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. 2020 Apr 15;22(4):470-479.
doi: 10.1093/neuonc/noz216.

Extensive brainstem infiltration, not mass effect, is a common feature of end-stage cerebral glioblastomas

Michael R Drumm  1 , Karan S Dixit  2 , Sean Grimm  2 , Priya Kumthekar  2 , Rimas V Lukas  2 , Jeffrey J Raizer  2 , Roger Stupp  2 , Milan G Chheda  3 , Kwok-Ling Kam  4 , Matthew McCord  4 , Sean Sachdev  5 , Timothy Kruser  5 , Alicia Steffens  1 , Rodrigo Javier  1 , Kathleen McCortney  1 , Craig Horbinski  1   4
Affiliations

Extensive brainstem infiltration, not mass effect, is a common feature of end-stage cerebral glioblastomas

Michael R Drumm et al. Neuro Oncol. .

Erratum in

Abstract

Background: Progress in extending the survival of glioblastoma (GBM) patients has been slow. A better understanding of why patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on why patients are dying.

Methods: The brains of 33 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated newer treatment strategies, such as more extensive surgical resection and adjuvant temozolomide.

Results: In older GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of all cases. Infiltration of tumor into the brainstem was noted in only 21% of those older cases. In the current series, only 10 of 33 (30%) GBMs showed mass effect (P = 0.0003), and only 1 (3%) showed herniation (P < 0.0001). However, extensive GBM infiltration of the brainstem was present in 22 cases (67%, P < 0.0001), with accompanying destruction of the pons and white matter tracts. There was a direct correlation between longer median patient survival and the presence of brainstem infiltration (16.1 mo in brainstem-invaded cases vs 9.0 mo in cases lacking extensive brainstem involvement; P = 0.0003).

Conclusions: With improving care, severe mass effect appears to be less common in GBM patients today, whereas dissemination, including life-threatening brainstem invasion, is now more pronounced. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival.

Keywords: autopsy; brainstem; glioblastoma; medulla; midbrain; pons; postmortem.

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Figures

Fig. 1
Fig. 1
Gross findings in postmortem GBMs. At the time of brain removal in Case 1, separation of the posterior fossa contents via midbrain transection revealed a swollen, discolored left cerebral peduncle (a, arrowhead) and left pons (b, arrowhead). After formalin fixation, coronal sections showed a relatively small area of hemorrhage and necrosis in the left temporal lobe (c, arrowhead), but no notable mass effect or midline shift. Axial sections of the brainstem again found the left pons to be swollen and discolored (d, arrowhead). In Case 2, the original tumor site in the right frontal lobe showed a resection cavity surrounded by glial scar (e, arrowhead), as well as streaks of yellow necrosis through the internal capsule headed toward the right cerebral peduncle (f, arrowhead). No mass effect was noted. Sections of the midbrain (g) and pons (h) revealed swelling and necrosis in the right cerebral peduncle and basis pontis, respectively (arrowheads). In (d), (g), and (h), anterior is up.
Fig. 2
Fig. 2
Case 1 histology. The original tumor site in the left temporal lobe showed large areas of viable tumor (a) and therapy-induced cellular atypia (c, arrowhead), as well as abundant therapy-related necrosis (b, d). In contrast, sections of the midbrain (e, g) and pons (i, k) showed viable tumor with pseudopalisading necrosis (e and i, arrowheads). At higher magnification, scattered tumor nuclei with therapy-associated atypia were observed (g, arrowhead). Tumor infiltration was heavy around pontine neurons (k). In the medulla, overall tumor burden was lighter (m, o), but still readily apparent (o, arrowhead). LFB highlighted massive loss of myelination in the midbrain (f, h), pons (j, l), and medulla (n, p). Compare with the undamaged white matter in Fig. 4. Scale bar in (p) = 400 µm at 40x and 80 µm at 200x.
Fig. 3
Fig. 3
Case 2 histology. As in Case 1, the GBM remaining in the original right frontal lobe site had a mixture of viable cells (a, c) and therapy-related necrosis (b, d). Tumor cells with therapy-induced atypia were frequent (c, arrowhead). The midbrain (e, g), pons (i, k), and medulla (m, o) all showed extensive tumor infiltration with pseudopalisading necrosis (e and i, arrowheads). Neurons comprising cranial nerve nuclei in the pons and medulla were surrounded by tumor (k and o, arrowheads). Extensive damage to the right cerebral peduncle in the midbrain (f, h) and white matter tracts in the right pons (j, l) and right medulla (n, p) was readily apparent via LFB. There was preferential loss of vertically oriented white matter tracts (right area in l) alongside mostly intact horizontal tracts of the middle cerebellar peduncles (left area in l). Compare with the undamaged white matter in Fig. 4. Scale bar in (p) = 400 µm at 40x and 80 µm at 200x.
Fig. 4
Fig. 4
Case 3 histology. In this case, the right parietal GBM, which was only biopsied, not resected, showed virtually no therapy-related changes (a, c) and spread to both hippocampal formations. Arrowhead in (b) denotes residual dentate gyrus in Ammon’s horn of the right hippocampus. Tumor mitoses were abundant in all sections, including within the hippocampi (d, arrowhead). Unlike Cases 1 and 2 (Figures 2 and 3), very little tumor infiltration or white matter damage (via LFB stain) was present in the midbrain (e–h), pons (i–l), or medulla (m–p). However, scattered infiltrating tumor cells and mitoses were found on detailed microscopic examination (see Supplementary Fig. 7). Scale bar in (p) = 400 µm at 40x and 80 µm at 200x.
Fig. 5
Fig. 5
Brainstem invasion and overall survival in postmortem GBMs. (A) The overall survival of patients in the current cohort was integrated with published data from several decades ago,,, and sorted by the presence or absence of brainstem invasion. Red circles or squares = cases from current cohort; blue circles or yellow squares = cases from older published cohorts. P-value was calculated via log-rank test. Bars = median survival. (B) Multiple large tracts of myelinated axons extend from the cortex through the midbrain into the pons, including fronto-pontine (orange), corticospinal (green), parieto-pontine (blue), and occipito-pontine (purple). (Temporo-pontine tracts are above and below the plane of the diagram.) Such tracts allow a GBM, arising anywhere in the cerebrum, direct access to vital brainstem structures.
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