Lymphoma is an awesome presentation .pdf

Can be a smart guide

1. Dr. Mekoya D. Mengistu
(MD, Internist, Assistant professor of Internal Medicine)

2. Questions?
What are the types of lymphoma?

What are the major risk factors?

What are the clinical presentation of a patient with lymphoma?

What are the major diagnostic modalities?

Staging of Lymphoma?

What are the major management options of a patient with lymphoma?

What are the major side effects of chemotherapies?

3. Defin: Lymphoma

+ Clonal malignant disorders that are derived from lymphoid cells: either precursor or
mature T-cell or B-cell

© usually originate in the lymph nodes, but they may originate in any organ of the body

° There are two types of lymphoma
+ Hodgkins Lymphoma
+ Non hodgkins Lymphoma

+ This two lymphomas differ in how they behave, spread and respond to treatment.

4. Epidemiology of lymphomas

+ 5 most frequently diagnosed cancer in both sexes
+ males > females
© incidence

+ Hodgkin lymphoma stable
+ NHL increasing(NHL—8-10XHL)

lung
colorectal
breast

20

10
0 L > Iymphoma}

ANA

Hodgkin

age adjusted i

1985 1990 1995 2000
Year

Fig Incidence of lymphomas in comparison with other cancers in Canada

5. Hodgkin's Lymphoma

v

Named after Thomas Hodgkin's.

v

It’s a cancer of lymphocytes almost in all cases they starts from the B subtype.

v

It can start at any lymphoid tissues mostly the LN and usually in the upper part
of the body

it spreads in contiguous manner and rarely hematogenous.

v

Thomas hodgkins (1898-1966)

v

Course of the disease is variable, but the prognosis has improved with modern
treatment

» The prototype cell is the Reed Sternberg's cells.

6. bebe mt

+ cell of origin: germinal centre B-cell

e Because It has high proliferative activity

+ Etiology: ? Infection — EBV paracortex

+ 2EBV sometimes causes DNA changes in B lymphocytes Nel

medullary

© this leads to the development of Reed-Sternberg cells, which are the cancer cells in HL.

» Reed-Sternberg cells (or RS variants) in the affected tissues

Normal Reed-Sternberg
lymphocyte. i Cell

‘afferent lymph vessel
capsule

trabecula
high

‘endothelial
venule

8. A possible model of pathogenesis of HL

transforming loss of apoptosis
event(s)
REV es
e-e-es me,
germinal e
centre RS cell
B cell inflammatory

response

9. Reed-Sternberg cells are the hallmark cells of Hodgkin's
lymphoma. They are large, often multinucleated or have a
bilobed nucleus with prominent eosinophilic inclusion-like
nucleoli, resembling an "owl's eye" appearance.

10. Classifications of HL

» Classification is based on microscopic features.
» Different types & may be treated differently.
» All types are malignant and there is no benign type.

» Generally there are two types
° Classic HD: are of four types

Nodular sclerosis (70%)
Mixed cellularity (25%)
Lymphocytic rich (5%)
Lymphocytic depletion (1%)
> Nodular lymphocytic predominant (5%)

R.E.A.L. Classification IHL World Health Organization (WHO) Classification
Nodular lymphocyte predominance | Nodular lymphocyte predominant HL
Classical Lymphocyte-rich HL™ Lymphocyte-rich classical HL.

Classical Nodular sclerosis HL

Nodular sclerosis classical HL

Classical Mixed cellularity HL Mixed cellularity classical HL

Classical Lymphocyte depletion HL | Lymphocyte depleted classical HL

11. o Nodular Sclerosing HL (70%)

+» Typically seen in young adults/adolescents &
involving Mediastinal & neck LN

» Characteristic cell is the lacunar type RS cells
» Overall prognosis is good
o Mixed Cellularity HL (25%)
+ Most common HL in pt > 50y/o, 4 predominance
» Classical RS cells abundant
« Assoc with B symptoms
» Commonly affects abdominal LN & spleen
+ Most common HL subtype in HIV +ve population

12. o Lymphocyte-rich HL (5%)
» Characterised by an inflitrate of many small
lymphocytes € RS cells; often an indolent disease
o Lymphocyte-depleted HL (1%)
+ Rare € lacks cellular infiltrate with numerous RS
cells
+ Seen in HL assoc with HIV
+ Patients usually w advanced stage disease
o Nodular Lymphocyte-predominant HL (5%)
» Characterised by large number of small resting
lymphocytes admixed with benign histiocytes
» Classical RS cells difficult to find
o Lympho-histiocytic (L&H) variant RS cell (popcorn cell)

13. Risk factors for HL
® Infections eg: EBV, HIV
Age bimodal distribution

© Gender: more common in males
° Socioeconomic status: higher status
Geographic location: more in westerns and less in Asians

+ Family history: accounts for 5%, twins has higher risk.
6

Fig. Bimodal age distribution of HL ¿

incidence! 100,000/annum
O + N° & 8 a

14. Clinical manifestations of HL:

* Clinical manifestation is variable
+ severity: asymptomatic to extremely ill
« time course: evolution over weeks, months, or years

+ Most patients present with palpable, non-tender Lymphadenopathy
70% localize to cervical or supraclavicular area or Axilla
The LAP is Firm, non tender, discrete
“contiguous spread
“The size may change spontanously
Alcohol induced pain at the site
© More than 50% pts have anterior mediastinal mass: can be initial manifestation

+ Extranodal sites relatively uncommon except in advanced disease

15. + Subdiaphramatic presentation of cHL is unusual and more common in older males
“Only 4% of HL are limited to below the diaphragm
25% of normal spleens harbour tumor
© 30-40% of HL patients have B-symptoms [70% in Ethiopia]
© B symptoms generally correlate with advanced stage and portend a worse prognosis.
Unexplained wt loss of more than 10% in 6months
Unexplained persistent or recurrent fever above 38°C in previous month

Recurrent drenching night sweats during the previous month

16. Classic hodgkins Lymphoma

17. + Occasionally HL presents with unusual manifestation:
«+ Severe and unexplained itching/pruritis
* Cutaneous disorders like erythema nodusum, ichthyosiform atrophy
# Paraneoplastic cerebellar degeneration, nephrotic syndrome, Hypercalcaemia,
# Immune hemolytic anemia and thrombocytopenia,

# Pain in LN on alcohol ingestion

18. Staging of HL

» Used to determine the extent of spread, to see prognosis and decide treatment options.

> Its based on
«+ Medical history
P/E
“Blood tests
«+ Biopsy of LAP, BM aspiration and biopsies
“Imaging :CXR, CT SCAN, MRI, PET, GALLIUM SCAN, BONE SCAN

19. Investigation

CBC: Mild to moderate NCNC anemia is common in HL
ESR, serum ferritin, haptoglobulin
CXR: demonstrate mediastenal mass, hilar LAP, Pleural effusion, parenchymal lung lesions

CT scan/Pet scan: for staging

Biopsy:
«+ Excisional /incisional biopsy
preferred and most common type of biopsy for an enlarged LN
“Core needle biopsy: Eg Mediastinal mass or Hilar LAP
“BM aspiration/biopsies: BM involvement of cHL is patchy and can be missed

Immuno-histocompatability

20. Ann arbor(with costs wold modification) Staging

» Stage I: HD is found in only 1 lymph node area or lymphoid tissues/organ such as thymus
Y The cancer is only in one extra-nodal organ

> Stage II: HD found in 2 or more LN areas on the same side(above or below) of diaphragm
Y The cancer extends locally from one lymph node area in to near by organs

> Stage III: HD found on LN area on both side of the diaphragm
Y TIE subdiaphragmatic involvement limited to spleen, splenic hilar LN, ciliac LN, portal LN
v TIL-2: extends to paraortic, iliac or mesentric LN

» Stage 4: Diffuse or desiminated involvement of 21extranodal organs beyond that designated as E
Any involvement of Liver ,bone marrow, lung ,CSF involvement

> BULKY DISEASE(X) : Ifpresent, needs intensive therapy.
» Defined as Mediatinal mass 21/3 of the chest, nodal mass > 10cm across the largest dimension.
» All stages are classified as (A) Absent or B-presence of B SYMPTOMS
> Add E-for localized, solitary involvement of extranodal deposit excluding liver and bone
» Add S: If spleen is involved, IF both use ES.

21. ° Clinical staging

Stage I Stage II Stage III Stage IV

Cs Zu os so

SN y KE RP
n n n A

22. STAGING OF HL (ANN ARBOR STAGING)

ve

==

NN (7 XD & 7 NN # 7
SRL VAT LA \GPol semer

2h PR KG DA ees
: J loss
h

. Stage ll: Stage Ill: Stage IV:
involvement of single involvement of two or involvement of lymph diffuse extralymphatic
lymph node region or more lymph node node regions on both disease (e.g. in liver,
single extralymphatic regionsonsameside sides of the bone marrow, lung,
site (lg) of diophragm; may diaphragm; may skin)

include localized include spleen (Ills)
extralymphatic or localized

23. Signs of poor prognosis:

A. For limited stages: include all asymptomatic stage I or II supradiaphragmatic disease without bulky

«+ the presence of any of the following factors is considered unfavorable
Age 250

Bulky disease(Eg, Mediatinal mass ratio(MMR)> 0.3)

ESR >30 with B symptoms or >50 with out B symptoms

>2 Ann Arbor sites

Massive splenic disease

Extranodal site

SS. KR

B. For advanced stages: Bad prognostic signs are
Age 245years

Male gender

Anemia Hgb <10.5g/dl

WBC215K

Lymphocyte <600/microL

Serum albumin <4

Stage IV

Bulky disease

En nr

24. Management of HL

© It is mainly guided by the clinical stage of disease but general health, types and
locations of the disease matters.

° General options:
“Chemotherapy
Radiotherapy
“Immunotherapy

“Higher dose chemotherapy with stem cell transplant

25. » Chemotherapy: are drugs used to kill cancer cells, can be given IV, po, intra thecal.
> It’s given in cycles for several weeks with the rest period.
> usually given at impatient bases.
> Different drug combinations are used
“In HD four drug combination is the standard
*ABVD is the treatment choice: every other wk
(ABVD: Adriamycine[Anthracyclin], Bleomycin, Vinblastin, Dacarbazine)

For limited stages: 4-6 cycles of ABVD followed by involved field Radiotherapy(IFRT)
For advanced stages: 6-8cycles followed by IFRT

# ABVD is superior to the MOPP

(MOPP: Chloroambucil, vincristin, procarbazine, predinisolone)

26. Treatment and Prognosis

Stage Treatment Overall 5 year survival
IA, IA ABVD x4 & radiation >90%
(non bulky)
IB, IIB(non bulky) ABVDX6 85%
+RT
Bulky 1A,1B, IIA, IIB ABVDX 6 85%
+RT
111,1 ABVDX6 70-80%

+ RT if bulky

27. Side effects of the therapy

+ The chemo or Radiotherapies attack fast growing cells: normal fast growing cells like hair

follicles, epithelial cells, marrow cells can also be affected resulting in the following side effects:
Y hair loss

Y mouse sores

y loss of appetite
Y nausea/ vomiting
y Diarrhea

Y Cytopenia-low CBC: increase the risk of infection, anemia, easy bleeding, fatigue
“+ Tumor lysis syndrome[TLS]: may happen usually in the 1* cycle of the treatment

v TLS is an oncologic emergency caused by massive tumor cell lysis
v releases of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation.

28. Table 1. Cairo-Bishop definition of laboratory tumor lysis syn-

drome.”
Value Change from baseline
Uric acid >476 umol/L (8 mg/dL) 25% increase
Potassium >6.0 mmol/L (or 6 mEq/L) 25% increase
Phosphorous 21.45 mmol/L (4.5 mg/dL) for 25% increase
adults
Calcium <1.75 mmol/L (7 mg/dL) 25% decrease

NB: Cairo-Bishop definition of TLS:-
“+ Dx of Lab criteria of TLS : abnormality in two or more of the following, occurring within three days
before or seven days after chemotherapy.

% Dx of Clinical criteria of TLS: lab TLS plus one or more of the following
+ increased serum creatinine (1.5 times upper limit of normal)
+ cardiac arrhythmia or sudden death
+ seizure

29. Long term complications of treatment

Infertility (ABVD is not associated with infertility)
%MOPP ; males > females
sperm banking should be discussed
“RT in males(testicles are shielded)
premature menopause
Secondary malignancy
AML: 5-7% with MOPP—after 4-Tyrs, (rare with ABVD)
Solid tumors usually occur after 10yrs
lung, thyroid, breast, skin
“NHL
cardiac disease: Adriamycine(Anthracycline) is known cardiotoxic: cardiomyopathy(DCMP)
Lung toxicity: Radiation pneumonitis, Bleomycine induced lung toxcity (IPF in 10% of pts)
Peripheral Neuropathy: Vincristin (Oncovin-brand name)

30. Non Hodgkin's disease

Is a cancer of lymphocytes,

They can be B orT cell lymphomas

B cell origin accounts for about 90% of NHL

Distinguished from HL up on recognition of Reed Stenberg cells

+ Differ from HL with respect to their biologic and clinical characteristics
Y HL-80-90% can be cured with chemo + Radio
Y But NHL has variable prognosis and natural history

° Unlike HD this are many types.
+ WHO classifies them based on
Y” microscopic feature,
Y” chromosomal feature and

Y” presence of certain proteins.

31. COMPARISONS OF HODGKIN’S AND NON-HODGKIN’S LYMPHOMA

Hodgkin’s Non-Hodgkin’s Lymphoma

Characteristic Lymphoma_ Low-grade Intermediate or High-grade
Site of origin: Nodal Nodal Nodal

(Extranodal-10%) (Extranodal-35%)
Nodal Centripetal Centrifugal Centrifugal
distribution: (Axial)
Nodal spread: Contiguous Noncontiguous Noncontiguous
Localized Common Rare Rare to common
Presentation:
Gastrointestinal Rare Common Common
Presentation:
BM involvement Yes No Yes
affects prognosis:
B-symptoms: Common ee Rare Rare (depends on stage)
Immunity =
Predominantly Cellular Humoral Humoral or Cellular
affected:
Curable by Yes No Yes

Chemotherapy:

32. HL Vs NHL

Category Survival of Curability To treat or not to
untreated treat
patients
Non-Hodgkin Indolent Years Generally not Generally defer Rx if
E asymptomatic
lymphoma Eg SLL, FL curable ame
Aggressive Months Curable in Treat
Eg DLCL some
Very aggressive Weeks Curable in Treat

Eg, Burkitt’s Lymphoma eee

Hodgkin lymphoma | All types Variable: months to yrs Curable in most Treat

33. Epidemiology of NHL

* Incidence is 8-10x the incidence of HL
+ Slightly male to female predominant
Patients with immune suppression are predisposed to NHL
+ The incidence rises steadily with age, especially after 40yrs
+ Aggressive NHL(Burkitt’s lymphoma and DLBCL) are most common in children

«+ DLBCL and indolent lymphoma including follicular lyphoma are most common in Addults

100

80

60

40

20

Incidence/100,000/annum

o

3173323333333
Fig. Age distribution of new NHL cases in Canada LLRÉSSSSS

34. Clinical manifestations of NHL

© Systemic manifestations
* fever, night sweats, weight loss, anorexia, pruritis [not common]
© Local manifestations—depends on the site of disease
“lymphadenopathy, splenomegaly most common
Y any tissue potentially can be infiltrated
+ pleural /pericardial effusions, ascites
* compression of structures (eg spinal cord, ureters, superior venacava syndrome)
+ bone marrow failure (infiltration)
° CNS infiltration

* immune hemolysis or thrombocytopenia

35. Risk factors of NHL

+ Age: older age >60,

*% Gender: most are common in males

% Exposure to chemicals: such as benzene
* Radiation exposure

# Immune system deficiencies

% Certain infections
° Infections that directly transform lymphoma: EBV, HTLV-1, HHV-8
° Infections that weakens immune system: HIV

° Infections that causes chronic immune stimulations: H. pylori, C. jejuni, HCV etc

36. Types of B cell NHL

Diffuse large B cell lymphoma(DLBCL)
The most common histologic type of NHL: 1/3" of NHL.
Appear large under microscope,

Average age is 60.

vvvv

Majority of patient present in advanced stage: III or IV
Y 40% of patients have B-symptoms and 50% have raised LDH
40% of patients have non-nodal sites including BM, CNS, GIT, thyroid, liver and skin

Involvement of BM, testis, breast, kidney, thyroid, liver and skin are at increased risk of CNS involvement

vv

v

Responds well for Rx: 3/4"" are symptoms free after initial Rx and more than half (60-65%) of all cured.
Has sub types
Y Primary meditational B cell lymphoma
Y Intravascular large B cell lymphoma
is a rare subtype of DLBCL in which lymphoma cells proliferate within the lumen of small blood vessels
most often presents with CNS and skin signs. The cutaneous variant of intravascular lymphoma is limited to the skin

Y Primary CNS lyphoma (PCNSL)- common in immune compromised(Eg. HIV), poor prognosis

y

37. Follicular lymphoma:
e 2nd leading cause of NHL: 1 in 5
+ it means it tends to grow in a circular pattern in LNs.
+ Occurs painless LAP at multiple sites and bone marrows.
* average age is 60

¢ Is slow growing, most patients have no raised LDH, and no B symptoms

+ treatment may not be required until it starts to cause symptoms.
© It responds well to treatment (sensitive to chemo) but cure is hard to achieve
+ Rx: Observe the asymptomatic patients b/c treatment has no mortality benefit[but Recurs]

+ Rx if Symptomatic: Rituximab or if large volume disease: R-CHOP

38. » Marginal zone B cell lymphoma-
o 2" most common indolent lymphoma
o 3 types: splenic MZL, Extranodal MZL of MALT(MALT Lymphoma), nodal MZL

MALT lyphoma is most commonly in stomach-cause is associated with H. pylori

» Chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma:
> 5-10% of all NHL

° in CLL cancer cells found in the blood and BM while in SLL cells are found mainly
in the LN and spleen.

> It is a slow growing, no cure but most live >10 years.

39. Burkett's lymphoma: accounts for 0.3-1.3% of NHL
° Highly active, aggressive form of NHL but cure rate 95% if treated
+ The cells have Starry sky appearance, Vacuolated cytoplasm

° presents with rapidly enlarging LN with explosive growth involving
jaw, chest &/or abdomen

+ More common in children and immune suppressed patients
+ Endemic form: is common in equatorial Africa and tropical region
Y Children, malaria endemic area
Y Associated with the EBV in ~100% of cases unlike 30% in sporadic form
° sporadic forms that occur in Western countries, EBV in 30% of ases

de
+ Immunodeficiency-associated cases: EBV in 40% of cases [

ww

40. Diagnosis of NHL

o History:
“*Progressively enlarged LN can be in the neck, abdomen, chest, skin and the brain.
“swollen abdomen,
“early satiety,
“chest pain or pressure,
“SOB
#B symptoms and extreme tiredness

P/E focus on LN, spleen examinations.

41. » Biopsies: is the only way to diagnose non- Hodgkin lymphoma
> Excisional/ incisional biopsies
° Fine/core needle biopsies
° Bone marrow aspiration/biopsies, LP, effusion analysis
> Lab tests:
° Immuno-histochemistry tests
o Flow cytometer
° Cytogenetic
° Molecular genetic tests
> Blood tests
> Imaging:
CXR
CT SCAN, MRI, PET
GALLIUM SCAN
BONE SCAN

42. Staging of NHL

e Tests for staging:
Hx, P/E
* Biopsies
+ Blood tests
«+ Imaging tests
« Bone marrow studies

e Ann-arbor staging was also adopted for NHL

43. International Prognostic Index

*_3)Prognostic Factors: Diffuse large B-cell lymphoma is the subtype of NHL in which the
impact of prognostic factors have been studied most thoroughly, and to a certain degree, it
has served as a paradigm for the study of prognostic factors in the other types of NHL.

d es on International prognostic index (1PI) for diffuse aggressive lymphoma:
u e
7 stg " A. Age: <60 or > 60 years: (> 60 years: Adverse prognostic factor, one point)
° Extension from the lymph node B. Stage: Stage Io I versus stage lor IV (Stages I and IV: Adverse prognostic factor, one point)

© Performance in daily activities
+ Serum LDH level
> Good prognostic indicators
> Age<60 E. LDH: < normal versus > normal: (> Normal: Adverse prognostic factor, one point)
© Stage 1& 2
> No lymphoma out side the lymph-node or only in one LN
° Able to function normally
+ Normal LDH

> POOR PROGNOSTIC FACTORS ARE THE OTHER SIDES OF GOOD INDICATORS

C. Number of extranodal sites: 0, 1 versus > 1: (> one site: Adverse prognostic factor, one point)

D. Performance status (ECOG Seale): 0, | versus 2, 3,4: (2,3, 4: Adverse prognostic factors, one point)

44. y

MANAGEMANT of NHL

General options:
«+ Chemotherapy
* Radiotherapy

+ Immunotherapy

«+ Higher dose chemotherapy with stem cell transplant

Different cycles of chemotherapy combinations are used
* CHOP(cyclophosphamide, doxorubicine, vincristine(Oncovin), predinsolone) &
++ CVP (Cyclophosphamide, Vincristine, prednisolone) are the treatment choice

+ CHEMO IS OFTEN COMBINED WITH IMMUNOTHERAPY ESPECIALLY THE MONOCLONAL antibody-
RITUXIMAB (R-CHOP or R-CVP) -Better outcome

«+ Rx of Burkett's lymphoma incudes CODOX-M(Cyclophosphamid, Vincristin, Doxorubicin and Methotrexate)

45. Treatment of HNL(DLBCL)

+ LIMITED(stage I, Il)
#NON BULKY(<10cm)
» 3-4cycles of R-CHOP followed by IF-RT

&BULKY(> 10cm)
+ 6cycles of R-CHOP followed by IF-RT or
° 8 cycles of R-CHOP

+ ADVANCED (stage III,IV)— 8cycles of R-CHOP

Adverse Effect: mostly similar as in HL

TLS is most common with Barkitt's lymphoma

46. Many Thanks