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Post-transplant malignant lymphoma
Post-Transplant Malignant Lymphoma Distinctive
Morphologic
ARTHUR J. MATAS,
Features Related to Its Pathogenesis
M.D.
BRUCE F. HERTEL, M.D. JUAN ROSAI,
M.D.
RICHARD L. SIMMONS, JOHN S. NAJARIAN,
M.D.
M.D.
Minneapolis, Minnesota
From the Departments of Surgery and Pathology, University of Minnesota, Minneapolis, Minnesota 55455. This study was supported by Grant AM 13083 from the U.S. Public Health Service. Requests for reprints should be addressed to Dr. Richard L. Simmons, Box 185-Mayo Memorial Building, University of Minnesota Hospitals, Minneapolis, Minnesota 55455. Manuscript accepted January 14, 1976.
716
November 1976
Malignant lymphoma developed in two patients after renal transplantation. In both, the central nervous system was involved. Histologic study of the tumors showed that they were composed of a monomorphous prollferation of cells characterized by a large vesicular nucleus, prominent basophlllc nucleolus and strongly py roninophlllc cytoplasm. The tumors thus would be classlfled as “diffuse large lymphold lymphomas with pyronlnophllia” or “immunoblastlc sarcomas” as described in the literature. Tumor cells resembled cells observed In the paracortex of antigenlcally stimulated lymph nodes, cells from malignant lymphomas in mice that were antigenlcally stimulated and from malignant lymphomas in patients with immunodeficiancy diseases or autoimmune disorders. The distinctive morphologic features of the tumors in the transplant recipients described provide further evidence that long-term antigenie stimulation may be important in their pathogenesis. The incidence of malignancy is increased in allograft recipients [ 11, and epidemiologic data show that the incidence of lymphoproliferative tumors has the greatest increase [ 21. These lesions have an unusual anatomic distribution; brain and spinal cord involvement occurred in 46 per cent of affected patients, and in 33 per cent the lesion was confined to these areas. This is in contrast to a 0.4 to 1.5 per cent involvement of the central nervous system in patients with malignant lymphoma who have not received transplants. Why malignant lymphomas in organ transplant recipients behave in such a bizarre fashion is unclear, although several hypotheses have been put forth [3-51. From January 1, 1968, to October 1, 1974, 523 renal transplants were performed in 452 patients at the University of Minnesota Hospitals. Patient selection, operative technic and postoperative management have been described previously [6,7]. In brief, following acceptance into the program, bilateral nephrectomy and splenectomy are performed prior to renal transplantation. Post-transplant immunosuppression therapy consists of the administration of antilymphocyte globulin, azathioprine and prednisone. Following renal transplantation, de novo lymphoreticular tumors have developed in two patients. We describe the pathologic findings in these two patients in order to further define the difference between these lesions and malignant lymphomas in patients who do not receive organ transplants. CASE REPORTS Case 1. A 50 year old woman with renal failure secondary to chronic glomerulonephritis received a cadaver renal transplant. Histocompatibility typing
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revealed two HL-A antigens in common between donor and recipient. Initial immunosuppression therapy consisted of the administration of antilymphoblast globulin [8], azathioprine and prednisone [7]. The postoperative course was uneventful and she was discharged three weeks after receiving the transplant, with normal renal function. Within six months of the transplantation, she was receiving 2.5 mg/kg azathioprine and 0.3 rng/kg prednisone. One year after the transplantation she experienced occipital headaches and expressive aphasia. Brain scan and cerebral angiography revealed a mass in the left mediofrontal region. Craniotomy was performed and a biopsy specimen was obtained. Postoperatively she received 4,000 rads to the left cerebral hemisphere and 5,500 rads to the left frontal lobe. She was discharged without weakness or aphasia. Ten months later behavioral changes developed; she had difficulty with mentation, emotional lability and a progressively deteriorating course until death 25 months after renal transplantation. No autopsy was performed. Case 2. A IO year old girl with renal failure secondary to hypocomplementemic glomerulonephritis received a renal transplant from her mother. She did well the first year after the transplant with the exception of two rejection episodes which responded well to therapy. One year after the transplant, she was receiving 1.5 mglkg azathioprine and 0.27 mg/kg prednisone. Thirteen months after the transplant she was admitted to the hospital with weakness, lethargy, fever and leukopenia. A chest roentgenogram showed bilateral nodular infiltrates. Bronchoscopy revealed a creamy exudate, but no bacteria, fungi or protozoa were seen. Open lung biopsy was performed to define a presumptive opportunisticinfection. Histologic sections, at that time, were interpreted as showing only chronic pneumonitis and pleuritis. Antibiotic treatment was begun and immunosuppression therapy discontinued. Three weeks after admission, cytomegalovirus (CMV) was reported in cultures of urine, sputum, bronchial washings and lung biopsy specimens. The patient had a progressive downhill course which was attributed to the systemic viral infection. Seven weeks after admission a Jacksonian seizure developed which started on the right side and became generalized. The seizure was associated with cardiopulmonary arrest, for which intubation and resuscitation were required. A postictal right hemiparesis persisted. An electroencephalogram was markedly abnormal with continuous spike and wave activity over the left hemisphere and independent foci in the left central and left occipital areas that suggested multiple lesions. She could not be weaned from the respirator and her condition continued to deteriorate. She
had a second cardiopulmonary arrest on the 59th hospital day (15 months after the transplant) from which she could not be resuscitated. MORPHOLOGY Cerse -1. Histologic evaluation of the brain biopsy specimen showed a highly cellular, widely infiltrating neoplasm with large areas of necrosis (Figure 1). Distention of Virchow-Robin spaces by tumor cells was a prominent feature. The tumor was composed of a monomorphous proliferation of cells characterized by large
MALIGNANT
LYMPHOMA-MATAS
ET AL.
[lo-121 oval nuclei containing one or several prominent basophilic nucleoli and finely distributed chromatin (Figure 2). The nuclear membranes were regular without significant wrinkling or cleaving. There was a moderate amount of amphophilic cytoplasm which was strongly pyroninophilic. Occasional plasmacytoid cells and mature plasma cells were present. No phagocytic activity was observed in the tumor cells. Case 2. At autopsy, malignant lymphoma was identified in the brain, liver and transplanted kidney, in the lung, heart and lymph nodes, but not in the bone marrow. The tumor was composed of a monomorphous proliferation of cells with large oval nuclei, prominent basophilic nucleoli and strongly pyroninophilic cytoplasm (Figure 3). The pattern was similar in all involved organs and the cytologic features were similar to those seen in Case 1. In the central nervous system, the tumor was present as multiple masses and diffusely in a perivascular distribution, frequently distending Virchow-Robin spaces. The liver grossly contained numerous tumor nodules up to 5 cm in diameter; microscopically, it also showed diffuse portal infiltration without significant sinusoidal involvement. The transplanted kidney showed widespread diffuse interstitial infiltration by tumor. Small aggregates of neoplastic cells were present in the myocardium. Lymph nodes were diffusely replaced by tumor. Retrospective review of the open lung biopsy specimen showed that the malignant lymphoma was present in the lung at the time of biopsy.
COMMENTS Penn et al. [9] and McKhann [lo] independently reported an increased incidence of cancer in the transpiant recipient in 1969; since that time 241 de novo malignancies in transplant recipients have been reported to Penn’s informal registry [ 11. This represents a significant increase over the number that would be expected to develop in the age-matched general population. Epidemiologic data compiled by Hoover and Fraumeni [ 21 disclosed that the incidence of lymphoreticular tumors showed the greatest increase. We have previously described our over-all experience with malignancy in patients before and after organ transplantation [ 111, and the two patients we describe in this report are the only ones in whom lymphoproliferative disorders developed. Most cases of malignant lymphoma reported in immunosuppressed patients have been classified under the broad term “reticulum cell sarcoma” or “histiocytic lymphoma,” the latter according to the Rappaport classification [ 121. Based on our material, we believe that many of these tumors represent a distinctive histologic entity. The classic histiocytic lymphoma is
November 1976
The American Journal of Medicine
Volume 61
717
POST-TRANSPLANT MALIGNANT LYMPHOMA-MATAS
ET AL
Figure 1. Case 1. Brain biopsy specimen of the tumor mass demonstrating perivascular infiltration typical of central nervous system lymphomas. Hematoxylin and eosin stain; original magnification X 120, reduced by 34 per cent.
Figure 2. Case 1. Higher magnification of the brain biopsy specimen demonstrating the monotonous population of uniform large cells with round to oval nuclei, multiple basophilic nucleoli and abundant cytoplasm. Hematoxylin and eosin stain; original magnification X 600, reduced by 32 per cent.
Ffgure 3. Case 2. Specimen of autopsy tissue from the cerebrum illustrating the perivascular as well as diffuse pattern of central nervous system involvement. Hematoxylin and eosin stain; original magnification X 120, reduced by 34 per cent. Met, higher magnification shows cells similar to those seen in Case 1 with more prominent plasmacytoid appearance. Hematoxylin and eosin stain; original magnification X 7,000, reduced by 34 per cent.
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1978
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Journal of Medicine
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POST-TRANSPLANT
characterized by a large, irregular, vesicular nucleus with a prominent eosinophilic nucleolus and abundant eosinophilic cytoplasm which is not pyroninophilic. By contrast, the lymphomas in our transplant recipients are composed of a monotonous proliferation of cells with large regular nuclei, diffusely distributed chromatin, several basophilic nucleoli and strongly pyroninophilic cytoplasm (Figures 1, 2 and 3). Similar cells are observed in the paracortex of antigenically-stimulated lymph nodes [ 13,141 and can be produced by stimulating peripheral lymphocytes with phytohemagglutinin in cultures [ 151. Dameshek [ 131 proposed the term “immunoblast” for such cells, and experimental evidence strongly supports their lymphocytic origin [15-181. In their functional classification of lymphomas, Lukes and Collins [ 16,171 propose the term “immunoblastic sarcoma” for lymphomas composed of these cells. They state that they have observed only B cell variants of such tumors, although it is not clear what studies were performed in determining cell types. Dorfman [ 191 uses the term “diffuse large lymphoid lymphomas with pyroninophilia” for such neoplasms in his working classification of non-Hodgkin’s lymphomas. At present, Dorfman’s terminology is appealing because it indicates the accepted cell of origin while describing the distinctive features whose significance is unclear. Regardless of the nomenclature used, these neoplasms should be recognized as a distinctive morphologic entity with a peculiar association with immunoglobulin abnormalities, congenital immune defects, Dilantine ingestion and chronic immune disorders such as severe rheumatoid arthritis, Sjogren’s syndrome and systemic lupus erythematosus [ 16,17,20]. The two malignant lymphomas we have observed in transplant recipients should be included in this subgroup of lymphomas. Review of photomicrographs published with case reports of post-transplant lymphoma reveals a similar histologic picture in some cases [21]. Lukes and Collins [ 16,171 state that the lymphomas in transplant recipients that they reviewed have been immunoblastic sarcomas. A complete morphologic review of the lymphomas recorded in the transplant tumor registry may be of value in substantiating these observations. The pathogenesis of the increased incidence of de novo cancer in the transplant recipient is unknown. It was at first thought that the immunosuppressive treatment used in these patients to prevent allograft rejection resulted in decreased immunosurveillance allowing neoplastic clones to develop and multiply. However, a number of observations suggest that this is not the entire explanation. First, all tumors are not increased in proportion to their occurrence in the general population as would were
be expected the
sole
if decreased
pathogenic
factor.
immunosurveillance
Second, in other groups of patients who did not receive transplants but
MALIGNANT
LYMPHOMA-MATAS
ET AL.
who did receive the same medications, the risk of cancer is not the same. Third, cure of disseminated tumor in a transplant recipient during maintenance of immunosuppressive therapy has been reported [22]. Fourth, the anatomic location of these lymphoproliferative tumors is unusual-in transplant recipients 46 per cent involve the central nervous system compared to 0.5 to 1.5 per cent in those who do not receive transplants. Finally, the histopathology of the lymphoreticular tumors differs from those occurring in the general population. Both long-term and repeated intermittent antigenic stimulation have previously been associated with an increased incidence of lymphoreticular neoplasms. Repeated injection of bovine serum albumin [23] or cells differing at weak histocompatibility loci [24] in mice results in a significantly increased incidence of lymphomas. A long-term graft versus host reaction results in a similar increase [25]. These tumors differ histologically from spontaneous lymphomas in mice and are similar to lymphoproliferative tumors in the transplant recipient in their monomorphous appearance [26,27]. In man, long-term antigenic stimulation of repeated malarial infection has been associated with the development of Burkitt’s lymphoma [28]. This tumor predominates in areas in which malaria is endemic, and children in these areas are probably exposed repeatedly. Areas in which malaria is eradicated show a corresponding drop in the incidence of Burkitt’s lymphoma [ 291. Interestingly, Burkitt’s lymphoma is also a monomorphous pyroninophilic tumor. Each of the tumor systems mentioned has been associated with virus infection. Long-term antigenic stimulation due to the graft versus host reaction or due to allogenic stimulation has been shown to result in oncogenic virus activation in the mouse [30,31], and Burkitt’s lymphoma has been linked to the Epstein-Barr virus (EBV) [32], a herpesvirus in man. Herpesviruses (cytomegalovirus [CMV], herpes simplex virus type 1 [HSV-11, herpes simplex virus type 2 [HSV-21 and Epstein-Barr virus [EBV]) infections are a common problem in transplant recipients [33]. The oncogenicity of these viruses has previously been demonstrated in both animals and man. These viruses have been associated with lymphoproliferative tumors, as well as carcinoma of the skin, lip, nasopharynx and cervix [34,35]. If long-term antigenic stimulation and viral activation play a role in the pathogenesis of the increased incidence of cancer in the transplant recipient, a possible explanation may be found for the unusual pattern of central nervous system involvement by these tumors. Herpesviruses have previously been shown to be neurotropic, EBV has been implicated in the pathogenesis of Bell’s palsy and the Guillain-Barre syndrome [36],
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MALIGNANT LYMPHOMA-MATAS
ET AL.
HSV-1 and HSV-2 have been shown to reside in dorsal root ganglia between overt infections [37,38], primary HSV-1 infection can result in encephalitis, and congenital CMV infection often affects the brain [36]. This neurotropism of the herpesviruses may thus explain the frequent central nervous system involvement by lymphoproliferative tumors in the transplant recipient. In summary, the morphologic features of these lymphoproliferative disorders occurring after organ
5.
6.
7.
8. 9.
10.
11.
12.
13.
14.
15.
16.
17. 18.
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transplantation are consistent with the theory that long-term antigenic stimulation may play an important role in their pathogenesis. Whether potentially oncogenie herpesviruses also play an important role is still speculative. The distinctive morphologic features described here offer additional support to the idea that long-term antigenic stimulation rather than lost immunosurveillance is important in the pathogenesis of this disease.
Penn I: The incidence of malignancies in transplant recipients. Transplant Proc 7: 323, 1975. Hoover R, Fraumeni JF: Risk of cancer in renal transplant recipients. Lancet 2: 55, 1973. Penn I: Malignant Tumors in Organ Transplant Recipients, New York, Springer-Verlag, 1970. Schwartz RS: A new concept of immunoregulation and its application to leukemia and lymphoma. Tumori 59: 383, 1973. Matas AJ, Simmons RL, Najarian JS: Chronic antigenic stimulation, herpesvirus infection and cancer in transplant recipients. Lancet 1: 1277, 1975. Kjellstrand CM, Simmons RL, Buselmeier TJ, Najarian JS: Recipient selection, medical management, and dialysis. Transplantation (Najarian JS, Simmons RL, eds), Philadelphia, Lea 81Febiger, 1972, p 415. Simmons RL, Kjellstrand CM, Najarian JS: Kidney: Technique, complications, and results. Transplantation (Najarian JS, Simmons RL, eds), Philadelphia, Lea & Febiger, 1972, p 445. Najarian JS, Simmons RL: The clinical use of antilymphocyte globulin. N Engl J Med 285: 158, 1971. Penn I, Hammond A, Brett S&eider L, Starzl TE: Malignant lymphomas in transplantation patients. Transplant Proc 1: 106, 1969. McKhann CF: Primary malignancy in patients undergoing immunosuppression for renal transplantation: a request for information. Transplantation 8: 209, 1969. Matas AJ, Simmons RL, Kjellstrand CM, Buselmeier TJ, Najarian JS: Increased incidence of malignancy during chronic renal failure. Lancet 1: 883, 1975. Rappaport H: Malignant lymphomas, Atlas of Pathology, section Ill, fascicle 8. Tumors of the Hematopoietic System, Washington, DC., Armed Forces Institute of Pathology, 1966, p 91. Dameshek W: “lmmunoblasts” and “lmmunocytes”-an attempt at a functional nomenclature. Blood 21: 243, 1963. Dorfman RF, Warnke R: Lymphadenopathy simulating the malignant lymphomas. Human Pathol 5: 519, 1974. Biberfeld P, Morphogenesis in blood lymphocytes stimulated with phytohemagglutinin (PHA). A light and electron microscopic study. Acta Pathol Microbial Stand [A], suppl 223, p 1, 1971. Lukes RJ, Collins RD: A functional classification of malignant lymphomas. The Reticuloendothelial System (Rebuck JW, Berard CW, Abell MR, eds), Baltimore, Williams 8 Wilkins, 1975, p 213. Lukes RJ, Collins RO: Immunologic characterization of human malignant lymphomas. Cancer 34: 1488, 1974. Nowell PC: Phytohemagglutinin: an initiator of mitosis in cultures of normal human lymphocytes. Cancer Res 20: 462, 1960.
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22.
23. 24.
25.
26. 27.
28.
29. 30.
31.
32.
33.
34. 35. 36.
37.
38.
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Dorfman RF: The Non-Hodgkin’s lymphomas. The Reticuloendothelial System (Rebuck JW, Berard CW, Abell MR, eds), Baltimore, Williams 8 Wilkins, 1975, p 262. Brand MM. Marinkovich VA: Primary malignant reticulosis of the brain in Wiskott-Aldrich syndrome. Report of a case. Dis Child 44: 536, 1969. Cho ES, Connolly E, Porro RS: Primary reticulum cell sarcoma of the brain in a renal transplantation recipient. J Neurosurg 41: 235, 1974. Simmons RL, Kelly WD, Tallent MB, Najarian JS: Cure of dysgerminoma with widespread metastases appearing after renal transplantation. N Engl J Med 283: 190, 1970. Metcalf 0: Reticular tumors in mice subjected to prolonged antigenic stimulation. Br J Cancer 15: 769, 1961. Walford RC: Increased incidence of lymphoma after injection of mice with cells differing at weak histocompatability loci. Science 152: 78, 1988. Schwartz RS, Beldotti L: Malignant lymphomas following allogenic disease: transitor from an immunological to a neoplastic disorder. Science 149: 15 11, 1965. Kersey JH: Personal communication, 1975. Gleichmann E, Gleichmann H, Schwartz R: Immunologic induction of malignant lymphoma: genetic factors in the graft-versus-host model. J Natl Cancer lnst 49: 793, 1972. O’Connor G: Persistent immunologic stimulation as a factor in oncogenesis with special reference to Burkitt’s lymphoma. Am J Med 48: 279, 1970. Burkitl DP, Wright DH: Burkitt Lymphoma, Edinburg, Livingstone, 1970. Hirsch MS, Phillips SM. Solnik C, et al.: Activation of leukemia viruses by graft versus host and mixed lymphocyte reactions in vitro. Proc Natl Acad Sci USA 69: 1069, 1972. Armstrong MY, Black FL, Richards FL: Tumor induction by cell-free extracts derived from mice with graft versus host disease. Nature (New Biol) 235: 153, 1972. Epstein MA, Achong BG, Barr YM: Virus particles in cultured lymphoblasts from Burkitt lymphomas. Lancet 1: 702, 1964. Simmons RL, Lopez C, Balfour H, et al.: Cytomegaloviruses: clinical virological correlations in renal transplant recipients. Ann Surg 180: 623, 1974. Klein G: Herpesviruses and oncogenesis. Proc Natl Acad Sci 69: 1056, 1972. Rapp F: Question: Do herpesviruses cause cancer? Answer: Of course they do. J Natl Cancer lnst 50: 825, 1973. Grose C, Henle W, Henle G, Feorino PN: Primary EpsteinBarr-virus infections in acute neurologic diseases. N Engl J Med 292: 392, 1975. Baringer JR, Swoseland P: Recovery of herpes-simplex virus from human trigeminal ganglions. N Engl J Med 288: 648, 1973. Baringer JR: Recovery of herpes simplex virus from human sacral ganglions. N Engl J Med 291: 828, 1974.
Morphologic
ARTHUR J. MATAS,
Features Related to Its Pathogenesis
M.D.
BRUCE F. HERTEL, M.D. JUAN ROSAI,
M.D.
RICHARD L. SIMMONS, JOHN S. NAJARIAN,
M.D.
M.D.
Minneapolis, Minnesota
From the Departments of Surgery and Pathology, University of Minnesota, Minneapolis, Minnesota 55455. This study was supported by Grant AM 13083 from the U.S. Public Health Service. Requests for reprints should be addressed to Dr. Richard L. Simmons, Box 185-Mayo Memorial Building, University of Minnesota Hospitals, Minneapolis, Minnesota 55455. Manuscript accepted January 14, 1976.
716
November 1976
Malignant lymphoma developed in two patients after renal transplantation. In both, the central nervous system was involved. Histologic study of the tumors showed that they were composed of a monomorphous prollferation of cells characterized by a large vesicular nucleus, prominent basophlllc nucleolus and strongly py roninophlllc cytoplasm. The tumors thus would be classlfled as “diffuse large lymphold lymphomas with pyronlnophllia” or “immunoblastlc sarcomas” as described in the literature. Tumor cells resembled cells observed In the paracortex of antigenlcally stimulated lymph nodes, cells from malignant lymphomas in mice that were antigenlcally stimulated and from malignant lymphomas in patients with immunodeficiancy diseases or autoimmune disorders. The distinctive morphologic features of the tumors in the transplant recipients described provide further evidence that long-term antigenie stimulation may be important in their pathogenesis. The incidence of malignancy is increased in allograft recipients [ 11, and epidemiologic data show that the incidence of lymphoproliferative tumors has the greatest increase [ 21. These lesions have an unusual anatomic distribution; brain and spinal cord involvement occurred in 46 per cent of affected patients, and in 33 per cent the lesion was confined to these areas. This is in contrast to a 0.4 to 1.5 per cent involvement of the central nervous system in patients with malignant lymphoma who have not received transplants. Why malignant lymphomas in organ transplant recipients behave in such a bizarre fashion is unclear, although several hypotheses have been put forth [3-51. From January 1, 1968, to October 1, 1974, 523 renal transplants were performed in 452 patients at the University of Minnesota Hospitals. Patient selection, operative technic and postoperative management have been described previously [6,7]. In brief, following acceptance into the program, bilateral nephrectomy and splenectomy are performed prior to renal transplantation. Post-transplant immunosuppression therapy consists of the administration of antilymphocyte globulin, azathioprine and prednisone. Following renal transplantation, de novo lymphoreticular tumors have developed in two patients. We describe the pathologic findings in these two patients in order to further define the difference between these lesions and malignant lymphomas in patients who do not receive organ transplants. CASE REPORTS Case 1. A 50 year old woman with renal failure secondary to chronic glomerulonephritis received a cadaver renal transplant. Histocompatibility typing
The American Journal of Medlclne
Volume 61
POST-TRANSPLANT
revealed two HL-A antigens in common between donor and recipient. Initial immunosuppression therapy consisted of the administration of antilymphoblast globulin [8], azathioprine and prednisone [7]. The postoperative course was uneventful and she was discharged three weeks after receiving the transplant, with normal renal function. Within six months of the transplantation, she was receiving 2.5 mg/kg azathioprine and 0.3 rng/kg prednisone. One year after the transplantation she experienced occipital headaches and expressive aphasia. Brain scan and cerebral angiography revealed a mass in the left mediofrontal region. Craniotomy was performed and a biopsy specimen was obtained. Postoperatively she received 4,000 rads to the left cerebral hemisphere and 5,500 rads to the left frontal lobe. She was discharged without weakness or aphasia. Ten months later behavioral changes developed; she had difficulty with mentation, emotional lability and a progressively deteriorating course until death 25 months after renal transplantation. No autopsy was performed. Case 2. A IO year old girl with renal failure secondary to hypocomplementemic glomerulonephritis received a renal transplant from her mother. She did well the first year after the transplant with the exception of two rejection episodes which responded well to therapy. One year after the transplant, she was receiving 1.5 mglkg azathioprine and 0.27 mg/kg prednisone. Thirteen months after the transplant she was admitted to the hospital with weakness, lethargy, fever and leukopenia. A chest roentgenogram showed bilateral nodular infiltrates. Bronchoscopy revealed a creamy exudate, but no bacteria, fungi or protozoa were seen. Open lung biopsy was performed to define a presumptive opportunisticinfection. Histologic sections, at that time, were interpreted as showing only chronic pneumonitis and pleuritis. Antibiotic treatment was begun and immunosuppression therapy discontinued. Three weeks after admission, cytomegalovirus (CMV) was reported in cultures of urine, sputum, bronchial washings and lung biopsy specimens. The patient had a progressive downhill course which was attributed to the systemic viral infection. Seven weeks after admission a Jacksonian seizure developed which started on the right side and became generalized. The seizure was associated with cardiopulmonary arrest, for which intubation and resuscitation were required. A postictal right hemiparesis persisted. An electroencephalogram was markedly abnormal with continuous spike and wave activity over the left hemisphere and independent foci in the left central and left occipital areas that suggested multiple lesions. She could not be weaned from the respirator and her condition continued to deteriorate. She
had a second cardiopulmonary arrest on the 59th hospital day (15 months after the transplant) from which she could not be resuscitated. MORPHOLOGY Cerse -1. Histologic evaluation of the brain biopsy specimen showed a highly cellular, widely infiltrating neoplasm with large areas of necrosis (Figure 1). Distention of Virchow-Robin spaces by tumor cells was a prominent feature. The tumor was composed of a monomorphous proliferation of cells characterized by large
MALIGNANT
LYMPHOMA-MATAS
ET AL.
[lo-121 oval nuclei containing one or several prominent basophilic nucleoli and finely distributed chromatin (Figure 2). The nuclear membranes were regular without significant wrinkling or cleaving. There was a moderate amount of amphophilic cytoplasm which was strongly pyroninophilic. Occasional plasmacytoid cells and mature plasma cells were present. No phagocytic activity was observed in the tumor cells. Case 2. At autopsy, malignant lymphoma was identified in the brain, liver and transplanted kidney, in the lung, heart and lymph nodes, but not in the bone marrow. The tumor was composed of a monomorphous proliferation of cells with large oval nuclei, prominent basophilic nucleoli and strongly pyroninophilic cytoplasm (Figure 3). The pattern was similar in all involved organs and the cytologic features were similar to those seen in Case 1. In the central nervous system, the tumor was present as multiple masses and diffusely in a perivascular distribution, frequently distending Virchow-Robin spaces. The liver grossly contained numerous tumor nodules up to 5 cm in diameter; microscopically, it also showed diffuse portal infiltration without significant sinusoidal involvement. The transplanted kidney showed widespread diffuse interstitial infiltration by tumor. Small aggregates of neoplastic cells were present in the myocardium. Lymph nodes were diffusely replaced by tumor. Retrospective review of the open lung biopsy specimen showed that the malignant lymphoma was present in the lung at the time of biopsy.
COMMENTS Penn et al. [9] and McKhann [lo] independently reported an increased incidence of cancer in the transpiant recipient in 1969; since that time 241 de novo malignancies in transplant recipients have been reported to Penn’s informal registry [ 11. This represents a significant increase over the number that would be expected to develop in the age-matched general population. Epidemiologic data compiled by Hoover and Fraumeni [ 21 disclosed that the incidence of lymphoreticular tumors showed the greatest increase. We have previously described our over-all experience with malignancy in patients before and after organ transplantation [ 111, and the two patients we describe in this report are the only ones in whom lymphoproliferative disorders developed. Most cases of malignant lymphoma reported in immunosuppressed patients have been classified under the broad term “reticulum cell sarcoma” or “histiocytic lymphoma,” the latter according to the Rappaport classification [ 121. Based on our material, we believe that many of these tumors represent a distinctive histologic entity. The classic histiocytic lymphoma is
November 1976
The American Journal of Medicine
Volume 61
717
POST-TRANSPLANT MALIGNANT LYMPHOMA-MATAS
ET AL
Figure 1. Case 1. Brain biopsy specimen of the tumor mass demonstrating perivascular infiltration typical of central nervous system lymphomas. Hematoxylin and eosin stain; original magnification X 120, reduced by 34 per cent.
Figure 2. Case 1. Higher magnification of the brain biopsy specimen demonstrating the monotonous population of uniform large cells with round to oval nuclei, multiple basophilic nucleoli and abundant cytoplasm. Hematoxylin and eosin stain; original magnification X 600, reduced by 32 per cent.
Ffgure 3. Case 2. Specimen of autopsy tissue from the cerebrum illustrating the perivascular as well as diffuse pattern of central nervous system involvement. Hematoxylin and eosin stain; original magnification X 120, reduced by 34 per cent. Met, higher magnification shows cells similar to those seen in Case 1 with more prominent plasmacytoid appearance. Hematoxylin and eosin stain; original magnification X 7,000, reduced by 34 per cent.
719
November
1978
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Journal of Medicine
Volume
61
POST-TRANSPLANT
characterized by a large, irregular, vesicular nucleus with a prominent eosinophilic nucleolus and abundant eosinophilic cytoplasm which is not pyroninophilic. By contrast, the lymphomas in our transplant recipients are composed of a monotonous proliferation of cells with large regular nuclei, diffusely distributed chromatin, several basophilic nucleoli and strongly pyroninophilic cytoplasm (Figures 1, 2 and 3). Similar cells are observed in the paracortex of antigenically-stimulated lymph nodes [ 13,141 and can be produced by stimulating peripheral lymphocytes with phytohemagglutinin in cultures [ 151. Dameshek [ 131 proposed the term “immunoblast” for such cells, and experimental evidence strongly supports their lymphocytic origin [15-181. In their functional classification of lymphomas, Lukes and Collins [ 16,171 propose the term “immunoblastic sarcoma” for lymphomas composed of these cells. They state that they have observed only B cell variants of such tumors, although it is not clear what studies were performed in determining cell types. Dorfman [ 191 uses the term “diffuse large lymphoid lymphomas with pyroninophilia” for such neoplasms in his working classification of non-Hodgkin’s lymphomas. At present, Dorfman’s terminology is appealing because it indicates the accepted cell of origin while describing the distinctive features whose significance is unclear. Regardless of the nomenclature used, these neoplasms should be recognized as a distinctive morphologic entity with a peculiar association with immunoglobulin abnormalities, congenital immune defects, Dilantine ingestion and chronic immune disorders such as severe rheumatoid arthritis, Sjogren’s syndrome and systemic lupus erythematosus [ 16,17,20]. The two malignant lymphomas we have observed in transplant recipients should be included in this subgroup of lymphomas. Review of photomicrographs published with case reports of post-transplant lymphoma reveals a similar histologic picture in some cases [21]. Lukes and Collins [ 16,171 state that the lymphomas in transplant recipients that they reviewed have been immunoblastic sarcomas. A complete morphologic review of the lymphomas recorded in the transplant tumor registry may be of value in substantiating these observations. The pathogenesis of the increased incidence of de novo cancer in the transplant recipient is unknown. It was at first thought that the immunosuppressive treatment used in these patients to prevent allograft rejection resulted in decreased immunosurveillance allowing neoplastic clones to develop and multiply. However, a number of observations suggest that this is not the entire explanation. First, all tumors are not increased in proportion to their occurrence in the general population as would were
be expected the
sole
if decreased
pathogenic
factor.
immunosurveillance
Second, in other groups of patients who did not receive transplants but
MALIGNANT
LYMPHOMA-MATAS
ET AL.
who did receive the same medications, the risk of cancer is not the same. Third, cure of disseminated tumor in a transplant recipient during maintenance of immunosuppressive therapy has been reported [22]. Fourth, the anatomic location of these lymphoproliferative tumors is unusual-in transplant recipients 46 per cent involve the central nervous system compared to 0.5 to 1.5 per cent in those who do not receive transplants. Finally, the histopathology of the lymphoreticular tumors differs from those occurring in the general population. Both long-term and repeated intermittent antigenic stimulation have previously been associated with an increased incidence of lymphoreticular neoplasms. Repeated injection of bovine serum albumin [23] or cells differing at weak histocompatibility loci [24] in mice results in a significantly increased incidence of lymphomas. A long-term graft versus host reaction results in a similar increase [25]. These tumors differ histologically from spontaneous lymphomas in mice and are similar to lymphoproliferative tumors in the transplant recipient in their monomorphous appearance [26,27]. In man, long-term antigenic stimulation of repeated malarial infection has been associated with the development of Burkitt’s lymphoma [28]. This tumor predominates in areas in which malaria is endemic, and children in these areas are probably exposed repeatedly. Areas in which malaria is eradicated show a corresponding drop in the incidence of Burkitt’s lymphoma [ 291. Interestingly, Burkitt’s lymphoma is also a monomorphous pyroninophilic tumor. Each of the tumor systems mentioned has been associated with virus infection. Long-term antigenic stimulation due to the graft versus host reaction or due to allogenic stimulation has been shown to result in oncogenic virus activation in the mouse [30,31], and Burkitt’s lymphoma has been linked to the Epstein-Barr virus (EBV) [32], a herpesvirus in man. Herpesviruses (cytomegalovirus [CMV], herpes simplex virus type 1 [HSV-11, herpes simplex virus type 2 [HSV-21 and Epstein-Barr virus [EBV]) infections are a common problem in transplant recipients [33]. The oncogenicity of these viruses has previously been demonstrated in both animals and man. These viruses have been associated with lymphoproliferative tumors, as well as carcinoma of the skin, lip, nasopharynx and cervix [34,35]. If long-term antigenic stimulation and viral activation play a role in the pathogenesis of the increased incidence of cancer in the transplant recipient, a possible explanation may be found for the unusual pattern of central nervous system involvement by these tumors. Herpesviruses have previously been shown to be neurotropic, EBV has been implicated in the pathogenesis of Bell’s palsy and the Guillain-Barre syndrome [36],
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HSV-1 and HSV-2 have been shown to reside in dorsal root ganglia between overt infections [37,38], primary HSV-1 infection can result in encephalitis, and congenital CMV infection often affects the brain [36]. This neurotropism of the herpesviruses may thus explain the frequent central nervous system involvement by lymphoproliferative tumors in the transplant recipient. In summary, the morphologic features of these lymphoproliferative disorders occurring after organ
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transplantation are consistent with the theory that long-term antigenic stimulation may play an important role in their pathogenesis. Whether potentially oncogenie herpesviruses also play an important role is still speculative. The distinctive morphologic features described here offer additional support to the idea that long-term antigenic stimulation rather than lost immunosurveillance is important in the pathogenesis of this disease.
Penn I: The incidence of malignancies in transplant recipients. Transplant Proc 7: 323, 1975. Hoover R, Fraumeni JF: Risk of cancer in renal transplant recipients. Lancet 2: 55, 1973. Penn I: Malignant Tumors in Organ Transplant Recipients, New York, Springer-Verlag, 1970. Schwartz RS: A new concept of immunoregulation and its application to leukemia and lymphoma. Tumori 59: 383, 1973. Matas AJ, Simmons RL, Najarian JS: Chronic antigenic stimulation, herpesvirus infection and cancer in transplant recipients. Lancet 1: 1277, 1975. Kjellstrand CM, Simmons RL, Buselmeier TJ, Najarian JS: Recipient selection, medical management, and dialysis. Transplantation (Najarian JS, Simmons RL, eds), Philadelphia, Lea 81Febiger, 1972, p 415. Simmons RL, Kjellstrand CM, Najarian JS: Kidney: Technique, complications, and results. Transplantation (Najarian JS, Simmons RL, eds), Philadelphia, Lea & Febiger, 1972, p 445. Najarian JS, Simmons RL: The clinical use of antilymphocyte globulin. N Engl J Med 285: 158, 1971. Penn I, Hammond A, Brett S&eider L, Starzl TE: Malignant lymphomas in transplantation patients. Transplant Proc 1: 106, 1969. McKhann CF: Primary malignancy in patients undergoing immunosuppression for renal transplantation: a request for information. Transplantation 8: 209, 1969. Matas AJ, Simmons RL, Kjellstrand CM, Buselmeier TJ, Najarian JS: Increased incidence of malignancy during chronic renal failure. Lancet 1: 883, 1975. Rappaport H: Malignant lymphomas, Atlas of Pathology, section Ill, fascicle 8. Tumors of the Hematopoietic System, Washington, DC., Armed Forces Institute of Pathology, 1966, p 91. Dameshek W: “lmmunoblasts” and “lmmunocytes”-an attempt at a functional nomenclature. Blood 21: 243, 1963. Dorfman RF, Warnke R: Lymphadenopathy simulating the malignant lymphomas. Human Pathol 5: 519, 1974. Biberfeld P, Morphogenesis in blood lymphocytes stimulated with phytohemagglutinin (PHA). A light and electron microscopic study. Acta Pathol Microbial Stand [A], suppl 223, p 1, 1971. Lukes RJ, Collins RD: A functional classification of malignant lymphomas. The Reticuloendothelial System (Rebuck JW, Berard CW, Abell MR, eds), Baltimore, Williams 8 Wilkins, 1975, p 213. Lukes RJ, Collins RO: Immunologic characterization of human malignant lymphomas. Cancer 34: 1488, 1974. Nowell PC: Phytohemagglutinin: an initiator of mitosis in cultures of normal human lymphocytes. Cancer Res 20: 462, 1960.
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Dorfman RF: The Non-Hodgkin’s lymphomas. The Reticuloendothelial System (Rebuck JW, Berard CW, Abell MR, eds), Baltimore, Williams 8 Wilkins, 1975, p 262. Brand MM. Marinkovich VA: Primary malignant reticulosis of the brain in Wiskott-Aldrich syndrome. Report of a case. Dis Child 44: 536, 1969. Cho ES, Connolly E, Porro RS: Primary reticulum cell sarcoma of the brain in a renal transplantation recipient. J Neurosurg 41: 235, 1974. Simmons RL, Kelly WD, Tallent MB, Najarian JS: Cure of dysgerminoma with widespread metastases appearing after renal transplantation. N Engl J Med 283: 190, 1970. Metcalf 0: Reticular tumors in mice subjected to prolonged antigenic stimulation. Br J Cancer 15: 769, 1961. Walford RC: Increased incidence of lymphoma after injection of mice with cells differing at weak histocompatability loci. Science 152: 78, 1988. Schwartz RS, Beldotti L: Malignant lymphomas following allogenic disease: transitor from an immunological to a neoplastic disorder. Science 149: 15 11, 1965. Kersey JH: Personal communication, 1975. Gleichmann E, Gleichmann H, Schwartz R: Immunologic induction of malignant lymphoma: genetic factors in the graft-versus-host model. J Natl Cancer lnst 49: 793, 1972. O’Connor G: Persistent immunologic stimulation as a factor in oncogenesis with special reference to Burkitt’s lymphoma. Am J Med 48: 279, 1970. Burkitl DP, Wright DH: Burkitt Lymphoma, Edinburg, Livingstone, 1970. Hirsch MS, Phillips SM. Solnik C, et al.: Activation of leukemia viruses by graft versus host and mixed lymphocyte reactions in vitro. Proc Natl Acad Sci USA 69: 1069, 1972. Armstrong MY, Black FL, Richards FL: Tumor induction by cell-free extracts derived from mice with graft versus host disease. Nature (New Biol) 235: 153, 1972. Epstein MA, Achong BG, Barr YM: Virus particles in cultured lymphoblasts from Burkitt lymphomas. Lancet 1: 702, 1964. Simmons RL, Lopez C, Balfour H, et al.: Cytomegaloviruses: clinical virological correlations in renal transplant recipients. Ann Surg 180: 623, 1974. Klein G: Herpesviruses and oncogenesis. Proc Natl Acad Sci 69: 1056, 1972. Rapp F: Question: Do herpesviruses cause cancer? Answer: Of course they do. J Natl Cancer lnst 50: 825, 1973. Grose C, Henle W, Henle G, Feorino PN: Primary EpsteinBarr-virus infections in acute neurologic diseases. N Engl J Med 292: 392, 1975. Baringer JR, Swoseland P: Recovery of herpes-simplex virus from human trigeminal ganglions. N Engl J Med 288: 648, 1973. Baringer JR: Recovery of herpes simplex virus from human sacral ganglions. N Engl J Med 291: 828, 1974.