Digestive system deep infiltrating endometriosis: What do we know

Abstract

Digestive system infiltrating endometriosis (DSIE) is an uncommon form of endometriosis in the digestive system. DSIE often occurs in the intestines (especially the sigmoid rectum), liver, gallbladder and pancreas. Clinically, DSIE presents with the same symptoms as endometriosis, including cyclic pain, bleeding and infertility, in addition to specific biliary/intestinal obstruction and gastrointestinal bleeding. Compared to general endometriosis, DSIE has unique biological behaviour and pathophysiological mechanisms. Most DSIEs are deep invasive endometrioses, characterized by metastasis to the lymph nodes and lymphatic vessels, angiogenesis, peripheral nerve recruitment, fibrosis and invasion of surrounding tissues. DSIE-related peripheral angiogenesis is divided into three patterns: angiogenesis, vasculogenesis and inosculation. These patterns are regulated by interactions between multiple hypoxia-hormone cytokines. The nerve growth factors regulate the extensive neurofibril recruitment in DSIE lesions, which accounts for severe symptoms of deep pain. They are also associated with fibrosis and the aggressiveness of DSIE. Cyclic changes in DSIE lesions, recurrent inflammation and oxidative stress promote repeated tissue injury and repair (ReTIAR) mechanisms in the lesions, accelerating fibril formation and cancer-related mutations. Similar to malignant tumours, DSIE can also exhibit aggressiveness derived from collective cell migration mediated by E-cadherin and N-cadherin. This often makes DSIE misdiagnosed as a malignant tumour of the digestive system in clinical practice. In addition to surgery, novel treatments are urgently required to effectively eradicate this lesion.

Keywords: aetiology; digestive system; endometriosis; intestines; molecular mechanisms.

FIGURE 1

DSIE angiogenesis, including angiogenesis, vasculogenesis and inosculation. Serum VEGF levels can be upregulated in response to HIF‐1α and COX‐2 stimulation, which negatively feedback inhibits the notch pathway and simultaneously regulates angiogenesis. EPCS recruits to endometriosis lesions by VEGF, FGF and other factors, differentiates and adheres to form neovascularization by oestrogen, ICAM‐1 and VCAM‐1. Finally, VEGF stimulates the process of Inosculation, which leads to the connection between each neovascularization or between neovascularization and existing vessels. Among them, the important factor VEGF was abundantly expressed in DSIE.

FIGURE 2

Mechanisms of nerve and fibre tissue formation and their interactions in DSIE. BDNF secreted by M1 macrophages in response to oestrogen interacts with the receptor TrkB to promote peripheral nerve growth in the lesion. NGF‐TrkA pathway, on the contrary, can promote nerve recruitment. TGF‐β1 secreted by M1 macrophages activates Smad3, and M1 macrophages are induced by the Smad2/Smad3 pathway to transform into M2 macrophages, which together with TGF‐β1 activate ReTIAR. Simultaneously, oxidative stress in the lesion activates the notch pathway and promotes lesion fibrosis. Additionally, nerve fibres enriched in the lesion can promote fibre formation via SP, CGRP.