Endometriosis-Associated Intestinal Tumor: A Case Report and Literature Review with Comprehensive Proteomic Data

A 53-year-old woman presented with rectal bleeding and was referred to a secondary hospital for further evaluation. She reported persistent dull pain in the lower abdomen but denied other gastrointestinal symptoms such as weight loss, vomiting, nausea, or diarrhea. The patient had no notable past medical history except for a prior anal fistula, and no relevant family history. The patient appeared well, with a body mass index of 21.8 kg/m 2 . Abdominal examination revealed no tenderness or palpable masses, and there was no enlargement of the spleen, liver, or lymph nodes. However, gynecological examination revealed a palpable mass in the pouch of Douglas with mild tenderness. Digital rectal examination identified a solid mass on the anterior wall of the rectum. Routine hematological and biochemical tests were within normal limits, including liver and renal function tests. Tumor markers, including carcinoembryonic antigen and carbohydrate antigen 19-9, were within normal ranges. However, CA125 was elevated at 148.0 U/mL (normal range: 0–35 U/mL), suggesting a potential gynecologic malignancy. Initial colonoscopy at the referring hospital revealed an 8-cm segmental stenosis in the rectum (Rb–Rs), suspected to result from extramural compression. Endoscopic biopsy was inconclusive, prompting referral for further investigation. Contrast-enhanced CT demonstrated a poorly defined 7-cm mass on the anterior rectal wall, with suspected extensive invasion into the uterus and prominent pelvic and lateral lymphadenopathy ( Fig. 1A ). Pelvic MRI showed circumferential wall thickening of the rectum with heterogeneous enhancement, raising suspicion for invasion into the uterovaginal junction ( Fig. 1B ). PET with 18 F-FDG-PET revealed significant tracer uptake in the rectal lesion and bilateral lateral pelvic lymph nodes ( Fig. 1C ). A second colonoscopy identified the tumor’s lower edge approximately 6 cm from the anal verge. Extramural compression was again observed, with partial mucosal ulceration resembling a villous tumor ( Fig. 1D ). However, biopsy specimens demonstrated only necrotic tissue and no evidence of malignancy. To establish a definitive diagnosis, a CT-guided needle biopsy was performed. Histopathological analysis confirmed adenocarcinoma. Immunohistochemical stains showed the tumor cells to be positive for PAX8, CK7, estrogen receptor (ER), and vimentin, and negative for CK20 and CDX2, findings consistent with a gynecologic origin ( Fig. 2A – 2F ). Based on the clinicopathological findings, the diagnosis of EAIT was established. Given the aggressive clinical presentation and precedent from previous case reports, the patient underwent posterior pelvic exenteration. The procedure included low anterior resection, total hysterectomy, bilateral salpingo-oophorectomy, vaginal cuff resection, and bilateral lateral pelvic lymph node dissection, in collaboration with the gynecology team. No macroscopic intraperitoneal metastasis was identified intraoperatively. Owing to bilateral tumor extension, resection of both pelvic plexus nerves was performed. Gross examination revealed a 70 × 67 × 48 mm tumor extending from the rectosigmoid junction to the upper rectum, located predominantly on the anterior rectal wall with mucosal ulceration ( Fig. 3A ), and invading the uterine cervix. Microscopically, the lesion displayed glandular and solid architecture, composed of columnar cells with eosinophilic and clear cytoplasm, mimicking endometrial-type glands ( Fig. 3B and 3C ). Foci of adjacent endometriosis were identified ( Fig. 3D ). Based on these findings, the tumor was diagnosed as endometriosis-associated endometrioid adenocarcinoma. Surgical margins were negative. No lymph node metastasis was identified, but ovarian metastasis was confirmed. The postoperative course was uneventful, except for the development of a neurogenic bladder. Because of the ovarian metastasis, six cycles of adjuvant chemotherapy with paclitaxel and carboplatin (TC regimen) were administered. The patient has remained disease-free for 3.5 years. Tumor tissue was obtained from the Tochigi Cancer Biobank. Samples were collected intraoperatively under the supervision of a certified pathologist and preserved in vapor-phase liquid nitrogen. Informed consent was obtained from the patient. Ethical approval was granted by the Tochigi Cancer Center Ethics Committee (Approval No. 21-A037). Proteomic profiling was performed using mass spectrometry, as described in the Supplementary Methods . A total of 9294 proteins were identified ( Supplementary Table 1 ), and the data have been deposited in the jPOST database (Accession Nos.: JPST004032 and PXD067723). The dataset is publicly available through the ProteomeXchange Consortium via the jPOST partner repository.

Endometriosis is a benign, non-neoplastic condition characterized by the ectopic proliferation of endometrial tissue. Approximately 80% of cases involve the ovaries, whereas about 12% affect the intestines, with the rectum and sigmoid colon being the most frequently involved sites. 1 ) Malignant transformation of intestinal endometriosis is exceedingly rare. The first case of endometriosis-associated adenocarcinoma was reported by Sampson in 1925. 2 ) Since then, only a few comprehensive reports have been published, including a notable series of 23 cases by Slavin et al. in 2000. 3 ) Despite these efforts, the clinicopathological and molecular features of EAITs remain poorly understood. In this report, we describe a rare case of rectal EAIT and provide an integrated clinicopathological analysis in the context of previously published cases, including 15 reported in the past literature. Additionally, we conducted a comprehensive proteomic analysis of the tumor tissue using mass spectrometry ( Supplementary Table 1 ). The resulting global protein expression profile was deposited in the publicly accessible Japan ProteOme STandard (jPOST) repository, providing a reference resource that may support future comparative analyses as more cases are accumulated.

Endometriosis is characterized by the presence of endometrial glands and stroma outside the uterine cavity. Although its etiology remains unclear, Sampson’s theory of retrograde menstruation is the most widely accepted hypothesis. According to this theory, endometrial fragments reflux through the fallopian tubes into the peritoneal cavity during menstruation, where they adhere to and infiltrate the pelvic organs. Endometriosis affects approximately 10%–15% of women of reproductive age. Based on anatomical distribution, it is classified into common sites (e.g., ovaries, uterosacral ligaments, pouch of Douglas, peritoneum), less common sites (e.g., intestines, ureters, bladder), and rare sites (e.g., lungs, pleura, soft tissues). 4 ) Among these, intestinal endometriosis represents the most frequent form of extrapelvic disease, occurring in 12%–37% of all endometriosis cases. The rectum and sigmoid colon are the most commonly involved intestinal sites (84%), followed by the colon (7%), cecum (5%), and appendix (3%). 5 ) While intestinal endometriosis is often managed conservatively, its malignant transformation—referred to as EAITs—is of major clinical concern. Approximately 0.7%–1.0% of all endometriosis cases undergo malignant transformation, with 78.7% of these occurring in the ovaries and the remaining 21.3% in extragonadal sites. 6 ) In a Japanese nationwide survey by Mandai et al., 7 out of 11 cases of malignant transformation in rare-site endometriosis involved the intestines. 4 ) EAITs are exceedingly rare, and no consensus exists regarding their optimal management. This study provides two main contributions. First, it represents the first attempt to investigate EAITs using proteomic analysis. Second, given that fewer than ten cases of EAIT have been reported in the Japanese population, presenting a Japanese EAIT case with proteomic analysis results is particularly noteworthy. In this study, proteomic analysis was prioritized over genomic or transcriptomic approaches to address the specific clinical and pathological questions raised by this rare case. While genomic and transcriptomic profiling are powerful tools for identifying recurrent molecular alterations across cohorts, their interpretability is inherently limited in single-case studies, particularly when the goal is to understand functional tumor biology. Proteomics captures the integrated downstream consequences of genetic, epigenetic, and transcriptional regulation, thereby providing a more direct representation of the tumor’s active molecular state. This feature makes proteomic profiling especially suitable for exploratory analyses aimed at linking molecular signatures with histopathological features and clinical behavior in rare or atypical presentations. To date, we have identified 56 previously reported cases published in the English literature, which are summarized in Table 1 . 3 , 7 – 37 ) The median age of onset ranged from 36 to 83 years, with a peak incidence in the 60s, followed by the 50s and 40s. About half of the patients presented with abdominal pain or gastrointestinal symptoms such as rectal bleeding, melaena, or hematochezia. Acute presentations, including bowel obstruction or peritonitis, were rare. Consistent with previous studies, the rectum was the most frequent site of EAITs. AWD, alive with disease; AWOD, alive without disease; BRBPR, bright red blood per rectum; BSO, bilateral salpingo-oophorectomy; DOC, died of other causes; DOD, died of disease; LLQ, left lower quadrant; TAH, total abdominal hysterectomy Histologically, endometrioid adenocarcinoma was the predominant tumor type (n = 34), followed by carcinosarcoma (n = 3), Müllerian adenosarcoma (n = 3), endometrial stromal sarcoma (n = 2), spindle cell carcinoma (n = 1), squamous cell carcinoma (n = 1), adenoacanthoma (n = 1), adenosquamous carcinoma (n = 1), and clear cell carcinoma (n = 1). This histological diversity underscores the heterogeneous nature of EAITs. Preoperative diagnosis remains challenging, largely owing to the submucosal or extrinsic growth pattern of these tumors. Conventional diagnostic modalities such as ultrasound, CT, and MRI have shown limited accuracy, with correct preoperative diagnosis reported in only 9%–22% of cases. 38 , 39 ) More recently, endoscopic ultrasound with fine-needle aspiration has emerged as a valuable tool for tissue diagnosis and should be considered early in the diagnostic work-up. 40 , 41 ) Immunohistochemistry also plays a critical role in differentiating EAITs from primary colorectal adenocarcinomas. While CK20 is commonly expressed in intestinal-type and Merkel cell carcinomas, CK7 positivity (in the absence of CK20) is typically seen in gynecological, breast, and lung adenocarcinomas. 42 ) Additionally, PAX8 and CDX2 staining provide further diagnostic guidance. PAX8 is a marker for Müllerian, renal, and thyroid tumors, 43 ) whereas CDX2 is a highly sensitive and specific marker for intestinal differentiation, particularly colorectal origin. Furthermore, vimentin and ER positivity supports an endometrioid phenotype. Therefore, the use of a panel of immunomarkers is recommended to distinguish EAITs from primary colorectal malignancies. Surgical resection remains the mainstay of treatment. Most reported cases have undergone en bloc resection with concurrent or non-concurrent hysterectomy and oophorectomy, although no formal guidelines recommend this approach. Given the common dissemination pattern of endometriosis through the uterus and adnexa, combined gynecological resection is generally favored. 42 ) According to Table 1 , 51 of 55 cases achieved R0/1 resection, and 94% of patients who survived for more than 1 year had undergone R0/1 surgery. In addition, lymph node metastasis appears to have a substantial impact on prognosis. Lymph node metastasis was identified in 12 of 38 cases for which lymph node status was available; recurrence occurred in 8 of these 12 patients in the lymph node-positive group, compared with 1 of 26 patients in the lymph node-negative group, indicating a markedly higher recurrence rate. This finding is consistent with the report by Tanaka et al., who analyzed Japanese case reports and demonstrated that the 5-year overall survival rate was 90.9% in the lymph node-negative group and 41.7% in the lymph node-positive group. 44 ) Taken together, these findings suggest that achieving complete resection is a key determinant of favorable outcomes, whereas lymph node metastasis is associated with poor prognosis and a high risk of recurrence. On this basis, we elected to perform posterior pelvic exenteration with bilateral pelvic lymph node dissection, including lateral pelvic nodes, with the aim of maximizing oncological clearance. Although this approach entails substantial surgical invasiveness, the patient was deemed fit for radical surgery. Furthermore, preoperative imaging demonstrated significant enlargement of the lateral pelvic lymph nodes, supporting the need for aggressive surgical clearance. In this context, the potential oncological benefit of complete tumor eradication was considered to outweigh the risks associated with the extensive procedure. The role of adjuvant chemotherapy or radiation therapy in EAIT remains unclear. Among patients with lymph node-positive disease listed in Table 1 , 7 of 12 received additional treatment, such as chemotherapy or radiation therapy. In most reported cases, chemotherapy regimens based on ovarian cancer protocols—most commonly paclitaxel and carboplatin—have been used empirically. Kawate et al. reported a favorable outcome using a regimen comprising cyclophosphamide, pirarubicin, and carboplatin in a patient with lymph node-positive disease; 31 ) however, the evidence remains anecdotal. Similarly, the role of radiation therapy is poorly defined, with no established evidence regarding optimal dose or irradiation field. Therefore, further investigation is warranted to establish optimal adjuvant treatment strategies and standardized protocols through collaborative efforts. Finally, we conducted proteomic analysis of the tumor using mass spectrometry. We acknowledge the inherent limitations of single-case studies, including the inability to draw generalized conclusions or establish causality. Accordingly, the present analysis should be regarded as exploratory in nature. Rather than serving as definitive evidence, the proteomic dataset generated in this study is intended to function as a reference molecular profile for this rare disease context. By providing a detailed protein-level characterization, this work offers a foundation for future comparative analyses, enabling subsequent studies to assess reproducibility, identify shared molecular features, and refine biological hypotheses as additional cases become available. Integrating such datasets across multiple cases may enable the identification of diagnostic biomarkers or novel therapeutic targets in EAIT.

We presented an extremely rare case of an EAIT. Although EAITs generally have a poor prognosis, our case suggests that aggressive surgical resection, including lymphadenectomy, followed by adjuvant chemotherapy may improve clinical outcomes. Further research is required to determine the optimal surgical approach, define the role of adjuvant therapies, and identify reliable prognostic indicators. Moreover, the proteomic data generated from this case, which are publicly available through a proteomic repository, provide a valuable resource for future comparative studies when integrated with additional cases.

endometriosis-associated intestinal tumors fluorine-18 fluorodeoxyglucose-PET

Results of comprehensive proteomic analysis of the tumor tissue using mass spectrometry. Detailed methods are described in the Supplementary Appendix.