EXPERIMENTAL AND CLINICAL TRANSPLANTATION

In 2020, an estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths occurred worldwide. Female breast cancer was the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0%), prostate (7.3%), and stomach (5.6%) cancers.¹ Because of effective screening strategies, especially for breast, colorectal, and cervical cancers, diagnoses are occurring at earlier stages and cumulative survival of patients with cancer is increasing. Overall, however, cancer incidence is rapidly growing worldwide. Cancer screening and early detection can lead to cures for many types of cancer. The relative 5-year cancer survival rate has improved over the past several decades for most cancer types. On the other hand, the number of people who would benefit from a solid-organ transplant is increasing. Increased organ demand has also resulted in dramatically increased waiting times. Continued organ shortages have resulted in evaluations of further potential donors, including people with cancer. Organs donated by deceased and living donors carry many risks, and these include transmission of cancer. Donors with a past history of cancer may be more appropriate for urgent or high-risk recipients. The literature related to donor-derived malignancy transmission is mostly limited to case reports, data registry series, and retrospective studies.² A first report of United Network for Organ Sharing (UNOS) transplant tumor registry data was published in 2000 by Kauffman and colleagues.² Between 1994 and 1996, UNOS recorded 14 705 deceased organ donors, which were used in 23 630 kidney, 10 697 liver, and 6527 heart transplants. Among the 14 705 donors, 257 donors had a past history of cancer. These 257 donors provided 650 organs to 650 separate recipients, including 397 kidney, 178 liver, and 75 heart transplants. In the report, 85% of donors with a cancer history had cancers from skin, brain, and genitourinary regions. The other common sites were breast, thyroid, and lymphoma, with throat/tongue cancer comprising only 10%. Most donors with a history of skin cancer or brain cancer had a tumor-free interval of less than 5 years. However, 75% of donors with a history of a genitourinary cancer and 75% of 88 donors with histologically defined cancers had cancer-free intervals of more than 5 years. In total, 188 organs were transplanted from donors whose cancer history was primary brain cancer. In 73% of the donors with primary brain cancers, the type of histological diagnosis was not specified, and the authors noted that probably some of the tumors were benign meningiomas and also it is possible that the number of highly malignant brain tumors (glioblastoma, medulloblastoma) was more than that recorded. The report also noted that there were no differences in survival rates for kidney and liver transplant recipients of organs from donors with cancer history versus no cancer history. Similarly, there were no differences in patient survival rates for heart transplant recipients of donors with cancer history versus no cancer history. Furthermore, there were 1544 posttransplant cancers reported in the entire cohort of 40 854 recipients (3.8%). The incidence was 2.7% for kidney, 3.2% for liver, and 8.8% for heart. In 28 posttransplant tumors, cancer types included skin (n = 18), posttransplant lymphoproliferative disorder (n = 2), and solid tumors (n = 8), but none of the recipient cancers were of the same histological type that had been recorded in the donor’s history. The authors concluded that risks of cancer transmission from donors with a history of nonmelanoma skin cancer and selected cancers of the brain appear to be small. Risks of tumor transmission with certain other types of cancer may be acceptable, particularly if the donor has a long cancer-free interval before organ procurement, although certain other cancers have a risk of high transmission. The primary limitation of that report was that most donors with brain tumors and with genitourinary tumors did not have a specific diagnosis of tumor type risk.² The largest transplant registry report was published 20 years ago by the same group. More than 34 000 deceased donors and 108 062 recipients were evaluated by contacting the transplant centers to verify that the reported tumors were of donor origin. There were 21 donor-related cancers from 14 deceased donors and from 3 living donors. Fifteen tumors were donor transmitted and 6 were donor derived. The study reported a deceased donor-related tumor rate of 0.04% (14 of 34 993), a donor-related tumor rate among transplanted organs from deceased donors of 0.017% (18 of 108 062), and a deceased donor-related tumor mortality rate of 0.007% (8 of 108 062). The authors concluded that the incidence of donor-related cancers in the United States was extremely rare. Donor-related tumor death rate was also extremely low, especially compared with wait list mortality.³ The Organ Procurement and Transplantation Network (OPTN) began collecting more detailed cancer data, including the type of tumor in those donors with a past history of cancer in 1999.⁴ This report was an update of OPTN/UNOS data on 39 455 deceased donors between 2000 to 2005 in whom 1069 had a past history of cancers. None of the donors had any evidence of an active cancer, with the exception of nonmelanoma skin cancers (basal cell and squamous cell) and donors with brain cancers. There were 2508 organs transplanted from the 1069 donors with a history of cancer: nonmelanoma skin cancers (n = 776) constituted the largest group, brain tumors (n = 642) constituted the second largest group, with glioblastoma being the most common tumor type, and uterine cervical cancers (n = 336) constituted the third largest group. The group also reported the cancer-free intervals of the donors with a past history of cancer. Most donors (60.0%) with nonmelanoma skin cancers had a cancer-free interval of <5 years. A cancer-free interval of only 0 to 5 years was reported for 40% of donors with renal cancers, but the total number was only 15 tumors. Similarly, the 66 donors with a past history of prostate cancer had a cancer-free interval of <5 years in 40.9% of cases. Most of the other donors with a history of the more common solid, nonskin malignancies had a cancer-free interval of >10 years. Donors with a history of central nervous system (CNS) tumors are an exception, with the cancer-free interval not reported in most cases; this may be because many of these patients had active malignancy at the time of donation. One donor with an active glioblastoma multiforme transmitted fatal tumors to 3 separate recipients (kidney, liver, lung). Only 1 donor with a history of cancer (but no known active malignancy) was reported to transmit a tumor; this was a fatal melanoma transmitted to a lung recipient. The donor died from head trauma but had a history of melanoma 32 years earlier. At 24 months, none of the other recipients from this donor (lung, liver, heart, 2 kidneys) developed a melanoma. The authors concluded that their data support the idea that current practices in donor selection have reduced the risk of tumor transmission. Among 2508 organ transplants from donors with a past history of cancer (2.2% of the 113 167 deceased donor organs transplanted from 2000 through 2005), successful transplants and improved length and quality of life were shown for many patients. High levels of potential donor-derived malignancy transmissions were reported to the OPTN between 2005 and 2009. Of 146 submitted reports, 20 confirmed donorderived cancer transmissions with 9 related deaths (lung cancer, lymphoma, neuroendocrine carcinoma, melanoma, and glioblastoma multiforme).⁵ Most donor-associated transmissions were renal cell carcinoma, with 64 such cases (43.8% of all malignancy reports) through 2009. The usual scenario of the “possible” donor transmission events consisted of detection of a small, usually well-differentiated renal cell carcinoma, restricted to the kidney. In this regard, several reports have suggested that small, solitary, and well-differentiated renal cell carcinomas may be resected at the time of organ procurement and the kidney used for transplant.^6,7 The ad hoc Disease Transmission Advisory Committee of the OPTN/UNOS formed an ad hoc Malignancy Subcommittee to advise on this subject. The Subcommittee reviewed the largely anecdotal literature and generated a framework to approach risk evaluation in this circumstance, which was published in 2011.⁸ Six levels of risk were revealed by consensus. A suggested approach to donor utilization was given for each category, knowing the priority to individual clinical judgment and often emergent clinical events. Categories were populated with specific tumors based on available data, including active or historical cancer. The risk categorization framework for donor tumor transmission was categorized between 0 (no significant risk) to 4 (high risk). Among their suggestions to risk categorizations were with regard to basal and squamous cell carcinoma of the skin without metastases and in situ cervical and vocal cord carcinoma and solitary papillary thyroid carcinoma (?0.5 cm), minimally invasive follicular thyroid carcinoma (?1 cm), and resected solitary renal cell carcinoma <1 cm and well differentiated (Fuhrman 1-2), which were accepted as having minimal risks of transmission (<0.1% risk of transmission). Malignant melanoma, active breast and colon cancer, cholangiocarcinoma, grade 3/4 brain tumors, leukemia/lymphoma, small cell carcinoma, metastatic carcinoma, sarcoma, all stage lung carcinoma, and renal cell carcinoma >7 cm were classified as having high risk (>10% risk of transmission). The group suggested that use of organs with low risk of transmission could be considered when the risk of death on the waiting list was weighed versus risk of organ use. Organs with intermediate risk could be considered for life-saving transplants for patients with an immediate risk of death. Organs with high transmission risk should not be accepted for organ donation. In a UK report, the risk of cancer transmission from donors characterized as having high or unacceptable risk was studied by analyzing transplant and cancer registry.⁹ Information on donors and recipients (1990-2008) was derived from the UK Transplant Registry. The cancer transmission risk of actual and potential/possible donors was classified according to guidelines for standard/ nonstandard or unacceptable/high. Donors with a nonstandard risk were those with a history of cancer (except unacceptable or high-risk tumors) and with a cancer-free interval of <10 years. Among 17 639 donors, 202 (1.1%) had a history of cancer, of which 73.8% had brain cancers. Of the 202 donors with cancer, 61 had cancers classified as having an unacceptable/high risk of transmission according to the guidelines. No cancer transmission was reported in 133 recipients of organs from these 61 donors. At 10 years posttransplant, the additional survival benefit gained by transplanting organs from donors with unacceptable/highrisk cancer was 944 life-years, with a mean survival of 7.1 years per recipient. The authors concluded that precise implementation of present guidelines is likely to result in overestimation of cancer transmission risk in some donors and commented that organs from some donors with cancers defined as unacceptable/high risk can be used safely. Eccher and colleagues reported on donor-transmitted cancer in kidney transplant recipients.¹⁰ They reviewed published case reports and series describing the outcomes of recipients with donor-transmitted cancer until August 2019. Among 128 articles that were analyzed, there were 234 recipients and 187 donors, with 18 (9.6%) living donors and 87 (46.5%) multiorgan donors. Of the multiorgan donors, 64 (73.6%) donated a kidney, with transmission of cancer in 41 donors (64.1%). The most common transmitted cancers were lymphoma (n = 48, 20.5%), renal cancer (42, 17.9%), melanoma (40, 17.1%), non-small cell lung cancer (n = 13, 5.6%), and neuroendocrine cancers comprising small cell lung cancer (n = 11, 4.7%) and choriocarcinoma (n = 10, 4.3%). Nine recipients (3.8%) developed leukemia, 6 (2.6%) developed glioblastoma, and 5 (2.1%) developed breast cancer. Melanoma and lung cancer had the worst prognosis, with 5-year overall survival of 43% and 19%, respectively, whereas renal cell cancer and lymphomas had a favorable prognosis with 5-year overall survival of 93% and 63%, respectively. Metastasis of cancer outside the graft was the most important adverse prognostic factor. Overall reporting was good, but a study limitation was incomplete information on donor cause of death and investigations at procurement.

Most Common Cancers Among Patients Who Are Organ Donors

The most common cancers among patients who can donate and who cannot donate organs are summarized below and described in (Table 1) and (Table 2)

Female breast cancer

Female breast cancer is the leading cause of global cancer incidence in 2020, with 2.3 million new cases. Extended, more effective breast cancer treatments have increased the prevalence of long-term survivors. Of note, breast cancer is not uniform in its biology, and late recurrences have been well described in some breast cancer subtypes. In 1 study, among 36 924 women with breast cancer, 20 315 were disease free at 10 years. Of these, 2595 developed late recurrence (incidence rate 15.53 per 1000 person-years) from year 10 to year 32 after primary diagnosis. Recurrences continued to occur up to 32 years after primary diagnosis. Women with high lymph node burden, large tumor size, and estrogen receptor-positive tumors had increased risk of late recurrence.¹¹ The OPTN/UNOS data showed 126 transplants of organs from donors with a history of breast cancer (mostly had >5 years of history of breast cancer) but no cancer transmission.⁴ Thus, patients with history of stage IA (T1N0 <20 mm tumor size) breast cancer with curative surgery, who are estrogen receptor negative, and who have a cancer-free period of >10 years can possibly be accepted as organ donors.^8,9

Worldwide, lung cancer is the second most commonly diagnosed cancer. Non-small cell lung cancer is the most common type of lung cancer. Because the symptoms of lung cancer are not apparent in the early stages, most patients with lung cancer are at an advanced stage at the time of diagnosis. Lung cancer is the leading cause of cancer death for men and women worldwide. In 2020, an estimated 1 796 144 people died worldwide from the disease.¹² The 5-year survival rate for lung cancer is 19%. Only 20% of lung cancer patients are diagnosed with stage I disease; patients with stage I disease have a 5-year survival rate of 60%. Five-year survival in patients with small cell lung cancer is lower than survival in patients with non-small cell lung cancer (23%). Circulating tumor cells have become potential diagnostic biomarkers for several types of cancer, including lung cancer. It is generally believed that circulating tumor cells are produced in the early stages of tumors and represent tumor micrometastasis or the presence of small residual lesions. Even in early stages, circulating tumor cells are well described for lung cancer.¹³ Because of the biology of the disease and the poor outcomes, patients with a history of any stage of lung cancer cannot be candidates for organ donation due to high risk of transmission.^8,9

Colorectal cancer

Almost 2 million new colorectal cancers occurred in 2020.¹ The 5-year survival rate is 91% for colorectal cancer and 82% for stage II disease. Late recurrence is shown in 1.6% of all surgically treated colorectal cancers. Results from the UK national transplant registry recommended that organs from donors with nonmetastatic colon cancer resected surgically at least 5 years before donation can be considered for transplant.⁹ The OPTN/UNOS findings suggested that patients with history of stage IA (pT1 or pT2, N0) colorectal adenocarcinoma who have had curative surgery and are cancer free for >5 years could be accepted as organ donors.⁸

The incidence of prostate cancer has increased dramatically in recent years due to improved cancer screening and detection mechanisms, with almost 1.4 million new cases. Most prostate cancers are diagnosed in the local and regional stages, which has a 5-year relative survival rate of almost 100%.¹⁴ Yin and colleagues analyzed incidental prostate cancer derived from a project that accrued prostate tissues for research from normal organ donors.⁷ At the Tissue Bank at Pittsburgh Medical Center, 340 prostates from organ donors who died suddenly from 1994 to 2007 were analyzed. Of the 340 donors, 41 (12%) were found to have incidental prostate carcinoma. However, no cases of donor-associated prostate adenocarcinoma were reported. The investigators suggested that many small and early prostate cancers may have limited potential for transmission with organ transplant. Thus, patients with prostate cancer with history of Gleason score ?7 and with curative treatment and who are cancer free >5 years can possibly be accepted as organ donors.^7,8

Thyroid cancer is responsible for 586 000 cases worldwide in 2020. Mortality rates from the disease are much lower, with a rate of 0.3 per 100 000.¹⁵ A study showed that papillary thyroid carcinoma was found among 7897 autopsies from 24 published series.¹⁶ Among 366 patients with papillary and follicular thyroid carcinoma, neither papillary carcinoma ?0.5 cm nor solitary minimally invasive follicular carcinoma < 2 cm showed extrathyroidal growth or lymph node metastasis.¹⁷ Thus, patients with history of thyroid solitary papillary carcinoma ?0.5 cm and minimally invasive follicular carcinoma <2 cm can possibly be considered as good candidates for organ donation.^8,17

Most renal cell carcinomas are found incidentally on imaging. According to the 2018 GLOBOCAN data, about 430 000 people/year are diagnosed with kidney cancer. Patients with localized renal cell carcinoma have relatively high survival rate (93%). Small renal cell cancers in donor kidneys can be excised and the kidneys can be safely transplanted. In their investigation of the Israel Penn International Transplant Tumor Registry database, Buell and his colleagues identified all small renal cell carcinomas that were resected before both deceased donor and living donor transplant.¹⁸ Fourteen kidneys were identified in which small renal cell carcinomas were noted at the time of procurement and in which the tumors were excised ex vivo and then transplanted. Eleven kidneys were obtained from living related donors and 3 were from deceased donors. Median tumor size was 2 cm (0.5-4 cm). All 14 tumors were of histological Fuhrman grade 2/6 (n = 8) or Fuhrman grade 1/6 (n = 6). All kidneys had pathologically confirmed negative margins. Median follow-up for this group was 69 months. No recurrences of tumors were shown in the recipients, and the 1-, 3-, and 5-year patient and graft survival rates were 100%, 100%, and 93%. The authors concluded that donor kidneys with small, incidental renal cell carcinoma and low histological grade (Fuhrman grade 1 and 2/6) can be managed with excision and then transplanted, with a low risk of tumor recurrence in the recipient. Thus, patients with history of resected grade 1 or 2 solitary renal cell carcinomas of <4 cm and who are cancer free for >5 years could be good candidates for organ donation.^8,18

Central nervous system tumors

Currently, Turkey and most other countries allow only patients with CNS tumors to be an organ donor because of the general acceptance that extracranial metastases cannot occur. However, are they truly safe? Some data have shown that some donors with CNS tumors may be harmful. In a retrospective review of more than 17 000 cases reported to the Israel Penn International Tumor Registry from 1970 to 2002,¹⁹ 62 cases were identified as recipients of organs from donors with a history of or active CNS malignancy. Of the organs recovered and transplanted from donors with astrocytoma, 14 were associated with at least 1 risk factor, including high-grade tumor (n = 4), prior surgery (n = 5), radiation therapy (n = 4), and systemic chemotherapy (n = 4). One tumor transmission was identified at 20 months posttransplant in which the patient died from metastatic disease. Twenty-six organs were transplanted from glioblastoma patients, with 15 showing risk factors, including high-grade tumor (n = 9) and prior surgery (n = 10). Eight transmissions were found with a range of 2 to 15 months posttransplant, with 7 patients who died from metastatic disease. Seven organs were used from donors with a medulloblastoma. Three transmissions were identified at a range of 5 to 7 months, all associated with ventriculoperitoneal shunts. Two medulloblastoma recipients died from metastatic disease, whereas the third was alive with diffuse disease. The rate of donor tumor transmission, in the absence of risk factors, was 7%, whereas, in the presence of 1 or more risk factor, this rate dramatically rose to 53% (P < .01). The investigators concluded that organs from donors with CNS tumors can be used if there is a low risk of donor tumor transmission and there is an absence of the following risk factors: highgrade tumors, ventriculoperitoneal or ventriculoatrial shunts, prior craniotomy, and systemic chemotherapy. Donors with CNS tumors should have low histologic grade lesions or benign tumors. They recommended that patients with 1 or more risk factors should not be organ donors or the organ should only be used if life-saving transplant is urgently needed. In a case of a patient who received bilateral lung transplants for pulmonary fibrosis from a donor with known glioblastoma, the lungs, heart, liver, and kidneys were procured after a lethal intracranial bleed and accepted for transplant by 4 centers. Four months later, the patient developed diffuse pulmonary infiltrates and mediastinal lymphadenopathy. Lung biopsy confirmed metastatic glioblastoma. The patient died 2 weeks after the diagnosis. The patient who received the donor liver also developed glioblastoma.²⁰

Hematological malignancies

Novel treatment approaches have resulted in long-term survival benefits of >10 years for some hematologic malignancies, including in patients with chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, and some patients with non-Hodgkin lymphoma. Although the 10- to 20-year survival rates of most patients with common hematologic malignancies have increased (except for acute leukemia), long-term survival is still low and no plateau in survival has been observed for most conditions. Thus, there may be continued late mortality, either from late effects of the disease or therapy. In patients with hematologic malignancies, <50% of patients are alive for more than 20 years. In long-term follow-up, relapse of the primary disease, chemotherapy, and/or radiotherapy induced long-term side effects, damage to the DNA, and the development of secondary malignancies, which particularly affected survival. Donor-derived malignant disorders can occur via direct transfer of tumor cells to the recipient or through development of malignancy in donor cells. Because of the risk of transmission of tumor cells to the recipient, donor banks for allogeneic hematopoietic transplantation, including the National Marrow Donor Programme and the World Marrow Donor Association, defer donors with a history of hematologic malignancy.^21,22 Thus, patients who have history of hematological malignancies and even long-term survivors cannot be candidates for organ donation.

Basal cell carcinoma of the skin is the most common malignancy in White populations and its incidence is increasing worldwide. Most nonmelanoma skin cancers are low grade and grow slowly. Nonmelanoma skin cancer is often found and treated early, so the prognosis is very good. Basal cell carcinoma rarely spreads to other parts of the body. Squamous cell carcinoma of the skin often has a low risk of coming back after treatment. The 5-year relative survival rate for basal cell carcinoma is 100%; the 5-year relative survival for squamous cell carcinoma is slightly less at 95%.²³ The UK national registry data showed that organs from 2 donors with the superficial spreading subtype of melanoma, diagnosed 8·and 9 years before donation in both patients, did not transmit the cancer. They stated that organs from those who have had melanoma but no features of recurrence for at least 5 years and melanomas of the superficial spreading subtype and thickness <1 mm are likely to have a low risk of transmission.⁹ Patients with history of resected basal cell carcinoma and squamous cell carcinoma with no metastases can be good candidates for organ donation.⁸ In addition, patients with a history of superficial spreading type tumor (Breslow) thickness <1 mm with curative surgery can be an organ donor.⁹

Organs from deceased or living donors with some types of certain current and past cancers may be safely used for transplant. The risk of transmission of cancer by a donor can be minimized by careful team work. The risk of cancer transmission must be balanced against the risk of a patient dying or becoming clinically worse during the period of waiting for a transplant on a case-by-case basis. This decision is made by the recipient’s surgeon. The evaluation and final decision require a multidisciplinary approach, clear recordings of patient data from the registry system, and discussion of the benefits and risks with the patient and the family before transplant. For a living donor, full and careful evaluation of clinical records and past history is important, whereas for a deceased donor, if possible, full examination of thoracic and abdominal cavity or imaging should also be done. If not present, histological characterization of present tumors should be done before transplant. Every single organ donor candidate with a cancer history should be carefully evaluated to be sure they are in remission with very low risk of recurrence. With this careful identification, this group of patients could be organ donors.

Volume: 20 Issue: 8 August 2022 - Supplement - 4

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