Small Bowel NETs (Carcinoids)

Introduction

Neuroendocrine tumors (NETs) originating from the small bowel have previously been denoted midgut carcinoid tumors. A review of diagnosis and treatment follows.

Epidemiology of small bowel NETs (midgut carcinoids)

The term carcinoid has been used for small bowel NETs since the first description of a carcinoid by Oberndorfer in 1907. Although neuroendocrine tumors can arise almost anywhere within the gastrointestinal tract, they are most common in the ileum (17.1%) and appear to exhibit very different prognoses depending upon the site and presumably their cell of origin. Different data bases from Europe and US are indicating that the annual incidence of carcinoid tumors is about 2.0 – 4.5/100,000. Ileal tumors have specifically increased in prevalence with an overall increase of 4 fold in black people and 2.5 fold in white population. The increase in incidence is probably mostly due to introduction of better diagnostic tools, as well as greater awareness of the entity by pathologists and clinicians. There are no known environmental risk factors for small bowel NETs and they are mostly sporadic, and extremely rarely familial. The tumors can develop at any age but the median age is 60 years, and are slightly more common in females than males 1.2:1.

Symptomatology of small bowel NETs (midgut carcinoids)

An early and accurate diagnosis of small bowel NETs (midgut carcinoids) is often delayed for many years, as most small bowel neuroendocrine tumors are small and the initial symptoms are diffuse and often classified as allergy, IBS (irritable bowel syndrome) or in conjunction with menopause. Progressive growth of the tumor may cause vague abdominal discomfort, due to intermittent obstruction or kinking of the small bowel caused by the fibrosis induced by the released hormones. There is usually a fibrotic reaction around the commonly present mesenteric metastases, leading to the classical apperance on CT scans, and which may cause fibrotic attachement to duodenum or colon, but may also extend retroperitoneally to obstruct the ureters. The fibrosis may also cause kinking and entrapment of small intestine causing obstruction of various degrees. In about 30-40% of cases midgut carcinoids are discovered at an emergency operation for ileus. The fibrosis and the mesenteric metastatic mass may also affect the mesenteric vessels, not by invading them but to obstruct them. Especially branches of the superior mesenteric vein are entrapped resulting in a venous stasis in the intestine. This may explain the abdominal pain and cramps, as well as functional malabsorption and diarrhea often associated with midgut carcinoid, regardless whether the patient suffer from a classical carcinoid syndrome or not.

 

Fig. 1 Mesenteric metastasis of a midgut carcinoid

Fig. 1 Mesenteric metastasis of a midgut carcinoid

 

As the disease advances, small bowel NETs (midgut carcinoids) frequently metastasize to the liver and later also to bone and brain.
Besides the abdominal symptoms due to intermittent or acute obstruction, the hormone release may cause the carcinoid syndrome (Fig. 1), typically consisting of cutaneous flushing (90%), diarrhea (70%), abdominal pain (40%), carcinoid heart disease (10-30%) and bronchoconstriction (<5%). The clinical symptoms are not generally apparent until liver metastases have occurred and the ability of the liver to metabolize the bioactive secretory agents of these lesions is exceeded. Bioactive substances involved in the syndrome are serotonin, tachykinins, histamine, catecholamines and dopamine. The carcinoid syndrome is present in 35-60% of the patients depending on the referral center. The carcinoid syndrome may be provoked by food, stress and alcohol intake. A rare manifestation of a carcinoid is pellagra-like skin lesion.

Diagnosis of small bowel NETs (midgut carcinoids)
Histopathology
Tumor specimens from small bowel NETs (primary tumor or metastases) obtained by biopsy or surgical resection should be analysed for neuroendocrine markers, such as chromogranin A (CgA), synaptophysin and neuron-specific enolase (NSE). The proliferation index should be established by Ki-67 immunostatining. If possible, staining of the specific somatostatin receptors (SST1-5) might be of value, but is not mandatory.

Biochemical markers
For patients with the carcinoid syndrome, the metabolites of serotonin in urine -  5-hydroxindolacetic acid (5-HIAA) - is the most important marker and has 88% specificity for a small bowel neuroendocrine tumor. An alternative may be measuring serotonin in plasma, but is not used much in clinical praxis. Serotonin-rich foods (bananas, avocados, plums, eggplants, tomatoes, pineapples and walnuts) as well as coffee and tee can provide false elevation of U-5-HIAA. Plasma levels of the CgA can be utilized as a general tumor marker for all types of neuroendocrine tumors (sensitivity 99%), and for small bowel NETs both in case of non-functioning tumors and those with carcinoid syndrome. False positive elevation of CgA concentrations may occur in renal impairment, atrophic gastritis and during proton-pump inhibitor therapy. Other informative biochemical markers for small bowel NETs include substance P and other tachykinins.

Radiology
CT scan and MRI are the basic examination methods for diagnosis and surveillance of small intestinal NETs. Characteristic findings include a mass originiating from the mesenteric lymph node metastases, with radiating strands of fibrosis (Fig. 2) and spiculation (calcification) with traction or fixation of the bowel. As the primary tumor usually is small it may not be visible on CT or MRI. MRI and CT are effective in the initial localisation of metastases, but the sensitivity and specificity are sub-optimal with a median detection rate of <80%.

Topographic Localisation
In a study of 500 patients who underwent capsule endoscopy for an occult bleeding, small intestinal NETs were identified in 2%. In a separate study of 20 patients with metastatic carcinoids and negative CT, capsule endoscopy identified the primary tumor in 45%. Fiberoptic enteroscopy is uncomfortable, time consuming and not widely available.

Fig. 2 Carcinoid flushing; chronic type

Fig. 2 Carcinoid flushing; chronic type

 

Nuclear Imaging
While radiology is useful in the initial identification and localization of small bowel NETs, nuclear imaging techniques are considerably more sensitive and specific in detecting the primary tumor as well as metastases. Somatostatin receptor scintigraphy (SRS) is a considered standard of care with a median detection rate of 89% and a sensitivity of about 85% (Fig. 3). Some carcinoids are too small to be detected with this technique and certain metastases fail to express adequate levels of somatostatin receptors 2 and 5. The degree of SRS-positivity is considered to be useful in prediction of the potential therapeutic effect of somatostatin analogs and tumor targeted radioactive treatment with radiolabelled somatostatin analogs.

Fig. 3 Octreoscan® of patient with “midgut carcinoid”. Liver and mesenteric metastases.

Fig. 3 Octreoscan® of patient with “midgut carcinoid”. Liver and mesenteric metastases.

 

Meta-iodobenzylguanidine (MIBG) is less sensitive for detecting carcinoid tumors than SRS, but may have some diagnostic utility when other techniques have failed. Position Emission Tomography (PET) detects accumulation of radiolabeled biological substances. The most useful tracers for detection of small bowel NETs are 11C-5-hydroxytryptophan (HTP), 18F-Dopamin and 68Ga-DOTA-Octreotate. The most sensitive marker is 11C-5HTP, which identify midgut carcinoid lesions in 95% and could visualize more lesions than CT and SRS in the patients. Today both SRS and PET are combined with CT or MRI giving particular high sensitivity and also anatomical localisation of the tumors. (Fig. 4)

Fig. 4 PET scanning with 68Ga-DOTA-Octreotide in patient with “midgut carcinoid”. Liver and lymph node metastases.

Fig. 4 PET scanning with 68Ga-DOTA-Octreotide in patient with “midgut carcinoid”. Liver and lymph node metastases.



Therapy of small bowel NETs (midgut carcinoids)

Surgery is the only treatment that can cure the patient, but due to delay in diagnosis most patients present metastatic disease at primary referral. Curative resections are possible in less than 20% of the patients. (For details – see the section of Surgery.) The systemic treatment includes biotherapy, chemotherapy and peptide receptor radiotherapy (PRRT).

Somatostatin analogs
The long-acting analogs, Sandostatin LAR® and Somatuline Autogel® have significantly improved the management of hormonal symptoms related to small bowel NETs. They are significantly reducing the circulating levels of hormones related to the clinical symptoms, but have also been demonstrated to induce reduction of tumor growth in patients with classical midgut carcinoid tumors. Standard doses are Sandostatin LAR® 20-30 mg i.m. or Somatuline Autogel® 90-120 mg s.c. every 4 weeks.


Interferon alpha
Interpheron alpha has been widely applied to cause control of clinical symptoms and tumor growth of classical midgut carcinoid tumors. The biochemical and clinical response rates are similar as for somatostatin analogs in the order of 40-60%, whereas significant tumor reduction is noticed in 10-15%. Stabilization of the disease is noticed in 40-60% of the patients over long periods of time. Doses are titrated individually 3-5 MU x 3-5/week s.c.

Others
Inhibitors of the tyrosine kinase receptor family PDGF, EGF and VEGF have been applied in patients with midgut carcinoid tumors with various response rates in the order of 10-20%. mTOR-inhibitors (Rapamycin) is currently in Phase II studies in patients with small bowel NETs and preliminary results are indicating responses in the order of 10-15%. Cytotoxic treatment usually plays a minor role in the management of classical low proliferating NETs, such as those originating from the small bowel. Different regimens including streptozotocin, doxorubicin, cisplatinum, carboplatin, taxanes and temozolomide has generated poor responses in the majority of patients, but may be ised in case of higher proliferation rate.

External-beam radiation therapy.
This treatment has limited effect on midgut carcinoid tumors, but may be of some help in palliative treatment of bone and brain metastases.

Peptide Receptor Radiotherapy (PRRT).
A recent introduction of PRRT appears promising using the 111Indium, 90Yttrium or 177Lutetium radionuclides linked to a somatostatin analog. Tumors expressing SST2 and SST5 can be specifically targeted and the current response rates for 177Lutetium-DOTA-Octreotate are 35-40% and tumor stabilization in up to 60% of the patients.

Surgical Treatment of small bowel NETs (midgut carcinoids)

 

Prognosis of small bowel NETs (midgut carcinoids)
The overall 5-year survival rate for a carcinoid tumors are about 60% for all stages, 75% for localised disease, 72% for regional disease and 45% for distant metastases. The survival data for midgut carcinoid tumors with distant metastases has not significantly improved over the last decades in general praxis. At dedicated centers of significant improved 5-year survival has now been reported to be as high as 75% for this group of malignant tumors. The median survival has been reported to be as long as 115 months.