Patients with an invasive and active malignancy are unsuitable for organ donation. 1 This includes all types of malignancies except for most skin carcinomas and certain localized tumors, such as some types of intracerebral malignancies. 2 However, a donor‐derived malignancy is sometimes occult at the time of transplantation and may be detected early after transplantation in the recipient. 3 This case report describes the transmission of breast cancer from a single organ donor to 4 recipients many years after donation. At the time of donation, it was unknown that the donor suffered from a malignancy.

The liver graft was allocated to a 59‐year‐old female recipient suffering from decompensated primary biliary cirrhosis. Four years later (in 2011), a tumor was detected in segment VIII of the liver graft and histologically proven to be donor‐derived metastasized ER+ breast cancer. A retransplantation was immediately proposed to the recipient, which she refused. She felt well and was afraid of potential postoperative complications she had experienced in 2007 after the liver transplantation. She decided to undergo an ablative procedure by means of extracorporeal proton radiation at another center, and there were radiological signs of complete response. After a long‐term stable disease, in 2014 (7 years after the transplant), the patient developed extrahepatic tumor progression that was mainly localized at the hilar region. She refused any further oncological treatment and died a few months later due to diffuse tumor progression.

A transplant nephrectomy was performed, which showed venous‐invasive growth and infiltration of hilus, calyx, and perirenal fat. The tumor could not be resected completely, and subsequent staging scans revealed rapid growth of local iliac tumor masses, abdominal lymph node metastases, and diffuse pulmonary metastases. After nephrectomy, the immunosuppression was stopped, and HLA antibodies increased. The patient was successfully treated with 6 cycles of paclitaxel and trastuzumab for 1 year, followed by trastuzumab once every 3 weeks. In August 2012, complete remission was noted. At the last follow‐up in April 2017, the patient was still free of tumors and wished to undergo a second transplant.

A 32‐year‐old male received the right kidney. After he was informed of the transmission of breast cancer to the lung recipient in 2010, regular tumor screening investigations were performed, including a chest X‐ray and ultrasound of the abdomen. In addition, a CT scan of the chest was performed in January 2011. All of the findings were unremarkable. In July 2011, the patient developed massive proteinuria (3 g/d), and antibody‐mediated rejection was suspected due to weak HLA‐class II antibodies. A biopsy showed widespread invasion of the renal allograft by ER+, PR+ adenocarcinoma, which appeared to be human epidermal growth factor receptor 2 positive. A CT scan of the transplanted kidney revealed several focal hypodense areas and a heterogeneous cortex.

Five years later, the patient presented with hypercalcemia, weight loss, and malaise. A CT scan of the abdomen showed multiple lesions in the liver. A liver biopsy revealed ER+, PR+ adenocarcinoma, which appeared to have spread to the kidney, liver, bone, spleen, and several organs in the digestive tract. After consulting with the patient and her family, active treatment was withdrawn and palliative care was started. The patient passed away 2 months after the initial diagnosis of metastatic breast cancer and 6 years after transplantation.

The left‐kidney recipient was a 62‐year‐old female. She underwent a postmortem donor kidney transplantation in April 2007 under highly urgent status because of an imminent lack of vascular access, which was limiting dialysis options. When Eurotransplant reported the death of the lung recipient in 2010 due to donor‐derived metastatic breast cancer, the situation was discussed with the patient. It seemed that removal of the transplant was not an option because of a lack of access. A CT scan of the transplanted kidney was performed, which excluded major pathology. Prophylactic antihormonal treatment was considered. However, because there were no data in the literature supporting this treatment, it was finally decided not to start antihormonal drugs.

The lungs were allocated to a 42‐year‐old female who suffered from end‐stage lung disease due to sarcoidosis with remitting pneumothoraces. In August 2008 (16 months after transplantation), the patient was admitted to the hospital because of transplant dysfunction. A chest X‐ray showed mediastinal lymphadenopathy. A mediastinal lymph node biopsy showed estrogen receptor and progesterone‐receptor positive (ER+, PR+) adenocarcinoma. The FES‐PET scan revealed abnormalities in the lungs and bones. The patient's immunosuppression was reduced. In September, a CT scan showed lesions in the liver and bones that were compatible with metastases. Six months later, she presented with increasing thoracic pain, hypercalcemia, and renal insufficiency. In August 2009, palliative care was started, and after a few days, the patient passed away.

The donor was a 53‐year‐old female who died from subarachnoidal bleeding. The donor report provided by Eurotransplant reported no relevant medical history nor aberrant findings or signs of malignancy according to a complete physical examination, laboratory testing, ultrasound of the abdomen and heart, chest X‐ray, and bronchoscopy.

Pathology images. For all images: top is hematoxylin and eosin (HE) staining, bottom left is estrogen receptor (ER) staining and bottom right is progesterone receptor (PR) staining. (A) Lung recipient. Liver biopsy with adenocarcinoma, which is ER and PR positive. (B) Left‐kidney recipient. Liver biopsy with adenocarcinoma, which is ER and PR positive. (C) Right‐kidney recipient. Kidney explant with adenocarcinoma, which is ER and PR positive

The 53‐year‐old donor in this case had no relevant medical history and donated her kidneys, lungs, liver, and heart. The heart recipient died of sepsis at 5 months after transplantation. The other 4 recipients developed donor‐derived breast cancer (proven by DNA microsatellite) within 16 months to 6 years after transplantation. Unfortunately, the double‐lung recipient, left‐kidney recipient, and liver recipient died due to the donor‐derived breast cancer. The right‐kidney recipient remains alive. After the diagnosis of breast cancer in the transplanted kidney, the patient underwent transplant nephrectomy, his immunosuppression was stopped, chemotherapy was initiated, and he achieved complete remission despite widely metastasized disease. A timeline and pathology images from 3 recipients are displayed in Figures 1 and 2 , respectively.

3 DISCUSSION

Many reports have shown that cancer transmission can occur in solid organ transplantation.4-8 However, this is the first report describing breast cancer transmission after a multiorgan procedure from 1 donor to 4 recipients. Furthermore, no studies have reported the transmission of a malignancy with such an extended interval between transplantation and the clinical manifestation of the tumor.

The risk of tumor transmission is between 0.01 and 0.05% for each solid organ transplant.9, 10 This low incidence implies that current practices of donor screening for malignancy are effective. However, once transmitted, there is high mortality due to the donor‐related malignancy in the recipient.10 In cases where transmission has been reported, the malignancy was usually not discovered before donation,5 as was the case in our donor.

It remains speculative in regard to how cancer was transmitted from the donor without any signs of a malignancy. One hypothesis is that the donor had metastasized breast cancer with metastasis or micro metastasis in each of the transplanted organs, which was able to progress after transplantation under the influence of immunosuppressive agents. Circulating tumor cells have been reported in stage I breast cancer.11 Another transplantation‐specific factor might be ischemia‐reperfusion injury. Warm ischemia stimulates quiescent tumor cells to lodge into the organs and induces a hypoxic tumor phenotype, which leads to the expression of various vasoactive genes that contribute to the mobilization of tumor cells.12-14 This hypothesis has also been proposed to explain the transmission of cancer through improbable sites of metastasis.

It remains unclear whether a predonation total‐body CT scan of the donor might have revealed the malignancy. The drawback of a routine postmortem CT scan for all donors is that it will increase clinically irrelevant findings, which might lead to more rejection of donors and a decrease of the already scarce donor pool. The extremely low rate of transmission of malignancies during transplantation proves the efficiency of the current guidelines. A complete medical examination, including a breast examination, should always be performed as described in the guidelines of the Organ Procurement and Transplantation Network (OPTN).

In the case we describe, the transmission rate was high. After documentation of transmission in the lung recipient, all of the remaining recipients eventually developed breast cancer. The time interval between the initial warning from Eurotransplant and presentation of cancer in the recipient was, however, long in some cases; the left‐kidney recipient presented with breast cancer years after the initial warning from Eurotransplant. This long time interval suggests that transplantectomy might be beneficial. It may prevent the development of metastasis and thus should be considered in all recipients after notification of cancer transmission in a recipient from a multiorgan donor.

Our case suggests that if a donor‐transmitted malignancy has developed in a kidney recipient, the best option for prevention and treatment is graft nephrectomy and the withdrawal of immunosuppression.15 The literature supports the finding that transplant nephrectomy is effective in cases.10, 16, 17 It is possible that in some cases after stopping the immunosuppressive drugs, an alloimmune response develops against the tumor cells. The increase in detectable anti‐HLA antibodies after nephrectomy in our right‐kidney recipient is in line with this hypothesis but could also partially reflect diminished absorption by the donor organ. However, the importance of the underlying immune system in cancer surveillance and therapy is supported by the recent success of checkpoint inhibitors, which demonstrate the unique potential of the immune system to fight even metastasized cancer.18 But again, not all tumors are alike, and the delayed occurrence of tumors in our patients may indicate successful immune control of the tumor for a prolonged period after transplantation.

At this moment, the occurrence of donor‐derived malignancies in recipients is well recorded. However, improvements could be made by including additional data from national transplant registries with a more detailed donor assessment. This would enhance our knowledge of tumor transmission in organ transplantation and help to make well‐informed assessments of donor risk.