lymphoma uglyar t.y. adapted from joe waller, md 2013 drs. wang and young and by david lee md, frcpc
Post on 24-Dec-2015
214 Views
Preview:
TRANSCRIPT
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
top related