RESIDENT & FELLOW SECTION

Pearls & Oy-sters: The critical role of
histopathology in diagnosing cancer-associated
necrotizing CNS vasculitis
Joshua Sheehan, MD, Jessica Tate, MD, Ryan Mott, MD, Carol Geer, MD, Rachel Wolfe, MD, Roy E. Strowd, MD,
and Amy Guzik, MD

®

Neurology 2018;90:808-811. doi:10.1212/WNL.0000000000005350

Correspondence
Dr. Strowd
rstrowd@wakehealth.edu

Abstract
Objective
To highlight the importance of a broad differential and histopathologic confirmation in patients
with newly diagnosed cancer with brain lesions atypical for CNS metastasis.
Methods
We report 2 cases of biopsy-proven CNS vasculitis in patients undergoing treatment for a newly
diagnosed nonmetastatic cancer. Comprehensive medical record review was performed to
identify the clinical presentation, representative neuroimaging, histopathologic features, and
response to treatment.
Results
Patient 1 presented 1 month into induction therapy of malignant vaginal squamous cell carcinoma (stage 3, T2N1M0) with acute episodic left-sided hemiparesis due to seizure activity
progressing to severe encephalopathy. Imaging revealed a right frontoparietal lesion while
systemic workup was unrevealing. Biopsy demonstrated necrotizing vasculitis. Patient 2 presented 6 months after diagnosis of right breast invasive ductal carcinoma (stage IIa, T2N0M0,
estrogen receptor–positive, progesterone receptor–positive, human epidermal growth factor
receptor–2 positive) with subacute bifrontal headaches with associated phonophobia. Imaging
showed hyperintense lesions involving the right temporoparietal region and systemic workup
was unrevealing. Brain biopsy showed a necrotizing vasculitis. Patient 1 was treated with
methyprednisolone and plasmapheresis and patient 2 was treated with prednisone. Both
patients showed complete resolution of symptoms shortly after treatment and improvement on
imaging.
Conclusions
These cases highlight the importance of comprehensive evaluation of new brain lesions in
patients with nonmetastatic solid tumors. Characteristics of new brain lesions in patients with
cancer that should raise suspicion of diagnoses other than brain metastasis include (1) primary
malignancy without regional or distant metastasis, (2) imaging without discrete mass-like
enhancement, and (3) cortically based location of lesions not at the gray–white matter junction.

From Wake Forest University School of Medicine (J.S.); and the Departments of Neurology (J.T., R.E.S., A.G.), Pathology (R.M.), Radiology (C.G.), and Rheumatology (R.W.), Wake Forest
Baptist Medical Center, Winston-Salem, NC.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

808

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Glossary
AChR = acetylcholinesterase receptor; ANA = antinuclear antibody; PCNSV = primary CNS vasculitis; SCNSV = secondary
CNS vasculitis.

Pearls
c

c

c

Cancer-associated CNS vasculitis is a rare but important
cause of new brain lesion in a patient with systemic
malignancy.
Characteristics of new brain lesions in cancer patients
that should raise suspicion of diagnoses other than brain
metastasis include (1) primary malignancy without regional
or distant metastasis, (2) imaging without discrete masslike enhancement, and (3) cortically based location of
lesions not at the gray–white matter junction.
Histopathologic confirmation is important in patients
with newly diagnosed cancer with CNS lesions atypical
for metastatic disease.

Oy-ster
c

Radiographic findings of CNS vasculitis are nonspecific
and can mimic neoplasm or other pathology.

Brain lesions are present on MRI in up to 40% of patients with
cancer.1 While the majority represent metastases, up to 11%
are radiographic mimics that are difficult to distinguish by
imaging alone.1 Metastatic disease typically appears as sharply
demarcated solid or ring-enhancing lesions with surrounding
edema.1 These imaging features, however, overlap with less
common etiologies including inflammatory, vascular, and infectious pathology. Histology remains the gold standard for
diagnosis and is critically important in atypical cases.2
We report 2 patients with early stage nonmetastatic systemic
cancer who developed new neurologic symptoms and cortically based brain lesions during first-line therapy.

Patient 1
A 70-year-old woman was diagnosed with malignant vaginal
squamous cell carcinoma (stage 3, T2N1M0) in March 2016.
Induction therapy consisted of radiation (45 Gy) and cisplatin
(40 mg/m2 weekly). One month into treatment (fraction 17/25
and cycle 3), she presented with acute onset of episodic left
hemibody weakness. CT of the head showed no acute hemorrhage or early ischemic findings. Once admitted, she developed
intermittent uncontrolled rhythmic left upper extremity jerking
concerning for seizure.
Continuous video EEG monitoring demonstrated an epileptogenic focus in the right central region and levetiracetam
was started. Brain MRI without contrast showed a linear,
cortically based right frontoparietal lesion of unclear etiology
(figure 1A). Repeat gadolinium-enhanced MRI (figure 1A)
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showed mass-like progression of cortical gyra swelling and
right precentral and postcentral gyral edema without enhancement. By day 8, imaging revealed increased swelling in
the gyri of the posterior right frontal and anterior right parietal
lobe with surrounding edema, hemorrhage, and local mass
effect (figure 1A). CT angiography of the head was not
suggestive for vasculopathy or aneurysm. Clinically, the patient
continued to demonstrate intermittent left-sided weakness.
Differential diagnosis included infectious encephalitis, simple
partial status epilepticus with secondary radiographic abnormalities, vasculitis, or chemotherapeutic toxicity. Brain metastasis was considered given the mass-like expansion (figure 1A)
but was considered less likely due to the lack of contrast
enhancement.
Lumbar puncture showed an inflammatory profile with no
evidence of malignancy on cytology (table e-1, links.lww.
com/WNL/A382). Systemic workup showed no evidence of
systemic infection or vasculitis. Autoimmune/paraneoplastic
testing revealed no classic antibody-associated encephalitides
or vasculitides except for an elevated acetylcholinesterase receptor (AChR) binding antibody (0.11 nmol/L).
Given the lack of definitive diagnosis with noninvasive testing,
brain biopsy was performed showing a nongranulomatous
necrotizing vasculitis characterized by fibrinoid necrosis of
leptomeningeal blood vessels and brain tissue gliosis (figure
e-1, links.lww.com/WNL/A381). There was no evidence of
systemic vasculitis and the patient was diagnosed with isolated
CNS vasculitis. Five days of IV methylprednisolone
(1,000 mg daily) was administered without clinical improvement. Cyclophosphamide and rituximab were deferred in
context of recent chemotherapy and instead the patient underwent 7 sessions of plasmapheresis with substantial cognitive and motor improvement. Brain MRI performed 2 weeks
following treatment showed improvement and she has
remained stable on a prednisone (20 mg) taper for 6 months.

Patient 2
A 67-year-old woman was diagnosed with right breast invasive
ductal carcinoma (stage IIa, T2N0M0, estrogen receptor–
positive, progesterone receptor–positive, human epidermal
growth factor receptor–2 positive) and subsequently underwent a lumpectomy. She presented with subacute worsening
of bifrontal headaches waking her from sleep. Headaches had
increased in frequency and severity over 6 months with associated phonophobia and lightheadedness but no aura, vision
changes, or other focal symptoms. Despite prophylactic and
abortive medications, she experienced minimal relief.
Neurology | Volume 90, Number 17 | April 24, 2018

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809

Figure 1 Radiographic progression of atypical brain lesions

(A) Case 1: top row: progression of high T2/fluid-attenuated inversion recovery (FLAIR) signal/edema in the right frontoparietal lobe; middle row: mild right
frontoparietal cortically based restricted diffusion, faint right frontoparietal gyral enhancement; bottom row: progressive susceptibility artifact (hemorrhage)
on gradient imaging in the region of signal abnormality. (B) Case 2: top row: progressive high T2/FLAIR signal/edema in right temporal and parietal lobes;
middle row: very faint leptomeningeal enhancement in region of edema; bottom row: progressive cortically based susceptibility artifact (hemorrhage) in
region of edema.

MRI brain was ordered for further evaluation and demonstrated a T2-weighted hyperintense mass lesion involving the right temporoparietal cortex with local swelling,
subtle leptomeningeal enhancement, and no restricted
diffusion on diffusion-weighted imaging (figure 1B).
Initial concerns included bran metastasis vs low-grade
glioma. Brain biopsy was recommended and revealed
a nongranulomatous necrotizing vasculitis with small leptomeningeal blood vessels with destructive changes (figure e-1,
links.lww.com/WNL/A381).
Lumbar puncture was negative for malignancy but showed
polyclonal lymphocytosis (table e-1, links.lww.com/WNL/
A382). Paraneoplastic and autoimmune testing was negative except for a weakly positive antinuclear antibody
(ANA) (1:40 speckled). There was no evidence of systemic
vasculitis and the patient was diagnosed with isolated CNS
vasculitis. She was started on an outpatient regimen of
prednisone 60 mg/d with no evidence of recurrent vasculitis at 12 months.
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Neurology | Volume 90, Number 17 | April 24, 2018

Discussion
Brain metastases may occur in up to 40% of patients with
cancer.1 The 2 cases presented here underscore the importance of a differential diagnosis in evaluating atypical cases of
new mass-like brain lesions in patients with cancer. Brain
metastasis was considered in both patients; however, clinical
and imaging findings were atypical for CNS metastasis, including early stage cancer without known systemic metastasis,
cortically based brain lesions, and atypical patterns of gadolinium enhancement. In these cases, a broad differential diagnosis was important and ultimately histopathology was
critical in confirming the rare diagnosis of CNS vasculitis.
CNS vasculitis is a rare form of vasculitis involving the cerebral vasculature. It is broadly categorized into primary
CNS vasculitis (PCNSV; also referred to as primary angiitis
of the CNS) and secondary CNS vasculitis (SCNSV) based
on the presence of systemic manifestations of vasculitis.
While SCNSV has been attributed to a wide array of systemic
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Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

vasculitides and inflammatory diseases, the causes of PCNSV
are largely unknown. CNS vasculitis has been rarely associated with systemic malignancy. Case reports of CNS vasculitis have been associated with Hodgkin disease,3
leukemia,4 and metastatic breast cancer.5 Similar to these
prior reports, our patients presented subacutely with insidious headache or focal neurologic deficit.
Radiographic findings were atypical for metastasis. Imaging
showed cortically based lesions that lacked the typical enhancing
pattern seen in metastasis. In case 1, the linear pattern of restricted diffusion concentrated in the right frontoparietal cortex
was initially suspicious for encephalitis. In case 2, glioma was
considered given the discrete mass-like nature of the lesion with
surrounding edema. This lesion did not demonstrate the typical
contrast enhancement of a breast metastasis and the atypical
location, faint leptomeningeal enhancement, and a susceptible
artifact on gradient echo sequences did not fit with the classic
pattern of a primary glioma. In both of these cases, imaging
characteristics were insufficient to establish a diagnosis and
further investigation with biopsy was warranted.
In these 2 cases, a histopathologic diagnosis of necrotizing
vasculitis was unexpected. As in these cases, ambiguous clinical presentation and radiographic imaging present diagnostic
and therapeutic predicaments, and providers must weigh the
benefits of early treatment with the risks of an invasive confirmatory biopsy. Given the risks of surgery and advancements
of noninvasive treatments including stereotactic radiosurgery
for managing cerebral metastasis in metastatic cancer, clinicians may consider therapeutic intervention without histopathologic confirmation.6 However, in both of these cases the
diagnosis of CNS vasculitis and subsequent choice of immunosuppressive treatment would not have been identified
without histopathologic evaluation.
Current treatment strategies for CNS vasculitis typically include
high-dose glucocorticoids with or without concurrent cyclophosphamide treatment, with rituximab or azathioprine reserved
as second-line treatment.7 In a retrospective review, Salvarani
et al.8 found a favorable response to treatment in 81% of patients,
highlighting the treatable nature of this condition and need for
early accurate diagnosis. Treatment of CNS vasculitis in patients
with a systemic malignancy undergoing chemoradiotherapy has
not yet been defined. Our first patient experienced clinical response to glucocorticoids followed by plasmapheresis. The importance of concomitantly treating the underlying cancer in
these patients is unknown; further research is warranted.
The etiopathogenesis of CNS vasculitis in patients with systemic
malignancy has not been determined. Recent literature suggests
cerebral amyloid deposits may trigger CNS vasculitis, but the
exact mechanism remains speculative.9 Interestingly, our first
patient developed PCNSV soon after initiation of radiation
therapy. Radiation therapy has been shown to affect immunologic activation,4 and the abscopal effect has been used to describe
distant response of metastatic lesions following local irradiation.10
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It has also been implicated in the formation of atherosclerosis and
cardiovascular complications11 through the systemic activation of
cytokines and growth factors (such as tumor growth factor–β1
and interleukin-1β).11 It is possible that a similar type of immune
modulation occurred in this patient that ultimately manifested in
CNS vasculitis, although this is difficult to assess.
The interplay between cancer and the immune system is
complex. In the last decade, awareness of paraneoplastic
neurologic syndromes has broadened with the description of
increasing numbers of specific cancer-associated antibodies.
Whether cancer-associated CNS vasculitis represents a paraneoplastic neurologic syndrome is not certain. Nonspecific
circulating antibodies (AChR, ANA) were present in both
cases without clear association to pathology.
These cases highlight the importance of a broad differential,
evaluating mimics, and pursuing a histopathologic diagnosis
for cancer patients presenting with a new brain lesion with
ambiguous radiographic and clinical findings.
Author contributions
Joshua Sheehan (medical student): lead role in writing
manuscript. Roy E. Strowd (faculty mentor): acquisition of
data, critical revision of manuscript for intellectual content.
Amy Guzik (faculty mentor): acquisition of data, critical revision of manuscript for intellectual content. Jessica Tate:
critical revisions, intellectual contribution. Rachel Wolfe:
critical revisions, intellectual contribution. Carol Geer: critical
revisions, intellectual contribution, figure design. Ryan Mott:
acquisition of data, figure design.
Study funding
No targeted funding reported.
Disclosure
The authors report no disclosures relevant to the manuscript.
Go to Neurology.org/N for full disclosures.
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Neurology | Volume 90, Number 17 | April 24, 2018

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811

Pearls & Oy-sters: The critical role of histopathology in diagnosing cancer-associated
necrotizing CNS vasculitis
Joshua Sheehan, Jessica Tate, Ryan Mott, et al.
Neurology 2018;90;808-811
DOI 10.1212/WNL.0000000000005350
This information is current as of April 23, 2018
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