2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Is Biopsy Safe in Children with Newly
Diagnosed Diffuse Intrinsic Pontine Glioma?
By Stephanie Puget, MD, PhD, Thomas Blauwblomme, MD, and Jacques Grill, MD, PhD
Overview: Diffuse intrinsic pontine gliomas (DIPGs), with a
median survival of 9 months, represent the biggest therapeutic
challenge in pediatric neuro-oncology. Despite many clinical
trials, no major improvements in treatment have been made
over the past 30 years. In most cases, biopsy is not needed for
diagnosis because DIPG diagnosis is based on a typical
clinical picture with radiologic evidence on magnetic resonance
imaging. Therefore, little data on newly diagnosed DIPG
have been published and are confounded by including autopsy
(i.e., postradiation therapy) cases. In most cancers, advancing
to cure has been linked to the discovery of relevant biomarkers,
only found by access to tissue. Therefore, to further
understand the biology of DIPG, fresh tissue samples must be
DIFFUSE INTRINSIC pontine gliomas (DIPGs), which
represent 15% of all childhood brain tumors, are inoperable
neoplasms. Response to radiation therapy is only
transient and chemotherapy has not improved long-term
survival. The development of targeted therapies for these
tumors has been hampered by the lack of knowledge of their
biology and many trials to date have been carried out based
on the misconception that DIPG biology is similar either to
its adult counterparts 1-3 or to other pediatric supratentorial
malignant gliomas. 1,4 Diagnosis is usually based on the
association of a short history of less than 2 months, cranial
nerves palsies, long-tract signs, and ataxia with typical
imaging findings. DIPG is usually described as an infiltrating
tumor mass of the pons, hypointense on T1 and hyperintense
on T2 and fluid-attenuated inversion recovery; by
definition, at least 50% of the pons should be involved.
Contrast enhancement, if any, is usually limited and annular.
Grading of these lesions has been difficult based on
small biopsies and could therefore not be linked to outcome.
Biopsy of these tumors has been controversial, and most
neurosurgical teams limit the use biopsy to patients with
lesions that have unusual presentation. However, the urgent
need to improve the prognosis for patients with these
devastating tumors has led to the reconsideration of the role
of stereotactic biopsy for patients with DIPG. This article
will address the feasibility and safety of stereotactic biopsy
for patients with DIPG, its diagnostic yield, and its role in
redefining this tumor by its molecular signature and profiling
targeted therapy.
Is It Safe to Perform a Biopsy for Patients Newly
Diagnosed with DIPG?
Stereotactic biopsies are now completely integrated in the
diagnosis and management of several intracranial lesions.
The role of stereotactic biopsy for patients with newly
diagnosed DIPG remains controversial, and currently the
general attitude is not to biopsy the tumors of these patients.
Stereotactic biopsy of brainstem tumors is an old procedure;
it became popular after the first report of this procedure
in 1978. 5 Ten years later, arguments against brainstem
biopsy were strong because it was believed to have no use, to
be dangerous, and to offer poor yield. 6-8 The 1993 manuscript
published by Albright and colleagues changed the
course of pediatric DIPG management by claiming that
obtained at diagnosis. However, most neurosurgical teams are
reluctant to perform biopsy in pediatric patients, citing potential
risks and lack of direct benefit. Yet, in reviewing 90
patients with and the published data on brainstem biopsy,
these procedures have a diagnostic yield and morbidity and
mortality rates similar to those reported for other brain
locations. In addition, the quality and quantity of the material
obtained confirm the diagnosis and inform an extended molecular
screen, including biomarker study—information important
to designing next-generation trials with targeted agents.
Stereotactic biopsies can be considered a safe procedure in
well-trained neurosurgical teams and could be incorporated in
well-defined protocols for patients with DIPG.
magnetic resonance imaging (MRI) “. . . scans provide images
that are virtually diagnostic of brainstem gliomas and
yield prognostic information equivalent to that obtainable
from biopsies ...”. 8 Since then, the neurosurgical world was
divided into “for” and “against” the brainstem biopsy. Despite
the reluctance of some neurosurgical teams, others
chose to perform biopsies of brainstem lesions in children
and adults for both unusual lesions and typical ones as part
of a clinical trial. 9-16 Papers on stereotactic biopsies in the
brainstem published in the last 20 years represent a substantial
amount of knowledge, yet unfortunately often report
mixed series of adults and children with a wide range of
diagnoses. These mixed series cite morbidity rates between
0% and 10% and mortality rates between 0% to 3% (Table 1).
However, when biopsy data on pediatric patients with DIPG
are extracted, the diagnostic yield ranges from 96% to 100%,
with no mortality and morbidity less than 5% for the largest
series.
Samadani and Judy performed a meta-analysis of 13
studies of stereotactic biopsy of brainstem lesions in 381
children and adults. 17 With a diagnostic yield of 96%, this
study reported one death attributable to a biopsy of a
vascular lesion in an adult, with rates of permanent and
transient neurologic deficits of 4% and 1%, respectively. A
few years later, a second meta-analysis on brainstem lesions
in pediatric patients was published by Pincus and colleagues.
13 This review of 192 children revealed a diagnostic
yield of 94.9%, and mortality and morbidity rates of 0.7%
and 4.9%, respectively. Recently, Rajshekhar and Moorthy
reported a series of stereotactic biopsies in 106 children with
brainstem masses. With no mortality or permanent morbidity
reported, the authors highlighted that “. . . this procedure
is safe in children and the benefits outweigh the risks
in patients who are appropriately selected to undergo this
procedure. . . ” 11 A few years ago, our group started to use
From the Necker Enfants Malades Hospital, Université Paris Descartes, Sorbonne Paris
Cité, France; Gustave Roussy Cancer Institute, Universite Paris Sud, Villejuif, France.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Stephanie Puget, MD, PhD, Department of Pediatric Neurosurgery,
Necker Enfants Malades Hospital, 149 rue de Sèvres, 75015 Paris, Université Paris
Descartes, Sorbonne Paris Cité, France; email: stephanie.puget@gmail.com
© 2012 by American Society of Clinical Oncology.
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