overview of lymphomas
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Overview of Lymphomas
Jessica Hals, DO
June 16th2005
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Definition
Lymphomas are malignant transformations
of normal lymphoid cells which reside
predominantly in lymphoid tissues
They are divided into two major types:
Non-Hodgkins lymphoma (NHL)
Hodgkins Lymphoma
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Some Stats1
It is estimated that there will be 63,740 newcases of lymphoma diagnosed in 2005.
56,390 are expected to be NHL
19,200 of these pts are expected to die fromNHL
7,350 are expected to be HodgkinsLymphoma
1,410 of these pts are expected to die
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How to Diagnosis NHL
The initial evaluation must establish:
The precise histologic type of NHL
The extent and sites of disease
The performance status of the patient
All of this is important to establishprognosis and treatment
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Where to start
As always with the H&P:
Key points to obtain in your history:
Lymphadenopathy: more than 2/3 of ptwill present with peripheral adenopathy
Ask about waxing and waning of lymph nodes
As about the duration of lymphadenopathy
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The History Contd
B Symptoms:
Fever defined as T>38C
Weight loss defined by unexplained loss of
>10% of body wt over 6 mos
Night sweats defined by drenchingnight
sweats
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The Physical Exam
Exam all sites of potential involvementincluding:
Waldeyers ring (tonsils, base of tongue,
nasopharynx)
Std L.N. sites (cervical, inguinal, etc) Liver and spleen
Abdominal L.N. (mesenteric, retroperitoneal)
Others: occipital, preauricular, epitrochlear, etc.
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Unusual Sites/Presentations
10-35% will have primary extranodal NHLand about 50% will have extranodal diseaseduring their illness
Most common site of extranodal disease isthe GI tract followed by the skin
Symptoms from extranodal disease usuallyassoc with aggressive NHL
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Extranodal Sites Testicular NHL accounts for ~1% of NHL and 2% of
extranodal NHL. It is the most common malign.involving the testis in men over 60 y.o
NHL can present as solitary lesion of bone
Renal involvement occurs in 2-14% of pts
Rarer sites include: prostate, bladder, ovary, orbit,heart, breast, salivary gland, thyroid and adrenal
gland Examine skin carefully and bx any suspiciouslesions
NHL can account for poorly differentiatedcarcinoma of unknown primary
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Diagnostic tests
Lymph node biopsy
Preferably to have an entire intact lymphnode over FNA or core bx
This allows the pathologist to accuratelydetermine the pattern of involvement andallows for enough tissue for immunologicand molecular testing
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Tests Contd
Bone marrow bx
This is to determine stage
Controversial whether bilateral orunilateral bxs are required.
Most oncologists advocate bilateral
biopsy
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Lab tests
CBC
Serum chemistries
LDH Uric acid
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Imaging tests
CT chest/abd/pelvis
PET scan
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Staging3
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The FLIPI Score
The IPI was designed for aggressivelymphomas. Few Follicular lymphomas fellinto the high risk group based upon the IPI
and therefore its application to FL wasbeing questioned
Therefore the FLIPI has been proposed asa prognostic score for follicular lymphomas
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FLIPI
Five factors:
Age >60
Ann Arbor stage III or IV
Hb 4
LDH >ULN
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FLIPI Risk Groups
Low risk: 0-1 adverse factor (5 &10yrOS=91% & 71% respectively)
Intermediate Risk: 2 adverse factors(5&10yr OS=78% & 51% respectively)
High risk: 3 or more (5&10 yr OS=52%&36% respectively)
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Aggressive NHL3
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Historical tx of aggressive NHL
In 1972 Levitt, et al reported curability oflarge cell NHL with combination chemo2
In 1975 DeVita et al described curing ptsusing COPP (Cytoxan, adriamycin,vincristine, procarbazine and prednisone)2
During the 70s this regimen was simplifiedto the classic CHOP regimen we use today(Cytoxan, adriamycin, vincristine andprednisone)
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TX of Early Stage
A SWOG protocol randomized pts to either3 cycles of CHOP followed by involved fieldXRT vs. 8 cycles of CHOP alone3
This showed that pts had a better 5 yr. PFSand OS with combined therapy
76% vs. 67%, PFS respectively
82% vs. 74%, OS respectively
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Early Stage Contd
The GELA trial2
: A French group has investigated a moreintensive chemo regimen. They randomized ptsto either 3 cycles of CHOP with XRT vs. ACVBP(adriamycin, Cytoxan, vindesine, bleomycin,
prednisone followed with consolidation withifosfamide, VP-16 and AraC)
This new regimen did improve EFS and OS, butat significant toxicity
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Advanced Stage Tx
CHOP is still the most commonly usedregimen, and now with the addition ofrituximab
Several groups are investigating moreaggressive chemo regimens
Here are a few:
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The German group2
They divided pts into three groups: younggood px, young poor px, and elderly
They then randomized pts to one of fourarms:
Arm 1: CHOP 21 (traditional 21 day cycle) Arm 2: CHOP 14 (14 day cycle of CHOP)
Arm 3: CHOEP 21 (CHOP+VP-16 q 21 days)
Arm 4: CHOEP 14 (above q 14 days)
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The German Results
CHOEP 21 improved EFS, but CHOP 14 and
CHOEP 14 improved EFS, CR and OS over stdCHOP 21
The Germans now consider CHOEP 14 preferredchemo for young good px pt
Based on the results of the MInT tx in young good
px pts (CHOP-like chemo w/ Rituxan), they also willadd Rituxan to their chemo
They are also using this same regimen for youngpoor px pts
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The French Approach3
Study randomized pts to 3 cycles
CHOP +XRT vs. 3 cycles ACVBP
followed by consolidation.
EFS (82% vs. 74%), OS (90% vs. 81%)
were in favor of the chemo only arm
Ongoing study using above +Rituxan
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The North Americans
CHOP+Rituxan considered std of care
Trials are ongoing to improveoutcomes
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Indolent NHL
Follicular lymphoma is most commontype of indolent NHL
Majority of pts present w/ stage III/IVdisease with multiple enlarged LN thathave been present for a long time
Generally not considered curable
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Natural Hx of Indolent NHL
Can have long symptom free intervals
Several studies show no OS advantage toearly treatment vs. waiting until progression
or symptoms develop. Can go for years w/o needing tx. and obs
alone is a feasible approach. Mediansurvival for stage III/IV is 7-10 yrs
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Tx Early Stage I/II indolent NHL
For stage I/II XRT may be reasonable
sole tx
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Tx for advanced disease
Chemotherapy remains the mainstay of treatment.
Various regimens exist CVP, Fludarabine, FC, FCR, CVP-R
All appear to have same RR
Rituximab can be used alone or in combo w/ otherregimens
Radio-labeled monoclonal antibodies are also available forrefractory/relapsed disease (Bexxar and Zevalan)
Transplantation has been investigated for relapseddisease
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Summary of Tx Indolent NHL
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Tx summary Contd
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Marginal Zone Lymphomas (MZL)
3 main types:
Splenic
MALT lymphoma
Nodal
Can occur in GI tract, salivary glands,thyroid, orbit, conjunctiva, breast and lung
Surgery or XRT usually sufficient to treat
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Splenic lymphoma
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MALT lymphomas Extranodal lymphoma associated w/
mucosal tissue ~5% of NHL, 50% of these are gastric
Most are stage I/II at presentation
Gastric MALTomas assoc w/ H.pylori
infection. Tx w/ Abx causes regression oflymphoma in majority of cases
XRT or resection can be used for other sitesof MALToma
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Extra-nodal MZL
Are extremely rare
Usually indolent
Surgery can be used w/ or w/o XRT
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Tx Mantle Cell Lymphoma
CVP (Cytoxan, vincristine, prednisone)
Hyper-CVAD (mtx, adriamycin,Cytoxan, vincristine, dexamethasone,
AraC-C) w/ and w/o rituximab has alsobeen used.
Relapses are common even after BMT
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AID-related lymphomas
AIDS defining malignancies: Kaposis sarcoma, NHL, primary CNS
lymphoma, invasive cervical carcinoma
AIDS related NHL:
Primary CNS lymphoma (PCNSL)
Systemic NHL
1 effusion NHL
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HIV related NHL
Usually in pts w/ CD4 count
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PCNSL in HIV
Usually w/ CD4 counts
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TX PCNSL
No established std since it is relativelyrare and has a poor px
XRT w/ steroids can prolong survival
HAART can prolong survival
Chemotherapy can be used but isgenerally poorly tolerated
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Primary Effusion Lymphoma
Originates on serosal surfaces ofperitoneal, pericardial and pleuralcavities and joint spaces
Generally will have genetic materialfrom HHV-8 and EBV
CD4 count typically
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Hodgkins Disease
It is estimated that in 2005 there will
be 7350 new cases of HD
There will be an estimated 1410deaths from HD in 2005
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Clinical Presentation
Bimodal distribution: peak in 20s and asecond peak over age 50
Most will present with asymptomatic
lymphadenopathy often in the neck Can manifest as mediastinal mass on CXR.
If large enough can cause symptoms such ascough, retrosternal cp or SOB
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Systemic Symptoms
B symptoms similar to those seen with NHL often
are present: Fever: Pel Ebstein (fever recurring at variable intervals of
several days to weeks and lasts 1-2 wks before waning)
Night sweats
Weight loss
Fatigue
Pruritus: uncommon, but when present is usu. generalizedand can precede overt HD by mos. to a yr.
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Other possible Symptoms
ETOH induced pain
Skin lesions (ichthyosis, acrokeratosis (Bazexsyndrome), urticaria, erythema multiforme,erythema nodosum, necrotizing lesions,hyperpigmentation, and skin infiltration )
Nephrotic syndrome Hypercalcemia
Anemia
eosinophilia
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Diagnosis As always a good H&P is priceless
CT C/A/P
PET scan
BM Bx if pt has B symptoms, clinical stage II-IV,anemia, leukopenia or thrombocytopenia
CBC, LDH, CMP
Lymph node bx (again an entire intact LN ispreferable)
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Classification
WHO/REAL Classification: Nodular Lymphocyte Predominant (CD30-
/CD15-/pan-Bcell +) non-classical RS cells Classical Hodgkins lymphoma:
(CD30+/CD15+/CD45-/panB and panT antigennegative) Reed-Sternberg Cells
Lymphocyte-rich
Nodular sclerosis
Mixed cellularity
Lymphocyte depleted
Unclassifiable classical HD
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Nodular Sclerosis Classical HL
Most common subtype
Most common in women, adolescents andyoung adults
often will have a mediastinal mass, lowercervical, supraclavicular L.N. w/ and orderlypattern of spread
Good Px
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Lymphocyte depleted
Classical HL
Least common subtype
Older men and HIV infected pts
Less peripheral adenopathy, more
abdominal adenopathy.
HSM may be prominent
BM often involved
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Lymphocyte-rich Classical HL
Older patients usually
More frequently present w/ mediastinal
mass Late relapses less common, but more
fatal
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Nodular Lymphocyte Predominant
HL
Only 3-8% of HL
More common in adults (median age 34)
More often localized disease
More common in men Slowly progressive w/ very favorableoutcomes
Can progress to large B-cell NHL
St i
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Staging
Cotswold Staging
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Cotswold Staging
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Overview of Treatment
HD is highly curable even after relapse
Stage and prognostic factors will
determine high vs. low risk diseaseand will drive treatment choices
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International Prognostic Score
7 factors:
Albumin 15,000/mcl
Lymphocyte count
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5yr freedom from progression
No factors: 84%
1 factor: 77%
2 factors: 67%
3 factors: 60% 4 factors: 51%
>5 factors: 42%
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EORTC definitions
Adverse Px factors identified in CSI-II pts.Used to define tx for CSI-II HD
Defined as follows: Large mediastinal adenopathy
Age over 50
B symptoms >4 LN regions involved
B Symptoms + ESR>30 or ESR >50 w/o Bsymptoms
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Historical Tx HL
In 1964 the NCI developed a four drugregimen that cured 50% of pts.
Thus MOPP (mechlorethamine, vincristine,
procarbazine, prednisone) became std Significant toxicity and secondary
malignancies made it imperative to find alt.regimens
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The birth of ABVD
ABVD was originally developed forMOPP resistant disease
In a head to head trial, ABVD had
higher CR, PFS, and OS than MOPP It also had less short and long term
toxicity.
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Favorable Px Stage I-II
2-4 cycles ABVD (adriamycin, vinblastine,
bleomycin, dacarbazine) followed byinvolved field XRT to original L.N. regions
XRT alone to involved and uninvolved L.N.regions
Stanford V (adriamycin, mechlorethamine,vinblastine, prednisone, vincristine,bleomycin, VP-16) for 8wks w/ involved fieldXRT
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Favorable Px Contd
Ongoing trials are attempting to
identify newer regimens and
determine the optimal number of
chemotherapy cycles to administer to
obtain the lowest relapse rate and
improve overall survival
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Unfavorable Stage I-II
XRT alone not generally accepted due to
high rate of relapses
4-6 cycles ABVD followed by XRT to
involved sites Treat 2 cycles past maximum response as
assessed on imaging studies to max. 8 cycles
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Tx Stage III-IV HD 6-8 cycles of ABVD most common regimen
used Hybrid regimens tested, but not better than
ABVD
BEACOPP (bleomycin, VP-16, adriamycin,
Cytoxan, vincristine, procarbazine,prednisone) is alt. regimen
Stanford V for 12 wks followed by IFXRTalso being tested
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Relapsed/Refractory HL
Bx area of relapse to prove pt has truly
relapsed and not developed an
infection/other malignancy
If tx w/ XRT only can still salvage w/ chemo
If late (>12mo) relapse after chemo, canuse different regimen or autologous
transplant
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Summary Contd
HL is considered a highly curabledisease
The best regimen remains to be
determined Many salvage regimens exist including
BMT
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References
1. Jemal, Ahmedin DVM, PhD, etal. CancerStatistics, 2005.CA A Cancer Journal forClinicians:55;10-30. 2005
2. Armitage, James MD et al. TheTreatment of patients with aggressive NHL.Oncology: 19(4, supp1);1-34
3 Up to Date 2005