Lymphoma new

Hematopoietic Malignancies

1048708 Lymphoma is a general term forhematopoietic solid malignancies ofthe lymphoid series

1048708 Leukemia is a general term for liquidmalignancies of either the lymphoidor the myeloid series

Conceptualizing lymphoma

bull neoplasms of lymphoid origin typically causing lymphadenopathy

bull leukemia vs lymphomabull lymphomas as clonal expansions of

cells at certain developmental stages

What is Lymphomabull Lymphomas are cancers that begin by

the ldquomalignant transformationrdquo of a lymphocyte in the lymphatic system

bull Many lymphomas are known to be due to specific genetic mutations

bull Follicular lymphoma due to overexpression of BCL-2 (gene that blocks programmed cell death)

What is the Lymphatic System

bull Made up of organs such as the tonsils spleen liver bone marrow and a network of lymphatic vessels that connect glands called lymph nodes

bull Lymph nodes located throughout the bodybull Lymph nodes filter foreign particles out of the

lymphatic fluid bull Contain B and T lymphocytes

Lymphatic Systembull Lymph nodes act as a filter to

remove bacteria viruses and foreign particles

bull Most people will have had ldquoswollen glandsrdquo at some time as a response to infection

Blood Cell and Lymphocyte Development

STEM CELLS

Multipotential myeloid cells

Multipotential lymphocytic cells

Differentiate amp mature into 6 Types of blood cells

red cells basophilsneutrophils monocyteseosinophils platelets

Differentiate amp mature into 3Types of lymphocytes

T lymphocytesB lymphocytesNatural Killer Cells

Lymphocytesbull Most lymphocytes are in lymph nodes

spleen bone marrow and lymphatic vesselsbull 20 of white blood cells in blood are

lymphocytesbull T cells B cells natural killer cellsbull B cells produce antibodies that help fight

infectious agentsbull T cells help B cells produce antibodies and

they fight viruses

T-Cells and B-Cells

1048708 Immature lymphocytes that travel to thethymus differentiate into T-Cells

ndash ldquoTrdquo is for thymus1048708 Immature lymphocytes that travel to thespleen or lymph nodes differentiate into Bcells

ndash B stands for the bursa of Fabricius which isan organ unique to birds where B cellsmature

ALLALL MM MM CLLCLL LymphomasLymphomas

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Myeloproliferative disordersMyeloproliferative disordersAMLAML

Lymphoidprogenitor T-lymphocytes

Plasmacells

B-lymphocytes

nanaiumliumlveve

B-cell development

stemcell

lymphoidprogenitor

progenitor-B

pre-B

immatureB-cell

memoryB-cell

plasma cellplasma cell

DLBCLFL HL

ALL

CLL

MM

germinalgerminalcentercenterB-cellB-cell

maturenaiveB-cell

Clinically useful classification

Diseases that have distinctbull clinical featuresbull natural historybull prognosisbull treatment

Biologically rational classification

Diseases that have distinctbull morphologybull immunophenotypebull genetic featuresbull clinical features

Classification

Classificationbull Usually classified by how the cells look

under a microscope and how quickly they grow and spreadndash Aggressive lymphomas (high-grade

lymphomas)

ndash Indolent Lymphomas (low-grade lymphomas)

Lymphoma classification(2001 WHO)

bull B-cell neoplasmsndash precursorndash mature

bull T-cell amp NK-cell neoplasmsndash precursorndash mature

bull Hodgkin lymphoma

Non-HodgkinLymphomas

Three common lymphomas

bull Follicular lymphomabull Diffuse large B-cell lymphomabull Hodgkin lymphoma

Follicular lymphomabull most common type of ldquoindolentrdquo

lymphomabull usually widespread at presentationbull often asymptomaticbull not curable (some exceptions)bull associated with BCL-2 gene

rearrangement [t(1418)]bull cell of origin germinal center B-cell

bull defer treatment if asymptomatic (ldquowatch-and-waitrdquo)

bull several chemotherapy options if symptomatic

bull median survival yearsbull despite ldquoindolentrdquo label morbidity and

mortality can be considerablebull transformation to aggressive lymphoma

can occur

Diffuse large B-cell lymphoma

bull most common type of ldquoaggressiverdquo lymphoma

bull usually symptomaticbull extranodal involvement is commonbull cell of origin germinal center B-cellbull treatment should be offeredbull curable in ~ 40

B-Cell Lymphoma (80) bull B-Cells help make antibodies which are

proteins that attach to and help destroy antigensbull Lymphomas are caused when a mutation arises

during the B-cell life cyclebull Various different lymphomas can occur during

several different stages of the cyclendash Follicular lymphoma which is a type of B-cell

lymphoma is caused by a gene translocation which results in an over expressed gene called BCL-2 which blocks apoptosis

T-Cell Lymphoma (15)bull The T-cells are born from stem cells

similar to that of B-cells but mature in the thymus

bull They help the immune system work in a coordinated fashionndash These types of lymphomas are categorized

by how the cell is affectedbull Anaplastic Large cell Lymphoma t-cell lymphoma

caused by a gene translocation in chromosome 5

Mechanisms of lymphomagenesis

bull Genetic alterationsbull Infectionbull Antigen stimulationbull Immunosuppression

Epidemiology of lymphomas

bull males gt femalesbull incidence

ndash NHL increasingndash Hodgkin lymphoma stable

bull in NHL 3rd most frequently diagnosed cancer in males and 4th in females

bull in HL 5th most frequently diagnosed cancer in males and 10th in females

Risk factors for NHLbull immunosuppression or immunodeficiencybull connective tissue diseasebull family history of lymphomabull infectious agentsbull ionizing radiation

Clinical manifestationsbull Variable

bull severity asymptomatic to extremely illbull time course evolution over weeks months or

years

bull Systemic manifestationsbull fever night sweats weight loss anorexia pruritis

bull Local manifestationsbull lymphadenopathy splenomegaly most commonbull any tissue potentially can be infiltrated

Other complications of lymphoma

bull bone marrow failure (infiltration)bull CNS infiltrationbull immune hemolysis or thrombocytopeniabull compression of structures (eg spinal

cord ureters)bull pleuralpericardial effusions ascites

Non-Hodgkinrsquos LymphomaStaging

bull Stage is the term used to describe the extent of tumor that has spread through the body ( I and II are localized where as III and IV are advanced

bull Each stage is then divided into categories A B and Endash A No systemic symptomsndash B Systemic Symptoms such as fever night sweats

and weight lossndash E Spreading of disease from lymph node to

another organ

Stage I Stage II Stage III Stage IV

Staging of lymphoma

A absence of B symptomsB fever night sweats weight loss

Staging

Symptomsbull Painful Swelling of lymph nodes located

in the neck underarm and groinbull Unexplained Feverbull Night Sweatsbull Constant Fatiguebull Unexplained Weight lossbull Itchy Skin

Cancer Sourcebook

Causes and Risk Factors

bull The Exact causes are still unknownndash Higher risk for individuals who

bull Exposed to chemicals such as pesticides or solvents

bull Infected w Epstein-Barr Virusbull Family history of NHL (although no hereditary

pattern has been established)bull Infected w Human Immunodeficiency Virus

(HIV)

Lymphomaorg

Diagnosis Staging Studies

bull Bone marrow aspiration and biopsybull Radionuclide scans bull GI x-raysbull Spinal fluid analysisbull CT scansbull Magnetic Resonance Imaging (MRI)bull Biopsy

Treatmentbull Non-Hodgkinrsquos Lymphoma is usually treated

by a team of physicians including hematologists medical oncologists and a radiation oncologist

bull In some cases such as for Indolent lymphomas the Doctor may wait to start treatment until the patient starts showing symptoms known as ldquowatchful waitingrdquo

Treatment Optionsbull Chemotherapybull Radiationbull Bone Marrow Transplantationbull Surgerybull Bortezomib (Velcade)bull Immunotherapy

bull Using the bodies own immune system combined with material made in a lab

Survival Ratesbull Survival Rates vary widely by cell type

and staging

ndash 1 Year Survival Rate 77

ndash 5 Year Survival Rate 56

ndash 10 Year Survival Rate 42Cancerorg

Hodgkin lymphoma

Thomas Hodgkin(1798-1866)

Classical Hodgkin Lymphoma

Hodgkin lymphomabull cell of origin germinal centre B-cell bull Reed-Sternberg cells (or RS variants)

in the affected tissuesbull most cells in affected lymph node are

polyclonal reactive lymphoid cells not neoplastic cells

A possible model of pathogenesis

germinalcentreB cell

transformingevent(s)

loss of apoptosis

RS cellinflammatory

response

EBV

cytokines

Hodgkin lymphomaHistologic subtypes

bull Classical Hodgkin lymphomandash nodular sclerosis (most common subtype)ndash mixed cellularityndash lymphocyte-richndash lymphocyte depleted

Epidemiologybull less frequent than non-Hodgkin

lymphomabull overall MgtFbull peak incidence in 3rd decade

Associated (etiological) factors

bull EBV infectionbull smaller family sizebull higher socio-economic statusbull caucasian gt non-caucasianbull possible genetic predispositionbull other HIV occupation herbicides

Clinical manifestationsbull lymphadenopathybull contiguous spreadbull extranodal sites relatively uncommon

except in advanced diseasebull ldquoBrdquo symptoms

Treatment and Prognosis

Stage Treatment Failure-free

survival

Overall 5 year

survivalIII ABVD x 4

amp radiation70-80 80-90

IIIIV ABVD x 6 60-70 70-80

Long term complications of

treatmentbull infertility

ndash MOPP gt ABVD males gt femalesndash sperm banking should be discussedndash premature menopause

bull secondary malignancyndash skin AML lung MDS NHL thyroid

breastbull cardiac disease

Lab Diagnostic Studies

bull Lymph node biopsybull Bone marrow aspiration and biopsybull Immunohistochemistry bull Flow cytometrybull Molecular Genetic studiesbull FISHbull Cytogenetics