Extraneural metastases of a cerebral glioma in a child: case report with literature review

Olga S. Regentova; Roman A. Parkhomenko; Oleg I. Shcherbenko; Fedor F. Antonenko; Natalya I. Zelinskaya; Nelly Sidibe; Pavel V. Polushkin; Andrey I. Shevtsov; Maria A. Bliznichenko; Valeria A. Deyanova; Vladimir A. Solodkiy

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South Russian

Journal of Cancer..

Vol. 5

No. 3, 2024

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South Russian

Journal of Cancer..

Vol. 5

No. 3, 2024

South Russian Journal of Cancer. 2024. Vol. 5, No. 3. P. 111-120

https://doi.org/10.37748/2686-9039-2024-5-3-10

https://elibrary.ru/pfvhlb

REVIEW

Extraneural metastases of a cerebral glioma in a child: case report with

literature review

O. S. Regentova1 , R. A. Parkhomenko1,2, O. I. Shcherbenko1, F. F. Antonenko1, N. I. Zelinskaya1,

N. Sidibe1, P. V. Polushkin1, A. I. Shevtsov1, M. A. Bliznichenko1, V. A. Deyanova1, V. A. Solodkiy1

1 Russian Scientific Center of Roentgen Radiology, Moscow, Russian Federation

2 RUDN University, Moscow, Russian Federation

olgagraudensh@mail.ru

ABSTRACT

Malignant gliomas make up 25 % of the central nervous system (CNS) tumors in adults and 8�15 % in children. About half of

such

gliomas

have

a

median

localization

and

are

designated

by the

term "diffuse

midline

gliomas"

(DMG). DMG in

children

are

typically localized in the area of the pons; in 78

% of such cases a heterozygous somatic mutation H3K27M is present. The

prognosis of H3K27M-mutant DSG is very unfavorable, with 2-year overall survival rate being less than 10 %. One of the ways of

progression of gliomas leading to the death of patients is the spread of the tumor in the form of metastases. Malignant gliomas

metastasize mainly into various structures of the CNS (according to autopsies � in about 20 % of patients with glioblastomas),

the probability of their metastases to other organs (so-called extraneural metastases), according to some evaluations, is quite

rare and doesn�t exceed 2 %. In our practice since 1993, which counts 1700 children with malignant gliomas, including 830

patients with DMG, we�ve observed only one patient with extraneural metastases. The article describes this case of a child

who died of the progression of the DMG�s extraneural metastases, despite the fact that chemoradiotherapy had achieved its

stabilization in the CNS. This patient with the initial lesion of the pons and cerebellum had massive metastasis to the lymph

nodes: supraclavicular, mediastinal, retroperitoneal

and inguinal

ones, as

well

as

to both pleural

cavities, which occurred about

one year after treatment of the progression, which had manifested in the form of continued growth of the primary tumor and

its dissemination in the central nervous system. The article provides literature data on the frequency, clinical manifestations

and possible treatment approaches for extraneural metastasis of brain gliomas. Extraneural metastases of those tumors occur

most often to the bones, lymphatic system, lungs, abdominal organs, soft tissues. The effective treatment for extraneural

metastases of gliomas has not been developed yet, which makes it urgent to solve this problem through multicenter studies.

Keywords: malignant glioma, brain, extraneural matastases, radiotherapy, chemotherapy

For citation: Regentova O. S., Parkhomenko R. A., Shcherbenko O. I., Antonenko F. F., Zelinskaya N. I., Sidibe N., Polushkin P. V., Shevtsov A. I., Bliznichenko

M. A., Deyanova V. A., Solodkiy V. A. Extraneural metastases of a cerebral glioma in a child: case report with literature review. South Russian Journal of

Cancer. 2024; 5(3): 111-120. https://doi.org/10.37748/2686-9039-2024-5-3-10, https://elibrary.ru/pfvhlb

For correspondence: Olga S. Regentova � Cand. Sci. (Med.), MD, head of Pediatric Radiation Oncology Department with beds for oncology patients, Russian

Scientific Center of Roentgen Radiology, Moscow, Russian Federation

Address: 86 Profsoyuznaya Street, Moscow 117997, Russian Federation

E-mail: olgagraudensh@mail.ru

ORCID: https://orcid.org/0000-0002-0219-7260

SPIN: 9657-0598, AuthorID: 1011228

Compliance with ethical standards: this research has been carried out in compliance with the ethical principles set forth by the World Medical Association

Declaration of Helsinki, 1964, ed. 2013. The study was approved by the Committee on Biomedical Ethics at the Russian Scientific Center of Roentgen

Radiology (extract from the protocol of the meeting No. 2 dated 09.12.2022). Informed consent has been received from all the participants of the study.

Funding: this work was not funded

Conflict of interest: the authors declare that there are no obvious and potential conflicts of interest associated with the publication of this article

The article was submitted 24.07.2024; approved after reviewing 15.08.2024; accepted for publication 25.08.2024

� Regentova O. S., Parkhomenko R. A., Shcherbenko O. I., Antonenko F. F., Zelinskaya N. I., Sidibe N., Polushkin P. V., Shevtsov A. I., Bliznichenko M. A.,

Deyanova V. A., Solodkiy V. A., 2024

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INTRODUCTION

Malignant gliomas are one of the most complex

and aggressive forms of neuro-oncological diseases.

Gliomas

of a

high

grade

of malignancy among all

tumors of the central nervous system (CNS) account

for up to 25 % in adults and 8�15 % in children. About

half of them in

childhood have

a median

localization

and are designated by the term "diffuse midline gliomas"

(DMG). In midline gliomas in children localized

in

the pontin area, a heterozygous

somatic mutation

H3K27M is noted in 78 % of cases. The prognosis of

H3K27M-mutant DMG is very unfavorable, with 2-year

overall

survival

rate being less

than

10

% [1�5].

One of the ways of progression of gliomas leading

to the death of the patient is the metastatic spread

of the tumor. Malignant gliomas metastasize mainly

into various structures of the central nervous system

(in about 20

%

of patients with glioblastomas

according to autopsies), the probability of their metastases

in other organs (so-called extraneural metastases),

according to some estimates, is very small

and doesn�t exceed 2

% [6, 7]. Extraneural metastasis,

although a rare phenomenon in diffuse midline

gliomas, is of critical importance in the context of

prognosis and further patient management tactics,

since it

can significantly worsen the quality of life

and reduce survival rate. The presented clinical case

highlights

the

need

for a

multidisciplinary approach

to the diagnosis and treatment of this pathology,

as well as makes the questions about the molecular

genetic mechanisms underlying the extraneural

spread of the tumor crucial. A review of the available

literature reflects current trends in research in this

field. When

compiling the

review, we

used Scopus,

MEDLINE, and Web of Science databases.

The study purpose was to describe the case of ex

traneural metastases of malignant glioma in a child

and compare it with the literature data, which will

allow us to outline the directions of further research

on this problem.

CASE REPORT

Patient N., 3.5 year old boy, began to have clubfoot

and developed wide base gait in 2021. He was consulted

by an orthopedist. The diagnosis was made:

flat-valgus

deformity of the feet. During the

following

month, there was a deterioration in gait in the form

of an increase in shakiness, he began to limp on his

left leg, began to stumble, and the motor skills of his

left hand deteriorated.

From the

anamnesis

of life: a

child

from IVF

pregnancy,

which proceeded without any abnormalities.

The delivery was urgent at 38 weeks. He was observed

by a neurologist for

perinatal central nervous

system damage, myotonic syndrome. Prior to the

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present disease, he suffered from acute respiratory

viral infections, right-sided purulent otitis media.

An MRI of the brain was performed on

08/03/2021: in the area of the Varolian bridge (mainly

in its left half) with extension to the left pedicle

and hemisphere of the cerebellum, an extensive

zone of diffuse signal change was visualized, hyperintensive

on T2, FLAIR, iso-hypointensive on T1,

with linear restriction of diffusion along the periphery,

without contrast enhancement, with the presence

in the hemisphere cerebellar areas of cystic transformation.

The bridge of the brain, the pedicle and

the hemisphere of the cerebellum were enlarged in

volume, with compression and displacement of the

IV ventricle laterally to the right, displacement of the

left amygdala of the cerebellum caudal to the level of

the foramen magnum, displacement of the medulla

oblongata ventrally;

along the anterior

surface of the

bridge was an exophytic component with compression

of the prepontine cistern, fouling of the main

artery. Conclusion: the picture of a diffuse lesion of

the brain stem, the left hemisphere of the cerebellum,

which

may correspond

to a

diffusely growing

glial

tumor

(fibrillar

astrocytoma? anaplastic

astrocytoma?),

with signs of mass effect, descending axial wedging,

occlusive internal hydrocephalus.

Neurological status on 08/04/2021:

one-time vomiting

occured, meningeal symptoms were negative, pupils,

eye slits were symmetrical, there was no violation of

the volume of movement and position of the eyeballs,

deviations of the head and tongue, phonation and swallowing

disorders; there

was

horizontal

fine nystagmus

when looking to

the sides;

tendon reflexes D <

S, left

Achilles reflex with clonus;

superficial and deep muscle

sensitivity was preserved;

gait was atactic,

with a wide

base

of support; the finger-nasal

test

with

pronounced

intention; in the Romberg pose

was

unstable, fell.

Ultrasound of the abdominal cavity and kidneys

on

08/04/2021: no pathological

signs

were

detected.

Chest

X-ray (in

the

posterior direct

projection, lying

position) on 08/04/2021: reduction of pneumatiza

South Russian Journal of Cancer 2024. Vol. 5, No. 3. P. 111-120

Regentova O. S. , Parkhomenko R. A., Shcherbenko O. I., Antonenko F. F., Zelinskaya N. I., Sidibe N., Polushkin P. V., Shevtsov A. I., Bliznichenko M. A., Deyanova V. A.,

Solodkiy V. A. Extraneural metastases of a cerebral glioma in a child: case report with literature review

tion with increased pulmonary pattern in the projection

of the medio-basal sections of both pulmonary

fields

was

noted. Conclusion: hypostatic changes

in the lungs.

He started on decongestant therapy with dexamethasone

on 08/04/2021. During the treatment of the

treatment, the general cerebral symptoms regressed,

and status-coordination disorders persisted. MRI of

the brain and spinal cord (native and with contrast

enhancement)

08/12/2021: in

addition

to the

MRI data

from 08/03/2021, there were no signs of metastasis in

the structures of the central nervous system.

The patient's mother refused the stereotactic

biopsy or partial removal of the tumor offered by

the neurosurgeon. Consultation by a radiologist revealed:

considering the anamnesis data,

MRI signs,

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the patient's age, the unresectable nature of the

tumor, conformal radiation therapy was indicated.

Surgical intervention was performed in the volume

of installation of a ventricular-peritoneal shunt

(VPS)

on 09/06/2021. From 09/08/2021 to 10/18/2021, he

received a course

of radiation

therapy to the

area of

the initial lesion in hyperfractionation mode (single

focal

dose of 1

Gy 2

times

a day with

an

interval

between

fractions

of 4

hours, 5

days

a

week), total

dose of 54 Gy. Since November 2021, he has

been under dynamic observation. PET/CT scan of

the brain on 11/29/2021 revealed: the PET

picture,

together with the MRI results, corresponded to the

features of diffuse glioma of the brain stem and left

hemisphere of the cerebellum with low amino acid

uptake (without PET signs of anaplasia). At the end

of April 2022, after acute respiratory viral infection,

bilateral purulent otitis media and sinus thrombosis

developed.

30.05.2022 MRI of the central nervous system

(native and with contrast enhancement):

the picture

of multidirectional dynamics was noted: stabilization

of tumor growth of the brain stem and the left

hemisphere of the cerebellum, negative dynamics in

the form of metastatic lesions along the ventricular

system and spinal cord.

Surgery was performed on 06/17/2022 with a VPS

revision. A stereotactic biopsy of a tumor of the lateral

ventricle was performed on 06/24/2022. Histological

and immunohistochemical examination

on 06/24/2022

showed: tumor cells express GFAR,

OLIG2, vimentin, focally S100. There was a reaction

with anti-NF in numerous axons, which indicated

a diffuse type of tumor

growth.

Single cells were

weakly positive with anti-p53. CD34 expression was

only in the vascular endothelium. The proliferative

index of Ki-67 reached 60�70 %, focally higher.

From 07/08/2022 to 08/16/2022, radiation therapy

was performed in the volume of craniospinal

irradiation, single radiation dose of 1.6 Gy, total dose

of 35.2 G. From 08/08/2022 to 08/10/2022, total

dose was increased to 40.0 Gy for the entire volume

of the spinal cord, in parallel from 08/08/2022

to 08/16/2022, a boost was performed on the area

of the ventricles of the brain, single radiation dose

of 1.8 G, total dose of 46 Gy. Simultaneously with

the course of radiation, he received chemotherapy

with temozolomide 75 mg/m2 daily as monotherapy.

A molecular study under the

One Foundaion

program

revealed amplifications: PDGFRA, MDM4, PIK3C2B,

as well as ATM � R3008C. Considering the

revealed amplification of PDGFRA, the patient was

offered imatinib therapy, which was not carried out

for organizational reasons. According to the control

MRI data, there

was

a positive

dynamics

of tumor foci

in the central nervous system, with further stabilization.

From September 2022

to June 2023, 8

courses

of temozolomide monotherapy were performed. After

that, treatment was interrupted due to the development

of an acute respiratory viral infection.

Since mid-July 2023, the mother began to notice

that the child was limping on his left leg. CT scans

of the organs of the thoracic cavity, abdominal cavity

and pelvis (native and with contrast enhancement)

revealed conglomerates of lymph nodes of the supraclavicular,

subclavian region on the right, anterior

thoracic wall, paraaortic group at the infrarenal level

with spread to

the inguinal canal on the left;

massive

right-sided pleural

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effusion; left-sided pleural

effusion; pyelocalicectasia on

the

left, decreased

function of the left kidneys. Considering the obtained

data, the presence of a systemic disease, lymphoma,

was suspected at this point. MRI of the central

nervous system showed stabilization of the size of

tumor foci compared to previous studies.

In August 2023, the child underwent a pleural

puncture,

as well as a puncture biopsy of the bone

marrow with its morphological examination and immunophenotyping:

data for systemic

blood disease

were not received. A

tumor

population of cells was

detected in the pleural fluid, which, according to

immunophenotyping data, did not express mark

��-�� 2024. �. 5, � 3. �. 111-120

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ers specific

to

lymphoproliferative diseases. On

08/21/2023, a biopsy of the inguinal lymph node

was performed, its histological examination from

09/01/2023 revealed signs of

a malignant tumor

with a glial phenotype. Conclusion: extraneural

metastasis

of the primary tumor of the central nervous

system could not be excluded. Protocol of immunohistochemical

examination dated 09/01/2023 of in

guinal lymph node tissues:

neoplastic

cells diffusely

expressed OLIG2, H2K27me3, CD56, SOX-10, INI1.

Subtotal expression of NKX2.2, GFAP, vimenin was

detected. Weak focal expression of NSE, FLI1, S100,

cyclin D1. Tumor cells were negative in reactions

with antibodies to panCK, EMA, TLE1, WT1, SMA,

mean-A, BCOR, ERG, synapophysin, myogenin, p53,

chromogranin A, TdT, desmin, CD20, CD3, CD99,

MSA. Protocol of molecular genetic research dated

09/01/2023: during the

FISH

study, no amplification

of the N-MYC gene, deletion of the SRD (1p36) gene,

deletion of the KMT2A (MLL) gene, rearrangements

of the FOXR2 gene, translocation of the EWSR1 gene

were found.

Palliative irradiation of tumor conglomerates in

areas of extraneural metastases was proposed, but

the patient did not come for this treatment. He died

on 01/11/2024 on the background of the progression

of extraneural metastases.

DISCUSSION AND LITERATURE REVIEW

The patient case reported above with an initial

lesion of the pons and cerebellum (DMG) had massive

metastases

to the

lymph

nodes: supraclavicular,

mediastinal, retroperitoneal, inguinal, as well

as to both pleural cavities, which occurred about

one year

after

treatment of progression, which had

manifested in the form of continued growth of the

primary tumor and its dissemination in the central

nervous system. It is not surprising that before biopsy

and molecular genetic studies, the development

of a second tumor,

including lymphoma, was

not ruled out. It is noteworthy that at the stage of

diagnosis

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of the

progression

of DMG, a stereotactic

biopsy was performed, which, of course, was necessary

to clarify the diagnosis, nevertheless, could

potentially contribute to the spread of the tumor, as

indicated by some publications listed below. At the

initial diagnosis in 2021, before the start the special

treatment, the patient underwent a complete exam

ination, including ultrasound of the abdominal cavity,

kidneys, chest X-ray, according to which no signs of

extraneural metastases were detected.

The first extraneural metastasis of glioblastoma

was described by Davis L. back in 1928. He called it

"spongioblastoma." The primary tumor in the 31-yearold

patient was localized in the left hemisphere of

the brain. Histologically confirmed metastases developed

in the soft tissues of the upper limb and in

the scapular region on the right, as well as in the left

lung;

they appeared approximately 5.5 months after

partial removal of the primary tumor [8].

Pietschmann S et al. (2015) analyzed 109 articles

and abstracts published in English or German

for the period from 1928 to 2013 (85 years), which

reported a total of 150 patients with extraneural

metastases of malignant gliomas of the brain. It is

noteworthy that more than half of the publications

they analyzed (describing 95 cases) were made after

1993. The age of patients at the initial diagnosis

ranged from 4 to 83 years (median 42 years). There

were only four

children (under

the age of 18) in this

combined cohort. The majority of patients had

a pathomorphological

diagnosis

of glioblastoma

(137, that is, 91.3 %), the remaining 13 (8.7 %) had

gliosarcoma. The time from the initial diagnosis to

the detection of extraneural metastases from these

publications was accurately determined for 71 patients.

Of these, 7

(that

is, one in ten)

had a primary

tumor and metastases diagnosed simultaneously.

Taking into account these patients, the period

from the diagnosis of glioblastoma or gliosarcoma

to the detection of metastases ranged from 0 to

81 months (median 9 months). The localization

of metastases

was

diverse: in

52

cases

they developed

in the organs of the chest (including in 45

patients � in the lungs), in 31 cases in the organs

of the abdominal cavity and retroperitoneal space

(including in 23 patients � in the liver). In addition,

metastases to bone or bone marrow were described

in 53 patients, to lymph nodes in 51, to muscles and

other soft tissues in 35, to skin in 11, to thyroid and

parathyroid glands in 6, to other organs (including

eyes

and

mammary glands)

in

4. A significant

proportion

patients had several localizations of metastases.

In

the

publications

included in

this

review [9],

a sufficient description of treatment after detection

of metastases was provided for 60 out of 150 patients

(40 %), in the rest, treatment was either not

South Russian Journal of Cancer 2024. Vol. 5, No. 3. P. 111-120

Regentova O. S. , Parkhomenko R. A., Shcherbenko O. I., Antonenko F. F., Zelinskaya N. I., Sidibe N., Polushkin P. V., Shevtsov A. I., Bliznichenko M. A., Deyanova V. A.,

Solodkiy V. A. Extraneural metastases of a cerebral glioma in a child: case report with literature review

reported or it did not include antitumor methods.

Twenty-nine patients after the detection of metas

tases were treated with any one antitumor method:

17 of them underwent surgery, 4 had radiation and

8

had

chemotherapy. In

31

patients

in

such

a

situation,

various combinations of these methods were

used, most often: chemotherapy + radiotherapy

(in 15) and surgery + chemotherapy + radiotherapy

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(in 10). In this review

[9], it was noted that extraneural

metastases of malignant glial tumors are more

often found in relatively young people, which can

serve as one of the arguments for the use of active

antitumor treatment in them. However, the authors

did not reveal a clear increase in survival with such

treatment tactics. Overall survival in extraneural

metastases was slightly better than survival in CNS

metastases, although this difference did not reach

the

confidence

limit. The

authors

were

unable

to

formulate any

specific

recommendations for

the

treatment of patients with extraneural metastases

of malignant glial tumors, since in the combined cohort

analyzed by them, treatment was very diverse

and

selected

individually [9].

Of high

interest

is

the

work

of De

Martino

L. et

al,

2023

[10], which describes the authors' own observation

of two children with extraneural metastases of

diffuse midline gliomas. In one of them, an 11-yearold

boy, diffuse midline bridge glioma was confirmed

by stereotactic biopsy. Loss of H3K27me3 and expression

of a protein associated with H3K27M mutation

were

detected in

tumor cells. At

the first

stage

of treatment, the patient underwent induction chemotherapy

with vinorelbine and nimotuzumab, followed

by irradiation of the tumor zone in the mode of conventional

fractionation, total dose 54

Gy (according

to the VMAT method). 5 months after diagnosis, CT

and MRI scans revealed extensive metastasis to the

soft meninges of the brain and spinal cord, as well

as

extraneural

metastases: in

the

sternum, vertebrae

and pelvic

bones.

Bone metastases were confirmed

by examining a biopsy of the left iliac

bone. He died

a month

later. The

second patient, a girl

of the

same

age, was diagnosed with median glioma in the region

of the IV ventricle with the H3K27M mutation. Total

resection of the tumor was performed, the diagnosis

was confirmed on the basis of histological and molecular

genetic examination of its tissue. As in the

first

patient, after chemotherapy with

vinorelbine

and

nimotuzumab, she underwent local radiation ther

apy (total dose 54 Gy, VMAT technique). However,

3 months after the end of the course of treatment,

she was diagnosed with progression in the area of

the original tumor, as well as in the ependyma of

the ventricles of the brain and its soft membranes.

Craniospinal irradiation (CSI) was performed in the

mode of classical fractionation, total dose 36 Gy,

followed by 15-month chemotherapy with irinotecan

and bevacizumab. After completion of CSR,

according to MRI data, a partial response of tumor

foci in the brain was detected, however, signs of me

tastases in the vertebrae appeared. CT scan of the

whole body made it possible to detect osteosclerotic

foci not only in the spine, but also in the ribs,

sternum, pelvic bones, in both shoulder and femur

bones. PET/CT with 18F-FDG revealed foci of mod

erate hyperfixation in the bones, however, repeated

biopsies of these foci did not reveal metastases.

Subsequently, she

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developed a lesion

of a large

number

of intra-thoracic and abdominal lymph nodes, as

well as pleural effusion, the study of which by drip

digital polymerase chain reaction revealed a mutation

H3.3A (c.83A>T, p.K28M), although cytological

examination of pleural effusion of tumor cells did not

detect. The patient died 2 years after the diagnosis of

median glioma, that is, 3 months after the detection

of pleural effusion. The authors of the description

of these two patients, while studying the medical

literature, found

publications

about

12

similar patients:

their age

ranged

from 4

to 36

years, the

localization

of extraneural relapses was diverse: bones,

lymph nodes, lungs, pleural cavity, liver, peritoneum,

muscles. One of these patients had abdominal metastasis

due to the spread of tumor cells along the

ventriculo-peritoneal

shunt

[11]. It

is

noteworthy that

the descriptions of 12 cases collected in the mentioned

review by De Martino L et al. (2023), were

published no earlier than 2014, that is, starting from

the time when the concept of "diffuse midline glioma"

was formed. The authors of this review express

concern that, probably, the frequency of ectraneural

metastases in patients with diffuse midline gliomas

is underestimated, since they are not routinely examined

to identify such metastases. The article points

to the possibility of increasing the risk of extraneural

metastases in connection with surgical interventions

on primary tumors. The following expressed in the

article may explain why extraneural metastases are

rare in malignant gliomas. Probably, outside the

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central nervous system, glioma cells are most often

destroyed by the immune system, and in the brain

these cells

are protected, being in

a microenvironment

favorable them. This hypothesis is confirmed

by descriptions of cases of extraneural glioblastoma

metastases in patients who had previously under

gone organ transplantation [12, 13].

The literature review made in the mentioned article

by De

Martino L et

al. [10], did

not

include

the

work

of Chinese

researchers

Ge

X et

al

[5], which

describes

the development of extraneural metastases

of diffuse median glioma of the brain stem region in

a 9-year-old boy. His

primary tumor was

diagnosed

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based on CNS MRI data followed by stereotactic

biopsy. The histological picture corresponded to

anaplastic astrocytic glioma (grade IV malignancy

according to World Health Organization (WHO)),

immunohistochemical examination revealed a protein

formed by the H3K27M mutation. Initially, there

was no dissemination in the brain and spinal cord.

Due to hydrocephalus, ventriculo-peritoneal bypass

surgery was performed. The patient underwent local

irradiation of the tumor area, total dose 50 Gy for

25 fractions with simultaneous of chemotherapy

with

temozolomide

at

a

daily dose

of 75

mg/mg2.

A

month after

the end of irradiation,

MRI showed

a

slight

decrease

in

tumor volume. The

patient

received

adjuvant

chemotherapy with

temozolomide:

5 cycles of 5 days, every 28 days, the daily dose of

this drug was 150 mg/mg2 in

the first

cycle, 200

mg/m2 in all subsequent cycles. 2

months after

the end of chemotherapy, the patient complained

of lowering of the right corner of the mouth, as

well as back and lumbar pain. MRI revealed the

progression of the primary tumor, dissemination

in the spinal cord and along the soft meninges, as

well as foci of destruction of the lumbar and sacral

vertebrae with pathological contrast enhancement.

PET-CT

revealed

a

diffuse

increase

in

metabolism

in the cervical, thoracic and lumbosacral spine. The

patient soon developed neck pain and urinary retention.

Despite an attempt at chemotherapy (one

cycle with vincristine and cyclophosphamide), no

improvement was achieved, and the patient died

1 month after the detection of tumor metastases.

The authors of all the above publications emphasize

that effective treatment programs for patients

with extraneural metastases of malignant gliomas

of the central nervous system have not yet been de

veloped. This is due to both the relative rarity of such

cases and their severity. Therefore, at least isolated

reports that indicate the possibility of prolonging the

life of such patients are so valuable.

As an example of such an observation, one can cite

the description of the case made by

Yang G et al [14].

Initially, an MRI scan revealed a tumor

lesion of the

right temporal and occipital lobes in the form of several

nodes in a 58-year-old man. In the tissue of a totally

removed tumor, histological examination revealed

signs of glioblastoma with areas of oligodendroglioma.

After the combined treatment (surgery, local

radiation therapy, total dose 60 Gy in conventional

fractions and chemotherapy with temozlolomide), no

tumor remnants were observed according to MRI.

However, six

months

after the

end

of treatment, a

local

relapse was detected, repeated radiation therapy

was performed to its area, total dose 30 Gy in five

fractions and several cycles of bevacizumab. It was

possible to achieve a partial response and an improvement

in the quality of life. However, after 2 years, while

there was stabilization of tumor foci in the brain, multiple

histologically confirmed metastases

were

found

in the right lung, and then in the bones. Since PD-L1

expression was detected in lung metastasis tissue,

and a slight increase in lung foci was noted during

treatment with bevacizumab and temozolomide, it

was decided to add pembrolizumab to the treatment.

5

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cycles

were

performed

with

this

drug. As

a

result,

a partial response was noted in the lung,

with a stable

state of tumor tissue in the brain. Temozolomide was

discontinued due to fatigue syndrome and lack of

methylation

of the

MGMT

promoter in

tumor tissue;

treatment with bevacizumab and pembrolizumab continued.

However, after a few months, bone metastases

developed, but the patient continued to receive the

same treatment due to the lack of any alternatives

at the disposal of his doctors. The progression of

metastases continued. However, the authors believe

that these drugs allowed to slow down this process.

As

a result, the patient

lived quite a long time after

the

diagnosis

of pulmonary metastases: 27

months,

while

in a series

of patients

with glioblastoma extraneural

metastases

published by Noch EK et al [15],

the average life expectancy after their detection was

5 months (from 1 to 16 months), it is noteworthy that

pembrolizumab was not used in them.

Undabeitia J et al [16] describe a case of extraneural

glioblastoma metastases in a 20-year-old

South Russian Journal of Cancer 2024. Vol. 5, No. 3. P. 111-120

Regentova O. S. , Parkhomenko R. A., Shcherbenko O. I., Antonenko F. F., Zelinskaya N. I., Sidibe N., Polushkin P. V., Shevtsov A. I., Bliznichenko M. A., Deyanova V. A.,

Solodkiy V. A. Extraneural metastases of a cerebral glioma in a child: case report with literature review

patient. The primary tumor was localized in the right

temporal region of the brain; its total removal was

performed, followed by chemoradiotherapy. Metastases

to both lungs and pleural cavities, as well as

to the pancreas and vertebrae, occurred 5 months

after surgery. Lung metastases were in the form of

infiltrations,

and they were confirmed by biopsy. Chemotherapy

with irinotecan and bevacizumab was

attempted, but the patient died.

In

the

case

report

by Kim

A.

V. et

al. a 16-year-old

patient is described, whose glioblastoma was initially

localized in the left parietal lobe of the brain. 6

months after the operation, supplemented by local

radiation and chemotherapy, it metastasized to the

V cervical vertebra, which was confirmed by histological

and immunohistochemical examination of

the tissue of this vertebra [17].

Razmologova

O.

Yu. and Sokolova

T.

V. reported

a case of glioblastoma metastases

in

the lungs

at

autopsy in a 64-year-old patient who died shortly

after surgery on glioblastoma of the left parietal lobe

of the brain. These

metastases

were

confirmed by

immunohistochemical method with determination

of glial fibrillary acid protein expression [18]. A similar

patient was described by Zhetpisbaev

B. and

Isakhanova

B.: a 53-year-old man underwent partial

removal of

a tumor

from

the temporal lobe of

the

right hemisphere, in the postoperative period there

was

a deterioration in the condition in the form of

depression of consciousness, unstable hemodynamics,

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the patient died. Histological examination of the

removed tumor tissue revealed glioblastoma. While

examining the left lung, a tumor

focus was accidentally

discovered, which, according to histological and

immunohistochemical studies, corresponded to glioblastoma

metastasis [19].

The information we have provided on the problem

of extraneural metastases of brain gliomas is based

on

two major reviews

[9

and 10] and descriptions

of

individual cases that were not included in them. In

the last 20�30 years, there has been an increasing

trend in the number of such publications. This can be

explained by the improvement of various components

of neuro-oncology, especially pathomorphology and

diagnostic radiology. In addition, the development

of surgical techniques, radiation therapy and drug

treatment

gives

patients

a

chance

to prolong their

life span, during which such metastases can manifest.

Despite the relative rarity of the occurrence of

extraneural metastases in patients with malignant gliomas,

there is still reason to believe that evaluations

of their frequency are underestimated. Apparently,

they remain unrecognized in many patients during

tumor progression in the central nervous system, nevertheless,

exacerbating the severity of the disease.

The validity of this assumption is confirmed by the

cases of occult metastases in the lungs [18 and 19].

CONCLUSION

In summary, extraneural metastases of malignant

gliomas of the brain are rare, but their probability

should be taken into account both when making

an initial diagnosis and during subsequent control

examinations, especially in patients who have undergone

various surgical interventions on tumors or

bypass operations. Despite the steadily increasing

number of publications on this topic, there is still no

accurate information about the frequency of such

metastases, about the optimal ways of their early

diagnosis, and effective therapeutic tactics have

not been developed in case of their occurrence. In

addition, the reason for the rarity of extraneural metastases

in CNS tumors is not clear; a meticulous

study of this issue could shed light on aspects of

the pathogenesis of these tumors, and therefore

open up new directions for their therapy. To solve

these problems, multicenter studies involving the

efforts of the leading neuro-oncological clinics are

highly needed.

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�., ��

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�., ��

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�., ��

�.

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��

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�., ��

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�. �� : ��

� ��

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Accessed:

19.08.2024.

Information about authors:

Olga S. Regentova � Cand. Sci. (Med.), MD, head of Pediatric Radiation Oncology

Department with beds for oncology

patients, Russian Scientific

Center of Roentgenoradiology, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0002-0219-7260, SPIN: 9657-0598, AuthorID: 1011228

Roman A. Parkhomenko � Dr. Sci. (Med.), MD, leading researcher at the Laboratory

of Radiation Therapy

and complex methods

of cancer

treatment, Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; Professor of the Department of Oncology and Radiology,

RUDN Medical Institute, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0001-9249-9272, SPIN: 9902-4244, AuthorID: 702112, Scopus Author ID: 6603021483

South Russian Journal of Cancer 2024. Vol. 5, No. 3. P. 111-120

Regentova O. S. , Parkhomenko R. A., Shcherbenko O. I., Antonenko F. F., Zelinskaya N. I., Sidibe N., Polushkin P. V., Shevtsov A. I., Bliznichenko M. A., Deyanova V. A.,

Solodkiy V. A. Extraneural metastases of a cerebral glioma in a child: case report with literature review

Oleg

I.

Shcherbenko

�

Dr.

Sci.

(Med.),

MD,

Chief

scientific

officer

at

the

Laboratory

of

Radiation

Therapy

and

complex

methods

of

cancer

treatment,

Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0003-0786-5448,

SPIN: 9818-9276, AuthorID: 485883

Fedor

F.

Antonenko

�

Dr.

Sci.

(Med.),

MD,

Professor,

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corresponding

member

of

RAS,

Head

of

the

Laboratory

of

Radiation

Therapy

and

complex

methods of cancer treatment, Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0001-5900-6755,

SPIN: 6582-8081, AuthorID:

261007, Scopus

Author ID: 6602615840

Natalya

I.

Zelinskaya

�

Cand.

Sci.

(Med.),

MD,

senior

researcher

of

the

Laboratory

of

Radiation

Therapy

and

complex

methods

of

cancer

treatment,

Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation

ORCID: https://orcid.org/0009-0000-5380-2056,

SPIN: 4092-4845, AuthorID: 123005

Nelly

Sidibe

�

Cand.

Sci.

(Med.),

MD,

radiation

oncologist

of

pediatric

radiation

oncology

department

with

oncology

sickbeds,

Russian

Scientific

Center of Roentgenoradiology, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0002-5556-0166, SPIN: 3660-6207, AuthorID: 1108540

Pavel

V.

Polushkin

�

Cand.

Sci.

(Med.),

MD,

researcher

of

the

Laboratory

of

Radiation

Therapy

and

complex

methods

of

cancer

treatment,

radiation

oncologist of pediatric radiation oncology department with oncology sickbeds, Russian Scientific Center of Roentgenoradiology, Moscow, Russian

Federation

ORCID: https://orcid.org/0000-0001-6661-0280,

SPIN: 7600-7304, AuthorID: 1099115

Andrey

I.

Shevtsov

�

Cand.

Sci.

(Med.),

MD,

radiation

oncologist

iНе можете найти то, что вам нужно? Попробуйте сервис подбора литературы.

of

pediatric

radiation

oncology

department

with

oncology

sickbeds,

Russian

Scientific Center of Roentgenoradiology, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0002-4539-5187,

SPIN: 5605-6768, AuthorID: 996411

Maria A. Bliznichenko � MD, clinical resident doctor of Pediatric Radiation Oncology Department with beds for oncology patients, Russian Scientific

Center of Roentgenoradiology, Moscow, Russian Federation

ORCID: https://orcid.org/0009-0007-4300-5759

Valeria A. Deyanova � MD, clinical resident doctor of Pediatric Radiation Oncology Department with beds for oncology patients, Russian Scientific

Center of Roentgenoradiology, Moscow, Russian Federation

ORCID: https://orcid.org/0009-0001-1203-2195

Vladimir

A.

Solodkiy

�

Dr.

Sci.

(Med.),

MD,

Professor,

Academician

of

RAS,

Director,

Russian

Scientific

Center

of

Roentgen

Radiology,

Moscow,

Russian Federation

ORCID: https://orcid.org/0000-0002-1641-6452,

SPIN: 9556-6556, AuthorID: 440543, ResearcherID: T-6803-2017, Scopus Author ID: 57193878871

Contribution of the authors:

Regentova O. S. � performed development of the research design, critical revision with the introduction of valuable intellectual content, final approval

of the published version of the manuscript, writing the text of the manuscript;

Parkhomenko R. A. � performed development

of

the

research design,

review of

publications on the

topic of

the

article,

writing the

text

of

the manuscript;

Shcherbenko O. I. � performed development

of

the

research design,

review of

publications on the

topic of

the

article,

writing the

text

of

the

manuscript;

Antonenko F. F. � review of publications on the topic of the article;

Zelinskaya N. I. � review of publications on the topic of the article;

Sidibe N. � review of publications on the topic of the article, technical editing;

Polushkin P. V. � review of publications on the topic of the article, technical editing;

Shevtsov A. I. � review of publications on the topic of the article;

Bliznichenko M. A. � review of publications on the topic of the article;

Deyanova V. A. � review of publications on the topic of the article;

Solodkiy V. A. � performed development of the research design, final approval of the published version of the manuscript.

Extraneural metastases of a cerebral glioma in a child: case report with literature review Текст научной статьи по специальности «Клиническая медицина»

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