Appendix cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Appendix cancer was first described in the published literature by Sir George Thos. Beatson, an English surgeon, in 1913. Development of surgical sciences revolutionized cancer care, appendix cancer was not an exception. Introduction of chemotherapy agents such as 5-fluorouracil (5-FU), irinotecan, oxaliplatin, vascular endothelial growth factor receptor inhibitors (bevacizumab), epidermal growth factor receptor inhibitors (cetuximab and panitumumab), aflibercept, regorafenib, inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1, 2,and 3), capecitabine as well as introduction of intraperitoneal chemotherapy including hyperthermic intraperitoneal chemotherapyadvanced appendix cancer treatment. Development of new Imaging modalities such as CT scan, MRI as well as specific imaging modalities such as somatostatin scintigraphy also transfigured approaching to the patients with appendix cancer. Genetic studies introduced novel horizons in approaching patients with appendix cancer.

There are two major subtypes of appendix cancer, adenocarcinomas and carcinoid tumors. While carcinoid tumors arises from enterochromaffin cells (Kulchitsky cells), which are secretory cells that are normally involved in neuroendocrine hormonal secretions, adenocarcinomas are the result of mutations in mucus producing epithelial cells. Their physiology, pathophysiology, genetic pathways, prognosis as well as epidemiology are different and hence, discussed separately. The progression to adenocarcinoma usually involves the KRAS, APC, TP53, and RAF pathways, While β-catenin, NF1, and MEN1 genes are major contributors of carcinoid tumors progression. Prevalence, risk factors, age distribution as well as prognosis are different in the two major types of appendiceal cancers, adenocarcinoma and carcinoid tumors. The estimated prevalence of appendix cancer is approximately 0.12 cases per 100,000 individuals in the United States.The incidence of appendix cancer increases with age; meanwhile, patients with carcinoid tumors are generally younger than their adenocarcinoma counterparts. The median age at diagnosis is 65 years for adenocarcinoma, compared to t 32-43 years (range, 6 to 80 years) for carcinoid tumors. Common risk factors in the development of appendix cancer are a combination of environmental and genetic factors. Common risk factors in the development of appendix cancer include age, sex, smoking, familial cancer disorders such as MEN1 Syndrome and HNPCC, as well as long standing chronic inflammatory disorders such as ulcerative colitis and Crohn’s disease.

Because of the location and size of appendix, most of the patients with appendix cancer may be initially asymptomatic. Early clinical features might include periodical unspecific abdominal pain, bloating, and nausea. Most of appendix cancer cases are discovered after surgical or histological evaluation of a patient with acute appendicitis, or are an accidental finding in imaging studies for the other reasons. If left untreated, the majority of patients with appendix cancer may progress to develop peritoneal carcinomatosis and metastasis. Prognosis is generally excellent and good in carcinoid tumors and adenocarcinoma respectively. Prognostic factors including tumor stage, tumor size, histologic as well genetic characteristics of appendiceal tumors were discussed in details. Either CT-scan or MRI are diagnostic study of choice for appendix cancer. Both MRI (particularly diffusion weighted MRI) and CT scan has been recommended as method of choice for disease staging. Histopathology is the gold standard test for the diagnosis as well as classification of appendix cancers. Patients with appendix cancer usually appear normal, might present with acute appendicitis or carcinoid syndrome. Laboratory findings consistent with the diagnosis of carcinoid tumors include , Chromogranin A (CgA), 5-HIAA (5-hydroxyindoleacetic acid) as well as Ki67. Some patients with colonic type adenocarcinoma may have elevated concentration of CEA and CA 19-9.

Abdominal CT scan is pretty helpful in the diagnosis and management of appendix cancer. Findings on CT scan suggestive of appendix cancer include soft tissue thickening, wall irregularity, calcification, internal septations, preappendiceal fat stranding as well as intraperitoneal free fluid. CT scan is also one of the best imaging modalities to assess disease burden, metastatic lesions as well as disease stage. Diffusion weighted MRI has been shown to be the modality of choice for peritoneal carcinomatosis evaluation. Positron emission tomography (PET) and scintigraphy are among other imaging modalities that may be helpful in the diagnosis and management of appendix cancer. Appendix cancer may also be diagnosed using scintigraphy, capsule endoscopy, enteroscopy, positron emission tomography (PET). Chromogranin A (CgA) and 5-HIAA (5-hydroxyindoleacetic acid) are among biochemical markers that might represent level of malignant cells activity in carcinoid syndrome.

Medical therapy in appendix cancer could be either supportive, palliative, or curative. While carcinoid tumors rarely need chemotherapy, systemic chemotherapy as well as hyperthermic intraperitoneal chemotherapy plus/minus early postoperative intraperitoneal chemotherapy (EPIC) and/or concomitant intravenous chemotherapy are mainstream of medical treatment in adenocarcinoma of appendix. Medical therapy is generally administered to control the symptoms in patients with carcinoid tumors and carcinoid syndrome.

Surgery is the mainstay of treatment for appendix cancer. The feasibility as well as determining the appropriate plan of surgery depends on the stage of appendix cancer at diagnosis. Tumor size plays the crucial role in determining the need for further surgery. Consensus based effective measures for the secondary prevention of appendix cancer include follow up history and physical examination, tumor marker measurements like CEA, CA-125, CA 19-9, follow up imaging studies, carcinoid tumor markers such serotonin, and specific imaging studies such as octreotide scintigraphy.

Appendix cancer was first described in the published literature by Sir George Thos. Beatson, an English surgeon, in 1913. Development of surgical sciences revolutionized cancer care, appendix cancer was not an exception. Introduction of chemotherapy agents such as 5-fluorouracil (5-FU), irinotecan, oxaliplatin, vascular endothelial growth factor receptor inhibitors (bevacizumab), epidermal growth factor receptor inhibitors(cetuximab and panitumumab), aflibercept, regorafenib, inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1, 2,and 3), capecitabine as well as introduction of intraperitoneal chemotherapyincluding hyperthermic intraperitoneal chemotherapyadvanced appendix cancer treatment. Development of new Imagingmodalities such as CT scan, MRI as well as specific imaging modalities such as somatostatinscintigraphy also transfigured approaching to the patients with appendix cancer. Genetic studies introduced novel horizons in approaching patients with appendix cancer.

Appendix cancer is classified according to the histological findings. According to WHO classification, there are four major groups of appendix cancer including epithelial tumors, non-epithelial tumors, secondary tumors, and hyperplastic (metaplastic) polyps. Carcinoid (well differentiated endocrine neoplasm), and adenocarcinoma are two major subtypes of epithelial tumors, making the majority of appendix cancer cases.

The pathophysiology of appendix cancer depends on the histological subtype. There are two major subtypes of appendix cancer, adenocarcinomas and carcinoid tumors. While carcinoid tumors arises from enterochromaffin cells (Kulchitsky cells), which are secretory cells that are normally involved in neuroendocrine hormonal secretions, adenocarcinomas are the result of mutations in mucus producing epithelial cells. Their physiology, pathophysiology, genetic pathways, prognosis as well as epidemiology are different and hence, discussed separately. The progression to adenocarcinoma usually involves the KRAS, APC, TP53,and RAF pathways, while β-catenin, NF1, and MEN1 genes are major contributors of carcinoid tumors progression.

Appendix cancer is a quite rare disorder. To study causality, cohort studies are needed. Because of very low incidence of appendiceal cancers, no cohort study was conducted to study casualty, and hence, there are no established cause for appendix cancer. To review risk factors for the development of appendiceal cancers, please click here.

Appendix cancer must be differentiated from benign appendix lesions (mucocele, acute appendicitis), colorectal cancers, adenexal masses (ovarian tumors), and carcinoid tumors of the other organs.

Epidemiology of appendix cancer should be discussed with respect to the major histological characteristics of the tumors. Prevalence, risk factors, age distribution as well as prognosis are different in the two major types of appendiceal cancers, adenocarcinoma and carcinoid tumors. The incidence of carcinoid tumor of appendix is approximately 0.075 per 100,000 individuals worldwide. The incidence of adenocarcinoma of the appendix is approximately 0.2 per 100,000 individuals worldwide. Appendiceal neoplasms account for approximately 0.4% of gastrointestinal tumors. The estimated prevalence of appendix cancer is approximately 0.12 cases per 100,000 individuals in the United States.The incidence of appendix cancer increases with age; meanwhile, patients with carcinoid tumors are generally younger than their adenocarcinoma counterparts. The median age at diagnosis is 65 years for adenocarcinoma, compared to 32-43 years (range, 6 to 80 years) for carcinoid tumors. There is no racial predilection to appendiceal cancers. Meanwhile, carcinoid tumors are slightly more prevalent among Caucasians and African-Americans. Generally appendiceal cancers affects men and women equally. While in adenocarcinoma, there is a male dominant pattern of prevalence, females are more commonly affected by appendiceal carcinoids than men.

Common risk factors in the development of appendix cancer are a combination of environmental and genetic factors. Common risk factors in the development of appendix cancer include age, sex, smoking, familial cancer disorders such as MEN1 Syndrome and HNPCC, as well as long standing chronic inflammatory disorders such as ulcerative colitis and Crohn’s disease.

There are insufficient evidences to recommend routine screening for appendiceal cancers. Meanwhile, patients with certain conditions like familial cancer syndromes as well as patients with long standing chronic inflammatory disease such as ulcerative colitis might drive a benefit from appropriate GI screenings according to the specific guidelines for their specific conditions.

Because of the location and size of appendix, most of the patients with appendix cancer may be initially asymptomatic. Early clinical features might include periodical unspecific abdominal pain, bloating, and nausea. Most of appendix cancer cases are discovered after surgical or histological evaluation of a patient with acute appendicitis, or are an accidental finding in imaging studies for the other reasons. Around one percent of all appendectomy specimens are malignant. Appendix cancer account for 0.5 percent of all intestinal neoplasms. If left untreated, the majority of patients with appendix cancer may progress to develop peritoneal carcinomatosis and metastasis. Prognosis is generally excellent and good in carcinoid tumors and adenocarcinoma respectively. Prognostic factors including tumor stage, tumor size, histologic as well geneticcharacteristics of appendiceal tumors were discussed in details.

Either CT-scan or MRI are diagnostic study of choice for appendix cancer. Both MRI (particularly diffusion weighted MRI) and CT scan has been recommended as method of choice for disease staging. Histopathology is the gold standard test for the diagnosis as well as classification of appendix cancers.

The majority of patients with appendix cancer are asymptomatic. Patients may complain of vague abdominal pain or discomfort and/or girdle size changes. However, most of them are presenting with acute appendicitis due to obstruction of the appendix by tumor, or present with malignancy complications like pseudomyxoma peritonei; the rest of diagnosed cases are result of serendipitous finding in imaging studies or discovered during laparotomy or laparoscopy because of cancer complications. The patients complains and presentation is influenced by the tumor histology and stage and ranges from a small asymptomaticadenocarcinoma to a metastatic carcinoid tumor with liver metastasis and carcinoid syndrome signs, symptoms and complications.

Patients with appendix cancer usually appear normal, pale or diaphoretic. If the patient with appendix cancer present with acute appendicitis which is quite common, abdominal tenderness, rebound tenderness, abdominal guarding, Rovsing’s sign, as well as Psoas sign might be present. Around 5% of the patients with appendiceal carcinoid tumors might develop carcinoid syndrome. Common physical examination findings of carcinoid syndrome include dehydration due to diarrhea, tachycardia as well as facial flushing, right heart murmurs like TR murmur is quit common. In patients with carcinoid syndrome, the presence of dermatitis, diarrhea, and dementia on physical examination is highly suggestive of Pellagra disease.

There are no diagnostic laboratory findings associated with appendix cancer in general. Laboratory findings consistent with the diagnosis of carcinoid tumors include , Chromogranin A (CgA), 5-HIAA (5-hydroxyindoleacetic acid) as well as Ki67. Some patients with colonic type adenocarcinoma may have elevated concentration of CEA and CA 19-9.

There are no specific ECG findings associated with appendix cancer; meanwhile, if a patient develop carcinoid syndrome, high frequency of low-voltage QRS complexes might be present.

There are no x-ray findings associated with appendix cancer. However, an x-ray may be helpful in the diagnosis of complications of acute appendicitis as one of the most prevalentpresentations of appendix cancer, which include appendix perforation and pneumoperitoneum. Appendix mucocele might present with calcification in plain abdominal X-rays. Metastaticbone lesions of both adenocarcinoma and carcinoid tumors of appendix are extremely rare but might present with osteolitic (adenocarcinom) and a mixture of osteosclerotic and osteolyticchanges (carcinoid tumors).

Ultrasound may be helpful in the diagnosis of appendix tumors, appendix mucocele, and appendicitis as the most prevalent complication of appendiceal cancers. There are no echocardiography findings associated with appendix cancer. However, an echocardiography may be helpful in the diagnosis of complications of carcinoid tumor. If a patient develop carcinoid syndrome, transthoracic echocardiography is the method of choice in the diagnosis and follow-up of carcinoid heart disease.

Abdominal CT scan is helpful in the diagnosis and management of appendix cancer. Findings on CT scan suggestive of appendix cancer include soft tissue thickening, wall irregularity, calcification, internal septations, preappendiceal fat stranding as well as intraperitoneal free fluid. CT scan is also one of the best imaging modalities to assess disease burden, metastatic lesions as well as disease stage.

Abdominal MRI may be helpful in the diagnosis of appendiceal cancer. Diffusion weighted MRI has been shown to be the modality of choice for peritoneal carcinomatosis evaluation.

Positron emission tomography (PET) and scintigraphy are among other imaging modalities that may be helpful in the diagnosis and management of appendix cancer.

Appendix cancer may also be diagnosed using scintigraphy, capsule endoscopy, and enteroscopy. Chromogranin A (CgA) and 5-HIAA (5-hydroxyindoleacetic acid) are among biochemical markers that might represent level of malignant cells activity in carcinoid syndrome.

Medical therapy in appendix cancer could be either supportive, palliative, or curative. While carcinoid tumors rarely need chemotherapy, systemic chemotherapy as well as hyperthermic intraperitoneal chemotherapyplus/minus early postoperative intraperitoneal chemotherapy (EPIC) and/or concomitant intravenous chemotherapy are mainstream of medical treatment in adenocarcinoma of appendix. Medical therapy is generally administered to control the symptoms in patients with carcinoid tumors and carcinoid syndrome.

Surgery is the mainstay of treatment for appendix cancer. The feasibility as well as determining the appropriate plan of surgery depends on the stage of appendix cancer at diagnosis. Tumor size plays the crucial role in determining the need for further surgery.

There are no established measures for the primary prevention of appendix cancer. Meanwhile selected high risk patients (for example patients with long standing ulcerative colitis, HNPCC, or patients with MEN1) might benefit from endoscopic as well as imaging workups, nevertheless no guideline is available.

There are neither evidence based guidelines nor RCTs for follow up of appendix carcinoid tumors. Meanwhile, consensus based effective measures for the secondary prevention of appendix cancer include follow up history and physical examination, tumor marker measurements like CEA, CA-125, CA 19-9, follow up imaging studies, carcinoid tumor markers such serotonin, and specific imaging studies such as octreotidescintigraphy.

Genetic studies revolutionized cancer treatment; appendix cancer is not an exception. Traditionally appendiceal cancers were approached the same as colorectal cancers. Recent genetic studies demonstrated that appendiceal tumors are clearly differ from colorectal cancers. Furthermore, It has been shown that mutation profiles are associated with the patients’ prognosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Appendix cancer was first described in the published literature by Sir George Thos. Beatson, an English surgeon, in 1913. Development of surgical sciences revolutionized cancer care, appendix cancer was not an exception. Introduction of chemotherapy agents such as 5-fluorouracil (5-FU), irinotecan, oxaliplatin, vascular endothelial growth factor receptor inhibitors (bevacizumab), epidermal growth factor receptor inhibitors (cetuximab and panitumumab), aflibercept, regorafenib, inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1, 2,and 3), capecitabine as well as introduction of intraperitoneal chemotherapy including hyperthermic intraperitoneal chemotherapyadvanced appendix cancer treatment. Development of new Imagingmodalities such as CT scan, MRI as well as specific imaging modalities such as somatostatin scintigraphy also transfigured approaching to the patients with appendix cancer. Genetic studies introduced novel horizons in approaching patients with appendix cancer.

• Appendix cancer was first described in the published literature by Sir George Thos. Beatson, an English surgeon, in 1913.^[1]

• Surgical sciences development

• First recorded appendectomy performed on December 6, 1735, at St. George’s Hospital in London.^[2]
• First reported anesthesia (December 1846. Ether anesthesia, Paris, France), although traditionally Persian surgeons such as Razi prescribed wine to sedate their patients before painful procedures.^[3]
• First laparoscopic operation in humans performed by Swedish surgeon, Hans Christian Jacobaeus, on 1910 in Stockholm.^[4]

• Chemotherapy

• Introduction of 5-fluorouracil (5-FU) the first coorectal chemotherapy agent, 1957.^[5]
• Introduction of Octereotide analogs to control symptoms of carcinoid syndrome.^[6]
• Intraperitoneal chemotherapy including hyperthermic intraperitoneal chemotherapy plus/minus early postoperative intraperitoneal chemotherapy (EPIC) by Spratt et al. in the 1980s.^[7]
• Development of new chemotherapy agents (1990s) such as:

• Irinotecan (approved for medical use in the United States in 1996)^[8]
• Oxaliplatin (approved for medical use in the United States in 2002)^[9]
• Vascular endothelial growth factor receptor inhibitors (bevacizumab)
• Epidermal growth factor receptor inhibitors (cetuximab and panitumumab)
• Aflibercept
• Regorafenib: inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1,2, and 3)
• Capecitabine or 5-FU with or without a platinum drug

• Development of new Imaging modalities

• CT scan, MRI as well as specific imaging modalities such as somatostatin scintigraphy revolutionized approaching to the patients with appendix cancer.

The following are a few famous cases of appendix cancer:

• Celebrated actress, Audrey Hepburn was the most famous victims of appendix cancer, she passed away in 1993.^[10]

• Stuart Scott, ESPN sportscast anchor was diagnosed with appendix cancer in 2007 and died 8 years later in 2015.^[11][12]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Appendix cancer is classified according to the histological findings. According to WHO classification, there are four major groups of appendix cancer including epithelial tumors, non-epithelial tumors, secondary tumors, and hyperplastic (metaplastic) polyps. Carcinoid (well differentiated endocrine neoplasm), and adenocarcinoma are two major subtypes of epithelial tumors, making the majority of appendix cancer cases.

• Appendix cancer may be classified according to WHO classification into 4 groups:^[1]

• Epithelial tumors
• Non-epithelial tumors
• Secondary tumors
• Hyperplastic (metaplastic) polyps.

• The table below summarizes the different types of appendix cancer according to the WHO classification.

WHO histological classification Tumors of the appendix (Adapted from WHO/IARC)[1]
Epithelial tumors	Non-epithelial tumors	Secondary tumors	Hyperplastic polyp
Adenoma Tubular Villous Tubulovillous Serrated Carcinoma Adenocarcinoma Mucinous adenocarcinoma Signet-ring cell carcinoma Small cell carcinoma Undifferentiated carcinoma Carcinoid (well differentiated endocrine neoplasm) EC-cell, serotonin-producing neoplasm L-cell, glucagon-like peptide and PP/PYY producing tumour others Tubular carcinoid Goblet cell carcinoid (mucinous carcinoid) Mixed carcinoid-adenocarcinoma Others	Neuroma Lipoma Leiomyoma Gastrointestinal stromal tumor Leiomyosarcoma Kaposi sarcoma Others Malignant lymphoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

The pathophysiology of appendix cancer depends on the histological subtype. There are two major subtypes of appendix cancer, adenocarcinomas and carcinoid tumors. While carcinoid tumors arises from enterochromaffin cells (Kulchitsky cells), which are secretory cells that are normally involved in neuroendocrine hormonal secretions, adenocarcinomas are the result of mutations in mucus producing epithelial cells. Their physiology, pathophysiology, genetic pathways, prognosis as well as epidemiology are different and hence, discussed separately. The progression to adenocarcinoma usually involves the KRAS, APC, TP53, and RAF pathways, while β-catenin, NF1, and MEN1 genes are major contributors of carcinoid tumors progression.

• The normal physiology of enterochromaffin cells is secretion of serotonin (5-HT), histamine, kallikrein, prostaglandins, and tachykinins.^[1]

• Glandular epithelial cells are responsible for mucus production.

• The pathophysiology of appendix cancer depends on the histological subtype.^[2]
• Adenocarcinoma arises from epithelial glandular cells, which are normally involved in mucous production.
• Carcinoid tumors arise from enterochromaffin cell, which are neuroendocrine cells that are normally involved in secretion of serotonin (5-HT), histamine, kallikrein, prostaglandins, and tachykinins.^[1]
• The pathogenesis of appendix cancer is characterized by an initial epithelial dysplasia, followed by the formation of cystic structures and angiolymphatic invasion. Subsequently, in the advanced stages of appendix cancer, tumor cells detach from the primary tumor mass and gain access to the peritoneal cavity.^[3]

Genes involved in the pathogenesis of carcinoid tumors of appendix include:^[4][5]

• β-catenin,
• NF1,
• MEN1

The development of appendiceal adenocarcinoma is the result of multiple genetic mutations such as:^[5]

• KRAS
• APC
• TP53
• RAF

• Conditions associated with appendiceal cancers include:

• Chronic inflammatory disease such as ulcerative colitis
• Familial cancer syndromes:^[5]

• MEN1 Syndrome
• Neurofibromatosis type 1
• Hereditary Non-polyposis Colorectal Cancer (HNPCC)
• Von Hippel-Lindau disease (VHL)
• Li-Fraumeni Syndrome

• On gross pathology, findings of appendix cancer, include:^[3]

• Well-demarcated mass
• Average size between 1 and 5 cm
• Gray or yellowish color
• Deformed appendix

• Adenocarcinoma

• Gray/yellow color
• Cystic structures with angiolymphatic invasion
• Appendix might be buried within the mass

• Carcinoid tumors

• Prevalent at the tip of appendix
• Generally less than 1 cm
• Gray or yellow
• Well-demarcated firm
• Intramural nodules that may narrow or obliterate appendiceal lumen
• Proximal tumors may cause obstruction and appendicitis

• Goblet cell carcinoids

• No gross tumor might be present
• Thickened appendiceal wall

The images below demonstrate different histopathological findings of appendix cancer

• On microscopic histopathological analysis findings will depend on the subtype of appendicular cancer.
• Common histopathological findings, may include:^[3]

• Cystic structures
• Angiolymphatic invasion

• Adenocarcinoma

• Intestinal, mucinous or signet ring cell types
• Coexisting acute appendicitis is common
• immunohistochemistry (IHC) might be positive for the following stains:^[6]
• MUC 2
• MUC5AC
• CK 8/18
• CK 13
• CK 19
• CK 20

• Carcinoid tumor

• Insular growth pattern of solid islands of uniform polygonal cells with minimal pleomorphism
• Retraction of peripheral tumor cells from stroma
• Angiolymphatic invasion is common
• Granular eosinophilic cytoplasm with either diffusely scattered or peripherally clumped granules
• Two types of well differentiated tumors: EC cell (serotonin producing) and rarely L-cell (enteroglucagon or peptide YY producing)^[7]
• IHC might be positive for S100

• Goblet cell

• GCC generally spares mucosa and infiltrates muscularis propria and periappendiceal fat
• Tumor cell clusters
• Crypt-like structures
• Tubules of mucus-secreting cells distended with mucin resembling goblet cells
• Eosinophilic cytoplasm resembling carcinoid tumors
• Pools of extracellular mucin
• Scattered Paneth cells in tumors with crypt like structures
• Extensive perineural invasion
• Carcinomatous growth pattern:
  • Cribriform growth pattern, solid sheets of infiltrating signet ring cells
  • Nuclear pleomorphism
  • Increased mitotic activity
• IHC might be positive for the followings:
  • Mucin (mucicarmine, PAS, PAS diastase, Alcian blue)
  • CEA
  • Cytokeratin (especially CK20)
  • lysozyme
  • Chromogranin A
  • Serotonin
  • Synaptophysin

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Appendix cancer is a quite rare disorder. To study causality, cohort studies are needed. Because of very low incidence of appendiceal cancers, no cohort study was conducted to study casualty, and hence, there are no established cause for appendix cancer. To review risk factors for the development of appendiceal cancers, please click here.

• Appendix cancer is a quite rare disorder. ^[1]
• To study causality, cohort studies are needed.
• Because of very low incidence of appendiceal cancers, no cohort study was conducted to study casualty, and hence, there are no established cause for appendix cancer.
• To review risk factors for the development of appendiceal cancers, please click here.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Appendix cancer must be differentiated from benign appendix lesions (mucocele, acute appendicitis), colorectal cancers, adenexal masses (ovarian tumors), and carcinoid tumors of the other organs.

• Appendix cancer must be differentiated from benign appendix lesions (mucocele, acute appendicitis), colorectal cancers, adenexal masses (ovarian tumors), and carcinoid tumors of the other organs.
• As appendix cancer manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype.

• Carcinoid tumors must be differentiated from other diseases that cause carcinoid syndrome sign and symptoms such as palpitation, facial flushing, and diarrhea.
• In contrast, adenocarcinomas and cystadenocarcinomas must be differentiated from other diseases that cause acute appendicitis or present with pseudomyxoma peritonei, such as colorectal cancers and appendix mucoceles.

Diseases		Clinical manifestations							Para-clinical findings
		Symptoms				Physical examination
									Lab Findings		Imaging				Histo- pathology
		Abdo- minal pain	Change in girdle size	Bowel freq- uency	Other symptoms	Abdo- minal mass	Abdo- minal tender- ness	Other physical exami- nation findings	5-HIAA and/or CgA	Other lab findings	CT scan	MRI	Utra- sounography	Other diagnostic studies and imaging modalities
Appendix cancer	Adeno- carcinoma1	+/-	-/+	<math>\downarrow</math>	Generally asympto- matic Appendicitis symptoms Nausea & vomiting, decreased appetite No gas or stool pass (intestinal obstruction) Bone pain (bone metastasis) Bloating (ascites)	–	–	Ascites Shifting dullness	–	CEA CA 19-9	Soft tissue thickening Wall irregularity Presence of pseudo- myxoma peritonei Calcification Internal septations Peri appendiceal fat stranding and intra- peritoneal free fluid which is a nonspecific finding Cystic lesion	Diffusion weighted MRI has been shown to be the modality of choice for peritoneal carcino- matosis Increased fluid signal on T2 weighted sequence Soft tissue mass in the appendix Invasion to the other structures	Dilated appendix Peri- appendiceal fluid collection Distinct appendix wall layers	Positron emission tomography (PET)	Gross pathology: Gray/yellow color Cystic structures with angiolymphatic invasion Appendix might be buried within the mass Microscopic pathology: Intestinal, mucinous or signet ring cell types Coexisting acute appendicitis is common IHC: MUC 2 MUC5AC CK 8/18 CK 13 CK 19 CK 20
	Carcinoid tumor2	+/-	–	<math>\uparrow</math>	Generally asympto- matic Flushing Palpitation Dyspnea	–	–	TR murmur Wheezing	+	Ki67: a reliable marker of cell proliferation				Somatostatin scintigraphy with 111-indium- octreotide Bone scintigraphy with 99mTc- methylene diphosphonate (99mTcMDP) Positron emission tomography (PET)	Gross pathology: Prevalent at the tip of appendix Generally less than 1 cm Gray or yellow Well- demarcated firm Intramural nodules that may narrow or obliterate appendiceal lumen Proximal tumors may cause obstruction and appendicitis Microscopic pathology: Insular growth pattern of solid islands of uniform polygonal cells with minimal pleomorphism Retraction of peripheral tumor cells from stroma Angio- lymphatic invasion is common Granular eosinophilic cytoplasm with either diffusely scattered or peripherally clumped granules Two types of well differentiated tumors: EC cell (serotonin producing) and rarely L-cell (enteroglucagon or peptide YY producing) IHC: Might be positive for S100
	Goblet cell carcinoid	+	+/-	<math>\uparrow</math>	Generally asympto- matic 60% present with acute appendicitis symptoms Nausea & vomiting decreased appetite (anorexia)	+/-	+	Ascites Shifting dullness May appear anemic	+/-	CK 20 CK 7 Synap- thosin pancreatic polypeptide CEA CA 19-9 CA -125	Unfortunately, compared to the other carcinoid tumors of appendix, GCC is more aggressive and patients with GCC generally present at higher stages. Hence, in addition to the above mentioned general findings for appendix cancers, imaging studies should look for evidences of peritoneal involvement, bone metastasis, lymphadenopathy, and metastatic lesions in ovaries and/or prostate.				Gross pathology: No gross tumor might be present Thickened appendiceal wall Microscopic appearance: GCC Generally spares mucosa and infiltrates muscularis propria and peri- appendiceal fat Tumor cell clusters Crypt-like structures Tubules of mucus-secreting cells distended with mucin resembling goblet cells Eosinophilic cytoplasm resembling carcinoid tumors Pools of extracellular mucin Scattered Paneth cells in tumors with crypt like structures Extensive perineural invasion Carcinomatous growth pattern: Cribriform growth pattern, solid sheets of infiltrating signet ring cells Nuclear pleomorphism Increased mitotic activity
Diseases		Abdo- minal pain	Change in girdle size	Bowel freq- uency	Other symptoms	Abdo- minal mass	Abdo- minal tender- ness	Other physical exami- nation findings	5-HIAA and/or CgA	Other lab findings	CT scan	MRI	Utra- sounography	Other diagnostic studies and imaging modalities	Histo- pathology
Appendix Mucocele	Mucosal hyperplasia	–	–	–	Generally asympto- matic Benign even after rupture	–	+/-	N/A	–	N/A	low attenuation well defined mass in RLQ near cecum Inflammation is the key to distinguish between appendicitis and mucocele Wall thickness does not distinguish between malignant and benign mucocele Intramural nodule is a sign of neoplastic lesions. 4	Rounded right iliac fossa mass T1: The signal depends on the mucin concen- tration, may be from hypointense to isointense T2: Hyperintense	Histo- logically benign Dilated fluid filled appendix in the RLQ. Thin appendiceal wall A focus of hyper- echogenicity Since generally there is no inflammation Surrounding fat is normal. No peri- appendiceal fluid or collection	N/A	Similar to hyperplastic colon polyp
	Simple or retention cyst	–	–	–		–	+/-	–	–	N/A					Degenerative epithelial changes because of obstruction
	Mucinous cyst- adenomas	+/-	+/-	<math>\uparrow</math><math>\downarrow</math>	Generally asympto- matic Rupture may lead to Pseudo- myxoma peritonei	+/-	+/-	If develop pseudo- myxoma peritonei: Ascites Shifting dullness	–	CEA CA 19-9					Histo- logically benign Similar to colon adenomatous polyps or villous adnomas
	Mucinous cystadeno- carcinomas	+/-	+/-	<math>\uparrow</math><math>\downarrow</math>	+/-	+/-	–		–	CEA CA 19-9					Glandular invasion into the stoma Pseudo- myxoma peritonei
Diseases		Abdo- minal pain	Change in girdle size	Bowel freq- uency	Other symptoms	Abdo- minal mass	Abdo- minal tender- ness	Other physical exami- nation findings	5-HIAA and/or CgA	Other lab findings	CT scan	MRI	Utra- sounography	Other diagnostic studies and imaging modalities	Histo- pathology
Ovarian cancer		+/-	+/-	+/-<math>\downarrow</math>	Pelvic/ abdominal pain or pressure Vaginal bleeding/ discharge Dyspnea GI disturbance	+	+/-	Ascites Shifting dullness Fever Pleural effusion	–	Depends on the underlying etiology Iron HCG LDH Calcium Estrogen Progestron Testos- terone AFP CA-125 Ki 67	Adnexal mass Adenexal Cyst (simple or complex) Fluid accumulation Endometrial thickening Calcification Pleural effusion Peritoneal involvement Lympha-denopathy	Adnexal mass Adenexal cyst (simple or complex) Except for Thecoma, ovarian masses are generally hyperintense on T1 and hypo or sointense on T2 imaging Fluid accumulation Endometrial thickening Calcification Pleural effusion Peritoneal involvement Lympha- denopathy	Adnexal mass Adenexal cyst (simple or complex) Fluid accumulation Increased Doppler flow Endometrial thickening Calcification	N/A	Depends on the tumor type. You may find the details here.
Colorectal cancer		+/-	+/-	<math>\uparrow</math><math>\downarrow</math>	Weight loss Fatigue Low caliber of stools Nausea and vomiting Mucus in stools Rectal prolapse in Carcinoids: Weight loss Weakness Flushing Wheezing Shortness of breath Palpitations Leg edema	+	+/-	Colonoscopy Adeno- carcinoma Polyps (villous, tubular, tubulo- villous) Ulcerating polyps Cancerous lesions Carcinoids Infiltrating, ulcerating or fungating lesions in the wall of colon	-/+(Carcinoid tumors)	Anemia Positive fecal occult blood test High levels of CEA and CA 19-9	luminal narrowing Intestinal wall thickening, Intus- susception, Bowel obstruction, Hepatic metastases, Intestinal perforation, Enlarged lymph nodes	Tumor mass and the extension of tumor to other structures liver, lung and brain Metastasis	Generally not recommended: may evaluate liver metastasis or presence of fluid in abdominal cavity, but it is neither sensitive nor specific.	PET scan, Endoscopy, Colonoscopy, Barium enema	Depends on the tumor type. You will find more information here
Pseudomyxoma peritonei		+	+	<math>\uparrow</math><math>\downarrow</math>	Bloating	–	+	Ascites Shifting dullness	–	Nonspecific Depends on the etiology of the disease	Low- attenuation Scalloping of the visceral surfaces differentiates pseudo- myxoma from other causes of peritonitis. Typically does not invade visceral organs or spread by lymphatic or hemato- genous routes unlike mucinous carcino- matosis	Charact- erized by a mass which is hypointense on T1-weighted MRI and hyperintense on T2-weighted MRI. MRI has better sensitivity in detecting ascites fluid and mucocele.	The echoes within pseudo- myxoma peritonei are not mobile. Echogenic septations within the gelatinous ascites. Scalloping of the hepatic and splenic margins	18F-FDG PET scan	Depending on WHO classification, whether it is low or high grade with cellular atypia or acellular mucin. ( DPAM, PMCA) Gelatinous ascites in peritoneum and visceral organs, usually underneath the right hemidiaphragm, liver. Omental cake IHC: CK 20 CDX2 MUC2 MUC5AC
Carcinoid syndrome		-/+	–	<math>\uparrow</math>	Flushing Palpitation Dyspnea	–	–	TRmurmur Wheezing	+	Depends on the tumor type: Ki67 N-terminal pro–B- type natriuretic peptide Substance P Neurotensin Bradykinin Human chorionic gonadotropin Neuro- peptide L Pancreatic polypeptide	Depends on the primary tumor location and type			Somatostatin scintigraphy with 111-indium- octreotide Bone scintigraphy with 99mTc- methylene diphosphonate (99mTcMDP) Positron emission tomography (PET) 123I-MIBG scintigraphy Capsule endoscopy (CE) Enteroscopy Angiography MR Angiography Endoscopic ultrasonography (EUS)	Salt and pepper nuclei Cellular uniformity Central ovoid nucleus Presence of ribbons, trabeculae, nesting, glands, gyriform, pseudorosettes Insulinoma (Amyloid deposition) Somatostatinom (Psammoma bodies) Hyaline globules IHC: Synaptophysin (almost always, strongly and diffusely expressed ) CGA CD56 and PGP ( less specific) PDX1 ISL1
Appendicitis 3		PU, RLQ	–	<math>\uparrow</math><math>\downarrow</math>	Nausea & vomiting, decreased appetite	+/-	+	Rebound tenderness Abdominal guarding Rovsing’s sign Psoas sign Obturator sign TR exam might reveal tenderness in the rectovesical pouch Tachypnea Tachycardia Hypotension Diaphoresis Pallor	–	Leukocytosis Left shift	Appendiceal wall thickening /perforation Peri- appendiceal inflammation, fluid accumulation, Fat stranding	Increased fluid signal on T2 weighted sequence	Evidences of inflammation Dilated appendix Peri- appendiceal fluid collection Distinct appendix wall layers	Tc-99m labeled anti- CD15 antibodies	Evidences of inflammation
Diseases		Abdo- minal pain	Change in girdle size	Bowel frequ- f ency	Other symptoms	Abdo- minal mass	Abdo- minal tender- ness	Other physical exami- nation findings	5-HIAA and/or CgA	Other lab findings	CT scan	MRI	Utra- sounography	Other diagnostic studies and imaging modalities	Histo- pathology

¹ Adenocarcinomas usually present with appendicitis, barely they might present with Pseudomyxoma peritonei; meanwhile pseudomyxoma peritonei is more prevalent in perforated mucocele, goblet cell tumor or high stages of adenocarcinoma.

² Generally appendix carcinoids are asymptomatic, they were only become symptomatic if they metastasize to the liver, or in rare cases make an obstruction and present with appendicitis which is quit uncommon in appendiceal carcinoids compared to appendiceal adenocarcinoma. Any patient with carcinoid syndrome should be evaluated for appendix carcinoids.

³ Every patient with appendicitis should be evaluated for appendix cancer, 0.5 in 100 appendicitis cases are because of appendix cancer.

⁴ Imaging is not a reliable method to distinguish between neoplastic and non-neoplastic lesions, hence every patient should undergo surgery, appendectomy and histopathologic evaluation of the lesion

*Abbreviations: RLQ: Right Lower Quadrant, AFP: Alpha-fetoprotein, HCG: Human chorionic gonadotropin, LDH: Lactate Dehydrogenase, CEA: Carcinoembryonic antigen, CA-125: Cancer antigen 125, 5-HIAA: Urinary 5-hydroxyindoleacetic acid , CgA: Serum Chromogranin A ,PU: Periumbelical, TR: Tricuspid regurgitation

References

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Epidemiology of appendix cancer should be discussed with respect to the major histological characteristics of the tumors. Prevalence, risk factors, age distribution as well as prognosis are different in the two major types of appendiceal cancers, adenocarcinoma and carcinoid tumors. The incidence of carcinoid tumor of appendix is approximately 0.075 per 100,000 individuals worldwide. The incidence of adenocarcinoma of the appendix is approximately 0.2 per 100,000 individuals worldwide. Appendiceal neoplasms account for approximately 0.4% of gastrointestinal tumors. The estimated prevalence of appendix cancer is approximately 0.12 cases per 100,000 individuals in the United States.The incidence of appendix cancer increases with age; meanwhile, patients with carcinoid tumors are generally younger than their adenocarcinoma counterparts. The median age at diagnosis is 65 years for adenocarcinoma, compared to 32-43 years (range, 6 to 80 years) for carcinoid tumors. There is no racial predilection to appendiceal cancers. Meanwhile, carcinoid tumors are slightly more prevalent among Caucasians and African-Americans. Generally appendiceal cancers affects men and women equally. While in adenocarcinoma, there is a male dominant pattern of prevalence, females are more commonly affected by appendiceal carcinoids than men.

• Epidemiology of appendix cancer should be discussed with respect to the major histological characteristics of the tumors.
• Prevalence, risk factors, age distribution as well as prognosis are different in the two major types of apendiceal cancers.^[1]
• According to the SEER database, adenocarcinoma accounted for 58% of appendiceal tumors.^[2]
• Carcinoid tumors comprise 50-77% of appendiceal malignancies.^[3]

• The incidence of carcinoid tumor of appendix is approximately 0.075 per 100,000 individuals, worldwide.^[4]
• The incidence of adenocarcinoma of the appendix is approximately 0.2 per 100,000 individuals, worldwide.^[5]

• Appendiceal neoplasms account for approximately 0.4% of gastrointestinal tumors.^[2]
• The estimated prevalence of appendix cancer is approximately 0.12 cases per 100,000 individuals in the United States.^[6]
• The estimated prevalence of adenocarcinoma of the appendix is 0.2 cases per 100,000 individuals, worldwide.^[6]

• The incidence of appendix cancer increases with age; meanwhile, patients with carcinoid tumors are generally younger than their adenocarcinoma counterparts.
• The median age at diagnosis is 65 years for adenocarcinoma, compared to 32-43 years (range, 6 to 80 years) for carcinoid tumors.^[7][4]
  • The patients with tubular carcinoids are significantly younger than the patients with goblet cell carcinoids.^[8]

• There is no racial predilection to appendiceal cancers.^[1]
• Meanwhile, carcinoid tumors are slightly more prevalent among Caucasians and African-Americans.^[9][10]
• A poorer survival has been reported for the black patients with carcinoid tumors.^[10][11]

• Generally appendiceal cancers affects men and women equally.
• While in adenocarcinoma, there is a male dominant pattern of prevalence, females are more commonly affected by appendiceal carcinoids than men.^[4][5]
• This might be because of high incidental appendectomies in women.
• Nevertheless, in the SEER database, the male to female ratio is approximately 1 to 1.^[1][7][5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Common risk factors in the development of appendix cancer are a combination of environmental and genetic factors. Common risk factors in the development of appendix cancer include age, sex, smoking, familial cancer disorders such as MEN1 Syndrome and HNPCC, as well as long standing chronic inflammatory disorders such as ulcerative colitis and Crohn’s disease.

• Common risk factors in the development of appendix cancers include:
  • Smoking: Smoking is a pretty well known risk factor for developing colorectal malignancies. An association was demonstrated between cigarette smoking and MSI-high, CIMP-positive, and BRAF mutation positive colorectal cancer subtypes.^[1]
  • Multiple endocrine neoplasia type 1 (MEN1) syndrome: An increased prevalance of carcinoid tumors has been reported in the patients with Wermer syndrome.^[2]
  • Age: Adenocarcinoma peak age is around 60s while carcinoid tumors are prevalent in 40s.^[3][4]

• Less common risk factors in the development of appendix cancers include:
  • Chronic inflammatory disease specially ulcerative colitis.^[5]
  • Sex^[4]
    • There is a male dominant pattern of prevalence in adenocarcinoma of appendix.
    • Although it is still controversial, most of the published studies demonstrated that females are more commonly affected by appendiceal carcinoids than men. ^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

There are insufficient evidences to recommend routine screening for appendiceal cancers. Meanwhile, patients with certain conditions like familial cancer syndromes as well as patients with long standing chronic inflammatory disease such as ulcerative colitis might drive a benefit from appropriate GI screenings according to the specific guidelines for their specific conditions.

• There are insufficient evidences to recommend routine screening for appendiceal cancers.
• Meanwhile, patients with certain conditions like familial cancer syndromes as well as patients with long standing chronic inflammatory disease such as ulcerative colitis might drive a benefit from appropriate GI screenings according to the specific guidelines for their specific conditions.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Because of the location and size of appendix, most of the patients with appendix cancer may be initially asymptomatic. Early clinical features might include periodical unspecific abdominal pain, bloating, and nausea. Most of appendix cancer cases are discovered after surgical or histological evaluation of a patient with acute appendicitis, or are an accidental finding in imaging studies for the other reasons. Around one percent of all appendectomy specimens are malignant. Appendix cancer account for 0.5 percent of all intestinal neoplasms. If left untreated, the majority of patients with appendix cancer may progress to develop peritoneal carcinomatosis and metastasis. Prognosis is generally excellent and good in carcinoid tumors and adenocarcinoma respectively. Prognostic factors including tumor stage, tumor size, histologic as well genetic characteristics of appendiceal tumors were discussed in details.

• The majority of patients with appendix cancer may be initially asymptomatic.
• Early clinical features might include periodical unspecific abdominal pain, bloating, and nausea.
• Most of appendix cancer cases are discovered after surgical or histological evaluation of a patient with acute appendicitis, or are an accidental finding in imaging studies for the other reasons.
• Around one percent of all appendectomy specimens are malignant.
• Appendix cancer account for 0.5 percent of all intestinal neoplasms.
• If left untreated, the majority of patients with appendix cancer may progress to develop peritoneal carcinomatosis and metastases.

• Common complications of appendix cancer include:
  • Acute appendicitis
    • Most of appendix adenocarcinomas present with acute appendicitis.
    • However, majority of carcinoids are located in the distal one third of the appendix, hence rarely present with appendicitis.
    • Merely 10 percent of appendiceal carcinoids are located at the base of appendix and may tend to obstruction and appendicitis.
  • Pseudomyxoma peritonei
  • Metastasis
  • Carcinoid syndrome
    • More commonly seen in midgut (appendix and small bowel) carcinoids.
    • Almost always (90%) seen in metastatic disease, typically liver is the involved organ.

• Major prognostic factors are tumor stage, tumor size, histologic as well genetic characteristics of appendiceal tumors. For TNM classification of tumors of the appendix, click here.^[1]

• Prognosis is generally excellent and good in carcinoid tumors and adenocarcinomas respectively.
• The overall 5-year survival rate for adenocarcinoma of appendix is approximately 71% (see the Table below).^[2]
• Tumor size plays a crucial role in determining prognosis.
  • Most of the appendiceal tumors are less than 2 cm in size and have a quite favorable prognosis since they barely metastasize.^[3][4]
• The prognosis varies with the histology of tumor.
• Carcinoid tumors are associated with a better prognosis among patients with appendiceal cancer.
• Localized carcinoid tumors are associated with the most favorable prognosis.
• The presence of tubular pathology is also associated with a particularly good prognosis among patients with appendix adenocarcinoma.
• Goblet cell carcinoids are generally more aggressive than other carcinoid tumors.
• According to surveillance, epidemiology and end results (SEER) database of the national cancer institute five-year appendiceal carcinoid survival rates were as follows:

• Tumor size <3 cm without regional nodal or distant metastases: 100 percent
• Tumor size between 2 and 3 cm plus regional node metastases / tumor size ≥3 cm with or without regional nodal or distant metastases: 78 percent
• Distant metastasis: 32 percent

Five year survival rates
Carcinoid tumors
localized disease 94% Regional disease 85% Distant metastases 34% Goblet cell 12.5% Tubular tumors are benign clinically
Adenocarcinoma
Nonmucinus Localized 95% Distant metastasis 0%* Mucinous adenocarcinoma localized 80% Distant metastasis 51%*
* Shows that mucinous adenocarcinomae are less aggressive than nunmnucinous tumors

• Poor prognostic factors for appendiceal adenocarcinoma are as follows:
  • Advanced stage
  • High grade
  • Non-mucinous histology
  • Spread of the tumor beyond the left lower quadrant
  • Presence of malignant cells outside of the visceral peritoneum of the appendix

• Poor prognostic factors in the presence of pseudomyxoma peritonei are as follows:
  • Abdominal distension
  • Weight loss
  • High histological grade
  • Morphological evidence of invasion of underlying structures

• Genetic prognostic markers of appendiceal cancers are as follows:
  • Genetic studies revolutionized cancer treatment; appendix cancer is not an exception.
  • Traditionally appendiceal cancers were approached the same as colorectal cancers.
    • Recent genetic studies demonstrated that appendiceal tumors are clearly differ from colorectal cancers. ^[5]
    • Presence of mutated TP53 and APC genes were significantly lower in appendiceal cancers compared to colorectal cancers.
  • It has been shown that mutation profiles are associated with the patients’ prognosis. ^[6]
    • Mutations in the TP53 significantly decrease life expectancy in patients with appendix cancer.
    • Regardless of tumor grade, TP53 mutations were associated with poorer outcomes.
    • Patients with GNAS mutations had a life expectancy of 10 years after diagnosis.
    • Appendiceal tumors with GNAS mutations rarely develop into high-grade tumors.

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