Cases & Commentaries

Endometriosis: A Common and Commonly Missed and Delayed Diagnosis

Commentary By Malcom Mackenzie, MD and Celeste Royce, MD

The Case

A 15-year-old girl with no prior medical problems developed disabling menstrual cramps and heavy bleeding at the onset of her first menstrual period. She immediately sought care from a gynecologist, who started her on an oral contraceptive pill to manage her symptoms, which were attributed to "bad periods."

Over the next 3 years, her dysmenorrhea continued, and she developed severe abdominal cramps, bloating, nausea and diarrhea. She was continued on oral contraceptives by her gynecologist. She saw her primary care provider for her severe diarrhea and was diagnosed with Irritable Bowel Syndrome with Diarrhea (IBS-D). No additional diagnostic testing was pursued at that time. She pursued a second opinion from another gynecologist who also attributed her symptoms to "bad periods," without having conducted any additional testing.

Nine years after the onset of her severe menstrual symptoms and six years after the onset of her disabling abdominal pain and diarrhea, she was referred to a gastroenterology (GI) specialist. The specialist performed a colonoscopy that showed only a "tortuous bowel." She was told that this finding confirmed her diagnosis of IBS-D. 

Three years later, the patient experienced “sharp” right-sided abdominal pain. She had an urgent computed tomography scan, which was interpreted as showing acute appendicitis, and was directed to the emergency room, where she was admitted for an emergency appendectomy by a general surgeon. At her postoperative appointment, the surgeon informed her that the procedure was prolonged due to endometriosis lesions close to the appendix. The patient was informed that these lesions caused the appendix to become infected. The surgeon did not call in a gynecological surgeon during the surgery or complete a biopsy. He also did not remove any of the suspected endometriosis as he feared causing further spread of endometriosis cells. The surgeon referred her to a gynecologist.

Once the diagnosis was made by the general surgeon, the patient continued to experience delays in accessing appropriate treatment due to medical insurance coverage issues and often intolerable medication side effects from hormonal treatments – metabolic changes with weight gain as well as psychological and emotional derangements including anxiety and depression. Ultimately the patient underwent a diagnostic laparoscopy to confirm endometriosis via biopsy, and definitive surgery: laparoscopic wide-field excision of the endometriosis, which was performed 12 years after her symptoms started.

Looking back, from the onset of her periods, the patient felt that her physicians had implied that the severity of her symptoms was due to a mental health condition. She stated that throughout this time, her symptoms were often dismissed as psychological and she was made to feel that “she was crazy.” Without a strong advocate (her mother), she felt that physicians would not have pursued additional diagnostic testing and effective treatment. 

The Commentary

By Malcom Mackenzie, MD and Celeste Royce, MD

This case demonstrates many typical features of both endometriosis and its misdiagnosis. Despite a prevalence of 1–8.6% of women of reproductive age, rising to 9-68% of infertile women, and 15-71% of women with chronic pelvic pain,1-3 it is often not diagnosed in a timely or accurate way. Average delays range from 6 to 11 years, often despite disabling and ongoing symptoms,4 with symptoms being “treated” for years despite patients not having received a definitive diagnosis.5 Endometriosis poses a particular diagnostic challenge both because it can involve multiple organs (see below) and because female pelvic pain itself is a highly complex, multifactorial and often difficult to treat condition. Nonetheless, the most commonly recognized etiology for chronic pelvic pain is endometriosis, adenomyosis and associated spasms of pelvic floor muscle.6

Missed Opportunities for a Timely Diagnosis and Treatment

Several aspects of this case illustrate common causes of the delay in diagnosis frequently observed with endometriosis. When the patient initially sought care, she was given a diagnosis of primary dysmenorrhea. Although primary dysmenorrhea is common,7 it is a diagnosis of exclusion; other etiologies should be considered. The first gynecologist seems to have not considered other etiologies as no testing was performed. This gynecologist may have not considered endometriosis in such a young adolescent, as this patient did not “fit” the more common presentation of an older adolescent or young adult. This problem has been described as “representativeness restraint” (or heuristic) because a physician focused on recognizing common patterns may overlook atypical variants of the disease. The patient’s symptom of heavy bleeding was particularly worrisome; evaluation for von Willebrand’s disease should be part of the workup for heavy bleeding at menarche. Imaging is not always indicated as part of the initial workup for primary dysmenorrhea, particularly if the patient’s menstrual cycles are regular. However, testing for sexually transmitted infections, coagulation disorders, and anemia should be performed, along with a physical exam to detect structural anomalies such as partially imperforate hymen. It is impossible to know if the first gynecologist considered endometriosis; since the initial treatment for endometriosis consists of non-steroidal anti-inflammatory agents and combined oral contraceptives, it is possible that these medications were prescribed for symptom relief and as empiric treatment of possible endometriosis. Premature closure on the diagnosis of dysmenorrhea resulted in no further investigation.

When the patient did not improve despite adequate first-line therapy for dysmenorrhea, an opportunity for improved care and diagnosis was missed. Persistent dysmenorrhea should have prompted further search for the etiology of her symptoms. Diagnostic evaluation may include imaging, but the gold standard for diagnosis of endometriosis is laparoscopy with peritoneal biopsy of any suspected lesions. Delaying or not considering diagnostic laparoscopy in a young adolescent may have reflected bias, in that the gynecologist may have assumed a young person would rather not have surgical scars or be physically exposed in the operating room, due to a potentially “unnecessary” surgery. This type of paternalism may play a role in gynecologists’ reluctance to suggest diagnostic surgery, and results in a missed opportunity for shared decision-making with patients and their families. Accepting a patient’s “painful periods” as a condition of womanhood is another stereotypical bias that may have played a role in limiting the workup.

The second gynecologist also contributed to the delayed diagnosis. This consultant clearly accepted the working diagnosis of primary dysmenorrhea and did not pursue further diagnostic testing. The cognitive bias of anchoring (wherein first diagnostic impressions persist or are even cemented despite contradictory evidence) seems to have prevented consideration of any other explanation.8 To be fair, however, the same hormonal management or variations of it – progesterone-only pills, implants, shots or intrauterine devices – would have been a standard treatment for either primary dysmenorrhea or endometriosis.

When the patient later developed gastrointestinal symptoms, the primary care provider made a diagnosis of IBS-D based on those symptoms. A search-satisfying diagnostic error9 seems to have then occurred, as no further workup was performed for several years. The lack of an evaluation for what is described as “severe” diarrhea is also concerning because other infectious or inflammatory gastrointestinal conditions could have been missed. As bowel involvement by endometriosis typically begins with serosal implants that later grow or erode into the mucosa, it is unlikely that endometriosis would have been identified, even if this patient had undergone imaging or colonoscopic evaluation. 

Indeed, when colonoscopy was performed several years later, no mucosal abnormalities were identified, leading to “confirmation” of the previous syndromic diagnosis of IBS-D. The gastroenterologist noted tortuosity, which may have been a sign of colo-sigmoid fixation to the pelvic sidewalls, the posterior uterine wall or the left pelvic brim. But tortuosity is a nonspecific finding of uncertain significance, and its link to a gynecologic condition (e.g., extraluminal endometriosis-induced tissue adherence) probably wasn’t recognized by the gastroenterologist as a cause of GI symptoms.

The Challenges in Diagnosing Endometriosis

This 15-year-old with menarchal onset of severe dysmenorrhea to the point of disability was appropriately seen by a gynecologist who rightly started hormonal suppression of her “bad periods.” The first line treatment, oral contraceptives (and presumably NSAIDs), was consistent with a diagnosis of endometriosis being considered. The workup for primary dysmenorrhea might include an ultrasound to look for anatomic abnormalities of the uterus, fallopian tubes or ovaries, but endometriosis most often is not “visible” on imaging, as adhesions can be difficult to identify via this diagnostic method.10 It is important for clinicians to consider the limitations of imaging studies when interpreting results, especially for endometriosis.11

Pain is the most common feature of endometriosis that leads patients to seek care. The main types of pain experienced by patients with endometriosis include:

  1. Dysmenorrhea - Pain with periods, initially cyclical. Not all endometriosis patients present with truly cyclic pain, but the presence of it does increase likelihood a patient has endometriosis. Missing school because of dysmenorrhea when in middle school has a high positive predictive value for this condition.12,13 Additional factors suggesting the diagnosis include a first-degree family history of endometriosis, cyclic dysmenorrhea that interrupts activities of daily living, and onset of dysmenorrhea with menarche.  Unfortunately, societal and cultural expectations of dysfunction and pain during menses are common, even when the severity of the pain leads to missed school or work, or to visits to the emergency department.
  2. Dyspareunia - Pain with intercourse, specifically deep pelvic pain, which may be unilateral and persist sometimes for hours or days after intercourse. This can be a compelling reason for patients to seek care but is often misinterpreted by patients and physicians as a normal consequence of sexual activity.

Another key difficulty in diagnosing endometriosis is that it does not necessarily present as a purely gynecologic condition. Ectopic endometrial tissue implants throughout the pelvis and abdomen may have deleterious effects on all involved structures, leading to pain and dysfunction of the involved organ(s). Implants may be on:

  1. Bowel - Leading to diarrhea, constipation, nausea, vomiting, bloating, rectal bleeding, food intolerances, and even bowel obstruction in advanced disease. Since implants are serosal, they are typically missed on colonoscopy, and since they are often microscopic or very small in size, they may not be visible on imaging. Many endometriosis patients carry a prior GI diagnosis, such as irritable bowel syndrome or Crohn’s disease, that was not determined through biopsy. Endometriosis has been found in 3-5% of appendix specimens removed at laparoscopy among women with chronic pelvic pain.14
  2. Bladder/Ureters - Leading to recurrent UTI-like symptoms, hematuria, painful voiding, incontinence, bladder spasm, and potentially to ureteral obstruction that can lead to renal failure. Many patients express histories or are diagnosed with “recurrent UTIs” despite having received no testing, or even negative test results, for them or carry a presumptive diagnosis of interstitial cystitis (IC) based on minimal cystoscopic findings. 
  3. Peripheral Nerves - Leading to leg pain, abdominal muscle pain, chronic back pain, and rarely to loss of function and disability. Cases associated with sciatica and paraplegia have been documented.15
  4. Diaphragm and Thorax - Leading to chronic shoulder pain, pleuritic chest pain, and sometimes to erosive lesions that may cause hemo- and pneumo-thorax and pericarditis.16

Given this possibility of multi-organ involvement, patients with endometriosis are often referred to multiple specialists, contributing to a delay in diagnosis while alternative etiologies are considered. Patients sometimes describe taking a “grand tour”17 of specialists including not just gastroenterologists but endocrinologists for metabolic syndrome/polycystic ovarian syndrome, rheumatologists for undifferentiated inflammatory conditions, neurologists for neuropathic conditions, and orthopedics for chronic back pain, leg pain or even shoulder pain. After many years of unremitting pain with no apparent cause (and sometimes earlier in their diagnostic journey), patients are commonly referred to psychiatrists for anxiety and depression, often as a consequence rather than the cause of pain.

The Correct Diagnosis is Finally Made

Not until the patient in this case had acute abdominal pain with appendicitis did she receive the correct diagnosis – and ironically, the diagnosis was made without a biopsy. It is commendable the general surgeon recognized endometriosis might be present; however, if the diagnosis is in doubt, biopsy of a representative lesion and removal of visible lesions is recommended.3 Biopsy is considered the gold standard for diagnosis, but the need for biopsy-proven disease has been debated.3 If a surgeon does not feel comfortable with performing a biopsy, as in this case, or is unsure of the need for one, holding an intraoperative gynecologic consultation is the preferred course of action, but referring a patient to a gynecologist postoperatively is also reasonable. However, the intraoperative management in this case demonstrated a lack of understanding by the general surgeon of the natural history of endometriosis; disease dissemination does not occur as a consequence of excisional biopsy – a confusion perhaps between the malignant and the benign (endometriosis).18

After further delays in the patient accessing care due to insurance issues, a gynecologist made a definitive diagnosis of the presence of endometriosis based on pathology.19 It is unclear from the literature if pathologic confirmation of diagnosis is cost-effective; a 2000 study showed three months of empiric treatment for endometriosis to be less costly than laparoscopy.20 A more recent Cochrane meta-analysis review points out that non-surgical diagnoses via physical findings combined with transvaginal ultrasound imaging have greater or similar accuracy and lower risks than laparoscopy and therefore approach the criteria required to replace laparoscopy.21 Shared decision-making about surgery should include a clear explanation of the risks and potential benefits of undergoing the surgery and take into account the patient’s preferences. In the adolescent population, an aggressive approach to primary dysmenorrhea may result in an unacceptably high rate of surgical intervention.22

For this patient, it seems clear that, given the failure of multiple trials of medical therapy, laparoscopic evaluation should have been performed much earlier. Surgical treatment of endometriosis by removal or ablation of recognized implants provides significant symptom relief, often long-lasting. The use of subsequent hormonal treatment or suppression is of unclear benefit.23 Absent surgical treatment, patients often continue to experience symptoms.24

According to the patient in this case, perhaps the most damaging aspect of the disease was not the symptoms or the side effects of treatment but rather the persistent dismissal of her symptoms as “normal.” This experience of “victim-blaming” – the implication that her symptoms were psychogenic or in some way self-induced – is commonly reported by endometriosis patients.25 Viewed in this light, the associated anxiety and depression are not unexpected. Alienation from the healthcare system due to emotional distress is common and may further delay diagnosis. Many endometriosis patients have an intuitive sense that something is desperately wrong as they suffer from persistent pain and dysfunction. Repeated dismissal of their symptoms and their experience is understandably devastating.25 On a health systems level, the historic and systemic under-investment in women’s health26 -  from education of trainees to research in effective treatments for conditions unique to women - magnifies the alienation and distrust that can develop from professional disregard of the lived experience of women who feel the pain of endometriosis and have often long suffered with its symptoms. The evaluation of adolescents with severe dysmenorrhea – who may have difficulty advocating for themselves - represents another realm in which healthcare professionals need to listen to and believe their patients.

Take-Home Points

  • The presentation of endometriosis often involves multi-organ symptoms.
  • The prolonged average time interval from symptom onset to diagnosis of endometriosis is the result of fundamental misconceptions and gaps in knowledge regarding the disease, its pathogenesis, natural history, presentation, limited utility of imaging, and treatment.
  • Because endometriosis often involves multiple organ systems including GI, genitourinary, peripheral nervous, and respiratory systems, patients are often referred to specialists who need to consider this diagnosis. Likewise, primary care physicians and gynecologists need to fully appreciate the myriad “non-gynecologic” manifestations of this disease.
  • Imaging studies to diagnose endometriosis frequently result in false negative findings and providers must consider the limitations of these studies instead of dismissing patients’ symptoms.
  • Failure of standard hormonal treatment to provide symptom control does not necessarily mean that the diagnosis of endometriosis is incorrect.
  • Accurate diagnosis of endometriosis requires active and empathetic listening to patients’ complaints, informed by an understanding of the presentation and additional medical history of the patient and, most importantly, avoidance of “normalizing” pain.
  • Although not germane to this particular case, it is important to note that endometriosis can occur in trans and non-gender-conforming people and lack of understanding this fact could make diagnosis in these populations even more challenging. Therefore, endometriosis should be considered in the differential diagnosis for any person presenting with chronic abdominal or pelvic pain.

 

Malcolm Mackenzie, MD
Assistant Professor
Harvard Medical School
Mount Auburn Hospital

Celeste Royce, MD
Assistant Professor of Obstetrics, Gynecology and Reproductive Biology

Harvard Medical School
Beth Israel Deaconess Medical Center

Acknowledgements:

The long standing process for submitting PSNet WebM&M case submissions is anonymous. Users may contribute by submitting a case at the following link: https://psnet.ahrq.gov/webmm/submit-case

Periodically, the Primary-Care Research in Diagnosis Errors (PRIDE) Learning Network, a collaborative project convened by the Brigham and Women’s Hospital Center for Patient Safety Research and Practice, and the State of Massachusetts Betsy Lehman Center for Patient Safety, will submit cases and commentaries to PSNet.  This case was produced in cooperation with the PRIDE Learning Network, PRIDE is funded by a grant from the Gordon and Betty Moore Foundation. The case was submitted by Madalene Zale, MPH and Allyson Bontempo, MA PhD candidate.

We acknowledge the support of the project RAs, Jason Ramos and Sevan Delgarian, and the assistance of the PRIDE project director Maria Mirica, PhD, in preparing this case discussion.  Editorial support and review for this case was provided by Narath Carlile, MD, MPH, and Gordon Schiff, MD.

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