Appendiceal Cancer and Tumors

Cancers and tumors (neoplasms) of the appendix are extremely rare groups of tumors and they most typically present either as appendicitis, a hernia filled with mucin, increasing abdominal girth, abdominal discomfort, an abdominal/pelvic mass, as an incidental finding on some form of imaging or at the time of surgery for a different indication. In women, they often spread to the ovaries and can be easily confused with ovarian cancer. Making the diagnosis of appendiceal cancer requires examination of a tumor specimen. After starting in the appendix, appendiceal tumors and cancers frequently spread inside the abdominal cavity. Depending on the type of tumor or cancer, this can lead to either the build-up of mucinous fluid in the abdomen known as pseudomyxoma peritonei (see separate Rare Disease Report) or a condition referred to as peritoneal carcinomatosis (growth of cancer cells in the abdominal cavity—see Related Disorders section). Treatment for appendiceal tumors and cancers varies depending on the stage (extent) of the disease and the subtype.

Synonyms of Appendiceal Cancer and Tumors

low-grade mucinous neoplasm of the appendix (LAMN)
high-grade mucinous neoplasms of the appendix (HAMN)
mucinous adenocarcinoma of the appendix
adenocarcinoma of the appendix
signet ring cell cancer of the appendix
goblet cell carcinoid
cystadenocarcinoma
nonmucinous adenocarcinoma
colonic type adenocarcinoma

Subdivisions of Appendiceal Cancer and Tumors

goblet cell carcinoid
low-grade mucinous neoplasm of the appendix (LAMN)
high-grade mucinous neoplasm of the appendix (HAMN)
adenocarcinoma: well-differentiated
adenocarcinoma: moderately-differentiated
adenocarcinoma: poorly-differentiated
adenocarcinoma: signet ring cell (SRC)

Causes

The exact cause of appendiceal cancer is unknown. There are no genetic, familial, or environmental factors known to cause this disorder. It does not run in families. One study has shown a correlation between the presence of the intestinal bacterium Helicobacter pylori and pseudonym peritonei from appendiceal neoplasms. This has prompted a clinical trial using antibiotic therapy to eradicate the bacteria. This study is still ongoing at the time of this report. Recent studies have shown that appendiceal cancer does have a unique genomic profile distinct from adenocarcinomas of the colon which may offer future, appendix-specific and targetable pathways for treatment.

It has, however, been postulated that appendiceal mucinous neoplasms (AMN, a major subset of appendiceal tumors) follow the same adenoma-carcinoma sequence as seen in colorectal carcinoma. This sequence begins with a point mutation in the KRAS proto-oncogene and then mutations and/or deletions in the TP53 gene on Chr 17p. Next, truncating mutations on the APC gene on 5q and the beta-catenin gene all contribute to its onset. An alternative microsatellite instability (MSI) theory has been postulated to result from mutations in nucleotide mismatch repair genes e.g., hMSH2, hMLH1, PMS1, PMS2, and GTBP.[rx][rx][rx]

Related Disorders

Peritoneal carcinomatosis is the spread and growth of cancer cells in the abdominal cavity. Cancers that are most frequently associated with peritoneal carcinomatosis include the gastrointestinal (colon, rectal, appendiceal, gastric, pancreas, small bowel, and gallbladder) and the gynecologic (ovarian, primary peritoneal, and uterine) cancers. Other cancers that can spread to the abdominal cavity include breast, esophagus, and melanoma. Gastrointestinal stromal tumors (GISTs) are a subtype of sarcoma of the intestine that can also present with multiple cancer tumors in the abdomen. Peritoneal mesothelioma is cancer that originates in the lining of the abdominal cavity (peritoneum) and presents with signs and symptoms of peritoneal carcinomatosis.

Symptoms

At the time of diagnosis, appendiceal cancer can be either localized to the appendix or have spread to other parts of the body –, particularly the abdominal cavity or peritoneum. For appendiceal cancers that are localized, the most common signs and symptoms are those of acute appendicitis – namely right lower abdominal pain. For appendiceal cancers that have already spread away from the appendix, the most common presenting signs and symptoms are vague abdominal discomfort and increasing abdominal girth. In men, the first presenting sign may be a hernia that gets distended by mucin. In women, the first presenting sign may be a pelvic mass that is presumed to be ovarian cancer. Due to the very thin wall of the appendix, finding appendiceal cancer that has already spread at the time of diagnosis is more common than finding confined to the appendix.

Due to the structure of the appendix (a long, thin-walled, finger-like projection of the right colon), it is easy for tumor or cancer cells to break through the wall and spread in the abdominal cavity. Consequently, most appendiceal cancers, even the less aggressive ones, tend to present at an advanced stage with peritoneal carcinomatosis. Once the cancer cells have spread, they continue to grow and may cause abdominal discomfort, distention, a fluid build-up called ascites or pseudonym peritonei (mucinous ascites), and intestinal blockage or dysfunction. Over time this can lead to decreased appetite, early satiety (feeling full after eating only a small amount), nausea, and vomiting.

Appendiceal cancers rarely spread outside the abdominal cavity, and it is most commonly seen in poorly-differentiated or signet ring cell (SRC) cancers. 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 the 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.

Diagnosis

Appendiceal tumors are broadly categorized into epithelial (mucinous, non-mucinous adenocarcinoma, and signet ring cell tumors) and non-epithelial (neuroendocrine tumors, lymphomas, and sarcomas). Goblet cell carcinomas are an aggressive type and share features from both broad groups. Sixty-five percent of all appendiceal tumors are of neuroendocrine origin, while adenocarcinomas make up about 20%.[rx][rx]

The mucinous group of neoplasms is a heterogeneous group ranging from simple adenomas to adenocarcinomas and complex pseudomyxoma peritonei.[rx] They are graded based on the degree of mucosal involvement as mucinous adenoma, low-grade appendiceal mucinous neoplasms (LAMN), which are confined to the mucosa of the appendix, and high-grade mucinous adenocarcinoma that is invasive and spread beyond the muscularis mucosa.[rx][rx] The diagnosis of mucinous neoplasms is largely dependent on the presence of mucin, and they stain diffusely positive for CK20 (100%), MUC5AC (80%), and DPC4 (71%) and negative for CK 7 (71%). This CK positivity pattern is similar to that of CRC.[rx]

Signet ring cell carcinomas are an aggressive group of epithelial tumors, with up to 60% of cases already showing distant metastasis at the time of diagnosis.[rx][rx]

Neuroendocrine tumors are often found at the tip of the appendix, are well-differentiated, and are relatively indolent in their course.[rx] Typical microscopic findings include uniform submucosal cell conglomerates in a nested or insular pattern that have nuclei showing the distinctive endocrine “salt and pepper” chromatin pattern. Chromogranin A is a useful biomarker to predict relapse even before there is radiographic evidence.[rx] As the appendix is primarily lymphoid tissue, appendiceal lymphomas may arise. The etiology is Burkitt lymphoma with a mean age of 18 years old and diffuse large B cell lymphomas in the elderly.[rx]

History and Physical

In over 50% of cases, the are no symptoms, and this malignancy is detected incidentally. However, most symptomatic patients, almost 30% of those with appendiceal cancer, would present as acute appendicitis.[rx] However, the histopathologic subtype of acute appendicitis identifies the possible rate of acute presentation of the tumor. As such, the most prevalent clinical presentation of the appendiceal adenocarcinoma is acute appendicitis. [rx] Factors that should increase suspicion for appendiceal neoplasm include age greater than 50 years with a family history of colon cancer or inflammatory bowel disease (IBD), features suggestive of chronic appendicitis, or the presence of unexplained anemia.[rx] The patient may have non-specific abdominal pain, right lower quadrant pain, weight loss, anorexia, fever, vomiting, features of intestinal obstruction from intussusception, and fatigue.[rx] Physical examination may reveal right lower quadrant abdominal tenderness with guarding, abdominal mass, presence of ascites, and features of metastatic disease. The patients with GEP-NETs who are complicated with hepatic metastasis might present with signs and symptoms related to carcinoid syndrome. [rx]

Because there are no unique features of appendiceal cancer in imaging studies such as ultrasound, CT scan, PET scan, or MRI, the actual diagnosis of appendiceal cancer 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. The finding of a dilated, mucin-filled appendix on a CT scan or MRI should prompt concern for an appendiceal tumor and an appendectomy should be considered. The different types of appendiceal tumors and cancers can be distinguished by the appearance of the cells under the microscope and by staining them for specific markers. Goblet cell carcinoid tumors tend to be easier to identify because of the unique combination of neuroendocrine and epithelial cells.

The mainstay of an initial evaluation is imaging studies. Sonographic findings include elongated or cystic lesions in the right lower quadrant (RLQ) with features of internal onion skin appearance representing lamellated mucin, which is a pathognomonic finding.[rx] A defect in the appendiceal wall with leakage may be indicative of a ruptured mucinous neoplasm.[rx] In patients presenting with features of acute appendicitis, a multidetector CT scan or MRI revealing an appendix greater than 15 mm with thickened or irregular walls is suspicious for neoplasia.[rx] Other CT findings that suggest PMP would include but are not limited to scalloping from metastatic deposits on serosal surfaces and cavities, and sometimes, a rim-like calcification may be noted.[rx] A percutaneous needle biopsy may be essential in confirming disseminated mucinous metastatic spread to the peritoneum.[rx] Plain x-rays of the abdomen are of little clinical value and may rarely show curvilinear iliac fossa calcification. Carcinoembryonic antigen (CEA) levels have some diagnostic and prognostic values with normal values indicating a better prognosis.[rx] Endoscopy is indicated in patients who have been diagnosed with mucinous adenocarcinoma as there is an increasing incidence of synchronous or metachronous colonic polyps and masses.[rx][rx] Histologic evaluation of the appendiceal specimen is required for a definitive diagnosis.

Evaluation of the ileocolic nodal basin along with a comprehensive hepatic assessment to exclude liver metastasis has an important role in the management of appendiceal cancers, including the GEP-NETs, formerly named carcinoid tumors. Moreover, peritoneal evaluation should be considered in the patients who are diagnosed with goblet cell carcinoma, and appendiceal mucinous neoplasms and the findings of the peritoneal cancer index score should be precisely recorded.[rx]

Despite the inconclusive role of abdominal radiological measures in the diagnosis of appendiceal cancer, malignant features of appendiceal cancers include wall irregularity and soft tissue thickening within a low attenuative, round, well-encapsulated cystic mass in the right or quadrant, is highly suggestive of neoplastic appendiceal mucocele. In these patients, further systematic evaluation to exclude the presence of ascites, peritoneal involvement, and scalloping of the liver surface, is mandatory. [rx]

Treatment

Once the diagnosis is established, a staging workup 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 made by 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 cancer cells and whether or not it is localized or disseminated. Most of the larger and more recent studies recommend surgical removal of the right side of the colon (right hemicolectomy) for moderately-, poorly-differentiated and SRC appendiceal cancers to ensure that all the disease has been removed and to test the regional lymph nodes for any cancer cells. There is some debate about the utility of right hemicolectomy for well-differentiated appendiceal cancers as the risk of spread to regional lymph nodes is low (<5%). LAMNs do not require a right hemicolectomy as they do not spread to regional lymph nodes.

For LAMNs that have not spread in the abdomen, an appendectomy is all that is required. For adenocarcinomas that have not spread to the abdomen, surgery to remove the right side of the colon where the appendix originates is recommended to determine if there has been any spread of cancer cells to the local lymph nodes. For tumors and cancers that have spread away from the appendix and into the abdominal cavity or the local lymph nodes, either intravenous chemotherapy and/or additional surgery to remove cancer, and often heated chemotherapy delivered directly into the abdomen (HIPEC) should be considered.

The role of right hemicolectomy in HAMN is still being determined.

For moderately-, poorly-differentiated and SRC appendiceal cancers that have spread to regional lymph nodes or other organs outside the abdominal cavity, the usual recommendation is for systemic (intravenous) chemotherapy. 5-fluorouracil-based chemotherapy regimens (the same that are used to treat colon cancer) are typically recommended. If cancer has spread in the abdominal cavity, cytoreductive surgery to remove cancer and abdominal perfusion with hyperthermic (heated) chemotherapy (a procedure known as HIPEC) to prevent cancer recurrence should be considered as part of the treatment regimen along with systemic chemotherapy. This should be performed at an experienced HIPEC center. For LAMN and well-differentiated appendiceal cancers that have spread to the abdominal cavity, the usual recommendation is cytoreductive surgery and HIPEC. 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.