NORD gratefully acknowledges Laura A. Lambert, MD, FACS, Huntsman Cancer Institute, University of Utah, and the Appendix Cancer/Pseudomyxoma Peritonei Research Foundation, for the preparation of this report.
Goblet cell carcinoids (GCC) of the appendix are a subtype of appendiceal cancer. GCC are defined by a unique combination of two types of cancer cells – neuroendocrine (carcinoid) and epithelial (adenocarcinoma). They are extremely rare with an estimated incidence of 1 per 2 million individuals. The average age of onset is between 50 and 55 years, and they affect men and women equally. They most typically present either as appendicitis or with abdominal pain and a mass. In women, they often spread to the ovaries and can be easily confused with ovarian cancer. Making the diagnosis of GCC requires examination of a tumor specimen. While GCC tend not to spread to other parts of the body outside the abdomen, they frequently spread inside the abdominal cavity. This condition is referred to as peritoneal carcinomatosis. Treatment for GCC often requires surgery to remove the right side of the colon where the appendix originates, and intravenous chemotherapy. If the GCC has spread in the abdomen, additional surgery to remove the cancer and heated chemotherapy delivered directly into the abdomen may be considered.
In addition to being quite rare, cancers and tumors of the appendix come in a wide variety of types. The most common type of tumor or cancer of the appendix is a neuroendocrine or carcinoid tumor. Neuroendocrine tumors (NETs) are derived from specialized cells that reside in the wall of the appendix called enterochromaffin (EC) cells. EC cells make chemicals that help facilitate gastrointestinal motility and digestion. The next most common type of cancer of the appendix is an adenocarcinoma. These are derived from the most abundant cells lining the inside of the appendix called epithelial cells. One of the functions of epithelial cells is to make mucin – a jelly-like substance that helps protect the lining of the intestine. Cells that make mucin are often referred to as goblet cells. Goblet cell (epithelial) carcinoids (neuroendocrine) (GCC) are an extremely rare subtype of cancer of the appendix with a unique biology. Unlike most cancers which arise from one particular cell type, GCCs, as the name implies, are characterized by the presence of cancer cells derived from both neuroendocrine (EC) and epithelial cells. Of the two cell types, the amount and appearance of the epithelial-derived cancer cells are most important in terms of prognosis and directing treatment.
At the time of diagnosis, GCCs can be either localized to the appendix or have spread to other part of the body – particularly the abdomen. For GCC that are localized, the most common signs and symptoms are those of acute appendicitis – namely right lower abdominal pain. For GCCs that have already spread away from the appendix, the most common presenting signs and symptoms are abdominal pain and a mass. Finding GCC that have already spread at the time of diagnosis is more common in women and 15-30% are initially diagnosed as having an ovarian cancer. There is a clear attraction of GCC to the ovary for a reason that is not yet known but it under investigation.
GCC rarely spread outside the abdominal cavity. However, once the cancer cells escape from the appendix, they can continue to grow in the abdominal cavity, on the surface of other organs such as the omentum, intestines, ovaries, uterus, liver, spleen and peritoneum (lining of the abdominal cavity). This condition is called peritoneal carcinomatosis (see Related Disorders) – which means growth of cancer cells within the abdominal cavity. Over time, without treatment, this condition can result in blockage of the intestines or loss of intestinal function.
Goblet cell carcinoids have been classified in several different ways as indicated below:
Group A (Typical GCC)
Adenocarcinoid ex GCC
Group B (signet ring cell)
Group C (poorly differentiated)
Group 1 (GCC with <25% adenocarcinoma) Group 2 (GCC with 25-50% adenocarcinoma) Group 3 (GCC with >50% adenocarcinoma)
The exact cause of GCC is unknown. One study has suggested a possible connection between schistosomiasis (a parasitic infection found in certain tropical and subtropical countries) and GCC, however a causal relationship has not been established and the vast majority of GCC occur in the absence of schistosomiasis. Recent studies have shown that GCCs do have a unique genomic profile distinct from adenocarcinomas and neuroendocrine tumors of the appendix which may offer future targetable pathways for treatment. There are no genetic, familial or environmental factors known to cause this disorder. It does not run in families.
GCC is very rare with approximately 1 case per 2 million individuals. The average age at the time of diagnosis is most frequently reported between 50-55. While most studies have reported that men and women are affected in equal numbers, a few have suggested a slightly increased frequency in women (2-3:1). Advanced GCCs tend to present more frequently in women and 15-30% of women are initially diagnosed with an ovarian cancer. Less than 1% of GCCs are accurately diagnosed prior to surgery.
Because there are no unique features of GCC on imaging studies such as ultrasound, CT scan, PET scan or MRI, the actual diagnosis of GCC cannot be made until a tumor specimen is examined by a pathologist. This is frequently accomplished at the time of appendectomy for appendicitis, surgery for an intestinal blockage or presumed ovarian cancer, or through a diagnostic tumor biopsy performed for an abnormal clinical or radiographic finding such as a palpable tumor or tumors seen on an imaging study. GCCs tend to be easier to identify because of the unique combination of neuroendocrine and epithelial cells.
Once the diagnosis is established, a staging work-up including imaging studies (most commonly a CT scan of the chest, abdomen and pelvis) and tumor marker blood tests (CEA, CA 19-9 and CA 125) should be performed. (Tumor markers are proteins related to the cancer cells that can be measured in the blood.) Treatment recommendations depend on both the histology (the microscopic structure of the tumor cells) of the GCC and whether or not it is localized or disseminated. Most of the larger and more recent studies of GCC recommend surgical removal of the right side of the colon (right hemicolectomy) to ensure that all the disease has been removed and to test the regional lymph nodes for any cancer cells. Many also recommend removal of the ovaries in post-menopausal women given the affinity of these tumors for the ovaries. In the study by Tang et al, for Tang A tumors which are confined to the appendix, the authors recommend appendectomy with negative margins (no tumor cells at the cut edge). These tumors should have no adenocarcinoma component and be confined to the inner layers of the wall of the appendix referred to as T1 or T2. For all other classifications (Tang B, Tang C, Tang A tumors that have penetrated more deeply into the wall of the appendix, or a positive margin after appendectomy), the authors recommend removal of the right side of the colon and the ovaries in post-menopausal women.
If the cancer has spread to regional lymph nodes or other organs outside the abdominal cavity, the usual recommendation is for systemic (intravenous) chemotherapy. 5-flourouracil-based chemotherapy regimens (the same that are used to treat colon cancer) are typically recommended. If the cancer has spread in the abdominal cavity, cytoreductive surgery to remove the cancer and abdominal perfusion with hyperthermic (heated) chemotherapy (a procedure known as HIPEC) to prevent cancer recurrence may be considered as part of the treatment regimen along with systemic chemotherapy. This should be performed at an experienced HIPEC center. Surveillance for cancer recurrence should include a history and physical exam, imaging studies of the chest, abdomen and pelvis and tumor markers (CEA, CA 19-9 and CA 125) every 6 months for the first two years and then yearly for at least 3 more years, with consideration of continued follow-up thereafter.
Due to the rarity of GCC, there are no GCC-specific clinical trials available at the time of this writing. However, there are a few appendiceal cancer-specific clinical trials available for which a person with GCC might be eligible. People with GCC may also be eligible for trials specific to peritoneal carcinomatosis and rare tumors.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
Information about current clinical trials is posted on this page on the ACPMP Research Foundation website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Nonaka D, Papaxoinis G, Lamarca A, Fulford P, Valle J, Chakrabarty B. A Study of Appendiceal Crypt Cell Adenocarcinoma (So-Called Goblet Cell Carcinoid and Its Related Adenocarcinoma). Hum Pathol. 2018 Feb;72:18-27. doi: 10.1016/j.humpath.2017.08.005. Epub 2017 Aug 18.
Reid MD, Basturk O, Shaib WL, et al. Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases. Mod Pathol. 2016 Oct;29(10):1243-53. doi: 10.1038/modpathol.2016.105. Epub 2016 Jun 24.
Lee LH, McConnell YJ, Tsang E, et al. Simplified 2-tier histologic grading system accurately predicts outcomes in goblet cell carcinoid of the appendix. Hum Pathol. 2015 Dec;46(12):1881-9. doi: 10.1016/j.humpath.2015.08.005. Epub 2015 Aug 22.
Olsen IH, Holt N, Langer SW, et al. Goblet cell carcinoids: characteristics of a Danish cohort of 83 patients. PloS one. 2015;10(2):e0117627.
Taggart MW, Abraham SC, Overman MJ, Mansfield PF, Rashid A. Goblet cell carcinoid tumor, mixed goblet cell carcinoid-adenocarcinoma, and adenocarcinoma of the appendix: comparison of clinicopathologic features and prognosis. Arch Pathol Lab Med. 2015 Jun;139(6):782-90. doi: 10.5858/arpa.2013-0047-OA.
Dimmler A, Geddert H, Faller G. EGFR, KRAS, BRAF-mutations and microsatellite instability are absent in goblet cell carcinoids of the appendix. Pathol Res Pract. 2014 May;210(5):274-8. doi: 10.1016/j.prp.2014.01.002. Epub 2014 Jan 31.
Jiang Y, Long H, Li T, Wang W, Liu H, Zhang X. Schistosomiasis may contribute to goblet cell carcinoid of the appendix. J Parasitol. 2012 Jun;98(3):565-8. doi: 10.1645/JP-GE-2865.1.
Tang LH, Shia J, Soslow RA, et al. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol. 2008 Oct;32(10):1429-43. doi: 10.1097/PAS.0b013e31817f1816.
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