Israel Penn

Orthotopic homotransplantation of the human liver.

Orthotopic Homotransplantation of the Human Liver Thomas Starzl;Carl Groth;Lawrence Brettschneider;Israel Penn;Vincent Fulginiti;John Moon;Herve Blanchard;Alfred Martin;Ken Porter; Annals of Surgery

Post-transplant malignancy: the role of immunosuppression.

Immunosuppressed organ allograft recipients have a 3- to 4-fold increased risk of developing tumours, but the risk of developing certain cancers is increased several hundredfold. With the exception of skin and lip cancers,most of the common malignancies seen in the general population are not increased in incidence. Instead, there is a higher frequency of some relatively rare tumours, including post-transplant lymphomas and lymphoproliferative disorders (PTLD), Kaposi’s sarcoma (KS), renal carcinomas, in situ carcinomas of the uterine cervix, hepatobiliary carcinomas, anogenital carcinomas and various sarcomas (excluding KS). Skin and lip cancers present some unusual features: a remarkable frequency of KS, reversal of the ratio of basal to squamous cell carcinomas seen in the general population, the young age of the patients, and the high incidence of multiple tumours (in 43%of the patients). Anogenital cancers occur at a much younger age than in the general population. Salient features of PTLD are the high frequency of Epstein-Barr virus-related lesions, frequent involvement of extranodal sites, a marked predilection for the brain and frequent allograft involvement.As the immunosuppressed state per se and various potentially oncogenic viruses play a major role in causing these cancers, preventative measures include reducing immunosuppression to the lowest level compatible with good allograft function and prophylactic measures against certain virus infections. Reduction of exposure to sunlight may also decrease the incidence of skin cancer. In addition to conventional treatments (resection, radiation therapy, chemotherapy) patients may receive antiviral drugs, interferon-α and various other manipulations of the immune system. A significant percentage of cases of PTLD and KS respond to reduction or cessation of immunosuppressive therapy.

Liver transplantation for cholangiocarcinoma: results in 207 patients.

BACKGROUND Because of the high incidence of recurrent tumor, many surgeons have become disenchanted with transplantation as a treatment for cholangiocarcinoma. METHODS The Cincinnati Transplant Tumor Registry database was used to examine 207 patients who underwent liver transplantation for otherwise unresectable cholangiocarcinoma or cholangiohepatoma. Specific factors evaluated included tumor size, presence of multiple nodules, evidence of tumor spread at surgery, and treatment with adjuvant chemotherapy and/or radiation therapy. Incidentally found tumors were compared to tumors that were known or suspected to be present before transplantation. RESULTS The 1, 2, and 5-year survival estimates using life table analysis were 72, 48, and 23%. Fifty-one percent of patients had recurrence of their tumors after transplantation and 84% of recurrences occurred within 2 years of transplantation. Survival after recurrence was rarely more than 1 year. Forty-seven percent of recurrences occurred in the allograft and 30% in the lungs. Tumor recurrence, and evidence of tumor spread at the time of surgery, were negative prognostic variables. There were no positive prognostic variables. Patients with incidentally found cholangiocarcinomas did not have improved survival over patients with known or suspected tumors. A small number of patients survived for more than 5 years without recurrence. However, this group had no variable in common that would aid in the selection of similar patients in the future. CONCLUSIONS Because of the high rate of recurrent tumor and lack of positive prognostic variables, transplantation should seldom be used as a treatment for cholangiocarcinoma. For transplantation to be a viable treatment in the future, more effective adjuvant therapies are necessary.

Merkel's cell carcinoma in organ recipients: report of 41 cases.

In the general population Merkels cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. More than 600 cases have been reported. MCC seems to be common in transplant recipients, with 41 cases being reported to the Cincinnati Transplant Tumor Registry, and another 11 in the transplant literature. In the general population, it is a disease of older adults, with only 51% of cases occurring below the age of 50 years. In transplant patients, the mean age at diagnosis was 53 (range 33-78) years, and 29% of recipients were <50 years old. The tumor appeared from 5 to 286 (mean 91.5) months after the transplant. Of 44 lesions that occurred in 41 patients, the distribution was similar to that seen in the general population, with 36% occurring on the head and neck, 32% on the upper extremities, 16% on the trunk, 9% at unknown sites, and 7% on the lower extremities. Twenty of the patients (49%) had 22 other malignancies, the great majority of which (91%) were other skin cancers. Treatment depended on the stage of the disease and included wide surgical excision, radical lymph node dissection, radiation therapy, and chemotherapy. In transplant patients, MCC probably proved to be more aggressive than in the general population in that 68% of patients developed lymph node metastases and 56% died of their malignancies. Furthermore, one third of surviving patients still have active cancers from which they may die. Also, follow-up of survivors has been relatively short, with a mean of only 18 (range 0-135) months.

Kaposi's sarcoma in organ transplant recipients: report of 20 cases.

SUMMARY There is an increased incidence of Kaposis sarcoma (KS) in organ transplant recipients in whom it comprises more than 3% of all de novo neoplasms. Any such patient who develops reddish blue macules or plaques in the skin or oropharyngeal mucosa, or has apparently infected granulomas that fail to heal, should be suspected of having KS. In 45% of the patients, the internal viscera are involved. This variety has a bad prognosis. Apart from conventional treatment with surgical excision, radiotherapy or chemotherapy, cessation, reduction, or modification of immunosuppressive therapy produces gratifying results in a significant number of patients.

Cancers following cyclosporine therapy

Malignancies developed in 141 organ transplant recipients treated with cyclosporine. The cancers showed important differences from those seen following conventional immunosuppressive therapy (CIT). They appeared an average of 20 months after cyclosporine and 60 months after CIT. Non-Hodgkins lympho

Cancers of the anogenital region in renal transplant recipients: analysis of 65 cases

There is a 100‐fold increase in the incidence of carcinomas of the vulva and anus in renal transplant recipients compared with the general population. Anogenital (anus, perianal skin, and external genitalia of both sexes) carcinomas occurred in 65 of 2150 renal transplant recipients who presented with 2298 different types of malignancy. Two‐thirds of the patients were female and one‐third male. They were much younger than persons with similar tumors in the general population. The average age of the females at the time of diagnosis was 37 years (range, 20–64) and of the males, 45 years (range, 34–62). The neoplasms occurred late after transplantation, an average of 88 months (range, 9–215), compared with an average of 56 months (range, 1–225.5) for all other post‐transplant malignancies. The lesions involved the vulva, penis, scrotum, anus, or perianal area. Two patients also had involvement of the urethral meatus. In several female patients, there was a “field effect” with multiple tumors of the squamous epithelium of the anogenital area, vagina, or uterine cervix. Lesions ranged from in situ carcinomas (in one‐third of the cases) to those with invasion of adjacent organs and lymph node metastases. Treatment varied from local excisions to radical vulvectomy, abdominoperineal resection, or penile resection, sometimes combined with excision of the inguinal lymph nodes. In several patients, there was a previous history either of condyloma acuminatum or herpes genitalis, suggesting a possible viral etiology of these tumors. Cancer 58:611‐616, 1986.

Malignant Tumors Arising De Novo in Immunosuppressed Organ Transplant Recipients

De novo malignant tumors have been observed throughout the world in 75 chronic survivors of organ transplantation, including 16 of our own patients. The incidence of tumors was approximately 80 times greater than in the average population in a comparable age range. Chronic uremia may have predisposed to the development of some of the tumors, but this has not yet been proved. It seems clear that the predominant etiology was chronic immunosuppression post-transplantation. Forty-four of the patients had epithelial tumors and in 31 the lesions were of mesenchymal origin. On the average the malignancies appeared 29 months after transplantation. Lymphomas showed an unusual predilection for involvement of the central nervous system. Carcinomas of the skin, lip, and uterine cervix were successfully treated by conventional techniques. On the other hand, carcinomas of the thoracic or abdominal organs and mesenchymal tumors led or contributed to early death in most cases. For this reason drastic reduction or even discontinuance of immunosuppression should be considered in the management of these latter tumors.

Malignant melanoma in organ allograft recipients

Three groups of tumors were studied. The first group was melanomas inadvertently transmitted from donors. Brain metastases from melanoma were often misdiagnosed in the donors as primary brain tumors or cerebral hemorrhage. Eleven donors provided organs to 20 recipients of whom 3 never manifested evidence of melanoma, 1 showed local spread of tumor beyond the allograft, and 16 had metastases. Of the last group 11 died from melanoma, but 4 patients had complete remissions following transplant nephrectomy and discontinuation of immunosuppressive therapy. The second group was Melanomas treated pretransplantation. Thirty patients had cutaneous melanomas and one an ocular melanoma. Six patients (19%) had recurrences posttransplantation. Three were treated < 2 years pretransplantation, 2 between 2-5 years pretransplantation, and one 120 months pretransplantation. The third group was De novo melanomas. Cutaneous melanomas occurred in 164 patients, melanomas of unknown origin in 8, and ocular melanomas in 5. Melanomas constituted 5.2% of posttransplant skin cancers compared with 2.7% in the general population. Unusual features of cutaneous melanomas were that 6 (4%) occurred in children, and 9 (5%) occurred in bone marrow recipients who were treated for leukemia. Forty-four patients (27%) who had cutaneous melanomas also had other skin cancers. Forty-seven of 68 patients (69%) had thick skin lesions (Clarks level III or greater or > 0.76 mm by Breslows technique). Lymph node metastases occurred in 32 patients (20%) with cutaneous melanomas. Fifty patients (30%) with cutaneous melanomas died of their malignancies, as did 5 with melanomas of unknown origin, and 1 with ocular melanoma. The risks of melanoma may be reduced by stringent selection of donors; by waiting at least 5 years between treatment of melanoma and undertaking transplantation; and, perhaps, by reducing sunlight exposure and by early excision of suspicious dysplastic lesions.

Primary kidney tumors before and after renal transplantation

Three groups of patients were reviewed. Primary carcinomas were found in donors kidneys of 47 recipients. In 30 instances a tumor was present at harvesting. When a neoplasm was removed immediately pretransplantation or early posttransplantation there were no recurrences in 14 recipients. In another two instances, a tumor was not removed or was incompletely excised pretransplantation and both recipients died of metastases. Fourteen other patients received kidneys from donors in whom the opposite kidney had a malignancy. Thirteen remained tumor-free and one had allograft nephrectomy for rejection 3 months posttransplantation when a carcinoma was found. In 17 recipients an allograft neoplasm was not recognized at harvesting. In 9 it was discovered at graft nephrectomy an average of 3 months posttransplantation. In a tenth patient a hypoechogenic area, found on routine posttransplant ultrasonography, progressively increased in size and proved to be malignant. Another 7 patients developed metastases from renal carcinomas an average of 12 months posttransplantation. Preexisting carcinomas were found in 350 recipients. Seventy-one patients with incidentally discovered tumors had no recurrences no matter when nephrectomy was performed in relationship to transplantation. Of 279 patients with symptomatic renal tumors, 70 (25%) had recurrences, 63% of which occurred in patients treated < or = 2 years pretransplantation. De novo cancers were found posttransplantation in 256 recipients. Renal carcinomas were 4.6% of posttransplant cancers compared with 3% of tumors in the general population. In 222 patients their own diseased kidneys were involved, in 24 tumors occurred in the allograft, and in 10 cases the site was not stated. Development of neoplasia seemed to be related not to the immunosuppressive therapy but to the underlying cause of renal failure, especially analgesic nephropathy. A disproportionate number of carcinomas (15%) involved the renal pelvis, most likely because of prior analgesic abuse.