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. 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.
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.
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. Neuroendocrine tumors account for the most common malignancy of the appendix. 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. An increased association with colonic neoplasia and chronic ulcerative colitis has been noted. 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.
Obstruction of the appendiceal lumen by the malignant cells leads to inflammation of the appendix, venous stasis, and, ultimately, infection of the appendix. In mucinous tumors of the appendix, there may be a cystic dilation of the appendix due to obstruction of the appendiceal lumen by mucoceles. These processes are the basis for the commonest clinical presentation of this disease, acute appendicitis.
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%.
The mucinous group of neoplasms is a heterogeneous group ranging from simple adenomas to adenocarcinomas and complex pseudomyxoma peritonei. 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. 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.
Neuroendocrine tumors are often found at the tip of the appendix, are well-differentiated, and relatively indolent in their course. 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. 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.
In over 50% of cases, the are no symptoms, and this malignancy is detected incidentally. However, most symptomatic patients would present as acute appendicitis. 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. 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. Physical examination may reveal right lower quadrant abdominal tenderness with guarding, abdominal mass, presence of ascites, and features of metastatic disease.
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. A defect in the appendiceal wall with leakage may be indicative of a ruptured mucinous neoplasm. 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. 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. A percutaneous needle biopsy may be essential in confirming disseminated mucinous metastatic spread to the peritoneum. 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. 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. Histologic evaluation of the appendiceal specimen is required for a definitive diagnosis.
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. 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. 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. 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.
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.
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. Five-year survival rates range from 27% to 93%. Signet ring cell tumors have the worst prognosis (27%) while neuroendocrine the most favorable (93%). The 10-year survival rate for mucinous adenocarcinoma is less than 10%.
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..
Adhesions and intestinal obstruction may usually occur in the setting of metastatic disease. Metastasis to ovaries and retroperitoneal as well as hydroureteronephrosis, a rare complication may occur.
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.
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.
|||Pickhardt PJ,Levy AD,Rohrmann CA Jr,Kende AI, Primary neoplasms of the appendix: radiologic spectrum of disease with pathologic correlation. Radiographics : a review publication of the Radiological Society of North America, Inc. 2003 May-Jun; [PubMed PMID: 12740466]|
|||Shaib WL,Assi R,Shamseddine A,Alese OB,Staley C 3rd,Memis B,Adsay V,Bekaii-Saab T,El-Rayes BF, Appendiceal Mucinous Neoplasms: Diagnosis and Management. The oncologist. 2017 Sep; [PubMed PMID: 28663356]|
|||Perucho M, Microsatellite instability: the mutator that mutates the other mutator. Nature medicine. 1996 Jun; [PubMed PMID: 8640546]|
|||Marra G,Boland CR, Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. Journal of the National Cancer Institute. 1995 Aug 2; [PubMed PMID: 7674315]|
|||Chung DC, The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology. 2000 Sep; [PubMed PMID: 10982779]|
|||van den Heuvel MG,Lemmens VE,Verhoeven RH,de Hingh IH, The incidence of mucinous appendiceal malignancies: a population-based study. International journal of colorectal disease. 2013 Sep; [PubMed PMID: 23695388]|
|||Hatch QM,Gilbert EW, Appendiceal Neoplasms. Clinics in colon and rectal surgery. 2018 Sep; [PubMed PMID: 30186049]|
|||McCusker ME,Coté TR,Clegg LX,Sobin LH, Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998. Cancer. 2002 Jun 15; [PubMed PMID: 12115365]|
|||Smeenk RM,van Velthuysen ML,Verwaal VJ,Zoetmulder FA, Appendiceal neoplasms and pseudomyxoma peritonei: a population based study. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2008 Feb; [PubMed PMID: 17524597]|
|||Shaib WL,Goodman M,Chen Z,Kim S,Brutcher E,Bekaii-Saab T,El-Rayes BF, Incidence and Survival of Appendiceal Mucinous Neoplasms: A SEER Analysis. American journal of clinical oncology. 2017 Dec; [PubMed PMID: 26270447]|
|||Marmor S,Portschy PR,Tuttle TM,Virnig BA, The rise in appendiceal cancer incidence: 2000-2009. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2015 Apr; [PubMed PMID: 25560182]|
|||Tirumani SH,Fraser-Hill M,Auer R,Shabana W,Walsh C,Lee F,Ryan JG, Mucinous neoplasms of the appendix: a current comprehensive clinicopathologic and imaging review. Cancer imaging : the official publication of the International Cancer Imaging Society. 2013 Feb 22; [PubMed PMID: 23439060]|
|||Bradley RF,Stewart JH 4th,Russell GB,Levine EA,Geisinger KR, Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review. The American journal of surgical pathology. 2006 May; [PubMed PMID: 16699309]|
|||Carr NJ,McCarthy WF,Sobin LH, Epithelial noncarcinoid tumors and tumor-like lesions of the appendix. A clinicopathologic study of 184 patients with a multivariate analysis of prognostic factors. Cancer. 1995 Feb 1; [PubMed PMID: 7828125]|
|||McGory ML,Maggard MA,Kang H,O'Connell JB,Ko CY, Malignancies of the appendix: beyond case series reports. Diseases of the colon and rectum. 2005 Dec; [PubMed PMID: 16258711]|
|||Ruoff C,Hanna L,Zhi W,Shahzad G,Gotlieb V,Saif MW, Cancers of the appendix: review of the literatures. ISRN oncology. 2011; [PubMed PMID: 22084738]|
|||Modlin IM,Kidd M,Latich I,Zikusoka MN,Eick GN,Mane SM,Camp RL, Genetic differentiation of appendiceal tumor malignancy: a guide for the perplexed. Annals of surgery. 2006 Jul; [PubMed PMID: 16794389]|
|||Stewart RJ,Mirakhur M, Primary malignant lymphoma of the appendix. The Ulster medical journal. 1986 Oct; [PubMed PMID: 3811021]|
|||Dixit A,Robertson JH,Mudan SS,Akle C, Appendiceal mucocoeles and pseudomyxoma peritonei. World journal of gastroenterology. 2007 Apr 28; [PubMed PMID: 17511043]|
|||Persaud T,Swan N,Torreggiani WC, Giant mucinous cystadenoma of the appendix. Radiographics : a review publication of the Radiological Society of North America, Inc. 2007 Mar-Apr; [PubMed PMID: 17374868]|
|||Madwed D,Mindelzun R,Jeffrey RB Jr, Mucocele of the appendix: imaging findings. AJR. American journal of roentgenology. 1992 Jul; [PubMed PMID: 1609724]|
|||Que Y,Wang X,Liu Y,Li P,Ou G,Zhao W, Ultrasound-guided biopsy of greater omentum: an effective method to trace the origin of unclear ascites. European journal of radiology. 2009 May; [PubMed PMID: 18328658]|
|||Carmignani CP,Hampton R,Sugarbaker CE,Chang D,Sugarbaker PH, Utility of CEA and CA 19-9 tumor markers in diagnosis and prognostic assessment of mucinous epithelial cancers of the appendix. Journal of surgical oncology. 2004 Sep 15; [PubMed PMID: 15334630]|
|||González Moreno S,Shmookler BM,Sugarbaker PH, Appendiceal mucocele. Contraindication to laparoscopic appendectomy. Surgical endoscopy. 1998 Sep; [PubMed PMID: 9716778]|
|||Miraliakbari R,Chapman WH 3rd, Laparoscopic treatment of an appendiceal mucocele. Journal of laparoendoscopic [PubMed PMID: 10235354]|
|||Panarelli NC,Yantiss RK, Mucinous neoplasms of the appendix and peritoneum. Archives of pathology [PubMed PMID: 21970481]|
|||Hoeffel C,Crema MD,Belkacem A,Azizi L,Lewin M,Arrivé L,Tubiana JM, Multi-detector row CT: spectrum of diseases involving the ileocecal area. Radiographics : a review publication of the Radiological Society of North America, Inc. 2006 Sep-Oct; [PubMed PMID: 16973770]|
|||Pai RK,Beck AH,Norton JA,Longacre TA, Appendiceal mucinous neoplasms: clinicopathologic study of 116 cases with analysis of factors predicting recurrence. The American journal of surgical pathology. 2009 Oct; [PubMed PMID: 19641451]|
|||Karande GY,Chua WM,Yiin RSZ,Wong KM,Hedgire S,Tan TJ, Spectrum of computed tomography manifestations of appendiceal neoplasms: acute appendicitis and beyond. Singapore medical journal. 2019 Apr; [PubMed PMID: 31069398]|
|||Leonards LM,Pahwa A,Patel MK,Petersen J,Nguyen MJ,Jude CM, Neoplasms of the Appendix: Pictorial Review with Clinical and Pathologic Correlation. Radiographics : a review publication of the Radiological Society of North America, Inc. 2017 Jul-Aug; [PubMed PMID: 28598731]|
|||Ahmed K,Hoque R,El-Tawil S,Khan MS,George ML, Adenocarcinoma of the appendix presenting as bilateral ureteric obstruction. World journal of surgical oncology. 2008 Feb 21; [PubMed PMID: 18291037]|