Appendix cancer pathophysiology

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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

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.

Pathophysiology

Physiology

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

• Glandular epithelial cells are responsible for mucus production.

Pathogenesis

• The pathophysiology of appendix cancer depends on the histological subtype.
• 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.
• 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.

Genetics

Genes involved in the pathogenesis of carcinoid tumors of appendix include:

• β-catenin,
• NF1,
• MEN1

The development of appendiceal adenocarcinoma is the result of multiple genetic mutations such as:

• KRAS
• APC
• TP53
• RAF

Associated Conditions

• Conditions associated with appendiceal cancers include:

• Chronic inflammatory disease such as ulcerative colitis
• Familial cancer syndromes:

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

Gross Pathology

Appendix carcinoid gross pathology. Courtesy of Dr.Robertson. Uploaded by James Heilman, MD. https://commons.wikimedia.org/wiki/File:Appendiceal_carcinoid_1.JPG

• On gross pathology, findings of appendix cancer, include:

• 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

Microscopic Pathology

The images below demonstrate different histopathological findings of appendix cancer

Low grade appendiceal mucinous neoplasm, MUC2 staining. Courtesy of Carlos Parra-Herran, M.D.http://www.pathologyoutlines.com/topic/ovarytumorappendiceal.html

Appendiceal adenocarcinoma, H and E staining. Courtesy of Carlos Parra-Herran, M.D.http://www.pathologyoutlines.com/topic/ovarytumorappendiceal.html

Typical microscopic appearance of a well differentiated carcinoid tumor (terminal illeum, H and E staining).Case courtesy of Dr Andrew Ryan, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/16308">rID: 16308</a>

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

• 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:
• 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)
• 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