How to Treat Deep Infiltrating Endometriosis

Endometriosis, bad enough when endometrial-like cells grow outside the uterus and on the surface of other organs, has an even more troubling variant called Deep-Infiltrating Endometriosis (DIE).  This is a severe form of endometriosis defined by these abnormal cells burrowing or invading deeper into tissues and affected organs, like the bowel and bladder.  Generally, the depth cutoff to fit this category is more than 5mm below the tissue surface.  This guide will shed some light on how we treat and potentially cure deep infiltrating endometriosis in the future. At this time, a long-standing cure is still a stretch, even for superficial endometriosis.  

Understanding Deep Infiltrating Endometriosis

The good news is that this condition is relatively rare, affecting only about 1% of women of reproductive age and only 20% of those with endometriosis.  The bad news is that molecular data suggests it may be a premalignant disease, along with endometrioma type. However, this is still undergoing research, and the malignancy potential remains low.  However, when genetic mutations are shared with an aggressive disease like cancer, this may help explain why endometrioma and DIE types of endo are more likely to cause more local anatomic distortion and harm with pain and subfertility impact, as well as increased metastatic potential (i.e., spread to other parts of the body even if there is no associated cancer). 

Anatomic Comparison of Endometriosis Types

Based on the anatomical location of endometriosis within the pelvic and abdominal cavities, there are three major types of endo:

• Superficial endometriosis (Peritoneal endometriosis or PEM): Lesions appear on the surface of organs outside the endometrium. Generally, but not always, they cause the least amount of tissue damage and distortion. 
• Ovarian endometriomas (OE): Dark cysts due to old collected blood, also called chocolate cysts, develop in or on the ovaries due to endometriosis.
• Deep infiltrating endometriosis: The most severe form, where the endometrial-like tissue invades deeper into the pelvic organs, wreaking more havoc.

Anatomic locations and clinical degree of disease form the basis for most of the staging systems that are currently used.  This is extremely “old school,” and we are about to step into a new age where molecular insights will help with diagnostics and treatment options because abnormal molecular pathways can be targeted with precision therapies.  

Molecular Comparison of Endometriosis Types

This is an evolving hot topic of research in endometriosis, which goes well beyond comparisons based on hormonal factors like receptor activity, up and down-regulation, and relative progesterone resistance.  It is too early to classify different types of endo by this gene mutation molecular pathway metric, but what is known so far might already help with recurrence and cancer risk mitigation.

What we know is as follows:

• Endometriosis overall (PEM, OE, and DIE types) is a disease of genetic and molecular heterogeneity,  meaning multiple genes are affected. Some of these are mutations exactly like those found in cancer, even if no cancer is present or even destined to develop. This means endo may not be one disease entity between different individuals but rather different ones with varying degrees of aggressiveness. On the other hand, in any given individual, there is research data to support “clonal” molecular signature similarities between all three types of endo, meaning one type (e.g., PEM) advances or progresses to the other (OE or DIE).  
• Mutations of interest include ARID1A, PIK3CA, KRAS, and PPP2R1A, among others
• Endometrioma type carries the highest risk of malignant degeneration, and ARID1A is considered to be one of the most important driver mutations to clear cell cancer.  
• DIE type has a wider range of mutations and is at a lower risk of malignant degeneration, but these mutations may contribute to its more aggressive behavior. 
• OE-type risk for malignant degeneration may be higher than that for DIE because the molecular micro-environment differs between these two, with the ovaries possibly being more “permissive” to malignant changes.  This does not negate the aggressive, invasive, and potentially metastatic nature of DIE in the absence of cancer. 
• Gene mutation expression varies based on epigenetic influences, including diet, lifestyle, toxin exposure, concurrent disease states, mind-body influence, etc. 

What does this all mean in summary?  Multiple genes are mutated in endometriosis, some of which may or may not lead to a low risk of cancer development but can dictate how aggressive endo types, especially DIE and OE,  can be in an individual.  These gene mutations can be suppressed or aggravated by epigenetic influences that you have some control over.  Evolving research is helping uncover diagnostic and prescription molecular treatment options based on all of this.   

Identifying Symptoms of Deep Infiltrating Endometriosis

The symptoms of DIE are similar to general endometriosis but usually more severe. They may include:

• Severe pelvic pain
• Painful urination (dysuria) of bleeding in the urine (hematuria)
• Painful menstruation (dysmenorrhea)
• Genital pain before, during, or after sex (dyspareunia)
• Digestive discomfort and rectal bleeding
• Distant symptoms like pain with breathing, related to possible diaphragm involvement

Causes and Risk Factors of Deep Infiltrating Endometriosis

Notwithstanding recent research advances, the exact cause of endometriosis, including DIE, is unknown.  A family history of endo and/or cancer are important to consider.  It is not likely that a single cause will be uncovered because of the probable multifactorial nature of endo.  However, molecular research is taking this to a different level. 

Diagnosing Deep Infiltrating Endometriosis

Since deep infiltrating endometriosis is an advanced form of endometriosis, its diagnosis can be challenging. Usually, multiple diagnostics are used, including medical history, physical examination, histological examination after surgery or upon biopsy (e.g., C-section scar endo), minimally invasive surgery, ultrasound, and MRI.  A 3-Tesla (“3T” for short) MRI is probably the most accurate modality, but it still has many shortcomings.  In other words, it can be helpful in planning for surgery but should not be used to determine definitively if DIE is present or not. It is as good as it gets but is imperfect, missing up to 20% of DIE. 

In many, if not most, cases, the diagnosis will only be apparent and confirmed at the time of surgery.  Since it is impossible to accurately predict the full extent of endo before surgery, this is the main reason that it is very prudent to pick the most skilled and experienced surgeon you can find. The more symptomatic you are, the more this is critical to your success. A botched surgery does not make it easier the second time around, and it exposes you to an increased risk of major complications.  

Treatment Options for Deep Infiltrating Endometriosis

Medical Treatments

Medical treatments for DIE are extremely limited and basically non-existent.  This is because the deep invasive infiltration of disease leads to scarring or fibrosis as your body tries to “wall off” or isolate  this disease and heal.  Any known medication cannot eliminate fibrosis.  What we are left with are pain relievers and hormonal options that are used in all forms of endo, for symptomatic relief and possibly some suppressive effect.

Integrative options are also an option for symptomatic relief, just as they are for any type of endo.  This includes mind-body-based biofeedback, nutrition, botanicals, essential oils, acupuncture and acupressure, electrical stimulation (TENS), etc.  It is best to formulate an integrative strategy with a relevant practitioner.  

Pelvic floor physical therapy (PFPT) is, of course, central to a treatment plan as well.  However, depending on lesion location, this should be undertaken with some caution due to possible disruption of deep lesions with internal therapies, making surgery potentially less effective.  A teamwork approach should be conducted to evaluate the best strategy.  

Surgical Treatments

Surgical excision of DIE lesions and associated fibrosis is by far the best path forward in most cases where DIE is anticipated and/or already diagnosed from prior surgery.  The usual admonitions of excision superiority over ablation are even more critical here because ablation or fulguration is totally useless for lesions of uncertain depth. Also, with ablation, there is an elevated risk of damaging tissues like the rectum, bladder, and ureters. 

A master surgeon is best equipped for DIE, and, in the author’s opinion, these types of cases should be performed robotically because of the far superior optics and wristed robotic instruments.  Further, the surgeon should either be able to handle bowel, bladder, and ureters, including reimplantation where required, or have a well-integrated team ready to participate in a planned fashion.  The problem is that it is hard to tell what will be required before surgery. Still, the best efforts through imaging-based mapping and attention to symptoms should be made to adequately prepare for resection/excision of anything found.   

DIE most definitely does not mean an automatic hysterectomy recommendation.  However, if childbearing is complete, this may need to be discussed for risk vs. benefit to remove all diseased tissue.  Similarly, the closer to menopause, the more disease and the higher the risk of malignancy due to family history or genetic testing, the more it is prudent to talk about the risk vs. benefit of ovarian conservation.  This should be highly individualized and thoroughly discussed for the best outcome. 

Considerations in Surgical Management

Indocyanine Green (ICG) Fluorescence

Indocyanine green (ICG) fluorescence imaging allows surgeons to visualize the details of the ureters and safely remove the maximum amount of infiltrating endometrial tissue without damaging the urinary tract.  It is also helpful to determine if a bowel segment that has been operated upon retains good blood supply and viability.  This helps avoid complications.  

Stenting During Partial Cystectomy or Ureteral Reimplantation

During bladder surgery for urinary endometriosis, surgeons can place stents (tiny plastic catheters) to help protect the ureters (the delicate tubes through which urine travels from the kidneys to the bladder) from further damage or to enhance healing after reimplantation.  

Pathology Evaluation

Other than standard pathology evaluation, research evidence suggests several newer assessments might be considered in DIE and OE.  Specifically, the more the disease looks clinically aggressive, the more the pathologist should ensure that there is no clear cell cancer component.  Beyond that, even with no evidence of cancer, the tissue specimens removed can be assessed for “mitotic index,” meaning whether the pathologist sees many dividing cells.  This is more often seen in aggressive disease, even in the absence of cancer.  This, in turn, may lead to consideration of some degree of well-tolerated hormone suppression (e.g., micronized progesterone) to potentially reduce recurrence risk. Finally, there are immunohistochemical (IHC) stains for some molecular abnormalities that gene mutations can spawn (e.g., ARID1A).  This is not readily available but can be considered, especially in a situation where cancer risk is elevated.  In the future, as discussed above, these aberrant molecular pathways will be targeted with precision therapies.  

Endometriosis and Fertility

Endometriosis, including DIE, can impact fertility. Consequently, surgeons should employ as many atraumatic surgical techniques as possible to avoid injuring delicate structures in the reproductive system and improve the chances of pregnancy.  This is optimized with the robotics platform. 

Conclusion

Deep infiltrating endometriosis adds a layer of complexity to the management of endo.  Surgery is the optimal therapy, followed by supportive care and strategies to mitigate recurrence if possible. Malignant degeneration is uncommon but possible, which means that, especially with a family history of cancer, genetics testing should be considered.  The more complex, the more the need for an endometriosis expert master surgeon in your corner. If the cancer risk is elevated for any of the reasons noted in this article, a gynecologic oncologist should be considered at least as a consultant.  

References:

The Diagnosis and Treatment of Deep Infiltrating Endometriosis

Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes – ScienceDirect