Lessons learned from the first 15 years of penile transplantation and updates to the Baltimore Criteria

Abstract

Since 2006, five penis transplants have been performed worldwide. Mixed outcomes have been reported, and two of the five penile transplants have required explantation. However, the long-term outcomes have been encouraging when compliance is implemented, whether standard induction and triple therapy maintenance, or single therapy maintenance. Follow-up monitoring of transplant recipients has enabled a synthesis of technical considerations for surgical success and has shown stable leukocyte counts and renal function after a donor bone-marrow-based immunomodulatory regimen followed by tacrolimus monotherapy as long as 3 years post-transplant, as well as continuous nerve regeneration of penile allografts 3 years post-transplant. Areas of uncertainty include the ethics of donor-recipient colour mismatch, surveillance for sexually transmitted infections and how to optimize patient compliance. Questions also remain with respect to the long-term immunological sequelae of penile tissue, functional outcomes, psychosocial implications and patient selection. Patient counselling should be modified to mention the possibility of long-term improvement in nerve regeneration and sufficient renal function with single-therapy maintenance, and to build a longitudinal dialogue and partnership between the patient and the multidisciplinary care team regarding the risks of sexually transmitted infection instead of surveillance.

Fig. 1. Technique employed in the Guangzhou penile transplant.

The patient originally presented with all native vascular structures intact. In this procedure, the dorsal penile arteries, superficial dorsal vein, and deep dorsal vein of the transplant were anastomosed to the equivalent recipient vessels. The transplant was explanted after 2 weeks owing to psychological rejection. DDV, deep dorsal vein; DPA, dorsal penile artery; SDV, superficial dorsal vein.

Fig. 2. Technique employed in the Baltimore penile transplant.

The patient originally presented with obliterated native deep penile arteries and cavernous arteries owing to an improvised explosive device detonation. The transplant included bilateral external pudendal arteries and veins. The left and right dorsal penile arteries of the transplant were anastomosed to the recipient left and right inferior epigastric arteries, respectively. The superficial dorsal vein of the transplant was anastomosed to the recipient’s right inferior epigastric vein, whereas the deep dorsal vein was anastomosed to the recipient’s left inferior epigastric vein. The transplant left external pudendal artery was supplied by an anastomosis between the supplying left transplant femoral artery and the recipient femoral artery. Likewise, the transplant left external pudendal vein drains to the left greater saphenous vein, which was anastomosed to the left recipient greater saphenous vein. This transplant maintains good long-term outcomes. DDV, deep dorsal vein; DPA, dorsal penile artery; EPA, external pudendal artery; EPV, external pudendal vein; FA, femoral artery; FV, femoral vein; GSV, greater saphenous vein; IEA, inferior epigastric artery; IEV, inferior epigastric vein; SDV, superficial dorsal vein.

Fig. 3. Technique employed in the Boston penile transplant.

The patient originally presented with obliteration of the native dorsal penile arteries. The transplant cavernous arteries were anastomosed to the equivalent recipient vessels. The right external pudendal artery of the transplant was anastomosed to the recipient right femoral artery, although this failed. The right dorsal penile artery of the transplant was successfully anastomosed to the recipient superficial femoral artery via a reversed distal leg vein graft. Finally, the deep dorsal vein of the transplant was anastomosed to its equivalent recipient vessel. This transplant maintains good long-term outcomes. CA, cavernous artery; DDV, deep dorsal vein; DPA, dorsal penile artery; FA, femoral artery.

Fig. 4. Technique employed in the first Cape Town penile transplant.

The patient originally presented with obliteration of the native dorsal penile arteries, superficial dorsal vein and deep dorsal vein, owing to botched circumcision. The left and right dorsal penile arteries of the transplant were anastomosed to the recipient left external pudendal artery and left inferior epigastric artery, respectively. The deep dorsal vein of the transplant was anastomosed to the recipient inferior epigastric vein. After 2 years and 8 months, half of the flap was lost owing to rejection, which was later reversed and reconstructed with skin grafts. DDV, deep dorsal vein; DPA, dorsal penile artery; EPA, external pudendal artery; IEA, inferior epigastric artery; IEV, inferior epigastric vein.

Fig. 5. Immunosuppressive protocols in penile transplantation.

The induction and maintenance protocols used, the antimicrobial, antiviral and antifungal regimens, and the reoperation and rejection episodes are reported by postoperative date. BM, bone marrow; MMF, mycophenolate mofetil.

Fig. 6. Leukocyte counts and renal function in the Baltimore patient after the operation.

a, White blood cell count and absolute neutrophil count during initial postoperative admission. Counts were highest in the early postoperative weeks, followed by resolution to normal ranges. Early peaks were associated with a haematoma evacuation on postoperative day 1 and a rejection-like episode on postoperative day 8. The peak on postoperative day 22 is associated with local inflammation at the time of biopsy; however, no evidence of rejection on histology was observed. b, White blood cell count and absolute neutrophil count after initial discharge. The peak at 19.6 months coinicides with treatment of a blotchy rash on a suprapubic portion of the transplant with clobetasol. Skin biopsy at 27.4 months revealed Banff grade III rejection requiring solumedrol 500 mg IV for 2 days. Peaks at 30.7 months and 36.7 months occurred at the time of two osteointegration sessions. c, Blood urea nitrogen and creatinine during initial postoperative admission. Blood urea nitrogen fluctuates at or above the normal range and creatinine is maintained within the normal range; this holds true even during a period of urinary retention during postoperative week 3. d, Blood urea nitrogen and creatinine after initial discharge. Creatinine grossly remains within normal limits. Blood urea nitrogen varies widely despite good urinary function throughout the long-term postoperative course. e, Glomerular filtration rate (GFR) during initial postoperative admission, showing maintenance within normal range with occasional fluctuations. f, GFR after initial discharge, showing maintenance within normal range with occasional fluctuations.

Fig. 7. Tissue histology in the Baltimore patient.

a, March 2018: 4× magnification shows Banff grade I/II rejection. b, March 2018: 10× magnification demonstrates mild perivascular infiltrate of lymphocytes and vacuolar change to basilar keratinocyte cytoplasm. c, March 2019: 4× magnification shows no signs of rejection and normal biopsy appearance. d, March 2019: 10× magnification shows no signs of rejection and normal biopsy appearance. e, June 2020: 4× magnification demonstrates multifocal areas of moderate perivascular and periadnexal lymphocytic inflammation. f, June 2020: 40× magnification demonstrating focal regions of dyskeratosis (circled).