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What is Appendix Cancer?
Appendix cancer is a malignancy that originates in the appendix, a small organ connected to the beginning of the colon. There are numerous types of appendix cancer, but most cases present as pseudomyxoma peritonei (PMP), characterized by pools of mucin that can spread throughout the abdominal cavity.
Appendix cancer is a rare malignancy, occurring in less than 1% of all appendectomies. [see References: 1] It originates from a malignant, mucinous growth in the appendix, the small tubular organ connected to the colon. Because of its location, these tumors cannot always be detected with a colonoscopy. The exact function of the appendix is unknown, but more recent studies suggest that it may house certain bacteria that aid in digestion and help replenish the digestive tract after a gastrointestinal illness.[2] Appendix cancer is very diverse and includes a variety of distinct types of tumors, ranging from mixed neuroendocrine and goblet cell carcinomas to mucinous adenocarcinomas.
An appendix cancer diagnosis will also include a description of its “grade”. Grade refers to how aggressive the cancer is, which is determined based on how much cancer cells look like normal healthy cells when viewed with a microscope. A less aggressive cancer would be considered low-grade, and a more aggressive cancer would be considered high-grade.
Appendix cancer most commonly presents as pseudomyxoma peritonei (PMP). PMP is a clinical syndrome characterized by pools of mucin and widespread peritoneal disease. Mucin is a jelly-like substance that the body produces to protect the lining of the stomach, intestines, and the appendix. Certain types of cancer cells produce mucin that may cause organs to rupture, such as the appendix, and build up in the abdomen. PMP is classified as either a low-grade, less aggressive form, known as disseminated peritoneal adenomucinosis (DPAM) or low-grade mucinous carcinoma peritonei (LGMCP), or a more invasive form known as peritoneal mucinous carcinomatosis (PMCA) or high-grade peritoneal carcinoma peritonei (HGMCP).[3] Overall 10-year survival for PMP is approximately 32%.[4, 5] However, survival is directly related to the grade of the tumor and the possibility of having a complete removal of all the tumors by an experienced surgical team.
When caught early, many types of appendix cancer are highly treatable. Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) is considered the standard of care treatment for all types of advanced appendix cancers. CRS refers to the aggressive surgical removal of all visible tumors. HIPEC is the infusion of heated chemotherapy throughout the abdominal cavity and is performed immediately following cytoreductive surgery.

Risk Factors
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Age: Average age of diagnosis is 40 years
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Gender: Occurs more frequently in females
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Smoking tobacco
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Family history of appendix cancer
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Certain medical conditions that affect the stomach’s ability to make acid, such as atrophic gastritis or Zollinger-Ellison syndrome.

Signs & Symptoms
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Appendicitis: Most cases are found during appendectomy for appendicitis
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Abdominal bloating
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Abdominal or pelvic pain/tenderness
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Unexplained weight gain/loss
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Changes in bowel function
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“Jelly Belly” - a nickname for the accumulation of mucinous, jelly-like material in the abdomen.

Evaluation
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Physical exam
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Imaging studies: CT scan, MRI or PET/CT scan
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Blood work to include tumor markers (CA 19-9, CEA, CA 125, CRP)
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Diagnostic laparoscopy may be recommended to assess the amount and location of the tumor or to determine if the tumor can be completely removed by CRS/HIPEC.
Key Facts
Rarity
Appendix cancer is rare and often misdiagnosed, making it important that specialized peritoneal surface malignancy surgeons and pathologists carefully review your case.
Survival Outcomes
Survival outcomes vary based on tissue subtype. Low-grade mucinous tumors are associated with the longest survival, while high-grade tumors, especially those with signet ring cells or goblet cells, are considered to have more aggressive behavior.
Complete CRS/HIPEC
Regardless of which subtype you have, the best survival is achieved with complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). In other words, the complete removal of all visible disease.
Chemotherapy
Given the lack of clear evidence, systemic chemotherapy should be reserved for patients who are not candidates for CRS/HIPEC, have high-risk pathology to help decrease recurrence after complete CRS/HIPEC, or are in a clinical trial.
Diagnosis and Prognosis
Although the recommended treatment for all advanced appendix cancers is CRS/HIPEC, prognosis and outcomes are highly dependent on the type of cancer. Therefore, accurately diagnosing these tumors is especially important for treatment and surveillance decisions. This can be challenging as the subtypes exist on a spectrum, and researchers are still working to determine the best classification system. Furthermore, many pathologists are unfamiliar with this rare disease. Do not be surprised if your CRS/HIPEC surgeon requests that your pathology slides be reviewed for additional opinions.
Carcinoid/Neuroendocrine Tumors
Appendix carcinoid tumors (also called neuroendocrine tumors or NETs) are commonly found towards the tip of the appendix and are usually detected in the early stages, without extensive abdominal disease. Although less likely than with other intestinal neuroendocrine tumors, appendix carcinoid tumors can secrete serotonin and other substances that cause carcinoid syndrome, characterized by diarrhea, skin flushing, and cardiac issues.[14] For an early stage diagnosis, an extended appendectomy or right hemicolectomy may be all that is required. The extent of primary tumor resection and prognosis depends on the size of the tumor. Early-stage carcinoid tumors have an excellent prognosis, with survival of greater than 30 years. In the rare event that they have spread beyond the appendix to the peritoneal cavity (under 12% of cases), complete surgical resection with or without HIPEC is recommended, with a 5-year survival ranging from 32-78% depending on the lymph node status, tumor grade, and presence of distant metastases.[15] Somatostatin analogs, such as octreotide, can help manage symptoms of carcinoid syndrome and prolong survival in patients with unresectable disease. Currently, the benefit of HIPEC for these carcinoid tumors is not well known.
DPAM/LGMCP
The most common appendix cancer subtype is low-grade mucinous carcinoma peritonei (LGMCP), which may also be referred to as DPAM or LAMN. This is a non-invasive subtype that is characterized by large mucin pools and few bland cancerous cells. It originates in a low or high-grade appendiceal mucinous neoplasm (LAMN/HAMN) and progresses to LGMCP/DPAM once it has spread beyond the appendix into the abdominal cavity.[3] It rarely spreads outside of the abdomen or to lymph nodes and is not known to respond to systemic chemotherapy.[16] It is the subtype associated with the longest survival, with median overall survival greater than 15 years after complete CRS/HIPEC. The 10-year overall survival ranges from 75-82%.[8, 17] Although less common than in other subtypes, recurrence can also occur in up to 30% of patients and median progression-free survival is 7-10 years after complete CRS/HIPEC.[18] Emerging evidence demonstrates that the number of cells present in the mucin is directly correlated to recurrence and overall survival, with acellular mucin associated with the best outcomes.[19, 20] Without complete CRS/HIPEC, survival shortens to under 5 years. Because these tumors illicit a large immune response, some oral chemotherapy agents with an anti-inflammatory component, such as capecitabine (Xeloda), may be offered in unresectable cases.[21]
PMCA/HGMCP
High-grade mucinous carcinoma peritonei (HGMCP), also referred to as PMCA, is an invasive mucinous adenocarcinoma. Outcomes vary based on tumor grade (well, moderately, or poorly differentiated) and the presence of lymph node involvement. Well-differentiated tumors with negative lymph nodes tend to have longer survival outcomes.[3] However, complete CRS with HIPEC is the best treatment for all HGMCP, with median overall survival ranging from 8-10 years.[8, 9, 17] Recurrence is more likely, occurring in up to 45% of patients around 4-5 years after CRS/HIPEC.[17, 18] Without complete CRS/HIPEC, survival shortens to approximately 2-3 years. Systemic chemotherapy with colon-type regimens (FOLFOX, FOLFIRI) may be recommended for patients with unresectable disease or as “preventative” treatment (adjuvant therapy) after complete CRS/HIPEC in patients who are at high risk for recurrence (i.e. positive lymph nodes or poorly differentiated).[11, 22]
PMCA-S/HGMCP-S
Signet ring cell carcinoma or PMCA-S is a type of high-grade mucinous carcinoma peritonei that is highly invasive and aggressive. Signet ring describes the shape of the cancer cells within the mucin, which are characterized by the nucleus pushed to the edge forming a ring and creating a higher propensity for lymph node and distant (extra-abdominal) metastases.[3] The prognosis largely depends on the amount of tumor and the extent of the disease. Patients with lower tumor burden (lower PCI score) and no extra-abdominal or lymph node metastases tend to have better survival outcomes. Some centers employ a “PCI cutoff” for signet ring cell tumors and will not perform CRS/HIPEC on patients above that cutoff point. However, some studies have shown that long-term survival can be achieved with CRS/HIPEC, even in patients with a lot of disease (high PCI), if all the visible tumors can be removed. After complete CRS/HIPEC, median overall survival is approximately 3 years, which improves to around 6 years in lymph node-negative patients.[17, 23, 24] Even after complete CRS/HIPEC, recurrence can occur in up to 65% of patients, with a median progression-free survival of approximately 2 years. Most patients with signet ring cells will be recommended to undergo systemic chemotherapy, before and/or after CRS/HIPEC.[18]
PMCA-G/HGMCP-G
Goblet cell carcinomas or PMCA-G is one of the rarest types of high-grade mucinous carcinoma peritonei that can often be mixed with signet ring and neuroendocrine features. Because of its mixed histology and low incidence, it is commonly misdiagnosed as a less aggressive neuroendocrine/carcinoid tumor.[25] However, it behaves more like a carcinoma and survival depends on the stage of disease at diagnosis and the presence of signet ring cells.[26] Once this cancer has spread beyond the appendix, the role of CRS/HIPEC is controversial. However, no other available treatment options can provide the same chance of long-term survival. Some single-center studies have reported a median overall survival of over 4 years, which includes some long-term survivors beyond 5 years, and a median progression-free survival of around 2 years.[18, 27]
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