What first drew you to pathology, and hematopathology in particular?
As a second-year medical student at Cornell University Medical College, I took a year-long pathology course that laid the foundation for my understanding of clinical medicine. It was in that course that I truly saw medicine come alive under the microscope. Pathology offered a window into the mechanisms of disease – pathobiology and pathogenesis – which fascinated me deeply.
I was fortunate to be part of a lab group led by two enthusiastic pathology residents who were passionate about teaching and destined for careers in academic medicine. Janet Mouradian went on to become Director of Surgical Pathology at New York Hospital, while Daniel Alonso later became Dean of Students at Cornell and the founding Dean of Cornell Medicine in Qatar. Their energy and commitment to the field were contagious and profoundly influenced my decision to pursue pathology.
My interest in hematopathology developed at a pivotal moment in medical science – when major discoveries in chemotherapy, immunology, and molecular biology were reshaping the field. Advances at the National Cancer Institute were transforming lymphoma treatment, making accurate disease classification more essential than ever. Meanwhile, new insights into immune function allowed pathologists to move beyond morphology and integrate immunologic and molecular data into diagnosis.
In the 1960s, two breakthroughs revolutionized our understanding of the immune system and its malignancies: first, the discovery that lymphocytes – once thought to be terminally differentiated – could transform into proliferative, blastoid cells in response to antigens or mitogens; and second, the recognition of distinct lymphocyte lineages (T cells, B cells, and natural killer cells) that were morphologically similar but functionally different. By the time I began my hematopathology fellowship in 1972, immunologists were just beginning to develop laboratory methods to distinguish these cell types – ushering in a new era for diagnostic pathology.
Looking back on your career so far, are there particular cases or discoveries that stand out as especially meaningful?
One of my first papers, published in the New England Journal of Medicine in 1974, proved to be pivotal. It demonstrated that the cells of what was then termed “nodular lymphoma” expressed the same receptors and markers as normal germinal center B cells. This finding provided critical evidence linking nodular lymphoma to the normal lymphoid follicle. The paper, which later became a Citation Classic, was among the first to show that neoplastic lymphoid cells recapitulate the functional properties of their normal counterparts. It also contributed to the adoption of the term follicular lymphoma for this tumor – now recognized as one of the most common lymphomas, particularly in Western populations.
Traditionally, hematopoietic differentiation has been viewed as a linear process, in which cells become progressively lineage-committed. However, clinical data have revealed that two hematopoietic tumors in the same patient may share identical genetic abnormalities, suggesting that neoplasms of one lineage can “transdifferentiate” into phenotypically distinct but genetically related tumors of another lineage. For example, we identified patients with lymphoblastic leukemias or lymphomas who later developed histiocytic or dendritic cell (H/DC) tumors. In these cases, both neoplasms carried identical immunoglobulin or T-cell receptor gene rearrangements, confirming a clonal relationship between the two.
While lineage plasticity is more common in precursor cell tumors, reprogramming of mature human B cells into other lineages had not been demonstrated prior to our work – though it had been shown in murine models. We later identified a series of H/DC tumors arising in patients with prior follicular lymphoma (FL). In every case, the FL cells harbored the characteristic BCL2/JH translocation, and the subsequent H/DC tumors carried the same BCL2/JH translocation and identical immunoglobulin gene rearrangements, confirming a shared clonal origin.
Our findings revealed that transdifferentiation of neoplastic B cells occurred through downregulation of the B-cell transcription factor PAX5 and upregulation of myeloid-associated transcription factors, such as CEBPβ. This work, published as a Plenary paper in Blood, provided some of the first evidence of lineage reprogramming in human lymphoid malignancies.
How has collaboration shaped your work?
A key aspect of my work has always been close collaboration with clinical oncologists, hematologists, and molecular biologists – partnerships that have been essential to advancing our research. These collaborations often extend internationally, frequently beginning with the exchange of an interesting case from a colleague abroad or through visiting pathologists and investigators who come to my laboratory to collaborate directly.
As a member of the International Lymphoma Study Group (ILSG) – a consortium of about 25 hematopathologists from the US, Europe, and Asia – we helped pioneer the modern classification of lymphomas and fostered a spirit of global cooperation in hematopathology. The ILSG was responsible for developing the Revised European-American Lymphoma (REAL) classification published in 1994. Following extensive validation in clinical trials, it was rapidly adopted as the international standard and became the foundation for the WHO classification, first published in 2001 and continuously updated over the past two decades.
Another highly successful international effort has been the Leukemia/Lymphoma Molecular Profiling Project (LLMPP), launched in 2002 and still active today. This collaboration brings together five to eight leading treatment centers and research groups, integrating the expertise of pathologists, clinicians, and basic scientists to advance the molecular understanding of hematologic malignancies.
What’s your favorite aspect of your work?
I truly enjoy examining challenging cases and solving complex diagnostic problems. Every day brings new puzzles to unravel – it’s a bit like being a detective, gathering clues and piecing together the answer. Working with residents and fellows adds another layer of fulfillment; watching them grow and advance in their careers is deeply rewarding. My fellows are my “apples,” and as the saying goes, the apples never fall far from the tree.
What’s the most difficult aspect of your work?
It is simply not having enough hours in the day. I typically spend 10 to 11 hours in the office each day and often come in at least one day on the weekend. I enjoy writing papers, but it requires focus and uninterrupted time – something rarely available during regular working hours.
I’ve also noticed that residents and fellows today don’t write as well as they once did; basic grammar and composition no longer seem to be emphasized in education. I’m well known for my red pen, which I use to mark up reports drafted by trainees, and I keep a copy of The Elements of Style by Strunk and White above my desk as a reminder of the importance of clear, proper English.
In your view, what are the most pressing diagnostic challenges in hematopathology today?
The growing reliance on needle core biopsies is presenting significant – sometimes insurmountable – diagnostic challenges. Evaluating the architecture of a lymph node is nearly impossible from a core biopsy alone. Many lymphomas are focal, so sampling error is a major concern. In addition, core biopsies often yield insufficient tissue for the full range of ancillary studies now required for accurate diagnosis. This limitation also reduces our ability to archive tissue for future clinical or research use, hindering both diagnostic precision and scientific advancement.
How do you see digital pathology, AI, and other emerging technologies influencing hematopathology and general practice?
We are only beginning to explore the use of AI in our work. I believe it holds great potential, but applying it effectively remains challenging – especially since tissue processing varies between laboratories, often introducing artifacts and subtle changes in cellular detail. Whole slide imaging, however, has already proven to be a valuable tool. It enhances efficiency in case review and makes it much easier to access and compare prior biopsies without the need to locate physical slides, which can sometimes be lost or misplaced.
Do you think current medical curricula adequately expose students to pathology as a specialty?
Medical students today often receive little or no exposure to pathology during their training and therefore rarely consider it as a career. With changes to medical school curricula, year-long pathology courses have largely been eliminated. We need to find new ways to introduce students to pathology – showing them its central role in medicine and inspiring the next generation to join the field.
What advice would you give to early-career pathologists navigating a rapidly changing field?
Pathologists must stay current with emerging technologies. Even when tests are performed by outside reference laboratories, it’s essential to understand the underlying methods and their limitations.
Equally important is maintaining close collaboration with clinicians. Accurate diagnosis often depends on having a complete and detailed clinical history. Too often, specimens arrive labeled only as a biopsy, with no background information provided. For our consultation cases, we do not accept submissions without adequate clinical history – and I believe all pathologists should adopt the same standard in their own practice.
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