Appendix cancer natural history, complications and 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]

Overview

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 below.

Natural History, Complications, and Prognosis

Natural History

• 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

Complications

• Common complications of appendix cancer include:
  • Acute appendicitis
    • Most of appendix adenocarcinmos present with acute appendicitis; on he other hand
    • 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

Prognosis

• Major prognostic factors are tumor stage, tumor size, histologic as well genetic characteristics of appendiceal tumors. TNM classification of tumors of the appendix has been shown in the Table below.

TNM classification of tumors of the appendix 1
Primary tumor (T)
Tx	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ: intraepithelial or invasion of lamina propria 2
T1	Tumor invades submucosa
T2	Tumour invades muscularis propria
T3	Tumor invades through muscularis propria into subserosa, or into non-peritonealized periappendiceal tissue
T4	Tumor directly invades other organs or structures and/or perforates visceral peritoneum
Regional Lymph Nodes (N)
Nx	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in 1 to 3 regional lymph nodes
N2	Metastasis in 4 or more regional lymph nodes
Distant Metastasis (M)
Mx	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
Stage Grouping
Stage 0	Tis N0 M0
Stage I	T1 N0 M0 T2 N0 M0
Stage II	T3 N0 M0 T4 N0 M0
Stage III	Any T N1 M0 Any T N2 M0
Stage IV	Any T Any N M1
1 The classification applies only to carcinomas. 2 This includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through muscularis mucosae into submucosa.

• Prognosis is generally excellent and good in carcinoid tumors and adenocarcinomae respectively.
• The overall 5-year survival rate for adenocarcinoma of appendix is approximately 71% (see the Table below).
• 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.
• The prognosis varies with the histology of tumor.
• Carcinoid tumors are associated with a better prognosis 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
  • Nonmucinous 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 appandiceal cancers were approached the same as colorectal cancers.
    • Recent genetic studies demonstrated that appendiceal tumors are clearly differ from colorectal cancers.
    • 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.
    • Mutations in the TP53 significantly decrease life expectancy in patients with appendix cancer.
    • Regardless of tumor grade, Tp 53 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.