RAIN Clinicopathologic Conference 2019 nasopharyngeal squamous cell - - PowerPoint PPT Presentation

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RAIN Clinicopathologic Conference 2019

Sara C. LaHue, MD

UCSF Department of Neurology

Nicole Rosendale, MD

UCSF Department of Neurology

Melike Pekmezci, MD

UCSF Department of Pathology

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Case

59-year-old man with a past medical history of remote nasopharyngeal squamous cell carcinoma, hypothyroidism, gallbladder polyps, and latent tuberculosis status-post 9-month course of isoniazid presented with progressive headache, nausea with emesis, and gait instability.

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History of Present Illness

• Well until 3 weeks prior to presentation:
• Developed nausea, vomiting, subjective fevers, and headache.
• Presented to outside hospital-affiliated Urgent Care Clinic.
• Continued to have emesis during appointment.
• Hospital transfer discussed but patient declined.
• Upcoming cholecystectomy for polyps already scheduled.

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History of Present Illness

• A few days later presented to Primary Care:
• Headache persisted.
• New intermittent bilateral leg weakness and right foot numbness,

resulting in gait instability.

• New hiccups.
• Underwent MRI brain and lumbar spine
• Results prompted admission to local hospital and then UCSF

transfer.

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Past Medical History

• Nasopharyngeal squamous cell carcinoma
• Diagnosed 1990s, status-post radiation and chemotherapy
• Hypothyroidism
• Latent tuberculosis
• Diagnosed 2016, completed 9-month course of isoniazid
• Gallbladder polyps
• Chronic gastritis with Helicobacter pylori infection
• Iron deficiency anemia

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Medications

• Levothyroxine 50mcg daily.
• Keppra 500mg twice a day and prednisone 50mg daily

(started prior to transfer)

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Social History

• Lives with wife in Milpitas, California; they have three

children.

• Originally from Hong Kong but lived in the United States for

decades.

• Retired computer engineer; works part-time as a consultant.
• No alcohol, tobacco or illicit drug use.
• Travel history: San Diego and Seattle (past year). Hong Kong

(two years prior), Mexico (fishing trip, two years prior).

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Family History

• Mother: liver cancer
• Maternal uncle: liver cancer
• Several family members had nasopharyngeal carcinoma.
• No family history of neurological disease.

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Physical Exam

• Vital Signs T 97.5°F, HR 58, BP 125/78 mmHg, RR 18
• General Cachectic appearance, otherwise unremarkable.
• Mental status Alert, fully oriented, but slowed responses.
• Cranial nerves Bilateral temporal disc blurring. Bilateral lateral gaze
• restriction. Pupils 4mm briskly reactive. Right-sided upper motor neuron

facial weakness.

• Motor Decreased bulk throughout. No pronator drift. Full strength.
• Sensory. Diminished to vibration in feet bilaterally.
• Reflexes 3+ right patella otherwise 2+ throughout.
• Coordination Intact finger-nose-finger and heel-knee-shin.
• Gait Wide based and imbalanced.

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Labs

• Normal BMP, CBC, LFTs
• Cerebrospinal fluid: Yellow-appearing fluid
• Tube 4:
• WBC 2 (monocyte predominant)
• RBC 199
• Protein 1836
• Glucose 75 (normal serum)

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CT Brain without Contrast

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MRI Brain – DWI

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MRI Brain – T2 FLAIR

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MRI Brain – T2 FLAIR

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MRI Brain with Gad

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T2 FLAIR

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T2 FLAIR Gad Enhanced

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T2 FLAIR Gad Enhanced

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T2 FLAIR Gad Enhanced

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Initial thoughts?

Nicole Rosendale, MD

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Approach

• Key points
• History
• Exam
• Evaluation & Treatment
• Broad differential diagnosis
• Further workup
• Diagnosis

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Key Points - History

• 59 year old man with:
• hypothyroidism
• remote nasopharyngeal carcinoma (1990s) s/p radiation and

chemotherapy

• latent TB s/p 9-months of isoniazid
• Subacute, progressive headache, persistent nausea/emesis
• More acute, intermittent bilateral leg weakness and right foot

numbness

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Key Points - Exam

• Cachectic
• Encephalopathic
• Papilledema & bilateral abducens palsy
• Right upper motor neuron facial weakness but normal power in

body

• Increased tone in legs
• Large fiber sensory neuropathy in feet
• Brisk R patellar reflex
• Wide based gait

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Key Points – Evaluation & Treatment

• Labs:
• Basic labs are normal.
• No CSF pleocytosis but markedly elevated protein and yellow in color

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Key Points – Evaluation and Treatment

• Imaging:
• Multifocal intraparenchymal and intraventricular cystic lesions on

MRI

• Partial ring enhancement of parenchymal lesions and intraventricular

lesions & leptomeningeal enhancement coating spinal cord

• Possible abnormality in lung apex
• Transferred on Keppra and prednisone

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Framework for creating a differential

• V
• I
• T
• A
• M
• I
• N
• S
• A = alcohol
• B = behavioral
• C = congenital
• D = degenerative
• E = endocrine
• K = karyotype

= vascular = infectious = toxic = autoimmune = metabolic = iatrogenic = neoplastic = structural

(toxic-metabolic) (malignancy) (neurodegenerative) (social, systemic)

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Initial differential diagnosis

• Neoplastic
• Nasopharyngeal

carcinoma

• Lymphoma
• CNS metastases
• Glioblastoma
• Subependymoma or other

intraventricular tumor

• Infectious
• Neurocysticercosis
• Tuberculosis
• Fungi
• Autoimmune
• Sarcoidosis
• IgG4-related disease

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Nasopharyngeal carcinoma

• Pros:
• Personal history
• Of cases reported, lung

involvement also present

• Plausible mechanism
• Cons:
• Met to CNS is rare
• Remote history

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Lymphoma

• Pros:
• Age (typically 40-70s)
• Presenting with encephalopathy,

focal deficits

• Cons:
• Usually homogenously enhancing
• Steroid responsive

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CNS metastases

• Pros:
• Cachectic
• Lung mass
• Cons:
• Intraventricular metastases are rare
• Typically ring enhancing, located at

the grey-white junction

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Other neoplasms

• Glioblastoma
• Most common primary brain tumor in adults
• Typically parenchymal with IV invasion
• Intraventricular tumors
• Ependymoma – pediatric tumor
• Central neurocytoma – typically younger (20-

40 y/o)

• Meningioma – homogenously enhance
• Subependymoma – correct age
• Wouldn’t explain spinal involvement

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Neurocysticercosis

• Pros:
• Traveled to an endemic area (Central &

South America, Asia, Africa)

• Racemose NCC is often basilar

predominant

• Cons:
• Seizures common
• No calcifications on head CT
• Typically ring enhancing

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Tuberculosis

• Pros:
• Non-specific headache, malaise,

focal deficits

• Basilar predominant
• Cons:
• Bland CSF
• Typically ring enhancement
• Underwent appropriate treatment

for latent TB

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Fungi

• Coccidiomycosis
• Typically leads to meningitis without parenchymal

lesions

• Many have concomitant spinal abnormalities
• Aspergillosis
• Typically disseminated
• Cryptococcus
• Usually in immunocompromised individuals
• Typically meningitis without discrete lesions

(cryptococcoma)

• Leads to CSF pleocytosis

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Sarcoidosis

• Pros:
• Encephalopathy, focal deficits (cranial

neuropathy), headache

• Bland CSF
• Lung lesion (although apical, not hilar)
• Cons:
• Steroid responsive
• Lesions are typically smaller

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IgG4-Related Disease

• Pros:
• Can have intraventricular involvement
• CSF pleocytosis is variable
• Cons:
• Typically presents over months to years
• Steroid responsive

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Summary of Differential Diagnosis

Neoplasm

• CNS metastases
• Lymphoma
• GBM

Infectious

• Neurocysticercosis

Autoimmune

• Sarcoid

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Further diagnostic considerations

• CT chest: characterize lung mass
• PET: evaluate for potential biopsy target
• Ophthalmologic exam: helpful for lymphoma, sarcoid
• Labs: ACE, NCC testing, beta-d-glucan, galactomannan
• Biopsy

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Hospital Course

• Initial concern for neurocysticercosis
• Started on Prednisone 50 mg daily
• Keppra 500 mg twice a day for seizure prophylaxis
• Neurosurgery was consulted: no role for EVD or surgery.
• Due to concern for deterioration with anti-parasitic medication

initiation, he was transferred to UCSF for further care.

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Hospital Course

• Initial differential included:
• Infection: neurocysticercosis, less likely atypical bacteria, fungal
• r mycobacterial
• Malignancy, especially metastatic
• Seen by Ophthalmology: no orbital or ocular cysts or infection
• Cycticercosis Ab serum: negative
• Could be negative in setting of early severe infection

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Serum Studies

Test Result HIV 1 & 2 PCR Negative Hep B Ag and Core Ab, HBV PCR Negative RPR Negative Strongyloides IgG Antibody Negative Histoplasma Capsulatum Antibody Immunodiffusion Negative Coccidioides immitis Antibody, Immunodiffusion Negative Cryptococcus Antigen Negative Angiotensin Converting Enzyme 17 (ref: 9-67 U/L)

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CSF studies trickled in …

Test Result Gram stain No organisms Bacterial/fungal/AFB Negative AFB Negative India ink Cytology Mild to moderately cellular … Whether these cells represent reactive histiocytes or tumor cells is difficult to determine, and at present are characterized as atypical. Coccidioides immitis Antibody, Complement fixation Negative Cryptococcal Antigen Negative Universal Microbial DNA Negative Angiotensin-Converting Enzyme 13.0 (normal < 2.5)

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CSF studies trickled in …

Test Result Gram stain No organisms Bacterial/fungal/AFB Negative AFB Negative India ink Cytology Mild to moderately cellular … Whether these cells represent reactive histiocytes or tumor cells is difficult to determine, and at present are characterized as atypical. Coccidioides immitis Antibody, Complement fixation Negative Cryptococcal Antigen Negative Universal Microbial DNA Negative Angiotensin-Converting Enzyme 13.0 (normal < 2.5) Cysticercosis antibody IgG Positive, 1.64

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Underwent right frontal brain biopsy

Hospital Course

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Nicole Rosendale, MD

Additional thoughts?

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Melike Pekmezci, MD

Pathology Results

Brain biopsy Right frontal horn

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GFAP

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OLIG2 Neurofilament IDH1 R132H p53

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MIB1

Diagnosis: Anaplastic Astrocytoma, IDH-wildtype, WHO grade III

Classification of Central Nervous System Neoplasms

• Metastatic
• Primary
• Glial
• Diffuse gliomas
• Ependymoma
• Other circumscribed gliomas
• Embryonal
• Glioneuronal
• Meningeal
• Mesenchymal
• Lymphoma
• Melanocytic……..

~20/100,000 ~5/100,000 pediatric ~27/100,000 adults

Ostrom QT et al. 2018 Neuro-Oncology PMID: 30445539

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Ostrom QT et al. 2018 Neuro-Oncology PMID: 30445539 Ostrom QT et al. 2018 Neuro-Oncology PMID: 30445539

Diffuse astrocytic and oligodendroglial tumors

• Diffuse astrocytoma, IDH mutant
• Gemistocytic astrocytoma, IDH

mutant

• Diffuse astrocytoma, IDH wildtype
• Diffuse astrocytoma, NOS
• Anaplastic astrocytoma, IDH mutant
• Anaplastic astrocytoma, IDH wildtype
• Anaplastic astrocytoma, NOS
• Glioblastoma, IDH wildtype
• Giant cell glioblastoma
• Gliosarcoma
• Epithelioid glioblastoma
• Glioblastoma, IDH mutant
• Glioblastoma, NOS
• Diffuse midline glioma, H3K27M-mutant
• Oligodendrogliomas, IDH mutant and

1p/19q codeleted

• Oligodendroglioma, NOS
• Anaplastic oligodendroglioma, IDH

mutant and 1p/19q codeleted

• Anaplastic oligodendroglioma, NOS
• Oligoastrocytoma, NOS
• Anaplastic oligoastrocytoma, NOS

II III IV II III IV

• Gliomatosis Cerebri

Other astrocytic tumors

• Pilocytic astrocytoma
• Pilomyxoid astrocytoma
• Subependymal giant cell astrocytoma
• Pleomorphic xanthoastrocytoma
• Anaplastic pleomorphic

xanthoastrocytoma

• Subependymoma
• Myxopapillary ependymoma
• Ependymoma
• Papillary ependymoma
• Clear cell ependymoma
• Tanycytic ependymoma
• Ependymoma, RELA fusion

positive

• Anaplastic ependymoma

Ependymal tumors Other gliomas

• Chordoid glioma of the third ventricle
• Angiocentric glioma
• Astroblastoma

Neuronal and mixed neuronal-glial tumors

• Dysembryoplastic neuroepithelial tumor
• Gangliocytoma
• Ganglioglioma
• Anaplastic ganglioglioma
• Dysplastic cerebellar gangliocytoma
• Desmoplastic infantile astrocytoma and

ganglioglioma

• Papillary glioneuronal tumor
• Rosette-forming glioneuronal tumor
• Diffuse leptomeningeal glioneuronal

tumor

• Central neurocytoma
• Extraventricular neurocytoma
• Cerebellar liponeurocytoma
• Paraganglioma

17 Astrocytoma Oligodendroglioma Oligoastrocytoma Astrocytoma, Grade II Anaplastic Astrocytoma, Grade III Glioblastoma, Grade IV Anaplastic Oligodendroglioma, Grade III Oligodendroglioma, Grade II 2007 WHO 2016 WHO 1926 H. Cushing

18 WHO 2016

IDH wildtype GBM GBM, IDH mutant GBM, IDH wildtype Astrocytoma Oligodendroglioma Oligoastrocytoma Oligodendroglioma IDH mutant and 1p/19q codeleted Astrocytoma, IDH mutant Astrocytoma, IDH wildtype IDH mutant 1p/19q codeletion 1p/19q intact

Modified from Louis DN et al. Acta Neuropathologica 2016 Pekmezci M, et al. Acta Neuropathologica 2017

Genetic alterations in pediatric diffuse high grade glioma H3K27M age and location

Solomon et al. (2015) Brain Pathology 26:5;569-580

95% 65% 53 % 0%

Diffuse midline glioma, H3K27M mutant, Grade IV

19 WHO 2016

IDH wildtype GBM GBM, IDH mutant GBM, IDH wildtype Astrocytoma Oligodendroglioma Oligoastrocytoma Oligodendroglioma IDH mutant and 1p/19q codeleted Astrocytoma, IDH mutant Astrocytoma, IDH wildtype IDH mutant 1p/19q codeletion 1p/19q intact

Modified from Louis DN et al. Acta Neuropathologica 2016

TP53 mutation ATRX mutation GBM, IDH wildtype Astrocytoma, IDH wildtype Diffuse midline glioma, H3K27M mutant, Grade IV H3K27M Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV TERT promoter mutations EGFR amplification Polysomy 9 and Monosomy 10 MET ampl/overexp PDGFRA ampl/overexp NF1 mutation PTEN mutation/deletion PIK3R1 mutation PIK3CA mutation TP53 mutation MDM2/MDM4 amp/overexp RB1 mutation/deletion Homozygous CDKN2A/B deletions Brat D, et al. 2018 cIMPACT-NOW update 3 Acta Neuropathologica PMID: 30259105

UCSF500 Cancer Panel

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Anaplastic Astrocytoma, IDH-wildtype, WHO grade III

Molecular changes worrisome but not diagnostic of Glioblastoma, WHO grade IV

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Sara C. LaHue, MD

Follow-Up

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Wait - but what about the

• Neurocysticercosis testing
• Initial CSF cysticercosis IgG positive, but serum studies negative.
• Repeat CSF and serum cysticercosis IgG studies also negative.
• Infectious Disease determined concomitant neurocysticercosis

very unlikely based on repeat CSF and serologic studies and biopsy results - no treatment indicated.

• Latent TB status post INH
• Quaniferion Gold was positive, but CXR was negative
• Consistent with treated latent TB. No further treatment indicated.

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Follow-Up

• Underwent 10 days of craniospinal radiation but developed

severe side effects:

• Severe bone marrow suppression with pancytopenia.
• Neutropenic fever with sepsis in setting of aspiration pneumonia.
• Became progressively weaker and debilitated.
• Radiation was no longer an option.
• Placed on hospice.
• Ultimately died within one month of his diagnosis.

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Thank you:

• Dr. Nicole Rosendale
• Dr. Melike Pekmezci
• Dr. Andy Josephson
• Dr. John Engstrom
• Dr. Maulik Shah
• Dr. Megan Richie
• Dr. Vanja Douglas
• Dr. Michael McDermott
• Dr. Nancy Ann Oberheim

Bush

• Dr. Steve Braunstein
• Dreama Messore RNCM
• The patient and his family.

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References

1.

Batista RR, Gasparetto EL. Uncommon Presentation of Intracranial Cryptococcoma in an Immunocompetent Patient. Am J

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Chandra V, Rock AK, Opalak C, et al. A systematic review of perioperative seizure prophylaxis during brain tumor resection: the case for a multicenter randomized clinical trial. Neurosurg Focus. 2017; 43(5): E18.

3.

Fritz D, van de Beek D, Brouwer MC. Clinical features, treatment and outcomes in neurosarcoidosis: systematic review and met—analysis. BMC Neurol. 2016; 16: 220.

4.

Haldorsen IS, Espeleand A, Larsson E-M. Central nervous system lymphoma: characteristic findings on traditional and advanced

• imaging. AJNR 2011; 32:984-992.

5.

Jurado R, Walker HK. Cerebrospinal Fluid. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths. 1990.

6.

Knipe H, Maller VG, et al. Intraventricular neoplasms and lesions. Radiopaedia. Available online at https://radiopaedia.org. Accessed 2/11/19.

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Lammering JC, Iv M, Gupta N, et al. Imaging Spectrum of CNS Coccidiomycosis: Prevalence and Significance of Concurrent Brain and Spinal Disease. AJR. 2013; 200(6): 1334-1346.

8.

Mahale RR, Mehta A, Rangasetty S. Extraparenchymal (Racemose) Neurocysticercosis and Its Multitude Manifestations: A Comprehensive Review. J Clin Neurol. 2015; 11(3): 203-211.

9.

Saadi A, Rajashekara S. Intramedullary spinal neurosarcoidosis. Rad Case Reports. 2012; 7(4): 739.

10.

Shen C, Ying H, Lu X, Hu C. Nasopharyngeal carcinoma with central nervous system metastases. Medicine. 2017; 96(49): e9175.

11.

Uña E. Intraventricular metastases from small cell carcinoma of the lung. BMJ Case Rep. 2012. PMID 22605865.