pt.1 k.gu.- clinical presentation k.g. was a 59 y.o. female in 1990 when she noted the development...
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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 analysisLymphoid
TLymphoid
BNatural
killer/myeloidMyeloid Other
‘90 ‘90 ‘90 ‘90 ‘90
CD2 21 CD19 50 CD56 CD13 CD10 66
CD3 20 Kappa 73 CD14 CD34
CD4 17 Lambda 2 CD15 CD41
CD5 21CD19/CD10
66 CD33 CD45 96
CD7 21 CD20 70HLA-DR
78
CD8 2CD20/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
FollicularLymphoma(Grade I)
Marginal zoneLymphoma
Small lymphocyticlymphoma/CLL
Frequency (%all lymphomas
22% 8 7
Age of onsetmedian
59 61 65
Stage atPresentation
Stage III/IVDisseminated
Stage I Stage IV
Response toTherapy
Good to mosttreatments,but incurableshort oftransplant
Frequently curable
Similar toFollicularlymphoma
5 yr survival 72% 74% 51%
Predominant sitepresentation
Nodal Extranodal Marrow/nodal
Pattern of nodalInfiltration
Follicular Diffuse Diffuse
Benign cellEquivalent
Germinalcentersmall cleavedcell
Marginal zoneLymphocyte
Virgin B cell
Dominant celltype
Small cleavedcell in mostcases, but canbe large cell
Mix of smalllymphocytes,plasma cells
Smalllymphocyteswith roundnucleus
Immunopheno-type
Positive: CD19 CD10, Bcl2+Negative: CD5-
Positive:CD19, Bcl2Negative:CD10, CD5
Positive:CD19, CD5CD23Negative:CD10
MolecularPathogenesis
t(14;18)Bcl2/JH
t(11;18),Trisomy 3
Trisomy 12
K. G. - 1994 biopsy
K. G. Biopsy 1994 - 50x
Pt. K.G.- Flow analysis
Lymphoid T Lymphoid B NK associated Myeloid Other
‘90 ‘94 ‘90 ‘94 ‘90 ‘94 ‘90 ‘94 ‘90 ‘94
CD2 21 CD19 50 90 CD56 CD13 CD10 66 63
CD3 20 10 Kappa 73 88 CD14 CD34
CD4 17 8 Lambda 2 4 CD15 CD41
CD5 21 10CD19/CD10
66 63 CD33 CD45 96 99
CD7 21 CD20 70 95HLA-DR
78 40
CD8 2 7CD20/CD5
<1 <1 GP-A
Pt. K.G. Diagnosis: 1990:Follicular lymphoma, Grade I1994: 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 Lymphoid B NK associated Myeloid Other
LN PB LN PB LN PB LN PB LN PB
CD3 19 <1 CD19 89 94 CD56 CD13 CD10 <1 <1
CD4 19 Kappa 86 97 CD14 CD34
CD5/CD20-
1 <1 Lambda 7 1 CD15 CD41
CD8 1CD20/CD5+
97 99 CD33 CD45
CD20/CD23+
<1 <1HLA-DR
FMC7 58 98
CD22 34 12 GP-A
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
FollicularLymphoma(Grade I)
Marginal zoneLymphoma
Small lymphocyticlymphoma/CLL
Mantle cellLymphoma
Frequency (%all lymphomas
22% 8 7 6
Age of onsetmedian
59 61 65 63
Stage atPresentation
Stage III/IVDisseminated
Stage I Stage IV Stage III/IV
Response toTherapy
Good to mosttreatments,but incurableshort oftransplant
Frequently curable
Similar toFollicularlymphoma
Poor response toall therapiesto date
5 yr survival 72% 74% 51% 27%
Predominant sitepresentation
Nodal Extranodal Marrow/nodal Nodal
Pattern of nodalInfiltration
Follicular Diffuse Diffuse Diffuse,nodular or“mantle zone”
Benign cellEquivalent
Germinalcentersmall cleavedcell
Marginal zoneLymphocyte
Virgin B cell Mantle cell
Dominant celltype
Small cleavedcell in mostcases, but canbe large cell
Mix of smalllymphocytes,plasma cells
Smalllymphocyteswith roundnucleus
Small cellwith irregularnucleus,similar tocleaved
Immunopheno-type
Positive: CD19 CD10, Bcl2+Negative: CD5-
Positive:CD19, Bcl2Negative:CD10, CD5
Positive:CD19, CD5CD23Negative:CD10
Positive:CD19, CD5,Bcl2Negative:CD10
MolecularPathogenesis
t(14;18)Bcl2/JH
Trisomy 3 Trisomy 12 t(11;14)Bcl1/JH
>70% 5 yr. surv 50-70% 5 yr. surv
30-49% 5 yr. surv <30% 5 yr. surv
Patient JCJC 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 analysisLymphoid T Lymphoid B NK associated Myeloid Other
CD2 CD19 95 CD56 25 CD13 CD10 98
CD3 18CD19/CD10
95 CD14 CD34
CD4 <1 Kappa 15 CD15 CD41
CD5 <1 Lambda 80 CD33 CD45
CD7 CD20 99HLA-DR
CD8 8 CD23 39 GP-A
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 analysisLymphoid T Lymphoid B NK associated Myeloid Other
CD2 CD19 95 CD56 25 CD13 CD10 98
CD3 18CD19/CD10
95 CD14 CD34
CD4 <1 Kappa 15 CD15 CD41
CD5 <1 Lambda 95 CD33 CD45
CD7 CD20 99HLA-DR
CD8 8 CD23 39 GP-A
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 follow-through 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)
StagingTherapyPrognosis
Table X: Indolent B cell lymphomas
FollicularLymphoma(Grade I)
Marginal zoneLymphoma
Small lymphocyticlymphoma/CLL
Frequency (%all lymphomas
22% 8 7
Age of onsetmedian
59 61 65
Stage atPresentation
Stage III/IVDisseminated
Stage I Stage IV
Response toTherapy
Good to mosttreatments,but incurableshort oftransplant
Frequently curable
Similar toFollicularlymphoma
5 yr survival 72% 74% 51%
Predominant sitepresentation
Nodal Extranodal Marrow/nodal
Pattern of nodalInfiltration
Follicular Diffuse Diffuse
Benign cellEquivalent
Germinalcentersmall cleavedcell
Marginal zoneLymphocyte
Virgin B cell
Dominant celltype
Small cleavedcell in mostcases, but canbe large cell
Mix of smalllymphocytes,plasma cells
Smalllymphocyteswith roundnucleus
Immunopheno-type
Positive: CD19 CD10, Bcl2+Negative: CD5-
Positive:CD19, Bcl2Negative:CD10, CD5
Positive:CD19, CD5CD23Negative:CD10
MolecularPathogenesis
t(14;18)Bcl2/JH
t(11;18),Trisomy 3
Trisomy 12
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 50-70% 5 yr. surv
30-49% 5 yr. surv <30% 5 yr. surv
The End !