EXPERIMENTAL AND CLINICAL TRANSPLANTATION

In patients affected by unresectable liver metastases from neuroendocrine tumor, liver transplant represents currently the only realistic chance for cure. The first attempt to establish selection criteria for liver transplant in patients affected by neuroendocrine tumor liver metastases was made by Mazzaferro and associates in 2007. We report the case of a 46-year-old man who came to our institution in 2006 with right upper quadrant abdominal pain. Diagnosis of rectal neuroendocrine tumor with bilobar liver nodules was made; the patient underwent transanal local resection. A liver biopsy confirmed the metastatic nature of the hepatic lesion, showing a low-grade neuroendocrine tumor (G1, proliferation index Ki-67 < 2%). The patient underwent 2 sessions of transarterial chemoembolization that resulted in stable disease. Afterward, the patient underwent a liver transplant, using the piggyback technique without a venous-venous bypass. His postoperative course was uneventful.

The patient has been disease-free for 3 years. Posttransplant treatment has played a key role in increasing the overall survival of the patient and assuring him a good quality of life. He died 9 years (102 mo) after liver transplant.

Key words : Liver metastases, Liver transplant, Neuroendocrine tumor

Liver transplant provides the only realistic chance of curing patients with unresectable liver metastases from neuroendocrine tumor. Mazzaferro and associates in 2007, with the Milan criteria, and Pavel and associates in 2012, with the European Neuroendocrine Tumor Society (ENETS) guidelines, made the first attempt to establish selection criteria for a liver transplant in patients affected by neuroendocrine tumor liver metastases. According to these studies, the selection criteria for performing a liver transplant are liver involvement < 50% of parenchyma without extrahepatic disease, well-differentiated neuroendocrine tumor (Ki-67 proliferation index < 10%), age < 55 years, primary tumor resected at least 6 months before transplant with contemporary stable hepatic disease during this time, and location of the primary tumor in the district drained by portal circulation (ie, the esophagus and the rectum are excluded because the liver is not considered the first site of hematogenous spread of malignant cells well from the primary site). Here, we report a case of a small rectal carcinoid tumor with extended liver metastases, treated with a local transanal excision and liver transplant with long-term follow-up.

In January 2004, a 46-year-old man was seen in our institution with right upper abdominal pain. The results of basic hematologic examinations were normal, and the results of functional hepatic examinations were aspartate aminotransferase 76 U/L, alanine aminotransferase 79 U/L, and gamma-glutamyl transpeptidase 776 U/L. Bilirubin, proteinogram, and coagulation examinations were within normal ranges. The results of ultrasonographic and computed tomographic scans of liver (Figure 1) showed a parenchyma almost completely occupied by multiple solid nodules; their radiologic pattern suggested secondary lesions. Tumor marker determination was as follows: α-fetoprotein, 124; chromogranin A, 207 μg/L; and neuron-specific enolase (NSE), 22 μg/L. Serotonin and its metabolites were normal.

The patient underwent an upper gastrointestinal endoscopy, the results of which were negative, and a colonoscopy that showed, at 6 cm from the anal verge, a polyp, with sessile base of 1.5 cm of diameter. Biopsies were concordant with a carcinoma. The OctreoScan (Mallinckrodt Medical, St. Louis, MO) showed only rectal and liver locations of the tumor. A colon echoendoscopy examination staged the rectal cancer as T2N0. The patient underwent a transanal local resection; the histologic examination of the specimen showed disease-free surgical margin. A liver biopsy was performed confirming the metastatic nature of the hepatic lesions, that is, a low-grade neuroendocrine tumor (G1) with proliferation index of Ki-67 <2 %. Liver disease was treated with 2 sessions of transarterial chemoembolization, which resulted in stable disease according to a modified Response Evaluation Criteria in Solid Tumors (mRECIST).¹ In consideration of the stability of the liver disease, the patient's case was discussed during transplant staff meeting, with agreement for liver transplant. The patient went on the liver transplant wait list. During this time, the patient was given treatment with somatostatin analogs.

A liver transplant was performed in January 2006. The transplant procedure, performed with the piggyback technique without a venous-venous bypass, lasted 7 hours, with a blood loss of 300 mL (Figure 2). The histologic examination of the specimen identified an epithelioid tumor with low mitotic activity, tumor cells that were positive for synaptophysin, LEU7, and NSE. The proliferation index Ki-67 was <10%. Histomorphologic and immunohistochemical data confirmed liver location of low-grade neuroendocrine tumor.

The patient’s postoperative course was uneventful and the patient was discharged home after 2 weeks. The patient underwent immunosuppressive therapy with FK-506.

Two years later, the patient underwent a total thyroidectomy and radiometabolic therapy for papillary-follicular thyroid carcinoma (pT2). Three years after the liver transplant, the patient reported pelvic pain. An OctreoScan showed pathologic uptake at the level of the right acetabulum-iliac wing, head/neck of the right femur, and left sacrum. He started external radiotherapy of the pelvis and the lumbar spine (30 Gy, 10 fractions) and zoledronic acid with regression of bone lesions. At the same time, the patient started immunosuppressive therapy with FK-506 and mechanistic target of rapamycin inhibitor. Four years after the transplant, the patient received therapy with somatostatin analogs with lanreotide and peptide receptor radionuclide therapy with 177 LU-DOTATATE (608 mCi total) for 1 year. After 2 years (6 years from the transplant) a computed tomographic scan showed multiple bilobar hepatic metastases. The patient resumed treatment with lanreotide. For 1 year of follow-up, the patient maintained normal liver function and patency of the liver vessels and biliary tract. The hepatic metastases had maintained an initial dimensional stability, and the patient showed a good performance status. Two years later, the patient presented progression of liver disease (Figure 3) with onset of liver failure. The patient died in June 2015, one hundred two months after the liver transplant.

The optimal treatment of patients with NET hepatic metastases remains debatable. In cases of metastatic NET limited to the liver, surgery is the first option, with a 5-year survival and disease-free survival at 5 years after liver resection varying from 46% to 85% and from 22% to 42%.² On the other hand, surgery is feasible only in fewer than 20% of cases for the bilobar involvement of the liver parenchyma at diagnosis³ and is generally indicated only if 90% of the tumor mass can be removed.^4,5

In view of the small percentage of patients eligible for resection, considering that the overall 5-year survival rate in case of untreated liver metastases from NET is approximately 30% to 40%,6 liver transplant can represent the only curative treatment for patients affected by NET bilobar liver metastases.

The first attempt to establish selection criteria for liver transplant in patients affected by NET liver metastases was done first by Mazzaferro and associates in 2007 with the introduction of Milan criteria, and then by Pavel and associates in 2012 with ENETS guidelines (Table 1).^1-7

We performed a literature review and found 32 articles, from 1989 to 2014 (Table 2), analyzing patient outcomes after liver transplant for NET liver metastases: data on approximately 1188 patients have been collected worldwide. Considering the lack of stringent generally adopted pretransplant selection criteria and of uniform follow-up protocols, which hamper critical assessment of the published results, the 5-year survival rate of liver transplant recipients for neuroendocrine tumors ranges from 0% to 90% (median 50%), resulting in a recurrence of the carcinoid tumors—the main cause of death. The 5-year disease-free survival rate ranges from 0% to 77% (median 29%). The risk of tumor recurrence remains a significant clinical problem after an LT, and only a few patients may be considered free of tumor 5 years after transplant, despite a careful pretransplant assessment. Nevertheless, a liver transplant could improve overall survival of patients with unresectable liver metastases from NET resistant to alternate treatments.

Our patient underwent liver transplant despite a locally advanced stage, with liver involvement greater than 50%, although the primary tumor was not a tributary of the portal vein. A long follow-up provided more meaningful information for the prognosis of such an unusual case; the patient had bone metastases at 3 years and overall survival of 9 years, similar to what has been reported in the literature, resulting in a liver transplant that was essential for the prognosis of our patient.

Histopathologic discrimination, primarily Ki-67 proliferation index determination, is important for predicting the recurrence risk and prognosis of neuroendocrine tumors. After a liver transplant, adequate immunosuppressive therapy is required, which might predispose the patient to a higher risk of tumor recurrence or de novo tumor occurrence, both in the short and long term.

In cases of recurrent malignancy of NET after liver transplant, several treatment options are available. Radiofrequency ablation should be considered in case of a single lesion, diameter < 3 cm, completely surrounded by liver parenchyma, at least 1 cm away from the liver capsule, and at least 2 cm from the hepatic veins or portal vein. Embolization of hepatic artery (ie, cisplatin, doxorubicin, mitomycin-C, iodized oil, and polyvinyl alcohol) might be considered, provided that there is good vascularization of the liver graft and that the liver metastases are hypervascular. In these circumstances, superselective arterial embolization could be performed. 90Y-microsphere radioembolization, more recently introduced in the treatment of NET liver metastases, has shown promising results, mostly in patients with low hepatic tumor burden, well-differentiated tumor, female sex, and no extrahepatic disease.⁸ Radioembolization also seems to be an effective and safe procedure if associated with peptide receptor radionuclide therapy.⁹ A liver resection after a liver transplant is technically feasible, but no data are available in the setting of NET. Additionally, chemotherapy can be given to NET patients who experience recurrence after liver transplant. If the somatostatin receptor functional imaging is avid, then radionuclide-targeted therapy with 177 LU-DOTATATE can be considered. In our case, posttransplant treatments have played a key role in increasing the overall survival of the patient and ensuring a good quality of life.

In conclusion, the prognosis of our patient was markedly improved by liver transplant. In fact, he was disease-free for 3 postoperative years and died 9 years after transplant, despite poor prognostic parameters. More prospective trials are needed to define universally accepted inclusion criteria, reliable predictors of better outcome, and optimal timing for liver transplant, eventually reviewing and extending the current standard.

Volume: 16 Issue: 4 August 2018

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