Overview of Lymphomas

Jessica Hals, DO June 16th 2005

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

Some 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 Hodgkins Lymphoma

1,410 of these pts are expected to die

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 establish prognosis and treatment

Where 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 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 drenching night sweats

The Physical Exam

Exam all sites of potential involvement including:
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.

Unusual 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 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 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 Contd
Bone marrow bx
This is to determine stage Controversial whether bilateral or unilateral bxs are required. Most oncologists advocate bilateral biopsy

Lab tests
CBC Serum chemistries LDH Uric acid

Imaging tests
CT chest/abd/pelvis PET scan

Classification3

Staging3

Prognostic Tools3

The FLIPI Score

The IPI was designed for aggressive lymphomas. Few Follicular lymphomas fell into the high risk group based upon the IPI and therefore its application to FL was being questioned Therefore the FLIPI has been proposed as a prognostic score for follicular lymphomas

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

FLIPI 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 NHL3

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

TX 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 Contd

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 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 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 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 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 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 Americans

CHOP+Rituxan considered std of care

Trials are ongoing to improve outcomes

Indolent 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 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 NHL

For stage I/II XRT may be reasonable sole tx

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/ 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 NHL

Tx summary Contd

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

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 of lymphoma in majority of cases XRT or resection can be used for other sites of MALToma

Extra-nodal MZL
Are extremely rare Usually indolent Surgery can be used w/ or w/o XRT

Mantle 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 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 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

HIV related NHL

Usually in pts w/ CD4 count <100cell/L High grade NHL, (diffuse large B cell immunoblastic variant or Burkitts lymphoma are most common) Indolent NHL are much less common Most present w/o adenopathy and w/ stage IV dz.

TX 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 HIV
Usually w/ CD4 counts <50cell/L 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 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 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/L

TX 1 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

Hodgkins 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 Presentation

Bimodal distribution: peak in 20s 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 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 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

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 is preferable)

Classification
WHO/REAL Classification:
Nodular Lymphocyte Predominant (CD30/CD15-/pan-Bcell +) non-classical RS cells Classical Hodgkins 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 Cell

Nodular 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 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

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 HL
Older patients usually More frequently present w/ mediastinal mass Late relapses less common, but more fatal

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

Staging

Cotswold Staging

Overview 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 Score 7 factors:

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

5yr freedom from progression

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

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 B symptoms

Historical 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 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-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 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

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

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 IFXRT also being tested

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, can use different regimen or autologous transplant

Summary

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 Contd

HL is considered a highly curable disease The best regimen remains to be determined Many salvage regimens exist including BMT

References

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