LYMPHOMAProfessor Dr. Rafi Ahmed Ghori

Department of MedicineLUMHS Jamshoro

OVERVIEW

• Concepts, classification, lymphogenesis• Epidemiology• Clinical presentation• Diagnosis• Staging• Three important types of lymphoma

EPIDEMIOLOGY AND AETIOLOGY OF HODGKIN LYMPHOMA Incidence

• Approximately 4 new cases/100 000 population / year

Sex Ratio

• Slight male excess (1.5:1)

Age

•Median age 31 years; first peak at 20-35 years and second at 50-70 years Aetiology

• Unknown. More common in patients from well-educated background and small families. Three time more likely with a past history of infectious mononucleosis but no casual link to Epstein-Barr virus infection proven

EPIDEMIOLOGY OF LYMPHOMAS

• 5th most frequently diagnosed cancer overall for both males and females

• Males > females• Incidence

• NHL increasing over time (Stage III or IV at Diagnosis)

• Hodgkin lymphoma stable

RISK FACTORS FOR NHL

• Immunosuppression or immunodeficiency• Connective tissue disease• Family history of lymphoma• Infectious agents• Ionizing radiation

WHO PATHOLOGICAL CLASSIFICATION AND INCIDENCE OF HODGKIN LYMPHOMA (HL)Type Histology Incidence

Nodular Lymphocyte predominent HLClassical HL Nodular sclerosing 70%

Mixed Cellularity 20%

Lymphocyte-rich 5%

Lymphocyte-depleted Rare

CLINICAL STAGES OF HODGKIN LYMPHOMA (ANN ARBOR CLASSIFICATION)Stage Definition

I Involvement of a single lymph node region (I) or extralymphatic site (IAE)

II Involvement of two or more lymph node regions (II) or an extralymphatic site and lymph node regions or the same side of (above or below) the diaphragm (IIE)

III Involvement of lymph node regions on both sides of the diaphragm with (IIIE) or without (III) localised extralymphatic involvement or involvement of the spleen (IIIS) or both (IIISE)

IV Diffuse involvement of one or more extralymphatic tissues, e.g. liver or bone marrow

A No systemic symptoms

B Weight loss, drenching sweats

The lymphatic structure are defined as the lymph nodes, spleen, thymus, Waldeyer’s ring, appendix and Payer’s patches

Stage I Stage II Stage III Stage IV

STAGING OF LYMPHOMA

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

THE CHALLENGE OF LYMPHOMA CLASSIFICATION

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

LYMPHOMA CLASSIFICATION(BASED ON 2001 WHO)

• B-cell neoplasms 70%• Precursor B-cell neoplasms• Mature B-cell neoplasms • B-cell proliferations of uncertain malignant

potential • T-cell & NK-cell neoplasms 30%

• Precursor T-cell neoplasms • Mature T-cell and NK-cell neoplasms • T-cell proliferation of uncertain malignant potential

LYMPHOMA CLASSIFICATION(BASED ON 2001 WHO)

• Hodgkin lymphoma 95%• Classical Hodgkin lymphomas

• NS 70% (nodular scl.)• MC 20% (mixed cell.)• LR 5% (lympho.rich)• LD RARE (lympho.dep.)

• Nodular lymphocyte predominant Hodgkin lymphoma 5%

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 Curable in some

Treat

Hodgkin lymphoma

All types Variable – months to years

Curable in most

Treat

MECHANISMS OF LYMPHOMAGENESIS

• Genetic alterations• Infection• Antigen stimulation• Immunosuppression

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) by bulky disease• 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

THREE TYPES OF LYMPHOMA WORTH KNOWING ABOUT

• Follicular lymphoma• Diffuse large B-cell lymphoma• Hodgkin lymphoma

NON-HODGKIN LYMPHOMAINCIDENCE

Diffuse large B-cell lymphoma

Follicularlymphoma

Other NHL

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• Although considered “indolent”, 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)

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

popcorn celllacunar cellclassic RS cell

(mixed cellularity) (nodular sclerosis) (lymphocytepredominance)

The Scream, 1893 Edvard Munch

Reed-Sternberg cell

A POSSIBLE MODEL OF PATHOGENESIS

germinalcentreB cell

transformingevent(s)

loss of apoptosis

RS cellinflammatory

response

EBV?

cytokines

HODGKIN LYMPHOMAHISTOLOGIC 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 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%

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

Case

• 25 year old woman• Persistent dry cough• Fever, NS, weight loss x 3 months• Left cervical lymphadenopathy (2 cm)• Left supraclavicular node (2 cm)• No splenomegaly

W.P. at presentation

CASE: DIFFERENTIAL DIAGNOSIS

• Lymphoma• Hodgkin• Non-Hodgkin

Llung cancer• Other neoplasms: thyroid, germ cell• Non-neoplastic causes less likely

• Sarcoid, TB, ...

WHAT NEXT?

• Needle aspirate of LN: a few necrotic cells• Needle biopsy of LN: admixture of B- and T-

lymphocytes. A few atypical cells.

CASE: LYMPH NODE BIOPSY

CASE: LYMPH NODE BIOPSY

CASE: LYMPH NODE BIOPSY

CASE: STAGING INVESTIGATIONS

• CT chest/abdo/pelvis• Bone marrow• Gallium scan

• Blood work: normal

STAGING INVESTIGATIONS

• Bone marrow normal• CT scan: L supraclavicular adenopathy; large

mediastinal mass; R hilum; no disease below diaphragm

• Gallium avid

What is her diagnosis and stage?

• Nodular sclerosis HD• Stage IIB• With bulky mediastinal mass

CASE: TREATMENT

• Discussion with patient • Treatment with ABVD x 6 cycles

• Constitutional symptoms gone after 1st cycle• Bulky mediastinal mass is a special situation

that merits additional radiation after chemotherapy

CASE: POST-ABVD

• Response to chemo, but residual mediastinal/hilar mass

• Repeat gallium scan negative, suggesting that residual mass may just be fibrotic tissue

• Proceed with radiotherapy as originally planned

CASE: POST-RADIOTHERAPY

• Serial CT scans did not show progression• patient remains in remission

Therapeutic guideline for Hodgkin Lymphoma

Indications for radiotherapy

• Stage I disease • Stage IIA disease with three or fewer areas involved • After chemotherapy to sites where there was originally bulk disease• To lesion causing serious pressure problems Indication for chemotherapy • All patients with B symptoms • Stage II disease with more than three areas involved • Stage III and IV disease

THE ChIVPP REGIMEN FOR HODGKIN LYMPHOMA Drug Dose

Chlorambucil 6 mg/m2 (up to 10 mg total) days 1-14 orally

Vinblastine 6 mg/m2 (up to 10mg total) days 1 and 8 i.v.

Procarbazine 100 mg/m2 days 1-14 orally

Prednisolone 40 mg/m2 days 1-14 orally