Deep Infiltrating Endometriosis: Current and Future Treatments
From molecular differences and symptom recognition to diagnosis, medical therapy, advanced surgical techniques, and what’s ahead.
How to Treat Deep Infiltrating Endometriosis
Endometriosis, already challenging when endometrial-like cells grow outside the uterus and on the surfaces of other organs, has a more troubling variant known as deep infiltrating endometriosis (DIE). This severe form is defined by abnormal cells burrowing or invading more than 5 mm below the tissue surface into affected organs such as the bowel and bladder. This guide outlines current approaches to managing DIE and how future advances may improve treatment. At this time, a long-standing cure remains out of reach, even for superficial endometriosis.
Understanding Deep Infiltrating Endometriosis
This condition is relatively uncommon, affecting about 1% of women of reproductive age and about 20% of those with endometriosis. Molecular data suggest it may be a premalignant disease, along with the endometrioma type; research is ongoing, and the malignancy potential remains low. Shared genetic mutations with aggressive diseases like cancer may help explain why endometrioma and DIE types are more likely to cause local anatomic distortion and harm, including pain and subfertility, and why they may have increased metastatic potential even without any associated cancer.
Anatomically, three major types of endometriosis are recognized based on location within the pelvic and abdominal cavities. Superficial endometriosis (also called peritoneal endometriosis or PEM) involves lesions appearing on the surface of organs outside the endometrium and generally, though not always, causes the least tissue damage and distortion. Ovarian endometriomas (OE) are dark cysts caused by old collected blood, commonly called chocolate cysts, that form in or on the ovaries due to endometriosis. Deep infiltrating endometriosis is the most severe form, in which endometrial-like tissue penetrates deeply into pelvic organs and causes more extensive damage.
Current staging systems rely largely on anatomic location and clinical degree of disease. This approach is considered “old school,” and a new era is emerging in which molecular insights are expected to improve diagnostics and treatment because abnormal molecular pathways can be targeted with precision therapies.
Molecular Comparison of Endometriosis Types
Research in this area extends well beyond hormonal factors such as receptor activity, regulatory changes, and relative progesterone resistance. Although it is too early to classify different types of endometriosis strictly by gene mutation pathways, what is known may already help with recurrence and cancer risk mitigation. In summary, multiple genes can be mutated in endometriosis, which may or may not lead to a low risk of cancer but can influence how aggressive DIE and OE are in an individual. These gene mutations may be suppressed or aggravated by epigenetic influences such as diet, lifestyle, toxin exposure, concurrent disease states, and mind–body factors. Ongoing research is uncovering diagnostic possibilities and molecularly guided therapies based on these findings.
Identifying Symptoms of Deep Infiltrating Endometriosis
Symptoms are similar to those of general endometriosis but are usually more severe. They can include severe pelvic pain, painful urination (dysuria) or blood in the urine (hematuria), painful menstruation (dysmenorrhea), genital pain before, during, or after sex (dyspareunia), digestive discomfort and rectal bleeding, and distant symptoms such as pain with breathing when the diaphragm is involved.
Causes and Risk Factors of Deep Infiltrating Endometriosis
Despite recent advances, the exact cause of endometriosis, including DIE, remains unknown. Family history of endometriosis and/or cancer is important to consider. Because the condition is likely multifactorial, a single cause is unlikely to be identified, and molecular research is pushing understanding to a deeper level.
Diagnosing Deep Infiltrating Endometriosis
As an advanced form of endometriosis, DIE can be challenging to diagnose. Multiple diagnostic modalities are typically employed, including medical history, physical examination, histological evaluation after surgery or biopsy (such as evaluation of a C-section scar endometriosis), minimally invasive surgery, ultrasound, and MRI. A 3-Tesla (“3T”) MRI is probably the most accurate imaging modality, yet it still has significant limitations. It can aid in surgical planning but should not be used to determine definitively whether DIE is present or absent, as it can miss up to 20% of DIE.
In many—if not most—cases, the diagnosis is only apparent and confirmed during surgery. Because it is impossible to precisely predict the full extent of disease beforehand, choosing the most skilled and experienced surgeon is prudent, particularly when symptoms are severe. A poorly executed surgery complicates subsequent procedures and increases the risk of major complications.
Treatment Options for Deep Infiltrating Endometriosis
Medical Treatments
Medical therapy for DIE is extremely limited and essentially non-existent in terms of disease eradication. Deep invasive disease triggers scarring or fibrosis as the body attempts to wall off and heal the area, and no known medication can eliminate fibrosis. Pain relievers and hormonal therapies used for other forms of endometriosis may provide symptomatic relief and possibly some suppressive effect.
Integrative strategies can help with symptom control in DIE much as they do with other types of endometriosis. Mind–body–based biofeedback, nutrition, botanicals, essential oils, acupuncture and acupressure, and electrical stimulation (TENS) are examples, and it is best to craft such an approach with a qualified practitioner.
Pelvic floor physical therapy (PFPT) plays a central role in treatment planning. Depending on lesion location, caution is advised with internal therapies because disruption of deep lesions can potentially make surgery less effective. A coordinated team approach is ideal to determine the best strategy.
Surgical Treatments
Surgical excision of DIE lesions and associated fibrosis is the best path forward in most cases where DIE is suspected or has been diagnosed previously. The usual emphasis on excision over ablation is even more crucial here because ablation or fulguration is not useful for lesions of uncertain depth and carries an elevated risk of damaging structures such as the rectum, bladder, and ureters.
A master surgeon is best suited for DIE. In the author’s opinion, these procedures should be performed robotically because of superior optics and wristed robotic instruments. The surgeon should be prepared to address bowel, bladder, and ureteral involvement, including reimplantation when necessary, or should work with a well-integrated team ready to participate as planned. Although it is difficult to predict all requirements preoperatively, careful imaging-based mapping and close attention to symptoms improve preparation for comprehensive resection or excision.
DIE does not automatically necessitate a hysterectomy. If childbearing is complete, the risks and benefits of hysterectomy may need to be discussed to ensure all diseased tissue is removed. As menopause approaches, and with more extensive disease or a higher malignancy risk due to family history or genetic testing, it becomes more prudent to weigh the risks and benefits of ovarian conservation. Decisions should be individualized and thoroughly discussed.
Considerations in Surgical Management
Indocyanine Green (ICG) Fluorescence
Indocyanine green (ICG) fluorescence imaging helps surgeons visualize the ureters and safely remove as much infiltrating endometrial tissue as possible without damaging the urinary tract. It is also valuable for assessing blood supply and viability in bowel segments that have been operated upon, reducing the risk of complications.
Stenting During Partial Cystectomy or Ureteral Reimplantation
During bladder surgery for urinary endometriosis, the placement of stents—tiny plastic catheters—can protect the ureters and enhance healing after reimplantation.
Pathology Evaluation
Beyond standard pathology, newer assessments may be considered in DIE and OE, especially when disease appears clinically aggressive. The pathologist should ensure there is no clear cell cancer component. Even without cancer, tissue can be evaluated for mitotic index to determine how many cells are dividing, a finding more common in aggressive disease and one that may prompt consideration of well-tolerated hormone suppression such as micronized progesterone to reduce recurrence risk. Immunohistochemical (IHC) stains can assess molecular abnormalities driven by gene mutations, such as ARID1A; while not readily available, they may be useful when cancer risk is elevated. In the future, these aberrant molecular pathways are expected to be targeted with precision therapies.
Endometriosis and Fertility
Endometriosis, including DIE, can affect fertility. Surgeons should prioritize atraumatic techniques to protect delicate reproductive structures and improve pregnancy prospects, a goal optimized with the robotics platform.
Key Molecular Facts at a Glance
- Endometriosis overall (PEM, OE, and DIE types) shows genetic and molecular heterogeneity, with multiple genes affected. Some mutations mirror those found in cancer even when no cancer is present or likely to develop. This suggests endometriosis may represent different disease entities between individuals, with varying aggressiveness. Within a single individual, research supports clonal molecular signature similarities between PEM, OE, and DIE, indicating that one type can progress to another.
- Mutations of interest include ARID1A, PIK3CA, KRAS, and PPP2R1A, among others.
- The endometrioma (OE) type carries the highest risk of malignant degeneration, and ARID1A is considered a key driver mutation for clear cell cancer.
- DIE has a broader range of mutations and a lower risk of malignant degeneration than OE, but these mutations may contribute to more aggressive behavior.
- OE may have a higher malignant degeneration risk than DIE because the ovarian microenvironment may be more permissive to malignant change; this does not negate the aggressive, invasive, and potentially metastatic nature of DIE in the absence of cancer.
- Gene mutation expression varies under epigenetic influences, including diet, lifestyle, toxin exposure, concurrent disease states, and mind–body factors.
Quick Reference: Prevalence and Imaging Performance
- Prevalence among reproductive-age women: about 1%
- Proportion among all endometriosis cases: roughly 20%
- 3-Tesla (3T) MRI: currently the most accurate imaging option, though it can still miss up to 20% of deep infiltrating endometriosis (DIE), so it shouldn’t be used as definitive proof for or against disease.
Conclusion
Deep infiltrating endometriosis adds complexity to the management of endometriosis. Surgery is the optimal therapy, followed by supportive care and strategies to mitigate recurrence where possible. Malignant degeneration is uncommon but possible, and with a family history of cancer, genetic testing should be considered. The more complex the situation, the greater the need for an endometriosis expert master surgeon. If cancer risk is elevated for any reason noted here, consultation with a gynecologic oncologist should be considered.