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Understanding the Diagnosis of Lymphoma

Spanish Society of Pathology Meeting
Madrid, Spain
8 February 2013
Thomas Grogan, M.D
Professor Emeritus, University of Arizona
Founder, Ventana Medical Systems
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Objective
Explain why the pathologist is so important in patient care.
Method
Medical case examples.
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The Pathologist as Diagnostician
Medical Cases:

Cases over diagnosed as Malignant Lymphoma (ML)
9 year old said to have tonsilar ML
54 year old said to have Hodgkin L

Cases under diagnosed as ML
10 year old said to have meningitis

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The Pathologists Role Beyond Diagnosis
The pathologist as prognosticator:
- 58 year old said to have follicular lymphoma
- 60 year old with SQ ML

The pathologist as determiner of therapy:
A 55 year old with CLL

The pathologist as communicator:
A 60 year old with retroperitoneal DLBCL

Medical Cases
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Requirements for the Proper
Diagnosis of Lymphoma
Correct handling of tissue
A well-done H&E
An expert microscopist
An adroit use of ancillary tests (IHC, ISH)
A complete knowledge of the WHO classification
An ability to integrate all findings
Sound judgment
Strong communication skills

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Patient #1
19 year old male with shortness of breath and impending airway
obstruction.

Prior history:
Diagnosis of congential, familial Cystic Fibrosis (CF)
Diagnostic tests
Sweat test: NaCL >60 mM/L
Mutation of CF gene ( CL
-
Channels)

Clinical course: 1988-2006
End stage, destructive lung disease:
Bronchiectasis
Recurrent bronchopneumonia

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Patient #1
Treatment: October 2006
Living-donor lung transplant
Immunosuppression: Cyclosporin A

Clinical course: January 2007
Shortness of breath
Impending airway obstruction
Tonsillar masses

Impression:
Post-transplant cancer (Lymphoma)



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Post-Transplant Tonsilar Mass
H&E
4X 60X
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Post-Transplant Tonsilar Mass
CD20 IHC
4X 60X
CD3 IHC
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Post-Transplant Tonsilar Mass
Ki-67 IHC
4X 60X
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Post-Transplant Tonsilar Mass
Kappa ISH
4X 4X
Lambda ISH
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Post-Transplant Tonsilar Mass
EBER ISH
4X 60X
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Post-Transplant Tonsilar Mass
4X
H&E CD20 IHC Ki-67 IHC
EBER ISH Kappa ISH Lambda ISH
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The Pathologist as Diagnostician
Medical Cases:

Cases over diagnosed as Malignant
Lymphoma (ML)
9 year old said to have tonsilar ML
54 year old said to have Hodgkin L

Cases under diagnosed as ML
10 year old said to have meningitis

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Patient #2: 54-year-old patient with abdominal pain
and recurrent infections
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Bone Marrow Biopsy
H&E suggests Hodgkin Lymphoma
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CD15 Lambda Kappa
Key Tissue Staining Results
IHC H&E ISH
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The Pathologist as Diagnostician
Medical Cases:

Cases over diagnosed as Malignant Lymphoma
(ML)
9 year old said to have tonsilar ML
54 year old said to have Hodgkin L

Cases under diagnosed as ML
10 year old said to have meningitis

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CNS Lesion in a 16 Year Old Boy
H&E Staining
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CD 45
CNS Lesion in a 16 Year Old Boy
CD 20 CD 3
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H&E
CNS Lesion in a 16 Year Old Boy
CD 30
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Primary CNS Anaplastic Large Cell Lymphoma
ALK-1 CD 30
H&E
CD 45
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The Pathologists Role Beyond Diagnosis
The pathologist as prognosticator:
58 year old said to have follicular lymphoma
60 year old with SQ ML

The pathologist as determiner of therapy:
A 55 year old with CLL

The pathologist as communicator:
A 60 year old with retroperitoneal DLBCL

Medical Cases
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The Pathologists Role Beyond Diagnosis
The pathologist as prognosticator:
58 year old said to have follicular lymphoma
60 year old with SQ ML

The pathologist as determiner of therapy:
A 55 year old with CLL

The pathologist as communicator:
A 60 year old with retroperitoneal DLBCL

Medical Cases
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Blood 79:2432-2437, 1992


46 PTL: 11 (24%) NCAM Positive

Sites of Involvement:
CNS (36%) Parathyroids
Muscle (18%) Pituitary
Nasopharynx Adrenals
GI (27%)

Conclusion: NCAM plays a role in the
behavior and localization of lymphomas

NCAM Positive T-Cell Lyphoma (PTL)
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m
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Polysialic Acid (PSA)
NCAM Associated N-Linked Oligosaccharride

Neurodeterminant in Neonatal Meningitis ( 2,8 Helix)

Recognition Molecule In Fish Egg Fertilization

In Man, Mediates Neurite Fasciculation, Neuronal
Migration and Neural Muscle Interaction

In Tumors May Enhance Metastasis
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Sanctuary Site Invasion via CAM
(NCAM, CD56)
CNS Invasion Via Polysialated CD56 On
T-Cell Lymphomas

Same Neurodeterminant As In Meningitis

Lymphoma Site Specificity Via CAM

Homophillic Binding: BBB, NMJ

CNS Scanning and Prophylaxsis

Serologic Correlate

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The Pathologists Role Beyond Diagnosis
The pathologist as prognosticator:
58 year old said to have follicular lymphoma
60 year old with SQ ML

The pathologist as determiner of therapy:
A 55 year old with CLL

The pathologist as communicator:
A 60 year old with retroperitoneal DLBCL

Medical Cases
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Bone Marrow Involvement with CLL
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Bone Marrow Involvement with CLL
TP53 17P -
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Aberration Occurrence Prognosis OS Treatments
13q ~30% Best
15-17
yrs.
Monitor
Trisomy 12 ~20% Intermediate 9-10 yrs. CD20 targeted agents
11q ~15% Poor 3-6 yrs.
Rituximab, with
alkylating agents
17p ~7% Very Poor 1-2 yrs.
Novel agents/+/or
allogeneic stem cell
transplant
Primary Genomic Aberrations Associated with CLL
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The Pathologists Role Beyond Diagnosis
The pathologist as prognosticator:
58 year old said to have follicular lymphoma
60 year old with SQ ML

The pathologist as determiner of therapy:
A 55 year old with CLL

The pathologist as communicator:
A 60 year old with retroperitoneal DLBCL

Medical Cases
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Medical Needs
The Patient The Lab/The MD
What do I have? Diagnosis
What caused it? Etiology: Infections/Genetic
What explains my symptoms? Pathogenesis
What are my prospects? Prognosis
Has it spread? Metastasis
What is my treatment? Therapeutic Targets
Will I be cured? Response Prediction
Will I be hurt? Toxicity Prediction
How will I be followed? Monitoring
Will it return?
Relapse
Will others in my family get it? Predisposition Screening
How will you communicate the results?
Medical Report
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60 year old female (G2 P2) with persistent nausea and
vomiting x 2 days.

Prior history:
Allergy to Iodine
Recurrent urinary tract infections x 3
Migraine headaches treated with cafergot

Clinical Impression:
Post prandial cholecystitis

PATIENT HISTORY
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CT SCAN: PRE TREATMENT
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CT GUIDED BIOPSY
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H & E: DIFFUSE LARGE CELL LYMPHOMA (DLCL)
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CD20
TARGET FOR CD20 RITUXIMAB (R)
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Antibody scheme to identify B-Cell
Malignant Lymphoma
16 Lymphoma Types
A
n
t
i
b
o
d
i
e
s

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Grogan, Candace J Grogan, Candace J
04360434 04360434
4/3/1945 4/3/1945
F F
Page: 26 of 82 Page: 26 of 82
Acq no: 3 Acq no: 3
KVp: 120 KVp: 120
mA: 200 mA: 200
Tilt: 0.0 Tilt: 0.0
RD: 417.96 RD: 417.96
University Med Center University Med Center
CT-ABD/PEL W/O CT-ABD/PEL W/O
10/2/2005 05:47:37 10/2/2005 05:47:37
2726123 2726123
LOC: 201.50 LOC: 201.50
THK: 5.0 THK: 5.0
FFS FFS
IM: 26 SE: 3 IM: 26 SE: 3
W: 426 W: 426
C: 55 C: 55
Z: 0.67 Z: 0.67
R R L L
A A
P P
cm cm
CT POST TREATMENT
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INSERT PHOTO HERE
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Interpreter of biomarkers in microanatomic context

Integrator of information
- Multiparameter data in context

Great Communicator
- Deliverer of the integrated results
- Provider of the patient-centric report

Role of the Pathologist

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Blood 101:4279, 2003
NEJM 202:540, 1998
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Medical Cockpit
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Virtuoso: Software Application

Virtuoso is a web based software application that allows
a user to view, manage, manipulate, analyze, report and
collaborate.

Virtuoso applications include:

Case Management
Image Viewing
Image Analysis

Telepathology (peer review,
remote consultations)
Real-time Collaboration
Customized Reporting


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Requirements for the Proper
Diagnosis of Lymphoma
Correct handling of tissue
A well-done H&E
An expert microscopist
An adroit use of ancillary tests (IHC, ISH)
A complete knowledge of the WHO classification
An ability to integrate all findings
Sound judgment
Strong communication skills

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The Importance of Context
Aoccdrnig to rscheearch at Cmabrigde Uinervtisy, it
deosnt mttaer in what oredr the ltteers in a wrod are,
the olny iprmoetnt tihng is taht the frist and lsat ltteer
be at the rghit pclae.

The rset can be a total mses and you can still raed it
wouthit a porbelm. Tihs is bcuseae the huamn mnid
deos not raed ervey lteter by istlef, but the wrod as a
wlohe.
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The Ideal Future

Multiparameter, multiplex results with morphology,
phenotype, and genotype with full definition of all
therapeutic targets communicated in a same day
patient report integrating pathology, radiology, surgery
and oncology findings.

Results communicated by a multitasking pathologist who
serves as diagnostician, lab director and information
integrator.
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We I nnovate Healthcare