Prognostic value of cerebrospinal fluid tumor cell count in leptomeningeal disease from solid tumors.

PURPOSE: Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs), such as CNSide assay, improved the sensitivity of LMD diagnosis, but prognostic value is unknown. This study assesses the prognostic value of CSF-TC density in patients with LMD from solid tumors. METHODS: We conducted a retrospective cohort study of patients with newly diagnosed or previously treated LMD from a single institution who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival. RESULTS: Of 31 patients, 29 had CSF-TCs detected on CNSide. Median (interquartile range [IQR]) CSF-TC density was 67.8 (4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median (IQR) survival from time of CSF-TC detection was 176 (89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival. An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively. CONCLUSIONS: CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.

Meningeal carcinomatosis with decreased visual acuity: a case report.

Meningeal carcinomatosis is a condition in which cancer cells diffusely metastasize to the cerebral pia mater in the cerebrospinal membrane or cerebrospinal cavity. It causes a wide array of symptoms according to the site of metastasis. The prognosis is poor, especially in metastasis from solid tumors. This study reports a case of meningeal carcinomatosis caused by advanced gastric cancer, manifested by headache and vision loss. The patient was a 69-year-old man who underwent head computed tomography (CT) and magnetic resonance imaging (MRI) for persistent headaches. No abnormal findings were found; however, his vision declined, convulsions occurred, and cerebrospinal fluid (CSF) cytology showed poorly differentiated adenocarcinoma. Therefore, meningeal carcinomatosis was diagnosed. The patient died after receiving FOLFOX therapy to relieve symptoms and prolong his life. An autopsy showed no invasion of the optic nerve or surrounding tissues. As the frequency of complications of meningeal carcinomatosis in solid cancers is rare, it is crucial to actively suspect and make an early diagnosis.

Role of intrathecal chemotherapy in the management of meningeal carcinomatosis in patients with breast cancer.

OBJECTIVE: To evaluate whether intrathecal chemotherapy improves clinical outcomes in patients with meningeal carcinomatosis. METHODS: This retrospective cohort study included consecutive patients with breast cancer diagnosed with meningeal carcinomatosis. Clinical and treatment data were collected from the patients' medical charts. The primary outcome was overall survival, and the secondary outcomes were time to neurological deterioration and reporting of clinical benefit. Logistic regression and Cox proportional hazard models adjusted for potential confounders were used to evaluate the clinical response and overall survival, respectively. RESULTS: Overall, 109 female patients were included, 50 (45.9%) of whom received intrathecal chemotherapy with methotrexate and dexamethasone. The median treatment duration was 3 weeks (range, 1-13 weeks). Patients treated with intrathecal chemotherapy were more likely to report clinical benefit (74% versus 57.7%, adjusted odds ratio [OR] = 9.0, 95%CI=2.6-30.9, p<0.001). However, there was no difference in the time to neurologic deterioration (hazard ratio [HR] = 0.96, 95%CI= 0.57-1.59, p=0.86). Patients who received intrathecal chemotherapy did not show an increase in overall survival compared with that of patients who did not receive intrathecal chemotherapy (median overall survival = 1.8 months, 95%CI= 1.27-3.0 versus 2.5, 95%CI= 1.9-3.9, adjusted HR = 0.71, 95%CI= 0.41-1.22, p=0.21). There was a significant interaction between intrathecal chemotherapy and systemic treatment, and patients who received systemic therapy without intrathecal chemotherapy had better overall survival than that of the no-treatment group (adjusted HR = 0.38, 95%CI= 0.20-0.70, p=0.002). CONCLUSION: Intrathecal chemotherapy did not increase overall survival or time to neurological deterioration and should not preclude or postpone systemic treatments.

Liquid biopsy in the setting of leptomeningeal metastases: a systematic review and meta-analysis.

PURPOSE: The blood-brain barrier can prevent circulating tumor DNA (ctDNA) derived from the central nervous system from entering the blood making it challenging to evaluate molecular features of leptomeningeal metastasis (LM). Accordingly, we sought to systematically compare the diagnostic power or significance of ctDNA derived from cerebrospinal fluid (CSF) compared to plasma ctDNA in patients with LM. METHODS: A systematic review and meta-analysis was performed under the PRISMA guideline. We used PubMed, EMBASE, and the EuroPMC to search the literature using combinations of the following terms: circulating tumor DNA, ctDNA, circulating tumor cell, brain metastasis, leptomeningeal metastasis, outcome(s), and prognosis. We included all available English language studies that compared the diagnostic significance of CSF derived and serum ctDNA. All eligible studies level of bias was assessed using the New Castle Ottawa Scale (NOS). RESULTS: Our meta-analysis from 6 included studies (n = 226) that confirmed the diagnostic power of liquid biopsies in detecting genomic alteration is better when taking a CSF-derived samples than from the plasma (RR 1.46 [0.93; 2.29]; I2 = 92%; p-value < 0.01). CONCLUSION: CSF ctDNA is better at describing molecular landscape for LM; such an understanding may ultimately help inform patient treatment and responses to therapy.

Cytopathological differential diagnosis of malignant tumor cells in the cerebrospinal fluid: A retrospective analysis.

Leptomeningeal metastasis is the spread of cancer to the leptomeninges and subarachnoid space and represents a dreadful complication of cancer. The most commonly responsible neoplasms are high-grade lymphomas, leukemias, and some solid tumors, chiefly breast and lung cancer as well as melanoma. Herein we report our ten-year retrospective experience on 715 cases of cerebrospinal fluid cytology, 21 (2.9%) of which were positive for leptomeningeal metastasis. Sample collection and processing, clinical history, interdisciplinary dialog, and ancillary techniques such as immunocytochemistry and flow cytometry are all fundamental in reaching the correct diagnosis and thus optimally caring for patients with leptomeningeal metastasis.

Leptomeningeal Metastases in Melanoma Patients: An Update on and Future Perspectives for Diagnosis and Treatment.

Leptomeningeal disease (LMD) is a devastating complication of cancer with a particularly poor prognosis. Among solid tumours, malignant melanoma (MM) has one of the highest rates of metastasis to the leptomeninges, with approximately 10-15% of patients with advanced disease developing LMD. Tumour cells that metastasise to the brain have unique properties that allow them to cross the blood-brain barrier, evade the immune system, and survive in the brain microenvironment. Metastatic colonisation is achieved through dynamic communication between metastatic cells and the tumour microenvironment, resulting in a tumour-permissive milieu. Despite advances in treatment options, the incidence of LMD appears to be increasing and current treatment modalities have a limited impact on survival. This review provides an overview of the biology of LMD, diagnosis and current treatment approaches for MM patients with LMD, and an overview of ongoing clinical trials. Despite the still limited efficacy of current therapies, there is hope that emerging treatments will improve the outcomes for patients with LMD.

Challenges in the diagnosis of leptomeningeal dissemination of glioblastoma in a patient with fever and xanthochromic CSF: a case report.

BACKGROUND: Leptomeningeal spread with carcinomatous meningitis is a severe complication of glioblastoma, with a poor prognosis. Diagnosis is challenging, as the sensitivity of classic diagnostic investigations remains low for detecting cerebrospinal fluid (CSF) tumor spread and exclusion of infectious causes is mandatory, especially if unusual clinical findings are present. CASE PRESENTATION: A 71-year-old woman was admitted to our hospital for recurrent episodes of high fever and xanthochromic meningitis, with subacute onset. Her past medical history was significant for a left temporal glioblastoma, treated with surgical resection and adjuvant chemo- and radiotherapy, with associated systemic immunosuppression secondary to chemotherapy. An extensive workup especially with molecular microbiology testing for exclusion of infectious causes was performed. CSF was analyzed for typical bacterial and viral causes, but also pathogens associated with immunosuppression, such as Listeria monocytogenes and Cryptococcus neoformans. A therapeutic trial of standard antituberculous drugs with repeated lumbar punctures were needed in order to exclude Mycobacterium tuberculosis and to confirm the diagnosis of carcinomatous meningitis by cytopathological examination of the CSF. CONCLUSIONS: The case describes an unusual clinical presentation of a patient with glioblastoma associated leptomeningeal dissemination, as high fever and xanthochromic CSF could raise important diagnostic and therapeutic challenges in the clinical practice. The diagnosis of carcinomatous meningitis requires an extensive workup for exclusion of infectious causes which is important for urgent oncologic treatment.

Cerebrospinal fluid-dissemination of a ovarian clear cell carcinoma: A leptomeningial carcinomatosis with diagnostic challenges.

Metastases from ovarian cancer to the central nervous system (CNS) are rare, in particular, isolated leptomeningeal metastases (LM) are extremely rare. The gold standard in the diagnosis of leptomeningeal carcinomatosis (LC) is the detection of malignant cells in cerebrospinal fluid (CSF) cytology. A 58-year-old woman diagnosed with ovarian cancer 2 years ago underwent lumbar puncture and CSF cytology in recent months due to new weakness, loss of strength in the lower extremities, and speech disorders. Magnetic resonance imaging CNS was simultaneously visualized and linear leptomeningeal enhancement was demonstrated. CSF cytology showed tumor cells as isolated cells or small clusters of tumor cells with large, partially vacuolated, and abundant cytoplasm, mostly with centrally located nuclei. Given her history of high-grade clear cell ovarian cancer,CSF cytology was positive for malignant cells and a diagnosis of leptomeningeal carcinomatosis was made by the neuro-oncology multidisciplinary tumor board. Since LM also implies a systemic disease, the prognosis is very poor, CSF cytology will play an important role in rapid diagnosis and will be useful both in the right choice of treatment and in the early initiation of palliative care.

Spectrum of EEG Findings in Patients with Leptomeningeal Carcinomatosis and Seizures: Correlation with Neurodiagnostic Results and Outcome.

Purpose: Leptomeningeal carcinomatosis (LC) is a devastating condition in patients with systemic malignancies or primary brain tumors. Although much is known about neuro-radiologic investigations, there is very little information about EEG findings in these patients. Whether EEG is correlated with cranial magnetic resonance imaging (MRI) results and survival has not been investigated. Methods: Medical records of 2340 adult patients with the diagnosis of brain tumor, either metastatic (Group 1) or primary (Group 2), between 2000-2021 were reviewed for the presence of LC and seizures. Demographic and clinical features, laboratory results and Karnofsky performance scores of included patients were noted. Available routine EEG recordings were re-evaluated. Any possible correlation between EEG findings-MRI and EEG findings-survival were investigated statistically. Results: Sixty-six patients with LC and seizures were identified. The most common malignancies were lung cancer and glioblastoma multiforme. Twenty-six EEG recordings of 17 patients in Group 1, and 13 EEGs of 9 patients in Group 2 were available for final analysis. The most common EEG characteristic was background slowing (73%). The most frequent findings were rhythmic periodic patterns or spike wave activity (27%). Sporadic epileptiform discharges (8%) or ictal recordings (4%) were very rare. None of the EEG features correlated with MRI results or survival. Conclusion: There are various EEG patterns in patients with LC and seizures. The most common findings are related to background activity, with rhythmic periodic patterns or spike wave activity being observed less commonly. EEG characteristics do not predict MRI findings or survival.

[Leptomeningeal carcinomatosis from duodenal papillary carcinoma].

A woman in her 50s presented with ataxia and repeated falls during 2nd line S-1 therapy for duodenal papillary carcinoma with metastasis. She was diagnosed with leptomeningeal carcinomatosis based on gadolinium contrast-enhanced magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination, although plain computed tomography (CT) and MRI of the head showed no intracranial occupying lesions. This is a rare leptomeningeal carcinomatosis case with duodenal papillary carcinoma as the primary lesion, although aggressive treatment was not possible due to the decreased consciousness level.

Leptomeningeal carcinomatosis in a patient with recurrent unresectable squamous cell carcinoma of the retromolar trigone-a brief report.

BACKGROUND: The reported incidence of leptomeningeal carcinomatosis is 3-8% in patients with solid tumours. More commonly, it has been described in the setting of advanced cancers of the lung, breast and malignant melanoma. CASE PRESENTATION: A 50-year-old diabetic patient with recurrent unresectable squamous cell carcinoma (SCC) of the right retromolar trigone (rT4bN0M0) presented with severe low backache and weakness in bilateral lower limbs 20 days after the completion of concurrent chemoradiotherapy. Contrast-enhanced MRI of the spine showed multiple nodular enhancing leptomeningeal lesions at the lumbar level and an intramedullary T2/FLAIR-hyperintense longitudinal lesion involving the central cord from C2 to C7 vertebral levels, suggestive of leptomeningeal metastases. Cerebrospinal fluid (CSF) analysis revealed pleocytosis, elevated protein and markedly decreased glucose. The CSF cytology revealed scattered large atypical cells, suspicious for metastasis. Non-contrast MRI of the brain showed a T2/FLAIR-hyperintense lesion involving the right caudate nucleus suggestive of either an acute infarct with haemorrhagic transformation or a haemorrhagic brain metastasis. During assessment, he had high-grade fever and was started on empirical intravenous antibiotics (ceftriaxone, vancomycin and subsequently meropenem) in line with the management for acute bacterial meningitis. Gram staining of CSF did not demonstrate the presence of any bacteria and the specimen was sterile on culture. He did not respond to empirical antibiotics, had a progressive downhill course and eventually died due to aspiration pneumonia. CONCLUSION: This brief report highlights the importance of awareness of leptomeningeal carcinomatosis as a possible cause of backache with sensorimotor deficit and autonomic dysfunction in a previously treated case of head and neck SCC.

Symptomatic leptomeningeal carcinomatosis: a rare presentation of chronic lymphocytic leukaemia relapse.

Central nervous system (CNS) involvement in patients with chronic lymphocytic leukaemia (CLL) is very rare and, when present, it is frequently asymptomatic. Rather, CNS involvement is more common in other haematological malignancies such as mantle cell lymphoma or diffuse large B cell lymphoma. The paucity of literature on CNS involvement in CLL underscores the importance of increasing awareness about its presentation, diagnosis and optimal management. We describe a case of symptomatic leptomeningeal leukaemic involvement as an atypical presentation of CLL relapse. A favourable clinical response was observed following systemic monotherapy with venetoclax.

Leptomeningeal metastases: the future is now.

Leptomeningeal metastases (LM) constitute an involvement of cancer which is associated with marked morbidity and mortality. The contemporary diagnostic and therapeutic management of LM from solid tumors is reviewed. Therapeutic modalities including systemic therapies, cerebrospinal fluid (CSF)-directed therapies, and radiation therapy are discussed. This is to provide context for how the field of LM management may evolve in the near term. The future directions currently undergoing investigation for diagnostic, response assessment, and therapeutic purposes are highlighted. This is done within the context of the pathophysiology of the disease. Specifically the role of CSF circulating tumor cells and cell free circulating tumor DNA in diagnosis and response assement are reviewed. Novel therapeutic approaches across a range of modalities are discussed. Numerous ongoing studies which have the potential to alter the management of LM are referenced.

A case report of prostate cancer with leptomeningeal metastasis.

BACKGROUND: Prostate cancer is the most prevalent cancer in men. However, leptomeningeal involvement by prostate carcinoma is a rare event. CASE: Here, we report a 69-year-old patient with castration-resistant metastatic prostate cancer who presented with headache and ataxia. Brain MRI revealed a huge invasive interaxial mass at right occipital lobe with diffuse thickening and enhancement of meninges, the arachnoid, and the pia mater, and he was diagnosed with leptomeningeal carcinomatosis. The patient received whole brain radiotherapy. CONCLUSION: Despite the fact that brain and leptomeningeal metastases are not very common in patients with prostate cancer, signs and symptoms of nervous system disorders should be assessed carefully, and consideration of such unusual metastases must be considered.

Meningeal carcinomatosis following a curative endoscopic submucosal dissection of early gastric cancer: a case report.

Meningeal carcinomatosis (MC) is reported to occur in 4%-15% of patients with solid tumors. MC is not commonly associated with gastric carcinoma and is extremely rare in patients with early gastric cancer (EGC). MC derived from EGC after curative endoscopic submucosal dissection (ESD) has not been reported before. We present a rare case of a 49-year-old patient who developed MC after curative ESD of EGC. The cancer was an ulcerated lesion approximately 1.0 cm in diameter in endoscopic appearance in the minor curvature of the gastric antrum. The pathological examination after ESD indicated high-grade intraepithelial neoplasia (1.3 × 2.1 cm in size) with localized moderately differentiated adenocarcinoma (0-IIc in tumor stage, intestinal type in Lauren classification), which was confined to the mucosal layer with an intact submucosal layer and muscularis propria. The lesion was removed entirely by curative dissection without vertical and horizontal resection margins involvement in pathology. Two months after ESD, the patient was readmitted for severe headache and vomiting. Cytological examination of the cerebrospinal fluid found malignant tumor cells, which were considered by pathologists to have metastasized from the stomach, further confirming MC derived from EGC. The patient's condition deteriorated dramatically, which prevented him from receiving further therapies, such as chemotherapy, and he died 3 days after the diagnosis of MC. In conclusion, EGC can cause MC, even after curative ESD. New neurological manifestations in patients with EGC can alert physicians to a diagnosis of MC, and more attention needs to be paid to evaluating the nervous system and establishing diagnostic and therapeutic strategies as soon as possible.

Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis.

PURPOSE: Cerebrospinal fluid (CSF) cytology is the gold standard diagnostic test for breast cancer leptomeningeal metastasis (BCLM), but has impaired sensitivity, often necessitating repeated lumbar puncture to confirm or refute diagnosis. Further, there is no quantitative response tool to assess response or progression during BCLM treatment. EXPERIMENTAL DESIGN: Facing the challenge of working with small-volume samples and the lack of common recurrent mutations in breast cancers, cell-free DNA was extracted from the CSF and plasma of patients undergoing investigation for BCLM (n = 30). ctDNA fraction was assessed by ultra-low-pass whole genome sequencing (ulpWGS), which does not require prior tumor sequencing. RESULTS: In this proof-of-concept study, ctDNA was detected (fraction ≥0.10) in the CSF of all 24 patients with BCLM+ (median ctDNA fraction, 0.57), regardless of negative cytology or borderline MRI imaging, whereas CSF ctDNA was not detected in the six patients with BCLM- (median ctDNA fraction 0.03, P < 0.0001). Plasma ctDNA was only detected in patients with extracranial disease progression or who had previously received whole brain radiotherapy. ctDNA fraction was highly concordant with mutant allele fraction measured by tumor mutation-specific ddPCR assays (r = 0.852; P < 0.0001). During intrathecal treatment, serial monitoring (n = 12 patients) showed that suppression of CSF ctDNA fraction was associated with longer BCLM survival (P = 0.034), and rising ctDNA fraction was detectable up to 12 weeks before clinical progression. CONCLUSIONS: Measuring ctDNA fraction by ulpWGS is a quantitative marker demonstrating potential for timely and accurate BCLM diagnosis and therapy response monitoring, with the ultimate aim to improve management of this poor-prognosis patient group.

Leptomeningeal carcinomatosis presenting with acute motor axonal neuropathy.

Leptomeningeal carcinomatosis is a rare, devastating, and mostly late-stage complication of various solid tumors and hematologic malignancies. The diagnosis can be challenging especially if malignancy is not in active phase or treatment was discontinued. A literature search revealed various unusual presentations of leptomeningeal carcinomatosis including cauda equina syndrome, radiculopathies, acute inflammatory demyelinating polyradiculoneuropathy, and others. To the best of our knowledge, this is the first case of leptomeningeal carcinomatosis presenting with acute motor axonal neuropathy variant of Guillain-Barré Syndrome and unusual cerebrospinal fluid findings known as Froin's syndrome.