Endometriosis-associated lesions during or after long-term estrogen-only therapy following hysterectomy: 2 cases

A 48-year-old woman, gravida 2, para 2, underwent laparoscopic hysterectomy and bilateral salpingo-oophorectomy for International Federation of Gynecology and Obstetrics 2009 stage IA, grade 1 endometrioid endometrial carcinoma at 44 years of age. She had undergone allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia at 31 years of age and subsequently received estrogen-progestogen MHT for treatment-related premature ovarian insufficiency from 32 years of age. At the time of hysterectomy, a solitary pelvic peritoneal “blueberry spot” suspicious for endometriosis was identified and cauterized without histologic confirmation. Histopathologic examination of the uterus and adnexa showed no evidence of endometriosis or adenomyosis. The specimen was removed intact transvaginally without morcellation or a retrieval bag. Following surgery, MHT was changed to transdermal estrogen-only replacement (17β-estradiol, ESTRANA® Tapes 0.72 mg; Hisamitsu Pharmaceutical Co., Inc., Tosu, Japan). Surveillance computed tomography (CT) demonstrated a gradually enlarging ileocecal mass suspicious for tumor recurrence. At presentation, her body mass index was 24.2 kg/m 2 . Her medical history included type 2 diabetes and dyslipidemia, and she was a former smoker. A 54-year-old woman with a history of symptomatic endometriosis underwent open hysterectomy and bilateral salpingo-oophorectomy at 46 years of age. Following surgery, she received continuous transdermal estrogen-only MHT (17β-estradiol, ESTRANA® Tapes 0.72 mg) for approximately 6 years. One year after discontinuation of estrogen-only MHT, at 53 years of age, she presented with vaginal bleeding lasting several days. Speculum examination revealed a small bluish lesion at the vaginal cuff. Pelvic imaging showed no additional lesions. Body mass index was not documented at initiation of MHT or at lesion diagnosis. She had no history of diabetes mellitus, dyslipidemia, hypertension, or smoking.

Surgical menopause can cause vasomotor symptoms and adverse long-term health effects, and menopausal hormone therapy (MHT) is an effective treatment when clinically appropriate [ 1 ]. After hysterectomy, estrogen-only MHT is commonly selected because a progestogen is generally not required for endometrial protection in women without a uterus; this approach is reflected in recommendations from international and national professional societies [ 1-3 ]. In women with prior endometriosis, however, recurrence and rare malignant transformation during or after estrogen-only MHT have been described [ 4 , 5 ]. Current guidance from the European Society of Human Reproduction and Embryology (ESHRE) and the European Menopause and Andropause Society (EMAS) therefore favors individualized treatment and advises avoiding unopposed estrogen in women with a history of endometriosis, even after hysterectomy [ 6 , 7 ]. Although recurrence and malignant transformation of endometriosis during or after MHT have previously been described, the diagnostic challenges posed by newly detected endometriosis-associated lesions in this setting remain clinically important. We present 2 cases of endometriosis-associated lesions identified during or after long-term estrogen-only MHT following hysterectomy and bilateral salpingo-oophorectomy.

Macroscopic examination of the resected specimen showed a 35 × 25 × 20-mm cystic lesion containing brownish fluid and yellowish-brown gelatinous material ( Fig. 4A and 4B ). Histopathologic examination of the resected specimen demonstrated a cystic lesion composed of endometrial glands and stroma within the subserosal layer of the cecum ( Fig. 4C ). Immunohistochemistry showed estrogen receptor and progesterone receptor expression in both glands and stroma, whereas cluster of differentiation 10 stained the stromal cells ( Fig. 4D and 4E ). Similar endometriotic lesions were also identified in the appendix. No ovarian stroma was identified in the surrounding tissue. These findings established the diagnosis of cecal and appendiceal endometriosis. Estrogen-only MHT was not interrupted during the diagnostic evaluation or perioperative period. At a postoperative conference, the option of continuing estrogen-only MHT was discussed based on the apparent complete macroscopic resection, while switching to combined estrogen-progestogen MHT was also considered. After discussion, the patient elected to continue estrogen-only MHT without a progestogen. Estrogen-only MHT was discontinued approximately 17 months after ileocecal surgery, when she was nearly 50 years old. At 23 months after surgery, approximately 6 months after discontinuation, surveillance CT showed no recurrence of endometriosis or endometrial carcinoma. Gross and histopathologic findings of cecal and appendiceal endometriosis (case 1). Gross and microscopic images of the resected ileocecal lesion demonstrate a cystic endometriotic lesion adjacent to the appendiceal base. Histopathology shows endometrial glands and stroma with minimal cytologic atypia. Immunohistochemistry demonstrates estrogen receptor expression in both glands and stromal cells and cluster of differentiation 10 (CD10) positivity in the stromal cells, supporting the diagnosis of endometriosis. (A) Gross examination of the resected specimen demonstrated a cystic lesion on the serosal surface adjacent to the appendiceal base. Arrowheads delineate the extent of the lesion. (B) The cut surface revealed a cystic lesion containing gelatinous material with a well-demarcated area. (C) Histopathologic examination demonstrated endometrial glands and stroma lining the cystic lesion with minimal cytologic atypia (hematoxylin–eosin stain; scale bar, 500 μm). (D) Immunohistochemistry showed estrogen receptor expression in both the endometrial glands and stromal cells (scale bar, 500 μm). (E) CD10 immunohistochemistry highlighted the endometrial stromal cells, whereas the glands were negative (scale bar, 500 μm). The vaginal cuff lesion gradually regressed during follow-up. A repeat vaginal biopsy demonstrated no residual atypical hyperplasia. She remains asymptomatic under periodic surveillance with speculum examination, colposcopy, and transvaginal ultrasonography. At 59 years of age, the lesion was barely visible on colposcopy.

Endometriosis-associated lesions may mimic cancer recurrence or present with posthysterectomy vaginal bleeding during or after long-term estrogen-only MHT. Histopathologic confirmation is essential because imaging findings and temporal association with MHT alone cannot establish the diagnosis or causality. MHT after hysterectomy in women with a history of or suspected endometriosis should be individualized according to current clinical guidelines and shared decision-making.

Because intra-abdominal recurrence of endometrial carcinoma could not be excluded, laparoscopic ileocecal resection with appendectomy was performed ( Fig. 3A and 3B ). Intraoperatively, a smooth, white cystic mass was identified within the mesenteric fat adjacent to the cecum and was resected en bloc with the ileocecal region and appendix ( Fig. 3C and 3D ). Laparoscopic and gross findings of the ileocecal lesion (case 1). Four intraoperative and gross specimen images demonstrate a well-circumscribed white cystic lesion within the terminal ileal mesenteric fat adjacent to the cecum. Gross examination shows the cystic lesion (arrow) after sectioning, revealing turbid fluid. (A, B) Laparoscopy revealed a well-circumscribed, white, smooth-surfaced cystic mass buried within the terminal ileal mesenteric fat adjacent to the cecum. Careful dissection exposed the lesion before en bloc resection. (C, D) Gross examination of the resected specimen demonstrated a cystic lesion adjacent to the terminal ileum (arrow). On sectioning, the lesion contained, turbid fluid. Estrogen-only MHT had already been discontinued approximately 1 year before the lesion was diagnosed. Because of the atypical histopathologic findings, surgical excision was considered. However, after multidisciplinary evaluation and repeated discussions with the patient over approximately 9 months, repeat pelvic MRI and vaginal biopsy demonstrated no lesion progression or residual atypical hyperplasia. Consequently, conservative management with close surveillance was selected instead of surgery.

The patient underwent annual chest-to-pelvis CT as postoperative surveillance for endometrial carcinoma. Surveillance CT performed 3 years and 4 months after initiation of estrogen-only MHT demonstrated a 21.8 × 27.3-mm cystic mass adjacent to the cecum. Retrospective review showed interval enlargement from a small lesion visible 1 year after therapy initiation ( Fig. 1A–1D ). Positron emission tomography (PET)/CT with 18F-fluorodeoxyglucose showed no abnormal uptake, and magnetic resonance imaging (MRI) demonstrated a well-defined unilocular cystic lesion without a solid component ( Fig. 1E and 1F ). The differential diagnosis included cystic mesothelioma and a peritoneal inclusion cyst. Serial imaging of an enlarging ileocecal mass mimicking tumor recurrence during estrogen-only menopausal hormone therapy (MHT) (case 1). Six radiologic images demonstrate progressive enlargement of an ileocecal cystic mass, indicated by arrows, from 45 to 48 years of age during estrogen-only MHT. Contrast-enhanced computed tomography (CT) showed poor enhancement, and magnetic resonance imaging (MRI) demonstrated a well-defined unilocular cystic lesion with homogeneous low T1 signal intensity. (A) CT at 45 years of age (1 year after initiation of estrogen-only therapy) showed a 4.9 × 6.5-mm ileocecal lesion (arrow), which was not recognized prospectively. (B) CT at 46 years of age (2 years after initiation of estrogen-only MHT) demonstrated interval enlargement to 14.1 × 8.5 mm; however, the lesion was again not recognized prospectively. (C) CT at 48 years of age (3 years and 4 months after initiation of estrogen-only MHT) first led to prospective recognition of the enlarging ileocecal mass. (D) Contrast-enhanced CT performed at 48 years of age showed a 21.8 × 27.3-mm mass with poor enhancement. (E) Axial T2-weighted MRI performed at 48 years of age demonstrated a well-defined unilocular cystic mass without a definite solid component and with fluid of slightly different signal intensity posteriorly. (F) Axial T1-weighted MRI performed at 48 years of age showed homogeneous low signal intensity. Colposcopically directed biopsy of the vaginal cuff lesion demonstrated atypical endometrial hyperplasia arising in vaginal cuff endometriosis ( Fig. 2A ). Histopathologic examination revealed atypical endometrial glands arising within endometriotic tissue ( Fig. 2B and 2C ). 18F-fluorodeoxyglucose PET/CT showed no evidence of distant metastasis, and pelvic MRI demonstrated no additional pelvic lesions. Atypical endometrial hyperplasia arising in vaginal cuff endometriosis (case 2). Colposcopy demonstrates a lesion at the vaginal cuff, and histopathology shows atypical endometrial hyperplasia arising in vaginal cuff endometriosis. (A) Colposcopy demonstrated erythema and bleeding at the 3-o′clock position of the vaginal cuff (arrow). (B) Low-power histopathology of a biopsy specimen from the bleeding site demonstrated atypical endometrial glands within endometriotic stroma (hematoxylin–eosin stain; scale bar, 500 μm). (C) Higher-magnification view confirmed atypical endometrial glands.

These 2 cases illustrate distinct diagnostic challenges posed by endometriosis-associated lesions identified during or after long-term estrogen-only MHT following hysterectomy and bilateral salpingo-oophorectomy. Recurrence and malignant transformation of endometriosis after MHT have previously been reported [ 4 , 5 ], and recurrence after surgery for endometriosis has also been evaluated in a randomized trial comparing hormone therapy with no treatment [ 8 ]. Case 1 presented with an ileocecal mass that mimicked recurrent endometrial carcinoma, whereas case 2 presented with posthysterectomy vaginal bleeding caused by atypical endometrial hyperplasia arising in vaginal cuff endometriosis. Although these cases cannot establish a causal relationship with estrogen-only MHT, they emphasize the need to consider endometriosis-associated lesions in both settings and to establish the diagnosis through histopathologic examination. Intestinal endometriosis may present as a mass lesion and is often difficult to distinguish from malignancy using imaging alone [ 9 , 10 ]. In case 1, a solitary pelvic peritoneal lesion suspicious for endometriosis was identified and cauterized at the initial hysterectomy. Histopathologic examination of the uterus and adnexa showed no endometriosis or adenomyosis. This finding suggests that occult or multifocal endometriosis may already have been present. Celomic metaplasia, stem/progenitor cell–related mechanisms, and iatrogenic implantation during transvaginal specimen extraction are alternative explanations [ 11-13 ]. However, because the specimen was removed intact without morcellation and no ovarian stroma was identified, the exact pathogenesis remains uncertain. Case 2 represents a different clinical scenario. Vaginal cuff endometriosis has occasionally been reported after hysterectomy and may present with posthysterectomy vaginal bleeding [ 13 , 14 ]. Recurrent postmenopausal endometriosis may become clinically apparent years after surgical menopause, and the precise timing of lesion development is often uncertain [ 4 ]. In our patient, atypical endometrial hyperplasia arising in vaginal cuff endometriosis was diagnosed 1 year after discontinuation of approximately 6 years of estrogen-only MHT. The lesion gradually regressed during conservative management without surgery. Because lesion development may have preceded clinical presentation, the temporal relationship neither establishes nor excludes a contribution of prior estrogen exposure. These findings emphasize the importance of histopathologic confirmation and individualized management in women presenting with posthysterectomy vaginal bleeding. Current ESHRE and EMAS guidance advises against estrogen-only MHT in women with a history of endometriosis, even after hysterectomy, supporting a combined estrogen-progestogen regimen when MHT is indicated [ 6 , 7 ]. At the same time, estrogen replacement provides substantial benefits for women who undergo bilateral oophorectomy before the natural age of menopause. Therefore, treatment should balance symptom relief against the potential risk of stimulating residual endometriotic tissue. In case 1, after shared decision-making, the patient elected to continue estrogen-only MHT following apparent complete macroscopic resection. However, apparent complete macroscopic resection did not exclude additional occult endometriotic foci that might be stimulated by unopposed estrogen. This individual decision and the absence of detected recurrence during limited follow-up, including the period after estrogen withdrawal, do not establish the safety of estrogen-only MHT. This report has several limitations. Because only 2 patients are described, no conclusions regarding incidence, relative risk, or causality can be drawn. Occult disease, residual disease, and iatrogenic implantation remain plausible explanations, particularly in case 1. Furthermore, postoperative hormone concentrations and molecular analyses were unavailable, limiting investigation of the underlying biological mechanisms. These cases emphasize the need to consider endometriosis-associated lesions in patients presenting with new abdominal masses or posthysterectomy vaginal bleeding during or after MHT, with histopathologic confirmation and individualized hormone management.