with shorter relapse-free survival.
Further detailed studies on chemotherapy-associated
effects are needed to validate and further elucidate the
spectrum of morphological changes. A variety of new
drugs and targeted agents are under development, and
there is little published experience related to their
morphological effects.66
Other ablative and emerging focal therapies
Novel ablative therapies have been used in the treat-
ment of BPH.67 Minimally invasive therapies that
ablate either the entire prostate gland or only a specific
portion of it are attractive as cancer treatments,
especially as alternatives to either radical prostatecto-
my, RT, or active surveillance.68
Cryotherapy has been used as an alternative to
traditional surgery for a number of years.68,69 This
technique causes localized tissue destruction by the
formation of an ice-ball and its subsequent thawing.
Ultrasound is generally used to monitor the size of the
ice-ball. There is marked tissue damage related to the
direct cooling effect and associated inflammation. In
some studies, the histological effects have been
assessed, and the observed changes are dependent on
the time when biopsies are taken after cryother-
 2011 Blackwell Publishing Ltd, Histopathology, 60, 153–165.
 Therapy-associated effects in the prostate gland 161

apy.70,71 Oedema and haemorrhage are identified in a recent study conducted by one of the current authors
the first few days, and tissue necrosis is identified (A.J.E.), viable adenocarcinoma was found in 63% of
thereafter. Stromal fibrosis, chronic inflammation and, 30 post-HIFU biopsy specimens (Figure 12).13 The
sometimes, foreign-body giant cell reactions may be positive biopsy findings were most commonly made
identified after a few months. The most common when PSA was elevated post-HIFU, but, in two of eight
histological findings in needle biopsy specimens after cases without elevated PSA, residual carcinoma was
cryotherapy include stromal fibrosis and hyalinization, identified. There are no treatment effects documented
basal cell hyperplasia, coagulative necrosis, and that would affect the assignment of Gleason score.
non-specific inflammation. Haemorrhage, haemosider- Furthermore, staining patterns for common immuno-
in deposition, dystrophic calcification, squamous and histochemical markers, including 34BE12, p63, and
urothelial metaplasia and oedema may be seen. AMACR, were unaffected by the HIFU treatment.
Residual carcinoma is frequently present in needle Photodynamic therapy (PDT) with a photosensitizing
biopsy specimens obtained post-cryotherapy.72 Often, agent has been used to treat prostate cancer.84,85 This
the carcinoma lacks any significant treatment effects. treatment results in thrombosis and coagulation of the
The tumour cells may show chromatin smudging and vascular bed when it is exposed to an appropriate light
cytoplasmic swelling. There is no significant effect on source, resulting in necrosis of adjacent tissue. Studies
Gleason score, which is generally assignable post- using PDT as salvage therapy after failed RT have been
cryotherapy. Relatively few radical prostatectomies carried out in one centre.84,85 Biopsy specimens
have been performed post-cryotherapy, but residual obtained 6 months after PDT have shown tissue
carcinoma is often detected.73 damage with zones of dense fibrous connective tissue,
Microwave thermotherapy has also been used as a usually with an absence of prostatic glandular ele-
treatment for BPH and prostate cancer. Tissue necrosis ments.13 Coagulative necrosis and granulation tissue
and other non-specific histological findings may be
identified post-microwave treatment, and destruction of
the prostatic urethra has been identified in radical
A
prostatectomy specimens obtained 1 week after the
microwave therapy.74
High-intensity focused ultrasound (HIFU) has been
used as a treatment for BPH and also for prostate
cancer, either as a primary modality or as salvage
therapy post-RT.75–79 HIFU therapy causes coagulative
necrosis by raising the local temperature to >60C.80 A
number of devices are available for either whole gland
or focal therapy, although HIFU has not been approved
as primary therapy for prostate cancer by the Food and
Drug Administration in the USA. Biopsy specimens
have been reported as negative in up to 90% of patients
who have been biopsied 3–6 months post-HIFU. Five- B
year biochemical and disease-free survival rates follow-
ing primary HIFU have been reported as 75% and 66%,
respectively.75,79
Morphological studies of prostate tissue post-HIFU
are few in number.81–83 Early studies documented
necrosis and haemorrhage in prostatectomy specimens
obtained 2 weeks after HIFU therapy. The changes
noted included acute and chronic inflammation, focal
coagulative necrosis, glandular atrophy, haemosiderin
deposition, reactive fibroblasts, stromal fibrosis, and
oedema. These changes were seen in the non-neoplas- Figure 12. Post-high-intensity focused ultrasound (HIFU) needle
tic tissue. Residual adenocarcinoma was identified in biopsy specimen. This biopsy specimen was obtained several months
after HIFU treatment. A, Note area of dense fibrosis in the core on
44% of patients, and no specific tumour effects were right and lower. Residual adenocarcinoma is present at the left and
noted in residual adenocarcinoma.83 The authors top. B, High-power photomicrograph of adenocarcinoma showing no
recommended Gleason scoring in these situations. In appreciable morphological effects.

 2011 Blackwell Publishing Ltd, Histopathology, 60, 153–165.

162 J R Srigley et al.
Figure 13. Needle biopsy specimen post-interstitial laser treatment.
Note the well-defined zone of coagulative necrosis surrounded by
non-specific fibroinflammatory reaction.
may also be seen. Viable adenocarcinoma can be
detected adjacent to the areas of treatment effect, and
no specific morphological features have been identified
that would preclude Gleason scoring.
Interstitial laser ablation is under development.
Under magnetic resonance imaging guidance, laser
fibres are inserted into the prostate gland, and temper-
atures are monitored during the treatment.86,87 Tissue
examined post-interstitial laser ablation shows all
defined areas of necrosis that correspond to the
specifically treated areas (Figure 13).84 These findings
can also be made in needle biopsy specimens 6 months
after treatment. Viable tumour may be detected, and no
specific morphological changes are known that would
preclude Gleason scoring. It is of interest that vital
staining based on cytokeratin 8 immunohistochemistry
shows no viable glandular tissue in the treated areas.13
Nutritional supplements and phytotherapy
Nutritional supplements, such as soy, selenium, tomato
paste, and green tea, have been used as potential
agents to prevent prostate cancer. Vitamins D and E
have also been advocated as potential chemopreventive
agents. No significant morphological effects caused by
these agents have been documented, either in benign
prostate tissue or in carcinomatous glands.1,12,13
Phytotherapy with extracts of Sabal serrulata (saw
palmetto) has been advocated as a treatment for BPH.
In one study, saw palmetto was reported to cause a
reduction in ‘perigranulomatous stromal edema, mu-
coid degeneration and congestive prostatitis’.88 There
were no documented effects on the epithelium. Another
study found no significant inflammatory process, but
the authors described the presence of so-called ‘epithe-
lial contracture’.89
It is fair to say that the morphological effects of saw
palmetto (and other herbal agents) need to be better
defined in the context of randomized controlled trials.
Conclusions
Patients with prostate cancer have a wide variety of
treatment options. Many of these therapies result in
structural changes in benign and malignant prostate
tissue. In some clinical settings, particularly when
hormonal therapy and RT is used, the morphological
effects on the cancer cells may make detection of
residual tumour difficult, and may result in changes
that would preclude Gleason scoring. It is important
for the pathologist to be aware of these changes and
to record appropriate observations in the pathological
record. It is also important to be aware of the
morphological effects of new and emerging ablative
and focal therapies as they adopted in clinical
practice.
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