20 C GROUP

Lo 1

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

Lymphatic System

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

Approach to Patient
Lymphadenopathy refers 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

Patient Age
Not palpable in newborn Palpable nodes are the norm in the cervical, axillary, and inguinal regions throughout early childhood Children < 5 years old
44% palpable nodes at check up 64% palpable nodes at sick visits

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

Size of Lymph Nodes

Rules of thumb:
Axillary and cervical nodes < 1 cm Inguinal <1.5 cm Epitrochlear <0.5 cm

Nodes tend to be larger in young children Odds of malignancy is higher in larger nodes especially those > 2 cm

Location of Lymph Nodes

Node 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

Quality of Lymph Nodes

Painful
Usually infection, especially if erythema, warmth, or fluctance Malignancy can cause node tenderness because of hemorrhage into node and stretching of capsule

Hard
Found in cancers because of fibrosis

Nonmobile
Become fixed from invasive cancers of inflammation in tissue surrounding nodes (ie TB or sarcoidosis)

SOFT, COMPRESSIBLE = NORMAL

Localized vs. Generalized Lymphadenopathy

Localized
Most commonly cervical then inguinal Can be infection/inflammation in the area drained by that node or infection of node itself

Generalized
Systemic disease

Localized Lymphadenopathy

 Bacterial Viral

Differential Diagnosis - Infection

Localized: Staph aureus, GAS, cat-scratch, tularemia, diphtheria Generalized : Brucellosis, leptospirosis, typhoid 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

Differential Diagnosis - Other

Malignancy
leukemia, lymphoma, metastasis from solid tumor

Immunologic
SLE, serum sickness, Langerhans cell histiocytosis, RA, Drug Reaction, dermatomyositis, CGD

Endocrine
Addison disease, hypothyroidism

Other
Amyloidosis, Kawasaki disease, Sarcoidosis, Churg-Strauss syndrome, Kikuchi disease, Castleman disease

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

Specific Causes of Lymphadenopathy

Lymphadenitis
Lymphadenitis enlarged, 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/2nd generation cephalosporin or dicloxacillin Clindamycin or Augmentin if anaerobe suspected (oral)

Ultrasound to determine if abscess I&D indicated if abscess present

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

Diagnostic Testing to Consider

Blood
CBC, ESR, LDH Specific Serologic testing (EBV, CMV, Bartonella)

Tuberculin Skin Testing Chest X-ray Biopsy

LO 2

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

ALL

CLL
nave

Lymphomas

MM

B-lymphocytes Plasma cells T-lymphocytes

Lymphoid progenitor

AML
Hematopoietic stem cell Myeloid progenitor

Myeloproliferative disorders
Neutrophils Eosinophils Basophils Monocytes Platelets

Red cells

B-cell development
stem cell lymphoid progenitor
progenitor-B

CLL

mature naive B-cell

germinal center B-cell

memory B-cell

MM DLBCL, FL, HL

ALL
pre-B immature B-cell plasma cell

Classification
Biologically rational classification
Diseases that have distinct morphology immunophenotype genetic features clinical features

Clinically useful classification

Diseases that have distinct clinical features natural history prognosis treatment

Lymphoma classification
(2001 WHO)
B-cell neoplasms
precursor mature
NonHodgkin Lymphomas

T-cell & NK-cell neoplasms

precursor mature

Hodgkin lymphoma

A practical way to think of lymphoma

Category Survival of untreated patients Years Curability To treat or not to treat

NonHodgkin lymphoma

Indolent

Generally not curable

Generally defer Rx if asymptomatic

Aggressive

Months

Curable in some
Curable in some Curable in most

Treat

Very aggressive Hodgkin lymphoma All types

Weeks

Treat

Variable months to years

Treat

Mechanisms of lymphomagenesis
Genetic alterations Infection Antigen stimulation Immunosuppression

Epidemiology of lymphomas
5th most frequently diagnosed cancer in both sexes males > females incidence
NHL increasing Hodgkin lymphoma stable

Incidence of lymphomas in comparison with other cancers in Canada

age adjusted incidence/100,000/yr
70 60 50 40 30 20 10 0 1985 1990 1995 Year
NHL Hodgkin lymphoma lung colorectal breast

2000

Incidence/100,000/annum
100 20 40 60 80 0

Age distribution of new NHL cases in Canada

Age (years)

0-1 1-4 5-9 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+

incidence/100,000/annum
0 1 2 3 4 5 6

Age distribution of new Hodgkin lymphoma cases in Canada

Age (years)

0-1 1-4 5-9 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+

Risk factors for NHL

immunosuppression or immunodeficiency connective tissue disease family history of lymphoma infectious agents ionizing radiation

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

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

Diagnosis requires an adequate biopsy

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

Staging of lymphoma
Stage I Stage II Stage III Stage IV

A: absence of B symptoms B: fever, night sweats, weight loss

Three common lymphomas

Follicular lymphoma Diffuse large B-cell lymphoma Hodgkin lymphoma

Relative frequencies of different lymphomas

Non-Hodgkin Lymphomas

Diffuse large B-cell Hodgkin lymphoma NHL Follicular Other NHL

~85% of NHL are B-lineage

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

 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

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%

Hodgkin lymphoma

Thomas Hodgkin (1798-1866)

Classical Hodgkin Lymphoma

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

RS cell and variants

classic RS cell
(mixed cellularity)

lacunar cell
(nodular sclerosis)

popcorn cell
(lymphocyte predominance)

A possible model of pathogenesis

transforming event(s) EBV? loss of apoptosis

cytokines

germinal centre B cell

RS cell inflammatory response

Hodgkin lymphoma Histologic subtypes

Classical Hodgkin lymphoma
nodular sclerosis (most common subtype) mixed cellularity lymphocyte-rich lymphocyte depleted

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

Associated (etiological?) factors

EBV infection smaller family size higher socio-economic status caucasian > non-caucasian possible genetic predisposition other: HIV? occupation? herbicides?

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

Treatment and Prognosis

Stage Treatment Failurefree survival 70-80% Overall 5 year survival 80-90%

I,II

ABVD x 4 & radiation ABVD x 6

III,IV

60-70%

70-80%

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

Overview
Concepts, classification, biology Epidemiology Clinical presentation Diagnosis Staging Three important types of lymphoma

Non-Hodgkins lymphomasdefinition 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 100 000
persons, - age distribution: middle-age patients and the elderly, - males are affected more often than females (1.5:1.0).

Non-Hodgkins lymphomas-Clinical features

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).

Histologic classification of nonHodgkins lymphomas

1. Rappaport 2. Lukes and Collins 3. Dorfman 4. Bennet et al., 5. Lennert 6. WHO 7. Working Formulation 1982 8. REAL 9. WHO 1966 1974 1974 1974 1974 1976 1994 1999

Histologic classification of nonHodgkins lymphomas - Working Formulation (WF)

1. Low grade 2. Intermediate grade 3. High grade

Histologic classification of nonHodgkins lymphomas - Working Formulation (WF) Low grade

A. - Small lymphocytic cell. B. - Follicular, predominantly small cleaved cell C. - Follicular mixed, small cleaved and large cell.

Histologic classification of nonHodgkins lymphomas - Working Formulation (WF)

Intermediate grade D. - Follicular, predominantly large cell. E. - Diffuse small cleaved cell. F. - Diffuse mixed, small and large cell. G. - Diffuse large cell.

Histologic classification of nonHodgkins lymphomas - Working Formulation (WF)

High grade H. - Large cell immunoblastic. I. - Lymphoblastic. J. - Small noncleaved cell: Burkitts

Non-Hodgkins lymphomas /NHL/

- clinical features

For the diagnosis of nonHodgkins lymphomas the histological examination of a lymph node is necessary!

Non-Hodgkins lymphomas histological classification

REAL /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas

Precursor B- or T-cell lymphomas Peripheral B- or T-cell lymphomas

REAL /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas

Precursor B cell lymphomas - acute lymphoblastic leukemia - lymphoblastic lymphoma

REAL /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas

Peripheral B cell lymphomas
- Chronic lymphocytic leukemia/lymphocytic lymphoma - Chronic prolymphocytic leukemia - Immunocytoma/lymphoplasmocytic lymphoma - Mantle cell lumphoma - Marginal zone lymphoma /MALT-type/ - Hairy cell leukemia

REAL /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas

Peripheral B cell lymphomas /continued/ - Follicle center cell lymphoma - Plasma cell myeloma/plasmocytoma - Diffuse large B cell lymphoma - Burkitts lymphoma - Splenic marginal zone B cell lymphoma

REAL /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas

Precursor T cell lymphomas - Acute lymphoblastic leukemia -Lymphoblastic lymphoma

REAL /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas

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 /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas

Peripheral T cell lymphomas/continued/
Angioimmunoblastic T cell lymphoma Angiocentric lymphoma Intestinal T cell lymphoma Adult T cell lymphoma/leukemia Anaplastic large cell lymphoma

Very aggressive non-Hodgkins lymphomas

B-, T-cell acute lymphoblastic leukemia B-, T-cell lymphoblastic lymphomas Burkitts lymphoma Adult T cell lymphoma/leukemia

High risk aggressive nonHodgkins 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 x normal. 5. Performance status < 80%.

Treatment results of aggressive nonHodgkins lymphomas according to the risk group

Risk group No of risk CR survival __________________factors ________%______________%______ Low Low intermediate High intermediate 0,1 2 3 87 67 55 5-year

73 50 43

High

4,5

44

26

Treatment results of patients under age 60 with aggressive non-Hodgkins lymphomas according to the risk group
Risk group survival No of risk CR 5-year

factors________%_______________%_________ Low 0 92 Low intermediate 1 78

High intermediate 2 57

87 69 46

High

46

32

Treatment results of aggressive advanced non-Hodgkins lymphomas using different chemotherapy programs
1. First-generation: CHOP - CR: 50-55%. Long-term survival: 35-50 %. 2. Second-generation: mBACOD, ProMACOMOPP - 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%

Comparative evaluation of treatment results in aggressive advanced nonHodgkins lymphomas

3-year survival ___%________________%____ CHOP mBACOD ProMACE-CytoBOM MACOP-B 41 46 46 41 1 5 3 6 Mortality

Southwest Oncology Group

Treatment results in patients over 60 years with aggressive advanced nonHodgkins lymphomas ______Program_____________________5-year
survival % CHOP mBACOD ProMACE-CytoBOM MACOP-B 45 39 41 23

Therapy of aggressive nonHodgkins lymphomas

1. Chemotherapy: CHOP
complete remission: 80% permanent cure: refractory/recurrent disease 6040-60% 30-50%

Recommended treatment of aggressive non-Hodgkins lymphomas

1. Low risk patients -CHOP 2. High risk patients - CHOP - ablative therapy and hematopoietuc stem cell transplantation

Treatment results of refractory/ recurrent aggressive non-Hodgkins lymphomas

1. Chemotherapy programs: DHAP, IMVP16, MINE, ESHAP 2. Complete remission: 3. 2-3-year survival: 20 - 30% 10%

Hematopoietic stem cell transplantation in aggressive non-Hodgkins lymphomas - Indications

1. Refractory disease 2. Relapse 3. High risk in CR 4. Lymphoblastic and Burkitts lymphomas

Treatment results of aggressive non-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%

Radiotherapy of aggressive nonHodgkins lymphomas

1. Exclusively in pathologic stage I and IE. 2. No indications for combined therapy.

Results of radiotherapy in pathologic stage I/IE aggressive non-Hodgkins lymphomas

1. 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 nonHodgkins lymphomas (lymphoblastic, Burkitts lymphomas)

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

- remission induction treatment as in ALL (High risk), - consolidation: a/ ablative therapy and hematopoietic stem cell transplantation (allogeneic or autologous) - CR: 80100% - 3-5 year survival (DFS) 5070% b/ high - dose cytarabine

Age-adjasted prognostic index in aggressive non-Hodgkins lymphomas

1. Disease stage (I, II vs. III, IV). 2. Serum LDH concentration (< 1x normal vs >1 x normal). 3. Performance status (80% vs < 80%).

Index

Age-adjasted International Prognostic