The experience in dealing with abnormal signal intensities in Children with Neurofibromatosis type 1

doi:10.21203/rs.3.rs-3237365/v1

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The experience in dealing with abnormal signal intensities in Children with Neurofibromatosis type 1

https://doi.org/10.21203/rs.3.rs-3237365/v1

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Background: We sought to define the radiologic features which could differentiate non-neoplastic from neoplastic T2 hyperintensities (T2Hs) identiﬁed on MRI in children with neurofibromatosis type 1(NF1) and identify lesions that most likely to require oncologic surveillance.

Methods: We conducted a single-center retrospective review of all available brain MRIs from 49 children with NF1 and 50 healthy pediatric controls. All T2Hs identified on MRI were characterized based on location, presence of T1 hypointensity, mass effect, contrast enhancement, edma, cystic lesion, or lesion related symptoms. Subsequently, all T2Hs were classified using newly established criteria as either unidentified bright objects (UBOs) or probable tumors. Lesion classification was pathologically confirmed in 6 NF1 cases.

Results: T2Hs were present in 35 (71.4%) individuals of the NF1 cohort. UBOs constituted the majority of T2Hs and were most frequently located in basal ganglia, cerebellar hemispheres, and brainstem. T2Hs of 7 NF1 patients were classified as probable tumors, and 6 children with probable tumors received surgical treatment. Five lesions of the six surgical children proved to be glioma.

Conclusion: T2Hs has been found to be a highly sensitive and specific marker for the diagnosis of NF1. With the application of standardized radiologic criteria, a high prevalence of probable brain tumors will be identiﬁed in this at-risk population of children, of which nearly 70% require treatment, emphasizing the need for appropriate oncologic surveillance for NF1 patients with probable brain tumors.

Neurofibromatosis type 1 (NF1) is one of the most frequent neurocutaneous disorders with a prevalence of one in 3,000–4,000 individuals in the general population.¹ UBOs are high signal lesions which was observed in 50–100% of NF1 patients on proton density or T2-weighted MRI.^1–4Most of these lesions are thought to represent non-neoplastic abnormalities.⁵ While, children with NF1 are at substantially increased risk for brain tumors, which may often appear as similar T2 hyperintensities (T2Hs). Prior studies have employed varying radiographic criteria to differentiate brain tumors from presumed non-neoplastic UBOs.⁵ The lack of standardization made it challenging to reliably interpret neuroimaging studies in patients with NF1, and to determine how best to monitor these MRI abnormalities. Since T2Hs were rarely biopsied or surgically resected, there is a pressing need for guidelines that discriminate between UBOs and brain tumors in this at-risk population.^5,6 To address this unmet need, we employed newly established radiographic criteria to comprehensively characterize these common MRI abnormalities, elucidate the characteristics that differentiate neoplastic from non-neoplastic T2Hs in NF1, and identify those lesions most likely to require further surveillance.

All individuals with the diagnosis of NF1, based on NIH diagnostic criteria or genetic testing, who had a brain MRI performed at our institution between June 1, 2016, and December 31, 2022 (n = 53), were retrospectively identified under an approved human subjects protocol at Soochow University. Four individuals were excluded from analysis due to inadequate or incomplete imaging. Demographic and clinical information, including age, sex, race, family history of NF1, diagnosis of an optic pathway glioma (OPG), genetic test results when available, diagnosis of a non-OPG tumor, pathology results when available, and treatment for any tumor were collected from electronic health records. Serial brain MRIs from healthy control patients (n = 50) were identified from clinical and research populations ascertained through the Children’s Hospital of Soochow University.

Classification of T2 hyperintensities

All available brain MRIs from both of the NF1 (n = 49) and control samples (n = 50) were obtained using standardized clinical protocols and were independently reviewed by two investigators. All T2Hs detected on fluid-attenuated inversion recovery(FLAIR) and T2-weighted sequences were individually characterized by (1) location, (2) presence of T1 hypointensity (yes or no), (3) presence of mass effect (yes or no), (4) presence of contrast enhancement (yes or no), (5) presence of cystic lesion (yes or no), (6) presence of lesion related symptoms (yes or no), (7) presence of edema (yes or no), (8)presence of low density of CT scan (if performed). Consensus regarding the characteristics of T2Hs was reached following training by an experienced neuroradiologist. Discrepancies or uncertainties about particular lesions were arbitrated by experienced neuroradiologist, who was blinded to diagnosis.

Lesions were classified as low likelihood of tumor if they had only T2 hyperintensity on MRI. Lesions were classified as intermediate likelihood of tumor if they had T2 hyperintensity and T1 hypointensity (or low density of CT scan). And T2Hs were considered to have a high likelihood of tumor if they have one of the following characteristics: (1)mass effect, (2)cystic lesion, (3)lesion related symptoms, (4) contrast enhancement or (5)edma.

A total of 99 individuals were included for analysis: 49 individuals with NF1 and 50 controls. Of the 49 individuals with NF1, 27 (55%) were male and the mean age was 6.9 years. Of the 50 individuals in the control group, 19 (41%) were male, and the mean age was 7.5 years.

T2Hs were present in 35 (71.4%) individuals in the NF1 cohort (Fig.1) and none of the control individuals, resulting in 71.4% sensitivity and 100% speciﬁcity for a diagnosis of NF1. Overall, a total of 93 unique T2Hs were identiﬁed in the NF1 cohort. Although these T2Hs were identiﬁed in all brain regions (except for neocortical gray matter), the three most common sites of T2Hs were the basal ganglia, cerebellum, and brainstem. Those individuals in the NF1 cohort who had no observable T2Hs on brain MRI (n = 14) include 10 children younger than 4 years old and 3 children older than 10 years old (Fig.2).

In a separate analysis, we found that lesions classiﬁed as intermediate likelihood of tumor showed similar characteristics, prevalence, and changes over time as those classiﬁed as low likelihood of tumor. Using the radiographic criteria outlined above, 7(7.5%) T2Hs were considered to have a high likelihood of tumor (Table.1). Six of the seven children with a high likelihood of tumor received surgical treatment to confirm the pathology. Five of the six lesions were proved to be glioma, and the other one was gliosis (Table.2). Therefore, we refer to all T2Hs with low or intermediate likelihood of tumor as UBOs, and all lesions meeting criteria for high likelihood of tumor as probable tumors.

Illustrative cases

Case1 is a 5 years old girl with a family history of NF1 who presented with multiple café-au-lait spots. MRI was performed at 5 years old which showed abnormal signal in bilateral basal ganglia (Fig.3A-F), OPG(Fig.3G) and subcutaneous mass of left eyelid (Fig.1H). The lesions of basal ganglia could not be visualized on T1-weighted and Diffusion Weighted Imaging(DWI) (Fig.3A,D), which showed hyperintensity on T2-weight, FLAIR and Apparent Diffusion Coefficient(ADC) (Fig.3B,C,E), without mass effect, contrast enhancement (Fig.3F), edema, or cystic appearance. The child also had no related clinical symptoms. So, the lesions were classiﬁed as low likelihood of tumor. The child has been closely followed up with regular MR for more than 5 years, and no significant changes have been found of the lesions.

Case2 is a 7-year-old girl who was diagnosed as NF1 according to the NIH Consensus Development Conference Criteria. She came to our hospital because of decreased muscle strength of the right upper limb. CT scan was performed which showed enlarged ventricles (Fig.4A). MRI was then performed which showed hydrocephalus and abnormal signal in the left basal ganglia with T1 hypointensity (Fig.4B) and hyperintensity on T2-weight, FLAIR，DWI and ADC (Fig.4C-F) without contrast enhancement (Fig.4G). The lesion has associated clinical symptoms and is thought to be associated with hydrocephalus. So, the lesion was classified as high likelihood of tumor. We subsequently performed a biopsy (Fig.4H) and confirmed that the lesion was high-grade glioma. The patient received radiation and chemotherapy and died 13 months after surgery.

Case 3 is a 12-year-old girl who was diagnosed as NF1 according to the NIH Consensus Development Conference Criteria. She came to our hospital because of intermittent headache for 6 months. MRI was performed which showed abnormal signal in basal ganglia and right occipital lobe (Fig.5). The T2Hs in both of basal ganglia and right occipital lobe had T1 hypointensity (Fig.5A). But the T2Hs in right occipital lobe also had contrast enhancement and edema (Fig.5B,C,F,G,H). The lesions in basal ganglia were classiﬁed as intermediate likelihood of tumor, and the lesion in right occipital lobe was classified as high likelihood of tumor. The surgery was performed to resect the lesion in the right occipital lobe which was proved to be high-grade glioma. The child died one year after surgery.

Case 4 is a 5-year-old girl who was diagnosed as NF1 according to the genetic test results. She came to our hospital because of delayed language development and walk unsteadily. CT scan was performed in outpatient which showed a low-density lesion in cerebellum (Fig.6A). MRI was also performed to determine the nature of the lesion (Fig.6B-G), which showed hypointensity on T1 and DWI (Fig.6B,E), hyperintensity on T2, FLAIR and ADC (Fig.6C,D,F) without mass effect, contrast enhancement (Fig.6G), edema, or cystic appearance. The lesion was classiﬁed as high likelihood of tumor due to associated symptom and a biopsy was performed (Fig.6H). The lesion was proved to be gliosis. The child has been closely followed up for more than 3 years and no significant changes have been found of the lesion.

Clinicians should be aware that the risk of center nervous system(CNS) tumors in NF1 patients is much higher than in the general population.^7–9 CNS tumors are a significant source of morbidity in children with NF1.⁵ However, differentiating neoplastic T2Hs from non-neoplastic T2Hs on neuroimaging studies continues to represent a major challenge for clinicians who evaluate and manage this at-risk population of individuals.⁵

In our cohort, the most common locations for T2Hs in children with NF1 are cerebellum, brainstem and basal ganglia. We demonstrate that T2Hs are present in most individuals with NF1, suggesting that T2Hs are a highly sensitive feature of NF1,especially in children between 4 and 10 years old which has been proved in our study.^10,11 In patients younger than 2 years old, UBOs are difficult to see because incomplete myelination of the brain results in an increased T2-weighted signal from the gray matter.^3,12 Therefore, the presence of T2Hs could not be a reliable diagnostic tool in children younger than 2 years old.^3,12 UBOs develop rapidly to produce maximal numbers and volumes between 4 and 10 years old.¹¹This is followed by a reduction in maximal number and volume that continues from late childhood to early adulthood. If growth of UBOs is revealed by serial examinations after 10 years old, careful follow-up should be done.^11,13,14 UBOs are rare in patients older than 20 years old.¹¹ UBOs are typically isointense with white matter on T1-weighted scans, do not have surrounding edema or mass effect, and do not enhance with gadolinium. They do not seem to be responsible for any neurologic deficits.^11,15They typically disappear with age and do not become cystic.^15,16 Basal ganglia UBOs sometimes show T1 prolongation, some mass effect, and it has been postulated that these may be Schwann cell or melanocyte-containing hamartomas.^11,13,17

Traditionally, it has been assumed that these MR imaging abnormalities in NF1 patients represent normal cells in atypical locations (hamartomatous lesions), areas of delayed or disordered myelination or areas of gliosis.^18,19 Pathological correlation performed in pediatric NF1 patients revealed that these UBOs were composed of atypical glial infiltrates, foci of microcalcifications, perivascular gliosis, areas of demyelination, and spongiform myelinopathy.¹⁸ In1997, Carella and Medicamento postulated that tumors might result from the degeneration of these white matter hamartomatous lesions known as UBOs.^18,20 In our study, lesion classification was pathologically confirmed in 6 NF1 cases. Only two patients’ tumor developed in the common site for UBOs, and they were not associated with any UBOs.

In this study, we employed more uniform criteria for T2Hs classification, and suggested that these standards should be employed in future studies to avoid misclassifying. It is recommended that neuroimaging surveillance be implemented for T2Hs classified as high likelihood of tumor, even in the absence of mass effect or contrast enhancement. Future prospective studies will be required to more completely define the natural history and growth trajectory of the T2Hs in NF1 patients, as well as to establish consensus guidelines for the routine surveillance.⁵ It is vital that these patients are investigated by MR, and that gadolinium is given on the first examination in all cases of NF1 referred for brain MR and on follow-up examinations if there has been any change of the T2Hs. At present, gadolinium-DTPA enhancement is still the best indication of malignancy. It is necessary to follow-up the children with NF1 if they have atypical T2Hs particularly between the ages of 7 and 12 years.²¹

Our study demonstrate that T2Hs are present in most individuals with NF1, suggesting that T2Hs are highly sensitive features of NF1. All T2Hs were classified using our newly established criteria as either unidentified bright objects (UBOs) or probable tumors. UBOs constituted the majority of T2Hs. Neuroimaging surveillance should be implemented for T2Hs classified as high likelihood of tumor, most of which require surgical removal.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflicts of interest.

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Table 1 Individualized data of seven patients with lesions classified as high likelihood of tumor.

Patient

gender

Age

(years)

Clinical presentation

Location

Imaging features

asymptomatic

decreased mulsle strength of the right limb

headache

decreased muscle strength of the right upper limb

torticollis

nausea and vomiting

walk unsteadily

cerebellum

left basal ganglia and lateral ventricle

right occipital lobe

left basal ganglia

medulla and cervical cord

right basal ganglia and temporal lobe

cerebellum

T1 hypointensity and contrast enhancement

presence of mass eﬀec and contrast enhancement

presence of mass eﬀect, contrast enhancement, edma, andT1 hypointensity

presence of mass eﬀect, and T1 hypointensity

presence of T1 hypointensity

Table 2 Treatment and outcomes of the 7 patients with lesions classified as high likelihood of tumor.

Patient

Treatment

Histology

Follow up

(months)

Outcome

Gross total excision

Biopsy

Biopsy and chemoradiotherapy

Follow-up

Partial excision and chemotherapy

Biopsy

pilocytic astrocytomas

subependymal giant cell astrocytoma

High grade glioma

glioblastoma

Low grade glioma

gliosis

Disease free

Dead

Disease free

No competing interests reported.

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The experience in dealing with abnormal signal intensities in Children with Neurofibromatosis type 1

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Abstract

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Introduction

Methods

Classification of T2 hyperintensities

Results

Discussion

Conclusions

Declarations

References

Tables

Additional Declarations

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