Appendix cancer overview
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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]
Overview
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.
Historical Perspective
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.
Classification
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.
Pathophysiology
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.
Causes
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.
Differentiating Appendix cancer from Other Diseases
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 and Demographics
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.
Risk Factors
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.
Screening
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.
Natural History, Complications, and Prognosis
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.
Diagnosis
Diagnostic Study of Choice
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.
History and Symptoms
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.
Physical Examination
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.
Laboratory Findings
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.
Electrocardiogram
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.
X-ray
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).
Echocardiography and Ultrasound
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.
CT scan
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.
MRI
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.
Other Imaging Findings
Positron emission tomography (PET) and scintigraphy are among other imaging modalities that may be helpful in the diagnosis and management of appendix cancer.
Other Diagnostic Studies
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.
Treatment
Medical Therapy
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
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.
Primary Prevention
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.
Secondary Prevention
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.
Appendix cancer future or investigational therapies
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.