Cancer, Intestinal Carcinoid


Article Author:
Mridula Krishnan


Article Editor:
Faiz Tuma


Editors In Chief:
Sherri Murrell


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
12/9/2018 7:52:50 PM

Introduction

Carcinoid tumor refers to a well-differentiated neuroendocrine tumor (NET) that originate commonly in the gastrointestinal tract (about 55%) or in other locations such as the lung, kidneys, or the ovaries. The exception to this includes pancreatic neuroendocrine tumors which are a separate entity called PNET. The term Carcinoid is the old name of NET originating from the intestine although many physicians are still using the term. The name was derived from the word "Karzinoide" to indicate the carcinoma-like appearance. It was believed to carry no malignant potential. Our knowledge and management of NETs have significantly developed since then.

Etiology

The exact etiology of NET tumor is unknown. There are risk factors associated with a higher incidence of the tumor such as a family history of neuroendocrine tumors or endocrine neoplasia[1][2][3]. These tumors have been identified in various locations including the lungs, bronchi, and gastrointestinal tract. Gastrointestinal NETS can be of foregut (respiratory tract, thymus), midgut (jejunum, ileum and right colon, stomach, proximal duodenum), and hindgut (distal colon, rectum) origin. NETs of the midgut (jejunum, ileum, appendix, and cecum) are associated with carcinoid syndrome.[4][5] 

Epidemiology

NETs are relatively rare tumors. But incidence of intestinal NETS is on the rise due to increased detection of these tumors on routine imaging for other purposes. Small intestinal carcinoids are mostly located in the ileal region which is 60 cm from the ileocecal valve. Colonic NETs are usually detected in elderly patients and are commonly located on the right side, particularly the cecum. Commonly, rectal carcinoids are incidentally discovered on imaging.[6][7][8]

Colorectal NETs are more frequent in the Asia/Pacific region than in Europe[9]. In Europe, small intestinal and stomach carcinoids are more prevalent. Intestinal NETs have also been found to be more prevalent among African Americans as compared to whites[10]. The most common age group of gastrointestinal NETs presentation is the seventh decade, and the median age s 63 years. 

Pathophysiology

Many secretory products have been identified in various intestinal NETs. The most commonly produced substances include serotonin, histamine, tachykinins, kallikrein, and prostaglandins[11]. When these substances are in the systemic circulation, they cause a spectrum of symptoms called Carcinoid syndrome. Not All carcinoid tumors cause carcionoid syndrome.

The metabolism of tryptophan is impaired in these patients with intestinal carcinoids. In a healthy individual only 1% of tryptophan is converted into serotonin whereas, in a patient with carcinoid, the majority of tryptophan is metabolized to serotonin. This serotonin is excreted in the urine as 5-hydroxy indole acetic acid (5-HIAA).[12] Carcinoid syndrome result from hepatic metastasis or tumor location bypassing the portal circulation as in retroperitoneal or ovarian tumors.

Histopathology

NET tumors arises from enterochromaffin cells, also called Kulchitsky cells[13]. These cells are considered neural crest cells at the crypts of Lieberkühn. The tumor is classified to three grades according to histopathologic aggressiveness. Grade 1 (Low grade), Grade 2 (intermediate grade), and Grade 3 (high grade). The classification is based on appearance, mitotic rates, behavior (invasion of other organs, angioinvasion), and Ki-67 proliferative index. The distinction between well and poorly differentiated tumors is by far the most important; G1 and G2 tumors are considered well differentiated, and G3 tumors are poorly differentiated. The use of the word "carcinoid" to describe primary intestinal NETs is considered obsolete, although many clinicians continue to use this term. Certainly, it remains standard nomenclature to continue to refer to the syndrome as carcinoid syndrome.

History and Physical

The clinical picture of carcinoid syndrome is caused by the mechanical effect of the tumor like any other GI tumor, and or the secreted hormones from the tumor[14]. Autonomic excitatory symptoms of the secreted hormones are occasionally identified and serve as a clue for the diagnosis. Small bowel NET can cause chronic or recurrent abdominal pain and may occasionally lead to small bowel obstruction[4].

In most cases, carcinoids may go unrecognized as patients may be asymptomatic until the advanced stages. It may manifest with secretory clinical symptoms in the presence of liver metastasis. Uncommonly, carcinoid of the ovary or kidneys may clinically manifest as Carcinoid Syndrome even in the absence of metastasis.

Typical history given by patients include gastrointestinal symptoms such as diarrhea and abdominal cramping[11]. Dermatological symptoms commonly manifest as flushing due to histamine release. Occasional signs include the presence of telangiectasias. Other systemic symptoms may also include wheezing as a result of bronchoconstriction due to the release of histamine by the tumor. Also, some tumors may secrete other peptide hormones such as insulin, glucagon, vasoactive intestinal peptide (VIP), secretin or gastrin which may produce other clinical manifestations.

Evaluation

Intestinal NETs are rare and slow-growing tumors. They infrequently pose diagnostic challenge to physicians. High index of suspicion should be maintained for intestinal symptoms that are not well explained otherwise. Once the tumor is suspected, work should be completed to verify and characterize the tumor. On occasions, tumors are found incidentally during work or surgery for other reasons. Once suspected the following  tests may aid the diagnosis:

Laboratory testing

A useful initial diagnostic test for carcinoid syndrome is 24 hours urinary excretion of 5-Hydroxy Indole Acetic Acid (5-HIAA). It has 90% sensitivity and specificity for the diagnosis of intestinal carcinoid. This may be falsely positive as a result of ingestion of certain drugs or serotonin rich foods. Other less commonly used tests include chromogranin A concentration and measuring urinary excretion of serotonin.[1]

Imaging

Once the biochemical assessment of carcinoid disease is completed, imaging studies in combined modalities facilitates tumor localization.[13] Various modalities have been used to detect intestinal carcinoids including CT, MRI and radiolabelled scans such as octreotide scan, and Gallium 68 DOTATATE scan[15].

Triple phase contrast-enhanced CT scan is most commonly used as it is widely available. CT scan sensitivity is low (50%). Some of the disadvantages of a CT scan are difficulty in detecting small tumors less than 1 cm in size and difficulty in distinguishing colorectal adenocarcinoma from colorectal carcinoid tumors due to their similarity in appearance. CT scan increases significantly with large or locally advanced tumors with mesenteric involvement with characteristic radiating dense soft tissue strands caused by thickened neurovascular bundles. Likewise, abdominal CT is thought to be helpful in identifying liver metastases. MRI modality is the most sensitive technique to detect liver metastasis and can be used as an alternative to CT scan.[15]

Octreotide scan has the advantage of detecting metastasis beyond the abdominal region. It is currently in use in conjunction with Positron emission tomography (PET) scanning to increase sensitivity to detect pathologic uptake in the abdominal region. Octreoscan diagnostic sensitivity in asymptomatic patients with gastrointestinal NE tumors has been estimated to be in the range of 80% to 90%.[16] For surveillance, the clinical value of the octreotide scan of patients with carcinoid is questionable due to the availability of highly sensitive CT scans.

Treatment / Management

The goal of treating intestinal NETs is to achieve symptoms control, tumor growth control, and biochemical control.[13] This can only be achieved through a multidisciplinary approach and multi-modality treatment. The treatment can be based on the extent of the disease. 

Treatment of Non-metastatic Intestinal Carcinoid:

Treatment of a localized disease is surgical resection with a negative margin. Surgery is the mainstay of treatment and only way to achieve a complete cure for primary intestinal NET. However, most patients have either synchromonus metastatic tumors or liver metastasis at the time of presentation due to the indolent nature of the tumor.

The extent of surgical resection depends on the size, location and local spread of the disease. The same principle of loco-regional control used in surgical treatment of midgut malignancies is followed. A small tumor of 1 cm size can be locally excised. This is particularly important in duodenal tumors where wider resection and pancreatico-duodenectomy can be avoided. Carcinoids of the small intestine have a high likelihood of metastasis, irrespective of the size. Therefore, patients without evidence of metastasis should be treated with resection of the involved area of the small bowel including the small bowel mesentery with curative intent. Colorectal carcinoid tumors are mostly more than 2 cm and are invasive. Patients without metastasis should be treated with partial colectomy and lymphadenectomy. When presented with complications like bowel obstruction, surgical treatment is indicated primarily to relive the bowel obstruction on an urgent basis. Segmental bowel resection with the involved mesentery and primary anastomosis is sufficient treatment for primary control and complication relief. [15]

Treatment of Metastatic Intestinal Carcinoid:

For patients with symptomatic carcinoid syndrome and unresectable disease, initial treatment is advised with a somatostatin analog. However, for patients with metastatic disease that is resectable without extrahepatic metastases, cytoreductive surgical resection is preferred over medical therapy. Surgical treatment of tumor related complication is indicated to control the complications.

Medical Management: 

  • Somatostatin analogues: These are first-line agents used for the treatment of symptomatic carcinoid. Right-sided includes octreotide and lanreotide which have been shown to be highly effective in controlling symptoms with intestinal carcinoid. A depot preparation of octreotide is available in the form of monthly intramuscular injections. These are usually well tolerated except for mild symptoms such as nausea or bloating.
  • Interferon: This may be an option for patients with advanced disease who have worsening symptoms while on treatment with somatostatin analogs or who are intolerant of somatostatin analog therapy, but it is less commonly used due to potential adverse effects.
  • Molecular-directed therapy: mTor inhibitors like everolimus are currently approved as second-line therapy for patients who have progressive symptoms despite the use of somatostatin analogues.

Treatment of Hepatic Metastasis:

Surgical liver resection in patients with hepatic metastasis has a role in symptoms relief and survival rate improvement.[17] Therefore, when a resectable hepatic metastasis is identified, appropriate liver resection should be considered as part of the surgical planning. 

Staging

Staging

The current TNM staging system is a combined staging for jejunoileal, duodenal, and ampullary neuroendocrine tumors. In the United States, the newer version has separate TNM classifications and prognostications for jejunoileal, and duodenal/ampullary tumors.[18][19][15]

Prognosis

NETs are slow growing indolent tumors. But they induce the same other consequences of uncontrolled tumor growth with mechanical and physiologic alteration of the gastrointestinal tract. Bowel obstruction, perforation, bleeding and altered function are possible complications of advanced intestinal NETs. Therefore, prognosis depends primarily on the tumor and disease stage, tumor location, presence of metastasis, presence of synchronous or metachronous tumors, and the histologic grade/differentiation. Overall, the prognosis of intestinal carcinoids is good. High overall survival rates were reported among intestinal NETs patients including patients with distant metastasis with a 5-year overall survival ranges between 40% to 85%.[20][21]

Pearls and Other Issues

Surveillance

There is limited evidence for recommendations for follow-up after surgical resection. For all resected small intestinal and colonic carcinoid tumors follow long-term surveillance as there is a risk of recurrence even 5 years following resection. For small intestinal carcinoids, the general recommendation for surveillance is with triple phase CT or MRI imaging. Tumors less than 2 cm in size are less likely to metastasize. Urine 5-HIAA and Chromogranin A are followed every six months for the first couple of days. This is followed by annual surveillance for four years followed by every 2 years up to 10 years after surgery.

 

Enhancing Healthcare Team Outcomes

The North American Neuroendocrine Tumor Society has released guidelines for management of midgut neuroendocrine tumors. The guidelines emphasize a multidisciplinary approach for optimal outcomes. While surgery is the ideal treatment for patients with localized lesions, recent studies reveal that cytoreductive surgery with heated intraperitoneal chemotherapy may improve survival in some patients with metastatic peritoneal disease. Because these tumors have an unpredictable behavior, lifelong surveillance is recommended. With expert care, many patients can have a good quality of life or even be cured. [22][23][24] (Level V) A team of general surgery, medical oncology, diagnostic radiology, endoscopy, pharmaceutical expertise, and nursing care should be available to participate in the care of this patient. [25] (Level V)

 


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Cancer, Intestinal Carcinoid - Questions

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A patient is seen in the GI clinic with abdominal pain. Examination reveals a tender abdomen with rebound and guarding. She is suspected of having appendicitis. The pathology report comes back saying that the upper half of the appendix has a carcinoid. Which of the following is false about carcinoids?



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What is the most common location of neuroendocrine tumors (carcinoids) in the gastrointestinal tract?



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A 17-year-old boy is admitted with right lower quadrant pain and fever. He says he has nausea and pain, which started in the mid-epigastrium and has now shifted to the right lower quadrant. On examination, he has rebound and guarding in the right lower quadrant, and his white blood cell count is 12.6. He undergoes an uneventful appendectomy. Two days later, the pathologist confirms a carcinoid tumor located at the tip of the appendix. It measures 1 cm. What is the next step in the management of this patient?



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What is the most common tumor of the appendix?



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What is the appropriate treatment for a patient with a 1centimeter carcinoid at the tip of the appendix?



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In a patient with a 2 cm carcinoid localized to the base of the appendix, what is the treatment of choice?



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A 56 year old is found to have an incident finding of a 1 cm carcinoid on the small bowel. There is no other pathology. Which of the following is the most appropriate treatment?



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You have just performed an appendectomy on a patient. Two days later the pathologist reports that there was a malignancy. What is the most common malignancy found in the appendix?



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A 45-year old male presents to the clinic with complaints of diarrhea and dry skin. He claims that his skin has been quite itchy lately and he seems to be more forgetful than usual. He did go to his primary care provider a few weeks ago for vague abdominal pain but was told that he had developed irritable bowel syndrome. He was started on vitamin B3 but his symptoms have persisted. All the other routine blood work appears normal. What is the next step in his management?



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A 34-year old patient presents to the clinic with complaints of cutaneous flushing, diarrhea and dry skin. He claims that his skin has been quite itchy lately and he seems to be more forgetful than usual. He did go to his general practitioner a few weeks ago for vague abdominal pain but was told that he had developed irritable bowel syndrome. He was started on vitamin B3 but his symptoms have persisted. All the other routine blood work appears normal. What blood test can you order that can help with diagnosis and prognosis of this patient?



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A 55-year old patient presents to the clinic with complaints of diarrhea and dry skin. He claims that his skin has been quite itchy lately and he seems to be more forgetful than usual. He did go to his general practitioner a few weeks ago for vague abdominal pain but was told that he had developed irritable bowel syndrome. He was started on vitamin B3 but his symptoms have persisted. All of the other routine blood work appears normal. You suspect that the patient has a lesion in his gastrointestinal tract. Endoscopic ultrasound will be of little use if this lesion is located in what region?



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A 59-year old patient presents to the clinic with complaints of diarrhea and flushing. He claims that his skin has been very itchy lately and he seems to be more forgetful than usual. He did go to his general practitioner a few weeks ago for vague abdominal pain but was told that he had developed irritable bowel syndrome. He was started on vitamin B3 but his symptoms have persisted. All of the other routine blood work appears normal. You suspect that the patient has a lesion in his gastrointestinal tract. What is the ideal test for detecting the tumor that this patient may have?



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You have just performed an appendectomy on a 17-year old male. The surgery was uneventful and the patient is discharged the next morning. Seven days later the pathologist reports that there was a carcinoid measuring 1 cm confined to the mucosal tip. What is the next step?



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You are performing an exploratory laparotomy in a patient with vague abdominal pain. During the exploration, you feel a small mass in the proximal ileum. After performing an enterotomy you observe that there is a 1 cm mass. A quick frozen section reveals that it is a carcinoid. What is the next step in your management?



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A 65-year-old male with no significant past medical history presents with complaints of a 6-week history of diarrhea and abdominal cramping. He denies nausea, vomiting, or hematochezia, but endorses a 12-pound weight loss. The physical examination is remarkable for flushing of the face, bilateral expiratory wheezes, and a right-sided systolic murmur. Twenty-four-hour urine testing reveals elevated levels of 5-hydroxyindoleacetic acid. Abdominal CT reveals a mass in the tip of the appendix. What is indicated by the presence of these findings?



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Cancer, Intestinal Carcinoid - References

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