Appendix cancer overview

Appendix cancer Microchapters
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Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology and Demographics
Differentiating Appendix cancer from other Diseases
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X-ray
MRI
CT scan
Echocardiography and Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
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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]

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 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.

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, adenocarcinomae and carcionid tumors. While carcinoid tumors arises from enterochromaffin cells (Kulchitsky cells), which are secretory cells that are normally involved in neuroendocrine hormonal secretions, adenocarcinomae are the result of mutations in mucous 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 tumor s progression.

Causes

Appendix cancer is a quit 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, click here.

Risk Factors

Alike other malignancies, 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 is insufficient evidence 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 like 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 metastases. Prognosis is generally excellent and good in carcinoid tumors and adenocarcinomae respectively. Prognostic factors including tumor stage, tumor size, histologic as well genetic characteristics 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 cancer.

History and Symptoms

The majority of patients with appendix cancer are asymptomatic. Patients may complaint 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 pseudomixuma 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 complaints and presentation is influenced by the tumor histology and stage. Range from a small asymptomatic adenocarcinoma 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 quit 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 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 prevalent presentations of appendix cancer, which include appendix perforation and pneumoperitoneum. Appendix mucocele might present with calcification in plain abdominal X-rays. Metastatic bone lesions of both adenocarcinoma and carcinoid tumors of appendix are extremely rare but might present with osteolitic (adenocarcinom) and a mixture of osteosclerotic and osteolytic changes (carcinoid tumors).

Echocardiography and Ultrasound

Ultrasound may be helpful in the diagnosis of appendix tumors, appendix mucucele, 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 pretty helpful in the diagnosis and management of appendix cancer. Findings on CT scan suggestive of appendix cancer include soft tissue thikenning, 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, 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.

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 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 carcionid 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 octreotide scintigraphy.

References

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