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 carcionid 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 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 tumors progression.

Pathophysiology

Physiology

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

Glandular epithelial cells are responsible for mucous 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 entrochromaffin 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.^[1]

Genetics

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

β-catenin,
NF1,
MEN1

The development of appendiceal adeocarcinoma 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

Gross Pathology

On gross pathology, findings of appendix cancer, include:^[1]

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 image below demonstrates gross pathology of appendix cancer.

Gross pathology appendix cancer

Microscopic Pathology

On microscopic histopathological analysis findings will depend on the subtype of appendicular cancer.
Common histopathological findings, may include:^[1]

Cystic structures
Angiolymphatic invasion

Adenocarcinoma

Intestinal, mucinous or signet ring cell types
oexisting acute appendicitis is common 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