Overview of Lymphomas.ppt oncology department

Ppt

1. Overview of LymphomasOverview of Lymphomas
Jessica Hals, DO
June 16
th
2005

3. Definition
•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

4. Some Stats
1
•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

5. 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

6. 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

7. The 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

8. The 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.

9. 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

10. 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

11. 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

12. Tests Cont’d
•Bone marrow bx
–This is to determine stage
–Controversial whether bilateral or
unilateral bx’s are required.
–Most oncologists advocate bilateral
biopsy

13. Lab tests
•CBC
•Serum chemistries
•LDH
•Uric acid

14. Imaging tests
•CT chest/abd/pelvis
•PET scan

15. Classification
3

16. Staging
3

17. Prognostic Tools
3

18. 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 it’s application to FL was
being questioned
•Therefore the FLIPI has been proposed as
a prognostic score for follicular lymphomas

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

20. 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)

22. Aggressive NHL
3

23. 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

24. Historical tx of aggressive NHL
•In 1972 Levitt, et al reported curability of
large cell NHL with combination chemo
2
•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)

25. 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 alone
3
•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

26. Early Stage Cont’d
•The GELA trial
2
:
–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

27. 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

28. 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:

29. The German group
2
•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)

30. 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

31. The French Approach
3
•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

32. The North Americans
•CHOP+Rituxan considered std of care
•Trials are ongoing to improve
outcomes

34. 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

35. 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

36. Tx Early Stage I/II indolent NHL
•For stage I/II XRT may be reasonable
sole tx

37. 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

38. Summary of Tx Indolent NHL

39. Tx summary Cont’d

40. 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

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

42. 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

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

44. 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)

45. 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

47. AID-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

48. HIV 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.

49. 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

50. PCNSL 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

51. 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

52. 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/µL

53. TX 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

55. Hodgkin’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

56. Clinical 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

57. 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.

58. 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

59. 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)

60. Classification
•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

61. Reed-Sternberg Cell

62. 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

63. 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

64. 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

65. Lymphocyte-rich Classical HL
•Older patients usually
•More frequently present w/ mediastinal
mass
•Late relapses less common, but more
fatal

66. 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

67. Staging

68. Cotswold Staging

69. 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

70. International Prognostic Score
•7 factors:
–Albumin <4g/dl
–Hb<10.5g/dl
–Male
–Age >45
–WBC>15,000/mcl
–Lymphocyte count <600/mcl

71. 5yr freedom from progression
•No factors: 84%
•1 factor: 77%
•2 factors: 67%
•3 factors: 60%
•4 factors: 51%
•>5 factors: 42%

72. 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

73. 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

74. 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.

75. 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

76. Favorable 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

77. 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

78. 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

79. 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

80. 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

81. Summary Cont’d
•HL is considered a highly curable
disease
•The “best” regimen remains to be
determined
•Many salvage regimens exist including
BMT

83. 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