1. Lymphoma
Uglyar T.Y.
Adapted from Joe Waller, MD 2013 Drs. Wang and Young and By David Lee MD, FRCPC

2. Conceptualizing lymphoma
neoplasms of lymphoid origin, typically causing lymphadenopathy
leukemia vs lymphoma
lymphomas as clonal expansions of cells at certain developmental stages

3. Myeloproliferative disorders
ALL MM
CLL
Lymphomas
naïve
germinal center
B-lymphocytes
Plasma
cells
Lymphoid
progenitor
T-lymphocytes
Hematopoietic
stem cell
AML
Myeloproliferative disorders
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloid
progenitor

4. B-cell development Bone marrow Lymphoid tissue CLL MM ALL DLBCL,
memory
B-cell
DLBCL,
FL, HL
ALL
CLL MM
stem
cell
germinal
center
B-cell
mature
naive
B-cell
lymphoid
progenitor
progenitor-B
pre-B
immature
B-cell
plasma cell
Bone marrow
Lymphoid tissue

5. Risk Factors • Mostly unknown, although both genetic and infectious
processes are suspected
• Living in Western countries, being of higher social class,
more educated.
• Genetic pre-disposition, clusters noted in siblings with
similar HLA genotypes.
– Mack et al: 99x risk in monozygotic vs dizygotic twins
• EBV (MC subtype)
• HIV+ pts have different patterns of spread, more
systemic sx, poor tolerance to chemo
• Children do better than adults

6. A practical way to think of lymphoma
Category
Survival of untreated patients
Curability
To treat or not to treat
Non-Hodgkin lymphoma
Indolent
Years
Generally not curable
Generally defer Rx if asymptomatic
Aggressive
Months
Curable in some
Treat
Very aggressive
Weeks
Hodgkin lymphoma
All types
Variable – months to years
Curable in most

7. Staging Stage I: a single LN region (on either side of the diaphragm)
Stage II: two or more LN regions of the same side of the diaphragm
Stage III: both sides of the diaphragm
Stage III-1: upper abd: splenic, celiac, portal LN only, <4 splenic
nodules
Stage III-2: lower abd: Paraaortic, mesenteric, pelvic
Stage III(S)+ Minimal: <4 splenic nodules
Stage III(S)+ Extensive: 5 or more splenic nodules
Stage IV: diffuse involvement of extralymphatic tissues, with or
without simultaneous LN involvement.
E subtypes: extranodal disease
S subtype: spleen involvement
“A” and “B”: absent or present “B” symptoms.
X subtype: bulky disease of > 1/3 thoracic diameter or > 10 cm

8. Lymph Node Regions

9. International Prognostic Score
In patients with Stage III-IV disease, each of the following factors
reduces survival by 7%:
Age >45
Male sex
Stage IV disease
Albumin < 4g/dL
Hb<10.5
WBC>15,000
Lymphoctes count <8% or ALC<600
Used for individualized treatment management

10. Mediastinal LAN

11. Presentation Painless lymphadenopathy – cervical nodes (80%)
– mediastinal (50%)
• SOB, CP, cough, SVC syndrome, or incidental
• 1/3 have B-symptoms:
– Fever>38C, drenching night sweats, >10% wt loss in prior 6
months
• Generalized pruritis (15%; poor prognosis)
• EtOH induced pain
• Mediastinal mass on routine CXR
• 90% of cased have contiguous LN spread

12. Other Manifestations SVC syndrome • Spinal Cord Compression
• Bone involvement
• Hepatic involvement
• Renal involvement
• Infections
• Immunologic
Abnormalities
• Rarely:
– Waldeyer's Ring,
Peyer's patches, CNS,
skin

13. Epidemiology of lymphomas
5th most frequently diagnosed cancer in both sexes
males > females
incidence
NHL increasing
Hodgkin lymphoma stable
Epidemiology
• ~8000 new cases of Hodgkin’s Disease in
the U.S. in 2008, causing ~1500 deaths
• M:F ratio is 1.3:1; more pronounced in
children
• Bimodal age distribution: 2-3rd decade,
and 6-7th decade.

14. Clinical manifestations
Variable
severity: asymptomatic to extremely ill
time course: evolution over weeks, months, or years
Systemic manifestations
fever, night sweats, weight loss, anorexia, pruritis
Local manifestations
lymphadenopathy, splenomegaly most common
any tissue potentially can be infiltrated

15. complications of lymphoma
bone marrow failure (infiltration)
CNS infiltration
immune hemolysis or thrombocytopenia
compression of structures (eg spinal cord, ureters)
pleural/pericardial effusions, ascites

16. Diagnosis requires an adequate biopsy Work Up
Diagnosis should be biopsy-proven before treatment is initiated
Need enough tissue to assess cells and architecture
open bx vs core needle bx vs FNA
Excisional biopsy
– Most commonly of cervical nodes
– Presence of RS cells is necessary but not sufficient
• Laparotomy
– 1960’s
– Determine extent of disease below diaphragm
– Largely eliminated by more effective chemo regimens
– EORTC study did not show survival benefit for
pathologic staging over clinical staging (Carde et al.
JCO 1993)

17. Adverse Prognostic Factors
• B symptoms esp. weight loss and night sweats.
• Pruritis
• Higher stage, esp.with bone marrow or organ
involvement.
• Bulky disease with large tumor burden. This includes
large mediastinal lymphadenopathy, which is >1/3 of
maximal thoracic diameter (T5-T6).
• Worrisome labs include ESR>70 and high serum copper.
• Older age
• LD type
• male

18. CHOP Chemotherapy Cyclophosphamide (Cytoxan)
Hydroxydaunorubicin (Adriamycin)
Oncovin (vincristine)
Prednisone

19. Follicular lymphoma most common type of “indolent” lymphoma
usually widespread at presentation
often asymptomatic
not curable (some exceptions)
associated with BCL-2 gene rearrangement [t(14;18)]
cell of origin: germinal center B-cell

20. defer treatment if asymptomatic (“watch-and-wait”)
several chemotherapy options if symptomatic
median survival: years
despite “indolent” label, morbidity and mortality can be considerable
transformation to aggressive lymphoma can occur

21. Diffuse large B-cell lymphoma
most common type of “aggressive” lymphoma
usually symptomatic
extranodal involvement is common
cell of origin: germinal center B-cell
treatment should be offered
curable in ~ 40%

22. Treatment Options: Aggressive Lymphomas
Diffuse large cell lymphoma, large cell anaplastic lymphoma, peripheral T cell lymphoma.
Very Aggressive
Burkitt’s lymphoma and lymphoblastic lymphoma.

23. Treatment Options for Advanced Stage Aggressive Lymphomas
Systemic chemotherapy
CHOP (± Rituxan for over 70 age group)
± Intrathecal chemotherapy
AIDS patients and CNS involvement
± Radiotherapy
Spinal cord compression, bulky disease

24. Burkitt’s Lymphoma
African variety: jaw tumor, strongly linked to Epstein-Barr Virus infection.
In U.S., about 50% EBV infection.
May present as abdominal mass.
Most rapidly growing human tumor.
Typical chromosome abnormality: c-myc oncogene linked to one of the immunoglobulin genes.

25. Burkitt’s Lymphoma
Treated with multidrug regimen similar to pediatric leukemia/lymphoma regimens.

26. MALT Lymphoma Mucosa-Associated Lymphoid Tissue
Chronic infection of the stomach by Helicobacter pylori.
Localized to the stomach, indolent course.
Can be cured in many cases by antibiotics against H. pylori.

27. Treatment Options for Early Stage Aggressive Lymphomas
Often in Stage I or II
potentially curable
disseminates through bloodstream early
must use systemic chemotherapy
CHOP x 6 cycles
CHOP x 3 cycles followed by radiotherapy

28. Hodgkin lymphoma
Thomas Hodgkin
( )

29. Classical Hodgkin Lymphoma
Hodgkin’s Disease

30. Hodgkin’s Disease One-seventh as common a snon-Hodgkin’s lymphoma.
Highly treatable and curable, even when disseminated.
Presence of Reed-Sternberg cell is necessary to make diagnosis.

31. Subtypes of Hodgkin’s Disease
Lymphocyte predominant
Nodular sclerosis
Mixed cellularity
Lymphocyte depleted
Unlike non-Hodgkin’s lymphoma, in Hodgkin’s Disease
the histologic subtype does not determine how the
disease is treated.

32. CHL Pathologic Variants
Nodular Sclerosis (NS) (70%)
• Large RS cells
• Cervical nodes
• Anterior mediastinum
• Adolescent patients
• Lymphocyte Rich (5%)
• Rare RS cells. Many lymphocytes. Age <35 y/o with localized disease. Good
prognosis. M>F (4:1).
• Lymphocyte Depleted (rare)
• Many RS cells, few lymphocytes
• Age > 50.
• Diffuse abdominal disease, marrow, and liver involvement. Most patients p/w
advanced disease
• Poorest prognosis
• Mixed cellularity (25%)
• Moderate RS cells, mixed infiltrate of neutrophils, eosinophils, and plasma cells.
• Age 30-50, EBV associated, developing countries
• Retro-peritoneal presentation
• Intermediate prognosis

33. Hodgkin lymphoma cell of origin: germinal centre B-cell
Reed-Sternberg cells (or RS variants) in the affected tissues
most cells in affected lymph node are polyclonal reactive lymphoid cells, not neoplastic cells

34. Histology • Reed-Stenberg Cell: “owl eyes”
– Large, with abundant cytoplasm, 2-3 nuclei with
prominent nucleolus “owl eyes” appearance
– NOT pathognomonic, can be reactive, infectious or
malignant
– RS cells stain for CD30/15+, but are CD45/20-
*Contrast w/ NLPHL which are CD30/15-,
CD45/20+

35. Reed-Sternberg cell

36. RS cell and variants classic RS cell lacunar cell popcorn cell
(lymphocyte
predominance)
(mixed cellularity)
(nodular sclerosis)

37. Molecular Biology The Reed Sternberg (RS) cell likely arises from
either lymphocyte or antigen-presenting cells of
the monocyte-macrophage line. Regarding
lymphocyte origin, 60% of RS cells have T or B
cell specific antigens, and B cells are the usual
target for EBV

38. Molecular Biology
• RS-like cells are found in several infectious, inflammatory, and
neoplastic conditions including infectious mononucleosis, reactive
lymphoid hyperplasia, and immunoblastic lymphoma.
• Thus, diagnosing Hodgkin’s depends on finding RS cells in the
appropriate clinical setting. The lymphocytes are predominantly CD-
4 positive T-cells.
• The BCL2 Oncogene is found in 1/3 of Hodgkins patients.
• The p53 suppressor gene is found in almost all Hodgkin’s patients
except those with lymphocyte predominant disease.
• The common t(14:18) translocation of B cell lymphoma are RARE in
RS cells.

39. A possible model of pathogenesis
loss of apoptosis
transforming
event(s)
EBV?
cytokines
germinal
centre
B cell
RS cell
inflammatory
response

40. Etiology of Hodgkin’s Disease
Reed-Sternberg cells are the malignant cells.
Minor population in the malignant tissues
many normal lymphocytes, eosinophils, other cells
Cell of origin is unknown: T, B, both, neither.
Some R-S cells contain EBV genomes.

41. Epidemiology less frequent than non-Hodgkin lymphoma overall M>F
peak incidence in 3rd decade

42. Clinical Features
T cell mediated immune deficiency, even in early stage disease. Prone to infections:
Herpes zoster (“shingles”) in one fourth of patients
Fungal or mycobacterial infections
Immune defect may persist even after lymphoma is cured.

43. Clinical manifestations:
lymphadenopathy
contiguous spread
extranodal sites relatively uncommon except in advanced disease
“B” symptoms

44. Clinical Features Predictable contiguous spread of disease:
cervical nodes to mediastinum or axilla
mediastinum to periaortic nodes or spleen, etc.
Basis for staging and treatment decisions.

45. Diagnosis Excisional biopsy of a lymph node.
Fine needle aspirate is not sufficient to make the diagnosis of Hodgkin’s disease.

46. Staging of Hodgkin’s Disease
Same as for non-Hodgkin’s:
H + P, labs, CT scans, bone marrow biopsy
PLUS:
Gallium scan
Lymphangiogram or staging laparotomy ONLY if results would affect treatment decisions

47. Treatment by Stage

48. Chemotherapy Regimens
MOPP
Mechlorethamine, Oncovin, Procarbazine, Prednisone
ABVD
Adriamycin, Bleomycin, Vinblastine, Dacarbazine
BEACOPP

49. Treatment Options
Often, patients who relapse after radiotherapy can be cured by salvage chemotherapy.
Combined chemotherapy and radiotherapy is given for bulky mediastinal masses.
Chemotherapy now being tested for earlier stages of the disease.

50. Late Complications of Hodgkin’s Disease
High incidence of second malignancies
leukemia first 10 years, solid tumors over time.
Leukemia in patients receiving alkylating agents or combined chemo/XRT.
Lung cancer and breast cancer in patients receiving XRT to chest. Lung cancer especially high in smokers.

51. Late Complications of Hodgkin’s Disease
Hypothyroidism after irradiation of the neck.
Constrictive pericarditis after radiotherapy to the mediastinum.
Infertility after use of alkylating agents.
Heart failure after Adriamycin treatment.

52. Treatment
Overall survival exceeds 80%, therefore therapy is evolving to
minimize toxicity while maintaining excellent disease control
The German Hodgkin's Study Group (GHSG) has performed a
number of trials with various iterations of treatment regimens
Major chemotherapy options:
 ABVD
 Doxorubicin, bleomycin, vinblastine, dacarbazine
 Most commonly prescribed regimen
 Stanford V
 Doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine,
bleomycin, and prednisone
 Overall lower doses bleo/doxo than ABVD
 BEACOPP
 Bleomycin, etoposide, doxorubicine, cyclophosphamide, vincristine,
procarbazine, and prednisone
 Dose dense
 Being studied for advanced disease