Journal of Neuro-Oncology
https://doi.org/10.1007/s11060-022-04232-z
CASE STUDY
Perilesional resection technique of glioblastoma: intraoperative
ultrasound and histological findings of the resection borders
in a single center experience
Carlo Giussani1,2 · Giorgio Carrabba1,2 · Chiara Benedetta Rui1,2 · Gaia Chiarello3 · Giovanni Stefanoni4 ·
Chiara Julita5 · Andrea De Vito6 · Maria Allegra Cinalli1,2 · Gianpaolo Basso1,6 · Paolo Remida6 · Giuseppe Citerio1,7 ·
Andrea Di Cristofori1,2
Received: 7 July 2022 / Accepted: 29 December 2022
© The Author(s) 2023
Abstract
Introduction The surgical goal in glioblastoma treatment is the maximal safe resection of the tumor. Currently the lack of
consensus on surgical technique opens different approaches. This study describes the “perilesional technique” and its outcomes in terms of the extent of resection, progression free survival and overall survival.
Methods Patients included (n = 40) received a diagnosis of glioblastoma and underwent surgery using the perilesional
dissection technique at “San Gerardo Hospital”between 2018 and 2021. The tumor core was progressively isolated using a
circumferential movement, healthy brain margins were protected with Cottonoid patties in a “shingles on the roof” fashion,
then the tumorwas removed en bloc. Intraoperative ultrasound (iOUS) was used and at least 1 bioptic sample of “healthy”
margin of the resection was collected and analyzed. The extent of resection was quantified. Extent of surgical resection
(EOR) and progression free survival (PFS)were safety endpoints of the procedure.
Results Thirty-four patients (85%) received a gross total resection(GTR) while 3 (7.5%) patients received a sub-total resection
(STR), and 3 (7.5%) a partial resection (PR). The mean post-operative residual volume was 1.44 cm3 (range 0–15.9 cm3).
During surgery, a total of 76 margins were collected: 51 (67.1%) were tumor free, 25 (32.9%) were infiltrated. The median
PFS was 13.4 months, 15.3 in the GTR group and 9.6 months in the STR-PR group.
Conclusions Perilesional resection is an efficient technique which aims to bring the surgeon to a safe environment, carefully
reaching the “healthy” brain before removing the tumoren bloc. This technique can achieve excellent tumor margins, extent
of resection, and preservation of apatient’s functions.
Keywords Brain tumors · Neurosurgery · Glioblastoma · Extent of resection · Progression free survival · En bloc resection ·
Perilesional resection · Intraoperative ultrasound
* Carlo Giussani
carlo.giussani@unimib.it
1
Department of Medicine and Surgery, School of Medicine
and Surgery, University of Milano-Bicocca, Milan, Italy
2
Neurosurgery, Fondazione IRCCS San Gerardo dei Tintori,
Via Pergolesi 33, 20900 Monza, MB, Italy
3
Neuropathology, Fondazione IRCCS San Gerardo dei
Tintori, Via Pergolesi 33, MB 20900 Monza, Italy
4
Neurology, Fondazione IRCCS San Gerardo dei Tintori, Via
Pergolesi 33, 20900 Monza, MB, Italy
5
Radiotherapy, Fondazione IRCCS San Gerardo dei Tintori,
Via Pergolesi 33, 20900 Monza, MB, Italy
6
Neuroradiology, Fondazione IRCCS San Gerardo dei Tintori,
Via Pergolesi 33, 20900 Monza, MB, Italy
7
Neurointensive Care Unit, Fondazione IRCCS San Gerardo
dei Tintori, Monza, Italy
13
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Journal of Neuro-Oncology
Introduction
Glioblastoma (GB) is a primary brain tumor with an infiltrative behavior that may affect both eloquent or non-eloquent areas of the brain [1–4]. Current standard of care
for GB involves tumor resection followed by adjuvant
chemo-radiation therapy according to the Stupp protocol
[5]. Gross total resection (GTR) of the contrast-enhancing
part of the tumor is known to influence survival outcome
of patients affected by this disease, while the benefits and
extent of supramarginal resection are still under debate
[6–9].
Owing to tumor location and its infiltrative nature,
and despite several tools being available to optimize the
extent of resection (EOR) such asneuronavigation, neurophysiological monitoring, intra-operative imaging,
microscopic fluorescence etc. [6, 10, 11], it is known that
it could be difficult in some situations to achieve a safe,
complete resection of the contrast-enhancing part of the
glioblastoma.
This fact is related to the infiltrative subcortical nature
of this disease that often does not have a cleavage plane
that allows a separation of the tumor from the surrounding
brain parenchyma. Until now, while surgery of extra-axial
lesions aims to find the dissection plane in-between the
brain and the tumor, in the case of intra-axial tumors two
main approaches can be performed: central debulking and
perilesional dissection [12–14].
In GBs, the first rule is to avoid any neurological deficit that can lead to the worsening of the prognosis of the
patient [15–17]. As a consequence, some neurosurgeons
approach GBs with an intralesional debulking approach
that aims to gradually remove the tumor with a piecemeal technique [13]. This technique comes from the idea
that beginning the resection in the middle of the tumor
and centrifugally widening the aspiration would be a
safe approach to enable the surgeon to stop when normal appearing white matter is reached. Other surgeons
may face GBs starting from the tumor boundaries with
a perilesional resection; a technique in which the GB is
resected in an enbloc fashion [12, 13]. In this way, the
surgeon has to figure out a cleavage plane that goes around
the tumor while the contrast-enhancing bit of the tumor
is left intact. According to a recent work by Sawaya and
Colleagues, perilesional resection of GBs leads to a higher
rate of GTRs and to a lower rate of neurological complications than in intralesional debulking. The increased overall
survival reported may be related to a more effective surgical cytoreduction than to the piecemeal technique [12].
In this work, we aimed to describe in detail the perilesional resection technique and to prospectively analyze the
histological findings of the surgical margins of a series of
13
40 consecutive patients with a histopathological diagnosis
of glioblastoma (WHO 2021), who underwent surgery at
our institution in order to better investigate the benefits of
en bloc resection with perilesional dissection.
Materials and methods
Patient selection
In this study we prospectively included 40 patients aged
more than 18 years old operated for GB resection from 2019
to 2020 at Azienda Socio Sanitaria Territoriale Monza—
Ospedale San Gerardo Monza, Italy. Patients who received
a different diagnosis to IDH wild-type GB were excluded.
All surgeries were performed using the perilesional dissection technique with intraoperative ultrasound (iOUS) and
neuronavigation. When surgical resection was considered
complete by the surgeon, at least one bioptic sample from
clean tumor cavities were collected and sent to the pathology department.
Data collection was performed prospectively and encompassed demographic data including age at diagnosis, sex,
side and site of the tumor, neurological deficits at presentation and/or after surgery, overall survival (OS) and progression free survival (PFS). Follow-up ended on 30th September 2022.
Extent of surgical resection (EOR) was measured according to Berger et al. 2011 based on pre-operative and postoperative volumetric T1-weighted with gadolinium brain
MRIs [18]. GTR was considered when 99% of the tumor volume was removed; while STR was considered when tumor
was removed from 98 to 80% and PR when below 80%.
Informed consent was obtained from all individual participants included in the study.
Surgical technique and sample collection
A tailored craniotomy with the aid of neuronavigation is
performed. After durotomy and exposure of the brain, a corticectomy around the most superficial part of the tumor is
performed. A sort of perilesional plane around the contrastenhancing part of the tumor is found through the tractionof
the tumor away from the normal appearing brain using dedicated spatulas (see Fig. 1).
In this way, the white matter is gradually and circumferentially suctioned until the bottom of the tumor is reached. This
circumferential movement allows the surgeon to perform the
hemostasis during the surgical resection progressively;it also
delineates a separation plane in the white matter (or at the
level of the arachnoid sulci when they form a part of the
dissection planes) that can be protected placing a cottonoid
pattie over another in a “shingles on the roof” fashion while
Journal of Neuro-Oncology
surgeon and checked with an iOUS, biopsy samples are randomly collected with dedicated forceps from the walls of the
surgical cavity that are not considered in relation to eloquent
areas (see Fig. 3). No surgical adjuncts are used in order to
avoid false negative results.
Histology
Fig. 1 Shows the identification of a perilesional plane through traction with dedicated dissection spatulas. A and B show a case of a left
parietal GB
the circumferential dissection is progressing. The use of neuronavigation and intraoperative ultrasound (iOUS) reduces
the risk of losing a correct trajectory around the tumor; in
this way, this is circumnavigated (see Fig. 2).
After the bottom is reached, a cottonoid pattie is placed
over the normal appearing white matter. When the tumor
has been circumnavigated, it can be detached from the bottom of the surgical cavity and removed enbloc with a film
of normal-appearing white matter attached to the contrastenhancing tumor. When the volume of the tumor mass does
not allow the surgeon to spatulate the white matter, it can be
centrally debulked, like in meningioma surgery, to permit
tractions (see Supplemental Fig. 1). Hemostasis is easily
performed with gentle retraction of the patties and coagulating the strips of white matter attached to them. An online
intraoperative video is available in the supplementary materials. After resection is considered completed by the primary
Histological diagnosis was performed by a dedicated pathologist blinded to the intraoperative and to post-operative
MRI findings. Diagnosis of GB was reviewed in accordance with the 2021 WHO criteria [3]. Routine screenings
for IDH mutation, LOH and MGMT status were performed.
Perilesional samples were considered free of tumor when
no tumoral cells wereidentified; infiltrated when increased
cellularity and atypical cells were found; and tumoral when
they resembled the histological findings of the tumor core
diagnosis. In Fig. 4 the kind of histological findings on perilesional biopsies are reported (see Fig. 4).
Results
In our series we included 40 patients, 26 males and 14
females with a median age of 66 years, affected by IDH
wild type GBs. MGMT was found to be hypermethylated
in 15 patients while none of the patients expressed LOH of
1p19q nor a mutation of IDH. Pre-operative median KPS
was 90 and ranged from 40 to 100. Pre-operative neurological deficits were present in 18 patients. Tumors were
left-sided in 18 cases and locations included 4 parietal
lesions, 16 temporal lesions, 14 frontal lesions, 5 occipital
lesions and 1 insular lesion. All patients were operated with
Fig. 2 Shows the circumnavigation of a case of a right frontoopercular GB: AT2-weighted
preoperative MRI; B,C
T1-weighted with gadolinium
pre-operative brain MRI. D–F
A dissection plane is found and
delimited with cottonoid patties
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Journal of Neuro-Oncology
Fig. 3 This figure shows a case of a right temporal GB operated with
the perilesional dissection technique. In this picture it is possible to
understand how US and MRI can look like similar pictures
Fig. 4 Example of histological
findings of perilesional biopsies.
A-B normal appearing brain;
C-D infiltration of perilesional
brain; E-F frankly tumoral
perilesional tissue
13
a circumferential perilesional technique by the senior author
(C. G.) as described in Methods.
Pre-operative tumor volume, in terms of contrast-enhancing lesion, ranged from 1.5 to 96.4 cm3. Thirty-four patients
(85%) received a GTR while 3 (7.5%) patients received a
sub-total resection (STR) and 3 (7.5%) patients received a
partial resection (PR). Mean post-operative residual volume
was 1.44 cm3 (range 0–15.9 cm3).
During surgery, a total of 76 margins were collected from
the surgical bed as described in Methods. Of the 76 samples,
51 (67.1%) were tumor free (like in Fig. 4 A, B) and 25
(32.9%) were infiltrated by the tumor (like in Fig. 4C, D). No
frankly tumoral samples (like in Fig. 4E, F) were isolated.
Seventy-one margins were collected among patients that
received a GTR: 21 (29.6%) appeared infiltrated by glioma
and 50 (70.4%) were tumor free.
Post-operative complications were present in 5 cases: one
patient developed expressive aphasia, two patients developed
a left-sided hemiparesis, one patient developed right-sided
hemiparesis and one patient developed left-sided hemiplegia. Permanent neurological deficits were reported in one
patient, while others recovered before starting adjuvant
treatments.
Journal of Neuro-Oncology
Among patients that received a GTR, 16/34 (51.6%) were
alive at the end of the follow-up without recurrence. The
median OS of all patients was 12.7 months; the median OS
in patients that received a GTR was 19.3 months, while the
median OS in patients without a GTR was 8.6 months and
all of these patients were dead from tumor progression at the
end of the follow-up. The median PFS was 13.4 months; in
particular 15 months in the GTR group and 9.6 months in
the STR-PR group.
Discussion
In our work we described the histological findings on the
surgical cavity of patients undergoing surgical resection of
GB with a specific technique: the perilesional resection.
This way of removing an intra-axial tumor resembles a sort
of enbloc resection that is usually performed during oncological surgery in other districts of the human body [12].
The technique described in our paper is a way of applying principles of general oncology to neurological surgery
and, given the low incidence of post-operative neurological
deficits described in our series, perilesional resection can be
considered a safe way of approaching a GB.
This technique was first described by Sawaia et al. in
[12]. In their work, a huge cohort of patients with GB operated with either central debulking or perilesional dissection
was described. In particular, they demonstrated that enbloc
resection of GB was associated with a better overall survival
and with a higher rate of GTR [12].
Starting from the work by Sawaia [12] and colleagues,
we wanted to understand those findings from a biological
point of view. In our cohort of patients, 76 margins from 40
patients were histologically analyzed with 50 samples with
no tumor. All patients with tumor free histological samples
had received a GTR and none of them had a post-operative
deficit. These findings can be considered very interesting
when compared with those found in some works reported
in literature with a similar numbers of patients [19, 20].
Only few reports are available in literature about histology
from tumoral margins with variable results. The work by
Kubben et al. [21] described the histological characterization of39 biopsies collected on the borders of the surgical
cavities of 10 patients with the aid of intraoperative MRI. In
their work all biopsy samples were characterized by the presence of an infiltrative tumor that could sometimes resemble
a lower grade glioma [21]. Other works report absence of
tumoral cells in the perilesional samples collected [22, 23].
In the work by Mangiola [22] and colleagues, no tumoral
cells were seen in the peritumoral margins taken far from
the tumor core except in a small sample of patients [22,
23]. Their findings may suggest that the region of sampling
may be of importance for histological results. Another work
was published by Eidel et al. in 2017 with a similar number
of patients enrolled in our study [20]. During their study,
they collected samples from stereotactic biopsies from both
contrast-enhancing and non-enhancing parts of GBs. They
found that the non-contrast-enhancing parts had the highest relative content of viable tumor cells [20]; but this may
reflect the fact that tumors selected for stereotactic biopsy
might be more diffuse and highly infiltrative ones than
tumors eligible for surgical resection.
In a recent work by Coburger et al. using iOUS, 5-ALA
and intraoperative MRI,only 1 in 33 patientsafter an assumed
GTR had perilesional margins free of tumor [19]. In their
work it is not clear which strategy was used to surgically
remove a GB, whether by perilesional or intralesional resection or both.
Such differences between our findings and the findings
reported in literature may be related to different factors: the
surgical technique used and the concomitant reduction of
tumoral cells density in the peripheral zone of the GB (as
reported by Mangiola in 2012) [22]. The small size of bioptic samples retrieved at the end of surgery may be another
factor affecting the results of our study although the size of
such samples can be compared to a common stereotactic
biopsy sample.
In a speculative way, surgical technique may influence
the findings of the results on biopsies on the perilesional
tissue. If we consider the study by Eidel: they performed
stereotactic biopsies on patients with GBs in the border of
the tumor at the passage between necrotic, contrast-enhancing and non-enhancing zones [20]. Their approach was not
resective, andas a consequence may deliver a detailed histological description of the peritumoral zone which is not
present in studies where the peritumoral zone is delineated
after a cytoreductive surgery. In fact, in the last scenario it
may be difficult to recognize the peritumoral zoneas it may
not lookthe same as in the pre-operative MRI scans sinceits
extension and location is modified (e.g. a brain shift during
tumor resection [24, 25]) and it undergoes reshaping due to
surgery. Moreover, as reported by several authors and also
in our series, in GB it is not always possible to achieve a
GTR since the tumor is not always easy to distinguish from
the apparently healthy brain. As a consequence, the surgical approach for resection may lead to different histological results on the biopsy sampled. In fact, the perilesional
resection may guide the surgeon to start the glioma resection
from “healthy” brain tissue with no neoplastic cellular density rather than starting the resection from frankly tumoral
areas. As described in the intraoperative images, surgical
resection aims to remove the tumor without looking at its
borders (see Fig. 5) and it can be considered a sort of supramarginal resection. In this way, in the case of perilesional
resection, the peritumoral zone with viable tumoral cells
may be removed during the dissection of the tumor from the
13
Journal of Neuro-Oncology
Fig. 5 Example of perilesional dissection technique for resection of a perirolandic tumor. The Corticospinal tract had been identified with a
monopolar probe and continuously monitored with a cortical motor strip during resection (B)
peritumoral brain; while in the case of central debulking, the
peritumoral zone is resected by the surgeon in a centrifugal
way and as a consequence, peritumoral tissue with viable
tumoral cells may be left behind. As a consequence, bioptic samples may be tumor free with the first technique and
tumor infiltrated with the second technique.
From a functional and morphological perspective,
GBs tend to form a bulk that displaces white matter bundles rather than infiltrating them [26]. In this view, central
debulking can lead to the start of the surgical resection from
the less eloquent area of the surgical cavity towards the more
potentially eloquent area of the surgical cavity. In this way, it
is possible to expose the most eloquent field of the surgical
cavity at the end of the procedure.
On the other hand, taking advantage of the tendency of
GBs to displace white matter bundles as described in DTI
studies [26], perilesional resection of the tumor does not lead
to resection of white matter bundles unless they are very
close to the tumor. This is why this technique resulted as safe
in our series with a low rate of post-operative deficits. Moreover, accurate surgical planning with tractography can lead
us to better understand and estimate the distance between
the tumor and the functionally intact white matter. Starting
from the findings at the pre-operative MRI, it is possible to
plan what white matter zones are at risk of surgical damage. Moreover, intraoperative neurophysiological monitoring can also help to preserve eloquent white matter bundles
and to define the distances between the tumor bulk and the
white matter tract to be preserved (see Fig. 5). In particular,
in order to preserve motor function during the perilesional
resection, we found Raabe’s technique with dynamic mapping of corticospinal tract [27] useful.
13
Taking into consideration the findings ofiOUS in
patients that received a GTR, it was possible to see that
the iOUS was able to confirm histologically tumor free
margins in about 70% of cases and a perilesional infiltrating front in about 30% of cases. In none of these cases a
frankly tumoral zone was found. This finding confirmed
that US is a good intraoperative tool to check for tumor
remnants, as proposed in pediatric brain tumor surgery
[28]. In our series, 6 patients received a STR-PR due to
highly extensive GB or due to a very close proximity to
eloquent white matter bundles that were at risk of intraoperative injury even with resection under neurophysiological monitoring.
Limits of the perilesional technique The perilesional
approach shows two challenging difficulties: first, the surgeon has to find a boundary plane between the contrastenhancing (CE) tumor and the perilesional “healthy” brain;
second, the surgeon has to plan the surgery carefully so as
to avoid damage of eloquent white matter tracts that may
be displaced by the tumor in order to avoid a resection of
the perilesional plane with functionally important white
matter tracts. Moreover, in some cases, this approach may
not be feasible due to tumor location. For example, in the
case of purely insular GBs, it may be difficult to find a safe
perilesional plane due to the vicinity of the tumor to the
sylvian fissure and the small perforating branches of the
middle cerebral artery; or it may be difficult in the case of
thalamic gliomas due to the involvement of deep white matter bundles. In these cases, it may be possible to mix the two
techniques (central debulking or perilesional resection) in
accordance with the brain anatomy. From the perspective of
biopsy sampling, our study is in contrast with the results of
Journal of Neuro-Oncology
other similar studies, although this may be related tothe site
of sampling and with the small sample size of the biopsy.
Even if tumor resection may be completed with a perilesional technique, GB still has a poor prognosis due to a high
recurrence rate;in any case, some encouraging data regarding the benefits of supramarginal resection of GBs have been
published [9, 29]. Taking into account the paper by Molinaro
et al. about supramarginal resection [9], enbloc resection
of GBs might increase the chances to obtain an extensive
supramarginal resection since this technique may allow the
quick removal of the contrast-enhancing part of the tumor as
a first surgical step. At the same time, it allows the exposure
of the remaining perilesional tissue which may be removed
in a second surgical step with ultrasonic aspirator, iOUS
and intraoperative neurophisiological monitoring in order to
functionally navigate through “healthy” white matter and to
prevent the risk of neurological deficits. Moreover, analyzing
the results by Molinaro et al. elderly patients (over 65 years
of age) do not seem to benefit from the supramarginal resection making the perilesional resection a good surgical option
[9].On the other hand, according to the findings published
by the group of Quinones-Hinojosa, the EOR of the nonCE part of the tumor can improve survival even if it is less
important than the EOR of the CE part of the tumor [30].
Limits of the study
Our study has some limitations that encompass the small
number of patients included. Moreover, our results are in
contrast with other publications, and this might be related to
the size of the perilesional biopsy sample taken. The selection of the biopsy site was another bias of our study although
a random selection of the biopsy site was the main policy
when the surgical bed was considered not adjacent to eloquent areas. Biopsy selection site can be considered a bias
per se since sampling could not be performed in the same
way for all patients but it needed to be tailored in accordance
with tumor location. In any case, the absence of neoplastic
cells in the majority of the samples may indicate that the
sampling was performed far away from the central core.
Conclusion
The perilesional resection of GBs is an efficient technique
which aims to bring the surgeon to a safe environment,
reaching the “healthy” brain carefully before removing the
tumoren bloc. This technique is safe, and can lead to good
tumor margins, a good rate of extent of resection, and the
preservation of a patient’s functions with low rate of neurological deficits and complications. Moreover, in the oncological view of maximizing the saferesection of GBs beyond
the CE tumor boundaries, this technique can efficiently allow
the neurosurgeon to quickly expose the infiltrative FLAIR
hyperintense part of the tumor.
Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s11060-022-04232-z.
Author contributions CG., ADC., GB.: concept and first manuscript
drafting GC., GC.: manuscript revision PR., MAC., CBR.: radiological data collection, revision and analysis; figures GC., GS, CJ.,ADV.:
clinical and histopathological data collection and figures.
Funding Open access funding provided by Università degli Studi di
Milano - Bicocca within the CRUI-CARE Agreement. The authors
have not disclosed any funding.
Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on
reasonable request.
Declarations
Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that
could be construed as a potential conflict of interest.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article's Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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