Objectives: Liver transplant has been shown to be a good treatment option for patients with nonresectable tumors that are limited to liver and that do not respond to medical treatment. In this study, our aim was to share our experience in management of patients with neuroendocrine tumors and liver metastasis by liver transplant with and without more extensive surgical interventions.
Materials and Methods: We performed a 6-year (2011-2017) retrospective study of data from the Namazi Hospital Transplant Research Center. Inclusion and exclusion criteria were determined based on pretransplant policy in our center. Our study included 15 patients with mean age of 33.3 years.
Results: Of the 15 patients included, 53.3% (n = 8) had liver transplant alone, 26.6% (n = 4) had multiorgan transplant, 6.66% (n = 1) underwent Whipple procedure and liver transplant, and 6.66% (n = 1) had segmental ileal resection and liver transplant. Six early mortalities occurred during the posttransplant hospital stay, and 2 patients with multiorgan transplant died in the follow-up period. In addition, 1 patient needed retransplant during follow-up due to chronic rejection.
Conclusions: In patients with neuroendocrine tumors, the therapeutic approach to the liver metastasis and the prognosis can be determined based on the natural history of the disease, severity and progression of symptoms, tumor biology, location, and differentiation. Early diagnosis and management are needed to allow less invasive treatment protocols, which could result in more favorable outcomes.
Key words : Liver metastasis, NETs, Surgical resection
Neuroendocrine tumors (NETs) are rare tumors that predominantly originate in the gastrointestinal (GI) tract and pancreas. These tumors mostly occur sporadically; however, patients with multiple endocrine neoplasia syndrome type 1 have a 30% chance of developing NETs.1
Neuroendocrine tumors can be categorized into functional versus nonfunctional tumors; this process is dictated by the ability of tumor cells to secrete neuropeptides and biogenic amines. Because most NETs that originate in the GI tract are nonfunctional and slow growing, patients usually present in later stages with metastases (40% to 80%), with the liver being the most common site (40% to 93%).1-3 Liver metastases is the major cause of mortality in these patients and usually is multifocal and bilateral at the time of presentation; however, metastases may be confined to the liver for a long time. In addition, large liver metastases may cause carcinoid syndrome and further compromise the patient’s quality of life.1,2,4
There are multiple treatment modalities in these patients, and surgery is usually the treatment of choice. Curative resection of the tumor may be done in patients who have no other systemic metastases on radiologic studies. However, because patients usually present with advanced stages of disease and have multilobar involvement of liver at the time of diagnosis, curative resection can only be considered in 20% of patients. In addition, the disease has a high rate of recurrence. Other treatment options include cytoreductive surgery, immunotherapy with somatostatin analog, chemoembolization, radiofrequency ablation, and cryosurgery.2,5
Although liver transplant has been generally abandoned in the treatment of patients with liver metastasis, due to its slow growing rate, there has been increased interest in liver transplant of selected patients with NET and liver metastases. This treatment has been shown to be a good option in patients with nonresectable tumors that are limited to the liver and that do not respond to medical treatment.1,3,6,7
In this retrospective study, we share our experience in management of patients with NET and liver metastasis by liver transplant with or without more extensive surgical interventions.
Materials and Methods
In this retrospective study, we analyzed all patients with metastatic NET who received liver transplant alone or with more extensive procedures, such as Whipple surgery, bowel resection, and multiorgan transplant, in our center (Namazi Hospital Transplant Ward, Shiraz University of Medical Sciences, Shiraz, Iran) from 2011 (which was ourfirst experience in this field) to 2017. Inclusion and exclusion criteria were based on pretransplant policies in our center. Inclusion criteria included presence of nonresectable well-differentiated NETs with confined liver metastases having unknown origin, having origin at the resectable primary site, or with previously resected primary tumor. Patients with metastases responsive to medical therapy, those with resectable NET liver metastases, and those with pathology other than NET were excluded.
Fifteen patients (9 female and 6 male patients) were included. Patients ranged from 14 to 50 years old, with mean age of 33.3 years. Seven patients had definite preoperative diagnosis of NET, and 8 patients had NET of unknown origin. However, a primary source of NET was diagnosed in 2 of these patients on posttransplant pathologic report. Thus, of 15 patients, 6 had NET of unknown primary origin, 5 had NET with pancreatic origin, and 4 had NET with small intestine origin.
Two patients had previous surgery of primary tumor, and others presented with liver metastases. All our transplanted organs had been from deceased donors, and all patients received whole livers except for 2 (patients 3 and 9). These 2 patients received right lobe liver transplant. Hepatectomy specimens were examined by our pathologists for Rindi classification. Endocrine markers were analyzed by immunohistochemistry.
Of the 15 patients with metastatic NET who had met criteria for transplant, 8 had underwent liver transplant alone, 4 had multiorgan transplant, 1 had combined liver and pancreas transplant, 1 patient had undergone Whipple procedure and liver transplant, and 1 had segmental ileal resection and liver transplant.
Patient 14 primarily had pancreatic NET; this patient required liver transplant 1 year after resection of the primary tumor when he presented with liver metastasis. However, the other 4 patients had primary site tumor in control at the time of transplant. All 5 patients had pathology reports that suggested well-differentiated NETs.
Of the 4 patients with NET of the small intestine, 1 patient (patient 6) received ileal resection 6 years before transplant to treat the primary site tumor. The patient presented with resectable liver metastasis but developed hepatic failure after liver resection and underwent emergent liver transplant.
Of total patients, there were 6 early mortalities during posttransplant hospital stay. Five of these patients had undergone multiorgan transplant (patients 1, 2, 4, 7, and 9) and 1 had received only liver transplant. This latter patient had primary nonfunction of the transplanted liver with unsuccessful early retransplant.
Two other patients who had multiorgan transplant died during follow-up. Patient 3 had recurrent infection leading to sepsis and died 11 months posttransplant. Patient 5 died 15 months posttransplant due to lung metastasis.
Over the follow-up period, 1 patient required liver retransplant due to chronic rejection. The remaining patients had good follow-up status. Table 1 summarizes patient data.
Neuroendocrine tumors are a special group of tumors with slow growth rate. These tumors can be divided into functional tumors, which have the potential to secrete discrete substances and cause different clinical pictures, and nonfunctional tumors, which usually present with multilobular liver metastasis.2 Liver metastasis may occur in about 75% to 80% of patients with NETs, and metastasis may be confined to the liver for a long time, which is considered as a poor prognostic factor. Patients with NETs in the GI system have more favorable prognosis than those with pancreatic NETs, as multiorgan transplant has a higher mortality rate.8,9 If the liver metastasis is not treated, the estimated 5-year survival rate is about 30% to 32%; this issue should be kept in mind when considering no treatment versus the success rate of any treatment modality.6 To detect small tumors and to find the source of the primary tumor, grading of the tumor must be accomplished precisely. According to the natural history of the disease, severity and progression of symptoms, tumor biology, location, and differentiation, clinicians can decide the therapeutic approach to liver metastasis and a prognosis can be determined.9 A surgical approach is usually preferred.
If possible, the primary tumor and liver metastasis should be completely resected and cytoreductive surgery may be recommended in advanced cases; however, in most instances, it is disseminated, multifocal, and nonresectable, and total hepatectomy and liver transplant may be considered as a curative or palliative alternative.6,9 However, mortality rates and possibility of recurrence after liver transplant are high, and liver transplant is usually considered in young patients with no other extrahepatic disease.8,10 Up to now, guidelines for performing liver transplant in these patients have not been established; therefore, there is a great need for further study and sharing experience in these cases.
In a large study from 1997 that discussed liver transplant as a treatment for NET tumors and liver metastasis, Le Treut and associates reported a mean patient survival rate of about 30 months.11 In another study from Lehnert and associates from 1998 of 103 patients who had liver transplant, the 2-year and 5-year survival rates were 60% and 47%, respectively.6 In patients who received a combination of liver transplant with Whipple or upper abdominal exenteration, those older than 50 years old had poorer prognosis.6 In our study, mortality occurred in 2 of 8 patients with liver transplant alone early posttransplant and at 16 months posttransplant, which was due to primary nonfunction and lung metastasis, respectively. However, the remaining 6 patients were still alive at follow-up, with the mean survival rate of 42 months and no disease recurrence. However, patient 6 developed delayed rejection 11 months after liver transplant and underwent a retransplant procedure.
Patients with multiorgan transplant have poorer prognosis and earlier mortality. In our study, 4 of 5 patients with multiorgan transplant died early in their hospital course due to acute respiratory distress syndrome, sepsis, organ failure, bleeding, and primary nonfunction, with one having a survival rate of 11 months. However, the patient with combined liver transplant and Whipple procedure was alive and disease free at follow-up (4 years posttransplant).
In another study by Lang and colleagues, median survival after liver transplant was about 55 months, and patients with extrahepatic tumors (either lymph node metastasis or primary tumor) had worse prognosis; thus liver transplant was not recommended.12 Le Treut and colleagues reported on patients with upper abdominal exenteration, observing that these patients had higher mortality rate and worse prognosis, as these patients had more extensive disease that needed more invasive procedures.13
We suggest that early diagnosis of NET can result in less invasive treatment protocols and result in more favorable outcomes.
DOI : 10.6002/ect.2019.0154
From the Transplant Research Center, Shiraz University of Medical Sciences,
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Mohammad Mostafa Safarpour, Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Table 1. Characteristics of Study Patients