Keywords
extra-axial - extracranial - recurrence - IDH mutant - glioma - metastases - astrocytoma
Introduction
Astrocytoma is a diffuse glial tumor with isocitrate dehydrogenase (IDH) mutant status
and can be graded between the World Health Organization (WHO) grades 2 and 4.[1]
[2] The IDH mutant status confers a better prognosis than its wild-type counterpart.[3] Upfront treatment with surgery and radiation is preferred in view of the high risk
of recurrence and transformation. Most recurrences are generally within the radiation
field, remote recurrence being uncommon.[4]
[5] Here, we present a case of grade 3 astrocytoma, post-treatment, with simultaneous
transformation into higher grade and remote intracranial recurrence as an extra-axial
lesion. This has not been reported previously, to the best of our knowledge.
Case Report
A 46-year-old male patient was diagnosed with a left parietal space-occupying lesion
extending to the peritrigonal area, splenium of the corpus callosum, and the left
occipital lobe. He underwent surgical resection for it, and histopathology revealed
an astrocytic IDH and TP53 mutant, the WHO grade 3 tumor with loss of Alpha-thalassemia/mental
retardation, X-linked (ATRX) gene. Subsequent postoperative magnetic resonance imaging
(MRI) showed the presence of residual disease for which he received radiation therapy
(RT) and adjuvant temozolomide (TMZ). After 1 month, post-RT imaging showed some residual
disease in the form of T2 intermediate areas. Considering IDH mutant status, it was
decided to continue TMZ ([Fig. 1A] and [B]).
Fig. 1 (A and B) Axial T2-weighted and post-contrast T1-weighted images showing diffuse infiltrating
lesion in the parieto-occipital lobe, extending up to the splenium of the corpus callosum
(white arrow) and the trigone of the left lateral ventricle. (index scan). No suspicious
enhancement is present.
Post 11 cycles of chemotherapy, he presented to the emergency services with vomiting,
altered sensorium, and right-sided hemiparesis. MRI at the time showed a new onset
large extra-axial predominantly cystic lesion with a peripheral papillary solid component
in the left high frontal region ([Fig. 2A–C]). The index tumor bed was stable. The cystic component was T1 hyperintense, and
T2 hypointense (features of subacute blood on MRI), which made us consider the possibility
of a subpial hematoma. Adjacent sulcal hyperintensity on T1-weighted images was seen,
raising suspicion of cerebral venous thrombosis (CVT). The other differentials proposed
were intracranial recurrence of the primary tumor, extra-axial recurrence, and a remote
possibility of a collision tumor with associated tumor bleed.
Fig. 2 (A–C) Axial T2-weighted, post-contrast T1-weighted, and sagittal T1-weighted images post-radiation
therapy and 11 cycles adjuvant chemotherapy showing new onset large extra-axial predominantly
cystic lesion with a peripheral enhancing papillary solid component in the left high
frontoparietal region (arrowhead). The index tumor bed showing no new lesion. The
cystic component is T1 hyperintense and T2 hypointense. Adjacent sulcal hyperintensity
is noted on the T1 weighted image.
The patient improved on conservative management with antiedema measures. Post a multidisciplinary
tumor board discussion, it was planned to observe the patient and continue TMZ. However,
a follow-up MRI after 4 weeks showed an increase in the lesion size ([Fig. 3A–C]). Hence, surgical resection of the lesion was done. Intraoperatively, an extra-axial
lesion was noted ([Fig. 4A, B]). The histopathology revealed a high-grade infiltrating (IDH-mutant) astrocytic
tumor, central nervous system WHO grade 4, with loss of ATRX ([Fig. 5A, B]). This suggests the same histomorphological features as the primary tumor with progression
to a higher grade.
Fig. 3 (A–C) Axial T2-weighted, post-contrast T1-weighted, and sagittal T1-weighted images post
4 weeks (on observation) showing an increase in the size of lesion and mass effect
with cystic component now being T1 hyperintense and T2 intermediate.
Fig. 4 (A) Intraoperative photograph of the tumor membrane (capsule) stuck to the normal brain.
(B) Solid component of the tumor along with the capsule stuck to the normal brain (white
arrow).
Fig. 5 (A, B) Hematoxylin and eosin stain low power (10x) and high power (40x) images of the resected
lesion showing tumor cells.
Postoperative scan 1 month later showed resection cavity with no other suspicious
enhancement or lesion ([Fig. 6A, B]). Adjuvant RT was also given to the postoperative bed. Five months post-surgery,
the patient developed back pain, for which MRI of the spine with screening of the
brain was done. This revealed nodular pachymeningeal enhancement along the right temporal
lobe and the periorbital dura along the left temporal convexity ([Fig. 7A, B]). Also noted were altered signal intensity lesions in the dorsolumbar vertebral
bodies ([Fig. 8A–C]). These findings in the given setting were suspicious for metastases, and a biopsy
from the vertebral body lesions was planned. However, the patient worsened clinically
and eventually succumbed to the disease. Hence, a pathological confirmation was not
possible.
Fig. 6 (A, B) Postoperative (1 month) axial T2-weighted and post-contrast T1-weighted image showing
surgical bed with gross total resection of the lesion. No suspicious lesion is noted.
Fig. 7 (A, B) Post-contrast T1-weighted images (5 months post-surgery) showing nodular pachymeningeal
enhancement along the right temporal lobe, the left frontotemporal lobe, and the periorbital
dura along the left temporal convexity (arrowheads).
Fig. 8 (A–C) Sagittal T2-weighted and post-contrast sagittal T1-weighted images (5 months post-surgery)
showing altered signal intensity enhancing lesions in multiple vertebral bodies (arrows).
Given the clinical features and imaging findings, we conclude this to be likely due
to disseminated disease. Thus, the case demonstrated both extra-axial and extracranial
recurrence.
Discussion
IDH mutant astrocytomas generally show increased progression-free survival compared
with de novo glioblastoma (IDH wild type). The standard of care currently is maximal
safe surgical resection and concurrent chemoradiation. Most of the patterns of failure
and recurrence post-therapy are within the gross tumor volume.[6] Malignant degeneration of IDH mutant tumors has been observed with acquisition of
additional genetic mutation and transformation into higher grade.[7]
TP53 mutant IDH mutant gliomas can show recurrence in remote intracranial regions.[8] The underlying pathogenetic mechanisms are not well understood. Nakae et al[4] have proposed the role of 8q gains and ability for interlobar metastases. Also hypothesized
is tumor migration through the tracks of major fiber bundles.[4]
Extra-axial tumors include a spectrum of tumors involving the extra-parenchymal tissue,
the majority of which have meningeal origin. The most common are meningiomas, which
demonstrate broad-based dural contact and the “dural tail sign.”[9] In contrast, gliomas are generally intra-axial. When they extend to involve the
dura, they may show features similar to meningiomas, including the dural tail sign.[10] This is common in peripheral glioblastomas.[11] The “cerebrospinal fluid (CSF) cleft sign” may help differentiate intra-axial and
extra-axial tumors, being positive in extra-axial tumors.[12] However, utility is limited in malignant meningiomas where it becomes difficult
to distinguish the location.
There have been case reports of primary extra-axial gliomas.[10]
[11]
[13]
[14] However, an extra-axial, remote intra-cranial recurrence of an IDH mutant glioma
has yet to be reported in our search of existing literature. In the present case,
due to the unlikely possibility of such a recurrence, we had considered other diagnoses
in keeping with the imaging findings.
The large extra-axial lesion with T2 hypointense and T1 hyperintense signal was suggestive
of signal characteristics of early subacute blood on MRI. The pattern of change of
T2 intensity into a more hyperintense signal was also similar to progression into
late subacute and chronic blood.[15] The surrounding sulcal T1 hyperintensity was assumed to be the hyperintense vein
sign seen in isolated cortical vein CVT.[16] Thrombosis of isolated cortical veins has been speculated to be a mechanism for
subpial hemorrhages.[17] In view of the imaging findings, we contemplated the possibility of a large subpial
hematoma with CVT. Subpial hematomas typically show blood deposition along the cortical
surface and are more common along the frontal lobe.[17]
[18] This was similar to our case, although subpial hematomas are rare in adults.[18]
Another unlikely differential considered was a collision tumor. These most commonly
involve a meningioma in collision with a glioma.[19] Here the meningioma component may be dural-based, which can give rise to an appearance
similar to the present case.[19] However, the rest of the imaging findings precluded the possibility. Also, we note
that in post-RT patients, radiation-induced meningiomas generally present after a
mean interval of around 10 years.[20]
Meningeal dissemination of gliomas is rare and is usually observed in the late stages
of the disease. Potential factors include the anatomical location (tumors near the
subventricular zone), ventricular entry during surgery, repeated resections, and depressed
immune function post-chemo and radiotherapy.[21]
Extracranial metastases of grade 4 astrocytomas have been reported in less than 0.5%
of cases. Common sites include the lymph nodes, bone, soft tissue, skin, and liver.[22]
[23] In skeletal metastases, vertebral bodies are most commonly involved,[24] likely through seeding from the Bateson plexus.[24] Spread via breakdown of the blood–brain barrier via tumoral vessels or invasion
of dural veins, lymphogenous, and hematogenous spread by direct extracranial bone
and soft tissue infiltration, through the CSF, by ventricular shunting are proposed
mechanisms.[24]
[25]
In the present case, nodular pachymeningeal enhancement and vertebral body lesions
were observed. The possible factors in the case include a history of multiple neurosurgical
procedures, which may have predisposed to CSF dissemination. Postoperative meningeal
enhancement is another differential; however, it usually shows smooth meningeal enhancement,
unlike the nodular enhancement noted in the present case. Also, the lack of such changes
in the post-surgical imaging and worsening clinical symptoms preclude this.
The unique features in our case include (1) site distant (frontal region) to primary
tumoral bed (parieto-occipital lobe), thus excluding the possibility of tumoral seedling
along the postoperative track; (2) extra-axial lesion with signal characteristics
of subacute blood, and possible pachymeningeal and extracranial spread in the form
of skeletal metastases. The progression of the lesion prompted intervention and pathological
confirmation.
Conclusion
We reported a rare presentation of recurrence in an IDH mutant astrocytoma as an extra-axial
lesion remote to the primary site and possible pachymeningeal, extracranial (vertebral
body lesions). A high index of suspicion and close clinicoradiological follow-up is
required to monitor the course of recurrence in post-treatment gliomas and guide appropriate
management strategies.