The Role of the Lymphatic System in Endometriosis: A Comprehensive Review of the Literature1

Abstract

Endometriosis is a benign gynecological disorder characterized by the presence of tissue resembling the endometrium in locations outside the uterus. The pathogenesis of endometriosis is still unknown; however, it is believed that the lymphatic system plays major roles in the development and progression of the disease. The lymphatic dissemination theory has been proposed to explain the presence of endometrial and/or endometriotic tissue in lymphatic vessels, lymph nodes, and rare sites, as well as high reoccurrence rates following treatment. Despite the importance of the lymphatic system in many aspects of endometriosis, there has been no previous thorough scientific update on its role in the disease. A review of scientific literature on the lymphatic system, lymphangiogenesis, and immunological changes associated with endometriosis was conducted. Lymphangiogenic potential is disturbed and lymphatic vessel density increased in the eutopic endometrium of women with endometriosis, likely promoting the entry of endometrial tissues into the lymphatic circulation. Endometriotic lesions and endometrial-like cells are present in uterine-draining nodes and various other pelvic lymph nodes. Immune responses are impaired in uterine-draining nodes, likely favoring the survival of endometrial cells and lesion establishment. In addition, lymphangiogenesis in endometriotic lesions may contribute to lesion growth and persistence, and promote the spread of endometrial cells to draining lymph nodes. The evidence reviewed in this paper supports the theory of lymphatic dissemination of endometriosis and highlights the roles of the lymphatic system in the pathogenesis and persistence of endometriosis. Understanding these roles is crucial for establishment of novel therapeutic approaches.

Pathogenesis of endometriosis: the genetic/epigenetic theory

“…''Deep endometriosis'' was described in 1990 as deeper lesions with a microscopic appearance of adenomyosis externa, with glands in phase with the endometrium and associated with severe pain (21). These lesions are generally unique, larger than 1 cm in diameter, with frequent invasion into the muscle of the bowel wall, and with occasional nerve invasion (22), a neurotropic effect (23,24), and some 20% lymph node involvement (25,26). The definition of deep endometriosis as lesions deeper than 5 mm under the peritoneum was later suggested because the biphasic frequency distribution of depth of lesions (27) indicated two populations overlapping at 6 mm of depth ( Fig.…”

Pathogenesis of deep endometriosis

“…These adenomyosis externa lesions occasionally invade nerves (14) and have some neurotropic effect (15,16). In most bowel lesions lymph nodes are invaded (17,18).…”

Pathophysiologic processes have an impact on the plasma metabolomic signature of endometriosis patients

“…A hypothesis based on the potential lymphatic spread of endometriosis has been recently suggested to explain the observations of endometrial and endometriotic tissue in lymphatic vessels and lymph nodes in some women (41) and as a possible mechanism associated with endometriosis recurrence (41,42). Regional lymph node involvement is a characteristic feature of malignant lesions that has also been described in women with endometriosis.…”