Recurring perineal endometriosis in a patient with von Willebrand disease

Endometriosis is a prevalent condition which occurs in an estimated 1 out of 10 women during their reproductive lifespan [1]. Worldwide, this translates to 190 million women with endometriosis. The most commonly occurring symptom is dysmenorrhea, but clinical pre- sentation and disease severity vary widely [1]. Endometriosis usu- ally involves the pelvic organs including the peritoneum, the genital organs, ligaments, bowels and/or urinary system. Less commonly, endometriosis may occur extra-abdominally in the thoracic cavity, abdominal wall, as well as in the perineum. In this case report we present a patient with repeated perineal endometriosis recurrence in an episiotomy scar, with a potential pathophysiological role of von Willebrand Disease (vWD). Case report We present a 34-year-old patient, with type 1 vWD, who visited the outpatient clinic of her local hospital in 2021 with a painful swelling in her episiotomy scar. She was multiparous after two vaginal deliveries. Her first delivery occurred in 2013 with an episiotomy, and was complicated by postpartum hemorrhage of 3,500 mL based on uterine atony and episiotomy wound bleed- ing, with vWD as predisposing factor. Desmopressin was admin- istered before her second delivery, which occurred in 2015 with- out complications. After her last delivery the patient did not use any form of hormonal contraception. The swelling was treated through incision and drainage, releasing a dark-brown fluid, which was not sent in for analysis. Two months later, the painful swelling re-emerged. Because of her comorbid vWD, she was referred to our tertiary hospital. At physical examination, a blue-colored swelling at the site of her episiotomy scar was observed, with a diameter of 1-2 cm. Due to the severity of her pain, she was directly admitted to the operating theater for drainage of the swelling. Based on clinical suspicion of endometriosis, the lesion was excised with a margin of neighbor- ing tissue under general anesthesia. Remaining tissue was elec- trocoagulated and the defect was closed primarily. Intravenous desmopressin, a vasopressin analog, was administered pre- and postoperatively as a hemostatic agent, inducing the production of von Willebrand factor. Endometriosis was diagnosed after histo- pathological analysis (Figure 1), and hormonal treatment with a combined oral contraceptive (COC) pill was started. Six months after initial presentation, while still using COC continuously, the patient returned with a recurrence of the pain- ful swelling in her episiotomy scar. A MRI was performed, showing a T2 non-well-demarcated soft tissue collection of 11 x 13 x 6 mm between vulva and anus. The T1 imaging revealed foci of high intensity, indicative of blood, therefore confirming the suspicion of a perineal endometriosis recurrence (Figure 2).

A 34-year-old para 2 with type 1 von Willebrand Disease (vWD) presented with blue-tinted swelling in her episiotomy scar. Endometriosis was diagnosed histologically after excision of the lesion. Local recurrence was diagnosed six months after excision, during the use of hormonal therapy. A re-excision was performed with a wider margin and plasma argon energy treatment of the remaining tissue. A second recurrence, also while on hormonal treatment, was treated with a repeat re-excision and lotus petal flap perineal reconstruction. Endometriosis in an episiotomy scar is a known, but very uncom- mon, manifestation of endometriosis, with an estimated incidence of 0.01%. Disease presentation and severity may be affected by vWD. As such, the management of endometriosis in patients with vWD may present additional challenges.

Endometriosis, von Willebrandt disease, episiotomy. Article history Received 3 Dec 2023 - Accepted 8 Mar 2024 Contact Velja Mijatovic, MD PhD; [email protected] Academic Endometriosis Center Department of Obstetrics & Gynaecology Amsterdam UMC Meibergdreef 9 1105AZ Amsterdam, The Netherlands DOI 10.53260/grem.2450107 Recurring perineal endometriosis in a patient with von Willebrand disease Annelien C. de Kat1*, Marieke Lemmers1*, Laura van Loendersloot1, Sabrine Kol2, Wouter B. van der Sluis3, Maaike Bleeker4, Jan H. van Waesberghe2, Velja Mijatovic1 * Joint first authors 1Endometriosis Center, Amsterdam University Medical Centers, Amsterdam, The Netherlands 2 Department of Nuclear Science and Radiology, Amsterdam University Medical Centers, Amsterdam, The Netherlands 3 Department of Plastic, Reconstructive and Hand Surgery, Amsterdam University Medical Centers, Amsterdam, The Netherlands 4 Department of Pathology, Amsterdam University Medical Centers, Amsterdam, The Netherlands 39 LicenseGynecological and Reproductive Endocrinology and Metabolism 2024; 5(1):38-41 von Willebrand disease and recurring endometriosis A second re-excision, containing a margin of 5-10 mm of sur - rounding tissue was performed. The tissue of the wound bed was treated with plasma argon energy to further decrease the risk of recurrence. In addition to the desmopressin adminis - tered pre- and postoperatively, TachoSil fibrin sealant patches were used for local hemostasis. Histological analysis supported again the diagnosis of endometriosis. Sixteen months after initial presentation, and 10 months after the second excision, the patient presented with a renewed painful swelling at the site of her episiotomy scar, which had appeared at the end of a hormone-free week (which she took every several months to prevent prolonged spotting complaints while using COCs). The resulting pain was such that the patient was unable to sit and had severe pain during defecation. Upon examination there were two blue-colored lesions with a diameter of 4-5 mm, located respectively right above the posterior commissure of the labia and ventrally of the anal sphincter, which were extremely sensitive to touch (Figure 3). A MRI was performed which revealed a peri- neal endometriosis lesion, adjacent to the sphincter complex but without signs of muscular infiltration. A second re-excision was performed, during which approximately 5 cm3 of endometriosis tissue (Figure 4) with a margin of 10 mm was removed and the remaining field of tissue was treated with argon plasma energy. The perineum was reconstructed using a pedicled, partly de-ep- ithelialized, lotus petal flap, based on internal pudendal artery perforators from the left groin area. Prophylactic measures to prevent blood loss were undertaken again, for which reason the patient was admitted until 5 days post-surgery. The hormonal treatment was switched to dienogest 2 mg continuously. At six weeks follow-up post-surgery the surgical site was healing ade- quately and without complications (Figure 5).

Although the occurrence of endometriosis in an episiotomy scar has been described previously [2-4], it rarely presents at this loca- tion, with an estimated prevalence of 0.01% [5]. The exact patho- physiology of endometriosis in a perineal scar remains unknown, but most consensus exists on the theory of transplantation and implantation of endometrial cells towards the perineum during vaginal delivery [5]. Figure 1 Histopathology indicating endometriosis tissue in the surgical excision of the episiotomy scar lesion (A); with focal signs of bleeding, iron deposits as a result of bleeding and multicellular endometrium-like stroma (B); and with progesterone receptor positivity (C). The re-excised lesion exhibits a similar image with focal endometrium gland ducts which stained PAX8 positive, consistent with a genital origin (D,E). Figure 2 MRI imaging (T1) showing perineal high-intensity foci, suggestive of endometriosis 40 License Gynecological and Reproductive Endocrinology and Metabolism 2024; 5(1):38-41 de Kat A. C. et al. The ‘classic diagnostic triad of perineal endometriosis’ has been described elsewhere [3] and additionally applies to our patient: 1. an episiotomy of past perineal tear during vaginal delivery; 2. a tender mass or nodule at the perineal lesion; and 3. progressive (cyclic) perineal pain. Physical examination should include the examination of the painful nodule, as well as the ano- rectal region and rectovaginal septum. Both ultrasound and MRI can be used as diagnostic modalities, however MRI is the pre - ferred imaging technique for precise measurement of the lesion size as well as an assessment of the involvement of the rectum and the anal sphincter complex. Furthermore, with endometriosis in the differential diagnosis, examination should include the iden- tification of endometriosis in the broader pelvic and intra-abdom- inal regions. In a cohort of 14 women with perineal endometrio- sis, 3 women (21%) were found to have pelvic endometriosis [6]. In this cohort there was a recurrence rate of 14%, with most pre- sentations within a year of initial treatment [6]. The treatment of perineal scar endometriosis is primarily surgical. A local excision of the nodule or lesions should be undertaken with up to 10 mm margin of healthy tissue, as an incomplete resection can lead to lesion recurrence. Subsequent treatment with plasma argon energy is additionally preferred to minimize the risk of recurrence [2,7]. The excised tissue should be examined histologically to confirm the diagnosis of endometri- osis as well as ruling out the possibility of malignancy, specifi- cally in recurrent disease, as malignant evolvement of perineal endometriosis has been described previously [8]. With larger per- ineal resections, a collaboration with a reconstructive surgeon seems advisable, to maximize postoperative cosmetic and func- tional outcomes and to minimize wound healing complications. vWD is the most common bleeding disorder, affecting up to 1% of the population based on abnormal laboratory param - eters alone [9]. This inherited condition occurs equally in men and women as well as across all races and ethnicities. However, women may be more symptomatic due to heavy menstrual bleed- ing periods. A combination of blood tests was used to diag - nose vWD, including vWF antigen, as well as a platelet bind - ing assay to differentiate between qualitative and quantitative defects. The three recurrences, despite adequate surgical mea - sures and continuous COC treatment, are striking in this case. In a study conducted by the American Centers for Disease Control (CDC) among 102 women with vWD, 30% of the women were found to have endometriosis, in comparison to 13% in the con- trol group (p=0.005) [10]. Moreover, a recent case reported recur- rent ovarian endometriomas in a 17-year-old vWD patient using continuous hormonal medication [11], similar to our patient who also had recurrences despite hormonal treatment. While the lit- erature is still scarce, the increased prevalence and seemingly more severe or treatment-resistant presentation of endometriosis suggest that the hematological hallmarks of vWD may directly influence the pathophysiology of endometriosis. It is possible that the increased bleeding tendency in vWD increased the risk of endometrial cell implantation and may have exacerbated the acti- vation of existing endometriosis lesions. Interestingly, however, a recent Mendelian randomization analysis demonstrated a causal relationship between the coagulation factors ADAMTS13 and vWF and the risk of endometriosis, with higher vWF antigen lev- els predisposing to the endometriosis development [12]. Consistent with these findings, ectopic endometrial cells in patients with adenomyosis generally appear to exhibit more angiogenic prop- erties and increased vWF antigen activity [13]. Taken together, there is a clear link between both increased and impaired coagulation and endometriosis, further highlight- ing the complexity of the disease and the impact of comorbidity on its pathophysiology. Although there is no evidence to date Figure 3 Two blue-colored lesions (diameter of 4-5 mm), located respectively right above the posterior commissure of the labia and ventrally of the anal sphincter 41 LicenseGynecological and Reproductive Endocrinology and Metabolism 2024; 5(1):34-37 HRT and Skin Aging to support the treatment of coagulation disorders as a means of improving the symptoms of endometriosis, awareness of such problems can be helpful in tailoring endometriosis treatment. In conclusion, while unlikely, endometriosis can occur in the perineum and can be included in the differential diagnosis of perineal swelling in women. Patients with vWD may present with more severe symptoms and/or recurring disease, increas - ing complexity and challenging clinicians to find an appropri - ate choice of therapy which has to be tailored to the needs of the patient.

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