ASCP Course 1301: Diagnostic Issues in Surgical Neuropathology

Mark L. Cohen, M.D.

Richard A. Prayson, M.D.

CLEVELAND CLINIC FOUNDATION

Upon completion of this course, participants should be able to:

1. Describe a rational approach to intraoperative neuropathologic consultation

2. Define diagnostic criteria for common surgically encountered neuropathologic lesions

3. Generate differential diagnoses for each of these neuropathologic entities

Intraoperative Consultation: What the surgeon wants to know

1. Sampling adequacya. For eventual diagnosisb. For ancillary studies

2. What operation to perform3. Appropriate postoperative

treatment4. What to tell the family5. WHAT IS IT ?!?

Intraoperative Consultation: What you should know

• Age• Location• History• Imaging

characteristics

Intraoperative consultation: Gross examination

Cardinal ordinances of neuropathologic IOC

NEVER

Process all of the abnormal appearing tissue

ALWAYS Include portions of the

softest, darkest regions of the specimen

Smear or Freeze?

Why I like smear

preparations•Speed•Sampling•Simplicity•Cytology•Sterility

Why RAP likes frozen

sections• Familiarity• Architecture• Evaluation

time

Who cares what you like?

What do other neuropathologists do?

92 Neuropathologists (from 14 countries) prefer:

Frozen only 20%

Cytology only 10%

Both FS & cytology 70%

Cytologic method

Crush/Smear 2/3

Touch prep 1/3

H&E stain 90%J Neurosurg 1999;91:454

The middle path

IOC: Diagnostic Algorithm

The tissue is

AbnormalNormal

Non-neoplasticGet more tissue Neoplastic

Representative? Tumor type

Tumor grade

IOC: Common Pathologic Diagnoses

Diagnosis Percentage of cases

High-grade glioma 40

Low-grade glioma 15

Metastatic carcinoma

15

Meningioma 15

CNS lymphoma 5

Abscess 5

Inflammatory 5

Intraoperative Consultation: Thoughts on age(ing)

Low-grade gliomas are sufficiently rare in middle-aged & elderly individuals that their apparent presence during intraoperative consultation is reason for concern

There are a significant number of low grade gliomas of childhood which appear malignant on first assessment - proceed with caution

Meningioma

Astrocytoma(WHO II)

Recurrent glioma(post-radiation)

Pilocytic astrocytoma

Myxopapillaryependymoma

Oligodendro-glioma

Lymphoma

Demyelination

Medulloblastoma

Off to the cases…

Heeeerrrs Richard!!

Case 6: Oligodendroglioma (WHO II)

These slowly growing neoplasms often manifest after several years of preoperative epileptic seizures and have a favorable prognosis regarding time till recurrence

Oligodendroglioma: Why Should I Care?

1. Biologic Behavior 2. Grading: “Double Indemnity”3. Molecular prognostication

Oligodendroglioma: Initial Clues

Low “P/C” ratio Arcuate vasculature

Subpial spread

Perineuronal satellitosis

Band-like cortical calcifications

“Germinal centers”

Minigemistocytes

Perinuclear halos (fried-eggs)

LIGOS

Astrocytomas

What is an oligodendroglioma?

Neurocytoma

Clear cellependymoma

Dysembryoplasticneuroepithelial tumor

Central neurocytoma

Neuropil islands Synaptophysin positive

Dysembryoplastic Neuroepithelial Tumor

Absence of satellitosis

Clear Cell Ependymoma

IHC in clear cell gliomas

Antigen Oligodendro-glioma

Neurocytoma Clear cellependymoma

GFAP +/- Rare Weak

Synapto Weak Strong Rare

Neu-N Rare Strong Rare

EMA Weak Negative Positive

Vimentin +/- Negative Positive

Molecular diagnosis of clear cell gliomas

Human Pathology, 2004

Anaplastic oligodendroglioma (WHO III)

Some tumors may develop histological features commonly found in glioblastomas..

Molecular subtyping of histologically-defined AOs

Molecular

genetics

1p/19q lossonly

1p lossother

1p intactP53

mutation

1p intactOther (e.g. EGFR amp)

Imaging FrontalParietal

FrontalParietal

TemporalRing-

enhanced

TemporalRing-

enhanced

Response

rate

100% 100% 33% 18%

Survival(years)

> 10 6 6 1.5

Pleomorphic nucleiBrisk mitotic ratePseudopallisading

Small cell glioblastoma

Indications for genotyping

• Anaplastic oligodendrogliomas– 1q/19p loss is a positive prognostic

indicator

• AO versus small cell GBM– intact 1p + EGFR amplification = small

cell GBM

• Grade II oligodendroglioma– Confirmation of diagnosis, if 1p deleted

(70%)

Caveat emptor: All 1p deletions are not created equal

• Whole 1p deletion associated with whole 19q deletion– Typical oligodendroglial morphology with good

overall and progression free survival• Distal 1p36 deletion associated with intact

or completely absent chromosome 19– More frequently seen in astrocytic tumors, and

characterizes a particularly aggressive group of gliomas

• FISH with 1p36 probe will not distinguish these two forms of 1p deletion

Case 7: Primary CNS Lymphoma (the 5% tumor)

• 5% of primary intracranial neoplasms – Median age = 55

• 5% of AIDS patients, usually late-stage – 3600-fold relative risk, median age =

40• 5% of post-transplant patients

– 50% confined to CNS• 5% of congenital immunodeficiencies

– Median age = 10

Supratentorial, periventricular, often multiple

Meningeal, ocular disease in ~20%

Modest peritumoral edema

Marked response to steroids

Primary CNS Lymphoma: Intraoperative Consultation

Smear

Crush

Pre-operative steroids = “Ghost tumor”

Angiocentric & angioinvasive

“Reticulin cell sarcoma”

No Satellitosis

Subclassification and analysis of proliferative

activity appears to be of no practical importance

Anti-CD20

Primary CNS Lymphoma: Prognosis

•Excellent initial response rate•Cerebral recurrence is typical•Median survival (treated)

–4 months (including AIDS)–9 months (immunocompetent)–2 years (tertiary care/clinical trials)

Hen’s teeth: Metastatic DLBCL

Primary dural lymphomaPrimary dural lymphoma

Intravascular lymphomatosis

Case 8: Tumor-like demyelinating lesion

Worrisome feature #1: Hypercellularity

Worrisome feature #2: Pleomorphism

Worrisome feature #3: Mitoses

Worrisome feature #4: Microvascular proliferation

Worrisome feature #5: Degeneration

Helpful feature #1: Inflammation

Helpful feature #2: Low N/C ratios

Helpful feature #3: Demarcation

Helpful feature #4: Xanthomatous histiocytes

Helpful features #5: Creutzfeldt astrocytes

Differential Diagnosis: Glioma

Differential Diagnosis: Liquefactive necrosis

Differential Diagnosis: Progressive multifocal leukoencephalopathy

Anti-CD68

Anti-GFAP

TLDL: Immunohistochemistry

TLDL: Outcome

•Resolution•Progression to MS•Rarely paraneoplastic•Rarely develop CNS lymphoma

Case 9: Medulloblastoma

A malignant, invasive embyonal tumor of the cerebellum with preferential

manifestation in children, predominant neuronal differentiation, and an inherent

tendency to metastasize via CSF pathways

Medulloblastoma vs. PNET

One-third of pediatric posterior fossa tumors

Peak incidence = age 770% are younger than 16Comprises 1% of adult primary CNS tumors

80% between ages 21 and 40 Rarely occurs beyond age 50

WHO IV (Classic, Desmoplastic, LC/A, MBEN)

5-year, event-free survival = 80%

“Classic” medulloblastoma (60%)

Desmoplastic medulloblastoma (10%)

Anti-synaptophysin

Reticulin-free “pale islands”

NBCCS/PTCH

Predominantly < 3 years of age

Medulloblastoma with extensive nodularity (< 5%)

Large cell/anaplastic medulloblastoma (25%)

Moderate anaplasia (15%) Severe anaplasia (10%)

5-year survival = 65% 5-year survival = 50%

• Local• Supratentorial

metastases• Leptomeningeal

dissemination• Extraneural

metastases

Medulloblastoma: Recurrence

Upon completion of this course, participants should be able to:

• Describe a rational approach to intraoperative neuropathologic consultation

• Define diagnostic criteria for common surgically encountered neuropathologic lesions

• Generate differential diagnoses based upon these neuropathologic entities

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