20 C GROUP

8/12/2019 20 C GROUP

1/90

8/12/2019 20 C GROUP

2/90

Lo 1

8/12/2019 20 C GROUP

3/90

Physiology & Anatomy

Lymphatic system

Open circulatory system

Part of immune system

Includes: lymph, lymphatic vessels, lymph

nodes, spleen, tonsils, adenoids, Peyer

patches, thymus Body has 600 lymph nodes

Lymph drains through nodes as it heads to

right lymphatic duct and thoracic duct

8/12/2019 20 C GROUP

4/90

LymphaticSystem

8/12/2019 20 C GROUP

5/90

Physiology & Anatomy

Lymph nodes are populated by:

Macrophages, dendritic cells, B and T

lymphocytes B Lymphocytes

Located in follicles and perfollicular area of

lymph nodes

T Lymphocytes

Interfollicular or paracortical area of lymph

nodes

8/12/2019 20 C GROUP

6/90

8/12/2019 20 C GROUP

7/90

Approach to Patient

Lymphadenopathyrefers to lymph nodes

that are abnormal in size, number or

consistency Consider:

Age of Patient

Size of Nodes

Location of Nodes

Quality of Nodes

Localized or generalized

Time course of the lymphadenopathy

8/12/2019 20 C GROUP

8/90

Patient Age

Not palpable in newborn

Palpable nodes are the norm in the

cervical, axillary, and inguinal regionsthroughout early childhood

Children < 5 years old

44% palpable nodes at check up

64% palpable nodes at sick visits

8/12/2019 20 C GROUP

9/90

Patient Age

The differential diagnosis is huge! But

consider age as you narrow it down.

For example: Preschool and early school age:

URI, AOM, Conjunctivitis

Teenagers Hodgkin lymphoma

STDs

8/12/2019 20 C GROUP

10/90

Size of Lymph Nodes

Rules of thumb:

Axillary and cervical nodes < 1 cm

Inguinal

8/12/2019 20 C GROUP

11/90

Location of Lymph NodesNode Groups

Occipital

Postauriclular Preauricular

Parotid

Submandibular

Submental

Superficial cervical Deep cervical

Supraclavicular

Deltopectoral

Axillary

Epitrochlear Inguinal

Popliteal

Region Drained

Posterior Scalp

Temporal & parietal scalp Scalp, ear canal, conjunctiva

Scalp, midface, ear canal and ear, parotid

Cheek, nose, lips, tongue, subman. gland

Lower lip, floor of mouth

Lower larynx, lower ear canal, parotid Tonsils, adenoids, scalp, larynx, sinuses

Mediastinum, lungs, abdomen

Arm

Arm, breast, thorax, neck

Medial arm below elbow Lower extremities, genitalia, abdomen

Lower leg

8/12/2019 20 C GROUP

12/90

Quality of Lymph Nodes

Painful Usually infection, especially if erythema, warmth, or

fluctance

Malignancy can cause node tenderness because ofhemorrhage into node and stretching of capsule

Hard Found in cancers because of fibrosis

Nonmobile

Become fixed from invasive cancers of inflammation intissue surrounding nodes (ie TB or sarcoidosis)

SOFT, COMPRESSIBLE = NORMAL

8/12/2019 20 C GROUP

13/90

Localized vs. Generalized

Lymphadenopathy Localized

Most commonly cervical then inguinal

Can be infection/inflammation in the areadrained by that node or infection of node

itself

Generalized Systemic disease

8/12/2019 20 C GROUP

14/90

Localized Lymphadenopathy

8/12/2019 20 C GROUP

15/90

Differential Diagnosis - Infection Bacterial

Localized: Staph aureus, GAS, cat-scratch, tularemia, diphtheria

Generalized : Brucellosis, leptospirosis, typhoid

Viral EBV, CMV, HSV, HIV, Hep B, Measles, Mumps, Rubella,

Dengue Fever

Myocobacterial TB, Atypical mycobacteria

Fungal Coccidiomycosis, Cryptococcosis, Histoplasmosis

Protozoal Toxoplamosis, Leishmaniasis Spirochetal

Lyme disease, symphilis

8/12/2019 20 C GROUP

16/90

Differential Diagnosis - Other

Malignancy leukemia, lymphoma, metastasis from solid tumor

Immunologic SLE, serum sickness, Langerhans cellhistiocytosis, RA, Drug Reaction, dermatomyositis,CGD

Endocrine Addison disease, hypothyroidism

Other Amyloidosis, Kawasaki disease, Sarcoidosis,

Churg-Strauss syndrome, Kikuchi disease,Castleman disease

8/12/2019 20 C GROUP

17/90

Time Course of Lymphadenopathy

When to biopsy Many advocate biopsy of concerning nodes that

have not decreased after 4-6 weeks or have not

normalized in 8-12 weeks Lymph nodes present for long time are not likely to

be malignant except for Hodgkins

Exposure medications, animals, uncooked meats,

unpasteurized milk Associated constitutional symptoms

Fever, night sweats, weight loss, pruritus,arthralgias, fatigue

8/12/2019 20 C GROUP

18/90

Specific Causes of

Lymphadenopathy

8/12/2019 20 C GROUP

19/90

Lymphadenitis

Lymphadenitisenlarged, inflamed, tender lymph nodes

Organisms: Staph aureus, GAS (80%)

Usually submandibular

Southwest US Yersinia pestis = Bubonic plague

Bartonella henselae = cat scratch

TB and atypical mycobacteria (M. avium and M. scrofulaceum)

Management Culture drainage or of pharyngeal exudate

Treatment 1st/2ndgeneration cephalosporin or dicloxacillin

Clindamycin or Augmentin if anaerobe suspected (oral)

Ultrasound to determine if abscess

I&D indicated if abscess present

8/12/2019 20 C GROUP

20/90

Infectious Mononucleosis

Symptoms fever, pharyngitis, lymphadenopathy (symmetric

involvement of posterior cervical nodes)

EBV, CMV, toxoplasmosis, Streptococcus,hep B, HIV

Testing

Monospot test (heterophile antibody) High false negative in < 4 YO and early illness

Specific serologic tests Elevated immunoglobulin M titer to viral capsid antigen

(Igm-VCA) indicates acute infection

8/12/2019 20 C GROUP

21/90

Diagnostic Testing to Consider

Blood

CBC, ESR, LDH

Specific Serologic testing (EBV, CMV,Bartonella)

Tuberculin Skin Testing

Chest X-ray Biopsy

8/12/2019 20 C GROUP

22/90

LO 2

8/12/2019 20 C GROUP

23/90

8/12/2019 20 C GROUP

24/90

ALL MMCLL Lymphomas

Hematopoietic

stem cellNeutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloid

progenitor

Myeloproliferative disordersAML

Lymphoid

progenitor T-lymphocytes

Plasma

cells

B-lymphocytes

nave

8/12/2019 20 C GROUP

25/90

B-cell development

stem

cell

lymphoid

progenitor

progenitor-B

pre-B

immature

B-cell

memoryB-cell

plasma cellDLBCL,FL, HL

ALL

CLL

MM

germinal

center

B-cell

mature

naive

B-cell

8/12/2019 20 C GROUP

26/90

Clinically useful

classification

Diseases that have distinct

clinical features

natural history

prognosis

treatment

Biologically rational

classification

Diseases that have distinct

morphology

immunophenotype

genetic features

clinical features

Classification

8/12/2019 20 C GROUP

27/90

Lymphoma classification

(2001 WHO) B-cell neoplasms

precursor

mature

T-cell & NK-cell neoplasms

precursor

mature

Hodgkin lymphoma

Non-Hodgkin

Lymphomas

8/12/2019 20 C GROUP

28/90

A practical way to think of lymphoma

Category Survival of

untreatedpatients

Curability To treat or

not to treat

Non-

Hodgkin

lymphoma

Indolent Years Generally

not curable

Generally

defer Rx if

asymptomaticAggressive Months Curable in

some

Treat

Very

aggressive

Weeks Curable in

some

Treat

Hodgkin

lymphoma

All types Variable

months to

years

Curable in

most

Treat

8/12/2019 20 C GROUP

29/90

8/12/2019 20 C GROUP

30/90

Epidemiology of lymphomas

5thmost frequently diagnosed cancer in

both sexes

males > females

incidence

NHL increasing

Hodgkin lymphoma stable

8/12/2019 20 C GROUP

31/90

Incidence of lymphomas in comparisonwith other cancers in Canada

Year

1985 1990 1995 2000ageadjustedincidence

/100,000/yr

0

10

20

30

40

50

60

70

Hodgkinlymphoma

NHL

breast

colorectallung

8/12/2019 20 C GROUP

32/90

Age distribution of new NHL cases inCanada

Age (years)

0-11-45-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+

In

cidence/100,000/annum

0

20

40

60

80

100

8/12/2019 20 C GROUP

33/90

Age distribution of new Hodgkinlymphoma cases in Canada

Age (years)

0-11-45-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+

inc

idence/100,000

/annum

0

1

2

3

4

5

6

8/12/2019 20 C GROUP

34/90

Risk factors for NHL

immunosuppression or immunodeficiency

connective tissue disease

family history of lymphoma

infectious agents

ionizing radiation

8/12/2019 20 C GROUP

35/90

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

8/12/2019 20 C GROUP

36/90

Other complications of

lymphoma bone marrow failure (infiltration)

CNS infiltration

immune hemolysis or thrombocytopenia

compression of structures (eg spinal

cord, ureters)

pleural/pericardial effusions, ascites

8/12/2019 20 C GROUP

37/90

Diagnosis requires an

adequate biopsy Diagnosis should be biopsy-proven

before treatment is initiated

Need enough tissue to assess cells andarchitecture

open bx vscore needle bx vsFNA

8/12/2019 20 C GROUP

38/90

Stage I Stage II Stage III Stage IV

Staging of lymphoma

A: absence of B symptoms

B: fever, night sweats, weight loss

8/12/2019 20 C GROUP

39/90

Three common lymphomas

Follicular lymphoma

Diffuse large B-cell lymphoma Hodgkin lymphoma

8/12/2019 20 C GROUP

40/90

Relative frequencies of different

lymphomas

Hodgkin

lymphomaNHL

Diffuse large B-cell

Follicular

Other NHL

Non-Hodgkin Lymphomas

~85% of NHL are B-lineage

8/12/2019 20 C GROUP

41/90

Follicular lymphoma

most common type of indolentlymphoma

usually widespread at presentation often asymptomatic

not curable (some exceptions)

associated with BCL-2 generearrangement [t(14;18)]

cell of origin: germinal center B-cell

8/12/2019 20 C GROUP

42/90

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 lymphomacan occur

8/12/2019 20 C GROUP

43/90

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%

8/12/2019 20 C GROUP

44/90

Hodgkin lymphoma

Thomas Hodgkin

(1798-1866)

8/12/2019 20 C GROUP

45/90

Classical Hodgkin Lymphoma

8/12/2019 20 C GROUP

46/90

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

Reed Sternberg cell

8/12/2019 20 C GROUP

47/90

Reed-Sternberg cell

8/12/2019 20 C GROUP

48/90

RS cell and variants

popcorn celllacunar cellclassic RS cell

(mixed cellularity) (nodular sclerosis) (lymphocyte

predominance)

A possible model of

8/12/2019 20 C GROUP

49/90

A possible model ofpathogenesis

germinalcentre

B cell

transforming

event(s)

loss of apoptosis

RS cellinflammatory

response

EBV?

cytokines

8/12/2019 20 C GROUP

50/90

Hodgkin lymphomaHistologic subtypes

Classical Hodgkin lymphoma

nodular sclerosis (most common subtype)

mixed cellularity lymphocyte-rich

lymphocyte depleted

8/12/2019 20 C GROUP

51/90

Epidemiology

less frequent than non-Hodgkin

lymphoma

overall M>F peak incidence in 3rd decade

8/12/2019 20 C GROUP

52/90

Associated (etiological?)

factors EBV infection

smaller family size

higher socio-economic status

caucasian > non-caucasian

possible genetic predisposition

other: HIV? occupation? herbicides?

8/12/2019 20 C GROUP

53/90

Clinical manifestations:

lymphadenopathy

contiguous spread

extranodal sites relatively uncommonexcept in advanced disease

B symptoms

8/12/2019 20 C GROUP

54/90

Treatment and Prognosis

Stage Treatment Failure-

free

survival

Overall 5

year

survival

I,II ABVD x 4

& radiation

70-80% 80-90%

III,IV ABVD x 6 60-70% 70-80%

8/12/2019 20 C GROUP

55/90

Long term complications of

treatment infertility

MOPP > ABVD; males > females

sperm banking should be discussed premature menopause

secondary malignancy

skin, AML, lung, MDS, NHL, thyroid,breast...

cardiac disease

8/12/2019 20 C GROUP

56/90

Overview

Concepts, classification, biology

Epidemiology

Clinical presentation

Diagnosis

Staging

Three important types of lymphoma

d ki l h

8/12/2019 20 C GROUP

57/90

Non-Hodgkins lymphomas-definition

and epidemiology

1. Definition: malignant disease of the lymphoid

system, highly heterogeneous, both histologically

and clinically.2. Epidemiology:

- annual incidence: 5-10 new cases per 100 000persons,

- age distribution: middle-age patients and the elderly,

- males are affected more often than females (1.5:1.0).

8/12/2019 20 C GROUP

58/90

Non-Hodgkins lymphomas-Clinicalfeatures

1. Constitutional symptoms (fever, night sweats,

weight loss)

2. Lymphadenopathy

(cervical, supraclavicular, axillary, inguinal,

mediastinal, retroperitoneal, mesenteric, pelvic).

3. Mediastinal adenopathy (T cell lymphoma)

4. Extralymphatic involvement (gastrointestinal,

testicular masses, solitary bone lesions, CNS).

5. Unexplained anemia and thrombocytopenia (

bone marrow infiltration).

8/12/2019 20 C GROUP

59/90

Histologic classification of non-Hodgkins lymphomas

1. Rappaport - 1966

2. Lukes and Collins - 1974

3. Dorfman - 1974

4. Bennet et al., - 19745. Lennert - 1974

6. WHO - 1976

7. Working Formulation - 1982

8. REAL - 1994

9. WHO - 1999

8/12/2019 20 C GROUP

60/90

Histologic classification of non-Hodgkins lymphomas - Working

Formulation (WF)

1. Low grade

2. Intermediate grade

3. High grade

8/12/2019 20 C GROUP

61/90


Formulation (WF)Low grade

A. - Small lymphocytic cell.

B. - Follicular, predominantly small

cleaved cell

C. - Follicular mixed, small cleaved and

large cell.

8/12/2019 20 C GROUP

62/90


Formulation (WF)

Intermediate grade

D. - Follicular, predominantly largecell.

E. - Diffuse small cleaved cell.

F. - Diffuse mixed, small and large

cell.

G. - Diffuse large cell.

8/12/2019 20 C GROUP

63/90

8/12/2019 20 C GROUP

64/90

Non-Hodgkins lymphomas

/NHL/

- clinical features

8/12/2019 20 C GROUP

65/90

For the diagnosis of non-Hodgkins lymphomas the

histological examination of alymph node is necessary!

8/12/2019 20 C GROUP

66/90

Non-Hodgkins lymphomas -

histological classification

8/12/2019 20 C GROUP

67/90

REAL /R i d E A i

8/12/2019 20 C GROUP

68/90

REAL /Revised European-AmericanLymphoma/-WHO classification of

non-Hodgkins lymphomas

Precursor B cell lymphomas

- acute lymphoblastic

leukemia

- lymphoblastic lymphoma

REAL /Revised European-American

8/12/2019 20 C GROUP

69/90



Peripheral B cell lymphomas

- Chronic lymphocytic leukemia/lymphocyticlymphoma

- Chronic prolymphocytic leukemia

- Immunocytoma/lymphoplasmocytic lymphoma

- Mantle cell lumphoma- Marginal zone lymphoma /MALT-type/

- Hairy cell leukemia

8/12/2019 20 C GROUP

70/90

8/12/2019 20 C GROUP

71/90

REAL /R i d E A i

8/12/2019 20 C GROUP

72/90



Peripheral T cell lymphomas

T cell chronic lymphocytic leukemia T cell chronic prolymphocytic leukemia

Large granular lymphocyte leukemia

/LGL/ Mycosis fungoides /Szary syndrome

Peripheral T cell lymphomas,

unspecified

REAL /R i d E A i

8/12/2019 20 C GROUP

73/90



Peripheral T cell

lymphomas/continued/Angioimmunoblastic T cell lymphoma

Angiocentric lymphoma

Intestinal T cell lymphomaAdult T cell lymphoma/leukemia

Anaplastic large cell lymphoma

8/12/2019 20 C GROUP

74/90

Very aggressive non-Hodgkinslymphomas

B-, T-cell acute lymphoblastic

leukemia B-, T-cell lymphoblastic lymphomas

Burkitts lymphoma

Adult T cell lymphoma/leukemia

8/12/2019 20 C GROUP

75/90

High risk aggressive non-

Hodgkins lymphomas

1. Age abowe 60 years.

2. Disease stage III and IV.3. Extranodal involvement of more

than 1 site.

4. Serum LDH concentration >1 xnormal.

5. Performance status < 80%.

Treatment results of aggressive non-

8/12/2019 20 C GROUP

76/90

Treatment results of aggressive nonHodgkins lymphomas according to the

risk group

Risk group No of risk CR 5-yearsurvival

__________________factors

________%______________%______

Low 0,1 87 73

Low intermediate 2 67 50

High intermediate 3 55 43

High 4,5 44 26

Treatment results of patients under age

8/12/2019 20 C GROUP

77/90

Treatment results of patients under age60 with aggressive non-Hodgkins

lymphomas according to the risk group

Risk group No of risk CR 5-yearsurvival

factors________%_______________%_________

Low 0 92 87

Low intermediate 1 78 69

High intermediate 2 57 46High 3 46 32

Treatment results of aggressive

8/12/2019 20 C GROUP

78/90

advancednon-Hodgkins lymphomas using

different chemotherapy programs

1. First-generation: CHOP

- CR: 50-55%. Long-term survival: 35-50 %.

2. Second-generation: mBACOD, ProMACO-MOPP

- CR: 70-80%. Long-term survival: 50-60%.

3. Third-generation: MACOP-B

- CR: 84%. Long-term survival: 75%

- CR: 52-57%. Long-term survival: 47-56%

8/12/2019 20 C GROUP

79/90

Treatment results in patients over 60

8/12/2019 20 C GROUP

80/90

pyears with aggressive advanced non-

Hodgkins lymphomas

______Program_____________________5-year

survival %

CHOP 45

mBACOD 39

ProMACE-CytoBOM 41

MACOP-B 23

8/12/2019 20 C GROUP

81/90

Therapy of aggressive non-Hodgkins lymphomas

1. Chemotherapy: CHOP

complete remission: 60-

80%

permanent cure: 40-60%

refractory/recurrent disease 30-50%

8/12/2019 20 C GROUP

82/90

Treatment results of refractory/

8/12/2019 20 C GROUP

83/90

Treatment results of refractory/recurrent aggressive non-Hodgkins

lymphomas

1. Chemotherapy programs: DHAP, IMVP16,

MINE, ESHAP

2. Complete remission: 20 - 30%

3. 2-3-year survival: 10%

Hematopoietic stem cell transplantation

8/12/2019 20 C GROUP

84/90

Hematopoietic stem cell transplantationin aggressive non-Hodgkins lymphomas

- Indications

1. Refractory disease2. Relapse

3. High risk in CR

4. Lymphoblastic and Burkittslymphomas

Treatment results of aggressive

8/12/2019 20 C GROUP

85/90

Treatment results of aggressivenon-Hodgkins lymphomas with

high risk

1. Ablative therapy and hematopoietic stem cell

transplantation - 5 year survival (DFS):70-90%

2. Consolidation chemotherapy (DHAP)

- 5-year survival (DFS):25-50%

8/12/2019 20 C GROUP

86/90

Results of radiotherapy in pathologic

8/12/2019 20 C GROUP

87/90

Results of radiotherapy in pathologicstage I/IE aggressive non-Hodgkins

lymphomas1. Complete remission -

90%

2. 10-year survival - 54%

- patients under 60 years - 75%

3. Chemotherapy - if one of the

following symptoms are present:

- bulk of disease (lymph node > 7 cm),- high serum LDH concentration,

- localization in gastrointestinal track,testicles

Therapy of very aggressive non-

8/12/2019 20 C GROUP

88/90

py y ggHodgkins lymphomas (lymphoblastic,

Burkitts lymphomas)

1. Previous results: 2-3 year survival:15%

2. At present

- remission induction treatment as in ALL (High risk),

- consolidation:

a/ ablative therapy and hematopoietic stem celltransplantation (allogeneic or autologous)

- CR: 80-100%

- 3-5 year survival (DFS) 50-70%

b/ high - dose cytarabine

Age-adjasted prognostic index in

8/12/2019 20 C GROUP

89/90

Age adjasted prognostic index inaggressive non-Hodgkins

lymphomas

1. Disease stage (I, II vs. III, IV).

2. Serum LDH concentration (< 1x normal vs >1 xnormal).

3. Performance status (80% vs < 80%).

Age-adjasted International PrognosticIndex

8/12/2019 20 C GROUP

90/90

20 C GROUP

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