HAEMATOPATHOLOGY A Leap Forward in Pathology (a Personal …

HAEMATOPATHOLOGY A Leap Forward in Pathology

(a Personal View)

Jerónimo Forteza Vila

Meeting of the Lymphoma Working GroupsHaematologic Tumours Line

One of the first references of Haematopathology in the One of the first references of Haematopathology in the literature is the description in 1832 entitled “literature is the description in 1832 entitled “On some On some morbid appearance of the absorbent glands and spleenmorbid appearance of the absorbent glands and spleen” ” by Thomas Hodgkin, prosector at the Guy hospital in by Thomas Hodgkin, prosector at the Guy hospital in London.London.

This paper which includes seven autopsy cases with This paper which includes seven autopsy cases with macroscopic description and clinical data clearly macroscopic description and clinical data clearly emphasizes the clinicopathologic correlation.emphasizes the clinicopathologic correlation.

Watercolor by Robert Carswell on Watercolor by Robert Carswell on an autopsy by Thomas Hodgkinan autopsy by Thomas Hodgkin

It was Sir Samuel Wilks, Professor of Pathology also from London, who later called these cases It was Sir Samuel Wilks, Professor of Pathology also from London, who later called these cases Hodgkin’s disease in his treatise “Hodgkin’s disease in his treatise “Enlargement of the lymphatic glands and spleen”.Enlargement of the lymphatic glands and spleen”.

The description by Hodgkin and the later review by Wilks only make reference to macroscopic The description by Hodgkin and the later review by Wilks only make reference to macroscopic Pathology and its clinical correlationPathology and its clinical correlation

Hodgkin’s disease has been Hodgkin’s disease has been histologically characterized by a histologically characterized by a proliferation with a minority of proliferation with a minority of neoplastic cells, Hodgkin cells and neoplastic cells, Hodgkin cells and Reed-Sternberg cells with its Reed-Sternberg cells with its variants, in a variable background variants, in a variable background formed by lymphocytes, formed by lymphocytes, eosinophils, histiocytes and eosinophils, histiocytes and plasma cells.plasma cells.

These tumor cells account for 0.1 These tumor cells account for 0.1 to 10% of all the cells.to 10% of all the cells.

Reed-Sternberg cell in Hodking’s lymphoma (HE; 100X)Reed-Sternberg cell in Hodking’s lymphoma (HE; 100X)

Paraffin-embedded tissue of one of the original cases byThomas Hodgkin Paraffin-embedded tissue of one of the original cases byThomas Hodgkin immunostained with CD15 (David Mason)immunostained with CD15 (David Mason)

Laser microdissectorLaser microdissector

B-cell mature, molecular studies B-cell mature, molecular studies (single-cell PCR)(single-cell PCR)

((Marafioti T and cols.Marafioti T and cols. NN EnglEngl JJ Med Med ((19971997)) 337: 337: 453-458453-458))

It is nowadays clear that It is nowadays clear that Hodgkin’s disease is a Hodgkin’s disease is a lymphoma and -more lymphoma and -more specifically- a predominently B-specifically- a predominently B-cell lymphoid proliferation, as cell lymphoid proliferation, as evidenced from its evidenced from its immunophenotype and its immunophenotype and its molecular make-up, the latter molecular make-up, the latter determined by single cell PCR determined by single cell PCR studies.studies.

Consequently, the current WHO Consequently, the current WHO classification has appropriately classification has appropriately and unequivocally chosen the and unequivocally chosen the term Hodgkin lymphoma.term Hodgkin lymphoma.

IgIg gene rearrangements gene rearrangements > 90%> 90%B-cell originB-cell origin

Ig gene somatic mutationsIg gene somatic mutations Germinal center originGerminal center origin

One cell analysisOne cell analysis

Loss of B-cell identityLoss of B-cell identity

Kaplan stageKaplan stage Current stageCurrent stage

Evolution of the clinical management of the Hodgkin’s Lymphoma

Hodgkin’s LymphomaA Paradigm in Oncohaematology

• Hodgkin’s disease was the first condition described from a Hodgkin’s disease was the first condition described from a cytological base of the neoplastic cells characteristics (Reed-cytological base of the neoplastic cells characteristics (Reed-Sternberg cell).Sternberg cell).

• This was the first neoplasia where the clinical course This was the first neoplasia where the clinical course correlated with affected anatomical regions.correlated with affected anatomical regions.

• The development of Oncology is understood through the The development of Oncology is understood through the chronology of Hodgkin’s disease treatment.chronology of Hodgkin’s disease treatment.– Gilbert (1925), treated the destruction of the lesion with radiotherapy.Gilbert (1925), treated the destruction of the lesion with radiotherapy.– Rosenberg (1968), combines radiotherapy and chemotherapy in the Rosenberg (1968), combines radiotherapy and chemotherapy in the

treatment of Hodgkin’s disease.treatment of Hodgkin’s disease.• This was one of the first neoplasias treated with This was one of the first neoplasias treated with

chemotherapy and radiotherapy.chemotherapy and radiotherapy.

Haematopathology

Basis for the development of new technologies in

Surgical Pathology

Jérôme Lejeune (Paris, 1926-1994)Jérôme Lejeune (Paris, 1926-1994)

Philadelphia Chromosome in Chronic Myeloid LeukemiaPhiladelphia Chromosome in Chronic Myeloid Leukemia

FUSSION PROTEINWITH TYROSIN-KINASE

ACTIVITY

22

bcr

abl

Ph

(22q -)

bcr -abl

9 9

(q+)

Philadelphia Chromosomet(9;22) translocation

Inhibitor of the BCR-ABL Tyrosin-Kinase in Chronic Myeloid LeukemiaInhibitor of the BCR-ABL Tyrosin-Kinase in Chronic Myeloid LeukemiaBrian J. Druker. N Eng J Med (2001) 344: 1031Brian J. Druker. N Eng J Med (2001) 344: 1031

Dr. Brian J. DrukerDr. Brian J. DrukerOHSU Cancer Institute, Leukemia Center OHSU Cancer Institute, Leukemia Center (Portland, Oregon, USA)(Portland, Oregon, USA)

Targeting the BCR-ABL tyrosine kynase in chronic myeloid leukaemiaTargeting the BCR-ABL tyrosine kynase in chronic myeloid leukaemia

N Engl J Med, 2001, Vol.344 (14): 1084-1086N Engl J Med, 2001, Vol.344 (14): 1084-1086

Numerical aberrations in cariotyping can be detected by FISH using Color Species Numerical aberrations in cariotyping can be detected by FISH using Color Species Banding (RxFISH)Banding (RxFISH)

Courtesy of Francesc Solé (Barcelona)Courtesy of Francesc Solé (Barcelona)

(A)(A) Burkitt’s Lymphoma (HE) (B)Burkitt’s Lymphoma (HE) (B) t(8;14) translocaton in Burkitt’s lymphoma (FISH)t(8;14) translocaton in Burkitt’s lymphoma (FISH)

Immunostaining for CD30 in a Reed-Sternberg cell in membrane and GolgiImmunostaining for CD30 in a Reed-Sternberg cell in membrane and Golgi

David MasonDavid Mason(Oxford)(Oxford)

César Milsten (Cambridge)César Milsten (Cambridge)Nobel Prize in Medicine, 1984Nobel Prize in Medicine, 1984

Reed-Sternberg and Hodgkin cells, Reed-Sternberg and Hodgkin cells, detected by double immunostaining:detected by double immunostaining:

CD15 (Golgi) in red and MiB-1 (nucleus) CD15 (Golgi) in red and MiB-1 (nucleus) in brownin brown

Ignacio Solas in La Coruña (1982), Ignacio Solas in La Coruña (1982), explaining the method of double labelling explaining the method of double labelling

published that year in the published that year in the Journal of Journal of HistochemistryHistochemistry by Bruno Falini and by Bruno Falini and

coworkerscoworkers

T-cell with E rosette of sheep erythrocytes, courtesy of Juan Rosai (1974)T-cell with E rosette of sheep erythrocytes, courtesy of Juan Rosai (1974)

““Helped to transform hematopathology from a difficult morphologic exercise into a Helped to transform hematopathology from a difficult morphologic exercise into a functionally oriented biologic science”(Berard)functionally oriented biologic science”(Berard)

Schrödinger wrote that the first Schrödinger wrote that the first half of the 20th century was the half of the 20th century was the age of the Physics and the age of the Physics and the second half was the age of second half was the age of BiologyBiology

J. Watson and F. CrickJ. Watson and F. Crick

Mantle cell lymphoma genotypes identified with CGH to BAC microarrays define a Mantle cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome.leukemic subgroup of disease and predict patient outcome. Courtesy of Dr. Jose Angel Courtesy of Dr. Jose Angel

Climent, CIMA (Navarra)Climent, CIMA (Navarra)

Haematopathology

A team work effort and consensus

(Paradigm of the globalisation of Pathology)

Pathologists, radiation oncologists, clinical oncologists, epidemiologists and statisticians who Pathologists, radiation oncologists, clinical oncologists, epidemiologists and statisticians who participated in the final meeting held at Palo Alto, California in 1980 and which generated the participated in the final meeting held at Palo Alto, California in 1980 and which generated the

Working Formulation of Non-Hodgkin’s Lymphomas for Clinical UsageWorking Formulation of Non-Hodgkin’s Lymphomas for Clinical Usage

Experts of the Working Formulation Group at Palo Alto (California, 1980). From left to right:Experts of the Working Formulation Group at Palo Alto (California, 1980). From left to right:G. O´Connor (WHO Classification), R. Dorfman (Dorfman Classification), K. Lennert (Kiel G. O´Connor (WHO Classification), R. Dorfman (Dorfman Classification), K. Lennert (Kiel

Classification), K. Henry (British National Lymphoma Investigation Classification), R. Lukes (Lukes Classification), K. Henry (British National Lymphoma Investigation Classification), R. Lukes (Lukes and Collins Classification), H. Rappaport (Rappaport Classification)and Collins Classification), H. Rappaport (Rappaport Classification)

(A)(A) Airlie House Meeting (1997); Clinical Airlie House Meeting (1997); Clinical Advisory Committee for the Lymphoma Advisory Committee for the Lymphoma Classification, previous WHO 2001.Classification, previous WHO 2001.

(D)(D) Airlie House Meeting (2007); Clinical Airlie House Meeting (2007); Clinical Advisory Committee for Nature Advisory Committee for Nature Lymphoid NeoplasmsLymphoid Neoplasms

Introduction to the History of Spanish

Haematopathology

(Data from Horacio Oliva)

History of Spanish Haematopathology (1)

• JOSE EZARQUÍ (1827)

• MANUEL HURTADO DE MENDOZA (1830)

• CARDENAL (1877)

• RAFAEL ARIZA Y ESPEJO (1877)

• GUSTAVO PITTALUGA (1876-1956)

• PEDRO FARRERAS VALENTI (1915-1968)

History of Spanish Haematopathology (2)

•MANUEL MORALES PLEGUEZUELO (1898-1967)

•GERÓNIMO FORTEZA BOVER (1911-1975)

Only two haematopathologists, Morales and Forteza, appear in the book by Karl Lennert, in the handbook of Lubarsch and Henke.

History of Spanish Haematopathology (3)

Dr. Morales PleguezueloDr. Morales Pleguezuelo Fundación Jiménez DíazFundación Jiménez Díaz(Madrid)(Madrid)

Dr. Gerónimo Forteza Bover in 1942 at Dr. Gerónimo Forteza Bover in 1942 at his first private Laboratory in Conde de his first private Laboratory in Conde de

Montornés street, no. 2 (Valencia)Montornés street, no. 2 (Valencia)

A personal viewA personal view

19471947

Clinical Laboratory of the School of Medicine (Valencia, 1965)Clinical Laboratory of the School of Medicine (Valencia, 1965)From left to right: Dr. José Esquerdo (Pathologist), Prof. Manuel Beltrán Báguena (full From left to right: Dr. José Esquerdo (Pathologist), Prof. Manuel Beltrán Báguena (full

proffesor of Internal Medicine) and Prof. Gerónimo Forteza Bover (haematopathologist)proffesor of Internal Medicine) and Prof. Gerónimo Forteza Bover (haematopathologist)

(A) W. Dameshek (1900-1969). “Lacking only are electron micrographs” (1964) (B) (A) W. Dameshek (1900-1969). “Lacking only are electron micrographs” (1964) (B) Periferal blood smear stained with May-Grümwald-Giemsa in Chronic Myeloid Leukemia Periferal blood smear stained with May-Grümwald-Giemsa in Chronic Myeloid Leukemia (C) Cariotype of Myeloid Chronic Leukemia with Philladelphia Chromosome (D) Atlas of (C) Cariotype of Myeloid Chronic Leukemia with Philladelphia Chromosome (D) Atlas of

Blood Cytology (1964)Blood Cytology (1964)

D

A

Dr. Gerónimo Forteza Bover (1965 and 1969) with an electron microscope at his Dr. Gerónimo Forteza Bover (1965 and 1969) with an electron microscope at his Laboratory in Jorge Juan 15, Valencia.Laboratory in Jorge Juan 15, Valencia.

This laboratory was the basis of the Cytologic Investigations Institute (1974)This laboratory was the basis of the Cytologic Investigations Institute (1974)

Histoautoradiography inHistoautoradiography inElectron MicroscopyElectron Microscopy

Dr. Gerónimo Forteza Bover at the Cytologic Investigations Institute, in a seminar Dr. Gerónimo Forteza Bover at the Cytologic Investigations Institute, in a seminar meeting (1974)meeting (1974)

Cytologic Investigations Institute at ValenciaCytologic Investigations Institute at Valencia(founded in 1970, Caja de Ahorros de Valencia)(founded in 1970, Caja de Ahorros de Valencia)

Dr. Gerónimo Forteza Bover was the first directorDr. Gerónimo Forteza Bover was the first director

Haematopathology and Spanish Histological

School

Pio del Rio Hortega

Histology laboratoryHistology laboratory

School of Medicine (Santiago, 1928)School of Medicine (Santiago, 1928)

MicrogliaMicroglia

During time lymphomas were called microgliomasDuring time lymphomas were called microgliomas

Fernando de Castro

Glomus caroticumGlomus caroticum

Electron microscopy of the Electron microscopy of the bone marrow innervationbone marrow innervation

Ulm (Germany)Ulm (Germany)

Bone marrow innervation with Bone marrow innervation with silver stainsilver stain

(Fernando de Castro’s (Fernando de Castro’s technique)technique)

W. Calvo and J. Forteza Vila (1969-1971)W. Calvo and J. Forteza Vila (1969-1971)

Haematopathology and the Spanish University

(Honoris Causa)

Karl Lennert (Universidad Autónoma de Madrid, 1995)Karl Lennert (Universidad Autónoma de Madrid, 1995)

Horacio Oliva and Francisco Nogales in Horacio Oliva and Francisco Nogales in the Honoris Causa Ceremony of Dr. H. the Honoris Causa Ceremony of Dr. H. Oliva (Granada, 1998)Oliva (Granada, 1998)

J. Rosai (Santiago de Compostela, 1999)J. Rosai (Santiago de Compostela, 1999)Honoris Causa speech “Apología de la Hematoxilina-Eosina”Honoris Causa speech “Apología de la Hematoxilina-Eosina”

Elaine Jaffe (Universidad de Barcelona, 2008)Elaine Jaffe (Universidad de Barcelona, 2008)Honoris Causa speech “The Microscope as a Tool for Disease Discovery”Honoris Causa speech “The Microscope as a Tool for Disease Discovery”

History of Spanish Haematopathology

Spanish Lymphoma Club

Lymphoma Symposiums (1975-1978)Hospital Juan Canalejo (La Coruña)

Dr. Carmen RivasI Lymphoma Symposium

(La Coruña, 1975)

II Lymphoma Symposium (La Coruña, 1978)II Lymphoma Symposium (La Coruña, 1978)

Horacio Oliva (II Lymphoma Symposium, La Coruña, 1978)Horacio Oliva (II Lymphoma Symposium, La Coruña, 1978)

Augusto Moragas (Santiago de Compostela, 1985)Augusto Moragas (Santiago de Compostela, 1985)

Haematopathology(Bench to Bedside – Bedside to Bench)

• The knowledge in Haematopathology has gone beyond classical The knowledge in Haematopathology has gone beyond classical morphological diagnoses to gain a better understanding of diseases and morphological diagnoses to gain a better understanding of diseases and prognosis.prognosis.

• It has strengthened Surgical Pathology and provided Haematology with It has strengthened Surgical Pathology and provided Haematology with firm and secure diagnoses, thus spearheading the advance of current firm and secure diagnoses, thus spearheading the advance of current Oncology.Oncology.

• Cytogenetics and biologic knowledge has taken targeted therapies to Cytogenetics and biologic knowledge has taken targeted therapies to other fields in Oncology.other fields in Oncology.

• Its advance and knowledge is the result of the incorporation of Its advance and knowledge is the result of the incorporation of immunological and biological advances in diagnosis and therapeutics, immunological and biological advances in diagnosis and therapeutics, and to a teamwork effort of interdisciplinary groups. and to a teamwork effort of interdisciplinary groups.

““Lecture of Anatomy of Dr. Nicolaes Tulp” – Rembrandt, 1632 (modified)Lecture of Anatomy of Dr. Nicolaes Tulp” – Rembrandt, 1632 (modified)Courtesy of Carlos Cordón (New York, USA)Courtesy of Carlos Cordón (New York, USA)