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CASE 1.

A 25 year old Hispanic woman presents with 2 week


history of easy bruising of her lower extremities,
a one day history of gum bleeding, and a 2 hour
history of continuous epistaxis. Three weeks
ago she had a normal menstrual period. During
the past week she has noted increasing fatigue.
PE revealed generalized pallor, multiple large
ecchymosis of her lower extremities plus
scattered petechiae (probably low platelets),
dried blood in both nares and blood blisters
involving buccal mucosa.
Labs
• Hb 7.0 gm/dl, MCV 90, RDW 16
• WBC ct of 8,000/μl
• Bilirubin 0.2 mg/dl
• Reticulocyte ct – 20,000/μl (n 50-100)
• Platelet ct – 10,000/μl (n 150-400)
• Fibrinogen – 100 mg/dl
• D-Dimer - >9999 (DIC => likely APL)
• APL = usually older ppl 60-70
• Diagnose with
• User normal white count
‘NORMAL’
Marrow –
mixture
White c 50%
Red c 25%
Megs 1%

Lymphs 10-15%
Plasma cells 2%
CASE 1 Acute promyelocytic leukemia - APL
is a variety of AML, known as FAB M3 (French
American British classification type 3)
- goes from M0 - M7.

Peripheral blood – ‘blasts’


– absence mature granulocytes
-absence platelets

Normal marrow comparison


Note spectrum of granulocytes,
plus erythroid series.

Marrow smear– almost replaced by


Marrow sections / biopsies

Marrow section – almost replaced by blasts

Normal marrow comparison.


Note spectrum of granulocytes,
plus erythroid cells and
Megakaryocytes & fat cells
The hypergranular form of APL features faggot
cells.
Multiple Auer rods, like a bundle of sticks or a
‘faggot’.
Auer rods in marrow section and at EM;
appear as tubules.
Presence of Auer rods = AML- not just APL
But not every AML case has Auer rods

Auer, John (1906). "Some hitherto


undescribed structures found in the large
lymphocytes of a case of acute leukaemia".
American Journal of the Medical Sciences 131
(6): 1002–1015
Flow: 99% accurate
Method for recognizing-
APL from other types AML CD2,13,33+ CD34-

t(15;17)

In 95% of cases of APL, retinoic acid


receptor-alpha (RARα) gene on chr 17 -
translocation with promyelocytic leukemia
gene (PML) on chr 15, t(15;17).
Produces new Fusion protein -PML RAR -blocks maturation
ATRA- all trans retinoic acid – lifts the block
Also used to Rx acne
CASE 2
A 50 year old Caucasian woman was seen by her
primary care doctor because of an 8 month
history of increasing fatigability. Physical
examination revealed an enlarged spleen.
Labs
• Hb 11.5 gm/dl, MCV 91, RDW 14
• Reticulocyte ct – 50,000/μl
• Bilirubin 0.2 mg/dl
• WBC – 150,000/μl
• Differential – 40% Segmented neutrophils
– 23% bands and metamylocytes
– 25% myelocytes
– 2% promyelocytes
– 10% lymphocytes
• Platelets – 300,000/μl
• Increased eosinophils and basophils are common in this
disease
CASE 2 CML
Chronic myelogenous leukemia

Peripheral blood – increased granulocytes


plus immature forms

Marrow- dominated by myeloid (granulocyte) series, with


Immature and mature forms;
rare erythroid cells or megakaryocytes.

Differs from AML in which there is little maturation


CML t(9;22) - Ph chromosome is the small #22

Produces a fusion product BCR-ABL


Activated tyrosine kinase
‘drives’ proliferation
GLEEVEC Imatinib
Novartis Sales 4B/y
Blocks BCR-ABL
activated tyrosine kinase
Causes such cells to die.
Does not affect normal cells.

--blocks other abnormal t kinases


CML t(9;22) in GIST tumors cKIT+ and mastocytosis etc
Detect by
FISH
or PCR
CML – usual form - blood
CML – accelerated form or ‘blast crisis’- blood

AML ALL

AML
Megakaryoblastic
PERIPHERAL BLOOD

CML CLL

ALL
AML
MARROW

CML CLL

normal

AML ALL
Methods for recognizing-
AML v ALL FLOW CYTOMETRY
is BEST
Complex panels
Sudan black

+ve in AML

Auer rods =
AML if present
peroxidase

+ve in ALL

Tdt
CASE 3
A 65 year old African American male was
referred for evaluation of an elevated
Hemoglobin level. He was asymptomatic. He
did give a history of erectile dysfunction. On
physical examination he had a palpable
spleen.
Labs
• Hb 19.0 gm/dl, MCV 83, RDW 16
• Reticulocyte ct – 80,000/μl
• WBC – 13,000 with
– 74% segs
– 10% lymphs
– 10% monocytes
– 3% basophils
– 3% eosinophils
• Platelets – 500,000/μl
CASE #3 Polycythemia vera

Peripheral blood smear appears


‘crowded’ due to numerous rbc s

In some cases
Somatic JAK2 mutations - platelets also increased
-Rbc may be hypochromic
Decreased EPO levels due to low iron

Leucocyte alkaline
phosphatase LAP +
Somatic JAK2 mutations
Inc function of Janus K2
Also a tyrosine kinase

Myeloid stem cell


in 95% cases PCV

But not specific - 50%


Essential thrombocythemia
Primary Myelofibrosis

What Happens if the Test Is Positive?


Having a positive JAK2 blood test does not
mean that you have or will develop PV.
However, you might develop PV or other MPNs
later in life. Targeted RX???
Cost c $1000.
PRV
MARROW
- Reduced fat
- Crowded
-All lineages increase-
-So still a ‘mixed’
appearance

normal
CASE #3
Polycythemia vera
Chronic congestion appearance.

Autopsy on a P Vera patient with long standing


hypertension due to hyper-viscous blood
Resulted in LVH due to ‘increased’ load
CASE 4
A 70 year old African-American presented with
pneumonia which was determined to be due
to the pneumococcus (strep pneumoniae). He
did not have a previous viral infection and he
was not an alcoholic. Previously he was in
excellent health.
Labs
• Hb 10.0 gm/dl
• WBC – 15,000 with increased segmented
neutrophilia and bands
• Platelet 400,000/µl
• Total Protein 9.5 gm/dl (usually 7-7.5)
• Albumin 3.0 gm/dl (low)
• Creatinine 2.0 mg/dl (high)
• Calcium 12.0 mg/dl (high)
CASE #4
Multiple myeloma = multiple marrow tumors

CASE #4
Multiple myeloma – spine and skull
typically affected
CASE #4
Multiple myeloma - plasma cell neoplasm –
more precisely B cell neoplasm with
maturation to plasma cells

Marrow smear

Marrow section
Marrow section
– immunohistochemsitry ‘stain’
showing monoclonal expression of Kappa
- no lambda

 >10% plasma cells

 Some times difficult to assess


CASE #4
Multiple myeloma

High globulin levels causes


rouleaux of rbcs

and casts in renal tubules


composed of ppt light chain
and TammHorsfall protein

Myeloma kidney
w. renal failure

Hypercalcemia
Also – renal damage
CASE #4
Multiple myeloma
The ‘definitive’ test

‘normal’

‘densitometry’
-comparing density of bands vs standards
gives accurate quantification
Serum protein CASE #4
electrophoresis Multiple myeloma
SPEP The ‘definitive’ test urine protein
Electrophoresis
PEP (Bence Jones
Protein -old term)

K Low MW
Light chain
Into urine Urine Immunofixation
This case K positive
Serum Immunofixation In a case of ‘Light chain
K G positive disease’ - 15-20% overall
CASE #4
Globulin----------albumin
Multiple myeloma
Protein
electrophoresis

Monoclonal
‘spike’
Protein
densitometry

Arc distorted and dense


-because of ‘spike’ Patient serum
In trough
Anti IG Antibody
Gives ppt arcs
Immunoglobulin

Arc long and curved normal serum


-due to diffuse polyclonal In trough
immunoglobulins Globulin----------albumin
Lymphoplasmacytic lymphoma
Lymphocytes and plasma cells
= Waldentrom’s Macroglobulinemia
IgM monoclonal ‘spike’
A Lymphoma - not a ‘myeloma’
CASE 5
A previously healthy 5 year old girl presents with
a 5 day history of fever (up to 102of) and sore
throat. Physical examination revealed an ill
appearing girl with a temp of 103, an
erythematous oropharynx with some exudate,
bilateral cervical adenopathy, and a palpable
spleen.
Labs
• Hb 11.5gm/dl
• WBC 14,300 with 50% lymphocytes which
appeared very atypical
• Platelets 200,000/µl
• Total protein 7.0 gm/dl
• Albumin 4.0gm/dl
• AST -150 (N <40)
• ALT – 125 (N <40)
• Alk ptase 275 (N <105)
CASE #5
Infectious
‘mononucleosis’

The ‘monucleosis’ cells are


activated lymphocytes, -
mainly T cells
The ‘monucleosis’ cells are not only in
the blood but throughout the
lymphoid tissues, where they may be
mistaken for a large cell lymphoma

Nodes in ‘mono’ - few cells and many cells

Phenotype –CD- marker studies


are helpful in sorting this out

Either
Spleen in ‘mono’
immunohistochemistry
Or
Flow cytometry
Flow cytometry on blood
or biopsy suspension :

B lymphoma/Lk Mono

CD 20+ 90% CD 20+ 26%


CD 3+ 12% CD 3+ 71%
CD 4+ 9% CD 4+ 42%
CD 8+ 4% CD 8+ 32%
K+ 5% K+ 15%
L + 80% L + 9%
DANGER

DO NOT misdiagnose as malignant


1. History
2. Serology
3. Phenotyping

Diffuse Large B Cell Burkitt Hodgkin Lymphoma


Monospot -- 96+ % specific
Sensitivity lower 70-90% - esp in children
Finger prick
Detects a X-reactive antibody at 2 weeks plus
False+ inc. ---infections, lymphoma, autoimmune dis

Other tests exist for EBV specific antibodies,


VCA (Capsid antigen ) -- IgG (recent) or IgM (prior)
EBNA (Nuclear antigen) -- prior
CASE 6
A 25 year old Caucasian woman presents with
cough of 4 weeks duration and shortness of
breath during the past 2 weeks when lying
down. She had never smoked. Her appetite
was good and she had no weight loss. P.E.
revealed a 5x5 cm non tender mass in the
right low neck. Chest film revealed a large
anterior mediastinal mass.
Labs

• Hb 12.0 gm/dl
• WBC 10,000/µl
• Platelet ct 300,000/µl
CASE # 6 mediastinal mass-- differential
diagnosis
Neoplasm of any organ/cell
in that location
+ metastatic disease
CXR
Hodgkin lymphoma – NS
B cell lymphoma
T cell lymphoma
Thymoma (epithelial)
PET Germ cell tumor
CARCINOMA (age, history)
CAT lung, esophagus ?
METASTASES

(Reactive nodes – eg TB )
(Thyroid goiter)

Fine Needle Aspirate

Bone??? ‘malignant cells’


Hodgkin’s Lymphoma
Nodular sclerosis

Hodgkin’s Lymphoma
Extranodal spread to lung

Hodgkin’s Lymphoma
Reed Sternberg cell CD30 CD15
Thymus
T lymphoblastic
- T ALL
mediastinal
‘non-Hodgkin’ Lymphomas

B large cell lymphoma


Peripheral T cell Lymphoma
Mediastinal B cell ML
Lymph nodes
Metastatic malignant neoplasms
- very variable appearance
-older age groups –common
- younger - rare

Usually need IHC


to sort out which it is
+ Germ cell tumors
+ Rare tumors
seminoma of almost
any other
cell type

+ Thymoma
carcinoma’ teratoma

Don’t forget
Non- malignant masses

Keratin IHC Thyroid goiter


CASE 7
A 47 year old Caucasian male presents with a 1
month history of intermittent low grade fever,
night sweats, and a 15 pound weight loss. In
addition, he has noted a lump in his left axilla
which has been increasing in size over the past
few weeks.
Physical Examination
T-101, P-100, R-18, BP 110/70. Slight
conjunctival pallor. There was a 5x3 cm non
tender mass in the left axilla but no other
adenopathy. C-P exam was normal. There was
no hepatosplenomegaly.
Labs
• Hb 12.6 gm/dl, MCV 90, RDW 14
• Absolute reticulocyte ct – 30,000/μl
• WBC ct of 8,500 with normal diff
• Platelet ct – 300,000/μl
• T. bilirubin 0.3 mg/dl
• LDH -1,000
• Hepatic tests – normal
• Creatinine 0.6 mg/dl
• Chest x-ray – normal
• Total protein – 7.0 gm/dl with albumin 3.8 gm/dl
CASE # 7 Non-Hodgkin Lymphoma- differential
diagnosis - B or T - numerous sub-types

Differential In favor Against


TB Normal CXR;
Axillary node v rare
in - intestinal TB
Non Hodgkin Isolated Ax node; -
- non tender
- High LDH
ALL N wbc, platelets.
Only slight anemia
Multiple myeloma Almost never nodal
N serum protein
CML May give tissue N wbc, platelets
mass, but rare Only slight anemia
Metastatic Young for most
male CA
SUSPECT LYMPHOMA DECISIONS

*Reactive (‘benign’) vs malignant


Biopsy (or FNA)
*Lymphoma (leukemia) vs metastasis

*Hodgkin vs Non-Hodgkin

*Sub-type, classification, B/T etc

Morphology –gold standard

Phenotype – flow
IHC
Gene RX - Ig / TCR

Genotype – t(8;14), t(14;18)


V. Malignant Lymphoma
Classification: Principal Types

Further sub-classified:

Non – Hodgkin ------ Hodgkin

T cell ----------------- B cell

B Sub-types
T
Sub-types Sub-types
Other criteria in diagnosis / nomenclature:
WHO also uses morphology

small v large cell lymphoma follicular v diffuse

Large cell
Small cell

All B cell type

Small cell Large cell


lymphocytic lymphocytic
Lymphomas lymphomas B cell type or
T cell type
Diffuse
process B or T
B either
B or T
Lymphoma
(or reactive)
Follicular
process
is B lymphoma
(or reactive)

CD markers
B -red
T -brown
B lymphoma

Decide B v T - Immunohistochemistry (flow cytometry)


THE POINT-- 3 common types - rest uncommon (ADULTS).
ADULTS NHL

Follicular 30%

Diff L B Cell 30%

Lymphoplasmacytic

Mantle cell MCL Small Lymphocytic 10%

Marginal zone MZL

Burkitt 10%
T cell 10%
CD19,CD20
Burkitt lymphoma
CD10
Endemic = the classic childhood form Ig rearranged
High EBV assoc t(8;14)
Sporadic -sometimes called Burkitt – like
30% EBV – may be other mechanisms

Malignant cells B cells.

Low mag – ‘starry sky’ Leukemic phase


( back ground histiocytes) Looks a bit like ALL