Cerebrospinal fluid cytology for the diagnosis of lung cancer brain metastasis: a case report

Introduction

Cerebrospinal fluid (CSF) cytological examination holds significant importance for the diagnosis and differential diagnosis of central nervous system (CNS) infections, hemorrhage, meningeal leukemia, lymphoma, and other related conditions. It serves as a pivotal diagnostic tool for clinicians engaged in differential diagnosis and clinical assessment. However, routine CSF tests, such as CSF routine examination and biochemical analysis, although supportive for diagnosis, lack specificity and cannot provide a timely and accurate diagnosis.

Nonetheless, CSF cytology can not only identify diagnostically significant cells, such as tumor cells, but also determine the type of CSF cytological response through the assessment of the quantity, morphology, and proportion of cells present in the CSF. When combined with clinical presentations, this provides direct evidence for the diagnosis and treatment of CNS disorders. Meningeal carcinoma (MC) is a type of malignant tumor that diffusely or multifocally spreads to the pia mater, which is the most severe neurological complication in patients with malignant tumors. With a relatively high incidence and mortality rate, this condition is commonly encountered in clinical practice. However, its lack of specific clinical manifestations often leads to misdiagnosis or delayed diagnosis. Consequently, the survival time for patients with MC is relatively short, and the efficacy of treatment remains uncertain. As a result of these challenges, the diagnosis and management of meningeal metastases have emerged as a hotspot in research, attracting considerable attention (1). We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-37/rc).

Case presentation

A 57-year-old Han Chinese male who had been exhibiting behavioral disorganization and emotional lability for 2 weeks was admitted to the Psychiatric Department of The First Hospital of Hebei Medical University with psychiatric symptoms.

The family reported that the patient began to exhibit psychiatric symptoms without any apparent precipitant 2 weeks prior, including impaired consciousness and cognitive dysfunction, manifesting as mutism without any apparent cause, depression, development of a paranoid personality, melancholy, poor emotional stability, irritability toward family members, discontent with everyone, agitation, a desire to undress, sometimes only wearing an upper garment and rummaging through the bedroom, unresponsive to inquiries from family members, and occasional lying in bed unresponsive and motionless. The patient was unable to recognize familiar individuals, did not recognize commonly used objects, exhibited a decline in calculation abilities (inability to perform simple arithmetic, such as 1+1), and had a significant decrease in activities of daily living (ADLs), being unable to articulate the need to use the bathroom or describe requirements for hydration and nutrition. Consequently, the family contacted emergency services and brought the patient to The First Hospital of Hebei Medical University for treatment. The outpatient department admitted the patient with a diagnosis of “organic psychosis”.

He had been diagnosed with lung adenocarcinoma during a physical examination the previous year and was subsequently treated with antineoplastic therapy (furmonertinib). The physical examination showed the patient had a heart rate of 84 beats per minute, a respiration rate of 16 breaths per minute, a blood pressure of 108/72 mmHg, and a temperature of 36.5 ℃. He was uncooperative during the mental status examination and lay in bed without speaking or moving.

Initial laboratory findings showed significantly elevated counts related to CSF total cell count, CSF white blood cell, mononuclear cell count, CSF biochemistry assay, and CSF protein level. A chemiluminescent immunoassay revealed an extremely high serum carcinoembryonic antigen level; mildly elevated neuron-specific enolase, lactate, and prolactin (PRL) levels; and lower triiodothyronine (TT3) and folate levels. Complete blood count (CBC), coagulation panel, tests for autoimmune encephalitis antibodies and paraneoplastic syndrome autoantibodies, tests for tumor markers and cytokines, and pathogen-targeted sequencing were sent out to the laboratory, which returned negative results (Table 1).

Cranial magnetic resonance imaging (MRI) revealed multiple abnormal intracranial nodular signals, it shows meningeal enhancement, consider the possibility of metastatic tumor. A chest computed tomography (CT) scan with X-ray imaging showed multiple micro- and small nodules in the left lung and the upper and middle lobes of the right lung, a cystic lesion in the right lobe of the liver, atherosclerosis of the aorta, and calcification of the left coronary artery. A CT scan of abdomen and pelvis revealed multiple cystic lesions in the liver and a calcified focus in the right lobe of the liver. Positron emission tomography-CT (PET-CT) revealed the following: (I) spotty, slightly hyperdense lesions in the right frontal and parietal cortices, with no uptake of fluorodeoxyglucose, which was possibly related to drug treatment; (II) a right nasal polyp; (III) multiple nonmetabolic micronodules in the upper lobes of both lungs; (IV) a cyst in the right lobe of the liver; (V) arteriosclerosis; and (VI) degenerative changes in the spine.

Based on the abovementioned results, MC was suspected, and the results of CSF cytology provided direct evidence, confirming this suspicion. CSF cytological analysis indicated abnormalities, with the presence of atypical cells at 4%, activated monocytes at 81%, monocytes at 10%, and lymphocytes at 5%. Figure 1 shows abnormal cells in the CSF, the blue arrows indicate tumor cells and the orange arrows indicate activated monocytes, as indicated by the arrows. Monocytes undergo morphological activation in pathological states upon stimulation by antigens or various physicochemical factors. Activated monocytes exhibit an increase in cell and nuclear size, irregular cell membrane, possible tumor-like protrusions, deepened cytoplasmic staining, and the appearance of vacuoles within the cytoplasm. Atypical cells exhibit large cell bodies, either mononuclear or binucleated. The nuclei are often displaced to the side, nucleoli are visible, the cytoplasm is abundant with strong basophilic staining, and some cell membranes display red villous-like structures.

Figure 1 Abnormal cells in the cerebrospinal fluid. Blue arrows indicate tumor cells; orange arrows indicate activated monocytes. Wright’s staining; magnification, ×1,000.

Based on the abovementioned tests, especially CSF cytology, the case was diagnosed as MC, and given the history of lung cancer, the patient was ultimately diagnosed with lung cancer brain metastasis. After confirmation of the diagnosis, the case was transferred to the local oncology hospital for treatment and management.

All procedures described in this case report were performed in accordance with the ethical committee of The First Hospital of Hebei Medical University and with the Declaration of Helsinki (as revised in 2013). Written informed consent for data publication was obtained from the patient’s relative because the patient was unable to provide it. A copy of the written consent is available for review by the editorial office of this journal.

Follow-up and outcomes

The local clinical diagnosis was consistent with that of The First Hospital of Hebei Medical University, and the treatment instructions were as follows: (I) rest, a semifluid diet, and minimization of infection and fatigue; (II) olanzapine tablets (5 mg) taken orally once daily, Aiyu capsules (1.05 g) taken orally 3 times daily, folic acid tablets (5 mg) taken orally once daily, and furmonertinib (160 mg) taken orally once daily; (III) scheduling of the subsequent cycle of treatment once a week; and (IV) if symptoms worsen, timely medical consultation is encouraged.

International multidisciplinary team (iMDT) discussion

Discussion among physicians at The First Hospital of Hebei Medical University

Medical oncology

The rapid advancement of modern medical technology has significantly improved the diagnosis and treatment of CNS diseases, yet CSF cytological diagnosis remains an irreplaceable technique. CSF analysis is critical to the diagnosis and therapeutic monitoring of various conditions, such as CNS infections, subarachnoid hemorrhage, spontaneous intracranial hypotension, idiopathic intracranial hypertension, demyelinating disease, and malignancy (2-4). Although routine CSF analysis, CSF biochemical testing, and CSF lactate measurement are used for the diagnosis and differential diagnosis of CNS infections and subarachnoid hemorrhage, they lack specificity. In contrast, CSF cytology, recognized as the gold standard for the diagnosis of MC (1), is an examination technique that uses cytocentrifugation or sedimentation techniques to collect CSF cells, after which being stained and examined under a microscope, are classified morphologically and characterized. Specifically, CSF cytology examines the number, morphology, and proportion of cells in the CSF, providing a more specific diagnostic approach.

CSF cytology plays a significant role in the diagnosis and therapeutic monitoring of various conditions, such as CNS infections, neoplasms, leptomeningeal leukemia/lymphoma (5), CNS autoimmune diseases, and subarachnoid hemorrhage (2,6-8). MC represents a rare type of CNS metastatic cancer, with the primary lesions often originating from malignancies such as lung and breast cancer (9-11). It is caused by the metastatic spread of malignant tumor cells that infiltrate the leptomeninges and subarachnoid space diffusely or focally. CSF cytology serves as the gold standard for the definitive diagnosis of MC and is a principal modality for monitoring therapeutic responses. The main morphological features of the tumor cells include an altered nuclear-to-cytoplasmic ratio, abnormal mitotic figures, enlargement of cells and nuclei, and variability in size, among others. MC predominantly affects middle-aged and older adult individuals, often presenting with a subacute onset and rapid clinical progression. The clinical manifestations are complex and diverse and lack specific symptoms and signs but primarily involve the brain, cranial nerve, and spinal cord. Symptoms of brain involvement include headache, vomiting, papilledema, meningeal signs, psychiatric symptoms, seizures, altered consciousness, convulsions, and cognitive dysfunction, among others. Our case primarily exhibited psychiatric symptoms, altered consciousness, and cognitive impairment.

The patient was initially admitted with a provisional diagnosis of organic mental disorder based on the chief complaint and mental symptoms. Subsequent CSF examination and CT scan results suggested a possible clinical diagnosis of MC, which was ultimately confirmed by the identification of atypical cells in CSF cytology. Given the patient’s history of lung cancer, the definitive diagnosis was metastatic lung cancer with MC, and this informed the precise treatment of the patient.

Although CSF cytology is a crucial diagnostic tool, it also faces certain limitations, such as frequent false-negative results. Therefore, when CSF cytology is used for diagnosis, it is necessary to consider the clinical presentation, imaging findings, and other ancillary diagnostic methods comprehensively. Future research should focus on further enhancing the sensitivity and specificity of CSF cytology to reduce the incidence of false-negative results. Concurrently, novel detection techniques and methodologies (12), such as circulating tumor DNA and circulating tumor cells (13) may be explored to improve the accuracy and efficiency of diagnosis.

Several issues on the diagnosis and treatment of this patient were further discussed as follows

Question 1: What is the optimal diagnostic approach for patients with lung cancer brain metastases if CSF cytomorphology examination is not performed?

Expert opinion 1: Dr. Muhammad Zubair Afzal

The patients with suspected brain metastases should undergo the brain imaging. The most sensitive tool to diagnose brain metastasis in suspected lung cancer patients is the MRI. However, CT scan has shown promise in case of large brain metastases, with associated hemorrhagic transformation, the vasogenic edema or the midline shift (14). In patients with brain carcinomatosis/leptomeningeal disease the brain imaging may not always be sensitive. The sensitivity of the MRI in case of leptomeningeal could be as low as 50% requiring additional testing such as the CSF evaluation, more specifically the cytological evaluation of the CSF to confirm the diagnosis (15). The brain imaging is always a right choice when the brain metastases are suspected.

Expert opinion 2: Dr. Toyoaki Hida

Although the gold standard for diagnosis of leptomeningeal disease is through CSF, abnormal MRI findings with the presence of neurological symptoms (non-specific generalized neurological symptoms, such as headaches, confusion, seizures, and radiculopathy) lead to leptomeningeal disease diagnosis.

Question 2: Are there corresponding CSF molecular biomarkers for the early diagnosis of patients with lung cancer brain metastases?

Expert opinion 1: Dr. Muhammad Zubair Afzal

New data is emerging regarding the molecular biomarkers that can more accurately detect the brain metastasis early in patents with lung cancer. There is an emerging technology to detect the presence of circulating tumor cells and cell free tumor specific DNA. These molecular biomarkers could track disease progression, and the treatment response. These molecular markers can also lead to the diagnosis of brain metastasis even before the radiographic evidence (16). In case of targeted mutations, potential biomarkers present in the CSF can also conclude the presence of the CNS/brain metastasis and leptomeningeal disease. Such markers are EGFR mutation. KRAS, CDKN2A, elevated VEGF-C, and elevated Ki-67 in the CSF can also provide the molecular imaging of the CSF involvement (17).

Expert opinion 2: Dr. Toyoaki Hida

There is growing evidence that analyses of cell-free DNA (cfDNA) from CSF could improve sensitivity and accuracy for diagnosing leptomeningeal metastases. Indeed, CSF cfDNA analysis may identify the same gene mutation such as EGFR as that detected in the lung cancer of the patient.

Question 3: Do the principal clinical manifestations of patients with lung cancer brain metastases include psychiatric symptoms? What other clinical manifestations are there?

Expert opinion 1: Dr. Muhammad Zubair Afzal

Brain metastases in lung cancer manifest in different ways. Most common symptoms are the focal due to the mass effect such as stroke like weakness manifesting in the form of focal weakness, focal sensory deficit, cranial nerves deficit, partial or generalized seizures, encephalopathy, slurred speech, blurry vision, cognition issues, lack of attention and focus, headaches, nausea, vomiting, memory deficit, change in personality, disinhibition, unsteadiness and balance issues (18).

Expert opinion 2: Dr. Toyoaki Hida

Patients with brain metastases may present with a wide variety of symptoms due to different areas of the brain being affected. The most common symptoms are headache or back pain, visual disturbances, nausea, vomiting, cranial nerve deficits, walking difficulties, seizures, cauda equina syndrome, and neurological defects including the onset of psychiatric disorders. Even so, these symptoms are mostly nonspecific.

Conclusions

The cytological identification of atypical cells in the CSF confirmed the diagnosis of MC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-37/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-37/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-37/coif). T.H. serves as an unpaid editorial board member of Translational Lung Cancer Research from January 2024 to December 2025. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures described in this case report were performed in accordance with the ethical committee of The First Hospital of Hebei Medical University and with the Declaration of Helsinki (as revised in 2013). Written informed consent for data publication was obtained from the patient’s relative because the patient was unable to provide it. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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