Small bowel neuroendocrine tumors

Åkerström G, Hellman P.

The small intestinal neuroendocrine tumor or midgut carcinoid is rare, but still prevalent among small intestinal neoplasms, and the most common cause of the carcinoid syndrome. Patients with this syndrome may be managed medically, with long-acting somatostatin analoges and interferon, with appreciable effects on symptoms and apparently increased longevity. This has forced efforts to remove intestinal and mesenteric tumors to prevent abdominal complications, and liver metastases to facilitate treatment of the carcinoid syndrome.

Definition and incidence

The name carcinoid was first used to describe unusual ileal tumors with more benign disease course than common large bowel carcinomas. Carcinoids are endocrine tumors, occurring in the entire intestine (as well as in thymus, lungs and pancreas). Tumors of the embryological midgut, e.g. the small intestine and ascending colon, are the classical carcinoids characterized by capacity to release serotonin. The term midgut carcinoid generally depicts the small intestinal carcinoids, since colon carcinoids are rare (< 5%). The annual incidence of midgut carcinoids may be ~0.5/100,000, they account for a small proportion of intestinal neoplasms, colorectal adenocarcinomas are 60 times more frequent (1). The small intestinal carcinoids are second to appendiceal carcinoids in prevalence, but often prevail in clinical series as they represent the most common (90%) cause of the carcinoid syndrome. Appendix carcinoids occur often in autopsy series, but are rarely of clinical significance. The midgut carcinoid is one of the most prevalent of the small intestinal neoplasms, being approximately as frequent as the small intestinal adenocarcinoma.

The carcinoid syndrome consists of diarrhea, flush, carcinoid heart disease, and more occasionally bronchospasm, attributed to various substances released from carcinoid tumors, serotonin, tachykinins, and others. Presence of the syndrome generally implies that the patient has liver metastases, only occasionally it is encountered when veins from retroperitoneal or ovarian lesions drain directly into the systemic circulation.

Morphologic features

The midgut carcinoid is generally located in the terminal ileum, as a flat and fibrotic submucosal tumor commonly measuring 1 cm or less. Adjacent, often smaller, multiple carcinoids may be revealed in one third of the patients, probably representing lymphatic dissemination. Mesenteric metastases occur irrespective of the size of the primary lesion. They are often conspicuously larger than (and often mistaken for) the primary tumor, and are typically associated with marked mesenteric fibrosis. The fibrosis will entrap loops of the small intestine and cause partial or complete intestinal obstruction, and may eventually involve and encase the mesenteric vessels with resulting venous stasis and ischemia in segments of the intestine. Fibrotic adhesions also tend to attach the ileal mesentery and the mesenteric root to the retroperitoneum, and may eventually together with tumor growth obstruct the horizontal duodenum and occasionally the transverse colon.

Tiny ileal carcinoids, the most common of midgut carcinoids, are almost invariably associated with conspicuously larger mesenteric metastases, with typically marked mesenteric fibrosis entrapping the intestines and eventually encasing intestinal vessels.

Further dissemination occurs with liver metastases; interestingly, approximately 10% of the patients may have liver spread without mesenteric involvement, apparently representing neoplasms with worse prognosis. At later stage extraabdominal spread may be revealed, involving the skeleton, lungs, CNS, peripheral lymph glands (supraclavicular lymph glands) and the skin.

Clinical presentation

The carcinoids are typically slow growing and symptoms of borborhygmia may have been present for years before pain attacks become more obvious (2). Thus, nearly half the midgut carcinoid patients will require more or less urgent surgery for intestinal obstruction, often with unknown diagnosis. Intestinal bleeding is rare, due to submucosal location of the primary tumor.

Other patients with less prominent abdominal symptoms may have unrecognized features of the carcinoid syndrome, with discrete flush precipitated by specific food or alcohol. The flush is typical, but may easily be overlooked especially in menopausal females. Diarrhea is the most common feature of the carcinoid syndrome, it may be slight and feeding related initially, and then more voluminous and secretory. Rare patients present with severe watery diarrhoea due to occlusion of a main mesenteric vein. It is likely that also more limited venous stasis or incipient venous ischemia in a segment of the intestine more commonly than appreciated contributes to the diarrhoea of carcinoid patients. Heart valve fibrosis, of e.g. the tricuspid and pulmonal valves, is a late consequence of the carcinoid syndrome, eventually leading to right sided heart failure with severe lethargy. This may require heart surgery with valve prosthesis replacement. Presence of heart disease has to be excluded by echocardiography prior to major abdominal surgery.

Patients with midgut carcinoids tend to present either with intestinal obstruction or merely with features of the carcinoid syndrome, which generally implies the existence of liver metastases.

Diagnosis

Laboratory: Raised urinary 5-hydroxy-indole-acetic acid (5-HIAA) excretion/24 hour collection is diagnostic of a midgut carcinoid, but is only elevated in presence of liver metastases. Plasma chromogranine A measurements is a more sensitive (but more unspecific) measure.

Radiology: Bowel contrast studies will rarely visualize the primary midgut carcinoid tumor, but may at more advanced disease stages show typical arcading and partial obstruction of entrapped intestines. Computed tomography (CT) may demonstrate a mesenteric (and retroperitoneal) tumor mass with typical radiating densities (an image considered pathognomonic for the midgut carcinoid), and may also visualize important relations to mesenteric vessels prior to surgery.

Ultrasound guided fine or semifine needle biopsies from liver or mesenteric metastases, with specimens stained with the Masson silver stain or for chromogranine, neuronspecific enolase, synaptophycine and others, will often settle the diagnosis.

111In-Octreotide, Octreoscan examination can determine the endocrine nature of the tumor, visualize mesenteric and liver metastases, and is of particular value for demonstration of extraabdominal spread, for instance to the skeleton.

Surgery of the mesenterico-intestinal lesion

When carcinoid patients are subjected to acute laparotomy with intestinal obstruction it is essential that the characteristic features of a midgut carcinoid are recognized (2). Surgery should aim to remove the primary intestinal tumor (s) and mesenteric metastases radically, since this may provide substantial periods of symptom-free survival without intestinal problems. The intestinal resection should be limited because carcinoid patients will do poorly if a short bowel syndrome is created. Intestinal by-passes should be avoided as far as possible, since ischemia may develop in a disengaged intestinal segment, and the procedure tends to complicate repeat surgery, which often becomes necessary.

Even when primary surgery is grossly radical, the midgut carcinoid is a tenacious tumor. The majority of patients will recur, often with liver metastases, if follow-up is extended to 10–20 years.

Half the patients with midgut carcinoids have advanced disease, with liver metastases and the carcinoid syndrome at time of diagnosis, and are principally subjected to medical therapy.

During medical treatment many patients with midgut carcinoids will experience intermittent, feeding-related abdominal pain, weight loss or malnutrition, which generally is not due to the carcinoid syndrome per se. These patients often require surgical intervention to alleviate partial or complete intestinal obstruction or threatening intestinal, mainly venous ischemia.

Even if the mesenteric metastases of midgut carcinoids may seem inoperable with entrapped loops of intestine and encasement of the mesenteric root, they can often be removed by dissection from the mesenteric vessels, with preservation of important collateral's along the intestine. Since abdominal complications remain a principal cause of disease – related death in carcinoid patients, prophylactic removal of the mesenteric tumor and involved intestine is recommended, before initiation of medical therapy, also in patients without abdominal symptoms (2, 3).

Medical treatment

Patients with metastatic disease and the carcinoid syndrome can be treated with Octreotide (Sandostatin), Interferon or a combination of these agents (4). Sandostatin offers the best subjective palliation, especially of the flush syndrome, generally has few side effects (steatorrhea, gall bladder dysfunction, a.o.) but has time limited effect, which can be prolonged by combination with Interferon. Interferon also affects symptoms, but may have anti-tumor effect as well, if side effects (flue-like symptoms, fatigue, hematologic problems, rare autoimmune reactions, a.o.) are tolerated. Sandostatin will generally also palliate diarrhoea, together with Loperamide, opiates, Cholestyramine, etc.. Chemotherapy may be considered in selected cases when biotherapy fails, although most of these treatment modalities lack appropriate randomized evaluation.

Sandostatin i.v. infusion (500 μg in 500 ml saline; 50 μg/hour) is recommended as prophylactis in order to prevent carcinoid crisis when patients with advanced carcinoids (and the carcinoid syndrome) undergo surgery or liver artery embolization.

Treatment of liver metastases

Liver resection, with formal hepatic lobectomy, atypical resection or merely debulking of liver metastases may provide marked relief of the carcinoid syndrome (2, 3, 5). Liver surgery is thus indicated in approximately 10% of the carcinoid patients, with major dominating or unilateral liver metastases, where it can be anticipated that at least 80–90% of the tumor volume can be excised. The indications for liver surgery may be widened by combination with other treatment modalities, such as cryo-, lazer- or radiofrequency (RF) wave length ablation. Virtually every patient will, however, recur with new liver tumor after resection or ablation, but with some years of symptom alleviation if treatment has been successful.

Liver artery embolization (possibly combined with local chemotherapy) may be used for treatment of liver metastases, when medical therapy fails or as part of the initial treatment.

Liver transplantation is still considered experimental and only advisable in selected carcinoid patients. Medical therapy may be more safe, considering the difficulty to prove absence of extrahepatic disease, and the risk that immunosuppression promotes growth of the tenacious carcinoid tumor.

Liver surgery may efficiently relieve symptoms of the carcinoid syndrome and facilitate treatment of metastases and the carcinoid syndrome.

Survival and life quality

Principal causes of death in patients with advanced carcinoids have been a failing carcinoid heart disease (40%) and cachexia due to advanced mesenterico-intestinal involvement (35%) (3). Survival for advanced carcinoids has in a recent series been median 9 years from diagnosis, 7 years with liver metastases and the carcinoid syndrome, and 8 years for patients with surgically treated intestinal ischemia. Survival prospects have been markedly lower for patients with heart valve fibrosis or a failing carcinoid heart disease, or extraabdominal metastases. Even with advanced disease many of the carcinoid patients have been able to maintain life quality or e.g. professional work when subjected to active medical treatment. However, randomized evaluations of the effects of medical and surgical treatment are generally lacking, due to the rarity of carcinoid tumors, but are warranted since many of these neoplasms may have an indolent course even without therapy. Of particular concern would be to identify patients where more aggressive medical and surgical approach is required (4).

Reports of improved survival and favorable life quality in patients with midgut carcinoids subjected to active medical management seem to support liberal attitude towards surgical removal of mesenteric tumors, and dominant liver metastases in order to facilitate treatment of the carcinoid syndrome and the tumor disease. The existence of alternative, efficient medical therapy implies that surgery generally has to be undertaken with minimal rate of complications and mortality.

References

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