DIFFUSE GLIOMA GROWTH: a guerrilla

war.

Dr Jiménez Arribas, PalomaNSG 3st year resident. May, 2014.

Glioblastoma (GBM)

The most common and most aggressive malignant primary brain tumor in humans.

Astrocitoma grade IV WHO.

Incidence of 2–3 cases per 100,000 in Europe and North America

Primary glioblastoma: the majority of GBMs.

- Arise without evidence of a less malignant precursor. - Mean age 55 years. - Short clinical history (<3 months)

Secondary glioblastoma: - Develops by malignant degeneration of low grade (II, III)

astrocitomas. - Younger patients (mean age 40). - Slower clinical course.

Histological findings:

Nuclear atypia Mitosis Neovascularization with endothelial

proliferation Areas of necrosis “Pseudopalisading cells”

• Overexpress hypoxia-inducible factor (HIF-1), and secrete proangiogenic factors.

• Around areas of necrosis. • Wave of tumor cells actively migrating away from central hypoxia

Special growth pattern:

In contrast to almost all other brain tumors, they infiltrate extensively in the neuropil (network of neuronal and glial cell processes)

This growth pattern is: Almost unique in this kind of tumors. A major factor in therapeutic failure.

Special growth pattern (trough white matter):

Uncinate fasciculus (simultaneous frontal and temporal lobe tumors)

Corpus callosum (butterfly glioma)

Radiological findings:

Ring-enhancing lesions Central necrotic área Enhancing rim (active tumoral cells) Severe perilesional edema

Radiological visualization of the invasive front is difficult

Tend to underestimate the extent of diffuse inflitrative glioma growth.

Radiological findings:

Multifocal gliomas: multiple lesions that come from an original lesion. Usually located in the same brain hemisphere.

Multicentric gliomas: multiple lesions not originated from the same lesion. Widely separated.

To understand the growth pattern of these tumors….

Guerrilla war metaphor

Like guerrilla warriors….

Tumors cells tend to invade individually or in small groups in foreign territory and to abuse pre-existent supply lines.

Visualization of the invasive front is problematic.

Like guerrilla warriors….

Glioma cells have specific qualities that allow a diffuse infiltration (Molecular background)

Internal system that coordinates inputs and outputs (membrane receptors).

Locomotor apparatus (dynamic remodeling of the cytoskeleton)

Trails to travel (myelinated fibers migration trough white matter tracts)

Tools to remove obstacles (proteases that degrade the ECM, cytokines that evade immune response)

Interactions between the cells and their microenvironment that guide the way

Like guerrilla warriors….

Conventional methods to fight glioma cells have limited effect or cause too much collateral damage (they tend to blend with normal brain), and a “search and destroy” tactic may be needed.

Treatment involves surgery, chemotherapy and radiation.

Surgery makes impossible a complete tumor removal in high grade gliomas.

No current treatment is curative. Standard treatment consists of the following:

Maximal surgical resectionRadiotherapy

Chemotherapy

The surgical goals are: To establish a pathologic diagnosis

To relieve any mass effect To facilitate adjuvant therapy

Maximum tumor resection, without affecting the vital brain structures and minimizing the risk of postoperative

neurological deficits.

Surgical options: Gross total resection (better survival)

Subtotal resectionBiopsy (for patients with a tumor located in an eloquent area of the brain,

patients whose tumors have minimal mass effect, and patients in poor medical condition who cannot undergo general anesthesia)

Outcome

The median survival time from the time of diagnosis without any treatment is 3 months

Factors affecting outcome:

Patient age (the most significant prognosticator)Performance status (Karnofsky score)

The extent of surgery (gross total / subtotal / biopsy)Tumor size and location

Outcome

The median survival time from the time of diagnosis without any treatment is 3 months

Factors affecting outcome:

Patient age (the most significant prognosticator)Performance status (Karnofsky score)

The extent of surgery (gross total / subtotal / biopsy)Tumor size and location

Surgery + XRT + Chemoterapy Median survival (weeks)

Estimated 2-year survival

< 40, frontal tumor (GTR) 132 (2,5 years) 65%

< 40, Not frontal tumor (GTR)

71 (1,3 years) 35%

40<age<65KPS > 70GTR/STR

63 (1,2 years) 17%

>6540< age<65 + KPS <8040<age<65 + KPS >80 + BIOPSY

37 (5 months) 4%

Conclusions

The special growth pattern of high grade gliomas has important diagnostic, prognostic and therapeutic implications.

Diffuse gliomas are unlikely to be cured by techniques that cannot selectively destroy neoplastic cells.

Knowing the mechanisms that allow glioma cells to difussely infiltrate in the neuropil may provide new therapeutic targets for recognizing, attacking and killing these cells.

The future…. Investigational therapies (gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins and antibodies)