- Donate
- Understanding Rare Disease
- Living with a Rare Disease
- Community Support
- Advancing Research
- Driving Policy
- Get Involved
- Rare Disease News
- Resource Library
- About Us
- For Clinicians & Researchers
- For Patient Organizations
Last updated: 8/16/2023
Years published: 2018, 2023
NORD gratefully acknowledges Erin P. Ward, MD, Assistant Professor of Surgical Oncology, Huntsman Cancer Institute, University of Utah and 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.
Summary
Goblet cell adenocarcinomas (GCA) of the appendix are a subtype of appendiceal cancer. GCA are defined by a unique combination of two types of cancer cells โ neuroendocrine (carcinoid) and epithelial (adenocarcinoma). These tumors are more aggressive than neuroendocrine tumors and are now treated and staged like appendiceal adenocarcinomas. They are extremely rare with an estimated incidence of 1 per 2 million individuals. The average age of onset is between 50 and 60 years, most patients are Caucasian (>80%) and they affect males and females equally. They most typically present either as appendicitis or with abdominal pain and a mass. In females, they often spread to the ovaries and can be easily confused with ovarian cancer. Making the diagnosis of GCA requires the examination of a tumor specimen. While GCA 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 GCA often requires surgery to remove the right side of the colon where the appendix originates, and intravenous chemotherapy. If the GCA has spread in the abdomen, additional surgery to remove the cancer and heated chemotherapy delivered directly into the abdomen may be considered.
Introduction
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. These cells make chemicals that help facilitate gastrointestinal motility and digestion. The next most common type of cancer of the appendix is 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 โ 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 adenocarcinomas (GCAs) are an extremely rare subtype of cancer of the appendix that can have characteristics of both adenocarcinomas and NETs. These tumors have had several names in the past, including goblet cell carcinoid, to try to reflect that these tumors often have aspects of adenocarcinoma (goblet cell), and NETs (carcinoid). Previously these tumors have been treated and staged more like NETs but we now know that these tumors are more aggressive than NETs and only rarely associated with hormone secretion. Although GCAs are distinct from appendiceal adenocarcinomas, they are now treated and staged like appendiceal adenocarcinomas.
At the time of diagnosis, GCAs can be either localized to the appendix or have spread to other parts of the body โ particularly the abdomen. For GCAs that are localized, the most common signs and symptoms are those of acute appendicitis โ namely right lower abdominal pain. For GCAs that have already spread away from the appendix, the most common presenting signs and symptoms are abdominal pain and a mass. Finding GCAs that have already spread at the time of diagnosis is more common in females and 15-30% are initially diagnosed as having an ovarian cancer. There is a clear attraction of GCAs to the ovary for a reason that is not yet known but it is under investigation.
GCAs rarely spread outside the abdominal cavity. However, once the cancer cells escape from the appendix, they can continue to grow in the abdominal cavity and 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) โ 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:
Tang Classification
Group A (typical GCA)
Group B (signet ring cell)
Group C (poorly differentiated carcinoma)
Taggart Classification
Group 1 (GCA with <25% adenocarcinoma) Group 2 (GCA with 25-50% adenocarcinoma) Group 3 (GCA with >50% adenocarcinoma)
Lee Stratification
Low-grade
High-grade
The exact cause of GCAs are unknown. One study has suggested a possible connection between schistosomiasis (a parasitic infection found in certain tropical and subtropical countries) and GCAs, however a causal relationship has not been established and the vast majority of GCAs occur in the absence of schistosomiasis. Recent studies have shown that GCAs 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.
GCAs are very rare with approximately 1 case per 2 million individuals. The average age at the time of diagnosis is most frequently reported between 50-60. While most studies have reported that males and females are affected in equal numbers, a few have suggested a slightly increased frequency in females (2-3:1). Advanced GCAs tend to present more frequently in females and 15-30% of females are initially diagnosed with an ovarian cancer. Less than 1% of GCAs are accurately diagnosed prior to surgery.
Because there are no unique features of GCAs on imaging studies such as ultrasound, CT scan, PET scan or MRI, the diagnosis of GCA 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. It can also be diagnosed during a tumor biopsy performed for an abnormal clinical or radiographic finding, such as a palpable tumor or tumors seen on an imaging study. GCAs tend to be easier to identify because of the unique combination of neuroendocrine and epithelial cells, although the presence of neuroendocrine cells is not required.
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 of the GCAs (the microscopic structure of the tumor cells) and whether it is localized or disseminated. Most of the larger and more recent studies of GCAs 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. Some also recommend removal of the ovaries in post-menopausal females given the affinity of these tumors for the ovaries. In very rare instances, when the tumor is localized to the appendix, low grade, and removed completely with an appendectomy, some may consider appendectomy alone, but this remains controversial.
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 GCA, there are no GCA-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 GCA might be eligible. People with GCA 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:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
Information about current clinical trials is posted on this page on the ACPMP Research Foundation website:
https://acpmp.org/clinical-trials
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Palmer K, Weerasuriya S, Chandrakumaran K, et al. Goblet cell adenocarcinoma of the appendix: a systematic review and incidence and survival of 1,225 cases from an English cancer registry. Front Oncol. 2022;12:915028. Published 2022 Jul 12. doi:10.3389/fonc.2022.915028
Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182-188. doi:10.1111/his.13975
Shyu S, Choudry H, Hall L, et al. Clinicopathological analysis of appendiceal goblet cell adenocarcinoma with peritoneal metastasis: World Health Organization grade predicts survival following cytoreductive surgery with intraperitoneal chemotherapy. Histopathology. 2020;77(5):798-809. doi:10.1111/his.14189
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.
NORD strives to open new assistance programs as funding allows. If we donโt have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDโs mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View report
Your donation will help more than 30 million Americans with a rare disease navigate their diagnosis, receive financial assistance, and access the care and support they deserve. Make your tax-deductible gift today!