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

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. Chief Complaint
 Progressive hearing loss, L > R and gait instability
for 3-4 months

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. 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. 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. 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. Family History
 Mother: Cancer (deceased after thoracic
surgery)

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. Allergies
 Levofloxacin

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. 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. 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. MRI brain, T1

14. MRI brain, T2

15. MRI brain, GRE

16. MRI brain, T1 post

17. DWI & ADC map.

18. MRI cervical spine, sagittal T1 & T2

19. MRI cervical spine, axial T1 / T2T1T2

20. MRI cervical spine, T1 post contrast

21. MRI lumbar spine, T1 / T2 sagittal

22. MRI lumbar spine, T1 post contrast

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. 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. 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. 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

28. Weber test

29. 1 tab. prn during conference

30. 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

31. 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.

32. 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

33. Drop
metastases…
Only in the book I do
NOT have…

34. 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.

35. 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

36. 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

37. 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.

38. 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.

39. - Benjamin R., Neurologic complications of prostate cancer. Am Fam Physician. 2002 May 1;65(9):1834-40.

40. 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

41. 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

42. 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.

43.  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…

44. CSF and cytology.
- Van Oostenbrugge RJ, et al, Neurology. 1999 Jul 22;53(2):382-5.

45. Le Rhun E, Taillibert S, Chamberlain M, Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int. 2013; 4(Suppl 4): S265–S288.

46. 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.

47. 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.

48. 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

49.  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 !

50. 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.

51. 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

52. 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.

54. 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

55. 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.

57. Impression
Choroid plexus carcinoma ?
Choroid plexus papilloma ?
Ependymoma ?
Doubt Leptomeningeal metastasis
secondary to prostate cancer

58. Hospital Course
 Brain biopsy performed.
 Diagnosis: Choroid plexus carcinoma

59. Matthew Z., Current management of choroid plexus carcinomas, Neurosurgical Review. April 2014, Volume 37, Issue 2, pp 179-192

60. 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”