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.

Efficacy of Slow Rate Ventriculolumbar Perfusion Chemotherapy for Leptomeningeal Carcinomatosis: Interim Result of a Phase II Study

BACKGROUND: To evaluate the efficacy of modified ventriculolumbar perfusion (VLP) chemotherapy with methotrexate on leptomeningeal carcinomatosis in terms of symptomatic response and side effects. METHODS: Previous infusion rate of 20 mL/h was reduced to 15 mL/h for the purpose of decreasing constitutional side effects of VLP such as nausea/vomiting, insomnia and confusion. The primary outcome was the response rate of increased intracranial pressure (ICP), and the secondary outcome was the occurrence of side effects compared to previous 20 mL/h trial. This interim analysis to validate the reduced infusion rate is not to affect the original effect of VLP chemotherapy. RESULTS: All forty-seven patients were enrolled including 22 patients with increased ICP. Thirteen patients out of these (59%) got normalized ICP after VLP chemotherapy. Moderate to severe (grade 2–3) confusion was observed in 3 patients (6%) and it was significantly reduced compared to those (23%) in the VLP 20 mL/h (p=0.017). Grade 2–3 nausea/vomiting was also reduced from 64% to 45% but failed to reach statistical significance (p=0.08). Median overall survival (OS) was 5.3 months (95% confidence interval, 3.55–7.05) and patients OS, who received maintenance VLP was significantly prolonged compared to patients who underwent induction VLP only (5.8 vs. 3.4 months, p=0.025). CONCLUSION: VLP of reduced perfusion rate (15 mL/h) showed compatible control rate of increased ICP at this interim analysis. Decreased moderate to severe side effects and prolonged OS in patients received maintenance VLP encourage us to evaluate the effectiveness of this trial further.

A Retrospective Analysis of the Clinical Outcomes of Leptomeningeal Metastasis in Patients with Solid Tumors

BACKGROUND: Leptomeningeal metastasis (LM) is an uncommon, but devastating complication of advanced cancer and has no standard treatment. Herein, we analyzed the clinical characteristics and outcomes of patients with solid tumors who were diagnosed with LM. METHODS: Between January 2007 and December 2017, we retrospectively analyzed the medical records of patients with solid tumors who were diagnosed with LM. RESULTS: A total of 58 patients were enrolled in this study. The median age of patients was 51 years (range, 27–72 years), and 62.1% had a poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) (>2). The common types of primary tumor were breast cancer (39.7%), gastric cancer (25.9%), and non-small cell lung cancer (20.7%). Forty-two patients (72.4%) were diagnosed with LM by MRI of the brain and/or spine and cerebrospinal fluid (CSF) analysis, 14 were diagnosed by CSF analysis alone, and 2 were diagnosed by MRI alone. Treatments for LM were performed in 53 patients (91.4%), and best supportive care was provided for 5 patients (8.6%). Intrathecal chemotherapy, radiotherapy, and systemic chemotherapy were administered in 43 (74.1%), 17 (29.3%), and 24 (41.4%) patients, respectively. The median overall survival of the entire cohort was 2.4 months (95% confidence interval, 1.0–3.7). In the analysis of prognostic factors for survival, a good ECOG PS (≤2), administration of systemic chemotherapy after LM diagnosis, and a prior history of brain radiation were associated with prolonged survival. CONCLUSION: Although the prognosis of LM in patients with solid tumors is poor, systemic chemotherapy might improve survival in selected patients with a good PS.

Response of Leptomeningeal Dissemination of Anaplastic Glioma to Temozolomide: Experience of Two Cases

The incidence of leptomeningeal dissemination (LMD) of anaplastic glioma has been increasing. LMD can be observed at the time of initial presentation or the time of recurrence. As a result of both rarity and unusual presentation, a standard therapy has not yet been suggested. In contrast to leptomeningeal carcinomatosis for systemic solid cancers, a relatively prolonged survival is observed in some patients with LMD of anaplastic gliomas. Treatment modalities include whole craniospinal irradiation, intra-cerebrospinal fluid (CSF) chemotherapy, and systemic chemotherapy. In some cases, response to temozolomide (TMZ), with or without combined radiation has been reported. Here, we report two cases of LMD of an anaplastic glioma. In one case LMD presented at the time of diagnosis, and in the other at the time of recurrence after radiation. CSF cytology was positive in both cases, and persisted in spite of intrathecal methotrexate chemotherapy. Later, TMZ was prescribed for progressing brain parenchymal lesions, and both radiological and cytological responses were obtained after oral TMZ treatment.

A Case of Isolated Leptomeningeal Carcinomatosis from Advanced Gastric Cancer / 대한소화기학회지

Leptomeningeal carcinomatosis (LMC) is rare metastatic form of gastric cancer. Most cases are diagnosed in the final stage after multiple distant metastasis. An 84-year-old woman was admitted with melena, headache and vomiting. Esophagogastro-duodenoscopy showed an ulceroinfiltrating lesion at the stomach (Borrmann class III), and biopsy revealed a signet ring cell carcinoma. The abdominal-pelvic CT showed no evidence of metastasis. A sudden decrease of consciousness was noted, but the brain CT showed no active lesion while the brain MRI revealed enhancement of leptomeninges. A lumbar puncture was performed and the cerebrospinal fluid study revealed malignant neoplastic cells. With family consent, no further evaluation and treatment were administered and she died six weeks after the diagnosis of gastric cancer. We report an extremely rare case of a patient who initially presented with neurologic symptoms, and was diagnosed LMC from advanced gastric cancer without any evidence of metastasis in abdomen and pelvis.

Retrospective Analysis of Cerebrospinal Fluid Profiles in 228 Patients with Leptomeningeal Carcinomatosis : Differences According to the Sampling Site, Symptoms, and Systemic Factors

OBJECTIVE: Elevated cell counts and protein levels in cerebrospinal fluid (CSF) result from disease activity in patients with leptomeningeal carcinomatosis (LMC). Previous studies evaluated the use of CSF profiles to monitor a treatment response or predict prognosis. CSF profiles vary, however, according to the sampling site and the patient's systemic condition. We compared lumbar and ventricular CSF profiles collected before intraventricular chemotherapy for LMC and evaluated the association of these profiles with patients' systemic factors and LMC disease activity. METHODS: CSF profiles were retrospectively collected from 228 patients who underwent Ommaya reservoir insertion for intraventricular chemotherapy after a diagnosis of LMC. Lumbar samples taken via lumbar puncture were used for the diagnosis, and ventricular samples were obtained later at the time of Ommaya reservoir insertion. LMC disease activity was defined as the presence of LMC-related symptoms such as increased intracranial pressure, hydrocephalus, cranial neuropathy, and cauda equina syndrome. RESULTS: Cell counts (median : 8 vs. 1 cells/mL) and protein levels (median : 68 vs. 17 mg/dL) significantly higher in lumbar CSF than in ventricular CSF (p<0.001). Among the evaluated systemic factors, concomitant brain metastasis and previous radiation were significantly correlated with higher protein levels in the lumbar CSF (p=0.01 and <0.001, respectively). Among the LMC disease activity, patients presenting with hydrocephalus or cauda equina syndrome showed higher lumbar CSF protein level compared with that in patients without those symptoms (p=0.049 and p<0.001, respectively). The lumbar CSF cell count was significantly lower in patients with cranial neuropathy (p=0.046). The ventricular CSF cell counts and protein levels showed no correlation with LMC symptoms. Carcinoembryonic antigen (CEA), which was measured from ventricular CSF after the diagnosis in 109 patients, showed a significant association with the presence of hydrocephalus (p=0.01). CONCLUSION: The protein level in lumbar CSF indicated the localized disease activity of hydrocephalus and cauda equina syndrome. In the ventricular CSF, only the CEA level reflected the presence of hydrocephalus. We suggest using more specific biomarkers for the evaluation of ventricular CSF to monitor disease activity and treatment response.

Intrathecal Trastuzumab Treatment in Patients with Breast Cancer and Leptomeningeal Carcinomatosis / Journal of the Korean Cancer Association, 대한암학회지

Leptomeningeal carcinomatosis is a fatal manifestation of metastatic breast cancer. Investigation of intrathecal (IT) trastuzumab for leptomeningeal carcinomatosis is currently underway; however, there has been no consensus. We report on two cases of human epidermal growth factor receptor 2 positive (HER2+) breast cancer following IT trastuzumab for leptomeningeal carcinomatosis. The first patient was treated with weekly IT 15 mg methotrexate plus IT 50 mg trastuzumab for 7 months, followed by IT trastuzumab (50 mg > 25 mg) for 18 months. The other patient received IT trastuzumab with systemic chemotherapy (trastuzumab and/or paclitaxel) for 13 months. Good control of leptomeningeal disease was achieved with IT trastuzumab in both patients, with survival durations of 20 and 29 months, respectively. We suggest that IT trastuzumab is a promising treatment for patients with HER2+ breast cancer and leptomeningeal carcinomatosis.

Intrathecal Trastuzumab Treatment in Patients with Breast Cancer and Leptomeningeal Carcinomatosis / Journal of the Korean Cancer Association, 대한암학회지

Leptomeningeal carcinomatosis is a fatal manifestation of metastatic breast cancer. Investigation of intrathecal (IT) trastuzumab for leptomeningeal carcinomatosis is currently underway; however, there has been no consensus. We report on two cases of human epidermal growth factor receptor 2 positive (HER2+) breast cancer following IT trastuzumab for leptomeningeal carcinomatosis. The first patient was treated with weekly IT 15 mg methotrexate plus IT 50 mg trastuzumab for 7 months, followed by IT trastuzumab (50 mg > 25 mg) for 18 months. The other patient received IT trastuzumab with systemic chemotherapy (trastuzumab and/or paclitaxel) for 13 months. Good control of leptomeningeal disease was achieved with IT trastuzumab in both patients, with survival durations of 20 and 29 months, respectively. We suggest that IT trastuzumab is a promising treatment for patients with HER2+ breast cancer and leptomeningeal carcinomatosis.

Tumor neuroectodérmico primitivo do terceiro ventrículo associado a metástase leptomeníngea / Primitive Neuroectodermal Tumor of the Third Ventricle Associated with Leptomeningeal Metastases

Os tumores neuroectodérmicos primitivos (PNET) são tumores malignos, não diferenciados, raramente apresentados na idade adulta, principalmente os de localização supratentorial. Apresentamos neste artigo o caso de um paciente de 19 anos, que nos chegou transferido de outro hospital com o diagnóstico de hidrocefalia. A existência do PNET associado a carcinomatose leptomeníngea foi comprovada como causa da hidrocefalia.

Primitive neuroectodermal tumors (PNET) are malignant tumors exceptionally present in adulthood, especially those with supratentorial location. In this article, we present the case of a young man who was transfer fromanother institutionwith the diagnosis of hydrocephalus; during his stay, we corroborated the presence of supratentorial PNET associated to leptomeningeal carcinomatosis that was a cause of hydrocephalus.

Primary Diffuse Leptomeningeal Gliosarcomatosis

Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare condition with a fatal outcome, characterized by diffuse infiltration of the leptomeninges by neoplastic glial cells without evidence of primary tumor in the brain or spinal cord parenchyma. In particular, PDLG histologically diagnosed as gliosarcoma is extremely rare, with only 2 cases reported to date. We report a case of primary diffuse leptomeningeal gliosarcomatosis. A 68-year-old man presented with fever, chilling, headache, and a brief episode of mental deterioration. Initial T1-weighted post-contrast brain magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement without a definite intraparenchymal lesion. Based on clinical and imaging findings, antiviral treatment was initiated. Despite the treatment, the patient's neurologic symptoms and mental status progressively deteriorated and follow-up MRI showed rapid progression of the disease. A meningeal biopsy revealed gliosarcoma and was conclusive for the diagnosis of primary diffuse leptomeningeal gliosarcomatosis. We suggest the inclusion of PDLG in the potential differential diagnosis of patients who present with nonspecific neurologic symptoms in the presence of leptomeningeal involvement on MRI.

Intracranial Meningioma with Leptomeningeal Dissemination : Retrospective Study with Review of the Literature

OBJECTIVE: The purposes of this article are to present 5 cases of intracranial meningioma with leptomeningeal dissemination (LD) and investigate the characteristics of this disease. METHODS: We present a retrospective case series of 5 females at our institutions (age ranged 21-72 years, mean 54.6 years) diagnosed with LD of an intracranial meningioma after surgery between 1998 and 2013. A database search revealed 45 cases with LD of meningioma in the English literature. Characteristic features were analyzed and compared. RESULTS: The incidence rate at our institutions of LD of meningioma was 0.9% (5/534). World Health Organization (WHO) grade was distributed as follows: I : 2, II : 2, and III : 1. Time to LD ranged from 2.5 months to 6.9 years; the patient with WHO grade III had the shortest interval to LD. The patient with an intraventricular meningioma (WHO grade II) had the second shortest interval to LD (1.7 years), and simultaneously revealed both LD and extraneuronal metastases. Four of 5 patients showed a disease progression, with the survival ranging from 1 month to 3.8 years after LD. Based on the literature, the initial tumor was an intraventricular meningioma in 9 patients, and their time to LD was shorter on average (mean 1.9 years). Histologically, 26 of 45 (58%) were initially diagnosed with a WHO grade II or III meningioma, and 6 of 19 patients (32%) with WHO grade I revealed malignant transformation. CONCLUSION: This study shows that intraventricular location and histologically aggressive features seem to increase the chance of LD of meningioma.

Recent Advancements of Treatment for Leptomeningeal Carcinomatosis

Treatment of Leptomeningeal carcinomatosis (LMC) from solid cancers has not advanced noticeably since the introduction of intra-cerebrospinal fluid (CSF) chemotherapy in the 1970's. The marginal survival benefit and difficulty of intrathecal chemotherapy injection has hindered its wide spread use. Even after the introduction of intraventricular chemotherapy with Ommaya reservoir, frequent development of CSF flow disturbance, manifested as increased intracranial pressure (ICP), made injected drug to be distributed unevenly and thus, the therapy became ineffective. Systemic chemotherapy for LMC has been limited as effective CSF concentration can hardly be achieved except high dose methotrexate (MTX) intravenous administration. However, the introduction of small molecular weight target inhibitors for primary cancer treatment has changed the old concept of 'blood-brain barrier' as the ultimate barrier to systemically administered drugs. Conventional oral administration achieves an effective concentration at the nanomolar level. Furthermore, many studies report that a combined treatment of target inhibitor and intra-CSF chemotherapy significantly prolongs patient survival. Ventriculolumbar perfusion (VLP) chemotherapy has sought to increase drug delivery to the subarachnoid CSF space even in patients with disturbed CSF flow. Recently authors performed phase 1 and 2 clinical trial of VLP chemotherapy with MTX, and 3/4th of patients with increased ICP got controlled ICP and the survival was prolonged. Further trials are required with newly available drugs for CSF chemotherapy. Additionally, new LMC biologic/pharmacodynamic markers for early diagnosis and monitoring of the treatment response are to be identified with the help of advanced molecular biology techniques.

A Case of Central Origin Vertigo in Breast Cancer with Brain Metastasis / 대한이비인후과학회지

The incidence of symptomatic brain metastasis among women with breast cancer ranges from 10 to 16%. A metastatic spread of breast cancer to either the brain parenchyma or the leptomeninges is generally a late feature of metastatic progression. The present case of a 55-year-old patient had been considered cured from breast cancer. However, she recently complained of severe dizziness, hearing impairment, and headache. Initially, it was considered to be Meniere's disease or vestibular migraine, although later dizziness, hearing impairment, and headache were aggravated in spite of medication. Pure tone audiometry showed left-sided sensorineural hearing loss, but her vestibular function was within normal range. She underwent a Gadolinium-enhanced magnetic resonance imaging, and a metastatic brain lesion was noted. With a review of the literature, we present this case of breast cancer with brain metastasis in a 55-year-old woman with vertigo and hearing loss.

Incidence and Risk Factors for Leptomeningeal Carcinomatosis in Breast Cancer Patients with Parenchymal Brain Metastases

OBJECTIVE: The objective of study is to evaluate the incidence of leptomeningeal carcinomatosis (LMC) in breast cancer patients with parenchymal brain metastases (PBM) and clinical risk factors for the development of LMC. METHODS: We retrospectively analyzed 27 patients who had undergone surgical resection (SR) and 156 patients with whole brain radiation therapy (WBRT) as an initial treatment for their PBM from breast cancer in our institution and compared the difference of incidence of LMC according to clinical factors. The diagnosis of LMC was made by cerebrospinal fluid cytology and/or magnetic resonance imaging. RESULTS: A total of 27 patients (14%) in the study population developed LMC at a median of 6.0 months (range, 1.0-50). Ten of 27 patients (37%) developed LMC after SR, whereas 17 of 156 (11%) patients who received WBRT were diagnosed with LMC after the index procedure. The incidence of LMC was significantly higher in the SR group compared with the WBRT group and the hazard ratio was 2.95 (95% confidence interval; 1.33-6.54, p<0.01). Three additional factors were identified in the multivariable analysis : the younger age group (<40 years old), the progressing systemic disease showed significantly increased incidence of LMC, whereas the adjuvant chemotherapy reduce the incidence. CONCLUSION: There is an increased risk of LMC after SR for PBM from breast cancer compared with WBRT. The young age (<40) and systemic burden of cancer in terms of progressing systemic disease without adjuvant chemotherapy could be additional risk factors for the development of LMC.

A Case of Cholangiocarcinoma with Brain and Leptomeningeal Carcinomatosis / 대한내과학회지

Cholangiocarcinoma is a malignant disease originating from the epithelium of the biliary tract, and its prognosis is dismal due to distant metastasis in its early stages. The most common metastatic sites are the intra-abdominal organs, lymph nodes, and lungs. A patient was diagnosed with intrahepatic cholangiocarcinoma and underwent surgical resection. During the follow-up period, metastases were detected at the remnant liver and both lung fields. Eleven months after resection, the patient complained of severe headache. An approximately 5-cm cystic mass was found at the left occipital lobe of the cerebrum, and metastatic malignant cells were present on cerebrospinal fluid cytology. The patient underwent whole-brain radiotherapy. We herein report a rare case of cholangiocarcinoma with cystic brain metastasis together with a review of the relevant literature.

Leptomeningeal Carcinomatosis in Solid Tumors; Clinical Manifestation and Treatment / 대한암학회지

PURPOSE: Leptomeningeal carcinomatosis occurs in about 5% of patients with solid tumor and is being diagnosed with increasing frequency as patients live longer and as neuro-imaging studies improve. In general, the most commom cancers that involved the leptomeninges are breast cancer, lung cancer, and malignant melanoma. MATERIALS AND METHODS: We investigated 25 patients presented with multiple neurologic symptoms and signs who were diagnosed with leptomeningeal carcinomatosis at the Yonsei Cancer Center from January 1990 to December 1999. RESULTS: The primary disease of leptomeningeal carcinomatosis were stomach cancer (10 cases), breast cancer (7 cases), lung cancer (5 cases), unknown primary cancer (2 cases) and common bile duct cancer (1 case). All patients were presented with multiple neurologic symptoms and signs involving the central nervous system (CNS), cranial nerve or spinal nerves. Twenty-one of twenty- five patients were treated with intrathecal chemotherapy, radiotherapy, or combination therapy. Fourteen of them (66.7%) experienced improvement or stabilization of neurologic symptom and sign. The median survival was 122 days (10-2190). CONCLUSION: In conclusion, although early diagnosis and active treatment of leptomeningeal carcinomatosis may improve the quality of life in selected patients, the median survival was relatively short. Therefore, new diagnostic and therapeutic strategy for leptomeningeal carcinomatosis were needed.

Brain Metastasis and Leptomeningeal Carcinomatosis in Breast Cancer / 대한암학회지

PURPOSE: Brain metastasis is estimated to occur in 20 to 40% of cancer patients, and meningeal involvement has been reported in 5% to 8% of cancer patients. Even if the prognosis is grave, standard treatment modality of brain metastasis or leptomeningeal carcinomatosis has not been established. We evaluated the prognosis and the clinical features of the brain and leptomeningeal metastasis of the breast cancer. MATERIALS AND METHODS: The 43 patients who was diagnosed as brain parenchymal metastasis or leptomeningeal carcinomatosis clinically, radiologically and/or cytologically were included in this study. The median age was 44(range: 27-61) years. RESULTS: The median duration from brain metastasis to death was 181 days(range: 8~1599), and the median duration from leptomeningeal carcinomatosis to death was 39 days(range: 25~152). Age(p=0.7174) and number of brain metastatic lesion(p=0.4097) did not influence the survival, but the presence of other systemic metastatic lesion affected the survival(p 0.0224). When we compared the survival rates of patients according to treatment modality, the patients with systemic chemotherapy versus patients without systemic chemotherapy showed differences(p= 0.0009). Patients treated with whole brain radiation only versus patients with whole brain radiation and other systemic management also showed different survival rate(p=0.0009). But intrathecal chemotherapy had no effect on survival. Well differentiated, solitary lesions were treated by operation and/or gamma-knife surgery, and their effects were good. CONCLUSION: Prolongation of survival was suggested with whole brain radiotherapy combined with systemic treatment in brain or leptomeningeal metastasis. Further study is expected to confirm this finding.