Endometrioid adenocarcinoma of the rectovaginal septum with invasion of the rectum: a case report and review of literature

Background: Malignant transformation of endometriosis in the rectovaginal septum is rare and usually misdiagnosed as a colorectal or gynecological tumor. We report a rare case of primary endometrioid adenocarcinoma of the rectovaginal septum with invasion of the rectum. Case presentation: A 57-year-old overweight woman presented with vaginal bleeding and self-reported left lower abdominal pain during the previous 2 weeks. Preoperative imaging showed a large pelvic mass with invasion of the rectum, suggestive of a gynecologic malignancy. Multiple endoscopic biopsies and immunohistochemical analyses of specimens was performed. The patient received joint gynecological-surgical laparotomy, and there were no intra- or postoperative complications. The histopathological diagnosis was rectovaginal endometrioid adenocarcinoma with rectum infiltration. The patient received adjuvant chemotherapy and achieved good treatment response, with no early complications. At 12 months after surgery, there was no evidence of recurrence.

A high index of clinical suspicion is required for the diagnosis of endometrioid adenocarcinoma in the rectovaginal septum. Surgery combined with additional chemotherapy or radiotherapy seems to be a standard treatment, and hormonal therapy is optional. The efficacies of other therapies, including targeted medication and immunotherapy, are unknown.

Endometrioid adenocarcinoma, Rectovaginal, Endometriosis, Malignant transformation, Diagnosis

Endometriosis is a chronic and benign gynecological dis- ease most common in women of reproductive age, in which endometrial tissue occurs outside the uterine cav- ity. The most common locations are the ovaries, fallo- pian tubes, vagina, broad ligaments, cervix, pouch of Douglas, gastrointestinal tract, rectovaginal septum, and appendix [ 1, 2]. This disease affects approximately 6 to 10% of women of reproductive age, and the most com- mon symptoms are chronic pelvic inflammation and pain (especially dysmenorrhea) and subfertility [ 3–5]. Deep-infiltrating endometriosis (DIE) is a sub-class of endometriosis which is defined by endometrial infiltra- tion of the peritoneum by more than 5 mm [ 6], and endometriosis of the rectovaginal septum is the most se- vere form [ 7]. Malignant transformation of endometri- osis is quite rare; it occurs in only 0.7 to 1% of patients with endometriosis, and 78.7% of these cases have ovar- ian malignancies [ 8, 9]. Primary adenocarcinoma of the rectovaginal septum is extremely rare and most cases are associated with benign endometriosis [ 10, 11]. In this article, we report a patient with a primary adenocarcin- oma arising from endometriosis in the rectovaginal septum with involvement of the rectum. © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. * Correspondence: [email protected] 1Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, Republic of China Full list of author information is available at the end of the article Yang et al. World Journal of Surgical Oncology (2019) 17:206 https://doi.org/10.1186/s12957-019-1743-0 Case presentation A 57-year-old post-menopausal woman (gravida 1, para 1) was admitted to the Gynecology Department of Shengjing Hospital (an affiliate of China Medical Univer- sity) presenting with vaginal bleeding and left lower ab- dominal pain for the previous 2 weeks. She had a caesarean section and myomectomy more than 20 years ago and denied any previous hormonal therapy. She was 155 cm in height and 65 kg in weight (body mass index (BMI): 27.1 kg/m 2). Her mother had a history of pancre- atic carcinoma and her father had a history of hepatic carcinoma. She reported no history of weight loss or change in appetite. The physical and vaginal examination indicated a pel- vic mass on the left side with poor mobility. The gynecological examination indicated that the vagina, cer- vix, and uterus appeared normal. The laboratory tests showed the serum level of CA125 was 207.5 U/mL (nor- mal < 35.0), CA199 was 59.9 U/mL (normal < 37), and HE4 was 206.9 U/mL (normal < 140.0), although the CEA and AFP levels were normal. A transvaginal ultrasound (TVS) showed an irregular complex mass (7.0 × 5.3 × 5.6 cm) in the recto-uterine pouch that had an unremarkable boundary, but had abundant vascularities on the septa and solid portion of the tumor (Fig. 1a). There was also invasion of the mass into the anterior wall of the rectum (Fig. 1b). The right ovary was normal but the left ovary was not visible. A pelvic ultrasound also showed multiple uterine leiomyo- mas. The endometrium was thickened and irregular, but there was no evidence of ascites, peritoneal implants, or other masses. We suspected ovarian carcinoma with invasion of the rec- tum, and thus performed a whole body FDG-positron emis- sion tomography (PET) (Fig.2). The F18-fluorodeoxyglucose PET/computed tomography (F18-FDG PET/CT) showed an irregular solid-cystic mass (5.0×4 . 3c m )i nt h er e c t o v a g i n a l fossa that had pathologic FDG-uptake and seemed to infil- trate the rectum. Thus, we also suspected a pelvic malignant tumor in- filtrating the rectum. A colonoscopy (Fig. 3) indicated an ulcerated lesion 10 cm from the anal margin that occu- pied about 1/3 of the lumen, in which the covering mu- cosa were pale and the surrounding mucosa were clustered. This exam also indicated a 0.5-cm polyp in the sigmoid colon. Multiple endoscopic biopsies were taken during this procedure. An endoscopic ultrasono- graphic examination indicated a protruding lesion (0.4 × 0.4 cm) in the fundus of the stomach (adjacent to the cardia) and another lesion with fixed echoes in the an- terior wall of duodenum (0.4 × 0.4 cm), which was be- tween the third and fourth layers of the duodenal wall. We did not treat these due to their small sizes. The pathological report of the biopsy specimen in- dicated evidence of a metastatic adenocarcinoma from a gynecological malignancy with rectum involvement. Thus, a joint gynecological-surgical laparotomy was performed. Radical hysterectomy, bilateral adnexect- omy, pelvic peritonectomy, pelvic lymphadenectomy, omentectomy, partial rectal resection with a low pel- vic colorectal anastomosis protected by ileostomy, and appendectomy were performed. During this cytore- ductive procedure, a 5.0-cm solid mass was identified in the recto-uterine pouch that closely adhered to the rectum and another 3.5-cm cystic mass on the upper rectovaginal septum. Because the mass did not invade the vagina, and considering the patient ’s quality of life, an upper vaginal resection with anastomosis was performed, so that the middle and lower segment of the vagina were retained. There were apparent adhe- sions in the pelvic cavity, especially between the tu- mors and the rectosigmoid. The bilateral adnexa were atrophic, without any obvious macroscopic tumor. There was no evidence of residual macroscopic le- sions or intraoperative complications after surgery. Analysis of the resected sp ecimens indicated the rec- tal specimen had a thickened wall with coarse mucosa and serosa (Fig. 4). When opening the cystic mass Fig. 1 Transvaginal ultrasound (TVA), showing an irregular complex mass in the rectovaginal fossa. a Abundant vascularities on the septa and solid portion of the tumor (arrows). b Invasion of the mass into the anterior wall of the rectum (arrows) Yang et al. World Journal of Surgical Oncology (2019) 17:206 Page 2 of 8 adhering to the rectum, the internal wall was gray- yellow in color with cauliflow er-like lesions. For histo- logical analysis, specimens were fixed in 10% buffered formalin, processed, and embedded in paraffin. Micro- scopic analysis indicated the tumor cells were acinar, Fig. 2 Positron emission tomography/computed tomography (PET/CT), showing a mass with fluorodeoxyglucose (FDG) uptake in the rectovaginal fossa. a CT image showing a cystic-solitary mass. b PET/CT image showing a mass with FDG uptake (maximum standardized uptake: 11.32). c, d FDG images Fig. 3 Colonoscopy indicating an ulcerated lesion of the rectum (arrow) Fig. 4 Section of the rectal specimen indicating a thickened wall Yang et al. World Journal of Surgical Oncology (2019) 17:206 Page 3 of 8 with papillary structures that were moderately differ- entiated, and heteromorphic cells were arranged in a sieve pattern (Fig. 5). Endometriosis was also evident in the left adnexa (Fig. 6). Immunohistochemical studies performed using the avidin-biotin peroxidase complex technique indicated positive staining for cytokeratin 7 (CK7), estrogen recep- tor (ER), paired box gene 8 (PAX-8), and Wilms tumor protein (WT-1), weakly positive staining for progester- one receptor (PR), and no staining for CK20, caudal- related homeobox 2 (CDX-2), vimentin, P53 proteins, and villin (Fig. 7). In addition, 10% of the cells were posi- tive for Ki-67 (data not shown). The final histopatho- logical diagnosis was rectovaginal endometrioid adenocarcinoma with rectum infiltration. Thus, the pa- tient received 6-month adjuvant chemotherapy and achieved good treatment response. The patient has been free of disease for 12 months since the surgery. A follow-up at that time, which included enhanced CT and TVS, showed no evidence of recurrence.

and conclusions Endometriosis is a common gynecological disease among premenopausal women that is characterized by uncontrolled endometrial cell proliferation, with local and distant spread of these cells [ 12]. Although endo- metriosis is not considered a premalignant disease, it may nonetheless have malignant potential and aggres- sive pathology, characterized by high local invasive- ness and recurrence [ 13]. In 1925, Sampson [ 14]f i r s t described malignant transformation in a patient with endometriosis. This condition may occur in 0.7 to 1% of women with endometriosis [ 15]; it is most com- mon in the ovary, but about 20% of cases have malig- nancies at extragonadal sites [ 16]. Sampson [ 14]a n d Scott [ 17] proposed four basic criteria for diagnosis of endometriosis-associated cancer: (i) malignant and be- nign endometrial cells coexist within the same tissue; (ii) the malignancy originates from the same tissue, without metastasis or infiltration from other sites; (iii) there are no other primary sites; and (iv) the adjacent endometriosis focus is contiguous with the endome- trioid carcinoma tissue. Our patient fulfilled all four criteria. The rectovaginal septum is a relatively common site for extragonadal endometriosis, followed by the ovary. Although endometriosis-associated rectovaginal adeno- carcinoma is extremely rare, it accounts for 70% of primary rectovaginal malignancies [ 18, 19]. A recent comprehensive review [ 19] found reports of fewer than 20 primary carcinomas of the rectovaginal septum aris- ing from endometriosis. We identified 8 full-text articles published in English between 1950 and 2018 that de- scribed 9 patients with primary endometriosis-associated carcinoma (Table 1). As expected, adenocarcinoma is the most common histologic type of extragonadal endometriosis-associated neoplasm (6 cases including the present patient). The less common histologic forms were clear cell carcinoma, stroma sarcoma, adenoa- canthoma, and carcinosarcoma [ 20]. Fig. 5 Histopathological findings (hematoxylin-eosin (H&E) staining, 100×). a Adenocarcinoma invasion of the rectum. b Solid part of the tumor, indicating heteromorphic cells arranged in a sieve pattern Fig. 6 Histopathological findings (H&E staining, 100×), showing endometriosis in the left adnexa Yang et al. World Journal of Surgical Oncology (2019) 17:206 Page 4 of 8 The etiology of rectovaginal endometriosis remains un- certain. One possible mechanism is the adhesion and growth of endometrial tissues that were deposited into the peritoneal cavity via retrograde menstruation. It is also possible that the origin is from metaplasia of the Müller- ian remnants in the rectovaginal septum [ 21]. Endometri- osis is an estrogen-dependent disease, and some evidence indicated that endogenous or exogenous hyperestrogen- ism may contribute to the malignant transformation [ 9]. Young et al. [ 22] reported a patient with rectovaginal endometriosis-associated adenocarcinoma who was taking high-dose unopposed estrogens (1.25 mg conjugated es- trogens per day) for 14 years after a subtotal hysterectomy. On the other hand, obesity also increases the risk for de- veloping cancer from endometriosis. Three of the 8 women with rectovaginal tumors arising from endometri- osis were obese (Table 1)[ 23, 24]. Our patient did not use unopposed estrogens, but her BMI was above normal. It is also interesting to note that 6 of the 10 (60%) cases we reviewed (including our patient) had previous lower ab- dominal/pelvic surgery, including hysterectomy. Thus, pelvic surgery itself could increase the risk for dissemin- ation of endometriotic lesions and malignant transformation of rectovaginal endometriosis. Okimura et al. [8] also mentioned this possibility. The average patient age was 43.2 years. Our patient was 57 years old, older than any of the other 9 pa- tients. Women with rectovaginal endometriosis –asso- ciated adenocarcinoma often complain of dyschezia, deep dyspareunia, abdominal or pelvic pain, and vagi- nal or rectal bleeding. Our patient ’s chief complaints were vaginal bleeding and left lower abdominal pain. In fact, due to the deep location of these tumors and the atypical clinical symptoms, diagnosis is often diffi- cult, so these tumors often remain latent for a long time before diagnosis. In the present case, the tumor was already more than 5 cm in diameter, and it had infiltrated the entire wall of the rectum upon diagno- sis. In all cases, diagnosis requires surgery and patho- logic examination. For the very few cases of previously reported rectovaginal septum tumors arising from endometriosis, modern imaging techniques were usually used for initial evaluation of local and regional extension of the tumor, but were insufficient for diagnosis because the resul ts are also consistent with uterine or ovarian tumors, just as in our patient. Fig. 7 Immunohistochemical (IHC) staining of tumor cells for 5 markers (100×). a PAX-8 (positive). b ER (positive). c CK7 (positive). d CK20 (negative). e CDX-2 (negative) Yang et al. World Journal of Surgical Oncology (2019) 17:206 Page 5 of 8 Table 1 Characteristics of our patient and previously reported patients with rectovaginal septum tumors related to endometriosis Author/year Patient age (years) Signs/symptoms Medical history Body type Laboratory tests Radiology/ultrasonic findings Histology Treatment Follow-up Dockerty et al. [ 1], 1954 54 Serosanguineous vaginal discharge Thyroidectomy ND ND ND Adenocarcinoma TH+BSO+LN/RT DOD 2 years Dockerty et al. [ 1], 1954 45 A small reddish area on the posterior lip of the cervix ND Obese Normal ND Adenocarcinoma TH+BSO+LN/RT NR 10 years Lash and Rubenstone [2], 1959 32 Severe low back pain, cyclic vaginal bleeding STH Obese Normal Upper and lower gastrointestinal roentgen studies were normal Adenocarcinoma Cervicectomy, RR ND Young and Gamble [ 3], 1969 47 Intermittent vaginal bleeding, pelvic pain, and a cul-de-sac mass STH ND ND ND Adenoacanthoma Pelvic exenteration+RT Unknown Goldberg et al. [ 4], 1978 48 A hemorrhagic nodule on the posterior vaginal wall Spontaneously aborted through a laceration ND ND ND Clear cell adenocarcinoma TH+LN+RR+resection of the upper half of the vagina Metastatic nodes 9 months later Addison et al. [ 5], 1979 37 Vagina1 and rectal bleeding TH+celiotomy+nephrectomy Obese ND ND Adenoacanthoma RT/CT DOD 1 year Yazbeck et al. [ 6], 2005 25 Lower abdominal pain and dyspareunia; painful retrocervical nodule Total thyroidectomy + appendectomy ND CA125: 700 U/mL US showed a heterogeneous pelvic mass; MRI confirmed the central pelvic mass. Papillary adenocarcinoma RT/TH+RR NR 2 years Ulrich et al. [7], 2005 51 Irregular vaginal bleeding Vaginal hysterectomy ND ND Pelvic MRI confirmed a tumor of the rectosigmoid colon Glandular and papillary tumor RR+BSO+vagina and parakolpium resection+LN+RT RE 2 years later Mabrouk et al. [ 8], 2011 36 Abdominal discomfort Unknown ND Ca125 and Ca19.9 were elevated CT scan showed a retro- uterine mass; US scan re- vealed both slightly en- larged ovaries and a retrocervical mass Clear cell and endometrioid adenocarcinoma TH+LN+omentectomy+appendicectomy+CT (cisplatinum)+RR□ NR 2 months Present case, 2019 57 Vaginal bleeding and left lower abdominal pain Caesarean section and myomectomy Overweight Ca125, Ca19.9, and HE4 were elevated US scan showed an irregular complex mass in the rectovaginal fossa, PET/CT showed a mass with FDG uptake in the rectovaginal fossa. Adenocarcinoma TH+LN+omentectomy+peritonectomy+appendicectomy+ partial rectal resection+CT NR 6 months RT, radiation therapy; TH, total hysterectomy; STH, subtotal hysterectomy; BSO, bilateral salpingo-oophorectomy; LN, lymph node dissection; CT, chemotherapy; RR, rectal resection; RE, recurrence; NR,n o recurrence; DOD, dead of disease; ND, not described; US, ultrasound; MRI, magnetic resonance imaging; PET/CT, positron emission tomography/computed tomography; FDG, fluorodeoxyglucose Yang et al. World Journal of Surgical Oncology (2019) 17:206 Page 6 of 8 Transvaginal ultrasound (TVS) is a first-line technique used to examine a pelvic mass and DIE. In particular, TVS can evaluate the exact location and extent of infiltration, which is important for determining the type and difficulty of sur- gery [25]. For instance, TVS of our patient showed a large mass in the recto-uterine pouch with rectal wall infiltration. Moreover, magnetic resonance imaging (MRI) can also help to evaluate deep lesions in the rectovaginal region. A meta- analysis by Guerriero et al. [ 4] demonstrated similar diag- nostic performance of TVS and MRI in the detection of DIE, confirming the role of TVS as a cost-effective first-line technique. Nevertheless, preoperative imaging techniques are only useful for estimation of the location and extent of infiltration, and cannot be used to determine malignant transformation of endometriosis. When rectum infiltration is suspected, diagnostic rectoscopy or colonoscopy should be performed, and endoscopic biopsies may also be needed for pathological examination. In our patient, pathological analysis of the colonoscopy biopsy specimen indicated a metastatic adenocarcinoma from a gynecological malignancy. After biopsy or resection of the tumor, immunohisto- chemical staining (IHC) may be essential to confirm the diagnosis. IHC staining using antibodies against ER, PR, CK7, PAX-8, CK20, and CDX2 is extremely useful for the differential diagnosis of endometrioid adenocarcinoma and primary intestinal adenocarcinoma. In particular, IHC staining for CK7 and CK20 can differentiate endometrioid and primary rectal carcinoma [ 26]. Many colorectal carcinomas are CK20-positive and CK7-negative, but gynecological tumors (including endometrioid carcinomas) are often CK20-negative and CK7-positive. PAX-8 is a spe- cific marker of Müllerian origin and is also expressed in gynecological tumors. Furthermore, the ER is expressed in most uterine endometrioid adenocarcinomas. On the other hand, CDX2 (a homeobox transcription factor) is expressed during normal intestinal development [ 27]. Thus, CDX2 expression may be positive in colorectal cancers and has high sensitivity for the differential diagnosis of colorectal adenocarcinoma [28]. Our patient had positive IHC stain- ing for CK7, ER, and PAX-8, and negative staining for CK20 and CDX-2, compatible with our diagnosis of endo- metrioid adenocarcinoma. There is currently no consen sus on the standard thera- peutic approach to be used for treating extraovarian endo- metriosis–associated malignancie s, and studies in the literature report the use of highly individualized treatments. However, primary surgical excision or radical resection of the tumor should be performed if feasible. Including our patient, 9 of 10 cases received surgery (Table 1). Among the previous 9 cases, 7 received total hysterectomy and/or salpingo-oophorectomy and 2 received local resection. Moreover, 6 patients received rectal resections and 6 pa- tients received lymph node dissections. Some clinicians have offered adjuvant therapy, including chemotherapy and radiotherapy. Therefore, chemotherapy may be the first- line adjuvant treatment for aggressive malignant transform- ation of extragonadal endometriosis [ 29]. Similar to treat- ments for endometrial cancer, the chemotherapeutic regimens typically consist of platinum-taxane combinations. The therapeutic value of chemotherapy for extragonadal endometriosis–associated cancer is unclear. Radiation ther- apy may be performed after surgery or for treatment of local recurrence after the pri mary surgery and chemother- apy. Because of the rarity of this disease, neoadjuvant ther- apy should be considered, as should hormone-therapy for gestagen receptor-positive endometriosis-associated cancers [30]. Primary endometrioid adenocarcinoma of the rectova- ginal septum has much better prognosis than endometrioid tumors at other sites [11]. In conclusion, endometrioid adenocarcinoma of the rec- tovaginal septum is a rare malignant tumor that requires a high index of clinical suspicion for successful diagnosis. Clinicians must differentiate this tumor from colorectal cancers so that the most appropriate treatment is adminis- tered. Because of the rarity of this tumor, we cannot draw any conclusions regarding preoperative diagnosis. We sug- gest clinical suspicion in patients previously diagnosed with endometriosis who present with abdominal pain and vaginal or rectal bleeding, especially in women taking un- opposed estrogens. Several imaging techniques can help evaluate local and regional extension of the tumor. IHC staining is essential for the final diagnosis. Surgery com- bined with chemotherapy or radiotherapy seems to be the standard treatment for rectovaginal malignancies arising from endometriosis, but hormonal therapy could be con- sidered depending on the individual patient. However, be- cause of the rarity of this condition, identification and characterization of additional patients is essential. The ap- plication of targeted medication and immunotherapy may help to improve prognosis. Abbreviations AFP: Alpha-fetoprotein; BMI: Body mass index; CA125: Cancer antigen 125; CA19-9: Cancer antigen 19-9; CEA: Carcinoembryonic protein antigen; CDX- 2: Caudal-related homeobox 2; CK7: Cytokeratin 7; CK20: Cytokeratin 20; DIE: Deep-infiltrating endometriosis; F18-FDG PET/CT: F18- fluorodeoxyglucose PET/computed tomography; ER: Estrogen receptor; HE4: Human epididymis secretory protein 4; IHC: Immunohistochemical; MRI: Magnetic resonance imaging; PAX-8: Paired box gene 8; PR: Progesterone receptor; TVS: Transvaginal ultrasound; WTP-1: Wilms tumor protein-1

Not applicable. Authors’ contributions HY designed and revised the manuscript. YQ performed the operation. WZ performed the pathological imaging. XLW edited the manuscript. JJG made contributions to the acquisition of data and imaging. All authors read and approved the final manuscript. Yang et al. World Journal of Surgical Oncology (2019) 17:206 Page 7 of 8 Funding This study was supported by research program from the National Natural Science Foundation of China (NSFC) (Grant No. 81501496). Availability of data and materials The datasets generated and analyzed during the present study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study was approved by the ethics committee of Shengjing Hospital of China Medical University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from the patient. Consent for publication All data published here are under the consent for publication. Written informed consent was obtained from all individual participants included in the study. Competing interests The authors declare that they have no competing interests. Author details 1Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, Republic of China. 2Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, Republic of China. 3Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, Republic of China. Received: 13 August 2019 Accepted: 6 November 2019

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