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Leptomeningeal metastases, differential diagnosis. CPC

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Presentation of a case, differential diagnosis of leptomeningeal metastases and drop metastases.

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Leptomeningeal metastases, differential diagnosis. CPC

  1. 1. Resident , PGY-3: Daniel Vela-Duarte, MD Chief Resident, PGY-4: Lilia Lovera, MD Mentor: José Biller, MD, FAAN, FACP, FAHA Clinical Pathological Conference
  2. 2. Chief Complaint  Progressive hearing loss, L > R and gait instability for 3-4 months
  3. 3. History of Present Illness  70-year-old, right-handed man, Veteran, presents with progressive sensorineural hearing loss (SNHL), L > R, with intermittent dizziness and gait instability for a few months.  No history of similar symptoms.  Total colectomy (8/12), for lower GI bleed due to diverticulitis, with resultant 50 pound (22.6 Kg) weight loss in the 6 months prior to presentation.
  4. 4. Review of Systems  + Occasional L sided facial numbness  + L eye lacrimation and blurriness  + Tinnitus  Pertinent Negatives  Headaches, nausea, vomiting, visual changes, confusion, seizure, Limb weakness/numbness/tingling.
  5. 5. Past Medical/Surgical History  Medical History  DM  HTN  COPD  Hyperlipidemia  Prostate cancer  Diverticulitis  SHNL L>R  Post-traumatic stress disorder  Obstructive sleep apnea  Gout  Surgical History:  Total Colectomy 8/2012, following lower GI bleed secondary to diverticulitis
  6. 6. Social History  Married. Lives with his wife.  Retired engineer. Served in Marine Corps.  Smoking: Former 1.5 PPD x 20 years; quit 25 years ago  EtOH: Previous heavy use; quit 25 years ago  Illicits: none  No recent travel outside the US.  During his service in 1960-70’s: Vietnam, Philippines, Cuba, Japan, Malaysia, Brazil, Panama, Guam (US-administered islands of the Central Pacific).  No toxic exposures
  7. 7. Family History  Mother: Cancer (deceased after thoracic surgery)
  8. 8. Medications  Amlodipine 10 mg daily  Pravastatin 40 mg QHS  Glipizide 10 mg BID  Metformin 500 mg BID  Sertraline 100 mg QHS  Trazodone 50 mg QHS PRN  Omeprazole 10 mg daily  Allopurinol 100 mg daily  Magnesium oxide 420 mg daily  Tamsulosin 0.4 mg QHS
  9. 9. Allergies  Levofloxacin
  10. 10. Physical Examination  Vital Signs:  BP 127/59mm Hg ; P 62/min ; T 35.8 C; RR 19/min. Ht 65’’; Wt 164 lbs (74.3 kg)  General Appearance: pleasant, no apparent distress  HEENT: anicteric sclera; oropharynx clear  NECK: Supple, No JVD, no thyromegaly  CV: RRR. No rubs, murmurs, or gallops  RESP: Clear to auscultation bilaterally  GI: NABS. Soft, nontender, nondistended.  Midline abdominal scar and ostomy bag R lower abdomen  EXT: No clubbing, cyanosis or edema.  SKIN: Warm, dry, no lesions, no rashes
  11. 11. Neurologic Examination  Higher Functions: alert, oriented to time, place and person. Normal recent and remote memory. Normal attention and concentration. Normal speech, fluency, repetition and naming.  Cranial Nerves: normal visual fields to confrontation; extra-ocular movements intact,  Horizontal nystagmus with rapid phase to the left; normal facial sensation; face symmetric, tongue midline  Bilateral hearing loss; (L > R) Decreased perception on left with Weber lateralized to L.  Motor System: normal bulk, tone, and strength throughout  Muscle Stretch and Plantar Reflexes:  Brisk reflexes x 4, except hypoactive at ankle reflexes. Bilateral flexor plantar responses.  Sensory System: normal light touch and pinprick.  Coordination: no dysmetria. Normal finger-to-nose, and heel-to-shin.  Gait and Station: normal gait and station, unable to perform tandem gait.
  12. 12. Initial Laboratory Studies:  TSH 1.55  VITAMIN B12 415  ESR 30 H (0-20)  CRP 0.36  CBC:  WBC 6.74  RBC 4.95  Hgb 14.5  Plt 219  CMP:  Sodium 139  Potassium 4.1  Chloride 103  CO2 26  BUN 18  Creatinine 0.8  Glucose 77  Magnesium 1.8  Phosphorus 3.7  Calcium 9.9  AST 19  ALT 39  Alk phosphatase 65  HIV 1/2 AB: negative  Blastomyces Ag Urine : negative  Histoplasma Ag Urine : negative  Histoplasma Ab Complement Fixation: negative  Histoplasma Ab Immunodiffusion: negative  Coccidioides complement fixation and diffusion: negative  Cysticercus Ab Serum : negative  Quantiferon TB : negative  ACE : negative
  13. 13. MRI brain, T1
  14. 14. MRI brain, T2
  15. 15. MRI brain, GRE
  16. 16. MRI brain, T1 post
  17. 17. DWI & ADC map.
  18. 18. MRI cervical spine, sagittal T1 & T2
  19. 19. MRI cervical spine, axial T1 / T2T1T2
  20. 20. MRI cervical spine, T1 post contrast
  21. 21. MRI lumbar spine, T1 / T2 sagittal
  22. 22. MRI lumbar spine, T1 post contrast
  23. 23. Additional Imaging  CT chest/abdomen/pelvis:  Enlarged prostate  Stable pulmonary nodules since 10/15/10, compatible with benign etiology.  Linear subsegmental atelectasis/scarring in the lower lungs  Emphysematous changes of the lungs suggesting COPD.  Calcified granulomata of the lungs, liver, and spleen with calcified mediastinal lymph nodes compatible with sequela from prior granulomatous disease  Small hiatal hernia  Interval colon resection with right lower quadrant ileostomy
  24. 24. Summary / Clinical discussion  Nodular lesion encasing CN VII and CN VIII  Possible Involvement of left dorsal and ventral cochlear nuclei  Possible compression of sensory nucleus of CN V  SNHL L > R, tinnitus.  Gait disturbance  Myelopathy
  25. 25. Summary of MRI data  Diffuse, poorly defined, hyperintense T1, nodular lesions, involving cerebellar vermis, bilateral cerebellopontine angle (CPA) and right cerebellar hemisphere (Tonsils and inferior lobe)  Diffuse hyperintense T2 nodular lesions in the right temporal pole, left parahippocampal gyrus, vermis and folium. Extraxial irregular, space-occupying lesion with diffuse nodularity compressing right cerebellar hemisphere  Axial gadolinium-enhanced T1-weighted MRI: Subtle peripheral, irregular rim of enhancement  Multiple nodular isointense, cervical, nodular, extraxial lesions in T1. Hypointense in T2, without cord signal and subtle enhacement on post-contrasted images.  Several small enchancing nodularities atached to the conus medullaris, cauda equina and filum terminale in lumbar spine MRI
  26. 26. Symptoms: Tinnitus  Subjective tinnitus  Pulsatile: sound perception is heartbeat-synchronous, neurovascular examination  Non-pulsatile  Conductive or sensorineural hearing loss  Paroxysmal tinnitus: Auditory nerve compression, superior canal dehiscence syndrome, Ménière’s disease, palatal myoclonus, migraine or epilepsy.  Objective tinnitus  The sound could be perceived by the examiner  AVM, Carotid stenosis, sinus venous thrombosis - Langguth B, et al, Tinnitus: causes and clinical management. Lancet Neurol. 2013 Sep;12(9):920-30 - Baguley D, et al. Tinnitus. Lancet. 2013 Nov 9;382(9904):1600-7
  27. 27. Weber test
  28. 28. 1 tab. prn during conference
  29. 29. Infection Histoplasmosis Coccidiomicosis Blastomycosis Tuberculosis Cerebral Abcesses Neurocysticercosis Neurosarcoidosis Neoplasm Primary CNS malignancy Glioma PCNSL PNET Pilocytic astrocytoma Ganglioglioma Ependymoma Hemangioblastoma Leptomeningeal metastases Glioblastoma multiforme medulloblastoma sPNET Ependymoma Germinoma Choroid plexus carcinoma Causes of Cerebellopontine angle syndrome Acoustic Neuromas Meningiomas Brainstem Gliomas CN V Neuromas Epidermoids Chordomas CN IX Neuromas Choroid Plexus Papillomas Hemangioblastoma Arachnoid Cysts Ectatic Arteries Aneurysms Basilar AICA PICA Angiomatous Malformations Leptomingeal metastases Breast cancer Lung cancer Melanoma Lymphoma and leukemia
  30. 30. Differential diagnosis Neurosarcoidosis  Granulomatous disease mediated by CD4+ helper T subtype 1 cells and mononuclear phagocytes and presence of noncaseating granulomas.  The presence of hilar adenopathy would support a unifying diagnosis of sarcoidosis.  How frequently patients with sarcoidosis will develop neurosarcoidosis?  Central nervous system involvement is seen in 14 - 27% of patients with systemic sarcoidosis, although only 3-15% are symptomatic  How frequent is neurosarcoidosis without systemic manifestations?  Disease limited to the CNS is rare, with incidence ranging between series from 1-17%  How useful are both ACE levels in serum and CSF ?  Levels are influenced by ACE gene polymorphisms. It lacks sensitivity and specificity. Positive and negative predictive values were only 84% and 74%, respectively  CNS infections or malignant tumors could have high CSF ACE levels - Studdy PR, Bird R. Serum angiotensin converting enzyme in sarcoidosis - its value in present clinical practice. Ann Clin Biochem 1989;26:13-18 - Kellinghaus C, Schilling M, Ludemann P. Neurosarcoidosis: clinical experience and diagnostic pitfalls. Eur Neurol 2004;51:84-88 - Lannuzzi MC, et al., Sarcoidosis.. N Engl J Med. 2007 Nov 22;357(21):2153-65.
  31. 31. Neurosarcoidosis  Signs and symptoms secondary to increased ICP resulting in hydrocephalus  Multiple CN palsies  Optic nerve is particularly involved.  Facial nerve palsy  Diabetes insipidus from pituitary involvement  Seizures  Weakness, paresthesias and dysarthria / dysphasia  Spinal cord involvement could present as myelopathy
  32. 32. Drop metastases… Only in the book I do NOT have…
  33. 33. Differential diagnosis Metastatic disease.  The slowly progressive course suggest a neoplastic process.  The patient’s smoking history and weight loss increased the suspicion of a systemic malignancy.  Cancers that commonly metastasize to the brain include  lung, melanoma, breast, kidney, and gastrointestinal tumors.  Small cell lung cancer can present with isolated or miliary brain metastases and is more commonly observed in supratentorial locations.  Pelvic and gastrointestinal tumors favor the posterior fossa.
  34. 34. Differential diagnosis Primary brain tumors  Glioma  80% of malignant primary brain tumors  Astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas  Low-grade gliomas generally do not enhance but demonstrate T2 FLAIR hyperintensity in a diffuse pattern  High-grade gliomas usually present as large contrast-enhancing lesions with surrounding edema seen as T2 FLAIR hyperintensity.  Primary central nervous system lymphoma  Medulloblastoma, need to be considered
  35. 35. Differential diagnosis Primary brain tumors (Continuation)  Primary central nervous system lymphoma  Lymphoma presenting solely in the central nervous system.  90% of these are diffuse large B-cell lymphoma  60% are supratentorial  Primitive neuroectodermal tumors (PNET)  Primary CNS tumors typically present with solitary lesions.  Cystic appearance:  Pilocytic astrocytoma  Ganglioglioma  Ependymoma  Hemangioblastoma
  36. 36. Cerebellopontine angle syndrome  Acoustic Neuromas (Schwannoma)  Meningiomas  Brainstem Gliomas  CN V Neuromas  Epidermoids  Metastases  Chordomas  CN IX Neuromas  Choroid Plexus Papillomas  Hemangioblastoma  Arachnoid Cysts  Hydatid, Cysticercosis  Ectatic Arteries  Aneurysms  Basilar  AICA  PICA  Angiomatous Malformations - Modified from: Barrow Quarterly, Vol.20, No 4, 2004 - Kendall B, Symon L. Investigation of Patients Presenting with Cerebellopontine Angle Syndromes. Neuroradiology. 1977 Apr 18;13(2):65-84.
  37. 37. Differential diagnosis Carcinomatous meningitis  Primary: Prostate cancer ?  Brain metastasis is rare in prostate cancer and occurs late in the course of the disease.  Usually represents the failure of hormone- deprivation therapy and the presence of disseminated disease.  Most common intracranial sites of prostate cancer metastasis are:  Dura/Leptomeninges (67 %)  Cerebrum (25 %)  Cerebellum (8 %)  Leptomeningeal metastasis (or carcinomatosis) is usually clinically silent - Benjamin R., Neurologic complications of prostate cancer. Am Fam Physician. 2002 May 1;65(9):1834-40.
  38. 38. - Benjamin R., Neurologic complications of prostate cancer. Am Fam Physician. 2002 May 1;65(9):1834-40.
  39. 39. Differential diagnosis Leptomeningeal metastases  Diffuse seeding of the leptomeninges by tumor metastases.  Symptoms caused by the effects of tumor on subarachnoid nerve roots  Direct invasion into the spinal cord  Space-occupying masses in the brain  Cisterns obstruction (CSF obstruction)  Diagnostic accuracy of CSF is only 50-60% after a single CSF study and 90% after the 3rd
  40. 40. Leptomeningeal metastases How does cancer reach the pia-arachnoid ?  Hematogenous spread to the arachnoid via the arterial circulation.  Most common route of metastasis for hematological malignancies  Less frequent in solid tumors  Vertebral and paravertebral metastases gain access through the dural and arachnoidal sleeves of nerve roots via the endoneural/perineural route or along coassociated lymphatics or veins  Direct spread from metastases located in the brain parenchyma that is in close opposition to the CSF  Metastases to the choroid plexus and subependyma with subsequent CSF dissemination  Iatrogenic spread
  41. 41. Patient characteristics and histology of the primary tumor in 45 patients with leptomeningeal metastases due to a solid or hematologic malignancy Characteristic Solid tumors Hematological malignancies Sex, F/M 20 / 10 5 / 10 Age range, y (mean) 19 - 78 (53) 16 - 67 (50) Histology Breast cancer 11 - Lung cancer 11 - Small-cell 5 - Non-small-cell 6 - Unknown primary 2 - Renall cell carcinoma 1 - Colon carcinoma 1 - Bladder carcinoma 1 - Medulloblastoma 1 - Pancreas carcinoma 1 - Dysgerminoma 1 - High-grade non–Hodgkin’s lymphoma - 10 Acute lymphoblastic leukemia - 5 Modified from: van Oostenbrugge RJ, Twijnstra A, Presenting features and value of diagnostic procedures in leptomeningeal metastases. Neurology. 1999 Jul 22;53(2):382-5.
  42. 42.  Sensitivity of a first LP is estimated at 45-55%, but can be increased to 80% with a second CSF examination  Sensitivity of CSF cytology increased from 68% to 97% for 3.5 and 10.5 ml samples,  Viability of cells depends on time between sampling and laboratory examination:  After 30 minutes, 50% of the cells remain viable,  10% of cells remain viable after 90 minutes Learning points…
  43. 43. CSF and cytology. - Van Oostenbrugge RJ, et al, Neurology. 1999 Jul 22;53(2):382-5.
  44. 44. Le Rhun E, Taillibert S, Chamberlain M, Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int. 2013; 4(Suppl 4): S265–S288.
  45. 45. Marker Associated malignancy Beta 2 microglobulin Lymphoma, infection, other tumors Beta glucuronidase Nonspecific CEA Colon, ovarian, breast, bladder, lung CA-125 Ovarian CA-15-3 Breast CA19-9 Adenocarcinoma, biliary disease CK-BB Small cell lung cancer GFAP Glioma HCG subunit Choriocarcinoma, embryonal and germ cell tumors 5-HIAA Carcinoid IgM Myeloma LDH isoenzyme D Carcinoma PSA Prostate CSF biochemical markers Modified from: UpToDate, Feb 2014. Alexis Demopoulos, MD, and Jerome Posner, MD.
  46. 46. Overall survival Le Rhun E, Taillibert S, Chamberlain M, Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int. 2013; 4(Suppl 4): S265–S288.
  47. 47. Differential diagnosis Leptomeningeal metastases  Primary intracerebral malignancies (Drop metastasis)  Glioblastoma multiforme (GBM) and anaplastic astrocytoma  medulloblastoma  sPNET  Ependymoma  Germinoma  Choroid plexus carcinoma  Widespread metastatic disease  Breast cancer - most common  Lung cancer - most common  Melanoma  Lymphoma and leukemia
  48. 48.  Special thanks to Dr. Frank Gaillard (Editor in chief) and Dr. Ahmed Abd Rabou (CNS Imaging editor) and the entire board of editors for making what Radiopaedia is today. A great learning tool for not only for Neurologist / Neuroradiologist but also for many other specialties. Most of the MRI’s in this talk were taken from radiopaedia, I do not have any affiliation but wanted to say thanks !
  49. 49. Differential diagnosis  Glioblastoma Multiforme  Most common adult primary intracranial neoplasm, 50% of astrocytomas  Preferential localization and spreading along the corpus callosum (butterfly glioma)  Primary GBM  Associated with p16 deletions  Mutations in the epidermal growth-factor receptor (EGFR) and hosphatase and tensin homolog (PTEN, 10q)  Secondary GBM  Associated with p53 mutations  Overexpresses the platelet-derived growth factor receptor  Loss of heterozygosity at 1p predicts longer survival  LOH at 10q: poor prognostic factor and chemoresistance.
  50. 50. Differential diagnosis  Medulloblastoma  30-40% of pediatric posterior fossa tumors.  Rarely seen in adults  Male predilection  The majority arise in the cerebellum  75% from the vermis  Unlike ependymomas they do not usually extend into the basal cisterns  In 40% of patients there is evidence of CSF seeding at the time of diagnosis  CSF seeding is common at presentation  Drop metastases  Leptomeningeal spread
  51. 51. Differential diagnosis Ependymoma  Neoplams arising from ependymal cells lining the ventricles  Common locations  Floor of the 4th ventricle (commonest location in children)  Spinal cord ependymoma  Myxopapillary ependymoma (conus medullaris)  Supratentorial ependymoma (40%, half are intraparenchymal)  60% of intracranial ependymomas are located in the posterior fossa  Possible extension through the foramina of Luschka and Magendie  Drop metastases  Intradural extramedullary spinal metastases that arise from intracranial lesions  Rare complication that occurs in about 1%  Most common in glioblastoma multiforme (GBM) Choi PP, Shapera S, What's your call? Drop metastases. CMAJ. 2006 Aug 29;175(5):475, 477.
  52. 52. Differential diagnosis Germinoma  Most common germ cell tumor (followed by teratomas)  Most common in pediatric population  90% of patients being younger than 20 at the time of diagnosis  Highly responsive to chemotherapy  Tend to arise from the midline, at the pineal region, suprasellar region or along the floor of the 3rd ventricle  Tendency to surround the pineal gland and have central calcification  Obstructive hydrocephalus  Parinaud syndrome
  53. 53. Differential diagnosis Choroid plexus carcinoma  Uncommon malignant neoplasm arising from the choroid plexus  Poorer prognosis than Choroid plexus papillomas  Usually presents with hydrocephalus in pediatric population  Potential CSF seeding (Drop metastases)  Associated with Li-Fraumeni, NF2, Aicardi and von Hippel- Lindau syndrome  p53 mutation: poorest prognosis TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors. Tabori et al, J Clin Oncol. 2010;28(12):1995.
  54. 54. Impression Choroid plexus carcinoma ? Choroid plexus papilloma ? Ependymoma ? Doubt Leptomeningeal metastasis secondary to prostate cancer
  55. 55. Hospital Course  Brain biopsy performed.  Diagnosis: Choroid plexus carcinoma
  56. 56. Matthew Z., Current management of choroid plexus carcinomas, Neurosurgical Review. April 2014, Volume 37, Issue 2, pp 179-192
  57. 57. Hospital Course Comment  Concezio Di Rocco, MD (Hannover, Germany)  “Choroid plexus carcinomas (CPC) remain one of the few tumors of the CNS which did not benefit of the progresses that have been recorded in surgical and medical management in the last decades”  “…The extreme rarity of this tumor prevents the oncologist to collect sufficiently large series in a relatively short period of time in order to evaluate the specific role of various factors that can influence the late outcome, such as the age of the patient, the location of the tumor, its invasiveness of surrounding structures, the presence of an associated hydrocephalus, the extent of surgical removal, and the effect of adjuvant treatments”