EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Liver retransplant was first performed by Starzl and colleagues in 1963, whose efforts were described to “have borne bitter fruit,” as only 6 of 27 (22%) patients survived longer than 6 months.^1,2 Because retransplant is the only treatment for irreversible graft failure after primary liver transplant (LT), further attempts demonstrated progress but with persistently increased mortality compared with primary LT.^3,4 Liver transplant recipients (and all organ transplant recipients) are at risk for de novo malignancies due to prolonged immunosup-pression.^5-7 Depending on the transplant center and the duration of follow-up, the incidence of malignancy in LT recipients varies from 2.6% to 26%.^8-10 A high incidence of head and neck cancer has been observed among LT recipients, and cancers of the head and neck are associated with have poor prognoses, especially in cases of advanced-stage disease.¹¹ Risk factors for nonskin solid-organ malignancies after LT include age, immunosup-pression, noninfectious environmental exposures (the most established of which are alcohol and smoking), infectious agents (discussed later), and underlying liver disease.^7,12,13

At Batumi Referral Hospital in Spring of 2019, a 44-year-old male patient was hospitalized to treat a 14-year anamnesis of viral hepatitis C. The diagnosis was liver cirrhosis with end-stage liver disease (ESLD). The Model for End-Stage Liver Disease score was 22, and the Child-Pugh score was C. Three days after admission, the patient received an orthotopic living donor LT (Fan method). The duration of the transplant surgery was 9 hours and 20 minutes. Immunosuppression was initiated according to a 3-component regimen: methylprednisolone (Medrol), tacrolimus, and mycophenolate mofetil. On posto-perative day 6, convulsions developed. Computed tomography angiography of the brain showed no damage, and the condition was assessed to be a toxic effect of tacrolimus. By this time, the concentration of tacrolimus in the blood was 9.4 ng/mL. Tacrolimus treatment was ceased, but hormone therapy was maintained, and the patient was transferred to cyclosporine. On postoperative day 17 (11 days after cessation of tacrolimus), the tacrolimus concentration was 75 ng/mL. Treatment was carried out in accordance with Asian and European protocols fulfilling suggested terms and volumes. The patient was discharged from the hospital on postoperative day 22 in a satisfactory condition.

Four months later, the patient noticed a dull feeling in the mouth accompanied by dysphagia. The problem progressed. At the next scheduled visit, the patient was examined by a head and neck surgeon followed by a cytological examination of the oropharynx, which led to a diagnosis of oropharyngeal squamous cell carcinoma at approximately 19 weeks after transplant (Figure 1a). Further research (computed tomography and magnetic resonance imaging) revealed the presence of metastases in the right submandibular area (cT3N2aM0).

At the first stage of treatment, a course of radiation therapy was recommended and initiated, which proceeded from October 2019 to December 2019. During this period, the patient underwent 3 courses of combined chemoradiotherapy (Figure 1b). In early 2020, approximately 22 weeks after the diagnosis of oropharyngeal squamous cell carcinoma, surgical treatment was performed to excise the connective tissue of the right half of the damaged neck with the metastatic conglomerate. The patient was discharged without complications 3 days later.

Throughout this period, immunosuppression was maintained at a low level, with methylprednisolone (4 mg) and cyclosporine (within 20-30 ng/mL). Approximately 2 months after the neck surgery, the patient was transferred to tacrolimus, the dose of which varied from 5 to 6.5 ng/mL. Approximately 4 months after the neck surgery (2 months after resumption of tacrolimus), the patient experienced general weakness, itching, and jaundice, and signi-ficant changes were reflected in the laboratory data: creatinine 112 μmol/L, total bilirubin 108 μmol/L, alanine transaminase 270 U/L, aspartate transaminase 306 U/L, γ-glutamyl transferase 569 U/L, alkaline phosphatase 621 U/L, and international normalized ratio 1.14. One month later, a liver biopsy study was performed and showed 80% preservation of histoarchitectonics of the parenchyma (Figure 2). The criteria for liver rejection were determined by 3 points: periportal infiltration, bile duct damage, and venous infiltration. The condition was assessed as chronic rejection, and according to the protocol (with appropriate consideration of oncology) we proceeded with pulse therapy. Approximately 17 weeks after the biopsy, we performed a complex study of the patient and confirmed the oncological recovery. Recurrence of oropharyngeal cancer was minimal. However, severe condition diagnosis was based on liver condition that time.

Three weeks after confirmation of oncological recovery, an orthotopic right lobe living donor liver retransplant (LDLrT) was performed. The duration of retransplant was 12 hours and 25 minutes. At 7 hours and 20 minutes, the damaged liver graft was removed (Figure 3a). The morphological study of the extracted liver graft confirmed that the normal architecture of the parenchyma was disturbed (Figure 3b). Immunosuppression proceeded according to the 3-component regimen of methylprednisolone, tacrolimus, and mycophenolate mofetil. On day 3, the patient became active and started eating. The results from Doppler sonography showed that the liver structure and flows were satisfactory: portal vein diameter 10 mm, hepatopetal flow, peak systolic velocity 40.26 cm/s, volume flow 855.68 mL/min; arterial flow antegrade peak systolic velocity 31.45 cm/s, and hepatic venous flow was hepatofugal. Clinical and laboratory indicators were within the permissible reference ranges. The patient was discharged from the hospital 19 days after the LDLrT. At 22 months after retransplant, the condition of both the health of the patient and the graft remained satisfactory. No oncological relapse was detected.

Early diagnosis and treatment of de novo malignancies can facilitate better prognosis and higher survival rates in patients with oropharyngeal squamous cell carcinoma.⁸ In our case, the posttransplant period proceeded without significant complications. Six months after the transplant, complaints were reported in the oral cavity area, and oropharyngeal squamous cell cancer cT3N2aM0 was diagnosed. The decision to avoid immunosup-pression at the time is an important dilemma to resolve and should be the subject of additional research. In the future, protocols for immunosup-pressive modification need to be established, to balance the need to prevent malignancies with the need to maintain transplanted organs.²⁶ Because of the immunosuppressive change, our patient’s immunosuppressive therapy was strengthened with everolimus concentration of 3 to 8 ng/mL paired with reduced tacrolimus concentration of 3 to 5 ng/mL. We also used pulse therapy, but the desired result was not obtained and irreversible processes of biliary fibrosis of the liver began. At 20 months after the first transplant and 12 months after completion of the full course of oropharyngeal cancer treatment (with surgery), the patient was healthy from an oncological point of view. However, as a result of the progressive chronic rejection of the liver, the patient developed ESLD.

We believe that, in the background of the developed oncological disease, reduction of immuno-suppression coupled with chemoradiotherapy became the provoking factor for the beginning of the graft rejection of later stage, which could not be stopped. Because retransplant is the only treatment for irreversible graft failure after primary LT, our team was faced with the task of LDLrT. When a patient presents with malignancy with clinical symptoms, there may be few therapeutic options.^14,15 Our decision was made in favor of retransplant by our multidisciplinary team. The LDLrT performed in early 2021 was successful, which was confirmed by the results at 22 months after retransplant, both by the functional stability of the liver and by the oncological purity.

Although our case is a sporadic result of LDLrT after an oncological complication (with a short follow-up period), in patients with ESLD, a living donor LT is an indispensable method of treatment. In the case of correctly selected patients and oncology, we think LDLrT should be used more actively. Our patient is living proof of the emerging paradigm of transplant oncology and demonstrates the potential for the fusion of transplant medicine and oncology to open new horizons in cancer treatment.

Volume: 21 Issue: 7 July 2023

FULL TEXT