Educational Case: Endometrial ectopia in endometriosis and adenomyosis

The article processing fee for this article was funded by an Open Access Award given by the Society of ‘67, which supports the mission of the Association of Pathology Chairs to produce the next generation of outstanding investigators and educational scholars in the field of pathology. This award helps to promote the publication of high-quality original scholarship in Academic Pathology by authors at an early stage of academic development. Carolyn Chen is supported by a Dubbs Scholar Fellowship Award from Thomas Jefferson University, and an NIH training grant T32 AR052273.

A 34-year-old G0P0 woman presents to her primary care physician with chronic pelvic pain. During the past year, she reports a dull abdominal pain in her right lower quadrant that worsens before and during the time of her monthly menses. One to two weeks prior to menses, the patient has bloating and dull abdominal pain. During menses, the patient has severe dysmenorrhea accompanied by loose stool and vomiting. She has not seen blood in her stool. The abdominal pain is not relieved with over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs). Her periods occur regularly every 28 days, and menses lasts 5–7 days with normal patterns of bleeding. The patient does not report heavy menstrual bleeding or bleeding in between her periods. She is sexually active and monogamous with her husband. Currently, she does not use any form of contraception as she and her husband have been actively trying to conceive for the past 13 months. So far, they have not had success and are concerned about infertility. Starting 6 months ago, the patient has also been having mild pain during intercourse. The patient has no past medical history, including sexually transmitted infections (STIs) or abnormal pap smears, no prior surgeries, and takes no medications other than daily prenatal vitamins. Her 30-year-old sister also suffers from dysmenorrhea, and she has no family history of cancer diagnosed before the age of 70 years old. The patient's vital signs are within normal limits. Abdominal examination shows pain upon deep palpation in the right lower quadrant (RLQ) with no guarding or rebound tenderness. Bowel sounds are present. Pelvic examination reveals adnexal tenderness with no palpable masses identified.

Objective FU2.3: Uterine Adenomyosis. Compare and contrast the pathology of adenomyosis with endometriosis. Competency 2: Organ System Pathology; Topic FU: Female reproductive—Uterus; Learning Goal 2: Nonneoplastic Uterine Disorders.

• Adenomyosis and endometriosis are benign diseases that localize to the uterine myometrium or extrauterine organs, respectively. 2 , 5 , 7 • Histologically, adenomyosis and endometriosis are characterized by ectopic, benign endometrial glands and stroma. 2 • The endometrial tissue in both diseases is physiologically normal and proliferates in response to estrogen, resulting in inflammation and cellular damage of surrounding tissue. 2 , 5 • Intestinal endometriosis may present with abdominal pain, diarrhea, and constipation. 10 • Diagnostic laparoscopy is the gold standard for diagnosis for endometriosis and results in significantly increased detection and diagnosis of endometriosis compared to MRI alone. 8 • Management of endometriosis relies on the conglomeration of multiple factors, including clinical presentation, imaging, response to medical treatment, extent of disease seen in diagnostic laparoscopy, and histological confirmation. 10 • Definitive diagnoses for adenomyosis and endometriosis are made through MRI and diagnostic laparoscopy, respectively. 5 , 8 , 12 • Adenomyosis commonly coexists with endometriosis and uterine leiomyomas. 13 Adenomyosis and endometriosis are benign diseases that localize to the uterine myometrium or extrauterine organs, respectively. 2 , 5 , 7 Histologically, adenomyosis and endometriosis are characterized by ectopic, benign endometrial glands and stroma. 2 The endometrial tissue in both diseases is physiologically normal and proliferates in response to estrogen, resulting in inflammation and cellular damage of surrounding tissue. 2 , 5 Intestinal endometriosis may present with abdominal pain, diarrhea, and constipation. 10 Diagnostic laparoscopy is the gold standard for diagnosis for endometriosis and results in significantly increased detection and diagnosis of endometriosis compared to MRI alone. 8 Management of endometriosis relies on the conglomeration of multiple factors, including clinical presentation, imaging, response to medical treatment, extent of disease seen in diagnostic laparoscopy, and histological confirmation. 10 Definitive diagnoses for adenomyosis and endometriosis are made through MRI and diagnostic laparoscopy, respectively. 5 , 8 , 12 Adenomyosis commonly coexists with endometriosis and uterine leiomyomas. 13

The patient has a colonoscopy which shows a prominent appendiceal orifice but is otherwise normal. The patient then undergoes diagnostic laparoscopy, which reveals scarring in the anterior cul-de-sac and round ligaments as well as adhesions of the right fallopian tube and ovary to the pelvic side wall. The laparoscopy is also notable for fullness in the appendix and a possible cecal mass. The cecal region of interest is resected from the serosal side during this procedure.

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 article.

Fig. 1 is taken from the laparoscopic biopsy of the cecum. Describe the histology of this tissue. Fig. 1 Histological section from the cecectomy specimen, taken laparoscopically. The stain used is hematoxylin and eosin with an original magnification of (A) 20x and (B) 100x. Arrows point to intestinal mucosa (red) and ectopic endometrial stroma (black). Contents within the dotted outline in (A) are magnified in (B). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) Fig. 1 Histological section from the cecectomy specimen, taken laparoscopically. The stain used is hematoxylin and eosin with an original magnification of (A) 20x and (B) 100x. Arrows point to intestinal mucosa (red) and ectopic endometrial stroma (black). Contents within the dotted outline in (A) are magnified in (B). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) Histology of the resected cecal tissue reveals stromal cells that are small and spindled without distinct cell borders and glandular epithelium with basally located round to oval nuclei with abundant apical eosinophilic cytoplasm. The ectopic endometrial mucosa and stroma is located within the transverse and longitudinal layers of the muscularis propria ( Fig. 1 A). The stroma appears loose, and the glands are intact with a smooth luminal contour. The endometrium appears to be in the proliferative phase as both stroma and glands have mitoses present ( Fig. 1 B). The ectopic endometrial stroma is also positive for CD10, a known endometrial tissue marker (not shown). 2 Notably, the histology of the proliferating endometrium is benign. There are no signs of nuclear atypia, increased mitotic activity, crowded irregular glands, or cytologic atypia ( Fig. 1 B). Endometriosis is composed of ectopic benign endometrial glands and stroma. In this patient's histology, there is normal endometrial glands and stroma in the muscularis propria of the cecum. Furthermore, positive CD10 on immunohistochemistry helps identifies the epithelium as endometrial stroma. 2 This confirms the pathologic diagnosis as intestinal endometriosis of the cecum. Endometriosis is defined by the presence of benign endometrial tissue located at the cervix or outside of the uterus. It most commonly affects organs located in the pelvis, including ovaries, fallopian tubes, bladder, intestines, and peritoneum. Less commonly, endometriosis can localize to the diaphragm, abdominal wall, or pleura. 4 It affects approximately 10% women of child-bearing age and is most frequently diagnosed between 30 and 40 years old. Despite its ectopic location, the endometrial cells and stroma are physiologically benign and proliferate in response to estrogen. The physiologic menstrual cycle of the endometrium occurring outside of the uterus results in inflammation and cellular damage of surrounding tissue. 5 Hormonally, the dominance of estrogen and resistance to progesterone drives endometriosis. The high estrogen level results in an increased synthesis of inflammatory cytokines, prostaglandins, and angiogenic factors and an upregulation of peripheral nerve fiber growth leading to heightened nociceptive pain. In tandem, progesterone resistance inhibits ovulation, decidualization of the endometrium and mammary gland development, thereby increasing the risk of sterility. 6 Endometriosis can present as ovarian cysts (endometrioma), superficial peritoneal lesions, deeper nodules that exceed 5 mm in depth (often leading to fibrosis and adhesions), and extrapelvic lesions. Staging as defined by the American Society for Reproductive Medicine is determined by the number of lesions and extent of adhesions. However, the clinical use of staging endometriosis is questionable as the staging does not correlate with either symptom presentation, prognosis, or recurrence. 5 The following theories of pathogenesis have been proposed for endometriosis: retrograde menstruation, benign metastasis, coelomic metaplasia, embryonic rest, and endometrial stem cell recruitment. 6 Retrograde menstruation involves endometrial cells traveling through fallopian tubes and implanting into the peritoneal cavity during menstruation. However, this theory is limited as it unlikely explains disease that occurs outside the peritoneal cavity. Benign metastasis is the theory that endometrial tissue may spread through the lymphatics during menstruation. This supports occurrence of endometriosis in distant locations and lymphatic nodes. Coelomic metaplasia theory proposes that mesothelial cells lining the visceral and abdominal peritoneum undergo a metaplastic process transforming them into endometrial glandular cells. This may explain ovarian endometrioma where the mesothelium lining the ovary transforms into endometriosis via metaplasia. In contrast, the embryonic rest theory applies the process of metaplasia to any embryonic cells of Wolffian or Mullerian origin, not only the mesothelium. Finally, the endometrial stem cell recruitment theory postulates that endometrial stem cells migrate through three mechanisms: (1) via menstrual blood to the peritoneal cavity during menstruation, (2) abnormal migration during organogenesis, or (3) angiolymphatic spread during menstruation. Importantly, this theory can explain all subtypes of endometriosis and ectopic spread of endometriosis beyond the abdominal cavity. 6 Risk factors with high association for endometriosis include diethylstilbestrol exposure, low birth weight, early age of menarche, short menstrual cycle, low body-mass index, low waist-to-hip ratio, and low parity. 5 Furthermore, endometriosis is also associated with the following co-existing conditions: uterine leiomyomas, adenomyosis, fibromyalgia, migraine, irritable bowel syndrome, ulcerative colitis, interstitial cystitis, depression, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, asthma, ovarian cancer, melanoma, thyroid cancer, and cardiovascular disease. 5 , 7 Patients with endometriosis may be asymptomatic or present with any combination of the following: dysmenorrhea, acyclic pelvic pain, dyspareunia, dyschezia, dysuria, infertility, somatosensory amplification, and fatigue. Those with bowel endometriosis may report bright red blood in the stool, melena, diarrhea or constipation. 5 To diagnosis endometriosis, TVUS, magnetic resonance imaging (MRI), and computed tomography (CT) scan can be used. However, direct visualization with diagnostic laparoscopy remains the gold standard and provides histological confirmation with biopsy. To compare diagnosis efficacy of laparoscopy vs MRI, the ENDO study performed a matched-exposure cohort study that showed a significant increase in endometriosis incidence in patients diagnosed with laparoscopy (41%) compared to MRI alone (7%). They concluded that endometriosis incidence is dependent on the diagnostic method. 8 Pharmacologic management includes pain control with NSAIDs and hormone therapy including oral contraceptive pills, progestins, and gonadotropin-releasing hormone agonists. Symptomatic lesions refractory to medical management as well as development of intussusception/obstruction are all qualifying indications for surgery. 9 , 10 Overall, management of endometriosis relies on the conglomeration of multiple factors, including clinical presentation, imaging, response to medical treatment, extent of disease seen in diagnostic laparoscopy, and histological confirmation. 10 , 11 Both endometriosis and adenomyosis are benign lesions characterized by ectopic endometrial glands and stroma. However, compared with endometriosis, which consists of cervical or extrauterine endometrium tissue, adenomyosis is defined by the presence of endometrial tissue within the myometrium ( Fig. 2 ). 12 One-third of patients with adenomyosis are asymptomatic. Like symptoms of endometriosis, adenomyosis may also present with pelvic pain, dysmenorrhea, dyspareunia, and infertility. Of note, abnormal uterine bleeding and menorrhagia may present in patients with adenomyosis but not in those with endometriosis. In adenomyosis, penetration of the endometrial glands past the endometrial-myometrial junction increases the likelihood of entrapped blood during menses. Risk factors for adenomyosis include multiparity, heavy menstrual bleeding, age greater than 40 years old, and prior cesarean section or uterine surgery. Notably, adenomyosis commonly occurs in patients with endometriosis or uterine leiomyomas. 2 , 12 Fig. 2 Histological section from a uterine specimen. The stain used is hematoxylin and eosin with an original magnification of (A) 40x and (B) 20x. Arrows point to ectopic endometrial glands and stroma. Contents within the dotted outline in (A) are magnified in (B). Fig. 2 Histological section from a uterine specimen. The stain used is hematoxylin and eosin with an original magnification of (A) 40x and (B) 20x. Arrows point to ectopic endometrial glands and stroma. Contents within the dotted outline in (A) are magnified in (B). Macroscopically, the uterus may appear enlarged. Microscopically, endometrial glands and surrounding stroma in the myometrium are often accompanied by varying degrees of fibrosis ( Fig. 2 ). Adenomyosis can present focally as a single lesion, diffusely with endometrial tissue present throughout the myometrium, or as a cyst. Surrounding smooth muscle hyperplasia is also frequently identified as a response to the destruction of normal myometrial architecture. Currently, there is no specific depth of endometrial invasion into the myometrium that definitively diagnoses adenomyosis. 12 Unlike endometriosis, which is diagnosed definitively via laparoscopy, adenomyosis is diagnosed through non-invasive imaging, including MRI and TVUS. Adenomyosis visualized through TVUS will show asymmetrical thickening of the uterine wall, intramyometrial cysts or hyperechoic islands, fan-shaped shadowing of the myometrium and translesional vascularity. In comparison, adenomyosis on MRI appears as an ill-demarcated, low-signal intensity area on T2-weighted imaging. 12 While the definitive treatment for adenomyosis is hysterectomy, this is not usually the first-line of management, especially in women of child-bearing age. Similar to endometriosis, adenomyosis is estrogen-responsive. Therefore, hormonal treatments for adenomyosis mirror those indicated for endometriosis. They include combined oral contraceptives, progestin-only contraception, and GnRH agonists. NSAIDs are also effective in symptom relief. In a 10-year retrospective population-based cohort study, a total of 333,693 women who were diagnosed with adenomyosis were studied. The overwhelming majority (90.8%) had menorrhagia or abnormal uterine bleeding, dysmenorrhea or pelvic pain, dyspareunia, and infertility. Co-occurrences with endometriosis and uterine leiomyomas were 18% and 47.6%, respectively. Importantly, the health care burden of patients with adenomyosis was substantial with 82% undergoing hysterectomies and 37.6% using chronic pain medications for at least 6 months. 13 Overall, endometriosis and adenomyosis are both characterized by the same histological features of ectopic endometrial glands and stroma that differ based on the location (intra vs extrauterine). They have a great deal of overlap in terms of presenting clinical symptoms, imaging modalities, and hormonal therapy. Importantly, both are benign diseases that are defined by ectopia.