Lymphomas the basics
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Lymphomas: The Basics. Brad Kahl, MD Assistant Professor of Medicine Director, UW Lymphoma Service. Lymphomas: NHL vs Hodgkin’s. EPIDEMIOLOGY Biology Classification Approach to the Patient. Hodgkin’s Disease. Epidemiology 14% of malignant lymphomas 0.5% of all malignancies

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Lymphomas the basics

Lymphomas: The Basics

Brad Kahl, MD

Assistant Professor of Medicine

Director, UW Lymphoma Service


Lymphomas nhl vs hodgkin s

Lymphomas: NHL vs Hodgkin’s

  • EPIDEMIOLOGY

  • Biology

  • Classification

  • Approach to the Patient


Hodgkin s disease

Hodgkin’s Disease

  • Epidemiology

    • 14% of malignant lymphomas

    • 0.5% of all malignancies

    • approximately 8000 new cases/yr in US

    • approximately 1500 deaths/yr

    • over past 30 years

      • age adjusted incidence rates declined appreciably

      • mortality rates declined substantially


Hodgkin s disease1

Hodgkin’s Disease

  • Epidemiology

    • men > women

    • whites > blacks > Asians

    • no clear risk factors, several implicated

      • EBV (pathogen or passenger)

      • HIV

      • woodworking, farming

      • rare familial aggregations


Nhl epidemiology

NHL: Epidemiology

  • Most common hematologic malignancy

  • 60,000 new cases annually

  • 6th leading cause of cancer death

  • incidence rising

    • overall incidence up by 73% since 1973

    • “epidemic”

    • 2nd most rapidly rising malignancy


Nhl epidemiology1

NHL: Epidemiology

  • Why the increase?

    • Increase noted mostly in farming states

    • MN #1, WI #7 NHL incidence

    • possible role of herbicides, insecticides, etc.

  • Other environmental factors?


Nhl epidemiology2

NHL: Epidemiology

  • Other risk factors

    • immunodeficiency states

      • AIDS, post-transplant, genetic

    • autoimmune diseases

      • Sjogrens

      • Sprue

    • infections

      • H. pylori, EBV, HHV-8


Epidemiology

Epidemiology

  • SEER 5 year survival data

  • NHLHodgkin’s

    • 1974-76:47.271.1%

    • 1977-79:48.173.0%

    • 1980-82:51.174.3%

    • 1983-9052.078.9%


Hodgkin s disease2

Hodgkin’s Disease

  • Epidemiology

  • BIOLOGY

  • Classification

  • Approach to the Patient


Hodgkin s disease3

Hodgkin’s Disease

  • Background

    • first described in 1832 by Dr. Thomas Hodgkin

    • characterized by the presence of Reed-Sternberg cells

      • multinucleated giant cells

      • described by Sternberg in 1898 and Reed in 1902

    • classified as an infectious disease until 1950’s


Reed sternberg cell

Reed-Sternberg Cell


Hodgkin biology

Hodgkin Biology

  • RS is a “crippled” germinal center B cell

    • does not have normal B cell surface antigens

    • micromanipulation of single RS followed by PCR demonstrates clonally rearranged, but non functional immunoglobulin genes

      • somatic mutations result in stop codon (no sIg)

      • no apoptotic deathmalignant transformation

    • unclear how this occurs; ? EBV

    • unclear how cells end up with RS phenotype


Hodgkin s disease4

Hodgkin’s Disease

  • Epidemiology

  • Biology

  • CLASSIFICATION

  • APPROACH TO THE PATIENT


Hodgkin lymphoma classification

Hodgkin Lymphoma Classification

  • “Classic” Hodgkin’s Disease

    • nodular sclerosis

    • mixed cellularity

    • lymphocyte depleted (very rare)

    • classical lymphocyte rich

  • HRS cells CD30 and CD15 positive

  • nodular lymphocyte predominant

    • HRS cells (L&H cells) have B cell markers

      • CD 20 and surface Immunoglobulin


  • Classic hodgkin lymphoma

    Classic Hodgkin Lymphoma


    Nodular sclerosing hodgkin lymphoma

    Nodular Sclerosing Hodgkin Lymphoma


    Approach to the patient

    Approach to the Patient

    • Hodgkin’s Disease

      • approach dictated mainly by where the disease is located rather (results of staging) than the exact histologic subtype

    • NHL

      • approach is dictated mainly by the histologic subtype rather than the results of staging


    Hodgkin s disease5

    Hodgkin’s Disease

    • Approach to the Patient

      • staging evaluation

        • H & P

        • CBC, diff, plts

        • ESR, LDH, albumin, LFT’s, Cr

        • CT scans chest/abd/pelvis

        • bone marrow evaluation

        • **PET or gallium scan**

        • **lymphangiogram or laparotomy**


    Ann arbor staging system

    Ann Arbor Staging System

    • Stage I: single lymph node region (I) or single extralymphatic organ or site (IE)

    • Stage II: > 2 lymph node regions on same side of diaphragm (II) or with limited, contiguous extra lymphatic tissue involvement (IIE)

    • Stage III: both sides of diaphragm involved, may include spleen (IIIS) or local tissue involvement (IIIE)

    • Stage IV:multiple/disseminated foci involved with > 1 extralymphatic organs (i.e. bone marrow)

    • (A) or (B) designates absence/presence of “B” symptoms


    Ann arbor staging system for hodgkin s disease and non hodgkin s lymphoma

    Ann Arbor Staging System for Hodgkin's Disease and Non-Hodgkin's Lymphoma

    Stage I Stage II Stage III Stage IV

    Reprinted with permission. Adapted from Skarin. Dana-Farber Cancer Institute Atlas of Diagnostic Oncology. 1991.


    Modified ann arbor staging

    Modified Ann Arbor Staging

    • “E” designation for extranodal disease

    • B symptoms

      • recurrent drenching night sweats during previous month

      • unexplained, persistent, or recurrent fever with temps above 38 C during the previous month

      • unexplained weight loss of more than 10% of the body weight during the previous 6 months

  • Criteria for bulk

    • 10 cm nodal mass

    • mediastinal mass > 1/3 thorax diameter


  • Hodgkin lymphoma

    Hodgkin Lymphoma

    • Treatment

      • approach depends upon stage, prognostic factors, and co-morbidities

      • Stage I-II

        • consider XRT, chemotherapy, or combined therapy

      • Bulky stage I-II

        • combined modality therapy

      • Stage III-IV

        • ABVD x 6-8 cycles gold standard


    Hodgkin lymphoma1

    Hodgkin Lymphoma

    • Adverse prognostic features for stage I & II (EORTC data)

      • more than 3 nodal sites

      • bulky adenopathy

      • ESR > 50

      • B symptoms

      • invasion into critical organs

      • male

      • age > 40

      • MC or LD subtype

    • should probably not receive XRT alone if any of the above present (excessive relapse rate)


    Hodgkin lymphoma2

    Hodgkin Lymphoma

    • Independent adverse prognostic factors

      • advanced stage (III-IV)

        • male sex

        • age > 45

        • albumin < 4 gm/dl

        • HgB < 10.5 mg/dl

        • stage IV disease

        • WBC count > 15,000/mm3

        • lymphocyte count < 600/mm3

          (Hasenclever et al, NEJM 339,1506-1514;1998)


    Hodgkin s disease6

    Hodgkin’s Disease

    • Role for Stem Cell Transplantation

      • clinical trials show benefit for patients who receive high dose chemotherapy followed by SCT for patients who have relapsed after initial therapy or for patients are primary refractory


    Hodgkin s disease7

    Hodgkin’s Disease

    • Results of Treatment

      • stage5 year overall survival

        • I90%

        • II90%

        • III80%

        • IV65%


    Hodgkin lymphoma3

    Hodgkin Lymphoma

    • Late Complications

      • depends upon treatment modality utilized

      • XRT vs. MOPP vs. ABVD vs. CMT

      • issues depends upon the age of patient

        • relative risks higher in younger patients

        • absolute risks higher in older patients

      • major focus of current clinical trials to to maintain high cure rate while minimizing late complication

        • shorter courses of chemotherapy with lower radiation doses in smaller fields

        • elimination of radiotherapy


    Hodgkin s future directions

    Hodgkin’s: future directions

    • Limited stage and good prognosis advanced stage

      • cure rate high

      • current goal is to minimize late complications

      • trials looking at CMT with less chemotherapy and less radiation

    • Advanced stage

      • cure rate around 50-70%

      • trial comparing ABVD to Stanford V

    • Clinical Trials


    Lymphomas the basics

    NHL

    • Epidemiology

    • BIOLOGY

    • Classification

    • Approach to the Patient


    Lymphoma biology

    Lymphoma Biology

    • Indolent vs. Aggressive NHL

      • key principle in understanding biology, and approach to the patient

      • Indolent = incurable

      • Aggressive = curable

      • WHY?

    • Chromosomal Abnormalities in NHL

      • frequent chromosomal translocations into Ig gene loci

        • t(8;14), t(2;8), t(8;22) Burkitt’s

        • t(14;18) follicular NHL


    Lymphoma biology1

    Lymphoma Biology

    • Aggressive NHL

      • short natural history (patients die within months if untreated)

      • disease of rapid cellular proliferation

    • Indolent NHL

      • long natural history (patients can live for many years untreated)

      • disease of slow cellular accumulation


    Lymphomas the basics

    NHL

    • Epidemiology

    • Biology

    • CLASSIFICATION

    • Approach to the Patient


    Nhl classification

    NHL: Classification

    • Historically- a mess

      • 1940s Gail and Mallory

      • 1950s Rappaport

      • 1970s Lukes-Collins

      • 1970s Kiel

      • 1982 Working

      • 1994 REAL

      • 1999 WHO


    Nhl classification1

    NHL: Classification

    • Key Points

      • cell size: small cell vs. large cell

      • nodal architecture: follicular vs. diffuse

    • Principle

      • More aggressive:diffuse, large cell

      • More indolent:follicular, small cell


    Nhl classification2

    NHL: Classification

    • Terminology (refers to natural history)

      • low grade = indolent

      • intermediate grade = aggressive

      • high grade = aggressive

    • Principle

      • indolent: slow growing, incurable

      • aggressive: rapidly growing, curable


    Lymphomas the basics

    NHL

    • Epidemiology

    • Biology

    • Classification

    • APPROACH TO THE PATIENT


    Nhl approach to the patient

    NHL: Approach to the Patient

    • Approach dictated mainly by histology

      • reliable hematopathology crucial

    • Approach also influenced by:

      • stage

      • prognostic factors

      • co-morbidities


    Nhl approach to the patient1

    NHL: Approach to the Patient

    • Staging evaluation

      • History and PE

      • Routine blood work

        • CBC, diff, plts, electrolytes, BUN, Cr, LFT’s, uric acid, LDH, B2M

      • CT scans chest/abd/pelvis

      • Bone marrow evaluation

      • Other studies as indicated (lumbar puncture, gallium, etc…)


    Nhl approach to the patient2

    NHL: Approach to the Patient

    • Indolent NHL: typical scenario

      • patient presents with painless adenopathy

      • otherwise asymptomatic

      • follicular small cell histology

      • average age 59

      • usually stage III-IV at diagnosis


    Nhl approach to the patient3

    NHL: Approach to the Patient

    • Indolent NHL: guiding treatment principle

      • early treatment does not prolong overall survival

    • When to treat?

      • constitutional symptoms

      • compromise of a vital organ by compression or infiltration, particularly the bone marrow

      • bulky adenopathy

      • rapid progression

      • evidence of transformation


    Nhl approach to the patient4

    NHL: Approach to the Patient

    • Indolent NHL: typical scenario

      • watchful waiting: 2-4 years

      • first remission length: 3-4 years

      • second remission: 2-3 years

      • third remission: 1-2 years

      • each subsequent remission shorter than prior

      • median survival 8-12 years for FLSC


    Nhl approach to the patient5

    NHL: Approach to the Patient

    • Indolent NHL: treatment options

      • watchful waiting

      • radiation to involved fields

      • single agent chemotherapy

        • chlorambucil + prednisone, fludarabine

      • combination chemotherapy

        • CVP, CF, FND, CHOP

      • chemotherapy + interferon

      • chemotherapy + monoclonal antibodies

      • monoclonal antibodies

      • radiolabeled monoclonal antibodies

      • stem cell transplantation


    Nhl approach to the patient6

    NHL: Approach to the Patient

    • Aggressive NHL: typical scenario

      • patients notes B symptoms of several weeks duration

      • work-up reveals pathologic adenopathy

      • histology: diffuse large cell lymphoma

      • about 50% patients stage I-II, 50% stage III-IV

      • average age 64

      • IPI score


    Nhl approach to the patient7

    NHL: Approach to the Patient

    • Aggressive NHL: treatment approach

      • Stage I-II: combined modality therapy

        • CHOP chemotherapy x 3 + IF radiotherapy

        • cure rate around 70%

      • Stage III-IV (also bulky stage II)

        • (R)CHOP chemotherapy x 6-8 cycles

        • cure rate around 40%

      • (R)CHOP is the standard


    Nhl approach to the patient8

    NHL: Approach to the Patient

    • International Prognostic Index

      • Risk Factors (0-5)

        • age > 60

        • two or more extranodal sites

        • performance status > 2

        • elevated LDH

        • stage III-IV

      • Age adjusted IPI (0-3)


    Cr and os stratified by ipi

    CR and OS stratified by IPI


    Nhl approach to the patient9

    NHL: Approach to the Patient

    • Is CHOP the best we can do?

      • R-CHOP may be better

      • National Trials opening looking at alternative strategies in poor prognosis DLCL

        • age adjusted IPI > 2

        • CHOP vs. CHOP + SCT

      • Risk stratification is the current trend in NHL

        • Sorting out role for stem cell transplantation

        • Sorting out role for innovative combinations


    Nhl approach to the patient10

    NHL: Approach to the Patient

    • Role for Autologous Stem Cell Transplantation

    • Aggressive NHL

      • clear benefit when used for aggressive NHL in first relapse in appropriately selected patients

      • 1/3 of these patients can be cured by SCT

    • Indolent NHL

      • no indication that patients are cured

      • no indication that OS is prolonged


    Nhl future directions

    NHL: future directions

    • Indolent

      • monoclonal antibodies (Rituximab)

      • radiolabeled monoclonal antibodies

      • chemotherapy combined with antibodies

      • antibodies combined with immunomodulators

    • Aggressive

      • risk stratification

      • CHOP vs. CHOP plus SCT

      • chemotherapy plus antibodies

    • Clinical Trials


    Summary

    Summary

    • NHL incidence increasing, Hodgkin’s decreasing

    • Hodgkin’s cure rate quite high

      • approach is dictated mainly by disease stage

    • NHL cure rate mediocre

      • approach is dictated mainly by histologic subtype

      • indolent vs. aggressive

        • indolent: watchful waiting perfectly acceptable for asymptomatic patients

        • aggressive: require aggressive treatment ASAP to achieve cure


    Lymphoma clinic

    Lymphoma Clinic

    • Multidisciplinary

      • radiotherapy-Dr. Scott Tannehill

      • hematopathology-Dr. Catherine Leith

    • Emphasis on clinical trials

      • formal testing of promising new therapies

    • Every Wednesday

    • Clinic phone #: 608-263-7022


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