MALIGNANT MELANOMA IN ORGAN ALLOGRAFT RECIPIENTS1,2 : Transplantation (original) (raw)
Of the various malignancies that occur in organ transplant recipients, skin cancers occupy a prominent role, as they constitute 37% of all de novo neoplasms (1-3). Squamous cell carcinomas have deservedly received a great deal of attention. Malignant melanoma(MM)* has received much less scrutiny, despite the fact that its incidence in the general population is rising rapidly(4). The problem of transmission of MM from donor to recipient, the fate of patients who had MM treated prior to transplantation, and the behavior of MMs that occur de novo after transplantation will be examined in this report.
MATERIALS AND METHODS
The data accumulated by the Cincinnati Transplant Tumor Registry (CTTR) from the fall of 1968 till May 1995 were examined.
RESULTS
Transmission of MM from donors. Eleven donors provided organs to 20 recipients (17 kidneys, 2 livers and one heart) (5, 6). Of these, 6 cadaver donors provided organs to 15 recipients, and the other 5 donors (4 cadaver, 1 living-related) each provided a kidney to 5 recipients. At the time of harvesting all donors were seemingly free of cancer but in retrospect, in at least 6 of the 10 cadaver donors (who provided organs to 13 recipients), the cause of brain death had been misdiagnosed as a primary brain tumor (3 donors) or cerebral hemorrhage (3 donors), whereas the underlying pathology was cerebral metastases of MM. Two donors had amelanotic melanomas one of which was mistaken for an oligodendroglioma.
The diagnosis of MM was subsequently made by autopsy examination in four cadaver donors. In one instance metastatic melanoma was found in what appeared to be a primary brain tumor. The diagnosis of MM of donor origin was made in one case using the polymerase chain reaction when tumor in an allograft was studied after allograft nephrectomy in the recipient (1). In the other cadaver donors the diagnosis of MM was presumed when multiple recipients of organs from that donor developed MM. In retrospect, review of previous hospital records revealed a history of MM in 4 of the donors. One had a black lesion removed from the face 6 months before death from a cerebrovascular accident (CVA); a second had a Clark's level III melanoma removed 3-4 years before death from a CVA; a third had two MMs removed 8 years and 2 years before death from the primary brain tumor, which contained metastatic MM within it (mentioned above); and one died, of what was thought to be a primary brain tumor, more than 7 years after treatment of a cutaneous MM that had spread to the inguinal nodes. The diagnosis was also missed in a living-related donor who complained of arm weakness at the time of donation. Postoperatively, the symptoms became worse and CAT showed a mass in the brain, biopsy of which demonstrated metastatic MM. The donor had no prior history of MM. He died of this malignancy within 6 months of donation. The recipient refused to have a transplant nephrectomy and subsequently developed metastatic melanoma.
Of the 20 recipients 16 developed metastatic MM from 2.5 to 42 (average 13, median 10.5) months after transplantation, 3 never manifested evidence of malignancy (follow-up 4, 44, and 198 months, respectively) and 1 had local spread beyond the allograft. Eleven of the 16 recipients died of the malignancy including both liver allograft recipients and the heart transplant recipient. Four other patients (all kidney recipients) had complete remissions of metastases following transplant nephrectomy and discontinuation of immunosuppressive therapy, and in one patient administration of α interferon. One additional patient was noted to have a dark “cyst” in the renal allograft after it was revascularized. A biopsy of it showed MM and allograft nephrectomy was performed. The allograft was in place for approximately 24 hr and the patient received immunosuppression for one day only. Two years later the patient was operated on for an incisional hernia in the allograft nephrectomy wound when a 1 cm mass of metastatic melanoma was found and excised. Currently the patient is receiving interferon therapy.
In the patient who had local spread of MM beyond the allograft, this was discovered 44 months after transplantation when the kidney was removed because of chronic rejection. The tumor and allograft were removed, and immunosuppressive therapy discontinued. The patient remained tumor free on dialysis till she died of unrelated causes 135.5 months after the nephrectomy.
Patients with preexisting MM. Thirty one patients had malignant melanomas removed from 332 months before to 1.5 months after transplantation(average 61, median 25 months). The MM involved the skin in 30 patients and the eye in 1. Twenty-seven patients received renal and 4 had cardiac allografts. Six of the recipients (19%), all of whom had received kidney transplants, developed recurrences after transplantation. Three had been treated less than 2 years before transplantation, 2 between 2 and 5 years before transplantation, and 1 120 months before transplantation. No information is available on the thickness of the MM in 5 of the patients, but in the sixth it was a Clark's level IV lesion of the forearm. These 6 patients died of MM from 6 to 30 (average 16) months after transplantation. In the remaining 25 patients follow-up was short (<24 months) in 11 (44%). The follow-up in all 31 patients, after transplantation ranged from 0.5 to 100(average 32, median 21.5) months.
Patients with de novo MM. Overall 8191 patients developed 8724 malignancies. Of these 3178 patients had skin cancers. Of 177 patients with MM there were 120 males and 57 females, whose age at the time of transplantation ranged from 4 to 73 (average 39, median 40) years. At the time of diagnosis of MM the ages ranged from 9 to 74 (average 44, median 46) years.
Eleven patients (6%) were aged 18 years or less. They were aged 4-18(average 12, median 11 years) at time of transplantation, and 9 to 34 (average 19, median 17.5) years at the time of diagnosis of MM. Six of the 11 MMs (55%) appeared during childhood. Four of the 11 patients (36%) were bone marrow allograft recipients. All eleven patients had cutaneous MM. Of all pediatric patients in the CTTR MM constituted 14% of skin cancers in patients who received transplants in childhood compared with 5% in those transplanted in adult life.
There were 145 kidney, 18 heart, 9 bone marrow, 2 liver, 2 pancreas, and 1 heart-lung recipient. MM appeared from 1 to 244 (average 61, median 46) months after transplantation.
The major immunosuppressive therapies used in the 9 bone marrow allograft recipients were total-body irradiation in all, combined with cyclophosphamide in 8. In addition, five patients received miscellaneous other chemotherapeutic agents, 4 patients received cyclosporine, and 1 azathioprine. Of 5 patients with ocular melanomas 3 were given combined azathioprine-cyclosporine based regimens, and two received azathioprine-based regimens. In addition, 3 patients were given antilymphocyte globulin (ALG). Of the 163 other solid organ recipients 86 were given azathioprine-based regimens, 66 combined azathioprine-cyclosporine regimens, and 16 cyclosporine-based regimens. In addition, 37 patients were given ALG, 10 OKT3, and 6 both ALG and OKT3.
In 8 patients (5%) MMs arose from unknown primary sites and appeared with metastases. Of these, 6 patients had visceral metastases, which were fatal in 5, while the last recipient is still alive with cancer. The seventh patient had a metastasis to the oropharynx excised and the eighth recipient had two subcutaneous masses around the knee excised but subsequently required excision of the iliofemoral nodes and local radiation therapy.
Another 5 (3%) MMs arose from the eye (uvea 2, one of which was 2-mm thick; intraocular 1; position not stated 1; conjunctiva 1 (arising in a preexisting nevus).
The 164 skin malignancies were 5.2% of the 3178 skin cancers in the CTTR. A total of 135 of 2850 skin cancers (5%) in renal transplant recipients were MM, 15 of 232 in cardiac recipients (6%), 9 of 15 skin cancers in bone marrow recipients (60%), 2 of 53 in liver recipients (4%), 2 of 21 in pancreas recipients (10%), and 1 of 5 skin cancers in heart-lung recipients (20%). The distribution of the 164 skin lesions was trunk 46 (28%), upper limbs 37 (23%), head and neck 36 (22%), lower limbs 24 (15%), and unspecified in 21 patients(13%). No description of the lesions was available in 83 patients. The other 81 are shown in Table 1. In four patients the MM arose in a preexisting nevus. Another 3 patients had multiple dysplastic nevi.
Lymph node metastases occurred in 32 of 164 patients (20%) with cutaneous melanoma. Of these 24 (75%) subsequently died of metastatic MM. The thickness of the lesions was recorded in 17 of the 32 patients. They are shown inTable 1.
The treatments given are summarized in Table 2. In the overall series of 177 patients 56 (32%) died of MM. Five of 8 patients with MM of unknown primary site died and the three survivors have been followed for 10.5, 12, and 35.5 months, respectively. One of 5 patients with ocular melanoma died of the disease (the lesion was 2-mm thick); one is alive with recurrent cancer 40 months after treatment; two others died of unrelated causes 9.5 and 149.5 months, respectively, after treatment; and one had a recurrence treated 120 months after initial treatment and is well 147 months later. Fifty of the 164 patients (30%) with cutaneous melanoma died of their malignancies. The 22 patients in whom the thickness of the lesions was recorded are shown in Table 1. With the exception of two patients, the 11 recipients with superficial spreading melanoma and in situ melanoma are alive. The other two patients also had squamous cell skin cancers; this caused the death of one patient 59 months after diagnosis of MM. In the other recipient, who died 42 months after diagnosis of MM, it is not clear whether lethal metastases were from squamous cell carcinoma (SCC) or MM. Fourteen patients with cutaneous melanoma died of other causes, and a hundred patients are currently alive, but three of them have recurrent disease. Overall follow-up of the 177 patients since diagnosis of their malignancies ranged from 2 to 305 (average 42, median 25) months.
In the overall CTTR series of patients with de novo malignancies, 6% had two or more different types of cancer. In contrast 62 of 177 (35%) of patients with MM had a total of 68 other types of neoplasm, 10 of which were present before transplantation, 2 of which occurred both before and after transplantation, and the remainder of which appeared after transplantation. Forty-six patients had other skin cancers (SCC 22; basal cell carcinoma [BCC] 13; SCC and BCC 11); 9 patients first presented with leukemia which was treated by bone marrow transplantation, and 1 kidney recipient developed leukemia after transplantation; 2 patients had carcinomas of the kidney; 2 had carcinomas of thyroid; and 8 had other malignancies. Forty-four patients (27%) of the 164 who had cutaneous MMs had other skin cancers.
DISCUSSION
Reports of isolated cases of inadvertent transmission of MM from donor to recipient have been published(7-12). Of all cancers in the CTTR that were inadvertently transplanted from donor to recipient MM is the most important (6), having afflicted 16 of 58 recipients (28%) who manifested distant metastases of the donors' neoplasms.
In evaluating potential donors a history of a previous MM should preclude use of any donor except one with a proven melanoma in situ. Even though an interval of 20 years or more has passed since treatment of the tumor it is prudent to avoid using organs from such an individual because of the occassional risk of MM causing late metastases. Since moles are commonly removed in the general population, a history of a mole per se should not exclude any potential donors. However, if a cadaver donor has an unexplained cerebral hemorrhage, or what appears to be a primary brain tumor, caution is necessary if there was something unusual about the mole-a history of rapid growth, change of color, wide excision, skin grafting, reexcision, or a large scar. Every effort should then be made to contact the original surgeon or obtain the patient's previous records to exclude a possible MM. At times, this may be very difficult to do, especially late at night or during the weekend. Even biopsy of a supposed primary brain tumor can occasionally be misleading as an amelanotic melanoma may be mistaken for an oligodendroglioma.
When harvesting organs any nodules, particularly if dark in color, should have a biopsy and frozen section examination(5, 6, 13). The great majority will turn out to be hemorrhagic cysts, but it is better to do too many biopsies than run the risk of missing a melanoma, particularly if amelanotic, or another neoplasm.
If possible, an autopsy should be obtained on every cadaver donor to rule out any unexpected malignancies (6, 13). However, permission is often withheld by family members and, generally, the organs have been transplanted by the time a final autopsy diagnosis is available. If metastatic melanoma is subsequently found in the donor, then all transplanted organs should be removed, whether kidney, liver, heart, or other organs, because the current CTTR experience indicates that there is an 85% chance that the allograft harbors melanoma cells. Thus far, renal, hepatic, and cardiac recipients have died of inadvertently transmitted metastatic MM.
In the rare event that a recipient of a renal allograft has MM in the graft and develops metastases the treatment of choice is to remove the transplant and discontinue immunosuppressive therapy (5, 6, 13). Should the metastases fail to regress as the patient's immune system recovers its ability to reject foreign tissue, the recipient may need additional radiotherapy, chemotherapy, or immunotherapy with interleukin-2 orα-interferon.
One previous study recommended a two-year waiting period between treatment and control of a preexisting malignancy and undertaking transplantation(14). This applied to most major cancers, with several exceptions for which a longer waiting period was recommended. One of these was MM. In view of the 19% recurrence rate in the present study, and because of the unpredictable behavior of MM, this waiting period should probably be extended to 5 years for most melanomas. Exceptions would be for melanoma in situ, for which no waiting period is necessary, and for very thin melanomas where, perhaps, a two-year waiting period may be sufficient.
In the general population immune factors appear to be more involved in the biologic behavior of melanoma than in many other cancers(15, 16). MM has unique surface antigens; stimulates specific cellular and humoral immune responses; shows more frequent responses to immunotherapy than other solid tumors; accounts for 11% of cases of spontaneous cancer regression; and shows a positive correlation between the density of the lymphocyte infiltrate in primary melanomas and patient survival(15, 16). It is, therefore, not surprising that there is an increased incidence of MM in immunosuppressed individuals. Three epidemiologic studies indicate a 3.8- to 5-fold increased incidence of de novo MM after transplantation (17-19). If nonmelanoma skin cancers and in situ carcinomas of the uterine cervix are excluded from the CTTR data, as they are from most cancer statistics cutaneous MM constitutes 2.6% of all cancers compared with 1% among men and 1.8% among women in the general population (4). In the present study ocular melanomas made up 3% of all MMs, considerably less than the 9% rate seen in the general population (20). In the community at large a small proportion of melanoma patients have lymph nodal or, more rarely, visceral metastases in the absence of a demonstrable cutaneous primary neoplasm (21). The present series is unusual in that 5% of patients had lesions arising from unknown primary sites and 6 of the 8 recipients had visceral metastases.
The CTTR findings are unusual in several other respects. Approximately 2% of melanomas in the community at large occur in patients under 20 years of age, and 0.3 to 0.4% occur in prepubertal children(22, 23). In the CTTR almost 4% of cutaneous melanomas occurred in children, and 14% of skin cancers in patients who received transplants during childhood were MM compared with 5% in those who received transplants in adult life.
Occasional examples of melanoma following bone marrow transplantation have been described (24). However, in the present series more than 5% of cutaneous melanomas occurred in such patients. In fact 60% of skin cancers in bone marrow allograft recipients in the CTTR were MM. In part, this high figure may be an artefact of the small numbers of these patients with MM and skin cancers in general. Another possible explanation may be derived from the threefold excess in MM incidence among employees of the Lawrence Livermore National Laboratory (25). Among the risk factors were exposures to radioactive materials and nuclear testing in the Pacific. Perhaps total-body irradiation given to all the bone marrow recipients in this series contributed to the increased incidence of MM among them.
In transplant patients three other possible risk factors for cutaneous melanoma must be considered: the presence of preexisting nevi, exposure to sunlight, and the influence of azathioprine. A surprisingly high proportion of posttransplant melanomas arise in dysplastic nevi (16), suggesting that immunosuppression in a host having melanoma precursors brings with it a particular susceptibility to neoplastic transformation(16). The sudden appearance of both ordinary and dysplastic nevi in transplant recipients has been reported(26, 27). In children who underwent renal transplantation there was a significant increase in the number of nevi as compared with controls (16). This strongly correlated with the duration of immunosuppression, suggesting that it may contribute to the development of nevi as well as melanomas (16).
In the present series 27% of patients with cutaneous melanomas had other skin cancers-BCCs, SCCs, or both. This finding is in keeping with epidemiologic studies in nontransplant patients in which a prior history of nonmelanoma skin cancer was a significant risk factor for melanoma(28-30). Exposure to sunlight plays an important role in the evolution of MM and other skin cancers. While the letter tumors are related to chronic exposure to ultraviolet light, MM is related to intense intermittent sun exposures particularly during childhood and adolescence (25). Perhaps some transplant patients resemble individuals with xeroderma pigmentosum in their sensitivity to sunlight. This rare autosomal recessive disorder is characterized by defective repair of DNA damage induced by ultraviolet light (25). Patients with this disorder have an enormously increased risk of developing skin cancers including MM.
In the present study 93% of patients with cutaneous melanomas and melanomas of unknown primary site (most likely cutaneous) (21) received azathioprine, with or without cyclosporine. Questions arise as to whether azathioprine may have contributed to the development of melanoma as its immidazole breakdown products sensitize the skin to sunlight(31), and its active metabolite 6-thioguanine is claimed to be a chemical carcinogen in the skin (32, 33). However, while azathioprine has been related to the development of dysplastic keratoses, BCCs, and SCCs in transplant patients(32, 33), there are no firm data to link it with the development of MM.
The immunosuppressed state per se plays an important role in the behavior of MM. The present study shows the profound effect that immunosuppressive therapy plays on the growth of inadvertently transplanted malignancies. These tumors, which could not be detected in the allograft at the time of transplantation, grew rapidly, and caused metastases and the deaths of 11 of 16 patients at a median interval of only 10.5 months after transplantation. It also appears that immunosuppressive therapy activated the growth of dormant nests of melanoma cells in patients who had been treated for preexisting melanomas, as all six patients who developed recurrences died of melanoma at an average of only 16 months after transplantation. In addition, a de novo ocular tumor, which first appeared after a renal transplant failed, grew significantly after another course of therapy was given with a second transplant (34).
Transplant patients with de novo cutaneous melanomas are unable to mount an appropriate cellular immune response to neoplastic cells, permitting the tumors to evolve rapidly (16). This may account for the high proportion of patients in the present series with thick lesions (>0.76 mm by Breslow measurements, or Clark's level III or greater). One of the cardinal histologic features of invasive melanoma is an exuberant lymphocyte/macrophage infiltrate, the density of which has a positive correlation with patient survival (35). In 13 of 14 patients in one study this response was either absent or impaired(16), and was attributed to the lympholytic properties of corticosteroids and azathioprine. This raises the question of whether immunosuppressive therapy should be reduced or discontinued in treating MM. This was done in only 10 patients in this series, too few from which to draw any conclusions. Contrary to clinical intuition, formal decision analysis techniques suggest that the benefits associated with continuing immunosuppression and maintaining allograft function outweigh the risks for patients who develop de novo cutaneous melanomas(36).
Can anything be done to preyent the development of MM? As with prophylaxis of other skin cancers, patients should be advised to minimize exposure to sunlight and instructed in the use of sunscreens and protective clothing(16). As dysplastic nevi are a marker for an increased risk of cutaneous melanoma, the skin of immunosuppressed patients with these lesions should be examined frequently and excisional biopsies performed on all suspicious lesions (16, 23).
Acknowledgments. The author wishes to thank his many colleagues throughout the world who have generously contributed data concerning their patients to the CTTR.
Footnotes
Presented at the 21st Annual Meeting of the American Society of Transplant Surgeons, May 17-19, 1995, Chicago, IL.
This work was supported in part by a grant from Department of Veterans Affairs.
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