경희대학교 의과대학·의학전문대학원

LYMPHOID MALIGNANCIES

• Definition

– Malignant counterparts of normal lymphoid cells

at distinct stages of differentiation

– Neoplastic transformations of cells that reside predominantly in lymphoid tissues

• Classification

– WHO classification

– Revised European-American Lymphoma Classification (REAL)

– Working formulation

– Lukes-Collins, Kiel and Lennert classification – Rappaport classification

Normal B cell differentiation & relationship to B cell lymphoma

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T Cell differentiation &

T Cell Malignancies

Etiology & Epidemiology

– Burkitt’s lymphoma(central Africa), Post-organ transplant lymphoma, Primary CNS diffuse large B cell lymphoma, Hodgkin’s disease, Extranodal nasal NK/T cell

lymphoma(Southern Asia, Latin America)

• HTLV-I

– Adult T cell leukemia/lymphoma(Japan, Caribbean)

• HIV

– Diffuse large B cell lymphoma, Burkitt’s lymphoma

• Hepatitis C virus: Lymphoplasmacytic lymphoma

• H. pylori: Gastric MALT lymphoma

• HHV 8

Etiology & Epidemiology

– Klinefelter's syndrome, Chédiak-Higashi syndrome,

Ataxia telangiectasia syndrome, Wiscott-Aldrich syndrome, Common variable immunodeficiency disease

• Acquired immunodeficiency disease

– Iatrogenic immunosuppression, HIV-1 infection,

Acquired hypogammaglobulinemia • Autoimmune disease

– Sjögren's syndrome, Celiac sprue, Rheumatoid arthritis,

Systemic lupus erythematosus • Chemical or drug exposures

– Phenytoin, Dioxin, phenoxyherbicides, Radiation,

Prior chemotherapy and radiation therapy

Clinical Presentation of NHL

• Painless peripheral lymphadenopathy

– firm, larger than 1cm, persist longer than 4weeks

• Waldeyer’s ring, epitrochlear, mesenteric node

– more common than Hodgkin’s disease

• Weight loss, fever, night sweat: 20%

• Thoracic symptom: 20%, superior vena cava syndrome • Abdominal symptom

– abdominal mass, splenomegaly, visceral obstruction sign

• Extranodal symptom

– Common in aggressive type

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Primary Extranodal NHL

• Lung

– Bronchovascular-lymphangitic, nodular, alveolar

• Liver

– Rare

– Infiltration or nodular

• Bone

– 5%

– Diffuse large B cell – Femur, pelvis, vertebrae

• Gastrointestinal

– 5%

– Diffuse aggressive histologies, MALT

• Skin • CNS

• Rare site: orbit, heart, breast, salivary gland, thyroid, adrenal

Ann Arbor staging system

• Specifically developed for Hodgkin’s disease

• Less useful in NHL

Ann Arbor staging system (I)

• Stage I

– single lymph node region

– single lymphoid structure(e.g., spleen, thymus, Waldeyers’s ring)

• Stage II

– two or more lymph node region on the same side of diaphragm – Mediastium is a single site

• Stage III

– both side of diaphragm

– III1: subdiaphragm, limited to spleen, splenic hilar nodes, celiac

nodes, portal nodes

– III2: subdiaphragm, paraaortic, iliac, mesenteric nodes plus

structures in III₁ • Stage IV

– Extranodal site(s) beyond that designated as “E” – More than one extranodal deposit at any location – Any involvement of liver or bone marrow

Ann Arbor staging system (II)

• A

– No symptom

• B

– Weight loss >10% during 6 months – Fever, >38° C

– Night sweat

• E

– Localized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow

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Stage I

Stage II

Stage III

Stage IV

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International Prognostic Index (IPI)

• Five clinical risk factors

– Age  60 years

– Serum lactate dehydrogenase levels elevated

– Performance status  2 (ECOG) or  70 (Karnofsky)

– Ann Arbor stage III or IV

– > 1 site of extranodal involvement

• Group for DLBL 5yr survival – 0,1 factor = low risk: 35% of cases; 73% – 2 factors = low-intermediate risk: 27% of cases; 51% – 3 factors = high-intermediate risk: 22% of cases; 43% – 4,5 factors = high risk: 16% of cases; 26%

• Group for DLBL with R-CHOP

– 0 factor = very good: 10% of cases; 94% – 1,2 factors = good: 45% of cases; 79% – 3,4,5 factors = poor: 45% of cases; 55%

Prediction of Survival in Diffuse Large-B-Cell Lymphoma Based on

the Expression of Six Genes

Izidore S. Lossos, Stanford University

N Engl J Med 2004;350:1828

10 The Use of Moleular Profiling

to Predict Survival after Chemotherapy for Diffuse

Large B Cell Lymphoma

N Engl J Med 2002;346:1937

“Lymphochip”(12,196 clones)

-genes for lymphoid cells

-Genes for cancer/immune function

Staging evaluation for NHL

• Physical examination

• Documentation of B symptoms

• Laboratory evaluation

– Complete blood counts, liver function tests, uric acid, calcium, serum

protein electrophoresis, seum ₂-microglobulin • Chest radiograph

• CT scan of abdomen, pelvis, and usually chest

• Bone marrow biopsy

• Lumbar puncture

– lymphoblastic, Burkitt’s, and diffuse large B cell lymphoma with

positive marrow biopsy, testicular and paranasal sinus involvement • Gastroscopy

– Waldeyer’s ring involvement

Clinical characteristics of common types of NHL

B cell chronic lymphocytic leukemia/small lymphocytic lymphoma

65 Rare 53 9 vs 91 33 72 3 51 Mantle cell lymphoma 63 Rare 74 20 vs 80 28 64 9 27 Extranodal marginal zone B

cell lymphoma of MALT type 60 Rare 48 67 vs 33 19 14 50 74 Follicular lymphoma 59 Rare 42 33 vs 67 28 42 4 72 Diffuse large B cell lymphoma 64

~25% of childhood NHL 55 54 vs 46 33 16 18 46 Burkitt's lymphoma 31 ~30% of childhood NHL 89 62 vs 38 22 33 11 45 Precursor T cell lymphoblastic lymphoma 28 ~40% of childhood NHL 64 11 vs 89 21 50 4 26 Anaplastic large T/null cell

lymphoma 34 Common 69 51 vs 49 53 13 9 77 Peripheral T cell non-

Hodgkin's lymphoma 61 ~5% of childhood NHL 55 20 vs 80 50 36 15 25

Principles of treatment

• Systemic chemotherapy

– Single agent or combination

• CHOP:

– cyclophosphamide, adriamycin, vincristine, prednisone • Interferon alpha

– Low grade NHL, cutaneous T cell lymphoma, Hairy cell

leukemia

• Radiation

– Bulky site

• New agent

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B cell lymphoid malignancy

• Precursor cell B cell neoplasms

– Precursor B cell lymphoblastic leukemia/lymphoma

• Mature (Peripheral) B cell neoplasms

– B cell chronic lymphoid leukemia/Small lymphocytic lymphoma

– Extranodal marginal zone B cell lymphoma of MALT type

– Follicular lymphoma – Mantle cell lymphoma

– Diffuse Large B cell lymphoma – Burkitt’s lymphoma/Leukemia

Indolent

Aggressive

B cell chronic lymphoid leukemia/

Small lymphocytic lymphoma

• CLL, 7% of NHL

• Asymptomatic lymphadenopathy

• Autoimmune hemolytic anemia &

thrombocytopenia, hypogammaglobulinemia,

red cell aplasia

• Tx

– Intermediate risk(Rei stage I-II)

• watch & waiting , median survival; > 7yrs

– High risk (Rei stage III-IV)

• Single agent chlorambucil or fludarabine

RAI Staging System

Mantle Cell Lymphoma

• 6% of NHL

• t(11;14) : bcl-1, IgH • Clinical presentation

– Median age 63

– Male are affected 4 time

– Lymphomatosis polyposis in large intestine,

Waldeyer’s ring involvement • Treatment

– Aggressive combination chemothx with stem cell

transplatation in younger patients

– HyperC-VAD(cyclophosphamide, vincristine, doxorubicin,

dexamethasone, cytarabine, methotrexate) in combination with retuximab

14

Extranodal marginal zone B cell lymphoma of

MALT type

• 8% of NHL, Localized (70%)

• Stomach, orbit, intestine, lung, thyroid, salivary

gland, skin, soft tissues, bladder, kidney, CNS

– Gastric presentation, H. pylori (95%)

• Relation to autoimmune process

– SjÖgren’s syndrome(salivary gland),

Hashimoto’s thyroiditis(thyroid)

• Good prognosis, 75% 5yr survival

• Tx

– Local therapy: surgery, radiation – Eradication of H. pylori

– Single or combination chemotherapy(DLBL component)

Follicular lymphoma

• 22% of NHL

• t(14;18)

, abnormal expression of

bcl-2

• Painless

multiple lymphadenopathy

– Including unusual site such as epitrochlear nodes

• Tx

– Spontaneous regression in 25%

– Asymptomatic: no treatment, watchful waiting

– Single agent or combination chemotherapy

– 50-75% CR, most relapse

– Fludarabine, interferon alpha, rituximab

– Autologous & allogeneic hematopoietic stem cell transplantation

Diffuse large B cell lymphoma

• Most common, 1/3 of NHL

• Primary mediastinal DLBL

– Young female

• Extranodal: GI tract, bone marrow

– Primary CNS lymphoma

• Tx

– Combination chemotherapy

• CHOP, R-CHOP(CD20+)

– Stage I, II: 70-90% cure – Stage III, IV

• CR: 60-70%, Cure; 50-70% of CR patients

– Autologous bone marrow transplantation

• Chemosensitive relapsed patients

Rituximab (anti-CD20 MoAB) in NHL

• Human-mouse monoclonal antibody against the

CD20

antigen present on B cells

• ADCC, complement-mediated toxicity and

induction of apoptosis

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CHOP+Rituximab vs CHOP alone in NHL

Event-free survival Overall survival NEJM 346:235, 2002

Burkitt’s lymphoma/Leukemia

• 1% of NHL, 30% of childhood NHL

• t(8;14): c-myc

• 3 type:

– Endemic(children in Africa), sporadic(western

countries), immunodeficiency-associated(HIV infection)

• Lymphadenopathy, intraabdominal mass

• CNS metastasis

• Most rapidly progressive human tumor

• Tx

– Delay in initiating treatment can be fatal

– Intensive combination chemotherapy, CNS prophylaxis – Cure: 70%

T cell lymphoid malignancy

• Precursor T cell malignancies

– Precursor T cell

lymphoblastic leukemia

/lymphoma

• Mature (Peripheral) T cell disorders

– Mycosis Fungoides

– Anaplastic large T/Null cell lymphoma

– Adult T cell lymphoma/leukemia

– Peripheral T cell lymphoma

• Angioimmunoblastic T cell lymphoma

• Extranodal T/NK cell lymphoma of nasal type • Enteropathy-type intestinal T cell lymphoma • Hepatosplenic gd T cell lymphoma

• Subcutaneous panniculitis-like T cell lymphoma Indolent

Aggressive

Precursor T cell lymphoblastic leukemia/lymphoma

• Children, young adult, male

• Mediastinal mass, hepatosplenomegaly

• CNS involvement

• Tx

– Intensive remission induction & consolidation regimen – Leukemia-like regimen

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Mycosis fungoides

• = cutaneous T cell lymphoma

• Mid-fifties, male, blacks

• Indolent

• Eczematous, dermatitic skin lesion

– Sezary’s syndrome: erythroderma & circulating tumor cells

• Tx

– Radiotherapy, topical glucocorticoids, topical nitrogen mustard, phototherapy, psoralen with ultraviolet A(PUVA)

• Early stage: cure

• Advanced stage: palliative

Adult T cell lymphoma/leukemia

• Southwestern Japan, Caribbean, blacks in

southeastern US

• HTLV-I

retrovirus

– Transplacental transmission, sexual transmission

• Pleomorphic abnormal

CD4

+

cells

• Antibodies to HTLV-I

• Lymphadenopathy, hepatosplenomegaly, skin

infiltration(papule, plaques),

hypercalcemia, lytic

bone lesion

Anaplastic large T/Null cell lymphoma

• CD30 (Ki-1)

• Anaplastic lymphoma kinase(

ALK

) protein

• t(2;5)

• Young male(median age, 33)

• Tx

– Aggressive lymphoma like regimen – 5-year survival, >75%

– ALK inhibitor crizotinib

Peripheral T cell lymphoma

• Characteristics

– Mature T cell immunophenotype

• CD4, CD8, NK-cell

– Adverse prognostic factor

• High IPI score, 5-year survival; 25%

• Angioimmunoblastic T cell lymphoma

– Generalized lymphadenopathy, fever, weight loss, skin rash, polyclonal hypergammaglobulinemia

• Extranodal T/NK cell lymphoma of nasal type

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Diseases confused with Lymphoma

• Autoimmune disease

– Sjögren’s syndrome, SLE, rheumatoid arthritis

• Infectious process

– EBV cytomegalovius, cat scratch disease

• Castleman’s disease

– IL-6, HHV-8

• Rosai-Dorfman disease

– Skin, upper airway, GI tract, CNS

• Lymphomatoid papulosis

– CD30+ cutaneous lymphoproliferative disorder

Hodgkin’s Disease

• Classical HD

Classical Hodgkin’s Disease

–

• Age-specific incidence, bimodal

– 15-30 yrs, after 50 yrs

• Nontender lymphadenopathy

– Neck, supraclavicular, axilla, mediastinal

• B symptom

– Fever(Pel-Epstein fever), night sweat, weight loss

• Cutaneous symptom

– Itching, erythema nodosum, ichthyosiform atrophy

• Paraneoplastic CNS symptom

– Cerebellar degeneration

• Immune hemolytic anemia, thrombocytopenia, hypercalcemia, pain in LN on alcohol ingestion

Diagnosis

• Pathologic classification

• DDx

– Inflammatory process, Mononucleosis, NHL, diphenylhydantoin-induced lymphadenopathy, nonlymphomatous malignancies

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Staging Procedures

• Essential for the selection of optimal therapy

• Clinical stage, Pathologic stage

• Staging procedure

– Same as staging of NHL – PET/Gallium scan

– Lymphangiogram, bipedal

• If radiologic expertise is available

– Staging laparotomy

• Rarely

Treatment

• > 90% cure rate

– No B symptom: >75%, long-term disease-free survival – B symptom: 50-70%, long-term disease-free survival

• Increasingly chemotherapy initially

• Radiation

Radiation Field

Treatment

• Early stages:

– Extended field radiation

– Brief course chemotherapy followed by RT

• Advanced stages:

– Complete course of chemotherapy

• ABVD:adriamycin, bleomycin, vinblstine,

dacarbazine

• MOPP:mechlorethamine, vincristine, procarbazine,

prednisone

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Treatment

• Relapse

– Still be cured

– Initial RT

• Excellent outcome with chemotherapy

– Initial chemotherapy

• Long initial remission: standard dose chemotherapy • Autologous bone marrow transplantation

Long-term complication of treatment

• Acute leukemia, in 10 years

• Carcinoma, >10 years

– Screening mammograms after 5-10 years – Discourage smoking

• Coronary artery disease

• Hypothyroidism

Nodular lymphocyte-predominant HD

• Distinct from classic HD

• Predominance of small lymphocytes

– rare Sternberg-Reed cells

• <5% of HD

• Relationship to NHL

– Clonal proliferation of B cells, J chain, CD45, epithelial membrane

antigen(ema),

– CD30(-), CD15(-): negative for marker of HD

• Chronic, relapsing, transform to DLBL

• Treatment

– Close followup

– RT for localized disease,

– Chemothx with HD regimen in disseminated disease