Glioblastoma recurrence [Neurosurgery Wiki]

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====== Glioblastoma recurrence ======

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[[Glioblastoma]] [[recurrence]] and [[glioblastoma progression]] are related concepts in the context of glioblastoma, but they are not the same, and it's important to understand the differences between them.

Glioblastoma Recurrence:

Definition: Glioblastoma recurrence refers to the reappearance of active tumor tissue after an initial treatment has been administered. This can occur at or near the original tumor site.

Timing: Recurrence typically occurs after a period of initial treatment and a variable period of stability or remission. It can happen weeks, months, or even years after the initial treatment.

Characteristics: Recurrent glioblastoma consists of tumor cells that survived the initial treatment, which may have been surgery, radiation therapy, and chemotherapy.

Diagnosis: Recurrence is usually confirmed through imaging studies, such as MRI or CT scans, which show new or enlarging areas of contrast-enhancing tumor.

Management: The management of recurrent glioblastoma often involves a different treatment approach than the initial therapy. Options may include additional surgery, alternative chemotherapy, experimental therapies, or palliative care.

[[Glioblastoma Progression]]:

Definition: Glioblastoma progression is a broader term that encompasses any changes in the tumor over time. It includes both the initial growth and the later recurrence of the tumor.

Timing: Progression can refer to the continuous growth or spread of the tumor from the time of diagnosis. It covers all stages of tumor growth, from the initial formation to the reappearance of active tumor cells in recurrence.

Characteristics: Progression may involve the tumor's aggressive growth, infiltration into surrounding brain tissue, and the development of treatment-resistant features.

Diagnosis: Progression is assessed through various clinical and imaging criteria, including changes in the size and characteristics of the tumor over time.

Management: The management of glioblastoma progression depends on the stage and extent of tumor growth. It often includes a combination of treatments, such as surgery, radiation, and chemotherapy, with the goal of delaying or controlling tumor growth.

In summary, glioblastoma progression is a broad term that encompasses the entire course of tumor growth and development, from diagnosis to recurrence. Glioblastoma recurrence specifically refers to the reappearance of tumor tissue after an initial treatment. Both are critical concepts in the clinical management and treatment of glioblastoma, but they occur at different points in the disease course and may require different approaches for diagnosis and treatment.
----


[[Glioblastoma]] has an unfavorable [[prognosis]] mainly due to its high propensity for tumor [[recurrence]]. It has been suggested that Glioblastoma recurrence is inevitable after a median survival time of 32 to 36 weeks
((Ammirati M, Galicich JH, Arbit E, Liao Y. Reoperation in the treatment of
recurrent intracranial malignant gliomas. Neurosurgery. 1987 Nov;21(5):607-14.
PubMed PMID: 2827051.
))
((Choucair AK, Levin VA, Gutin PH, Davis RL, Silver P, Edwards MS, Wilson CB.
Development of multiple lesions during radiation therapy and chemotherapy in
patients with gliomas. J Neurosurg. 1986 Nov;65(5):654-8. PubMed PMID: 3021931.
)).

Less than 10% of recurrent gliomas recur away from the original tumor site
((Choucair AK, Levin VA, Gutin PH, et al.
Development of Multiple Lesions During Radiation
Therapy and Chemotherapy. J Neurosurg. 1986;
65:654–658)).

A merely anatomical analysis of the glioblastoma growth pattern cannot reliably provide prognostic information. The occurrence of most recurrences next to the resection margin and the high percentage of growing residual tumors underline the importance of complete resections
((Nestler U, Lutz K, Pichlmeier U, Stummer W, Franz K, Reulen HJ, Bink A; 5-ALA 
Glioma Study Group. Anatomic features of glioblastoma and their potential impact 
on survival. Acta Neurochir (Wien). 2015 Feb;157(2):179-86. doi:
10.1007/s00701-014-2271-x. Epub 2014 Nov 14. PubMed PMID: 25391974.
)).

===== Natural history =====

The natural history of recurrent Glioblastoma, is largely undefined for the following reasons: 

1) Lack of uniform definition and criteria for tumor recurrence

2) Institutional variability in treatment philosophy

3) The heterogeneous nature of the disease, including location of recurrence and distinct mechanisms believed to contribute to known subtypes of Glioblastoma.


The [[criteria]] used to define recurrent [[glioblastoma]] Glioblastoma remain ambiguous due to the varied presentation of new lesions. First, the infiltrative nature of Glioblastoma cells makes it difficult to eliminate microscopic disease despite macroscopic gross-total resection. Studies have shown that Glioblastoma recurrence most often occurs in the form of a local continuous growth within 2 to 3 cm from the border of the original lesion
((Durmaz R, Erken S, Arslantas A, et al: Management of glioblastoma multiforme: with special reference to recurrence. Clin Neurol Neurosurg 99:117–123, 1997))
((Halperin EC, Burger PC, Bullard DE: The fallacy of the localized supratentorial malignant glioma. Int J Radiat Oncol Biol Phys 15:505–509, 1988))
((Lee SW, Fraass BA, Marsh LH, et al: Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys 43:79-88,1999)).
===== Etiology =====
One of the factors that cause recurrence is the strong migratory capacity of Glioblastoma cells. Wanibuchi et al.,  reported that actin, alpha, cardiac muscle 1 ([[ACTC1]]) could serve as a marker to detect Glioblastoma migration in clinical cases
((Wanibuchi M, Ohtaki S, Ookawa S, Kataoka-Sasaki Y, Sasaki M, Oka S, Kimura Y, 
Akiyama Y, Mikami T, Mikuni N, Kocsis JD, Honmou O. Actin, alpha, cardiac muscle 
1 (ACTC1) knockdown inhibits the migration of glioblastoma cells in vitro. J
Neurol Sci. 2018 Jul 17;392:117-121. doi: 10.1016/j.jns.2018.07.013. [Epub ahead 
of print] PubMed PMID: 30055382.
)).


Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of [[cancer stem cell]]s (CSC) that contributes to tumor propagation, maintenance, and treatment resistance. 

These cells are associated with vascular niches which regulate glioma stem cells (GSC) self-renewal and survival. 

Studies suggest that while blood vessels support glioma stem cells, these tumor cells in turn may regulate and contribute to the tumor vasculature by transdifferentiating into endothelial cells directly or through the secretion of regulatory growth factors such as [[vascular endothelial growth factor]] (VEGF) and [[hepatoma derived growth factor]] (HDGF)
((Jhaveri N, Chen TC, Hofman FM. Tumor vasculature and glioma stem cells:
contributions to glioma progression. Cancer Lett. 2014 Dec 16. pii:
S0304-3835(14)00783-6. doi: 10.1016/j.canlet.2014.12.028. [Epub ahead of print]
PubMed PMID: 25527451.)).

Intratumoral heterogeneity and the presence of these CSCs may contribute to the treatment-resistant nature of Glioblastoma and its propensity to recur in patients
((Cancer Genome Atlas Research Network: Comprehensive ge- nomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068, 2008))
((Nickel GC, Barnholtz-Sloan J, Gould MP, McMahon S, Cohen A, Adams MD, et al: Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence. PLoS ONE 7:e35262, 2012)).

==== Questionable cells ====
Zhou et al. conducted a [[comprehensive review]] of existing [[literature]] and studies on GBM, focusing on the identification and characterization of questionable [[cell]]s (Q cells). Advanced [[imaging]] [[technique]]s, such as [[diffusion tensor imaging]] (DTI), [[magnetic resonance spectroscopy]] (MRS), and [[positron emission tomography]] (PET), were utilized to identify Q cells beyond the tumor core. They also analyzed the functional properties, cellular [[microenvironment]], and physical characteristics of Q cells, as well as their implications for surgical [[resection]].

The review revealed that Q cells exhibit unique functional attributes, including enhanced invasiveness, metabolic adaptations, and resistance mechanisms. These cells reside in a distinct cellular microenvironment and are influenced by physical properties such as solid stress and [[stiffness]]. Advanced imaging techniques have improved the identification of Q cells, enabling more precise surgical resection. Targeting Q cells in therapeutic strategies could significantly reduce the risk of GBM recurrence.

The presence of Q cells in the peritumoral brain zone (PBZ) and beyond is a critical factor in GBM recurrence. Current treatments, which primarily target tumor cells in the TC, are insufficient to prevent recurrence due to the neglect of Q cells. Future research should focus on understanding the mechanisms influencing Q cells and developing targeted therapies to improve patient outcomes
((Zhou Y, He Q, Huang G, Ouyang P, Wang H, Deng J, Chen P, Liang X, Hong Z, Zhang X, Qi S, Li Y. Malignant Cells Beyond the Tumor Core: The Non-Negligible Factor to Overcome the Refractory of Glioblastoma. CNS Neurosci Ther. 2025 Mar;31(3):e70333. doi: 10.1111/cns.70333. PMID: 40104956.)).
===== Diagnosis =====

[[Glioblastoma recurrence Diagnosis]].

===== Differential Diagnosis =====

[[Glioblastoma recurrence Differential Diagnosis]].

===== Treatment =====
see [[Glioblastoma recurrence treatment]].

===== Outcome =====

see [[Glioblastoma recurrence outcome]].

===== Case series =====

see [[Glioblastoma recurrence case series]].

===== Case reports =====

A 52-year-old woman was admitted for management of [[Glioblastoma recurrence]]. After tumor removal surgery, the patient experienced sustained [[Cerebrospinal fluid fistula]] from the [[wound]] despite reparative attempts. The plastic surgery team performed wound repair procedure after remnant tumor removal by the neurosurgery team. [[Acellular dermal matrix]] was applied over the mesh plate to prevent Cerebrospinal fluid fistula and the postoperative status of the patient was evaluated. No sign of Cerebrospinal fluid fistula was found in the immediate postoperative period. After 3 years, there were no complications including Cerebrospinal fluid fistula, [[wound dehiscence]], and [[infection]]. Lee et al. hereby propose this method as a feasible therapeutic alternative for preventing Cerebrospinal fluid fistula in patients experiencing wound problem after neurosurgical procedures
((Lee H, Eom YS, Pyon JK. A method to prevent Cerebrospinal fluid fistula:
Reinforcing acellular dermal matrix. Arch Craniofac Surg. 2020 Feb;21(1):45-48.
doi: 10.7181/acfs.2019.00535. Epub 2020 Feb 20. PubMed PMID: 32126620.
)).
----

Corns et al. describe the case of a patient with [[Glioblastoma recurrence]] encroaching on [[Broca's area]]. [[Gross total resection]] of the tumour was achieved by combining two techniques, [[awake craniotomy]] to prevent damage to eloquent brain and [[5-aminolevulinic acid  fluorescence guided resection]] to maximise the extent of tumour resection. This technique led to gross total resection of all [[T1]]-[[contrast enhancement]] tumour with the avoidance of neurological deficit. They recommend this technique in patients when [[awake surgery]] can be tolerated and gross total resection is the aim of surgery
((Corns R, Mukherjee S, Johansen A, Sivakumar G. 5-aminolevulinic acid guidance 
during awake craniotomy to maximise extent of safe resection of glioblastoma
multiforme. BMJ Case Rep. 2015 Jul 15;2015. pii: bcr2014208575. doi:
10.1136/bcr-2014-208575. PubMed PMID: 26177997.
)).

===== References =====