Educational Case: Endometriosis

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A 24-year-old woman with no previous medical history presents to her gynecologist after 6 months of worsening dull, diffuse pelvic pain and heavier than usual menstrual periods. Her last menstrual period was approximately 4 weeks ago. She reports constant pelvic pain that is worse during menstruation, sharp in nature, and more prominent on her right side. She also reports dyspareunia and dysuria, both of which are worse during menses. She does not report fever, amenorrhea, nausea, vomiting, diarrhea, and dyschezia. She reports a family history of uterine and ovarian cancer and denies family history of breast cancer. She further describes that prior to these symptoms, her cycle would last between 29 and 32 days, and she would bleed for about 4 days, using between 2 and 3 pads on her heaviest day of flow. Currently her cycle length has not changed, but she notes that she now bleeds closer to 6 days per cycle and requires 4–5 pads per day. She does not report any history of significant disease. She takes over-the-counter ibuprofen for her pain symptoms but does not otherwise take any other medications or supplements. She is currently sexually active with one male partner and utilizes barrier contraceptives. She has had no prior pregnancies and expresses future desire for pregnancy.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see https://www.academicpathologyjournal.org/pcme . 1 Objective FU2.4: Abnormal Uterine Bleeding. Discuss the causes of abnormal uterine bleeding, including hormonal disturbances, anovulatory cycle, endometriosis, acute and chronic endometritis, and endometrial polyps. The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see https://www.academicpathologyjournal.org/pcme . 1 Competency 2: Organ System Pathology; Topic FU: Female Reproductive – Uterus, Cervix and Vagina; Learning Goal 2: Non-neoplastic Uterine Disorders.

• Abnormal uterine bleeding is defined by irregularities of frequency, duration, regularity, and flow volume related to menstruation. • The PALM-COEIN classification system developed by FIGO describes the structural and nonstructural causes of abnormal uterine bleeding. Structural causes of abnormal uterine bleeding include polyps, adenomyosis, leiomyoma, and malignancy, while nonstructural causes include coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic, and a category for causes that cannot otherwise be classified. • Adenomyosis and endometriosis share presenting symptoms, but adenomyosis is the growth of endometrial tissue specifically within the myometrium, while endometriosis involves endometrial tissue grows anywhere outside of the uterus. • Endometriosis is a common disease that may affect up to 10% of reproductive-age women and has a wide range of clinical presentations that are dependent on the location of endometrial lesions. Chronic cyclic pelvic pain that worsens in prior to onset of menses is among the most common presentations. Other presentations may include abnormal uterine bleeding, dysuria, dyspareunia, and noncyclic pain. • Common gross pathologic findings include red-blue to yellow-brown nodules of ectopic endometrial tissue on the serosal surface at sites of involvement, as well as “powder burn” lesions. More advanced stages of disease may have thick fibrous adhesions. Microscopic findings include endometrial glands and stroma, as well as hemosiderin-laden macrophages in extrauterine tissue. • The etiology of endometriosis is complex and not entirely understood, though mechanisms thought to be implicated include retrograde menstruation, coelomic metaplasia, and lymphatic dissemination of endometrial tissue. • Peritoneal cavity bleeding associated with endometriosis causes local inflammation that leads to self-sustaining production of prostaglandins, resulting in chronic pain that is not necessarily associated with the menstrual cycle. This chronic inflammation may also lead to formation of fibrous adhesion that cause strictures and alter local anatomy, leading to complications such infertility, ectopic pregnancy, urinary retention, and constipation. • First line treatment for endometriosis includes a combination of NSAIDs and hormonal contraceptives, though a patient's reproductive goals will influence the recommendation of hormonal therapies. Conservative surgical treatments include laparoscopic excision and ablation of endometrial lesions, though hysterectomy remains an option for those with symptoms refractory to conservative medical and surgical management. Abnormal uterine bleeding is defined by irregularities of frequency, duration, regularity, and flow volume related to menstruation. The PALM-COEIN classification system developed by FIGO describes the structural and nonstructural causes of abnormal uterine bleeding. Structural causes of abnormal uterine bleeding include polyps, adenomyosis, leiomyoma, and malignancy, while nonstructural causes include coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic, and a category for causes that cannot otherwise be classified. Adenomyosis and endometriosis share presenting symptoms, but adenomyosis is the growth of endometrial tissue specifically within the myometrium, while endometriosis involves endometrial tissue grows anywhere outside of the uterus. Endometriosis is a common disease that may affect up to 10% of reproductive-age women and has a wide range of clinical presentations that are dependent on the location of endometrial lesions. Chronic cyclic pelvic pain that worsens in prior to onset of menses is among the most common presentations. Other presentations may include abnormal uterine bleeding, dysuria, dyspareunia, and noncyclic pain. Common gross pathologic findings include red-blue to yellow-brown nodules of ectopic endometrial tissue on the serosal surface at sites of involvement, as well as “powder burn” lesions. More advanced stages of disease may have thick fibrous adhesions. Microscopic findings include endometrial glands and stroma, as well as hemosiderin-laden macrophages in extrauterine tissue. The etiology of endometriosis is complex and not entirely understood, though mechanisms thought to be implicated include retrograde menstruation, coelomic metaplasia, and lymphatic dissemination of endometrial tissue. Peritoneal cavity bleeding associated with endometriosis causes local inflammation that leads to self-sustaining production of prostaglandins, resulting in chronic pain that is not necessarily associated with the menstrual cycle. This chronic inflammation may also lead to formation of fibrous adhesion that cause strictures and alter local anatomy, leading to complications such infertility, ectopic pregnancy, urinary retention, and constipation. First line treatment for endometriosis includes a combination of NSAIDs and hormonal contraceptives, though a patient's reproductive goals will influence the recommendation of hormonal therapies. Conservative surgical treatments include laparoscopic excision and ablation of endometrial lesions, though hysterectomy remains an option for those with symptoms refractory to conservative medical and surgical management.

Objective FU2.3: Uterine Adenomyosis. Compare and contrast the pathology of adenomyosis with endometriosis. Competency 2: Organ System Pathology; Topic FU: Female Reproductive – Uterus, Cervix, and Vagina; Learning Goal 2: Non-neoplastic Uterine Disorders.

Fig. 1 is a representative image of the gross appearance of an endometrioma on laparoscopy. They are often described as a “chocolate cyst” because of their dark coloration stemming from blood filling the endometriotic tissue. These lesions are biopsied to confirm the suspected endometriosis diagnosis. Fig. 2 is a representative image of a low-power histology slide with hematoxylin and eosin stain taken from a biopsy of an ovarian endometrioma. On the histology slide, the endometrial glands and stroma can clearly be seen surrounded by normal ovarian tissue. Fig. 1 Representative image of right ovary with “chocolate cyst” appearance of ovarian endometrioma. Image from Copyright © 2012 Schipper and Nezhat, publisher and licensee Dove Medical Press Ltd. ( https://pmc.ncbi.nlm.nih.gov/articles/PMC3422109/ ), shared under CC BY-SA 3.0 license terms ( https://creativecommons.org/licenses/by-sa/3.0/legalcode ). Fig. 1 Fig. 2 Intermediate magnification representative image of hematoxylin and eosin-stained histological findings from biopsy of ovarian lesion, demonstrating endometrial glands and stroma among normal ovarian tissue. Image courtesy of Copyright © 2011 Michael Bonert, MD, FRCPC ( https://commons.wikimedia.org/wiki/File:Endometriosis_of_the_ovary.jpg#Licensing ), shared under CC BY-SA 3.0 license terms ( https://creativecommons.org/licenses/by-sa/3.0/legalcode ). Fig. 2 Representative image of right ovary with “chocolate cyst” appearance of ovarian endometrioma. Image from Copyright © 2012 Schipper and Nezhat, publisher and licensee Dove Medical Press Ltd. ( https://pmc.ncbi.nlm.nih.gov/articles/PMC3422109/ ), shared under CC BY-SA 3.0 license terms ( https://creativecommons.org/licenses/by-sa/3.0/legalcode ). Intermediate magnification representative image of hematoxylin and eosin-stained histological findings from biopsy of ovarian lesion, demonstrating endometrial glands and stroma among normal ovarian tissue. Image courtesy of Copyright © 2011 Michael Bonert, MD, FRCPC ( https://commons.wikimedia.org/wiki/File:Endometriosis_of_the_ovary.jpg#Licensing ), shared under CC BY-SA 3.0 license terms ( https://creativecommons.org/licenses/by-sa/3.0/legalcode ).

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The characteristic “chocolate cyst” appearance on laparoscopy, as well as the presence of endometrial glands and stroma on biopsy of involved serosa, confirms the diagnosis of endometriosis. Endometriosis is a gynecologic disorder characterized by the presence of ectopic endometrial tissue present outside of the uterus. Despite the high prevalence of the disease affecting up to 10% of reproductive-age women and causing significant clinical consequences such as dysmenorrhea, pelvic pain, and infertility, no single definitive pathogenic mechanism has been identified. 8 Several proposed theories include: retrograde menstruation, coelomic metaplasia, lymphatic spread, and the extrauterine stem/progenitor cell theory. The most supported of these theories, originally proposed by Sampson in 1927 and since supported by research in animal models, involves retrograde menstruation through the fallopian tubes. 9 , 10 In this theory, viable portions of endometrium shed during menstruation move backwards through the fallopian tubes and eventually into the peritoneal cavity to implant on structures such as the ovaries, bladder, and peritoneal wall. This theory is straightforward and supported by observations that women with menstrual outflow obstructions have an increased incidence of endometriosis. 8 The retrograde flow theory, however, does not account for cases of endometriosis found outside of the peritoneal cavity or cases of premenarcheal endometriosis. An alternate theory that could explain cases of extraperitoneal endometriosis is known as the coelomic metaplasia theory, which postulates that endometriosis originates from cells that undergo endometrial metaplasia in response to certain substances, namely estrogen. 8 , 11 This theory can explain extraperitoneal endometriosis, as well as rare cases of endometriosis in biological males undergoing estrogen therapy and biological females with Mullerian agenesis. 12 , 13 Another theory involves the transfer of endometrial tissue through lymphatic drainage to distant sites, a mechanism reminiscent of metastatic spread of malignant cells. 14 Lymphatic spread by this mechanism has been supported by findings of endometriosis within distant lymphatic sites such as para-aortic lymph nodes. 15 It has also been suggested that stem cells within bone marrow may develop into endometrial stroma and then travel and implant at sites outside of the uterus. 6 This theory may offer an explanation as to how endometrial lesions occur in areas of the body that are not directly related to the uterus. Endometrial lesions can be one of three types: superficial peritoneal, ovarian endometrioma, and deep infiltrating endometriosis. Superficial peritoneal lesions occur when endometrial cells implant on the peritoneum and are able to grow in the surrounding peritoneal fluid; they and can be red, black, or white peritoneal lesions. 16 Ovarian endometriomas are classified as ovarian cysts that contain brown endometrial fluid and are encased in endometrial epithelium, often described as “chocolate cysts”. 17 Deep infiltrating endometriosis (DIE) does not currently have an agreed-upon definition, but is most commonly defined as endometriosis lesions that are over 5 mm deep under the peritoneal surface. 18 In addition to classification, endometrial lesions may also be staged based on the degree and location of invasion, using scoring systems such as one proposed by Lee et al. in 2021. 19 Endometriotic implants themselves, specifically DIE lesions, display molecular alterations similar to malignant tissues. The implants release proinflammatory and angiogenic factors such as prostaglandin E2 (PGE2), interleukin-1beta (IL-1β), tumor necrosis factor alpha (TNFɑ), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and matrix metalloproteases (MMPs). These factors are released by the lesions themselves as well as recruited macrophages. DIE lesions must withstand unfavorable environments such as the bowel and vagina, and thus utilize differentiation strategies involving the induction and control of specific inflammatory pathways, such as those involving sphingosine-1-phosphate (S1P) and IL-1b, as well as neovascularization via overexpression of VEGF. 20 , 21 They also utilize MMPs to remodel the extracellular matrix to further support their survival. 6 Estrogen plays a large role in endometrial lesion survival. The enzyme aromatase, which is usually absent in regular endometrial stroma, is present in endometriotic stromal cells. This leads to increased estrogen production and endometriotic lesion proliferation. PGE2 is also able to induce the local production of estrogen. Deoxyribonucleic acid (DNA) alterations within endometriotic tissue also lead to increased responsiveness of the stroma to estrogen, further amplifying increased estrogen production. Additional DNA alterations occur in tumor suppressor genes such as Kristen rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit alpha (PIK3CA), protein phosphatase 2 scaffold subunit alpha (PPP2R1A), and AT-rich Interaction Domain 1A (ARID1A). These mutations are hypothesized to contribute to the aggressive nature of endometriotic lesions, especially DIE. In some cases of concurrent endometriosis and ovarian carcinoma, the malignant lesions have the same mutations as the endometriotic lesions, suggesting that these driver mutations in tumor suppressor genes play a role in pathogenicity of premalignant and malignant lesions. There is an association between endometriosis and ovarian cancers, such as clear cell type and endometrioid type, with some studies showing as high as a threefold increase in ovarian cancer in patients with endometriosis compared to those without. 6 Population studies have shown an over two-fold increased risk of developing endometriosis in the daughters of affected mothers when compared to those unaffected, implying a genetic component to the development of endometriosis. 22 Other studies have found an association between endometriosis and the HLA-B7 (Human Leukocyte Antigen) allele, which inhibits the cytotoxic capabilities of NK-like T lymphocytes and allows for ectopic growth of endometrial tissue. 23 While endometriosis and adenomyosis present with similar symptoms including, but not limited to, dysmenorrhea, menorrhagia, and noncyclic pelvic pain, adenomyosis is defined as growth of endometrial tissue specifically within the myometrium, whereas endometriosis is the growth of endometrial tissue anywhere outside of the uterus. Adenomyosis is more common in parous females, while there is a lower risk of endometriosis in nulliparous females. 24 Additionally, adenomyosis is more commonly diagnosed in females aged 35–50 years, while endometriosis is more commonly diagnosed in females aged 25–29 years. 25 Transvaginal ultrasound and MRI are key imaging studies to differentiate between these two disease processes. Findings on transvaginal ultrasound in adenomyosis include uterine enlargement, asymmetrical enlargement of the anterior or posterior myometrium, and heterogenous and poorly circumscribed areas within the myometrium. 26 Findings in endometriosis include ovarian cystic endometriomas, free fluid in the pouch of Douglas, and solid hypoechoic endometriotic nodules. 27 On MRI, focal or diffuse junctional zone hyperplasia within the myometrium is seen in adenomyosis, whereas in endometriosis, lesions that contain blood such as endometriomas “powder burn” lesions will demonstrate an intense T1 signal. 26 , 28 Regardless of the location of the lesions, patients typically present initially with cyclical worsening of symptoms. The ectopic endometrial tissue is responsive to the cyclical pattern of hormones during the menstrual cycle; dysmenorrhea and menorrhagia experienced with endometriosis is due to the shedding of ectopic endometrial tissue, and this bleeding in sites outside of uterus leads to different symptomology and later complications in different patients, such as dyspareunia, abdominal adhesions, and dysuria. One of the most common sites for endometriosis is the ovaries, and cystic lesions at this location are known as endometriomas. Repeated menstruation into these cysts leads to a buildup of blood and tissue debris, giving these cystic lesions a characteristic chocolate-filled appearance. 8 Other common sites for endometriosis include uterine serosa, fallopian tubes, and uterosacral ligaments. Bladder and urinary tract endometriosis are relatively rare, and symptoms of hematuria and dysuria are more common, along with urgency and frequency. Rectosigmoid colon involvement can present with gastrointestinal symptoms including dyschezia, hematochezia, constipation, or diarrhea. Rectal symptoms warrant imaging with transrectal ultrasound to screen for colorectal cancer, given the similar presenting symptoms. Complications of endometriosis depend on several factors, including the size and location lesions as well as the extent of disease. Patients with any cause of abnormal uterine bleeding, including endometriosis, are at increased risk for developing iron deficiency anemia. Endometriosis may also result in chronic pain. Arachidonic acid is released by phospholipase A2 during menses due to endometrial shedding and bleeding. This is presented to cyclooxygenase 2 (COX2), which converts it to prostaglandin H2 (PGH2), which is then converted to prostaglandin E2 (PGE2). PGE2 is known to be responsible for pain by binding to the prostaglandin E receptors (EP) 1–4. This process, originally set off by phospholipase A2, is self-sustaining, as PGE2 induces COX2 production, which further increases the production of PGE2, leading to chronic pelvic pain. 29 Chronic bleeding into the peritoneal cavity leads to local inflammation, contributing to the cyclic pain observed with endometriosis; this local inflammation may also cause formation of fibrous adhesions between nearby structures. These adhesions are a component of the chronic, noncyclic pain observed in patients with endometriosis, as well as a myriad of complications such as constipation, urinary retention, and infertility. Infertility is a particularly notable complication of endometriosis, as infertility is the primary presenting symptom among 30–40% of patients with endometriosis, and in many cases, may be the only complaint. 6 The pathogenesis of infertility is multifactorial, with inflammation and adhesions contributing to structural causes of infertility, while dyspareunia decreases the frequency of sexual intercourse. 11 Endometriosis is also associated with an increased risk of ectopic pregnancy due to obstruction of the uterotubal junction. Additional pregnancy-related complications include increased risk of miscarriage, placenta previa, antepartum or postpartum hemorrhage, and preterm births along with rare cases of endometrioma rupture during pregnancy. 30 , 31 As previously mentioned, endometriotic lesions behave similarly to malignant tissues, with some of the same driver mutations, and confer a slight elevation in risk for development of ovarian cancer. 32 First-line treatments for endometriosis are nonsteroidal anti-inflammatory drugs (NSAIDs) because they are safe over-the-counter options that directly inhibit the cyclic production of prostaglandins implicated in the disease process leading to chronic pain. NSAIDs are typically combined with hormonal contraceptives in treatment of endometriosis, but the patient's desire regarding pregnancy and overall reproductive goals are taken into consideration when determining whether to recommend hormonal therapy. If pregnancy is not an immediate desire, then combined estrogen/progestin oral contraceptives are usually next line treatments. If pregnancy is desired, gonadotropin-releasing hormone analogs and Danazol are usually next. 33 It should be noted that Danazol has teratogenic possibilities and should be discontinued if the patient becomes pregnant. Hormonal therapies treat endometriosis by producing either a high progesterone or low estrogen environment, known as pseudopregnancy or pseudomenopausal states, respectively. If medical therapy fails, surgical ablation and excision can be used to remove deposits and endometriomas, respectively. If the patient does not desire pregnancy in the future and has failed medical and conservative surgical treatments, hysterectomy can also be considered. 33