Pathology: Understanding Disease States
Elaine S. Jaffe, MD, is Distinguished Investigator at the National Institutes of Health National Cancer Institute (NCI). She is the final arbiter for challenging diagnostic problems submitted to her worldwide, personally reviewing more than 2,000 cases annually. The FASEB Excellence in Science Lifetime Achievement Award recognizes her pioneering work in the fields of hematology and hematopathology. Over the past 50 years, her work has changed how the diagnosis of lymphoma is made worldwide.
The award also recognizes Jaffe as a devoted educator and mentor. She has been recognized numerous times for her excellent teaching in the clinical setting and the laboratory. She consistently publishes with trainees as the first author of her manuscripts. Jaffe provides guidance to these trainees on how to perform clinical research and how high a bar is required to publish meaningful results.
Can you briefly discuss your background and what you do in your current role?
Jaffe: My parents were both immigrants to the U.S., born in shtetls (villages) in what is now Ukraine. My father was born in Steblov, and my mother in Ryzhanovka. My father's father, who was a cantor, came to the U.S. in 1914 with his two oldest children, expecting the rest of the family to follow once he was settled. They had cousins already living in New York to facilitate their arrival. However, World War I delayed the rest of the family's departure, including my father, his three younger siblings, and his mother. My father was the "man of the house " for the next seven years.
He was a strong figure but being the head of the household for seven years helped mold his personality. He arrived in the U.S. at age 16 and immediately went to work as an apprentice in the diamond trade. He worked his way up in the business, eventually establishing his firm in New York's diamond district on 47th Street. My mother was an active participant in his business, traveling to NYC each day with him to work. Thus, while she was not a "traditional" working mother with her independent career, she was a good role model for me.
My parents were typical of many immigrant families in having the drive to succeed in their new homeland. Our house was always the center for extended family events and gatherings. Political events and intense debate usually dominated conversations. My older sister, Louise, ahead of me by eight years in school, headed off to Cornell where she majored in government, graduating Phi Beta Kappa in 1957.
As a diagnostic hematopathologist, many of my seminal publications have had their inception in a clinical diagnostic case. My clinical and investigational studies have been intertwined to enhance our understanding of disease. I believe that disease discovery and disease definition are critical first steps in elucidating pathogenesis. Most insights into the molecular pathogenesis of lymphomas have followed on the heels of a precise description based on clinical, pathological, or immunophenotypic grounds. The discovery of the disease–often recognized by an astute pathologist or clinician, nearly always precedes the discovery of gene or genes. However, the process is iterative, such that knowledge of the genetic pathogenesis provides new diagnostic tools, which help define the disease and its borderlands.
Hematopathology is a field that requires close collaboration between the pathologist and the clinician. In hematopathology, the clinical findings are integral to making the correct diagnosis, but the hematopathologist is part of the clinical team in many other respects. Clinicians often seek my opinion about the clinical management for rare conditions they may encounter in their practice, exemplifying the collaborative nature of patient care. We receive about two thousand cases in consultation each year, many of which are submitted from academic teaching hospitals.
When did you decide to become a pathologist? Were you inspired by someone (or something)?
Jaffe: While it would be convenient to say that I always knew that hematopathology would be my life’s work, my career has been characterized by serendipity and being in the right place at the right time. Nevertheless, I cannot imagine another career path in medicine besides pathology. As a second-year medical student at Cornell University Medical College, I had a yearlong course in pathology. It formed the basis for the subsequent clinical years, and I feel I acquired most of my knowledge of clinical medicine in that course.
I saw pathology as laying the groundwork for understanding all disease states. Looking at a microscopic slide of diseased tissue provides a wealth of information regarding the pathogenesis and pathophysiology of disease. Pathologists are very visual in their approach, and many pursue art or photography as hobbies. Most are very adept at recognizing faces or images, as well as discerning the varied microscopic patterns that inform us about the diagnosis and the underlying pathobiology.
At Cornell, we had the usual series of lectures taking us through various organ systems. Most of these were not very memorable. However, I had the good fortune to be in a lab group directed by two eager pathology residents who were destined to pursue careers in academic medicine and were excited about teaching. Dr. Janet Mouradian completed her pathology residency at Cornell and stayed on as a staff surgical pathologist, ultimately becoming Director of Surgical Pathology at New York Hospital. Dr. Daniel Alonso also stayed at Cornell, eventually becoming Dean of Students. He continued his career in administration, becoming the founding Dean of Cornell Medicine in Qatar, the first American medical school to be set up overseas.
Your nomination includes the research you’ve conducted and published. What drew you to this field of research? What do you wish to achieve with your research?
Jaffe: I entered the field of lymphoma research at a unique time when all of the planets were aligned, creating great opportunities. It was an era when dramatic advances were being made in chemotherapy at the NCI led by Vincent DeVita, Paul Carbone, George Canellos, Bruce Chabner, and many others. The advances in therapy made it more important and relevant to sort out different diseases among the many different types of lymphoma. At the same time, immunology and molecular biology advances enabled us to take hematopathology beyond pure morphology. However, it is the integration of all of these disciplines that has really changed the way we diagnose lymphomas. My goal is to recognize new diseases and define currently known diseases as a method to improve therapy and patient care.
What discovery are you most proud of?
Jaffe: The idea of malignant transformation of cells through a multistep process of accumulating genetic and molecular events is well accepted and recognized in solid tumors. These concepts have been difficult to apply in the lymphoid system, where the cells naturally circulate and colonize different tissues. Our studies in recent years have focused on these early lesions, both follicular lymphoma in situ and, more recently, mantle cell in situ. We first described follicular lymphoma in situ in 2002, but its clinical significance remained uncertain. In a recent study, we reevaluated our original series and more recently diagnosed cases to develop criteria for distinguishing FLIS from partial involvement by follicular lymphoma (PFL). FLIS can be reliably distinguished from PFL and has a very low rate of progression to clinically significant FL. However, even PFL tends to present with more localized disease. FLIS may represent the tissue counterpart of circulating t(14;18)-positive B-cells. In recent work, we have explored the genetics of these early lesions, showing stepwise increase in genetic complexity from FLIS, PL, follicular lymphoma Grade 1-2, and follicular lymphoma Grade 3. This study is of important clinical impact because it provides crucial guidance to pathologists and clinicians encountering patients with these in situ lesions.
This discovery followed on the heels of my early work on follicular lymphoma, recognizing it as a B-cell neoplasm related to the lymphoid follicle. Published in the New England Journal of Medicine, it became a citation classic.
Much of my work has revolved around FL as a model for underlying B-cell lymphomas and the immune system. Our work provided evidence for lineage plasticity in mature B-cells derived from follicular lymphoma; we identified cases of histiocytic/dendritic cell sarcoma clonally related to the underlying follicular lymphoma, having common IG gene rearrangement pattern, and sharing the BCL2/IGH translocation as an early even in a hematolymphoid stem cell. Our report was the first to document lineage switch in mature lymphoid cells in the human system and to provide a mechanism for transdifferentiation through alterations in transcription factor expression. Our subsequent work identified distinguished genomic alterations associated with the lineage switch in the original neoplastic clone. These studies opened new insights into the basis of cellular differentiation.
The Excellence in Science Award also celebrates your contributions to the broader scientific community and your history of training students and postdoctoral fellows. What have you found the most meaningful about such service?
Jaffe: Mentoring trainees and lab members has been a major focus of our group, and the success that our trainees have had since leaving the NIH is evidence of our dedication to these goals. Since my appointment as head of the Hematopathology Section in 1980, we have trained more than 75 clinical fellows in hematopathology. More than 75 percent of our fellows stay in academic medicine. Most of them have gone to leadership positions, such as head of a hematopathology unit or head of a department. In addition, I have trained early-career fellows from countries in Europe, Asia, and South America, who have returned to their home countries to continue their careers in pathology and research. In 2001 I received the Outstanding Mentor Award from the National Cancer Institute and the Distinguished Clinical Teacher Award in 2006 from the NIH Clinical Fellows Committee.
As president of the Society for Hematopathology, I had the opportunity to help bring about worldwide consensus for the classification of all hematolymphoid neoplasms, represented by the World Health Organization classification published in 2001. This was the first internationally accepted classification on a worldwide basis. The citation for the Lennert Prize from the European Association for Haematopathology stated, “… for your merits in developing a unique lymphoma classification, erasing the differences between both Atlantic sides and your enormous and successful effort to integrate basic research and clinical diagnosis in the quotidian life of Haematopathology.” We worked hand in hand with pathologists, clinicians, and scientists during Clinical Advisory Committee meetings to achieve this consensus and acceptance.
Having a worldwide impact on my discipline is extremely gratifying and brings me great joy and satisfaction.
What does it mean to you to receive the Excellence in Science Award?
Jaffe: I am extremely humbled by this award, especially when I look at the outstanding scientists who received it before me. I have always thought of myself as more of a clinician than a basic scientist. My daily work involves making diagnoses that will impact patient lives–hopefully for the better. However, the most exciting part of my work is discovery–identifying new diseases and understanding their pathogenesis. I truly practice bench to bedside and back again. It is gratifying to see clinical and translational research recognized in this way.
What advice would you give to young women entering this field?
Jaffe: Pick an area of work that excites you. I look forward to coming to work every day. You won’t do well if you don’t enjoy what you are doing. When you start a project, take it to completion. I find some young physicians are distracted by too many shiny objects and do not follow through on studies to completion or resolution. Not every project is successful, but you have to make an effort to complete it and not move on prematurely to another venture.
Elaine S. Jaffe, MD, is a member of the American Society for Investigative Pathology, a FASEB member society.