Overview of LymphomasOverview of LymphomasOverview of LymphomasOverview of Lymphomas

Jessica Hals, DO

June 16th 2005

DefinitionDefinition

• Lymphomas are malignant transformations of normal lymphoid cells which reside predominantly in lymphoid tissues

• They are divided into two major types: – Non-Hodgkin’s lymphoma (NHL)– Hodgkin’s Lymphoma

Some Stats1Some Stats1

• It is estimated that there will be 63,740 new cases of lymphoma diagnosed in 2005.

• 56,390 are expected to be NHL– 19,200 of these pts are expected to die from

NHL• 7,350 are expected to be Hodgkin’s

Lymphoma– 1,410 of these pts are expected to die

How to Diagnosis NHLHow 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 establish prognosis and treatment

Where to startWhere to start

• As always with the H&P:

• Key points to obtain in your “history”:– Lymphadenopathy: more than 2/3 of pt

will present with peripheral adenopathy• Ask about waxing and waning of lymph nodes• As about the duration of lymphadenopathy

The History Cont’dThe History Cont’d

– B Symptoms:• Fever defined as T>38ºC• Weight loss defined by unexplained loss of

>10% of body wt over 6 mos• Night sweats defined by drenching night

sweats

The Physical ExamThe Physical Exam• Exam all sites of potential involvement

including:– Waldeyer’s 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.

Unusual Sites/PresentationsUnusual Sites/Presentations

• 10-35% will have primary extranodal NHL and about 50% will have extranodal disease during their illness

• Most common site of extranodal disease is the GI tract followed by the skin

• Symptoms from extranodal disease usually assoc with aggressive NHL

Extranodal SitesExtranodal 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 suspicious lesions

• NHL can account for poorly differentiated carcinoma of unknown primary

Diagnostic testsDiagnostic tests

• Lymph node biopsy– Preferably to have an entire intact lymph

node over FNA or core bx– This allows the pathologist to accurately

determine the pattern of involvement and allows for enough tissue for immunologic and molecular testing

Tests Cont’dTests Cont’d

• Bone marrow bx– This is to determine stage– Controversial whether bilateral or

unilateral bx’s are required. – Most oncologists advocate bilateral

biopsy

Lab testsLab tests

• CBC

• Serum chemistries

• LDH

• Uric acid

Imaging testsImaging tests

• CT chest/abd/pelvis

• PET scan

Classification3Classification3

Staging3Staging3

Prognostic Tools3Prognostic Tools3

The FLIPI ScoreThe FLIPI Score

• The IPI was designed for aggressive lymphomas. Few Follicular lymphomas fell into the high risk group based upon the IPI and therefore it’s application to FL was being questioned

• Therefore the FLIPI has been proposed as a prognostic score for follicular lymphomas

FLIPIFLIPI

• Five factors:– Age >60– Ann Arbor stage III or IV– Hb <12g/dL– Number of nodal areas >4– LDH >ULN

FLIPI Risk GroupsFLIPI Risk Groups

• Low risk: 0-1 adverse factor (5 &10yr OS=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)

Aggressive NHL3Aggressive NHL3

Tx Aggressive NHLTx Aggressive NHL

• Are highly curable lymphomas• If early disease present (localized,

non-bulky stage I or II) may use XRT only for cure

• However, most advocate combined therapy for early stage disease

Historical tx of aggressive NHLHistorical tx of aggressive NHL• In 1972 Levitt, et al reported curability of

large cell NHL with combination chemo2

• In 1975 DeVita et al described curing pts using COPP (Cytoxan, adriamycin, vincristine, procarbazine and prednisone)2

• During the 70’s this regimen was simplified to the classic CHOP regimen we use today (Cytoxan, adriamycin, vincristine and prednisone)

TX of Early StageTX of Early Stage

• A SWOG protocol randomized pts to either 3 cycles of CHOP followed by involved field XRT vs. 8 cycles of CHOP alone3

• This showed that pts had a better 5 yr. PFS and OS with combined therapy

– 76% vs. 67%, PFS respectively– 82% vs. 74%, OS respectively

Early Stage Cont’dEarly Stage Cont’d• The GELA trial2:

– A French group has investigated a more intensive chemo regimen. They randomized pts to either 3 cycles of CHOP with XRT vs. ACVBP (adriamycin, Cytoxan, vindesine, bleomycin, prednisone followed with consolidation with ifosfamide, VP-16 and AraC)

– This new regimen did improve EFS and OS, but at significant toxicity

Early Tx SummaryEarly Tx Summary

• For most patients with early, non-bulky (<10cm) stage I or II, 3 cycles of CHOP followed by involved field XRT is std

• The role of using rituximab in early stage is gaining evidence:

– Early studies suggest a benefit to adding rituximab to chemotherapy

Advanced Stage TxAdvanced Stage Tx

• CHOP is still the most commonly used regimen, and now with the addition of rituximab

• Several groups are investigating more aggressive chemo regimens

• Here are a few:

The German group2The German group2

• They divided pts into three groups: young good px, young poor px, and elderly

• They then randomized pts to one of four arms:

– 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)

The German ResultsThe German Results• CHOEP 21 improved EFS, but CHOP 14 and

CHOEP 14 improved EFS, CR and OS over std CHOP 21

• The Germans now consider CHOEP 14 preferred chemo 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 will add Rituxan to their chemo

• They are also using this same regimen for young poor px pts

The French Approach3The 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

The North AmericansThe North Americans

• CHOP+Rituxan considered std of care

• Trials are ongoing to improve outcomes

Indolent NHLIndolent NHL

• Follicular lymphoma is most common type of indolent NHL

• Majority of pts present w/ stage III/IV disease with multiple enlarged LN that have been present for a long time

• Generally not considered curable

Natural Hx of Indolent NHLNatural Hx of Indolent NHL

• Can have long symptom free intervals• Several studies show no OS advantage to

early treatment vs. waiting until progression or symptoms develop.

• Can go for years w/o needing tx. and obs alone is a feasible approach. Median survival for stage III/IV is 7-10 yrs

Tx Early Stage I/II indolent NHLTx Early Stage I/II indolent NHL

• For stage I/II XRT may be reasonable sole tx

Tx for advanced diseaseTx 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/ other

regimens– Radio-labeled monoclonal antibodies are also available for

refractory/relapsed disease (Bexxar and Zevalan)– Transplantation has been investigated for relapsed

disease

Summary of Tx Indolent NHLSummary of Tx Indolent NHL

Tx summary Cont’dTx summary Cont’d

Marginal Zone Lymphomas (MZL)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

Splenic lymphomaSplenic lymphoma

• <5% NHL• Median age 65• Present w/ splenomegaly, lymphocytosis• Course is indolent. Survival 70% @10yr• Tx of choice is splenectomy

MALT lymphomasMALT 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 of lymphoma in majority of cases

• XRT or resection can be used for other sites of MALToma

Extra-nodal MZLExtra-nodal MZL

• Are extremely rare

• Usually indolent

• Surgery can be used w/ or w/o XRT

Mantle Cell LymphomaMantle Cell Lymphoma

• Considered intermediate aggressive. Median survival is 3-4 yrs.

• Median age of 63 w/ male predominance.

• Usually stage IV at dx• Distinctive features include: Cyclin

D1+ and t(11:14)

Tx Mantle Cell LymphomaTx Mantle Cell Lymphoma

• CVP (Cytoxan, vincristine, prednisone)• Hyper-CVAD (mtx, adriamycin,

Cytoxan, vincristine, dexamethasone, AraC-C) w/ and w/o rituximab has also been used.

• Relapses are common even after BMT

AID-related lymphomasAID-related lymphomas

• AIDS defining malignancies:– Kaposi’s sarcoma, NHL, primary CNS

lymphoma, invasive cervical carcinoma

• AIDS related NHL:– Primary CNS lymphoma (PCNSL)– Systemic NHL– 1º effusion NHL

HIV related NHLHIV related NHL

• Usually in pts w/ CD4 count <100cell/µL• High grade NHL, (diffuse large B cell

immunoblastic variant or Burkitt’s lymphoma are most common)

• Indolent NHL are much less common• Most present w/o adenopathy and w/ stage

IV dz.

TX systemic AIDS related NHLTX systemic AIDS related NHL

• “std” chemo considered CHOP, although there is controversy.

• Rituximab is investigational but early studies suggest synergism

• HAART therapy should be continued or initiated

• These pts do worse than in HIV(-) pts

PCNSL in HIVPCNSL in HIV

• Usually w/ CD4 counts <50cell/µL• Present w/ focal or non-focal neurological

symptoms:– confusion, lethargy, memory loss, hemiparesis,

aphasia, and/or seizures that have usually been present for less than three months

• DX w/ MRI/LP/EBV DNA in CSF/brain bx/rule out toxoplasmosis

TX PCNSLTX PCNSL

• No established std since it is relatively rare and has a poor px

• XRT w/ steroids can prolong survival• HAART can prolong survival• Chemotherapy can be used but is

generally poorly tolerated

Primary Effusion LymphomaPrimary Effusion Lymphoma

• Originates on serosal surfaces of peritoneal, pericardial and pleural cavities and joint spaces

• Generally will have genetic material from HHV-8 and EBV

• CD4 count typically <100cells/µL

TX 1º Effusion NHLTX 1º Effusion NHL

• Very poor px so data is limited• Some success reported w/ XRT• Chemo has been used in the form of CHOP• HAART should be administered also• Clinical trial when available

Hodgkin’s DiseaseHodgkin’s Disease

• It is estimated that in 2005 there will be 7350 new cases of HD

• There will be an estimated 1410 deaths from HD in 2005

Clinical PresentationClinical Presentation

• Bimodal distribution: peak in 20’s and a second 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 as

cough, retrosternal cp or SOB

Systemic SymptomsSystemic 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. generalized

and can precede overt HD by mos. to a yr.

Other possible SymptomsOther possible Symptoms• ETOH induced pain• Skin lesions (ichthyosis, acrokeratosis (Bazex

syndrome), urticaria, erythema multiforme, erythema nodosum, necrotizing lesions, hyperpigmentation, and skin infiltration )

• Nephrotic syndrome• Hypercalcemia• Anemia• eosinophilia

DiagnosisDiagnosis• 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 is

preferable)

ClassificationClassification• WHO/REAL Classification:

– Nodular Lymphocyte Predominant (CD30-/CD15-/pan-Bcell +) non-classical RS cells

– Classical Hodgkin’s lymphoma: (CD30+/CD15+/CD45-/panB and panT antigen negative) Reed-Sternberg Cells

• Lymphocyte-rich• Nodular sclerosis• Mixed cellularity• Lymphocyte depleted• Unclassifiable classical HD

Reed-Sternberg CellReed-Sternberg Cell

Nodular Sclerosis Classical HLNodular Sclerosis Classical HL

• Most common subtype• Most common in women, adolescents and

young adults• often will have a mediastinal mass, lower

cervical, supraclavicular L.N. w/ and orderly pattern of spread

• Good Px

Mixed Cellularity Classical HLMixed Cellularity Classical HL

• More common in males• More aggressive, but still curable• Pts usually older and more likely to

have B symptoms• More commonly in underdeveloped

countries

Lymphocyte depleted Classical HL

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

Lymphocyte-rich Classical HLLymphocyte-rich Classical HL

• Older patients usually

• More frequently present w/ mediastinal mass

• Late relapses less common, but more fatal

Nodular Lymphocyte Predominant HL

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 favorable

outcomes• Can progress to large B-cell NHL

StagingStaging

Cotswold StagingCotswold Staging

Overview of TreatmentOverview of Treatment

• HD is highly curable even after relapse

• Stage and prognostic factors will determine high vs. low risk disease and will drive treatment choices

International Prognostic ScoreInternational Prognostic Score• 7 factors:

– Albumin <4g/dl– Hb<10.5g/dl– Male– Age >45– WBC>15,000/mcl– Lymphocyte count <600/mcl

5yr freedom from progression5yr freedom from progression

• No factors: 84%• 1 factor: 77%• 2 factors: 67%• 3 factors: 60%• 4 factors: 51%• >5 factors: 42%

EORTC definitionsEORTC 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 B

symptoms

Historical Tx HLHistorical Tx HL

• In 1964 the NCI developed a four drug regimen 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

The birth of ABVDThe birth of ABVD

• ABVD was originally developed for MOPP 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.

Favorable Px Stage I-IIFavorable Px Stage I-II

• 2-4 cycles ABVD (adriamycin, vinblastine, bleomycin, dacarbazine) followed by involved 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 field XRT

Favorable Px Cont’dFavorable Px Cont’d

• 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

Unfavorable Stage I-IIUnfavorable 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

Tx Stage III-IV HDTx 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 IFXRT also being tested

Relapsed/Refractory HLRelapsed/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, can

use different regimen or autologous transplant

SummarySummary

• The lymphomas represent a heterogeneous spectrum of disease

• Aggressive NHL are generally curable with modern chemotherapy

• Indolent NHL are not usually curable, but are very treatable w/ chemo

Summary Cont’dSummary Cont’d

• HL is considered a highly curable disease

• The “best” regimen remains to be determined

• Many salvage regimens exist including BMT

ReferencesReferences

• 1. Jemal, Ahmedin DVM, PhD, etal. “Cancer Statistics, 2005.”CA A Cancer Journal for Clinicians:55;10-30. 2005

• 2. Armitage, James MD et al. “The Treatment of patients with aggressive NHL.” Oncology: 19(4, supp1);1-34

• 3. Up to Date 2005