Lymphoma

Uglyar T.Y.

Adapted from Joe Waller, MD 2013 Drs. Wang and Young and By David Lee MD, FRCPC

Conceptualizing lymphoma

• neoplasms of lymphoid origin, typically causing lymphadenopathy

• leukemia vs lymphoma

• lymphomas as clonal expansions of cells at certain developmental stages

ALLALL MM MM CLLCLL LymphomasLymphomas

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Myeloproliferative disordersMyeloproliferative disordersAMLAML

Lymphoidprogenitor T-lymphocytes

Plasmacells

B-lymphocytes

nanaïïveve

B-cell development

stemcell

lymphoidprogenitor

progenitor-B

pre-B

immatureB-cell

memoryB-cell

plasma cellplasma cell

DLBCL,FL, HL

ALL

CLL

MM

germinalgerminalcentercenterB-cellB-cell

maturenaiveB-cell

Risk Factors

• • Mostly unknown, although both genetic and infectious • processes are suspected • • Living in Western countries, being of higher social class, • more educated. • • Genetic pre-disposition, clusters noted in siblings with • similar HLA genotypes. • – Mack et al: 99x risk in monozygotic vs dizygotic twins • • EBV (MC subtype) • • HIV+ pts have different patterns of spread, more • systemic sx, poor tolerance to chemo • • Children do better than adults

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

Staging

• Stage I: a single LN region (on either side of the diaphragm) • Stage II: two or more LN regions of the same side of the diaphragm • Stage III: both sides of the diaphragm • Stage III-1: upper abd: splenic, celiac, portal LN only, <4 splenic • nodules • Stage III-2: lower abd: Paraaortic, mesenteric, pelvic • Stage III(S)+ Minimal: <4 splenic nodules • Stage III(S)+ Extensive: 5 or more splenic nodules • Stage IV: diffuse involvement of extralymphatic tissues, with or • without simultaneous LN involvement. • E subtypes: extranodal disease • S subtype: spleen involvement • “A” and “B”: absent or present “B” symptoms. • X subtype: bulky disease of > 1/3 thoracic diameter or > 10 cm

Lymph Node Regions

International Prognostic Score

• In patients with Stage III-IV disease, each of the following factors

• reduces survival by 7%: • • Age >45 • Male sex • Stage IV disease • Albumin < 4g/dL • Hb<10.5 • WBC>15,000 • Lymphoctes count <8% or ALC<600 • Used for individualized treatment management

Mediastinal LAN

Other Manifestations

• SVC syndrome • • Spinal Cord • Compression • • Bone involvement • • Hepatic involvement • • Renal involvement • • Infections • • Immunologic • Abnormalities • • Rarely: • – Waldeyer's Ring, • Peyer's patches, CNS, • skin

Epidemiology of lymphomas

• 5th most frequently diagnosed cancer in both sexes• males > females• incidence

– NHL increasing– Hodgkin lymphoma stable– Epidemiology – • ~8000 new cases of Hodgkin’s Disease in – the U.S. in 2008, causing ~1500 deaths – • M:F ratio is 1.3:1; more pronounced in – children – • Bimodal age distribution: 2-3rd decade, – and 6-7th decade.

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

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

Work Up • 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 • Excisional biopsy • – Most commonly of cervical nodes • – Presence of RS cells is necessary but not sufficient • • Laparotomy • – 1960’s • – Determine extent of disease below diaphragm • – Largely eliminated by more effective chemo regimens • – EORTC study did not show survival benefit for • pathologic staging over clinical staging (Carde et al. • JCO 1993)

Adverse Prognostic Factors

• • B symptoms esp. weight loss and night sweats. • • Pruritis • • Higher stage, esp.with bone marrow or organ • involvement. • • Bulky disease with large tumor burden. This includes • large mediastinal lymphadenopathy, which is >1/3 of • maximal thoracic diameter (T5-T6). • • Worrisome labs include ESR>70 and high serum copper. • • Older age • • LD type • • male

CHOP Chemotherapy

• Cyclophosphamide (Cytoxan)

• Hydroxydaunorubicin (Adriamycin)

• Oncovin (vincristine)

• Prednisone

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%

Treatment Options:Aggressive Lymphomas

Aggressive

• Diffuse large cell lymphoma, large cell anaplastic lymphoma, peripheral T cell lymphoma.

Very Aggressive

• Burkitt’s lymphoma and lymphoblastic lymphoma.

Treatment Options for Advanced Stage Aggressive

Lymphomas• Systemic chemotherapy

– CHOP (± Rituxan for over 70 age group)

• ± Intrathecal chemotherapy – AIDS patients and CNS involvement

• ± Radiotherapy– Spinal cord compression, bulky disease

Burkitt’s Lymphoma

• African variety: jaw tumor, strongly linked to Epstein-Barr Virus infection.

• In U.S., about 50% EBV infection.• May present as abdominal mass.• Most rapidly growing human tumor.• Typical chromosome abnormality: c-

myc oncogene linked to one of the immunoglobulin genes.

Burkitt’s Lymphoma

• Treated with multidrug regimen similar to pediatric leukemia/lymphoma regimens.

• Treated with multidrug regimen similar to pediatric leukemia/lymphoma regimens.

MALT Lymphoma

• Mucosa-Associated Lymphoid Tissue

• Chronic infection of the stomach by Helicobacter pylori.

• Localized to the stomach, indolent course.

• Can be cured in many cases by antibiotics against H. pylori.

Treatment Options for Early Stage Aggressive

Lymphomas• Often in Stage I or II

– potentially curable– disseminates through bloodstream early– must use systemic chemotherapy

• CHOP x 6 cycles• CHOP x 3 cycles followed by radiotherapy

Hodgkin lymphoma

Thomas Hodgkin(1798-1866)

Classical Hodgkin Lymphoma

Hodgkin’s Disease

Hodgkin’s Disease

• One-seventh as common a snon-Hodgkin’s lymphoma.

• Highly treatable and curable, even when disseminated.

• Presence of Reed-Sternberg cell is necessary to make diagnosis.

Subtypes of Hodgkin’s Disease

• Lymphocyte predominant• Nodular sclerosis• Mixed cellularity• Lymphocyte depleted

• Unlike non-Hodgkin’s lymphoma, in Hodgkin’s Disease

• the histologic subtype does not determine how the• disease is treated.

CHL Pathologic Variants • Nodular Sclerosis (NS) (70%) • • Large RS cells • • Cervical nodes • • Anterior mediastinum • • Adolescent patients • • Lymphocyte Rich (5%) • • Rare RS cells. Many lymphocytes. Age <35 y/o with localized disease. Good • prognosis. M>F (4:1). • • Lymphocyte Depleted (rare) • • Many RS cells, few lymphocytes • • Age > 50. • • Diffuse abdominal disease, marrow, and liver involvement. Most patients p/w • advanced disease • • Poorest prognosis • • Mixed cellularity (25%) • • Moderate RS cells, mixed infiltrate of neutrophils, eosinophils, and plasma cells. • • Age 30-50, EBV associated, developing countries • • Retro-peritoneal presentation • • Intermediate prognosis

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

Histology

• Reed-Stenberg Cell: “owl eyes” • – Large, with abundant cytoplasm, 2-3 nuclei with • prominent nucleolus “owl eyes” appearance • – NOT pathognomonic, can be reactive, infectious or • malignant • – RS cells stain for CD30/15+, but are CD45/20- • *Contrast w/ NLPHL which are CD30/15-, • CD45/20+

Reed-Sternberg cell

RS cell and variants

popcorn celllacunar cellclassic RS cell

(mixed cellularity) (nodular sclerosis) (lymphocytepredominance)

Molecular Biology

• The Reed Sternberg (RS) cell likely arises from

• either lymphocyte or antigen-presenting cells of

• the monocyte-macrophage line. Regarding • lymphocyte origin, 60% of RS cells have T or

B • cell specific antigens, and B cells are the

usual • target for EBV

Molecular Biology

• RS-like cells are found in several infectious, inflammatory, and • neoplastic conditions including infectious mononucleosis, reactive • lymphoid hyperplasia, and immunoblastic lymphoma. • • Thus, diagnosing Hodgkin’s depends on finding RS cells in the • appropriate clinical setting. The lymphocytes are predominantly CD-• 4 positive T-cells. • • The BCL2 Oncogene is found in 1/3 of Hodgkins patients. • • The p53 suppressor gene is found in almost all Hodgkin’s patients • except those with lymphocyte predominant disease. • • The common t(14:18) translocation of B cell lymphoma are RARE in • RS cells.

A possible model of pathogenesis

germinalcentreB cell

transformingevent(s)

loss of apoptosis

RS cellinflammatory

response

EBV?

cytokines

Etiology ofHodgkin’s Disease

• Reed-Sternberg cells are the malignant cells.• Minor population in the malignant tissues

– many normal lymphocytes, eosinophils, other cells

• Cell of origin is unknown: T, B, both, neither.• Some R-S cells contain EBV genomes.

Epidemiology

• less frequent than non-Hodgkin lymphoma

• overall M>F

• peak incidence in 3rd decade

Clinical Features

• T cell mediated immune deficiency, even in early stage disease. Prone to infections:– Herpes zoster (“shingles”) in one fourth of

patients– Fungal or mycobacterial infections

• Immune defect may persist even after lymphoma is cured.

Clinical manifestations:

• lymphadenopathy

• contiguous spread

• extranodal sites relatively uncommon except in advanced disease

• “B” symptoms

Clinical Features

• Predictable contiguous spread of disease:– cervical nodes to mediastinum or axilla– mediastinum to periaortic nodes or spleen,

etc.

• Basis for staging and treatment decisions.

Diagnosis

• Excisional biopsy of a lymph node.

Fine needle aspirate is not sufficient to make the diagnosis of Hodgkin’s disease.

Staging of Hodgkin’s Disease

Same as for non-Hodgkin’s:

• H + P, labs, CT scans, bone marrow biopsy

PLUS:

• Gallium scan

• Lymphangiogram or staging laparotomy ONLY if results would affect treatment decisions

Treatment by Stage

Stage Therapy % Cure

IA XRT 95

IIA XRT 85

IB, IIB XRT (Total Nodal) 70

IIIA XRT 70

IIIB, IV Combination Chemo 50

Chemotherapy Regimens

• MOPP

– Mechlorethamine, Oncovin, Procarbazine, Prednisone

• ABVD

– Adriamycin, Bleomycin, Vinblastine, Dacarbazine

• BEACOPP

Treatment Options

• Often, patients who relapse after radiotherapy can be cured by salvage chemotherapy.

• Combined chemotherapy and radiotherapy is given for bulky mediastinal masses.

• Chemotherapy now being tested for earlier stages of the disease.

Late Complications ofHodgkin’s Disease

• High incidence of second malignancies– leukemia first 10 years, solid tumors over

time.

• Leukemia in patients receiving alkylating agents or combined chemo/XRT.

• Lung cancer and breast cancer in patients receiving XRT to chest. Lung cancer especially high in smokers.

Late Complications ofHodgkin’s Disease

• Hypothyroidism after irradiation of the neck.

• Constrictive pericarditis after radiotherapy to the mediastinum.

• Infertility after use of alkylating agents.

• Heart failure after Adriamycin treatment.

Treatment • Overall survival exceeds 80%, therefore therapy is evolving to • minimize toxicity while maintaining excellent disease control • The German Hodgkin's Study Group (GHSG) has performed a • number of trials with various iterations of treatment regimens • Major chemotherapy options: • ABVD • Doxorubicin, bleomycin, vinblastine, dacarbazine • Most commonly prescribed regimen • Stanford V • Doxorubicin, vinblastine, mechlorethamine, etoposide,

vincristine, • bleomycin, and prednisone • Overall lower doses bleo/doxo than ABVD • BEACOPP • Bleomycin, etoposide, doxorubicine, cyclophosphamide,

vincristine, • procarbazine, and prednisone • Dose dense • Being studied for advanced disease