Analysis of clinical characteristics of leptomeningeal metastasis with band-like high signal in the brainstem

LIN Hui-xia, LIU Ting, YANG Yi-hao, LI Fei, LIANG Bin-ji, LI Li-juan, LI Zhi-qun,LI Qifu?

1. Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou 570102,China

2. Key Laboratory of Tropical Brain Science Research and Translation in Hainan Province Hainan, Haikou 570102, China

Keywords:

ABSTRACT Objective: The aim was to analyse the clinical features of leptomeningeal metastasis with banded high signal in the brainstem.Methods: In this paper, we report two cases of lung adenocarcinoma with soft meningeal metastasis, collected from the First Affiliated Hospital of Hainan Medical College, and searched the databases of CNKI, Wanfang, VIP, PubMed, Web of Science, and other databases which reported the MRI manifestation of "brainstem bandlike high signal", and collected the patients' past medical history, symptoms, signs, genetic findings, cerebrospinal fluid manifestation, treatment, and prognosis.Result: A total of 28 patients were included, of whom 26 had a history of lung adenocarcinoma and 2 were found to have occupational changes in the lungs.Magnetic resonance imaging (MRI) showed a band-like high signal in the ventral part of the brainstem on T2- FLAIR, symmetrical on both sides, which could extend to the cerebellar peduncles, with high signals on diffusion-weighted imaging (DWI), low signals on apparent diffusion coefficient (ADC), and long T1 signals on T1-weighted imaging, long T2 signals on T2 weighted imaging, and no long T2 signals on enhancement scan.T1-weighted imaging was a long T1 signal, T2-weighted imaging was a long T2 signal, and no enhancement was seen on enhanced scanning.Conclusion: It is important to recognize leptomeningeal metastasis of lung cancer, and the non-enhancing band of high signal in the brainstem on T2-FLAIR and DWI is likely to be the characteristic manifestation of leptomeningeal metastasis of non-small cell lung cancer.

1.Introduction

Leptomeningeal Metastasis (LM), also known as meningeal carcinomatosis, is a complication of malignant tumors, commonly seen in lung cancer, breast cancer, lymphoma, leukemia, and malignant melanoma, etc., which is characterized by the infiltration of cells of various malignant tumors into the cerebrospinal fluid, the soft meninges, and the subarachnoid space, which causes a series of neurological deficits symptoms[1].The incidence of soft meningeal metastasis is 3.8% in non-small cell lung cancer, especially in patients with Epidermal Growth Factor Receptor (EGFR) mutations[2].Due to the difficulty of chemotherapeutic agents to cross the blood-brain barrier to reach the lesion site, the prognosis of patients with soft meningeal metastases is poor, with an average survival period of 3-6 months[3].Abnormal manifestations of brainstem nonenhancing banded high signal on T2- FLAIR in MRI have been reported[4-13].In this study, we retrospectively analyzed the clinical presentation features and imaging manifestations of patients with molluscum contagiosum metastasis with banded high signal in the brainstem and speculated on the possible pathophysiological mechanisms.

2.Data and methods

2.1 General information and methods

In this study, 28 patients who attended the First Affiliated Hospital of Hainan Medical College and whose MRI findings were reported as “brainstem band-like high signal” in the search database were included in the study, including 10 males, 15 females, 3 cases of unknown sex, aged 38-96 years, with a mean age of 58.46±13.16 years.Past medical history, symptoms, signs, genetic findings,cerebrospinal fluid manifestations, treatment and prognosis of the included patients were collected and organized.

Inclusion criteria: 1.Magnetic resonance manifestation of ventral banded high signal in the brainstem; 2.Molluscum contagiosum metastasis confirmed by clinical manifestations, laboratory or pathological examination; 3.History of extracranial primary tumor.Exclusion criteria: clear brainstem lesions such as acute cerebral infarction, autoimmune encephalitis and other non-tumor lesions.

2.2 Statistical Methods

Measurement information is expressed as mean ± standard deviation ( if it conforms to normal distribution, and as median if it is not normally distributed, and counting information is expressed as example or rate (%).

3.Results

3.1 Clinical manifestations

Twenty-eight patients had non-characteristic clinical manifestations,mainly presenting with symptoms of chronic cranial hypertension caused by hydrocephalus, including non-specific symptoms such as dizziness, headache, nausea, and vomiting; symptoms of cranial nerve damage such as the scooter nerve and the facial nerve, as well as symptoms of cerebral parenchymal damage, such as epileptic seizures and cognitive deficits, which were mostly combined in most of the patients.Twenty-six patients had a history of lung cancer,including 24 cases of adenocarcinoma of the lung and 2 cases of adenocarcinoma of the lung + squamous carcinoma; and two cases Lung space-occupying changes were found, and malignant tumors were considered.25 patients were previously found to have lung cancer, followed by molluscum contagiosum metastases; 3 patients had neurological as the first symptom, and further examination revealed space-occupying changes in the lungs.23 patients had a combination of parenchymal brain, lung, and bone metastases.(Table 1)

Fig 1 (Case 1): the patient is a female, 72 years old, A, DWI shows high signal; B, ADC shows low signal; C, T1-weighted imaging suggests that the lesion is a long T1 signal; D, high signal on T2 FLAIR; E, enhancement is seen in T1 enhancement of the cerebellar peduncle; F, cerebrospinal fluid cytology reveals anisotropic cells, with large nuclei, nucleoli are seen, the cytoplasm is highly eosinophilic and the cytoplasm is seen to be vacuolated or tumorous in some cells.

Tab 1 Clinical data of brainstem ventral band-like high signal cases

Note: “-” : no relevant clinical information; LM: Leptomeningeal Metastasis; EGFR: Epidermal growth factor receptor.

3.2 Imaging Findings

Cranial MRI of 28 patients showed a band of high signal on the ventral side of the brainstem in T2- FLAIR, symmetrical on both sides, extending to the cerebellar peduncle, with high signal on diffusion-weighted imaging (DWI), and low signal on Apparent Diffusion Coefficient (ADC); long T1 signal on T1-weighted imaging, and long T2 signal on T2-weighted imaging.The brainstem lesions of four patients changed after LM treatment: one patient [6]received intrathecal injection of cytarabine and methotrexate and the diffusion restriction disappeared, but the T2-FLAIR continued to show a low signal, the ADC was high signal, the apparent diffusion coefficient (ADC) was high signal, and the T1-weighted imaging was a long T1 signal, the T2 weighted imaging was a long T2 signal, and the enhancement scan did not show enhancement.five cases combined with cerebellar metastasis, of which four cases saw enhancement of the metastatic lesions, one combined with the left medial frontal metastasis, which saw slight enhancement of changes.T2-FLAIR continued to show high signal; one patient[8] had T2-FLAIR high signal disappear after whole-brain radiation therapy,and brainstem high signal reappeared after 2-month follow-up; one patient[9] also had shrinkage of the brainstem lesion after intrathecal injection of cytarabine and methotrexate; and one patient had disappearance of the brainstem lesion after erlotinib chemotherapy.

3.3 Pathological Examination

Malignant cells were found in the cerebrospinal fluid of 19 patients, and atypical cells were found in the cerebrospinal fluid of 1 patient.Representative case 1 (see Figure 1) cerebrospinal fluid cytomorphological examination: microscopic examination of a small number of anomalous cells, monocyte activation phenomenon is significant, anomalous cells considered tumor cells may be large;anomalous cell characteristics: large nuclei, nuclear chromatin coarse, visible nucleoli; cytoplasm is highly basophilic, some cells can be seen in the cytoplasm of the vacuole or tumorous protuberances.

3.4 Genetic examination

Malignant cells were found in the cerebrospinal fluid of 19 patients, and atypical cells were found in the cerebrospinal fluid of 1 patient.Representative case 1 ( Figure 1) cerebrospinal fluid cytomorphological examination: microscopic examination of a small number of anomalous cells, monocyte activation phenomenon is significant, anomalous cells considered tumor cells may be large;anomalous cell characteristics: large nuclei, nuclear chromatin coarse, visible nucleoli; cytoplasm is highly basophilic, some cells can be seen in the cytoplasm of the vacuole or tumorous protuberances.

4.Discussion

LM patients usually have no special symptoms and signs.They are characterized by difficult diagnosis and high misdiagnosis rate in the clinic.Early diagnosis and identification of risk features are key factors in the treatment of patients.In this study, we summarized and analyzed the patients’ clinical data and auxiliary examinations, and found that the patients were specific in genetic testing, cerebrospinal fluid cytology and imaging examinations.The study is discussed in the context of national and international literature in order to help clinicians to further improve their understanding of this disease.

4.1 Relationship between gene mutation status and brain metastasis

The majority of LM patients with brainstem banded high-signal imaging features have lung adenocarcinoma with EGFR gene mutations, and adenocarcinoma tumors usually have a higher propensity for brain metastasis than lung cancers of other cell types(e.g., squamous cell carcinoma), and molluscum contagiosum metastasis is more common in non-small-cell lung carcinomas with mutations in the EGFR gene[2].It has been shown that EGFR drives the invasive capacity of cells mainly through the downstream pathways of phosphatidylinositol 3-kinase/protein kinase B and phospholipase Cγ, and that EGFR plays a more important role in cell migration and metastasis to brain tissues than 231-BR cells during cell proliferation[15].Therefore, EGFR-mutated lung adenocarcinomas have a higher propensity for brain metastasis.Some scholars further found that EGRF tyrosine kinase inhibitortreated patients with EGFR-mutated advanced non-small cell carcinoma had a lower rate of central nervous system progression,suggesting that EGRF tyrosine kinase inhibitor can delay the occurrence of brain metastasis[14].In this paper, 28 patients had lesions located in the pons, pons and medulla oblongata.Chen et al[16] found that metastases were often located in the left cerebellum,left precuneus and right precentral gyrus in the EGFR mutationpositive group, and brain metastases were often located in the left posterior cerebellum in the ALK mutation-positive patient group.Another study also showed that exon 19 mutations occurred more commonly in the caudate shell, cerebellum, and temporal lobe than exon 21 deletions, suggesting that the type of mutation may affect the site of metastasis of cancer cells to the intracranial area[17].Therefore, we suggest that different gene mutation types may be associated with the onset of invasion and the site of metastatic colonization of malignant tumors.

4.2 Cerebrospinal fluid cytology and liquid biopsy

The gold standard for LM diagnosis is cerebrospinal fluid cytology, and the diagnosis of molluscum contagiosum metastasis can be confirmed by finding tumor cells in the cerebrospinal fluid.Typical tumor cells have features such as variable cell size, large nuclei, disproportionate nucleoplasmic ratio, and increased nuclear division, which are easy to distinguish from other cells.However,the sensitivity of cerebrospinal fluid examination is low, in this paper, many cases in the first time to obtain cerebrospinal fluid did not detect malignant cells, in multiple lumbar puncture before the detection of tumor cells.Pellerino[18] and other studies found that the sensitivity of the first lumbar puncture is only 44-67%, the patient usually need to repeat lumbar puncture on the sampling of cerebrospinal fluid in order to improve the detection rate, repeated sampling sensitivity can be improved to 84-91% after repeated sampling.Several new techniques have been developed to improve the detection of circulating tumor cells in cerebrospinal fluid.In a prospective study, circulating tumor cells (CTC) were detected by epithelial cell adhesion molecule (EpCAM) immunoflow cytometry in 81 patients with clinically suspected LM but not confirmed by MRI, and CTC were determined to be highly sensitive for the diagnosis of LM, with sensitivities in the range of 75%-100% and specificities in the range of 84%-100%.84%-100%, which is more sensitive than traditional cerebrospinal fluid cytology[19].Many cerebrospinal fluid biopsy techniques are being rapidly developed,but there are still no uniform diagnostic thresholds and guidelines for methods of performing cerebrospinal fluid biopsies, and further studies are needed to clarify the thresholds and criteria for LM individuals.Therefore, due to the low detection rate of biological tests, it is particularly important to seek other disease features and imaging markers for LM.

4.3 Magnetic resonance findings and pathophysiological mechanism

Magnetic resonance is currently the best noninvasive method for detecting LM, and any manipulation of meningeal irritation(including surgery and lumbar puncture) may affect the results of magnetic resonance examination and lead to the appearance of false-positive results, so it is necessary to improve the magnetic resonance examination prior to the lumbar puncture to improve the accuracy of the imaging examination[20].The presence of linear or curvilinear, nodular, focal or diffuse enhancement of the limbic meninges often suggests limbic metastasis.In this paper, we review 28 patients with diffusion-weighted imaging (DWI) that differed from the common imaging manifestations of LM, all of which had high signal and low apparent diffusion coefficient (ADC).DWI is an imaging modality commonly used in the clinic for the evaluation of ischemic strokes, abscesses, and tumors of the central nervous system.High signal on DWI and low signal on ADC are thought to be a form of diffusion limitation and are associated with cytotoxic edema and extracellular interstitial space narrowing[21].Malignant tumor cells are characterized by rapid proliferation and large nuclei,a histopathological property that reduces the space for extracellular matrix and water plasmids to diffuse outside the cell[22], resulting in reduced ADC values.Some scholars have hypothesized that the most likely cause of brainstem lesions is infiltration of malignant cells in the cerebrospinal fluid reservoir around the brainstem into the microvasculature leading to microinfarction based on imaging manifestations[4].Yokota[11] et al.reported that after 5 months of antitumor therapy with erlotinib in a patient with meningeal carcinoma, follow-up revealed that this patient had lost the banded hypersignal on FLAIR and DWI of MRI, suggesting that the banded hypersignal in the brainstem was associated with tumor invasion correlation, and this change is reversible.

Case 1 reported in this paper showed enhancement of the parenchymal metastatic brain lesion and no enhancement of the ventral brainstem lesion on magnetic resonance enhancement scan.This is similar to the case reported by Obara[13] in which the patient had no enhancement of the brainstem lesion and enhancement was seen in the left temporal lobe lesion.However, there is still uncertainty as to the reason for the absence of enhancement of ventral brainstem lesions in enhanced MRI.The blood-brain barrier is an important structure that protects brain tissue from injury and prevents the invasion of harmful substances in the circulating blood.Factors affecting MRI enhancement include the size of the open window of the blood-brain barrier, local blood flow, surface area of capillaries, and energy-dependent pumps[24].Enhancement in the brain parenchyma may occur due to a greater disruption of the blood-brain barrier, with a larger open window size allowing gadolinium chelates to pass through, in addition to richer local blood flow, larger surface area, and energy pump activity, all of which are involved in gadolinium transport into the blood-brain barrier,ultimately affecting the enhancement of the brain parenchyma.Magnetic resonance enhancement may also be related to targeted therapies, which can lead to microvascular regression and inhibition of neovascularization[23], making it difficult for gadolinium to reach the lesion site.The case in this article was treated with targeted drugs before the development of soft meningeal metastases, which may be an important reason for the lack of enhancement of the brainstem lesion.In conclusion, the reasons for incomplete enhancement of the nervous system are complex, but as the disease progresses,enhancement of the lesion may occur after further disruption of the blood-brain barrier by tumor cells.Hatzoglou et al[26] found in a retrospective study that in a patient with a primary CNS tumor with LM, the patient’s imaging findings showed that the patient had an initially non-enhancing soft meningeal metastatic lesion on the left cerebellar earthworm, and that the site eventually showed enhancement after 15 months.after which the site eventually showed enhancement.The reason for the lack of enhancement in all of the cases we observed may be that the patient died within a relatively short time after the discovery of the chondroplasma metastasis, and thus no enhancement of the ventral brainstem lesion was observed,a hypothesis that needs to be confirmed by following up the imaging performance and biopsy of the lesion site for a longer period of time.In this paper, we analyzed the clinical features of 28 rare cases of non-enhancing band-like high signal in the ventral side of the brainstem on T2-FLAIR and DWI.This finding may be a characteristic manifestation of molluscum contagiosum metastasis secondary to non-small-cell lung cancer, and it also reminds the clinicians to highly suspect molluscum contagiosum metastasis when they find such characteristic imaging manifestations of the case in the clinic, even if malignant cells are not detected in the cerebrospinal fluid.

Authors’ contribution

Huixia Lin: data collection, statistical analysis and processing, and article writing; Ting Liu: topic selection and design; Yihao Yang:quality assessment of the article, Qifu Li: feasibility assessment of the topic selection, and revision of the article; Fei Li, Binki Liang,Lijuan Li, Zhiqun Li: data collection.