Neoadjuvant peptide receptor radionuclide therapy and modified multivisceral transplantation for an advanced small intestinal neuroendocrine neoplasm: an updated case report.

Small intestinal neuroendocrine neoplasms (SI-NEN) frequently metastasise to regional lymph nodes, and surgery is the mainstay of therapy for such patients. However, despite the possible use of advanced surgical techniques, the resection of both primary and locoregional diseases is not always attainable. Intestinal and multivisceral transplantation has been performed in a small number of patients with conventionally nonresectable, slow-growing tumours threatening the mesenteric root but has remained controversial. The use of donor skin in "sentinel flaps" in transplantation theoretically offers advantages in tailoring immunosuppression and monitoring for rejection. We represent (with extended follow-up) the first case of a patient with inoperable extensive mesenteric metastases from SI-NEN, who underwent neoadjuvant peptide receptor radionuclide therapy before a modified multivisceral transplant with a concomitant vascularised sentinel forearm flap. At 48 months after transplantation, our patient remained at full physical activity with no evidence of disease recurrence on either tumour biochemistry or radiological imaging. ©2017 Clift A.K. et al., published by De Gruyter, Berlin/Boston.

Introduction

Neuroendocrine neoplasms (NEN) represent the commonest type of small intestinal (SI) tumours [1], [2]. Despite their relative indolence in terms of survival time compared to SI adenocarcinomas, SI-NEN display a strong predilection for nodal and distant metastasis, namely to the mesentery and the liver, respectively. Indeed, although the majority of SI-NEN are low-grade, well-differentiated entities, institutional case series have demonstrated that the identification of regional lymph node metastases at initial presentation may approach 90% [3]. Accordingly, the surgical intervention for disease control often encompasses the extirpation of locoregional disease and also the resection of hepatic deposits if present and surgery is recognised as the cornerstone in therapeutic strategy in patients with resectable disease [4], [5].

The aggressive surgical management of regional deposits is mandated in patients with extensive mesenteric spread, given the risks of intestinal obstruction and encasement of superior mesenteric vessels causing intestinal ischaemia. Although several complex methods have been developed to render previously unresectable tumours (i.e. those in apposition to the coeliac and superior mesenteric vessels or with retroperitoneal extension) amenable to surgery, such as ultrasound-guided superior mesenteric vein stenting [6], free dissection of the superior mesenteric artery and vein at the inferior pancreatic border [7] and multivisceral ex vivo autotransplantation [8], [9], many patients still suffer from unresectable disease.

The relatively newly embraced concept of “transplantation oncology” has occupied a small albeit highly controversial role in intra-abdominal tumours, including NEN. Orthotopic liver transplantation is an increasingly accepted option in highly selected patients with NEN metastatic to the liver [10], with recent reports inferring outcomes similar to those observed in hepatocellular carcinoma [11], [12]. Experience with SI and multivisceral transplantation (MVT; with or without the liver) for slow-growing intra-abdominal tumours such as NEN threatening the mesenteric root is limited, although outcomes associated with allografts containing the SI in general appear to be improving [13], [14]. A number of small case series including patients with NEN have been reported, predominantly from Scandinavian centres (Table 1) [11], [15], [16], [17], [18]. Lastly, a relatively new approach in transplantation surgery is the vascularised sentinel forearm flap (VSFF) notably used in facial transplantation. A VSFF comprises a skin allograft obtained from the same donor as another composite tissue graft and enables the monitoring for immune rejection via monitoring the transplanted area on the recipient’s forearm [19], [20]. Briefly, the theoretical basis of using a VSFF is that the appearance of a rash on the graft may indicate a rejection reaction suggestive of concomitant rejection of the “primary” graft, in this case, the intra-abdominal allograft. The careful monitoring of this sentinel site has obvious ramifications on immunosuppression and may accordingly permit the tailoring of immunosuppressive regimens.

Table 1:

Overview of previously published experience with multivisceral transplantation for neuroendocrine tumours.

Author (year)	Cohort size (NEN)	Percentage with liver metastases	Primary tumour location/type	Recurrence data	Survival data
Tzakis et al. (2012) [8]	2	N/S	‘Carcinoid’, VIPoma	24-months post-transplant in 1 patient	Death of recurrent disease at 24-months in 1 patient
Olausson et al. (2007) [15]	5	100%	Pancreas	25-months and 48-months post-transplant in 1 patient each, respectively	2 deaths within 4-months post-transplant; 1 death at 27 months post-transplant
Gedaly et al. (2011) [11]	13	100%	N/S	23% at 1-year, 50% at 3-years, and 68% at 5-years, post-transplant	80% overall survival at 1-year, 64% at 3-years, 48% at 5-years
Mangus et al. (2013) [16]	4	100%	Insulinoma, gastrinoma, ‘carcinoid’, VIPoma	10-months and 23-months post-transplant in 1 patient each, respectively	1 death at 10 months post-transplant
Varkey et al. (2013) [17]	6	100%	Pancreas	100%	67% at 2 years

NEN, neuroendocrine neoplasms; N/S, not specified; VIPoma, vasoactive intestinal peptide-oma.

Here, we present the extended follow-up data for a patient with SI-NEN with unresectable bulky mesenteric metastases managed with peptide receptor radionuclide therapy (PRRT) before undergoing combined modified liver-free MVT (MMVT) and a VSFF from the same donor. The initial report on this patient was published by our group in 2015 [21]. This is the first case of its type to demonstrate the use of PRRT as a neoadjuvant concept in MMVT and also to implement the use of a VSFF as a tool for proactive monitoring of immunosuppression in MMVT for a NEN.

The case – initial investigations

Our male patient presented at age 44 with haematuria and intermittent abdominal pain in 2009. There were no other symptoms or any significant previous medical or family history. A standard computed tomography (CT) scan of the abdomen was performed, which demonstrated a complex and partially calcified left-sided renal cyst, and also identified within the mesentery a suspicious 10×9×6 cm heterogeneously enhancing mass. The latter was subjected to ultrasound-guided biopsy, in which histopathology confirmed to be a well-differentiated grade 1 (Ki-67 <1%) NEN with clear expression of the archetypal neuroendocrine markers synaptophysin and chromogranin A (CgA) evident on immunohistochemical analysis. Subsequent routine NEN-specific biochemistry included serum CgA and chromogranin B (CgB) and urinary 5-hydroxyindoleacetic acid (5-HIAA) in 24 h urine – all were markedly elevated relative to reference ranges: 395 pmol/L (0–60 pmol/L), 349 pmol/L (0–150 pmol/L) and 643 μmol/L (0–40 μmol/L), respectively.

The patient subsequently underwent imaging with 68Ga-DOTATATE positron emission tomography (PET)/CT, which demonstrated marked radiotracer uptake in the aforementioned mesenteric mass [standard uptake value (SUV)=27] and in a lymph node in the aortocaval groove (SUV=10). Thereafter, after multidisciplinary and patient discussion, it was decided that the patient would undergo an exploratory laparotomy in April 2010. This identified a stage IV (i.e. extending retroperitoneally) tumour bulk, which was circumferentially encasing the mesenteric vessels (Figure 1). Meticulous intraoperative exploration and ultrasound elucidated several additional, mostly subcentimetre, lymph nodes scattered through the mesentery close to the ileum but no evidence of hepatic metastases.

Figure 1:

Bulky mesenteric lymph node metastases as observed at laparotomy.

On a multicentre, multidisciplinary team discussion of therapeutic strategy in this conventionally unresectable tumour, the option of MMVT was raised and the patient was referred to the Oxford Transplant Centre for formal review with regard to possible intestinal transplantation.

Clinical management

Given the setting of unresectable, metastatic disease from a low-grade NEN, the patient received four cycles of PRRT with 177Lu-DOTATATE. Each cycle was administered after 12-week intervals with a cumulative radiation dose of 28 GBq, with no adverse effects associated with treatment. Standard nephroprotective amino acid infusions were administered. Post-PRRT 68Ga-DOTATATE PET/CT in February 2013 did not identify any additional sites of disease or progression in size of the previously identified lesions, but the SUV had increased in both the mesenteric bulk and the aortocaval node (Figure 2). Tumour biochemistry values had also increased throughout PRRT, with post-PRRT CgA and CgB results of 2200 pmol/L (initially 395 pmol/L) and 450 pmol/L (initially 349 pmol/L), respectively.

Figure 2:

Pretreatment 68Ga-DOTATATE PET imaging clearly demonstrating pathological radiotracer uptake corresponding to mesenteric metastases and also a lymph node metastasis in the aortocaval groove.

The patient underwent MMVT with VSFF at the Oxford Transplant Centre in March 2013. During operation, the mesenteric mass was noted to now involve both the duodenum and the pancreas, but there was still no evidence of liver metastases. As part of the MMVT, the stomach, pancreas, spleen, SI and right and transverse colon were exenterated, and the aortocaval lymph node was resected. The donor thoracic aorta was used to construct a “jump” graft from the recipient thoracic aorta to act as an arterial supply to the multivisceral graft. The venous return for the graft was constructed by means of a portal-portal anastomosis. A temporary ileostomy was formed.

The VSFF was retrieved from the same donor and comprised a 10×5 cm elliptoid composite skin island flap derived from the territory overlying the radial artery, with subcutaneous tissues, fascia, cephalic vein, lateral cutaneous nerve and the radial artery with venae comitantes. In the recipient, an incision under a tourniquet was made over the ulnar artery territory of the left arm (nondominant) and deepened to the artery and its venae comitantes. The VSFF was flushed with a cold preservative solution immediately after retrieval, transported without freezing and ultimately revascularised with an anastomosis between the donor’s radial artery and the recipient’s ulnar artery on the left arm. The venous outflow for the VSFF was established by the connection of donor and recipient venae comitantes and anastomosis between the donor’s cephalic vein and the recipient’s basilic vein. Lastly, the donated lateral cutaneous nerve was coapted to a branch of the recipient’s medical cutaneous nerve.

Regarding immunosuppression, the reperfusion of transplanted organs was covered with 500 mg methylprednisolone, and induction immunosuppression included 30 mg intravenous alemtuzumab (Campath) within 6 h of reperfusion, with a second dose 24 h later. Initial maintenance immunosuppression used tacrolimus with target trough levels between 8 and 12 ng/mL. The immediate postoperative course was uneventful.

The histopathological analysis of the resected tumour confirmed a well-differentiated, grade 1, multifocal SI NEN (7 tumours up to 11 mm in size) with attendant large mesenteric lymph node metastases up to 120 mm in size encasing the mesenteric vessels. Disease stage was confirmed as pT3N1M0L1V0R0 using the ENETS/WHO criteria [22]. Immunohistochemical analyses again demonstrated strong expression of chromogranin and synaptophysin, focal expression of CK19 and no expression of glucagon, insulin, gastrin, and somatostatin.

Two months after transplantation, the patient underwent a biopsy of his VSFF due to a maculopapular rash suggestive of rejection. The diagnosis of acute rejection was made in accordance with the Banff 2007 Working Classification of Skin-Containing Composite Tissue Allograft Pathology classification [23]. Endoscopy with intestinal biopsy was performed, which demonstrated no evidence of rejection in the abdominal organ graft. Therefore, the patient was treated with three 500 mg doses of methylprednisolone and topical tacrolimus cream, with which the rash resolved completely. A daily dose of 10 mg oral prednisolone was added to the patient’s maintenance immunosuppression regimen.

The patient successfully underwent an uncomplicated reversal of his ileostomy in January 2014, and on his last follow-up 48 months after transplantation, he remained on full enteral nutrition with a stable weight and at full physical activity. His NEN-related serum (CgA and CgB) and urine (5-HIAA) biochemical markers normalised after transplantation and have remained within reference ranges throughout follow-up. Furthermore, routine follow-up imaging with magnetic resonance imaging (MRI) or CT every 6 months and 68Ga-DOTATATE PET/CT annually have yet to identify any evidence of disease recurrence.

Discussion

Contrary to the increasingly accepted role within the armamentarium for liver transplantation in metastatic gastrointestinal NEN, the use of multivisceral allografts attracts considerably more controversy. Although initial results with the former were disappointing, the development of strict patient selection criteria and advances in immunosuppression have resulted in favourable outcomes that are not significantly inferior to those observed in hepatocellular carcinoma [10], [24]. Five-year overall survival after orthotopic liver transplantation for metastatic NEN may reach 90% in recent case series, justifying its use as a well-timed (i.e. not a “last resort”) intervention in carefully selected patients with nonresectable liver metastases [4]. Furthermore, recent evidence has suggested a significant benefit to liver transplantation over nontransplant techniques [25]. Nevertheless, 5-year recurrence rates may range between 50% and 90% [12], [26], [27], [28], which highlights the known difficulties with the insidiously progressive behaviour of low-grade NEN and also the necessity of novel strategies facilitating long-term control both neoadjuvant and adjuvant in nature.

Experience with intestinal transplantation and MVT in general is steadily growing, with reported indications including abdominal catastrophes and slow-growing intra-abdominal tumours, such as NEN. As aforementioned, this arena within the realm of transplant oncology is highly debated due to disparities in outcomes from different centres. The report by Gedaly et al. [11] described the use of MVT in 13 patients with NEN (primary tumour origin not clearly stated) associated with 1-, 3- and 5-year survival of 80%, 64% and 48%, respectively, whereas in a series of 10 NEN patients with liver metastases treated at Indiana University over 8 years, an overall survival rate of 80% was attained (personal communication [16]). A more cautious outlook has been advocated by Varkey et al. [17] in their report of 6 patients with metastatic pancreatic NEN, demonstrating a 67% overall survival at 2 years. With small sample sizes, variation in the quality of documentation in case reports/series, and different primary tumour sites, the evidence regarding MVT/MMVT for NEN is far from conclusive. Of the approximately 30 cases of intestinal transplantation/MVT for NEN reported, to our knowledge, none have clearly detailed the procedures and outcomes specifically in SB NEN.

Our strategy in this patient centred on four facets:

Use of PRRT as a neoadjuvant modality,

Radical removal of a classically nonresectable tumour,

Restoration of abdominal anatomy and physiology with a multivisceral graft, and

Use of a second soft-tissue graft from the donor to aid posttransplant management.

The use of PRRT in metastatic, unresectable, low-to-intermediate grade NEN that exhibit high expression of somatostatin receptors may attain tumour response rates of approximately 33% [29], [30], [31]. There have also been a small number of reports in which PRRT has been used as a neoadjuvant therapy in NEN, specifically to attempt to downsize tumours and render them resectable [32], [33], [34], [35]. To our knowledge, our report is the first to report the use of PRRT as a neoadjuvant therapy specifically in transplantation. A major concern in our patient was that, despite the lack of evidence of hepatic disease on morphological and functional imaging, micrometastases not detectable with these methods may have existed and could have subsequently manifested throughout a period of immunosuppression. Indeed, currently available gold-standard imaging methods significantly understage true disease burden by up to 50% [36]. Given the strong avidity of this patient’s disease for somatostatin receptor-targeted imaging tracers, the patient was offered PRRT with 177Lu-DOTATATE before radical treatment with an aim to treat/stabilise the main tumour bulk and eradicate microdisease. An “all-in-one” approach to transplantation avoided the risks of managing an ultra-short gut with a high output stoma, plus deterioration in liver function with total parenteral nutrition that would have presented if we had proceeded with intestinal exenteration with transplantation on a later date.

The theoretical benefits of a sentinel marker in solid-organ transplantation include the noninvasive monitoring of immunosuppression with possible ramifications on preventing rejection and avoiding the morbidity associated with excessive immunosuppression. Our rationale for concomitant transplantation of a VSFF was to aid the clinical team in distinguishing between possible causes of posttransplant bowel dysfunction should they arise, specifically infective causes or an immunological rejection, which would be characterised by the lack of and presence of a rash, respectively. Although the histopathological appearances of both phenomena may be similar, the treatments for each are obviously different. The use of a VSFF has been documented in facial transplantation [37]. The usefulness of skin more generally as an immunological tool has also been reported in abdominal wall transplantation, where it may serve as an immune modulator resulting in improved graft survival, lower rejection rates, and lower rates of incorrectly diagnosed rejection in patients receiving solid-organ transplants and abdominal wall transplants [38].

In conclusion, this case represents a truly novel approach to the treatment of metastatic SI NEN due to its unique integration of several treatment concepts. Given the favourable outcome documented so far, specifically a lack of both biochemical and radiological disease recurrence and that the patient remains at full physical activity at 4 years of follow-up, we believe that this approach could be used in other, strictly selected patients in the future.

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