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Leptomeningeal metastasis

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Leptomeningeal metastasis

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Leptomeningeal metastasis

  1. 1.  Introduction  Epidemiology  Pathophysiology  Clinical Presentation  Diagnosis  Treatment  Case discussion
  2. 2.  Introduction  Epidemiology  Pathophysiology  Clinical Presentation  Diagnosis  Treatment  Case discussion
  3. 3.  Leptomeninges – defined as the Pia mater and the arachnoid.  Ability to metastasize from the primary tumor and spread to distant sites in the body is a cardinal feature of malignancy.  Invasion of leptomeninges or CSF by cancer is called leptomeningeal metastasis (LM) or neoplastic meningitis.
  4. 4.  Carcinomatous meningitis → carcinoma  Meningeal gliomatosis → malignant glial tumors  Leptomeningeal metastasis → solid tumors  Lymphomatous meningitis → lymphoma  Leukemic meningitis → leukemia
  5. 5.  Historically, LM were often diagnosed at autopsy.  1978 : Among 2375 autopsies of cancer pts, LM occurred in 8%1  2008 : Metastasis to the brain parenchyma is relatively common, occurring in 9% to 15% of cases in autopsy studies of patients who die of cancer,3 and tumors can also metastasize to the dura or to the leptomeninges.4 1-Postner, Intracranial metastanses from systemic cancer, Advances in Neurology 1978 3-DeAngelis L, Posner J. Neurological complications of cancer. 2nd ed. New York,NY: Oxford University Press, 2008 4-Suki D, Abouassi H, Patel AJ, et al. Comparative risk of leptomeningeal disease after resection or stereotactic radiosurgery for solid tumor metastasis to the posterior fossa. J Neurosurg 2008;108(2):248Y257
  6. 6.  LM known for well over 100 years5; it was once thought to be rare but has been diagnosed more frequently in recent years. 3-DeAngelis L, Posner J. Neurological complications of cancer. 2nd ed. New York,NY: Oxford University Press, 2008 4-Suki D, Abouassi H, Patel AJ, et al. Comparative risk of leptomeningeal disease after resection or stereotactic radiosurgery for solid tumor metastasis to the posterior fossa. J Neurosurg 2008;108(2):248Y257 5-Eberth C. Zur Entwickelung des Epithelioms (Cholesteatoms) der Pia und der Lunge. Virchows Arch 1870;49:51Y63
  7. 7.  Multiple reasons for the increased frequency of diagnosis of LM › Improved diagnostic methods → MRI › More frequency use of MRI › Survive longer → more effective Tx, and LM tends to be a late-stage development › Use of agents that do not cross the blood brain barrier eg, trastuzumab in breast cancer and gefitinib or erlotinib in non- small cell lung cancer
  8. 8.  Introduction  Epidemiology  Pathophysiology  Clinical Presentation  Diagnosis  Treatment  Case discussion
  9. 9.  Clinically diagnosed LM affect ~ 5% of pt with metastatic cancer but undiagnosed or asymptomatic involvement is more common2  In Autopsy studies → the frequency of LM averages 19% of pts with cancer pts.6  LM is diagnosed in 7 › 4-15% of pt with solid tumors › 5-15% of pt with leukemia and lymphoma › 1-2% of pt with primary brain tumor 2-Marc C., The Neurologist 2006;12: 179–187 6-Glass JP, Melamed M, Chernik NL, et al. Malignant cells in cerebrospinalfluid (CSF): the meaning of a positive CSF cytology. Neurology 1979;29:1369 –1375. 7-Chamberlain MC. Carcinomatous meningitis. Arch Neurol. 1997;54:16–17.
  10. 10.  Adenocarcinoma is the most frequent histology.2  Breast, lung and melanoma are the most common primary sites to LM.2  >70% presents in pts with widely disseminated and progressive systemic cancer 2  20% present after a disease-free interval2  5-10% be the first manisfestation of cancer2 2-Marc C., The Neurologist 2006;12: 179–187
  11. 11. Marc C.,Neuroplastic Meningitis, The Neurologist 2006:12 : 180
  12. 12. Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):328–342.
  13. 13.  Median age › 56 yr (19-87 yr)  Median Karnofsky Performance Scale Score › 70 (10-100)  Length of time from initial cancer Dx to Dx of LM › 0-22.6 yr  Median interval times › Solid tumor 2 yr › Hematologic primary tumor 11 months 2-Marc C., The Neurologist 2006;12: 179–187
  14. 14.  Mortality/Morbidity8 › Median survival;  7 months for LM from Breast cancers  4 months for LM from Small cell lung cancers  3.6 months for LM from Melanomas › Without therapy, survive 4-6 weeks (death with progressive neurologic dysfunction) › With therapy, most pts die from the systemic complication of their cancer 8-R Andrew Sewell, Leptomeningeal Carcinomatosis , Medscape
  15. 15.  Treatment remains palliative, and median survival is typically in the range of 2 to 3 months.  In the MSKCC series › Overall median survival was 2.4 months (95% CI, 1.9-3.1). › Median survival for patients with solid tumors was 2.3 months (95% CI,1.7-2.6) › Median survival for patients with hematopoietic tumors was a slightly better 4.7 months (95%CI, 2.7-6.8) 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  16. 16. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  17. 17.  Introduction  Epidemiology  Pathophysiology  Clinical Presentation  Diagnosis  Treatment  Case discussion
  18. 18.  Cancer cells reach the meninges by various routes9 1. Direct extension from contiguous tumor deposits 2. Hematogenous spread, either through the venous plexus of Batson or by arterial dissemination 3. Through centripetal migration from systemic tumors along perineural or perivascular spaces 9-Roelein h., Leptomeningeal metastases, Cancer treatment and research, Springer 2005
  19. 19.  Tumor cells may also invade the spinal or cranial nerves, cerebral cortex, or spinal cord via the Virchow-Robin spaces  Cancer cells are transported by CSF flow resulting in disseminated and multifocal neuraxis seeding of LM  Tumor infiltration is most prominent at the base of brain (basillar cisterns), the dorsal surface of the spinal cord, and the cauda equina
  20. 20. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  21. 21. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  22. 22.  Introduction  Epidemiology  Pathophysiology  Clinical Presentation  Diagnosis  Treatment  Case discussion
  23. 23.  LM classically presents with pleomorphic clinical manisfestations encompassing synmptoms and signs in 3 domains › Cerebral hemispheres › Posterior fossa/Cranial nerves › Spinal cord and roots
  24. 24. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  25. 25. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  26. 26. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  27. 27.  The finding of multifocal neuraxis disease in a patient with known malignancy is strongly suggestive of LM  1/3 patients with LM to present with isolated syndromes such as symptoms of raised intracranial pressure, cauda equina syndrome, or cranial neuropathy.
  28. 28.  Introduction  Epidemiology  Pathophysiology  Clinical Presentation  Diagnosis  Treatment  Case discussion
  29. 29.  The evaluation begins with a careful history, seeking complaints suggestive of multifocal involvement.  The diagnosis of LM is straightforward in the patient with advanced cancer, multifocal signs and symptoms, typical imaging findings, and positive CSF cytology. Pathophysiology, clinical features, and diagnosis of leptomeningeal metastases (carcinomatous meningitis), Uptodate
  30. 30.  MRI and CSF are complementary, and the use of both increases diagnostic accuracy.10  An enhanced MRI of the symptomatic region of brain or spine should be obtained prior to doing a lumbar puncture (LP) or ventricular tap.  A positive CSF cytology establishes the diagnosis of LM. 10-Straathof CS, de Bruin HG, Dippel DW, Vecht CJ. The diagnostic accuracy of magnetic resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis. J Neurol 1999; 246:810.
  31. 31.  Patients may be diagnosed with LM when one of the following criteria is met:11 1. Positive CSF cytology 2. Positive LM biopsy 3. Positive MRI in a pateint with a clinical syndrome compatible with the diagnosis 4. Abnormal CSF biochemical markers consistent with LM 11-Roelein h., Leptomeningeal metastases, Cancer treatment and research, Springer 2005
  32. 32.  MRI should be performed in pt with suspected LM.  MRI with gadolinium enhancement(MR-Gd) is the technique of choice to evaluate patients with suspected leptomeningeal metastasis.  T1-weighted sequences, with and without contrast, combined with fat suppression T2- weighted sequences, constitute the standard examination.
  33. 33.  Highly sensitive for diagnosis of LM from solid tumors (76-100%)  Less sensitive for hematopoieric tumors  MSKCC › 98% of solid tumor → MRI positive for LM 88% › 88% of hematopoietic tumor → MRI positive for LM 48%
  34. 34.  Typical MRI findings › Leptomeningeal enhancement in LM can be linear but often has irrigularity or nodularity › Often visible in the subarachnoid space, cerebellar folia, or cortical surface, and tumor masses, especially at the base of the brain, with or without hydrocephalus13  Occasionally, frank LM are not seen on MRI, but bulky subependymal disease or multiple small sulcal metastases suggest the diagnosis13 13-Pathophysiology, clinical features, and diagnosis of leptomeningeal metastases (carcinomatous meningitis), Uptodate
  35. 35.  In patients with encephalopathy and no localizing findings on MRI, the diagnosis may be suggested by positron emission tomography (PET) demonstrating diffusely diminished glucose utilization in an otherwise normal-appearing brain13 13-Pathophysiology, clinical features, and diagnosis of leptomeningeal metastases (carcinomatous meningitis), Uptodate
  36. 36.  MRI can show linear enhancement of the entire cord and linear or nodular enhancement of the cauda equina.13  Occasionally, clumping of nerve roots at the cauda equina suggests the diagnosis if contrast enhancement is not seen.13  A spinal tumor may obstruct CSF flow, resulting in hydrocephalus 13-Pathophysiology, clinical features, and diagnosis of leptomeningeal metastases (carcinomatous meningitis), Uptodate
  37. 37.  CSF analysis is the gold standard for diagnosis of LM.12  The presence of malignant cells in the CSF is diagnostic of LM. (sensitivite 71% → 86% → 93% →…)12  The CSF is abnormal in nearly all patients, but many abnormalities are non-specific.11  Abnormalities include11 1. increased opening pressure (200 mm of H2O) 2. Increased leukocytes (4/mm3) 3. elevated protein (50 mg/dL) 4. decreased glucose (60 mg/dL) › which, though suggestive of LM, are not diagnostic. 11-Roelein h., Leptomeningeal metastases, Cancer treatment and research, Springer 2005 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):328–342.
  38. 38. Marc C.,Neuroplastic Meningitis, The Neurologist 2006:12 : 181
  39. 39. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  40. 40.  Tumor markers (eg, CEA, PSA, CA-15-3, CA-125, and MART-1 and MAGE-3 in melanoma) may provide evidence for CSF dissemination of disease, even when serial cytological evaluations are negative.13  Level of tumor markers are compared between CSF and Serum if CSF level greater than 1% of that in the serum is virtually diagnostic of LM.12 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342. 13-Pathophysiology, clinical features, and diagnosis of leptomeningeal metastases (carcinomatous meningitis), Uptodate
  41. 41.  Use of monoclonal antibodies for immunohistochemical analysis in LM does not significantly increase the sensitivity of cytology alone.  However, in the case of leukemia and lymphoma, antibodies against surface markers can be used to distinguish between reactive and neoplastic lymphocytes in the CSF.
  42. 42.  Cytogenetic studies have also been evaluated in an attempt to improve the diagnostic accuracy of LM.  Flow cytometry and DNA single cell cytometry, techniques that measure the chromosomal content of cells, and fluorescent in situ hybridization (FISH) that detects numerical and structural genetic aberrations as a sign of malignancy can give additional diagnostic information but still have a low sensitivity.  In cases where there is no manifestation of systemic cancer and CSF examinations remain inconclusive, a meningeal biopsy may be diagnostic.
  43. 43.  Introduction  Epidemiology  Pathophysiology  Clinical Presentation  Diagnosis  Treatment  Case discussion
  44. 44.  The evaluation of treatment of LM is complicated by the lack of standard treatments  The difficulty of determining response to treatment given the suboptimal sensitivity of the diagnostic procedures and that most patients will die of systemic disease, and the fact that most studies are small, nonrandomized,and retrospective  However, it is clear that treatment of LM can provide effective palliation and in some cases result in prolonged survival.  Treatment requires the combination of surgery, radiation, and chemotherapy in most cases
  45. 45.  Goals of treatment › The goals of treatment include stabilizing or improving neurologic function, prolonging survival and if these are not possible  Prognosis › depending upon the tumor type and extent of both neurologic and systemic disease  Patient › Good risk vs Poor risk patient
  46. 46.  The palliative regimen can include the following components: › RT can be useful for relief of symptoms caused by localized leptomeningeal metastases. › Analgesics are given for persistent pain. › Anticonvulsants should be reserved for patients with seizures (10 to 20 percent of cases) and should not be administered prophylactically. › Serotonin reuptake inhibitors or stimulant medications (eg, modafinil, methylphenidate) may be beneficial for patients with significant depression or fatigue.
  47. 47.  Treatment is directed at controlling the tumor.  RT is used to treat bulky or symptomatic areas of leptomeningeal disease, intrathecal (IT) or systemic chemotherapy is given to achieve therapeutic concentrations in the CSF
  48. 48.  Surgery  Chemothery › Regional › Systemic  Radiotherapy
  49. 49.  Use in treatment of LM for the placement of 1. Intraventricular catheter and subgaleal reservoir for administration of cytotoxic drugs 2. Ventriculoperitoneal shunt in pts with symptomatic hydrocephalus  Drugs can be instilled into the subarachnoid space by lumbar puncture or via an intraventricular reservior system
  50. 50.  2 basic types of reseviors 1. Rickham reservior : a flat rigid reservior placed over a burr hole 2. Ommaya resevior : a dome-shaped resevior  Reserviors are generally placed over nondominant frontal region, catheter is placed into frontal horn of the lateral ventricle or close to the foramen of Monro.  Correct placement of the catheter by noncontrast CT prior to its use for drug administration, and frequently it will show a small amount of air in both frontal horns.
  51. 51.  Used in treatment of LM for 1. Palliation of symptoms, such as a cauda equina syndrome. 2. To decrease bulky disease such as coexistent parenchymal brain metastases. 3. To correct CSF flow abnormalities demonstrated by radionuclide ventriculography. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  52. 52.  RT appears to be more effective at relieving symptoms than does IT chemotherapy.  Standard treatment for LM includes palliative RT (30 to 36 Gy in 3 Gy daily fractions) to sites of symptomatic or bulky disease.  Suggest administering RT to sites of obstruction of CSF flow, as demonstrated by a radionuclide CSF flow study, prior to IT chemotherapy. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  53. 53.  To avoid excess myelosuppression and other toxicity such as severe fatigue, esophagitis, diarrhea, and nausea, focal rather than craniospinal RT is preferred.  Radiation is usually targeted to symptomatic areas even in the absence of MRI abnormalities: › Cranial irradiation is used in patients with isolated cranial neuropathies or focal collections of malignant cells causing noncommunicating hydrocephalus. › Patients with lower extremity weakness, or bladder or bowel dysfunction, generally receive lumbosacral spine irradiation. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  54. 54.  Chemotherapy is the only treatment modality that can treat the entire neuraxis.  Systemic VS Intrathecal CMT 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  55. 55.  Systemic chemotherapy is limited by › Penetration of drug into the CNS › Degree of chemoresistance of primary tumor  High doses of Methotrexate (3 – 8 g/m2) or cytarabine (3 g/m2) produce high enough serum levels to allow for therapeutic levels in CSF, but very low permeability.  Capecitebine, thiotepa and temozolomide cross BBB more effectively and potent for treatment LM. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  56. 56.  Systemic chemotherary use in pt with concomitant parenchymal, dural or systemic metastasis.  Choice of agent depend on › Tumor histology › Prior drug exposure 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  57. 57.  IT CMT is the mainstay of treatment for LM.  IT chemotherapy infuse directly into the subarachnoid space via › Lumbar puncture › Intraventricular reservoir (Ommaya)  Methotrexate, thiopeta, cytarabine or sustained-release cytarabine can be used.  Minimizes systemic S/E and eliminate BBB or blood-CSF barrier drug penetration. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  58. 58. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  59. 59.  Most common toxicity is an acute aseptic meningitis, occuring 2-4 hr after drug instillation. › Corticosteroids can be used to prevent or treat  IT injection via LP can result in inadvertent subdural or epidural drug delivery. 12-Jennifer L. Clarke, Leptomeningeal Metastasis From Systemic Cancer, Continuum Lifelong Learning Neurol 2012;18(2):32–342.
  60. 60. Marc C.,Neuroplastic Meningitis, The Neurologist 2006:12 : 180
  61. 61.  LM often causes communicating hydrocephalus → ↑ ICP  Elevated ICP is treated initially with dexamethasone, and a dose of 8 mg twice a day is usually effective. › Dexamethasone should be started early and the dose reduced as quickly as possible until the lowest effective dose is achieved.  Dexamethasone → RT → Ventriculoperitoneal shunting → Reservoir + IT CMT
  62. 62. Diagnosis Supportive care Treatment Poor prognosis Good Prognosis CNS imaging Bulking disease or symptomatic sites No bulky diasease Ommaya placement Marc C.,Neuroplastic Meningitis, The Neurologist 2006:12 : 180
  63. 63. Bulking disease or symptomatic sites Supportive care Radiation therapy Ommaya placement CSF flow study Marc C.,Neuroplastic Meningitis, The Neurologist 2006:12 : 180
  64. 64. CSF flow study CSF flow block Normal CSF flow IT ChemotherapyRT to site of block CSF flow study CSF flow block Normal CSF flow Marc C.,Neuroplastic Meningitis, The Neurologist 2006:12 : 180
  65. 65.  Introduction  Epidemiology  Pathophysiology  Clinical Presentation  Diagnosis  Treatment  Case discussion
  66. 66.  A 40 year-old women presented with progressive headache for 3 weeks. She notices that the headache was aggrevated by lying down or cough. The headache did not respond to acetaminophen  She had breast cancer diagnosis 2 years ago with positive axillary LNs.  She was treated with neoadjuvant chemotherapy (doxorubicin and cyclophosphamide), followed by docetaxel and tratuzumab with complete cycles.
  67. 67.  Her neurological examination showed papilledema.  MRI brain demonstrated T1-weighted gadolinium-enhanced of leptomeninges coating along brainstem and cerebellar folia.  CSF showed 10 WBC, protein of 82 mg/dL, and glucose of 64 mg/dL.  Cytology demonstrated numerous malignant cells.
  68. 68.  A 60 year-old man presented with progressive right facial palsy, followed by bilateral lower extremities weakness and urinary incontinence for 3 weeks. He also had mid-thoracic back pain.  He has been diagnosed with stage IIIA non- small cell lung cancer with metastasis to ipsilateral mediastinal LNs.  He was treated with cisplatin and etoposide followed by surgery 1 year ago.
  69. 69.  Neurological examination revealed right facial palsy (UMN), bilateral legs weakness (gr III), more severe on left side, with decreased reflex on right knee jerk and left ankle jerk.  MRI spine showed gadolinium enhancing lesion along cauda equine.  CSF showed 15 WBC, protein 72 mg/dL and glucose 20 mg/dL.  Cytology showed malignant cells.
  70. 70. A. brain abscess B. leptomeningeal carcinomatosis C. paraneoplastic cerebellar degeneration D. pseudotumor cerebri E. viral meningitis
  71. 71. A. breast cancer B. lung cancer C.melanoma D. prostate cancer E. thyroid cancer
  72. 72. A. intrathecal chemotherapy B. lumbar CSF drainage C. radiation therapy D. surgical debulking E. systemic chemotherapy
  73. 73. A. basal ganglia B. cauda equina C. cerebral cortex D. cervical spinal cord E. thalamus

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