Keywords
skull base tumor - acute lymphocytic leukemia
Introduction
Acute lymphocytic leukemia (ALL) is a progressive cancer characterized by the proliferation
of immature lymphoid cells in the bone marrow, blood, and extramedullary sites. Typically,
most cases of ALL are diagnosed in the pediatric population. In fact, ALL is the most
common form of childhood cancer, accounting for up to 25% of cancers in children under
the age of 15 years.[1] Although childhood ALL is highly curable, relapsed disease is a significant problem
that contributes to morbidity and mortality.[2]
[3] For patients with relapse, the 5-year survival rate is estimated to be between 25
and 50%.[4]
[5]
[6]
[7]
[8]
The central nervous system (CNS) is one of the most common sites of extramedullary
ALL relapse and can occur as isolated recurrence or alongside bone marrow involvement,
both of which have devastating consequences.[9]
[10] Given the poor outcomes in patients with CNS relapse, understanding how ALL recurrence
involving intracranial infiltration presents and can be managed is essential.
Here, we describe the case of a patient with late isolated CNS relapse of ALL in the
form of an extensive skull base lesion, who was effectively treated nonsurgically
with chemotherapy and radiation, which led to a drastic decrease in the size and intensity
of the lesion.
Case Presentation
An 11-year-old girl with a history of standard-risk B-cell ALL 7 years prior presented
with left facial droop, recurrent mastoiditis/otitis, and right elbow swelling. She
was first diagnosed with SR-ALL at 18 months of age and was enrolled on study DFCI
11-001. She went into remission and completed 2 years of therapy with minimal complications.
When she presented presently, physical examination was limited due to agitation. She
had a notable left facial droop and swelling of her left ear and mastoid with bony
prominence, though the area was not tender or erythematous. A peripheral cranial nerve
VII palsy was observed, without evidence of other cranial nerve dysfunction. She was
able to move all extremities and demonstrated normal strength and sensation. The remainder
of her exam was noncontributory.
Magnetic resonance imaging (MRI) of the brain revealed a large skull base lesion centered
on the sphenoid bones and clivus with extensive intracranial, nasopharyngeal, and
left neck extension ([Fig. 1]). The mass encapsulated the left VII and VIII cranial nerves, dorsally displacing
the pons and medulla, and filling the left cavernous sinus. The lesion was biopsied,
and cerebrospinal fluid (CSF) was obtained for cytologic examination. Pathologic evaluation
revealed the tumor was consistent with relapsed pre-B ALL rather than a new second
malignancy. Moreover, CSF from the lumbar puncture (LP) showed 15% blast-like cells,
with tissue flow from the tumor further being consistent with relapsed pre-B ALL.
Notably, the blasts were negative for the B-cell biomarker CD19. The bone marrow biopsy
was negative, suggesting late isolated CNS relapse.
Fig. 1 Sagittal (A) and coronal (B) T1-weighted magnetic resonance imaging from 2020 of the patient's initial relapse
prior to therapy demonstrating a large skull base lesion centered on the sphenoid
bones and clivus.
She was started on reinduction chemotherapy as per AALL1331, with systemic mitoxantrone,
dexamethasone, vincristine, and pegaspargase and weekly intrathecal methotrexate,
cytarabine, and hydrocortisone, which she tolerated well (ClinicalTrials.gov identifier:
NCT02101853). End of induction LP and bone marrow biopsy showed no residual disease.
End of induction MRI brain scans, however, showed that while the intracranial lesion
decreased significantly, there remained a residual mass centered on the left skull
base, with mass effect upon the brainstem. Prolonged systemic chemotherapy was continued
as per AALL1331. Surgery was not considered due to the extensive intracranial component
of the lesion and the high risk of the procedure. Given the absence of CD19 positivity
on the leukemic cells, the patient was also ineligible for CAR-T cell therapy targeting
CD19, and no open clinical trials were available. While allogeneic hematopoietic stem
cell transplantation was considered, the patient's parents decided to forego the treatment
in favor of a targeted radiotherapy and chemotherapy approach.
The patient received chemotherapy for approximately 2 years as per AALL1331 and targeted
radiation (24Gy) to the lesion. Her treatment was complicated by fungal pneumonia.
MRI scans of the brain at the end of therapy showed a remarkable decrease in the size
and intensity of the skull base lesion as compared to the MRI scan taken 2 years prior,
although her facial droop persisted ([Fig. 2]). Given the duration of treatment for the chemotherapy was exhausted, a discussion
at tumor board yielded a decision to monitor the residual lesion and consider biopsy
and excision if the mass started to re-grow.
Fig. 2 Sagittal (A) and coronal (B) T1-weighted magnetic resonance imaging from 2022 following the completion of chemotherapy
and radiotherapy demonstrating the reduction in the size of the skull base lesion.
Unfortunately, 5 months after completing therapy, the patient presented to the hospital
with worsening facial droop and neck pain. MRI scans showed the skull base lesion
was stable, but there was a new finding of diffuse leptomeningeal enhancement ([Fig. 3]). She subsequently had an initial LP, which showed no blasts but elevated intracranial
pressure (ICP) to 41 and a white blood cell count of 35,000/mm3. Repeat LP 1 week later revealed 20% blast cells confirming CNS relapse. Bone marrow
biopsy was negative for leukemic infiltration and computed tomography scan further
revealed communicating hydrocephalus and possible obstruction from crowding cerebellar
tonsils at the level of the foramen magnum. The patient had emergent external ventricular
drainage placement for increased ICP and eventually underwent ventriculoperitoneal
shunt placement. She also received biweekly intrathecal therapy until the CSF was
cleared of blasts.
Fig. 3 Coronal magnetic resonance imaging (A) and axial computed tomography (B) scans 5 months after completing therapy depicting a stable skull base lesion and
new leptomeningeal enhancement.
Currently, she is receiving monthly intrathecal therapy consisting of methotrexate,
hydrocortisone, and cytarabine, and a bone marrow biopsy every 2 months to evaluate
for disease. Given her extensive ALL history and CNS recurrence, bone marrow transplantation
was once again recommended. The risks and benefits of transplantation in alignment
with the family's wishes have been an ongoing discussion. The patient has been tolerating
chemotherapy well and has not had any headaches or emesis. CSF remains negative for
leukemia.
Discussion
Currently, there is no unified treatment plan for CNS relapse in ALL and evaluating
the best course of treatment for these patients can be challenging. Depending on the
degree of intracranial invasion, strategies typically involve a combination of the
following: cranial radiation, conventional chemotherapy, hematopoietic stem cell transplantation,
and, more recently, immunotherapies.[11]
[12] Early isolated CNS relapses, defined by past literature as relapse less than 18
months from diagnosis, are often treated with intensive systemic chemotherapy followed
by hematopoietic stem cell transplant if patients are eligible.[13]
[14] For late isolated CNS relapses, there has been relative success with clinical trials
using high-dose chemotherapy and cranial radiation.[11] While the utilization of radiation has improved survival, it is known to have several
long-term side effects including cognitive and growth impairments.[15]
[16]
Here, we report a case of a young patient with relapsed recurrent ALL involving the
CNS who was treated with a nonsurgical multidisciplinary approach that drastically
reduced the tumor size. The patient's initial relapse with a large skull base lesion
and intracranial involvement is an interesting and uncommon presentation of relapsed
CNS-ALL. The patient's early recurrence of leptomeningeal disease is another uncommon
presentation of relapsed ALL. Lastly, and most importantly, the patient's radiographic
response to standard chemotherapy and radiation was unexpected and profound, highlighting
how a patient with relapsed CNS-ALL can be managed nonsurgically. Many available treatment
options for CNS relapse involve a high risk of toxicity, making such interventions
suboptimal in certain patients. Here, however, we demonstrate the profound effect
of chemotherapy and radiotherapy in reducing the size of an extensive skull base lesion,
saving the patient from the risks associated with surgery.
While our therapeutic approach had a significant impact on the growth of the lesion,
complications with this strategy did arise. The early recurrence of the patient's
CNS disease, in the form of leptomeningeal enhancement and hydrocephalus, despite
intensive chemotherapy, was unfortunate and unexpected. While we believe our course
of therapeutic action was the most appropriate given the patient's history of disease
and family wishes, it is clear that more effective forms of therapy for CNS-ALL are
needed. In order to truly develop an optimal form of therapy, it is crucial to first
identify more diagnostic and prognostic biomarkers for relapsed CNS-ALL. Such an endeavor
would allow for the identification of patients who are at high risk of CNS relapse
as well as the development of more targeted therapies to better manage these patients
in the future.
In summary, we report a unique case of an 11-year-old girl with a history of SR-ALL
who presented with relapsed CNS-ALL in the form of a large skull base lesion with
intracranial involvement. The patient's initial relapse, additional early recurrence
of leptomeningeal disease, and response to standard chemotherapy and radiation make
our case particularly unusual. We demonstrate the intricate decision-making process
behind optimizing a treatment plan for such a nuanced case of CNS-ALL and show how
similar patients can be managed without the use of surgical interventions. Moving
forward, we believe it is important to be able to identify patients at risk of relapsed
CNS-ALL, as this would allow for swift clinical action to be taken before progression
of disease. Through early identification as well as the development of more targeted
therapies for intracranial disease, we will be able to better manage and treat patients
with relapsed ALL involving the CNS.
