Surgical treatment of small bowel NETs (midgut carcinoids)

Introduction
Small bowel neuroendocrine tumors (NETs), also denoted midgut carcinoids should always be considered for surgical treatment. Various considerations including metastatic surgery is outlined below.

Surgical treatment of small bowel NETs (midgut carcinoids)

Preoperative considerations. Primary tumours in the small intestine are submucosal, small and flat around 1 cm in size, sometimes only some millimeters in size and hard to recognize. Not rarely are several tumors present in the small intestinal submucosa, possible being intramural metastases. Mesenteric lymph node metastases are present in high frequency, and may be small and easy to remove or extensive and unresectable.
Liver metastases are common and treatment of these has been proven beneficial for the patients. Surgery for midgut carcinoid tumours, primary, mesenteric as well as liver metastases have been reported to be beneficial, both regarding symptoms and on survival.

Survival of patient with midgut carcinoid disease with and without
Survival of patient with midgut carcinoid disease with and without
primary tumour resected at the University Hospital in Uppsala, Sweden.

 

Survival of patients with midgut carcinoid disease with and without
Survival of patients with midgut carcinoid disease with and without
liver metastases treated at the University Hospital in Uppsala, Sweden

 

Before surgery the diagnostic procedures should include establishment of the biochemistry by measuring the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) excreted in 24-hour urine samples and plasma chromogranin A which reflect the tumour load, and is important in the continuous management of the patient. A CT scan should be performed for planning of the surgery, especially the extent of mesenteric lymph node metastases and eventual retroperitoneal extension. Also, the relation to the mesenteric artery and vein is crucial to ascertain before surgery, which mandates examination of venous and arterial phases of contrast enhancement.

Coronary section of a mesenteric mass in a patient with a midgut carcinoid tumour.
Coronary section of a mesenteric mass in a patient with a midgut carcinoid tumour.
The mass is occluding the venous blood flow in the mesenteric vein (arrow).

 

The extent of liver metastases should be noted, and eventual concomitant liver surgery or peroperative radiofrequency ablation (RFA) planned for. In addition, a somatostatin receptor scintigraphy (Octreoscan) is efficient to detect extra-abdominal metastases. Positron emission tomography with the serotonin precursor 5-hydroxytryptophan, labelled with 11C (5HTP-PET), is also efficient in identifying the small intestinal carcinoids.

Surgery of small bowel NETs. About 30-40% of patients with small bowel NETs (midgut carcinoids) are subjected to emergency laparotomy due to intestinal obstruction. A finding at surgery of a small ileal tumor and larger mesenteric lymph node metastases associated with mesenteric shortening and fibrosis should lead to suspicion of a midgut carcinoid tumour.

 

Schematic drawing of a typical extent of mesenteric lymph node metastases due to midgut carcinoid disease.
Schematic drawing of a typical extent of mesenteric lymph node metastases due to midgut carcinoid disease.

 

Since hormonal release may occur due to peroperative tumor handling a somatostatin analogue infusion should be immediately commenced (Sandostatin – 500 ug in 500 ml NaCl at a rate of 50-100 ug /hour). The primary tumor should be removed, and if possible also the mesenteric mass by wedge resection and direct anastomosis. The same operation is performed in elective cases, although patients with difficult mesenteric masses may be more aggressively treated electively than in the emergency situation. The aim of the latter is to relieve the ileus. After follow-up biochemical and radiological confirmation of diagnosis and extent of disease a second surgical procedure is performed where the mesenteric mass and liver metastases are dealt with. Thus, re-operation is strongly recommended to remove any remaining mesenteric tumor, which can otherwise be expected to cause future abdominal complications. However, the majority of patients have had subacute symptoms slowly exaggerating during many years. Diagnosis is often set when liver metastases and signs of the carcinoid syndrome presents. Preoperative treatment with somatostatin analogues and interferon is often beneficial to control hormonal symptoms. Patients operated for midgut carcinoid tumours should be monitored life-long, since recurrence is common, although being symptom-free for long periods. Generally, prophylactic surgery at an early stage is advantageous before extensive involvement of mesenteric vessels and fibrotic entrapment occurs.

Surgical technique. Most of the mesenteric masses originates to the right of the mesenteric artery, extending distally to the left of the ileocolical artery and proximally to the lower duodenal border. This implies that most of them can be removed with sparing of the main arterial supply to the small intestine. We usually dissect the intestinal mesenteric root from the retroperitoneum to the duodenal and pancreatic level, most easily performed after mobilization of the right colonic flexure and the right colon.

Sometimes a proximal part of the mesenteric mass is necessary to be left in situ after cleavage of the tumor. Intestinal by-pass should be avoided, because ischemia may develop in the by-passed intestinal segment and since such a procedure severely complicates further surgery, not seldomly needed for midgut carcinoid tumours.
Reoperations may be needed for these tumors, due to chronic pain, obstruction and suspicions of intestinal ischemia. Although these patients may suffer from carcinosis and spread fibrosis, reoperations are important in order to improve quality of life in the view of a still comparably good prognosis. These redo surgical procedures may be extremely difficult including risk for fistulation. In our own series we have documented alleviation of abdominal symptoms, clearance of intestinal ischemia and benefit on survival after following the above mentioned recommendations on especially the mesenteric mass.

Surgical treatment of liver metastases to neuroendocrine tumors (NETs)
Liver metastases may be treated using biotherapy (somatostatin analogues and interferon), liver embolisation, radiolabelled somatostatin analogue therapy (PRRT), chemotherapy (dependant on the diagnosis), but also by surgical procedures such as resection, radiofrequency ablation (RFA) and liver transplantation.

Surgical treament and RFA of liver metastases. The most commonly surgically treated patient have small bowel NET (midgut carcinoid) with multiple liver metastases. Some of these may still be considered for surgical therapy, if it is possible to clear the liver by combinations of RFA and surgery or combinatory surgical procedures. Also, even in case of multiple metastases, large and dominant metastases are beneficial to remove surgically in order to reduce hormonal levels and thereby morbidity and risks for carcinoid heart disease. Formal lobectomies or parenchyma-saving liver resections should be performed for resectable tumors. A common location for liver metastases from midgut carcinoid tumours is segment 2 and 3 which comparably easy may be removed in conjunction with primary surgery. The development of surgical and anesthesiological techniques including low central venous pressure surgery now allow safe hepatic surgery to be performed, also in case of bilateral metastases. Combinations of RFA have also been documented as beneficial for symptoms as well as survival for patients with multiple liver metastases.

Radiofrequency ablation (RFA) of liver metastases. Radiofrequency ablation (RFA) has recently been introduced as an efficient and safe method for ablation of moderately large liver metastases from several different primary tumors. A needle is introduced by ultrasound guidance into the liver metastasis, followed by application of alternating current, which causes ionic agitation in the surrounding tissue leading to destruction of a sphere of approximately 3-4 cm in diameter.

 

Principle of RF tretament of a metastasis, here encased by the parachute-like radiofrequency needle introduced into the liver.
Principle of RF treatment of a metastasis, here encased by the parachute-like radiofrequency needle introduced into the liver.

This procedure may be performed percutaneously,
laparoscopically or during open surgery.

 

Percutaneous RF treatment in a patient previously operated for major liver resection.
Percutaneous RF treatment in a patient previously operated for major liver resection.

The larger the tumor is the less efficient is the method, which may lead to repetitive treatment or necessitates reduction of hepatic blood flow during the RFA procedure, usually by applying clamping of the hepatic artery and the portal vein (Pringle maneuver). However, surgical resection is still the golden standard, and no study has yet documented that RFA is similar or superior to classical liver surgery. Tumors, larger than 3 cm and those lying close to larger vessels are less efficient to treat by RFA. The reason for the latter is the cooling effect of the circulating blood flow. No randomized trials are available in the literature clarifying the role and efficiency of RFA at this level of evidence. Our own retrospective analyses indicate that reduced morbidity and reduced biochemical tumor markers are present after RFA, at least for patients with midgut carcinoid disease. Complications are rare after RFA, in our own hands around 5 %. Severe complications include destruction of centrally located bile ducts resulting in bile leakage or stenosis, and destruction of adjacent organs, especially the transverse colon and the gall bladder. Therefore, we avoid RFA treatment in the hepatic hilum as well as those close to the surface. Post-RFA bleeding has been of no larger problem for us.

Radiological apperance after RF treatment (central scar in right liver lobe). In the edge of the left liver lobe a remaining liver metastasis is present, and at the dorsal aspect of the right liver lobe a benign cyst.
Radiological appearance after RF treatment (central scar in right liver lobe). In the edge of the left liver lobe a remaining liver metastasis is present, and at the dorsal aspect of the right liver lobe a benign cyst.

 

Liver transplantation. Liver transplantation may be considered for patients with liver metastases from midgut carcinoids, because of generally slow disease progression, but also for occasional patients with pancreatic NETs. However, very few patients have been transplanted leading to difficulties in interpreting the outcome. Various reports have reported 5-year survival of between 24-48% for patients with NETs, possibly due to different selection procedures between centers. For patients suffering from small bowel NETs one should bear in mind the extremely high recurrence rate, leading to an apparent risk for the new liver to become the site for new metastases. A selected group of patients with pancreatic NETs may have a better outcome. A relation to degree of differentiation is obvious, where different centers have limits of 5 or 10% to allow liver transplantation.