Transcript Pt.5 S.N.- Clinical presentation

Pt.1 K.Gu.- Clinical presentation
 K.G. was a 59 y.o. female in 1990 when she noted the
development of enlarged lymph nodes in her left inguinal
region. A lymph node biopsy yielded a diagnosis of
lymphoma, and subsequent staging yielded evidence of
periaortic, bilateral inguinal, and bilateral axillary lymph
node involvement, and bone marrow infiltration.
 In 1994, the patient noted enlargement of a right inguinal
lymph node, and another lymph node biopsy was
performed.
K.G.- 1990 biopsy
K. G. - 1990 biopsy 50x
Pt.1 K.G.- Flow analysis
Lymphoid
T
Lymphoid
B
‘90
Natural
killer/myeloid
‘90
CD2
21
CD19
50
CD3
20
Kappa
73
CD4
17
CD5
Myeloid
‘90
CD56
Other
‘90
‘90
CD13
CD10
66
CD14
CD34
Lambda 2
CD15
CD41
21
CD19/
CD10
66
CD33
CD45
96
CD7
21
CD20
70
HLADR
78
CD8
2
CD20/
CD5
<1
GP-A
K.G.-Bcl2
immunohistochemistry
Pt. 1 K.G. Diagnosis:
1990: Follicular lymphoma, Grade I
Frequency of lymphomas
Indolent versus aggressive
 Indolent











Small lymphocytic
lymphoma/CLL
Follicular lymphoma, Grades
1/2
Extranodal Marginal zone
lymphoma of MALT type
Nodal marginal zone
lymphoma
Splenic marginal zone
lymphoma
Hairy cell leukemia
Lymphoplasmacytic
lymphoma
Plasma cell myeloma
Plasmacytoma
Cutaneous T cell lymphoma
Cutaneous CD30+ anaplastic
large cell lymphoma
Aggressive






Prolymphocytic
leukemia
Large B cell lymphoma
Burkitt lymphoma
Mantle cell lymphoma
Anaplastic large cell
lymphoma
All peripheral T cell
lymphomas
Divides B and T
Pt K.G. Diagnosis:
1990: Follicular lymphoma, Grade I
Therapy 1990
Prognosis 1990
Table X: Indolent B cell lymphomas
Frequency (%
all ly mphomas
Age of onset
median
Stage at
Presentation
Response to
Therapy
5 yr survival
Predominant si te
presentation
Pattern of nodal
Inf iltration
Benign cell
Equivalent
Dominant cell
type
Im muno pheno
-type
Molecular
Pathogenesis
Follicular
Lymphoma
(Grade I)
22%
Marginal zo ne
Lymphoma
Small lymphocytic
lymphoma/CLL
8
7
59
61
65
Stage III/I V
Disseminated
Good to most
treatments,
but incurable
short of
transplant
72%
Stage I
Stage IV
Frequently
curable
Similar to
Follicular
lymphoma
74%
51%
Nodal
Extranodal
Marrow/nodal
Follicular
Diffuse
Diffuse
Germinal
center
small cle aved
cell
Small cl eaved
cell i n most
cases, but can
be large cell
Positive: CD19
CD10, Bcl2+
Negative: CD5-
Marginal zo ne
Lymphocyte
Virgin B cell
Mix o f small
lymphocytes,
plasma cells
t(14;18)
Bcl2/JH
t(11;18),
Trisomy 3
Small
lymphocytes
with round
nucleus
Positive:
CD19, CD5
CD23
Negative:
CD10
Trisomy 1 2
Positive:
CD19, Bcl2
Negative:
CD10, CD5
K. G. - 1994 biopsy
K. G. Biopsy 1994 - 50x
Pt. K.G.- Flow analysis
Lymphoid T
Lymphoid B
‘90 ‘94
‘90
‘94
CD19
50
90
73
CD2
21
CD3
20
10
Kappa
CD4
17
8
CD5
21
10
CD7
21
CD8
2
7
NK associated
Myeloid
‘90 ‘94
CD56
Other
‘90 ‘94
‘90 ‘94
CD13
CD10
66
63
88
CD14
CD34
Lambda 2
4
CD15
CD41
CD19/
CD10
66
63
CD33
CD45
96
99
CD20
70
95
HLADR
78
40
CD20/
CD5
<1
<1
GP-A
Pt. K.G. Diagnosis:
1990:Follicular lymphoma, Grade I
1994: Progression to diffuse large
cell lymphoma
Therapy 1994
Prognosis1994
Clinical follow-up
K G. lessons
 Follicular lymphomas are the second most common type of lymphoma seen in
Western countries
 Most are disseminated at diagnosis, Stage III or IV
 In the most common forms, Grades 1 and 2, they are indolent lymphomas

Mean survival >7 years
 Pathogenesis due to failure of apoptosis, programmed cell death


Caused by translocation, t(14;18)(q32;q21)
Produces constitutive expression of Bcl2, an anti-apoptotic protein, so cell
immortalized, but small replicating fraction and slow growth of tumor
 Therapy during indolent phase based on age, stage, symptoms


Until recently, felt to be incurable, but controllable
Watch and wait vs limited chemotherapy vs transplant
 Can progress to large cell lymphoma



More aggressive disease due to activation of cell cycle mechanism
Now increased growth fraction plus defective cell death
Requires more aggressive multiagent chemotherapy vs transplant
K. G. Lessons 2
 Large B cell lymphoma can present de novo
 Most common type of lymphoma in Western countries
 Classic type of aggressive lymphoma, a disease of
excessive cell growth and replication

Morphologic manifestation is large cell with “vesicular” chromatin
pattern and prominent nucleoli, and increased mitoses
 Median survival in absence of effective therapy less than 2
years
 Most will respond to aggressive, multiagent therapy

Overall, 60% will relapse, 40% can be cured
K G-lessons
Prognostic factors in diffuse large cell
lymphoma:

International Prognostic Index factors
•
•
•
•
•
Age
Stage
LDH level
Number of extranodal sites
Performance score
K G.-lessons
 Prognostic factors in diffuse large cell lymphoma:

International Prognostic Index factors
•
•
•
•
•

Age
Stage
LDH level
Number of extranodal sites
Performance score
Biologic predictors
• Cytogenetics
• Upregulated proteins
• Microarray pattern
– Follicular center cell phenotype
– Activated B cell phenotype
Pt.2 S.N.- Clinical presentation
 S.N. was a 56 y.o. male in May, 1996 when he noted the
onset of fever, night sweats, and weight loss. Physical
examination revealed splenomegaly and a right upper
quadrant mass. Radiologic study and MRI revealed
mediastinal lymph nodes and jejunal thickening. A CBC
revealed a WBC of 12,000, with 50% atypical
lymphocytes. A laparotomy was performed at an outside
hospital, with lymph node and liver biopsies. A bone
marrow study was subsequently performed at DHMC.
Pt.2 S.N.- Lymph node
Pt.2 S.N.- Lymph node CD3
Pt.2 S.N.- Lymph node CD3
Pt.2 S.N.- Liver biopsy
Pt.2 S.N.- Peripheral blood
Pt.2 S.N.- Peripheral blood
Pt.2 S.N.- Bone marrow
Pt.2 S.N.- Bone marrow
Pt.2 S.N.- Flow cytometry
Lymphoid T
LN
CD3
19
CD4
19
CD5/
CD20-
1
CD8
1
Lymphoid B
PB
<1
<1
LN
PB
CD19
89
94
Kappa
86
Lambda
NK associated
LN
CD56
Myeloid
PB
LN
Other
PB
CD13
CD10
97
CD14
CD34
7
1
CD15
CD41
CD20/
CD5+
97
99
CD33
CD45
CD20/
CD23+
<1
<1
FMC7
58
98
CD22
34
12
HLADR
GP-A
LN
PB
<1
<1
Pt.2 S.N.- CD5
Pt. S.N.- Cyclin D1
Pt. SN- Diagnosis: mantle cell
lymphoma
Therapy 1996
Current therapy approach
Prognosis 1996
Clinical follow-up
Lessons-the indolent lymphoma imitator
Table X: Indolent B cell lymphomas
Follicular
Lymphoma
(Grade I)
22%
Marginal zo ne
Lymphoma
Small lymphocytic Mantle cell
lymphoma/CLL
Lymphoma
8
7
6
59
61
65
63
Stage III/I V
Disseminated
Good to most
treatments,
but incurable
short of
transplant
72%
Stage I
Stage IV
Stage III/IV
Frequently
curable
Similar to
Follicular
lymphoma
Poor response to
all therapies
to date
74%
51%
27%
Predominant si te
presentation
Pattern of nodal
Inf iltration
Nodal
Extranodal
Marrow/nodal
Nodal
Follicular
Diffuse
Diffuse
Benign cell
Equivalent
Germinal
center
small cle aved
cell
Small cl eaved
cell i n most
cases, but can
be large cell
Marginal zo ne
Lymphocyte
Virgin B cell
Diffuse,
nodular
or
Тmantle zoneУ
Mantle cell
Mix o f small
lymphocytes,
plasma cells
Small
lymphocytes
with round
nucleus
Frequency (%
all ly mphomas
Age of onset
median
Stage at
Presentation
Response to
Therapy
5 yr survival
Dominant cell
type
Im muno pheno
-type
Positive: CD19 Positive:
CD10, Bcl2+
CD19, Bcl2
Negative: CD5- Negative:
CD10, CD5
Molecular
Pathogenesis
t(14;18)
Bcl2/JH
Trisomy 3
Positive:
CD19, CD5
CD23
Negative:
CD10
Trisomy 1 2
Small cell
wi th irregular
nucleus,
similar to
cleaved
Positive:
CD19, CD5,
Bcl2
Negative:
CD10
t(11;14)
Bcl1/JH
>70% 5 yr. surv
30-49% 5 yr. surv
50-70% 5 yr. surv
<30% 5 yr. surv
Patient JC
JC is a 22 yo male who presented to his local MD in March,
2001 with severe back spasms, initially treated with NSAIDS.
He then developed increasing abdominal and left shoulder pain,
fatigue, and 15 lb weight loss over the next six weeks, followed
by night sweats seven days before admission to DHMC. Initial
chest and abdominal X-rays at an outside hospital were
negative, but a subsequent abdominal CT scan detected a
retroperitoneal mass estimated at 18x11x8.5cms and a smaller
soft tissue mass in the right anterior abdomen. Chest CT
revealed bilateral axillary adenopathy. The abdominal wall
mass was biopsied. The patient was transferred to DHMC.
Physical examination here detected additional adenopathy at the
angle of the jaw. Labs WBC 9300, Hgb 12.7gr., Platelets 288K,
BUN 10, LDH 664, other LFT’s normal.
J.C. - Abdominal wall mass
biopsy
J.C. abdominal wall mass-50x
J.C.- Flow cytometric analysis
Lymphoid T
CD2
Lymphoid B
CD19
95
NK associated
CD56
25
Myeloid
Other
CD13
CD10
CD3
18
CD19/
CD10
95
CD14
CD34
CD4
<1
Kappa
15
CD15
CD41
CD5
<1
Lambd a 80
CD33
CD45
CD7
CD8
8
CD20
99
HLADR
CD23
39
GP-A
98
J.C. Diagnosis: Burkitt
Lymphoma
Bone marrow negative for lymphoma
CSF positive for Burkitt lymphoma
Treatment
Prognosis
Current status
Burkitt lymphoma-lessons
 2% of all lymphomas in adults
 1/3 of all lymphomas in children
 Increased incidence in HIV disease
 Very aggressive B cell lymphoma

Can present as acute leukemia or with leukemic component
 Pathogenesis: Translocations bringing the myc cell cycle
control gene/oncogene normally on chromosome 8 to sites
of constitutively expressed B cell antigen receptor genes/
promoters




Results in excessive myc production and constant replication
T(8;14) Ig heavy chain gene
T(2;8) Ig kappa light chain gene
T(8;22) Ig lambda light chain gene
Burkitt lymphoma
In Africa, associated with Epstein-Barr virus
(endemic Burkitt’s)


Not so in US (non-endemic Burkitt)
In US, usually presents in abdomen, often with acute
abdomen/bowel obstruction
Until 10 years ago, rapid fatal, with median
survival <1year
Now cure rates >80% in children, 40-50% in
adults (less in HIV setting)
Requires very aggressive, multiagent therapy
Pt. O.I.- Clinical presentation
 O.I. was a 61 y.o. male in April, 1997 when he noted the onset of
discomfort in his right groin and testicle with walking, accompanied by
a small nodule in his right groin. A CT scan of the abdomen and pelvis
revealed a right retroperitoneal mass extending into the pelvis. A
needle biopsy of the retroperitoneal mass was performed at an outside
hospital, which led to a diagnosis of undifferentiated neoplasm
suspicious for large cell lymphoma. A week later, the patient was
transferred to DHMC for further evaluation and treatment. In the
interim period, the mass demonstrated rapid enlargement, with an LDH
level rising from 1200 to 7000U. A repeat needle biopsy and aspirate
were performed at DHMC for further characterization of the tumor.
Sufficient cells were obtained to perform flow cytometric analysis.
Material for cytogenetics was also submitted.
Pt. O.I.- Needle biopsy 1
Pt. O.I.- Needle biopsy 1
Pt. O.I.- Needle bx 1
Pt. O.I.- Needle bx 1- CD20
Pt. O.I.- Needle biopsy 1- CD3
Pt. O.I.- Needle biopsy 2
Pt. O.I.- Biopsy 2-Touch imprint
Pt. O.I.- Flow analysis
Lymphoid T
CD2
Lymphoid B
CD19
95
NK associated
CD56
25
Myeloid
Other
CD13
CD10
CD3
18
CD19/
CD10
95
CD14
CD34
CD4
<1
Kappa
15
CD15
CD41
CD5
<1
Lambd a 95
CD33
CD45
CD7
CD8
8
CD20
99
HLADR
CD23
39
GP-A
98
Pt. O.I. Diagnosis:
Small noncleaved lymphoma,
non-Burkitt type
(Burkitt lymphoma, variant type,
by WHO)
Therapy
Prognosis
Clinical outcome
Pt. J.L.I.
JLI was a 74 y.o. male in spring 2001 when he noted a decrease
in appetite and intermittent nausea which progressed to
epigastric pain. Upper GI series with small bowel followthrough and abdominal CT were non-diagnostic. Endoscopic
examination was abnormal and urease breath test was positive
for helicobacter pylori. Helicobacter antibacterial therapy was
initiated. The patient was then referred to DHMC for follow-up
endoscopy and biopsies.
JLI-gastric endoscopic biopsy
JLI gastric biopsy
JLI-gastric biopsy
JLI-gastric biopsy
Kappa light chain
Diagnosis: Extranodal Marginal
zone lymphoma of mucosal
associated lymphoid tissue
(MALT)
Staging
Therapy
Prognosis
Table X: Indolent B cell lymphomas
Frequency (%
all ly mphomas
Age of onset
median
Stage at
Presentation
Response to
Therapy
5 yr survival
Predominant si te
presentation
Pattern of nodal
Inf iltration
Benign cell
Equivalent
Dominant cell
type
Im muno pheno
-type
Molecular
Pathogenesis
Follicular
Lymphoma
(Grade I)
22%
Marginal zo ne
Lymphoma
Small lymphocytic
lymphoma/CLL
8
7
59
61
65
Stage III/I V
Disseminated
Good to most
treatments,
but incurable
short of
transplant
72%
Stage I
Stage IV
Frequently
curable
Similar to
Follicular
lymphoma
74%
51%
Nodal
Extranodal
Marrow/nodal
Follicular
Diffuse
Diffuse
Germinal
center
small cle aved
cell
Small cl eaved
cell i n most
cases, but can
be large cell
Positive: CD19
CD10, Bcl2+
Negative: CD5-
Marginal zo ne
Lymphocyte
Virgin B cell
Mix o f small
lymphocytes,
plasma cells
t(14;18)
Bcl2/JH
t(11;18),
Trisomy 3
Small
lymphocytes
with round
nucleus
Positive:
CD19, CD5
CD23
Negative:
CD10
Trisomy 1 2
Positive:
CD19, Bcl2
Negative:
CD10, CD5
JLI-followup
Gastric ultrasound was performed to assess the depth of infiltration and
status of perigastric lymph nodes
Completion of helicobacter antibiosis led to recurrent pain
A second course of antibiotic therapy was added
Treatment plan:
Repeat biopsies and helicobacter studies were performed q3mos for next
year
Patient improved with disappearance of pain and increased appetite/weight
gain
Biopsies continued to show foci of persistent clonal disease for next few
months, then negative
Extranodal lymphomas of MALT
type
 Lymphomas of the Mucosal Associated immune system-extranodal
 Indolent lymphomas that break all the rules


Mix of cell types
Benign germinal centers can be seen intermixed with malignant marginal
cells
 Location associated therapy
 Excellent long term survival, though can have very late recurrences
 Can however undergo further mutations, with a small subset
progressing to large cell lymphoma
 Intriguing interaction with helicobacter infection in gastric lymphoma
MALT Lymphoma-pathogenetic
pathways
>70% 5 yr. surv
30-49% 5 yr. surv
50-70% 5 yr. surv
<30% 5 yr. surv
The End !