The term tumor surveillance implies that the immune system provides key defense mechanisms against the development of cancer. In 1968, Dr. Starzl reported at several national or international medical conferences that erosion of this shield by chronic antirejection treatment was the probable cause of newly developing (de novo) malignancies in his organ recipients and those elsewhere [ref 1]. The most common tumors were B-cell lymphomas that later were linked to the Epstein-Barr virus and called post-transplant lymphoproliferative disorders (PTLD) (Figure 1). Other tumors included facial and uterine cervical cancers and Kaposi sarcomas that are associated with the Herpes virus family. Dr. Starzl developed the subject fully in Chapter 17 of his 1969 book, Experience in Hepatic Transplantation and in a monograph that presaged today’s cellular immunotherapies for cancer (Transplantation Reviews 7:112-145, 1971). Dr. Israel Penn, who joined Dr. Starzl’s Colorado team in July 1968, established an International Registry of these oncologic complications [ref 1]. Two decades later, the contributed cases had ballooned to more than 5000.
Between 1970 and 1984, the hypothesis of immune surveillance had lost credibility, largely because no support for it could be found in the nude mouse model of immune deficiency. The concept was revitalized by Dr. Starzl’s 1984 report in The Lancet describing the regression and disappearance of the B cell lymphomas (PTLDs) after reduction or stoppage of immunosuppression in kidney, liver, and heart recipients [ref 2]. Because the cases provided the first documented examples of immune surveillance of a human malignancy, the article became one of the most highly cited in the transplantation and oncology literature (1100 citations by 2011). A follow-up pathology study [ref 3] generated another 600 citations. The cellular and molecular basis for these observations has been explored in hundreds of subsequent experiments. Inexplicably at the time, but understandable after the microchimerism discoveries of 1992 (See: Discovery of Microchimerism, A New Transplant Immunology Paradigm, Generalization of the Transplant Paradigm and Therapeutic Implications) regression of the tumors frequently occurred after immunosuppression withdrawal without rejection of the organ graft.
From the standpoint of tumor immunosurveillance, the theoretical 1971 paper did not garner the attention that the evidence-based publications attracted over subsequent years. As Lai et al. observed (Transplant Int 1-2, 2012), the critical papers for the development of a field are not necessarily the most often cited, as their message is often usurped by subsequent works that absorb the message and themselves become the carriers of the information. This so-called "obliteration by incorporation" [Garfield E, JAMA 2;257; 1987] is a natural evolution due to the tendency to cite the most recent publications that typically have been written after the battles have been fought and the “obviously wrong” hypotheses have been found to be, indeed, correct. The very real effects of this self-evident statement are borne, in this field and others, by those who have run this gauntlet of reprobation.
From a more objective standpoint, the 3 primary references regarding transplant-associated neoplasia have been cited 2116 times and continue to be referenced several decades after publication (Figure 2). This work introduced a new model of therapy for transplant recipients who developed these tumors and continues to be applied today despite the introduction of numerous antineoplastic agents over the years. The 1971 paper establishing the hypothetical foundation of these papers adds an additional 109 citations, bringing the total to 2225. All told, Dr. Starzl authored 37 publications related to cancer immunology, with 5159 citations to date.
- Penn I, Hammond W, Brettschneider L, Starzl TE: Malignant lymphomas in transplantation patients. Transplant Proc 1:106-112, 1969.
- Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, Rosenthal JT, Hakala TR, Shaw BW Jr, Hardesty RL, Atchison RW, Jaffe R, Bahnson HT: Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1:583-587, 1984.
- Nalesnik MA, Jaffe R, Starzl TE, Demetris AJ, Porter K, Burnhan JA, Makowka L, Ho M, Locker J: The pathology of post transplant lymphoproliferative disorders occurring in the setting of cyclosporin A-prednisone immunosuppression. Am J Pathol 133:173-192, 1988.
- See Cancer Immunology Appendix for complete references and rank order citations
Annual cumulative citation frequency for all publications within Theme of Cancer Immunology