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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5209_Библиотеки_им_академика_М_И_Перельмана.pdf
Pathologic Assessment
andImplications Following Focal
Therapy ofProstate Cancer
RafaelE.Jimenez, DivyangiParalkar,
AlessiaCimadamore, AndrewEvans,
andMahulB.Amin
38
Introduction
Assessment of prostate tissue after focal therapy
has resulted in novel challenges for the surgical
pathologist. Independent of the modality used,
the application of focal therapy results in, by denition, the division of the prostate into two distinct areas: a treated and an untreated zone. For
each of these areas, therapy success from both the
clinical and pathologic standpoints will be
R. E. Jimenez (*)
Division of Anatomic Pathology, Laboratory
Medicine and Pathology, Mayo Clinic,
Rochester, MN, USA
e-mail: jimenez.rafael@mayo.edu
D. Paralkar
University of Southern California Keck School of
Medicine, Los Angeles, CA, USA
A. Cimadamore
Department of Medicine (DAME), University of
Udine, Institute of Surgical Pathology, Udine, Italy
e-mail: alessia.cimadamore@uniud.it
A. Evans
Genitourinary Pathology, Cortellucci Vaughan
Hospital, Mackenzie Health, Vaughan, ON, Canada
e-mail: Andrew.Evans@MackenzieHealth.ca
M. B. Amin
Pathology and Lab Medicine, University of
Tennessee Health Sciences System,
Memphis, TN, USA
USC Keck School of Medicine, LabCorp,
Los Angeles, CA, USA
e-mail: mamin5@uthsc.edu
dened differently. (Table38.1) Ideally, that portion of the prostate undergoing treatment should
be completely free of residual clinically signicant cancer and is expected to show morphological changes associated with the specic treatment
modality utilized. In principle, the persistence of
clinically signicant tumor (large volume grade
group 2 [Gleason 3 + 4] or ≥ grade group 3
[Gleason 3+4]) should be considered a failure of
therapy; although, for most modalities, it is
unknown to what degree persistent tumors manifest the same biological behavior as an untreated
disease. The untreated area should ideally be
pathologically free of tumor or harbor exclusively low-grade clinically insignicant tumor.
Clinically insignicant cancer is dened as a
tumor in which active surveillance would be considered as a treatment modality, and histopathologically, they include tumors with a grade group
1 (Gleason 3+3) or, at most low volume grade,
group 2 tumors that lack cribriform architecture
or intraductal carcinoma, as per most active surveillance guidelines [1]. The untreated portion
should thus be thoroughly investigated to exclude
aggressive disease and monitored with active surveillance if clinically insignicant disease is
present.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
T. J. Polascik et al. (eds.), Imaging and Focal Therapy of Early Prostate Cancer,
https://doi.org/10.1007/978-3-031-66754-1_38
455
456
Table 38.1 Desired oncologic/pathologic outcome in focal therapy
Treated zone Untreated zone
Desired oncologic
outcome
Expected pathologic
ndings
Clinical follow-up Imaging/biopsy interrogation for evidence
Eradication of targeted disease Absence of cancer or clinically signicant
Specic therapy related changes
Absence of residual tumor
of recurrent tumor
R. E. Jimenez et al.
disease
Absence of tumor or at most small Gleason
3+3 (grade group 1) tumors
Active surveillance protocol
Assessment ofTreated Area
All modalities of focal therapy create localized
tissue necrosis by generating tissue damage upon
the application of some type of energy or cellular
insult. With the possible exception of brachytherapy, the insult does not discriminate between
neoplastic and nonneoplastic tissue, and thus, the
mechanisms and morphologic changes in both
components would be similar. Given that the
desired endpoint is complete necrosis of the targeted lesion, the result is usually a discrete area
of necrosis and tissue destruction within the prostate and immediately adjacent tissue, with the
consequential inammatory and reparative
response. Each distinct technique results in subtle
but distinct morphologic changes, and the surgical pathologist will likely be requested not only
to determine the presence or absence of residual
viable tumor but also to assess the degree of tissue damage as a method of providing feedback as
to whether the technique was appropriately
applied. Familiarity with the particular changes
associated with each technique is thus necessary
for a proper evaluation of the treated area
(Table 38.2). Currently, there are only a small
number of published studies on the histopathological changes associated with newer partial
therapy modalities, with most of these encompassing only a small number of cases.
Postbrachytherapy Treatment Changes
Changes associated with radiation have been
well characterized in the prostate pathology literature, given the popularity of external beam
radiation as a whole gland treatment modality.
The changes are similar whether the method of
delivery is external beam radiation or brachytherapy, with the latter being the most likely
modality in which focal radiation therapy is currently applied.
In contrast to most other techniques, radiation
can achieve tumor eradication without complete
obliteration of the adjacent benign tissue. Thus,
residual benign prostatic glands are usually seen
in areas of brachytherapy, although their morphology is markedly altered by the radiation.
Typical histologic changes in benign tissue
include a decreased ratio of tumor glands to
stroma, atrophy, and squamous-like metaplasia
of the non-neoplastic glands. Atrophy is predominant in the secretory cells, while the basal cells
show atypical pleomorphic nuclei with smudged
chromatin and cytoplasmic vacuolization. This
cytologic atypia and pleomorphism tend to be
marked, frequently resembling neoplastic
changes to the inexperienced observer
(Fig. 38.1a). The fact that prostatic adenocarcinoma is rarely a pleomorphic tumor should provide reassurance that the atypical cells are not
neoplastic in nature [2]. Paneth-like cells and
mucinous metaplasia may also be seen. Changes
in the adjacent elements include stromal brosis,
arterial luminal narrowing due to myo-intimal
proliferation, foam cells within vessel walls, and
brosis and atrophy of seminal vesicles [3].
Despite the striking cytological changes, lowpower examination reveals a retention of the lobular architecture of the normal prostatic
parenchyma. Radiation-induced changes in the
benign glandular elements can persist for prolonged periods of time, up to 5 years postbrachytherapy [4].
38 Pathologic Assessment andImplications Following Focal Therapy ofProstate Cancer
Table 38.2 Summary of histopathologic changes according to focal therapy modality
Focal therapy modality Expected pathologic ndings
Brachytherapy Radiation atypia, squamous metaplasia. Neoplastic glands variable
degrees of response
HIFU Coagulative necrosis with inammation, followed by brosis. Corpora
amylacea within spaces lacking epithelium
Cryotherapy Coagulative necrosis, squamous metaplasia, hemorrhage
Interstitial laser ablation therapy Coagulative necrosis and “ghosts” of malignant glands
Photodynamic therapy Hyaline scars, atrophic glands, coagulative necrosis. Organized thrombi
Irreversible electroporation Necrosis with neutrophilic inltrate. Reactive broblasts and
hemorrhage
Interstitial microwave thermal therapy Coagulative necrosis
Radiofrequency interstitial tumor
ablation
Coagulative necrosis
457
a
c
Fig. 38.1 Radiation-induced changes in prostatic adenocarcinoma and benign prostatic glands. (a) Typical
appearance of benign prostatic glands following radiation
therapy, characterized by prominent, irregular basal cells
with smudged dark chromatin. (b) Typical H&E appearance of prostatic adenocarcinoma on needle biopsy performed 18months after external-beam radiation therapy,
showing malignant acini distributed in a haphazard manner within the prostatic stroma. (c) Immunohistochemical
staining with a p63/high molecular weight keratin/
b
d
AMACR cocktail showing the expected absence of basal
cells (evidenced by a lack of brown staining with p63/high
molecular weight keratin) and positive staining for
AMACR (red staining). This prole provides additional
support for the diagnosis of prostatic adenocarcinoma
with radiation-induced treatment effects. (d) High magnication H&E appearance of the malignant glands shown
in (a) showing the typical degenerative nuclear changes
and vacuolated clear cytoplasm seen following radiation
therapy. Gleason grading is not applicable in this setting
458
R. E. Jimenez et al.
Prostatic adenocarcinoma shows a spectrum
of changes that vary in severity according to the
degree of therapy effect in the tumor glands. The
most affected tumor tissue shows inltrative
abortive glands and single cells with prominent
cytoplasmic vacuolization, pyknotic nuclei, and
disappearance of nucleoli (Fig. 38.1b–d). The
least affected tumor tissue is indistinguishable
from the untreated tumor, with amphophilic
cytoplasm, enlarged nuclei, and prominent
nucleoli. A grading scale to assess the severity of
the treatment effect has been proposed and correlated with chances of recurrence (in the setting
of external beam radiation) (Table 38.3) [5].
According to the proponents of this grading
scale, tumors with scores of 1 or 2 in biopsies
taken at 24-months posttherapy biopsy show
morphology almost identical to untreated tumors
and are associated with recurrence rates of 55%.
Tumors with scores in the intermediate range of
3–4 have local failure rates of around 30%.
Tumors showing severe treatment effects, with
total treatment grades of 5–6, have 5-year
disease- free survival rates that are similar to negative biopsies and could be considered “indeterminate” for residual tumor [6]. However, in a
recent study, no statistically signicant difference in biochemical disease-free survival was
found between the different degrees of therapy
effect in patients undergoing high dose rate
brachytherapy boost for intermediate-risk PCa at
routine 2-year biopsy [7]. Gleason scoring is not
applicable to radiation-treated tumors that demonstrate the effect of therapy. Gleason score
should be only applied to tumors with absent or
minimal therapy effect while avoiding it for
tumors with marked effect, given the severe
alteration of the tumor’s architecture [4, 8]. The
issue of how to grade or assess radiation effect in
tumors with prior radiation therapy has not been
addressed in recent consensus statements on
prostate cancer grading from genitourinary
pathology societies [9, 10].
In general, identication of a haphazard,
inltrative distribution of the glandular elements at low-power microscopic examination is
the best way to differentiate residual tumor
from benign glandular elements. In difcult
cases, immunohistochemical staining with
basal cell markers (p63, keratin 34βE12, keratin 5/6) and alpha- methylacyl- CoA racemase
(AMACR) is extremely useful, as the differences in immunophenotype between benign
and malignant glands are maintained in the setting of radiation therapy (Fig. 38.1c). Some
authors have investigated the use of proliferation markers such as Ki67 to provide an objective assessment of the viability of the tumor
cells [11, 12], although this is not currently routinely recommended.
A long-term complication of radiation therapy
and brachytherapy is the development of a histologic subtypes of prostatic carcinoma, usually a
dedifferentiated forms, including carcinosarcoma
[13–15], small cell carcinoma [16], or squamous
cell carcinoma [17]. Development of these alternate histologies is usually associated with a dismal prognosis.
Table 38.3 Grading of post radiation treatment effect in prostate biopsies. It was proposed by Bocking and Aufferman
and Crook etal. subsequently modied the grading scheme
Cytoplasmic
0 No identiable treatment effect
1 Swelling and microvesicular change
2 Vacuolization and voluminous cytoplasm, ruptured cytoplasm, lipofuscin accumulation
3 Single tumor cells or dilated glands
Nuclear
0 No identiable treatment effect
1 Nuclear enlargement with smudging and visible nucleoli
2 Large bizarre nuclei with smudging and rare or absent nucleoli
3 Pyknotic, small nuclei
Adapted from Evans etal. [3]
38 Pathologic Assessment andImplications Following Focal Therapy ofProstate Cancer
459
Post High-Intensity Focused Ultrasound (HIFU) Treatment Changes
HIFU therapy uses highly energetic ultrasound
waves, which rapidly increase the temperature
within the affected area, causing tissue destruction
and coagulation necrosis. Early reports of the
effects of HIFU on canine prostates found subtotal
hemorrhagic liquefactive necrosis in 90% of the
gland [18, 19]. In human prostates, radical prostatectomy (RP) specimens 2 weeks after HIFU treatment show a spectrum of morphological changes
from subtle ultrastructural cell damage to frank
necrosis [20, 21]. The treated tumor is associated
with loss of cytokeratin 8, implying severe cellular
damage [21]. In a 65-year-old man treated with
radical cystoprostatectomy for a prostate-rectal
stula from postradiation salvage HIFU, histological changes of dense brosis, neuronal proliferation, and chronic inammation were noted where
prostatic tissue should have been located, with no
evidence of residual cancer [22].
Changes in needle core biopsy are dependent
on the timing of the biopsy. In an examination of
needle biopsies taken 6 months after HIFU treatment, necrosis, often accompanied by acute,
chronic, or granulomatous inammation, was
noted in 72% of the cases, with mild to moderate
brosis in all biopsies [23]. In 44% of their cases,
residual adenocarcinoma was present; little to no
treatment changes were seen among the glands,
raising the possibility of insufcient delivery of
thermal energy. In another study of needle biopsies taken at a mean of 14 months after HIFU,
coagulation necrosis was much less prevalent
(only 4 of 30 cases), with well-developed brosis
being more common (Fig. 38.2a, b), usually
associated with hemosiderin deposition, granulation tissue, and corpora amylacea within spaces
lacking epithelium (Fig. 38.2c) [24].
Adenocarcinoma was present in 63% of cases,
and the authors found that it lacked any morphologic evidence of therapy effect and that Gleason
grading could be easily performed. Most of the
patients with positive post-HIFU biopsies had
a
b
Fig. 38.2 Prostate biopsy following high-intensity
focused ultrasound (HIFU) therapy. (a) Marked HIFUinduced brosis is seen in the core fragment on the right
in this biopsy performed 15months after HIFU therapy
for clinically low-risk prostate cancer. In contrast, the core
fragment on the left shows residual prostatic adenocarci-
c
d
noma and adjacent stroma, showing no obvious effects of
HIFU therapy. (b) Note the sharp interface between the
HIFU-induced brosis and the unaffected prostate parenchyma. (c) Corpora amylacea within stroma are commonly seen. (d) Residual adenocarcinoma after HIFU.The
tumor does not display a signicant therapeutic effect
460
R. E. Jimenez et al.
Gleason scores less than or equal to their preHIFU biopsies, along with similar or lower percentage tissue involvement. Cases with higher
posttreatment Gleason scores all showed biochemical failure. Additionally, the tumor immunophenotype was not altered by the therapy, and
the application of common markers yielded the
expected results (Fig. 38.2d). Similarly, both
Dalor etal. and Walter etal. found a preserved
immunophenotype in residual tumors in patients
who underwent post-HIFU biopsy [25, 26].
Post Cryotherapy Treatment Changes
Cryotherapy induces tumor ablation through multiple pathways, including mechanical cell destruction by the formation of ice crystals, necrosis, and
the induction of apoptosis through metabolic, vas-
a
cular, and immune pathways [27]. The initial
experience on six patients revealed coagulative
necrosis in the proximity to the cryosurgery probe,
with squamous metaplasia of glandular epithelium and hemorrhagic areas observed further
away. A larger study on 30 biopsies performed on
a man at 19-months postcryotherapy revealed
chronic inammation, myxoid stromal change,
and stromal hemosiderin [28]. Additional ndings
include stromal brosis, necrosis, calcications,
acute inammation, granulomas, hemorrhage,
vessel wall thickening with prominent endothelial
cells, and squamous metaplasia (Fig. 38.3).
Residual benign glands, when present, did not
show signicant histopathologic changes.
Recurrent or residual prostatic adenocarcinoma
was present in 36% of cases, almost half of them
with a higher Gleason score compared to the pretreatment biopsy. The residual neoplastic glands
b
c
Fig. 38.3 Prostate biopsy following cryotherapy. (a)
Cryotherapy induces extensive coagulative necrosis and
adjacent brosis. (b) Necrotic tumor is characterized by
“ghost” glands that maintain the architecture of the origi-
d
nal glands but lose all cytologic detail. (c) Area of hyalinized brosis with minimal cellularity. (d) More cellular
area of brosis, with broblasts and hemosiderin-laden
macrophages, indicative of prior hemorrhage
38 Pathologic Assessment andImplications Following Focal Therapy ofProstate Cancer
461
did not show evidence of tumor effect [28].
Similarly, Koppie etal. found that of 111 biopsies
in patients with 24 or more months of follow-up,
41 (37%) displayed residual /recurrent prostate
cancer [29]. Ellis et al. also found that of 35
patients who underwent biopsy, 14 (40.0%) contained adenocarcinoma at a mean of 12.0months
post-treatment. However, they caution that 13
(37%) of these had been taken from the side of the
prostate that was not initially treated [30].
Post Laser Ablation Changes
Laser ablation induces tissue necrosis by thermal
injury, and thus, the ndings are similar to those
of HIFU, including a sharp interface between
treated and untreated tissue, the former characterized by coagulative necrosis and “ghosts” of
malignant glands (Fig. 38.4). Lindner et al.
described four patients who underwent RP after
laser ablation therapy and found that the ablation
zone was characterized by homogeneous areas of
coagulation necrosis, surrounded by a small hemorrhagic rim, devoid of vital glandular tissue
[31]. The vitality of the residual glands was
assessed by the use of cytokeratin 8, which
demonstrated an abrupt transition of positive
(vital) glandular tissue and negative (ablated)
glands. The points of insertion of the laser bers
were easily identied in the whole mount sections of the RP specimen, and the absence of
residual tumor in between the two bers was evident. The ablation zone extended all the way to
the prostate capsule. Also, there was a good correlation between MRI and whole mount H&E
histological examination and an even better correlation with the loss of cytokeratin 8 immunohistochemical staining. Oto et al. published
results on 6-month postprocedure biopsy for nine
patients that underwent laser ablation: seven
patients had no evidence of residual/recurrent
disease, while 2 showed Gleason 3+3 adenocarcinoma [32]. A retrospective review of the ablation images revealed incomplete coverage of the
lesion site by the ablation zone for the two
patients with positive follow-up biopsies.
Similarly, Lee etal. reported that 12 of their 13
patients who had laser ablation therapy had no
residual cancer on follow- up biopsy [33]. The
a
Fig. 38.4 Prostate biopsy following interstitial laserablation therapy. (a) Low magnication view of a prostate
needle biopsy performed 5–6months after primary interstitial laser-ablation therapy. Note the core fragment on
the right, where the sharp interface between treated and
untreated tissue is readily apparent (denoted by the aster-
b
isk). (b) High magnication view showing the ablation
zone characterized by a peripheral rim of brosis between
the unaffected parenchyma and the ablated tumor, which
is characterized by coagulative necrosis and “ghosts” of
malignant glands
462
R. E. Jimenez et al.
remaining patient had Gleason 3+4=7 adenocarcinoma. An additional patient developed a
new mpMRI abnormality away from the treated
area that, upon biopsy, revealed 3+3 adenocarcinoma. Both cases were subsequently re-ablated.
Post Photodynamic Therapy Changes
Photodynamic therapy uses photosensitizing
drugs that are pharmacologically inactive until
they are exposed to light in the presence of oxygen. Once activated, the drug forms reactive oxy-
Fig. 38.5 Prostate
biopsy following
photodynamic therapy
(PDT). (a) Low
magnication overview
of a needle biopsy
obtained 8 months
following salvage PDT
after incomplete primary
radiotherapy. The tissue
above the asterisk shows
no appreciable treatment
effect, while that below
the asterisk shows a
marked range of brosis.
(b) A high magnication
view of adenocarcinoma
and stroma from the top
of the core in A shows
no treatment effect. (c)
High magnication view
of tissue located at the
asterisk in A.The
adenocarcinoma shows
no appreciable treatment
effects, while the
adjacent stroma shows
moderate brosis. (d) A
high magnication view
of the end of the core in
A shows dense scarring
resulting from the PDT
therapy
a
gen species that are directly responsible for
thrombosis and tissue destruction around the
optical ber. For prostate cancer, the photosensitizers are administered orally or intravenously
and activated in the prostate by a low-power laser
light delivered with optical bers. Histopathologic
changes associated with photodynamic therapy
include hemorrhagic necrosis with inammation,
gland destruction, atrophy, and vascular thrombosis in the treated area, ultimately followed by
dense brosis (Fig.38.5) [4, 34]. Aebisher etal.,
in an invitro study, described the histopathological changes according to different concentrations
b
c
d
38 Pathologic Assessment andImplications Following Focal Therapy ofProstate Cancer
463
of photosensitizers in the tissue. They ranged
from chromatin condensation and stromal edema
with low concentrations of photosensitizer, to
severe architectural alteration, prominent chromatin condensation, and pyknotic nuclei with
higher concentrations [35]. Eymerit-Morin et al.
described the histopathologic ndings in 6-month
follow-up biopsies of 53 patients who underwent
focal photodynamic therapy; these comprised
sharply demarcated hyaline scars, rare atrophic
glands, mild chronic inammatory inltrate,
hemosiderin deposition, and coagulative necrosis
[36]. Vascular lesions such as intimal hyaline
brosis or organized thrombi were not prominent. Seventeen of the 53 patients had residual
carcinoma in the treated lobe, all located outside
the scarred area, usually close to the capsule
(which was intentionally avoided). The Gleason
score was upgraded in 5 patients. The viable carcinoma glands did not display any therapy-related
changes and were easily recognized in most cases
with routine histology. The PCM301 trial, a randomized trial of partial gland ablation with vascular targeted phototherapy versus active
surveillance for low-risk prostate cancer, reported
a signicantly lower number of biopsies positive
for signicant cancer in patients after ablation
versus those that were managed with active surveillance (14 vs 41%, p<0.001) [37].
Post Irreversible Electroporation Changes
viable ducts displayed squamous metaplasia. A
recent study reported 16 patients who underwent
IRE 4 weeks prior to scheduled RP [40].
Microscopic assessment of the ablation zone
showed areas of brosis, necrosis, and ghosttubuli with eosinophilic cytoplasm, surrounded
by a hemorrhagic area corresponding with the
location of the electrodes on ultrasound. Mild to
moderate inammation, basal cell hyperplasia,
and urothelial metaplasia were also seen. No skip
lesions (residual viable tissue) were identied in
the ablated area. The prostate capsule was affected
by the IRE treatment in most cases, showing an
invasion of adipocytes and lipophages in the capsule. IRE effects were observed extending into the
neurovascular bundle in the majority of patients,
where it was recognized as eosinophilic degeneration of the cytoplasm and pyknotic nuclei of the
nerves. Prostatic urethra damage was seen in nine
patients, manifested by denudation of the urothelium. Tissue outside the ablation zone contained
multifocal adenocarcinoma in 15 patients, with
the diameter of the dominant tumor area ranging
from 3 to 18mm. Four tumors extended into the
extraprostatic tissue. More recently, Ting et al.
reported on 25 patients who underwent IRE; of
the 21 who underwent follow-up biopsy, 5 (21%)
had signicant disease on follow-up biopsy.
However, 4 of these were in the eld adjacent to
the ablation zone, suggesting that a wider margin
around the area of concern is required to ensure
adequate treatment [41].
Irreversible electroporation (IRE), or electropermeabilization, is a nonthermal ablation technique
by which cell membrane permeability to ions and
macromolecules is increased by exposing the cell
to short electric current pulses, creating permanent cellular and tissue damage. The electric current pulses are delivered by needle electrodes
percutaneously placed in the tumor under ultrasound guidance [38]. A small study by Neal etal.
describes the ndings in two patients who underwent RP after IRE [39]. The treatment areas
exhibited extensive necrosis with inammatory
neutrophilic inltrate, surrounded by an area of
reactive broblasts and hemorrhage. The adjacent
Interstitial Microwave Thermal Therapy
Interstitial microwave thermal therapy (IMT)
induces tissue damage by heating tissue to cytotoxic levels of 55–70° C. The electromagnetic
energy, which increases kinetic energy by rotating cellular molecules, is delivered to the prostate
by the insertion of microwave antennas through
the perineum. Only a few studies have been published that include histopathologic analysis after
IMT.In a report of ndings in canine prostates,
Cheng etal. described three discrete zones within
hours of IMT, one characterized by its resem-
464
R. E. Jimenez et al.
blance to untreated tissue, with the glandular and
stromal architecture intact but nuclei appearing
pyknotic. The second zone had a ghost-like
appearance due to disrupted cell membranes and
vessels; extravasated red blood cells were present. The third zone had similar cellular changes
with vascular dilatation and interstitial hemorrhage [42]. A study on ve RP specimens performed 1 week after IMT delivered
trans-urethrally, revealed sharply circumscribed
necrosis with the nonviable zone wider at the
base, gradually decreasing toward the apex. The
prostate cancer was generally localized in the
peripheral zone at depths greater than microwave
penetration, whereas the thermally damaged
zone appeared in the transition zone circumferential to the prostatic urethra [43].
Radiofrequency Ablation
Radiofrequency ablation generates temperatures
of around 100° C and induces coagulative necrosis. The radiofrequency energy is delivered by a
precise placement of needle electrodes into the
previously localized tumor. Zlotta etal. reported
on 13 RP specimens removed immediately and
after 1-week post radiofrequency interstitial
tumor ablation. Macroscopically, large hemorrhagic areas were visible; microscopically, they
were characterized by intense interstitial edema
and fading of the cell borders with cytoplasmic
hypereosinophilia. Glandular retraction and desquamation of the epithelium in the glandular
lumen were seen [44]. Another study reported on
follow-up needle core biopsies on 11 patients
who underwent RITA.Seven had negative biopsies at 6 months and 6 of 9 at 12 months after
RITA [45]. Aydin etal. similarly reported negative biopsies after focal bipolar radiofrequency
ablation in 7 of 10 patients studied [46].
Monitoring oftheNontreated Area
As stated above, in a successful partial therapy,
the nontreated area should harbor no neoplastic
disease, or at worst low-grade (grade group 1) or
low-volume grade group 2, clinically insignicant, surveillable tumors. It is well known that
prostate cancer is a multifocal disease in 57–91%
of cases [47–51]. Despite this, Liu etal., by using
a high-resolution genome-wide survey of singlenucleotide and copy-number polymorphisms,
concluded that different, anatomically distinct
metastases within the same patient originated
from a single precursor cell [52]. This notion is
central to the concept of index tumor, which proposes that the biological behavior of prostate cancer is determined, in multifocal tumors, by its
most aggressive lesion, usually that one that has
the largest size, highest grade, or highest stage
within the prostate [53]. Index tumor determination by mpMRI or transperineal template-guided
mapping biopsy is highly accurate [54]. The largest tumors usually have the highest Gleason
score, up to 98% of patients in one study [55].
However, in a series of 122 men, 20% had
Gleason 7 non-index tumors, including 5% with
tumors ≥4+3, the majority of which were missed
by MRI [56]. Further, non-index tumors have
been reported to locally invade [50] and metasta-
size [57, 58]. Focal therapy series treating the
index lesion only have reported detection of clinically signicant disease arising in the outeld, or
untreated, area at 6-month biopsy [59]. It remains
unclear whether outeld recurrence is due to disease progression as a result of eld change or previously undetected small foci of cancer. Data on
histological assessment of untreated zone is difcult to interpret as not all series that report
residual adenocarcinoma post focal therapy specify the location or even grade of the positive cores
[60]. Nonetheless, the published data provides
evidence supporting active surveillance of the
untreated area and having a low threshold to
intervene in case of suspicion of clinically signicant tumor. Documentation of clinically signicant disease in the untreated area should
prompt further therapy, either whole-gland therapy or additional focal therapy.
Multiple active surveillance protocols have
been employed, and the majority of the series
include clinical assessment with digital rectal
examination, PSA/ PSA kinetics, and rebiopsy at
12–18 months, followed by trigger-based biop-