Dr. Luis M. Zetina Toach Oncomdica.

Multimdica Guatemala

Linfomas no Hodgkin Enfoque biologico

Dr. Luis m. Zetina Toache Hemato-Oncologia Oncomedica. Multimedica

 It is much more important to know what kind of patient has a disease, than to know what kind of disease a patient has
Caleb Parry. 18th Century physician, Bath.

We used to think our fate was in our stars. Now we know, in large measure, our fate is in our genes
J.D Watson. Time Magazine 20 March 1989

PRINCIPALES CAUSAS DE MORTALIDAD

33.5%

% DEL TOTAL DE MUERTES

23.5%

6.7% 4.3% 4.0%

3.7%

2.2%

1.4%

1.2%

1.2%

1.2%

US data/Adapted from Cancer Journal for Clinicians, 1994.

Incidence
Incidence Rates by Race Race/Ethnicity All Races White Black Male 23.5 per 100,000 men 24.4 per 100,000 men 18.3 per 100,000 men Female 16.4 per 100,000 women 17.2 per 100,000 women 12.2 per 100,000 women

Asian/Pacific Islander
American Indian/Alaska Native a Hispanic b

15.5 per 100,000 men

11.8 per 100,000 men 19.1 per 100,000 men

10.9 per 100,000 women

10.0 per 100,000 women 14.6 per 100,000 women

Female cancer statistics

Estimated incidence Estimated deaths

Melanoma of skin Thyroid Breast Lung & bronchus

3% 2% 30% 12% 2% 11% 4% 6% 2% 4% 22%

2% 15% 25% 5% 2% 11% 5% 2% 5% 4% 2% 21%

Brain & other nervous system Breast Lung & bronchus Pancreas Stomach Colon & rectum Ovary Uterine corpus Non-Hodgkins lymphoma Leukemia

Pancreas
Colon & rectum Ovary Uterine corpus Urinary bladder Non-Hodgkins lymphoma All others

Multiple myeloma
All others

Adapted from Greenlee RT, et al. CA Cancer J Clin. 2000;50:16.

Male cancer statistics

Estimated incidence Estimated deaths

Melanoma of skin Oral cavity & pharynx

4% 3%

3% Esophagus
31% Lung & bronchus 5% Pancreas 3% Liver & intrahepatic bile duct

Lung & bronchus 14% Pancreas Kidney & renal pelvis 2% 3%

3% Stomach
10% Colon & rectum 11% Prostate 3% Urinary bladder

Colon & rectum 10% Prostate 29%

Urinary bladder
Leukemia Non-Hodgkins lymphoma

6% 3% 5%

4% Leukemia
5% Non-Hodgkins lymphoma 22% All others
Adapted from Greenlee RT, et al. CA Cancer J Clin. 2000;50:16.

All others 19%

Incidence

Incidence

Figure 111-1 Age-specific incidence of Hodgkin's lymphoma by tertile of neighborhood socioeconomic status, California, 19881992. (Reprinted with permission from Clarke C, Glaser S, Keegan T, et al: Neighborhood socioeconomic status and Hodgkin's lymphoma incidence in California. Cancer Epidemiol Biomarkers Prev 2005;14:14411447.)

Linfomas Breve Historia

1832 Thomas Hodgkin reporta On Some Morbid Appearances of the Absorbent Glands and Spleen. Algunos casos revisados por IHQ eran Linfomas no Hodgkin.

describen

* En 1898 y 1902 Carl Sternberg y Dorothy Reed describe la celula patognomonica de Enf .Hodgkin Una celula sin paternidad. Se desconocia su origen.
* En 1845 R. Virchow separa leucemia de aleucemia y lo nombra como linfosarcoma * 1942 propuesto por Gall y Mallory se separa Enf .Hodgin de Linfomas no Hodgkin o unicelulares.

a .

Linfoma Burkitt

Linfomas Breve Historia

60 aos buscando como clasificarlos 1956. Rappaport por tamao y arquitectura: Pequea, grande , intermedia. 1965. Kiel basado en origen T o B 1974. Clasificacion de Luckes y Collins. T o B y describe varias entidades 1982. De Vita y Kaplan proponen Working Formulation. Bajo, intermedio y alto grado 1997. Real . Basado en inmunofenotipo, genotipo, morfologia y clinica. 2001. WHO. Jaffe E.S., Harris N.L., Stein H., et al: World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC PressLyon (France)2001.

Fig.2

Diagnosis of BL. (A)Hematoxylin-eosin stain, IHC for CD20 and the proliferation marker Ki-67, and amplificationof the oncogene c-myc (arrow) by the FISH technique. (B)Standard cytogenetics showing translocations t(8;14), t(2;8), and t(8;22). (C)Map of chromosome 8 showing the location of c-myc and the FISH probe design of thedual-color break-apart probe in red and green. This technique isuseful in cases in which there may be multiple translocation partners associatedwith a known genetic breakpoint. This labeling scheme features two differently coloredprobes that hybridize to targets on opposite sides of a breakpoint of myc. (D)On the metaphase cell, the dual-color break-apart probe hybridizes to chromosomes8 (red) and 14 (green) (arrows) in a cell with a translocationt(8;14), whereas the other uninvolved c-myc homolog probe on chromosome 8 (yellow,arrowhead) remains intact. (E) Seriesof interphase cells shows a pair of normal green/red signals in two cells with noc-myc rearrangement (arrowheads) and two BL interphase cellswith one red signal and one green signal (long arrows), suggestiveof c-myc rearrangement. (Courtesy of Jonathan Said, MD, and Nagesh Rao, MD, Los Angeles,CA.)

Lymphoid neoplasms: World Health Organization classification

B-cell neoplasms Precursor B-cell neoplasm Precursor B-cell lymphoblastic leukemia/lymphoma Precursor B-cell acute lymphoblastic leukemia

Mature (peripheral) B-cell neoplasms B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma Hairy cell leukemia Plasma-cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type Nodal marginal zone B-cell lymphoma (with/without monocytoid B cells) Follicular lymphoma Mantle-cell lymphoma Diffuse large B-cell lymphoma Mediastinal large B-cell lymphoma Primary effusion lymphoma Burkitt's lymphoma/Burkitt-cell leukemia

Lymphoid neoplasms: World Health Organization classification

T-cell and natural killer cell neoplasmsPrecursor T-cell neoplasm Precursor T-lymphoblastic lymphoma/leukemia Precursor T-cell acute lymphoblastic leukemia Mature (peripheral) T-cell neoplasms T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive natural killer cell leukemia

Adult T-cell lymphoma/leukemia (human T-lymphotropic virus type 1-positive) Extranodal natural killer/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic - T-cell lymphoma Subcutaneous panniculities-like T-cell lymphoma Mycosis fungoides/Sezary syndrome Anaplastic large-cell lymphoma, T/null cell, primary cutaneous type Peripheral T-cell lymphoma, not otherwise characterized Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma, T/null cell, primary systemic type

Incidence

Frequency of NHL in adults. MALT, mucosa-associated lymphoid tissue. (Data from Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1998;16:278095.)

TABLE 196-1 -- FACTORS ASSOCIATED WITH THE DEVELOPMENT OF NON-HODGKIN'S LYMPHOMA

IMMUNE ABNORMALITIES

Inherited disorders Severe combined immunodeficiency disease Common variable immunodeficiency disease Wiskott-Aldrich syndrome Ataxia-telangiectasia X-linked lymphoproliferative disorder Acquired disorders Solid organ transplantation Acquired immunodeficiency syndrome Methotrexate therapy for autoimmune disorders Rheumatoid arthritis Sjgren's syndrome Hashimoto's thyroiditis Chlamydia psittaci Campylobacter jejuni Occupational and environmental exposure Herbicides Organic solvents Hair dyes

Infectious agents Epstein-Barr virus Human T-cell lymphotropic virus type I Human herpesvirus 8 Hepatitis C virus Helicobacter pylori Borrelia burgdorferi Chlamydia psittaci Campylobacter jejuni Occupational and environmental exposure Herbicides Organic solvents Hair dyes Ultraviolet light Diet Smoking

Today we have a clearer understanding of the cellular pathways involved in cancer

Most human tumours require deregulation of all of these processes
Unlimited cell growth Insensitivity to antigrowth signals
Cancer

Reduced sensitivity to apoptosis

Limitless replicative potential Development and maintenance of vasculature (angiogenesis) Invasion and metastasis

Hanahan, et al. Cell 2000

pathogenesis
oncogene activation loss of tumor suppressor genes caused by chromosomal translocation, deletion, or mutation or by introduction of exogenous viral genomes into the human chromosome

TABLE 196-3 --

CHROMOSOMAL TRANSLOCATIONS CHARACTERISTIC OF NON-HODGKIN'S LYMPHOMA (NHL)

NHL Subtype Translocation Genes Involved Diffuse large B-cell t(3q27) BCL6 t(14;18)(q32;q21) IgH, BCL2 t(18;14)(q24;q32) MYC (c-Myc), IgH Burkitt's t(8;14)(q24;q32) MYC, IgH

Frequency (%) 35 1520 <5 100% have one of these, most commonly t(8;14)

t(8;22)(q24;q11) Follicular Mantle cell ALCL

MYC, IgL 90 >90 >80 of ALK+ ALCLs

t(2;8)(p12;q24) IgK, MYC t(14;18)(q32;q21) IgH, BCL2 t(11;14)(q13;q32) BCL1, IgH t(2;5)(p23;q35) ALK, NPM

MALT

t(11;18)(q21;q21) API2, MALT1

t(14;18)(q21;q32) IgH, MALT1 t(1;14)(p22;q32) BCL10, IgH

35
20 10

Table 112-4 -- Major Molecular Translocations in Non-Hodgkin's Lymphomas

NHL Histologic Type
Lymphoplas matic lymphoma Follicular lymphoma

Translocation t(9;14)(p13;q32)

% 50

Protooncogene Involved
pax-5

Mechanism of Proto-oncogene Activation

Transcription deregulation Transcription deregulation

Proto-oncogene Function Transcription factor regulating B-cell proliferation and differentiation Negative regulator of apoptosis

t(14;18)(q32;q21) t(2;18)(p11;q21) t(18;22)(q21;q11)

90

bcl-2

Mantle cell lymphoma MALT lymphoma

t(11;14)(q13;q32) t(11;18)(q21;q21) t(1;14)(p22;q32)

70 50

bcl-1/cyclin D1 api2/mlt bcl-10

Transcription deregulation Fusion protein Transcription deregulation Transcription deregulation Transcription deregulation

Cell cycle regulator api2 has antiapoptotic activity Antiapoptosis (?) Transcriptional repressor required for GC formation Transcription factor regulating cell proliferation and growth

Diffuse large B-cell lymphoma Burkitt's lymphoma

der(3)(q27)

35

bcl-6

t(8;14)(q24;q32) t(2;8)(p11;q24) t(8;22)(q24;q11)

80 15 5 60

c-myc

Anaplastic large T-cell lymphoma

t(2;5)(p23;q35)

npm/alk

Fusion protein

alk is a tyrosine kinase

Estructura Celular

DNA

Estructura del DNA Watson y Crick. 1953

Cristalografa Rx. Rosalind Franklin. 1950

Dogma Central de Biologia

CICLO CELULAR

Enzimas fase S
Topoisomerasa

Telomerasa

Mitosis

Muerte Celular Programada APOPTOSIS

Guardian del Genoma

ARF: ADP Ribosylation Factor mdm2: mouse double minute

ubiquinitisacion

53 Kd

ARF

p21 p27

cdk2

ATM: A
Ras: Retrovirus associated sequences MDM2 Myc: mielocytomatosis virus
MDM2: Murine double minute 2 HIF 1a: Hypoxia inducible factor ARF: ADP Rybosilation Factor/p16 ATM: Ataxia Telangiectasia Mutated

Funciones del p53

Detencin del ciclo celular en el punto de control G1/S si reconoce el dao en el ADN para evitar su replicacin. Activacin de protenas de reparacin del ADN cuando reconoce dao o mutacin en el ADN. Iniciacin de la apoptosis si el dao en el ADN es irreparable para evitar as la proliferacin de las clulas que contienen ADN anormal.

Anti Apoptosis Familia Bcl-2

Cytotoxic T Lymphocytes

Oncogenes proto-oncogenes
Protooncogen: Gen que promueve la divisin celular normal Oncogn: Protooncogen mutado que produce crecimiento neoplasico

Tipos: - Her-2: Receptor de factores de crecimiento - Ras: Molecular de transduccin de seales - c-myc: Factor de transcripcin - Src: Rous sarcoma. Actividad Tirosina Kinasa - Bcl2: Protena que bloquea apoptosis - hTERT: Enzima de replicacin celular - c-Abl: Abelson . Leucemia Mieloide Crnica - EGFR: Carcinoma de Clulas escamosas

Genes supresores

Rb: Retinoblastoma, cancer de vejiga, pulmon, oseo, mama p53: Involucrado en muchos canceres humanos ATM: Ataxia Telangiectasia Mutated. Predisposicion a radiacion UV VHL: Von Hippel Lindau. Asociado a cancer renal PTEN: Phosphatase Tensin Homolog. Ca endometrio, gliomas, etc.

Oncogenes

Kinasa: agrega grupo P Fosfatasa: remueve P

Control de ciclo celular ciclinas y genes supresores

pathogenesis
inhibition of apoptosis by bcl-2, which occurs in normal germinal center cells, appears to play an important role in lymphomagenesis loss of p53 function is associated with decreased apoptosis and clinical drug resistance Abnormalities in the p53 gene, located on the short arm of chromosome 17, at 17p13, have also been associated with a poor clinical outcome in CLL and are found in half of patients with a Richter's transformation Bcl-6 protein functions as a transcription factor that binds a specific DNA sequence and represses transcription from linked promoters. It is important in the normal functioning of the germinal center B cells and is required for germinal center cell formation during the antigen-driven immune response.

pathogenesis
The quantitative overexpression of c-myc has been shown to result in deregulation of cellular growth and is capable of blocking phenotypic maturation. Hence, c-myc overexpression appears to be central to the pathogenesis of BL, and it is thought that the translocation occurs in pre-B-cell development during the normal rearrangement of the immunoglobulin loci. Deregulation of bcl-1 leads to overexpression of its gene product cyclin-D1, which promotes progression from G1 to S of the cell cycle.[52] Unlike DLBCL, most patients are incurable and have a relatively short median survival of 3 to 5 years.[53] c-myc on chromosome 8 and one of the three immunoglobulin chain loci. These translocations occur with a respective frequency of 80%, 15%, and 5% on chromosomes 14, 22, and 2, respectively, which encode in turn for the immunoglobulin heavy chain and lambda and kappa light chains

Enfoque nuevos requeridos

Invasion

Angiogenesis/ vasculatura

Transduccion de seales

M G2 G1

G0

Ciclo Celular

Metastasis

Apoptosis

STEM CELL Lymphoblast Bone Marrow

Germinal center DLCL

On exposure to antigen NMZBCL

MM

Antigen-dependent B lymphocyte maturation in the lymph-node follicle. Several lymphoma subtypes are thought to represent malignant clonal expansion of lymphocytes at different stages of development.[5] Neoplastic expansion of B immunoblasts (1) might lead to diffuse large B-cell lymphoma. Neoplastic expansion of small marginal-zone memory B cells (2) might lead to nodal marginal-zone B-cell lymphoma and expansion of plasma cells (3) leads to multiple myeloma.

Cel.tronco

pre-pre cel. B

Diferenciacin cel. B y marcadores de sup. pre-B cell pre-B cel pre-B cel

immad. B cell

TDT CD 19

madura B cel

activada B cell

plasma cell

CD 20 CD 22
CD 21 CD 38

Cel.precursoras leucemias

Linfomas cel. B

mieloma mltiple

Table 112-3 -- Typical Immunophenotype of the Major Subtypes of Non-Hodgkin's Lymphoma

Follicular
CD20+, CD3-

Small Lympho cytic

CD20+, CD3-

MALT
CD20+, CD3-

Margi nal Zone, Nodal

CD20+, CD3-

Mantle Cell
CD20+, CD-

Diffuse Large B-Cell

CD20+, CD3-

Medias tinal Large B-Cell

CD20+, CD3-

Burkitt
CD20+, CD3-

Lym hoblastic
CD20-, CD3+

Peri pheral T-Cell

TIC Large T/Null Cell

CD20-, CD3+

CD10+, CD5-

CD10-, CD5+

CD10-, CD5-

CD10-, CD5-

CD10-, CD5+

CD10-, CD5-

Tdt+

CD30+, CD15-

CD23+

CD23-

CD23-

CD24-, PRAD1+

Tdt-

EMA+, ALK+

International Prognostic Index

prognosis of patients with aggressive non-Hodgkin's lymphoma.

One point is assigned for each of the following risk factors: Age greater than 60 years Stage III or IV disease Elevated serum LDH ECOG/Zubrod performance status of 2, 3, or 4 More than 1 extranodal site The sum of the points allotted correlates with the following risk groups: Low risk (0-1 points) - 5-year survival of 73% Low-intermediate risk (2 points) - 5-year survival of 51% High-intermediate risk (3 points) - 5-year survival of 43% High risk (4-5 points) - 5-year survival of 26%

Follicular Lymphoma International Prognostic Index (FLIPI)

One point is assigned for each of the following adverse prognostic factors: Age greater than 60 years Stage III or IV disease Greater than 4 lymph node groups involved Serum hemoglobin less than 12 g/dL Elevated serum LDH The sum of the points allotted correlates with the following risk groups: Low risk (0-1 points) - 5 and 10-year survivals of 91% and 71%, respectively Intermediate risk (2 points) - 5 and 10-year survivals of 78% and 51%, respectively High risk (3-5 points) - 5 and 10-year survivals of 53% and 36%, respectively

Mantle Cell Lymphoma International Prognostic Index (MIPI)

The point values are assigned as follows: 0 points: Age less than 50 years, ECOG performance status of 0-1, LDH less than 0.67 of the upper limit of normal, or WBC of less than 6,700 cells/mcl 1 point: Age 50-59, LDH 0.67-0.99 of the upper limit of normal, or WBC 6,700 to 9,999 cells/mcl 2 points: Age 60-69, ECOG performance status of 2-4, LDH 1-1.49 times the upper limit of normal, or WBC 10,000-14,000 cells/mcl 3 points: Age 70 or greater, LDH 1.5 times the upper limit of normal or greater, and WBC of 15,000 cells/mcl or greater The sum of the allotted points correlates with the following risk groups: Low risk (0-3 points) - median survival not yet reached Intermediate risk (4-5 points) - median survival of 51 months High risk (6-11 points) - median survival of 29 months

Staging Ann Arbor

Stage I Involvement of a single lymph-node region or lymphoid structure (eg, spleen, thymus, Waldeyers ring) or involvement of a single extralymphatic site (IE) Stage II Involvement of two or more lymph-node regions on the same site of the diaphragm (II) or localized contiguous involvement of only one extranodal organ or side and its regional lymph-nodes with or without other lymph node regions on the same side of the diaphragm (IIE) Stage III Involvement of lymph-node regions on both sides of the diaphragm (III), which may also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of only one extranodal organ side (IIIE) or both (IIISE) Stage IV Disseminated (multifocal) involvement of one or more extranodal organs or tissues, with or without associated lymph-node involvement or isolated extralymphatic organ involvement with distant (non-regional) nodal involvement

Note: The number of anatomic regions involved may be indicated by a subscript (eg, II3)