Appendix Cancer

Article Author:
Azeberoje Osueni
Article Editor:
Yuvraj Chowdhury
Updated:
7/5/2020 1:33:26 PM
PubMed Link:
Appendix Cancer

Introduction

Appendiceal malignancies are a rare group of tumors often found incidentally during surgical removal of the appendix. Histologically, this malignancy accounts for 0.5-1 % of all biopsy specimens following appendectomies.[1][2] Clinically, this condition most commonly presents as acute appendicitis due to obstruction of the appendiceal lumen. As it is for all malignancies, early detection is critical as the late diagnosis could lead to much poorer outcomes.

Etiology

The mechanisms that result in appendiceal malignancies are not well understood. 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.[3][4][5]

Epidemiology

Cancer of the appendix is observed in less than 2% of appendiceal specimens. There has been a steady rise in the number of appendectomies performed in the United States, as well as the incidence of appendiceal cancer.[6][7] Neuroendocrine tumors account for the most common malignancy of the appendix.[7][8][9] Although appendiceal adenocarcinoma is more frequently found amongst men in their 6 to 7 decade of life, in recent decades, there has been a decrease in the age at diagnosis.[10] An increased association with colonic neoplasia and chronic ulcerative colitis has been noted.[2] The appendix is the third most common site for neuroendocrine tumors after the rectum. At the time of diagnosis, over a third of cases are metastatic.[11]

Pathophysiology

Obstruction of the appendiceal lumen by the malignant cells leads to inflammation of the appendix, venous stasis, and, ultimately, infection of the appendix.[7] In mucinous tumors of the appendix, there may be a cystic dilation of the appendix due to obstruction of the appendiceal lumen by mucoceles.[12][13] These processes are the basis for the commonest clinical presentation of this disease, acute appendicitis.

Histopathology

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%.[8][9]

The mucinous group of neoplasms is a heterogeneous group ranging from simple adenomas to adenocarcinomas and complex pseudomyxoma peritonei.[12] 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 are invasive and spread beyond the muscularis mucosa.[14][7] 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.[2]

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.[15][16]

Neuroendocrine tumors are often found at the tip of the appendix, are well-differentiated, and relatively indolent in their course.[17] 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.[17] 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.[18]

History and Physical

In over 50% of cases, the are no symptoms, and this malignancy is detected incidentally. However, most symptomatic patients would present as acute appendicitis.[19][1] 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.[7] 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.[12] Physical examination may reveal right lower quadrant abdominal tenderness with guarding, abdominal mass, presence of ascites, and features of metastatic disease.

Evaluation

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.[12] A defect in the appendiceal wall with leakage may be indicative of a ruptured mucinous neoplasm.[12] 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.[20] Other CT findings that suggest PMP would include but not limited to scalloping from metastatic deposits on serosal surfaces and cavities, and sometimes, a rim like calcification may be noted.[21] A percutaneous needle biopsy may be essential in confirming disseminated mucinous metastatic spread to the peritoneum.[22] 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 value with normal values indicating a better prognosis.[23] 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.[20][14] Histologic evaluation of the appendiceal specimen is required for a definitive diagnosis.

Treatment / Management

Surgical therapy is the mainstay of therapy for cancers of the appendix; however, advanced cases with distant metastasis may be surgically unresectable. Laparoscopic intervention is not recommended as it increases the risk for intraoperative rupture and metastatic spread.[24] Appendectomy with a wide mesoappendix resection in order to rule out lymph node involvement can both be diagnostic and curative as most appendiceal tumors are diagnosed following histologic evaluation of appendiceal specimen.[25] Other surgical modalities such as a right hemicolectomy are indicated when there is nodal involvement, a large neuroendocrine tumor with unclear margins, and greater than 3 mm meso-appendiceal invasion.[26] Cytoreductive surgery and heated intraperitoneal chemotherapy are particularly useful in mucinous tumors of the appendix. Surgically unresectable epithelial tumors of the appendix with distant metastasis may benefit from 5 fluorouracil-based adjuvant chemotherapy and palliative care.

Differential Diagnosis

An appendiceal mass may be mistaken for any one of the following conditions. They include acute appendicitis, cystic lymphangioma, mesenteric cyst, retroperitoneal cyst, ovarian cyst, ovarian cancer, and Meckel diverticulum.[27]

Prognosis

Prognosis is dependent on the histologic type, advanced stage, and grade, spread of mucin beyond the RLQ as well as the presence of cellular mucin.[12] Five-year survival rates range from 27% to 93%. Signet ring cell tumors have the worst prognosis (27%) while neuroendocrine the most favorable (93%).[8] The 10-year survival rate for mucinous adenocarcinoma is less than 10%.[28]

Complications

Pseudomyxoma peritonei (PMP) represents the growth of neoplastic mucinous producing cells in the peritoneal cavity with a resulting mucinous ascites. PMP may be the presenting stage for a majority of patients and is classified based on the grade as disseminated peritoneal adenomucinosis (DPAM) associated with LAMN and has fewer mitotic figures and simple epithelial cells and high-grade peritoneal mucinous adenocarcinomatosis (PMAC) usually associated with mucinous adenocarcinoma.[10][29][7].

Adhesions and intestinal obstruction may usually occur in the setting of metastatic disease.[21] Metastasis to ovaries and retroperitoneal as well as hydroureteronephrosis, a rare complication may occur.[30][31]

Deterrence and Patient Education

Appendiceal tumors usually present clinically with features of acute appendicitis and are often diagnosed following histologic examination of appendectomy specimen. It is important to follow up on the histological examination of appendectomy specimens to ensure tumors of the appendix are not missed.

Enhancing Healthcare Team Outcomes

Although appendiceal neoplasms are rare, over 50% of cases are asymptomatic, and a third of cases are metastatic at the time of diagnosis leading to poorer outcomes. It is therefore essential that an interprofessional team comprising the surgeons, physician assistants, nurse practitioners, and radiologists have a very high index of suspicion and communicate effectively especially in the presence of risk factors like chronic appendicitis in older patients, colonic neoplasia and chronic ulcerative colitis to ensure reduced morbidity and mortality. In addition to these, the services of the palliative care team, social workers, and case managers would be important to contribute to the care of these patients.


References

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