Lymphoma
description
Transcript of Lymphoma
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LymphomaUglyar T.Y.
Adapted from Joe Waller, MD 2013 Drs. Wang and Young and By David Lee MD, FRCPC
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Conceptualizing lymphoma
• neoplasms of lymphoid origin, typically causing lymphadenopathy
• leukemia vs lymphoma• lymphomas as clonal expansions of
cells at certain developmental stages
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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
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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
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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
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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
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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
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Lymph Node Regions
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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
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Mediastinal LAN
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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
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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.
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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
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complications of lymphoma
• bone marrow failure (infiltration)• CNS infiltration• immune hemolysis or thrombocytopenia• compression of structures (eg spinal
cord, ureters)• pleural/pericardial effusions, ascites
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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)
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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
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CHOP Chemotherapy• Cyclophosphamide (Cytoxan)• Hydroxydaunorubicin (Adriamycin)• Oncovin (vincristine)• Prednisone
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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
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• 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
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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%
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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.
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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
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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.
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Burkitt’s Lymphoma• Treated with multidrug regimen similar
to pediatric leukemia/lymphoma regimens.
• Treated with multidrug regimen similar to pediatric leukemia/lymphoma regimens.
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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.
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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
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Hodgkin lymphoma
Thomas Hodgkin(1798-1866)
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Classical Hodgkin Lymphoma
Hodgkin’s Disease
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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.
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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.
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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
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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
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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+
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Reed-Sternberg cell
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RS cell and variants
popcorn celllacunar cellclassic RS cell
(mixed cellularity) (nodular sclerosis) (lymphocytepredominance)
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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
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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.
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A possible model of pathogenesis
germinalcentreB cell
transformingevent(s)
loss of apoptosis
RS cellinflammatory
response
EBV?
cytokines
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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.
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Epidemiology• less frequent than non-Hodgkin
lymphoma• overall M>F• peak incidence in 3rd decade
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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.
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Clinical manifestations:• lymphadenopathy• contiguous spread• extranodal sites relatively uncommon
except in advanced disease• “B” symptoms
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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.
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Diagnosis• Excisional biopsy of a lymph node.
Fine needle aspirate is not sufficient to make the diagnosis of Hodgkin’s disease.
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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
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Treatment by StageStage Therapy % Cure
IA XRT 95 IIA XRT 85 IB, IIB XRT (Total Nodal) 70 IIIA XRT 70 IIIB, IV Combination Chemo 50
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Chemotherapy Regimens• MOPP
– Mechlorethamine, Oncovin, Procarbazine, Prednisone
• ABVD– Adriamycin, Bleomycin, Vinblastine,
Dacarbazine• BEACOPP
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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.
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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.
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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.
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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