An unusual colo-ovarian fistula of advanced colorectal carcinoma: A case report and literature review

The fistula produced between the lower gastrointestinal tract and the ovary is an extremely rare condition, with few cases presented in the literature ( 1-20 ); therefore, there is no consensus regarding its diagnosis, therapeutic strategy and prognosis. The establishment of therapeutic management depends on the topography of the fistula, the benign or malignant nature of the tumor, the primary tumor (digestive or ovarian), the type and grade of the tumor, and the patient's age and comorbidities. Due to the rare occurrence of spontaneous colo-ovarian fistulas caused by malignant tumors, clinical and imaging findings [ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), colonoscopy and barium enema] make it difficult to establish its existence preoperatively ( 15 , 21 ). The most frequent causes of the appearance of colo-ovarian fistulas are determined by the evolution of primary ovarian cancers or the malignant transformation of mature cystic teratomas (MCTs), with extremely rare cases being due to colorectal or appendicular cancer ( 12 ). In the evolution of advanced stages of ovarian cancer [stages III-IV according to the International Federation of Gynecology and Obstetrics (FIGO) classification], either intestinal obstructive syndromes or, more rarely, fistulas between the ovary and adjacent structures can be observed ( 22 ). In a number of cases, the poor prognosis of ovarian cancer is due to late detection in advanced stages in the absence of symptoms, with the invasion of the muscular serous layer of the colon by extrinsic tumor compression ( 8 , 13 ). Colorectal cancer can be complicated by spontaneous perforation in advanced stages in ~12% of cases, with fistulization being found in 20% of cases in sigmoid colon cancer secondary to local necrosis after chronic inflammatory processes ( 23 ). There is no known data on the incidence of spontaneous colo-ovarian perforations in the case of malignant tumors, with a reported incidence of 0.7% due to benign ovarian cystic tumors or 1-2% due to malignant transformation of MCTs ( 9 , 24 ). Patients may be asymptomatic and may experience bleeding or obstructive episodes depending on the topography of the fistula and the organ involved. The pathogenesis of the fistula formation is based on the local inflammatory process of the intestinal wall and the tumor invasion adjacent to the organ. Histologically, features of the fistulas, including necrotic, ulcerative, malignant infiltrative and chronic inflammatory areas, can be observed ( 21 ). The current study aims to present the extremely rare case of a patient with high-grade mucinous colorectal carcinoma with perforation at the level of the rectosigmoid junction into the metastatic ovarian tumor and to review the literature related to cases with colo-ovarian fistulas caused by the evolution of colorectal tumors, ovarian cancer or malignant transformed MCTs.

In patients with advanced stages of colorectal or ovarian cancer, intestinal obstructive syndromes may occur more frequently, with fistulas rarely occurring between the ovary and adjacent structures ( 14 ). Colonic fistulas of malignant origin are also rare and are reported most frequently in association with the bladder (colo-vesical) ( 25 ), vagina (colo-vaginal) ( 26 ), uterus (colo-uterine) ( 27 ), small intestine (colo-enteral) ( 28 ) and skin (colo-cutaneous) ( 29 ), but rarely with the ovary (colo-ovarian) ( 30 ). Due to the rarity of this pathology, an electronic search from inception was performed in the PubMed ( https://pubmed.ncbi.nlm.nih.gov ) and Web of Science (https://webofscience. com/wos/woscc) databases, regardless of language. The key medical subject heading terms used in the electronic search technique were ‘colo-ovarian fistula’, ‘colorectal carcinoma’, ‘ovarian carcinoma’ and ‘malignant cystic teratoma’. As a result, 20 studies were identified that presented 21 cases of colo-ovarian fistula occurrence as a complication of malignancy, of which 10 cases were reported as the consequence of the evolution of advanced stages of ovarian cancer ( 11-20 ), 10 cases were reported with malignant transformation of MCT ( 1-10 ) and 1 case was reported with uncertain localization (colorectal or ovarian) ( 31 ), with no cases of certain colorectal origin. According to histopathological analysis, the distribution of the 11 cases with primary ovarian cancer was as follows: 5 cases with serous cystadenocarcinoma ( 11 , 12 , 16 , 18 , 20 ), 1 case with mucinous cystadenocarcinoma ( 14 ), 1 case with a mixed germ cell tumor ( 13 ), 1 case with serous cystadenoma of low malignant potential ( 13 ), 2 cases with clear cell adenocarcinoma ( 15 , 17 ) and 1 case with squamous cell carcinoma ( 19 ) ( Table II ). Previous reports documenting the evolution of advanced colorectal cancer to a large bowel fistula with the involvement of a metastatic ovarian tumor are extremely rare. In this context, the present study reports a specific case of colorectal mucinous adenocarcinoma perforating a metastatic ovarian tumor at the level of the rectosigmoid junction. In addition, it is worth noting that fistulas in the recto-sigmoid region can also be more frequently associated with benign ovarian tumors, predominantly teratomas ( 32 , 33 ). The clinical manifestation of ovarian or colorectal cancer is polymorphic, with the majority of patients being asymptomatic, but with others presenting with gastrointestinal symptoms (vomiting, nausea, constipation, diarrhea, bloating, early satiety and rectal bleeding), urinary frequency, abdominal or pelvic discomfort, abdominal pain and an abdominal mass ( 9 ). Patients may also exhibit pleural effusion or bowel occlusion syndrome in advanced stages. Full-thickness extension into the bowel mucosa, resulting in fistula formation, is an exceedingly rare event ( 34 ). MCTs can undergo a malignant transformation in 1-2% of cases, most frequently in menopausal patients in the fifth and sixth decades of life, with the histopathological forms encountered being small-cell carcinoma and adenocarcinoma (mucinous with a poor prognosis) ( 9 , 35 , 36 ). From the review of the literature, clear differences were observed in terms of mean age between the group with MCTs, at 66.9 years (range, 48-90 years) and the group with ovarian carcinomas, at 58.5 years (range, 27-77 years). No differences were observed in terms of the mean maximum diameter of the ovarian tumor in the group with MCTs (14.4 cm) and that of the group with ovarian carcinomas (15.1 cm), with this parameter being independent regarding the prognosis of these patients. The mechanism of fistula formation in an MCT is initiated by the chronic inflammatory reaction of its contents to the adjacent organs. Furthermore, sepsis, torsion or vascular changes favor the breakthrough of the cyst into the peritoneal cavity, and malignant transformation of MCT is not a determining factor ( 33 , 37 ). In ovarian cancer, the appearance of a primary fistula is due to the progression of the implants on the ovarian serosa, and the size and the stage of the tumor, unlike the appearance of a secondary fistula, which appears as a late complication after surgery or after chemotherapy and radiotherapy ( 4 , 38 ). In advanced stages of ovarian cancer, fistula formation may result from direct malignant invasion of adjacent structures. Tumor spread usually occurs by contiguous extension, initially involving the colonic seroasa and muscularis propria, while mucosal infiltration and full-thickness bowel perforation are extremely rare. Another possible cause of fistulization can be the evolution of inflammatory phenomena from endometriosis ( 17 ). A peculiarity in the present case is the presence of an IUD discovered on the CT scan years after the onset of menopause. It is well known that using an IUD for long periods can lead to pelvic actinomycosis, a granulomatous disease that can cause a chronic inflammatory process with the formation of granulation tissue, fibrous tissue, necrosis and abscesses. The diagnosis of this pathology is a challenge due to the non-specific clinical manifestations, being characterized by nausea, vomiting, weight loss, transit disorders, fever, or imaging identification of a tumor mass or fistula. Thus, in many cases, it easily mimics a colonic neoplasia. Cultures are usually negative, and the histopathological diagnosis is performed by identifying actinomycotic structures ( 39 ). In patients with ovarian cancer experiencing sepsis and an acute abdomen, it is crucial to consider the possibility of recto-sigmoid colon perforation. A quick diagnosis and emergency surgical intervention are important in managing this condition. US examination may yield inconclusive results due to the presence of gaseous interposition. Therefore, a pelvic CT scan assumes paramount importance, revealing the presence of air within the adnexal mass. The imaging diagnosis of the fistula can identify either an extravasation of barium on the X-ray examination or the presence of gas bubbles at the tumor level on the CT scan. A colonoscopy can identify the area of interest that can be biopsied on direct inspection. The presence of the fistula cannot specify the diagnosis of the primary tumor, this being all the more difficult to achieve when an ovarian mass is evident on imaging ( 21 ). Achieving an early diagnosis of the perforation followed by urgent surgical intervention is also important for the patient's prognosis. The X-ray examination of the abdomen can highlight a possible air collection in ~50% of cases, and as a result, it has been gradually replaced by CT evaluations. Routine US cannot achieve a correct imaging assessment of the case regarding perforation, but it can evaluate ovarian/colorectal tumor formation. CT, contrast enhanced CT and MRI increase the detection rate of fistulas, and evaluate the ovarian/colorectal tumor and the preoperative and postoperative imaging balance ( 15 ). Colonoscopy is used only in selected cases, as it usually does not provide data on the presence of fistulas, a possible alternative that is provided by 3.0-Tesla MR colonography ( 40 ). Establishing the origin of the primary tumor is important regarding therapeutic management. The initial differentiation is essential between ovarian and digestive tumors and later between colorectal and appendicular tumors if these tissues have a degree of infiltration. Sometimes, it is difficult to make the differential diagnosis between ovarian and colon carcinomas, especially in advanced stages with peritoneal carcinomatosis or metastatic disease. At presentation in the current study, serum CA125, CA19-9 and CEA levels were measured as part of a targeted diagnostic evaluation. This combination is not routinely required for all adnexal masses: CA125 is generally the principal initial serum marker, whereas CA19-9 and CEA are added selectively when a mucinous ovarian neoplasm or gastrointestinal origin is suspected. Later, performing immunohistochemical staining with CK7, CK20, CDX2, SATB2 and PAX-8 allowed the differentiation of the primary ovarian origin from that of a tumor of the lower intestinal tract. To distinguish between a primary ovarian carcinoma and a metastatic colorectal carcinoma of the ovary, the CK7 marker is used ( 41 ). CK7 is positive in 96% of ovarian adenocarcinomas and 25% of ovarian metastases of colorectal cancer, especially high-grade tumors and those located on the right side ( 42 ). CK7+ colorectal tumors have a negative prognosis, with a lower survival rate compared to CK7-tumors, regardless of tumor location, grade or stage ( 43 ), as in the case of the present patient. Meagher et al ( 44 ) revealed use of a new marker SATB2, which, together with CK7, completes the immunohistochemical profile of primary mucinous ovarian tumors (CK7 + /CK20 - /PAX8 + /SATB2 - ) of colorectal carcinomas, to improve the prognosis and ensure a correct chemotherapy scheme ( Table III ). The differentiation between colorectal and appendicular origin is difficult, this being based less on the evaluation of the operative specimen and more on next-generation sequencing of the APC gene mutations that are more frequent in colorectal cancer and the activation of KRAS-mediated signaling pathways and GNAS in appendiceal cancer ( 45 ). The differential diagnosis of suspected colo-ovarian fistula when CT reveals a gas-containing adnexal mass includes tubo-ovarian abscess, infected or fistulizing ovarian neoplasm, and colo-vesical or colo-uterine fistula. Sigmoid volvulus, Meckel's diverticulum and enteric duplication cysts are considered more accurate radiological mimics of a gas-containing abdominal or pelvic lesion than direct differential diagnoses of a confirmed colo-ovarian fistula ( 11 , 46 ). Therapeutic approaches may vary depending on the patient's condition. Conservative measures such as fasting, intravenous fluids and antibiotics may be successful. Alternatively, direct surgical drainage of the abscess or ultrasound/CT-guided percutaneous drainage may be considered temporarily ( 47 ). However, a surgical approach remains the preferred choice, allowing for both fistula treatment and maximal tumor cytoreduction ( 16 ). This may involve en bloc resection of the tumor, uterus, ovaries, fallopian tubes and perforated rectosigmoid colon, with the possibility of primary colorectal anastomosis, with or without a protective stoma (colostomy) or a Hartmann procedure, depending on the location of the colorectal perforation ( 48 ). In the review of the literature, it was identified that conservative treatment of the fistula was carried out in only 1 case ( 18 ), with the rest being solved surgically. The goal of surgery for colorectal cancer complicated by a colo-ovarian fistula is complete en bloc oncological resection of the primary tumor and all directly involved adjacent structures. In the present case, Hartmann's procedure was selected to achieve tumor resection and adequate source control while avoiding a high-risk primary anastomosis. A complete margin-negative (R0) resection was achieved, representing the prognostically relevant surgical outcome, rather than the use of Hartmann's procedure itself. Postoperative survival is, in most cases with an inauspicious prognosis, influenced by age, preoperative preparation, tumor size, the degree of anaplasia, the stage of the disease, preoperative CA125 levels, the degree of sepsis, chemotherapy, the extent of the surgical debulking, comorbidities, metastatic disease, and the extent and curative aspect of the surgical intervention. Although an en bloc resection of the lesion is often performed, this is mainly palliative and less curative regarding the extension and evolution of metastatic ovarian disease ( 14 ). In conclusion, the current study reported an extremely rare presentation of a case of primary colorectal cancer with perforation at the level of the rectosigmoid junction, with a colo-ovarian fistula and diffuse peritonitis, which was suspected on computed tomography and diagnosed intraoperatively. Due to the peritonitis and the intestinal resection, chemotherapy, although necessary, was delayed, contributing to an unfavorable prognosis. These cases continue to represent a real diagnostic and therapeutic challenge due to the very low incidence of colo-ovarian fistulas, the initial intraoperative difficulties in specifying the primary tumor (colorectal or ovarian cancer), the histological and therapeutic challenges, the increased morbidity, the associated prognostic complications and the lack of specific protocols.

A 68-year-old woman presented to the Emergency Department, at Ramnicu Sarat Municipal Hospital (Buzau, Romania) in May 2024 with abdominal pain that had started suddenly 10 days ago and had increased in intensity and become sharp in the last 3 days. This pain was associated with vomiting, nausea, constipation and loss of appetite. The patient had known for 2 years about a right ovarian tumor with no suspicious ultrasound characteristics, but at that time, had refused further investigations and surgery, as well as neglecting the recommended periodic monitoring. According to the patient's medical history, the patient was undergoing antihypertensive treatment. In April 2024, at the same hospital, the patient underwent a colonoscopy, which, upon withdrawal of the colonoscope, revealed a sessile polyp with modified mucosa, ~1.5 cm in size, located 8 cm from the anal orifice. Furthermore, a 2-cm exulcerated, vegetative tumor formation was visualized 7 cm from the anal orifice, bleeding when touched with the colonoscope. At the beginning of May 2024, MRI of the pelvis with contrast medium revealed a formation with polycyclic contour, heterogeneous structure, and areas of necrosis and hemorrhage, with maximum axial diameters of 100/96 mm and cranio-caudal diameters of 90 mm, with apparent origin at the level of the right ovarian lodge. The structure had a multicystic appearance, delimited by irregular walls, with solid nodules and hemorrhagic areas with horizontal level included. The mass described covered adjacent intestinal loops, with infiltration of their walls and the associated mesentery. It was closely adjacent to the urinary bladder, raising the suspicion of invasion of the right half of the posterior wall. The mass also involved the distal sigmoid colon and rectosigmoid junction, with evidence of mural invasion. The appearance was suggestive of a pelvic tumor block with apparent origin at the level of the right ovary, with bladder, enteral and colonic invasion. A right external iliac adenopathy with a diameter of 12 mm was also noted. Upon the current admission, at the clinical examination, the patient presented with tachycardia and hypotension; the abdomen was distended, diffusely tender, and had a palpable mass in the lower region up to the umbilicus. Rectal and vaginal examinations revealed fingertip tenderness. Blood tests revealed the following results: Hemoglobin, 10.2 g/dl (normal range, 11.7-16.1 g/dl); white blood cells, 18x10 3 µl (normal range, 4-10x10 3 µl); 90% neutrophils (normal range, 45-80%); and platelets, 160x10 3 µl (normal range, 150-450x10 3 µl). Further results included the following: Oxygen saturation, 90% (room air); creatinine, 2.1 mg/dl (normal range, 0.55-1.02 mg/dl); blood-urea-nitrogen, 102 mg/dl (normal range, 6-24 mg/dl); random blood sugar, 119 mg/dl (normal range, 80-130 mg/dl); C-reactive protein, 62 mg/dl (normal value, <0.5 mg/dl); and negative blood cultures. No specific changes were observed in the electrocardiography. The preoperative abdominal US showed a tumor mass with a complex echoic structure measuring 17x14 cm in the lower abdomen, with a small amount of fluid in the pouch of Douglas ( Fig. 1A ). The CT scan without contrast revealed a pelvic tumor mass involving the sigmoid colon loop, an ovarian tumor, ascites and multiple gas foci, indicating a possible fistula between the two adjacent structures ( Fig. 1B and C ). Furthermore, the axial CT examination highlighted the presence of an intrauterine device (IUD) ( Fig. 1D ). Informed consent for investigations and treatment was obtained from the patient at admission. After the preoperative preparation of the patient, an emergency median laparotomy under general anesthesia was performed. Intraoperative abdominal cavity inspection revealed ~400 ml of cloudy free fluid, a retro-uterine pelvic abscess towards the right iliac fossa, a right giant ovarian tumor attached to the rectosigmoid junction with perforation at its level, and intimate adherent to the small intestines, the apex of the appendix and the bladder ( Fig. 2A-C ). Macroscopic examination of the surgical specimen identified the fistulous tract on the resected rectosigmoid with an area of adjacent ovarian tissue ( Fig. 2D ). A sample of peritoneal fluid was collected for culture and cytological examination. Further surgical procedures performed on the patient included a total hysterectomy with bilateral adnexectomy, appendectomy, omentectomy, rectosigmoid junction resection with the Hartmann procedure, partial cystectomy and intraperitoneal drainage. Postoperatively, the patient was admitted to the Intensive Care Unit for 5 days and received intravenous broad-spectrum antibiotics consisting of meropenem at a dose of 1 g every 8 h and metronidazole at a dose of 500 mg every 8 h for 5 days to control intra-abdominal sepsis. After 17 days, the patient was discharged with a colostomy and urinary catheter for 6 weeks. In the current case, intraperitoneal hyperthermic chemotherapy was not performed as the infusion machine was not available. The histopathological aspect of the examined sections suggested a mucinous-type malignant tumor proliferation. Surgical specimens were fixed in 10% neutral buffered formalin (~4% formaldehyde) at room temperature (20-25˚C) for 24 h, processed routinely and embedded in paraffin. Next, 3-4-µm thick sections were prepared and stained at room temperature with hematoxylin for 5 min, followed by eosin-ethanol for 2 min. Slides were examined using an Olympus BX43 optical microscope (Olympus Corporation) at original magnifications of x100, x200 and x400. The corresponding magnification and scale bar are provided in the legend of each figure. To accurately establish the tumor histotype (primary tumor of the digestive tract, appendix or rectum, or primary ovarian tumor), immunohistochemistry tests were required, which highlighted the diagnosis of high-grade carcinoma with ‘signet ring’ cells of digestive origin ( Fig. 3A-F ). The immunohistochemical result revealed that the tumor tissue was positive for cytokeratin 20 (CK20), homeobox protein CDX-2 (CDX2) and CK7, and negative for special AT-rich sequence-binding protein-2 (SATB2) and paired box protein Pax-8 (PAX8), which established the colorectal origin of the tumor. The samples were fixed in 10% neutral buffered formalin at room temperature for 40 min, followed by dehydration and routine cleaning before inclusion in paraffin. The tissue blocks were sectioned at a thickness of 4 µm and mounted on glass slides. The antibodies used and their specifications are presented in Table I . After incubation with primary antibodies, the sections were treated with antibody detection systems. All sections were examined under an Olympus BX43 light microscope (Olympus Corporation) at a total magnification of x100, x200 and x400, as appropriate. Histological examination of the colonic wall fragments revealed infiltrative tumor proliferation involving the full thickness of the wall, and extending to the serosa. Extracellular mucin pools occupied ~70% of the tumor area in the examined fragment. Within these mucin pools, the tumor cells were arranged in islands and cords or dispersed individually. The cells were small and round to polygonal, exhibiting ‘signet ring’ morphology and marked pleomorphism. They contained clear intracytoplasmic vacuoles and eccentrically located hyperchromatic nuclei. Numerous typical and atypical mitotic figures were identified. Only small, focal areas showed a desmoplastic stromal reaction, accompanied by a sparse chronic inflammatory infiltrate. Lymphovascular and perineural invasion were present ( Fig. 4A-E ). At 2 months post-surgery, the patient presented to the Emergency Room at Ramnicu Sarat Municipal Hospital with nausea, vomiting and suspicion of an intestinal obstruction. MRI examination of the abdomen and pelvis with intravenous contrast revealed dilated bowel loops, suspected carcinomatosis and a small amount of intraperitoneal free fluid ( Fig. 5 ). The CA125 level was 645 IU/ml (reference range, 0-35 U/ml), the CEA level was 4 ng/ml (reference range, 0-5 ng/ml) and the CA19-9 level was 26 U/ml (reference range, 0-37 U/ml). On the same day, an emergency laparotomy was performed, which revealed a frozen pelvis and diffused peritoneal carcinomatosis over the intestine, colon, spleen, liver and diaphragm. Intraoperatively, the intestine could not be released from the pelvis, requiring an ileostomy as a palliative procedure. The patient was discharged with an improved condition. Due to the advanced stage of colorectal cancer and the unfavorable evolution in a short time, it was determined that the patient would not benefit from palliative chemotherapy. A total of 10 days after surgery, the patient's condition quickly deteriorated and they succumbed to their condition. Tissue microarray sections were cut at a thickness of 4 µm, mounted onto glass slides, and incubated in an oven for 1 h. Target retrieval was performed using the PT-Link automated system (Dako; Agilent Technologies, Inc.) at a high pH. The slides were incubated at 97˚C for 30 min. Once the temperature cooled to 65˚C, the slides were removed, immersed in a wash buffer for 10 min, and allowed to equilibrate to ambient room temperature. Staining, detection systems and antibody incubation. Endogenous peroxidase activity was blocked by treating the sections with a blocking peroxidase solution for 5 min, followed by three sequential rinses in wash buffer. The primary antibodies (CK7, CK20, CDX2, SATB2, or PAX8), all in ready-to-use formats, were applied to the sections and incubated for 20 min. Following three successive washes in wash buffer, target visualization was achieved using automated secondary detection systems matched by manufacturer specification. For the Dako primary antibody (CDX2), the Dako EnVision FLEX HRP polymer detection system (Dako; Agilent Technologies, Inc.) was applied. For the Bio SB primary antibodies (CK7, CK20, SATB2 and PAX8), the micro-polymer-based Bio SB PolyDetector HRP detection system (Bio SB, Inc.) was utilized. Sections were incubated with the respective horseradish peroxidase polymer for 20 min. After another 20-min interval and three additional washes in wash buffer, the signal was developed by incubating the slides with 3,3'-diaminobenzidine substrate for 5 min. The slides were then rinsed three times in wash buffer. Counterstaining and examination. The sections were counterstained with hematoxylin for 1 min. Dehydration was carried out through systematic immersion in a graded alcohol series, ranging from 96 to 100% alcohol. Finally, the slides were cleared with three changes of xylene, loaded into an automated glass coverslipper and prepared for optical microscopy. Within the panel, CK7 and CK20 served as cytoplasmic markers to evaluate specific epithelial lineages, CDX2 and SATB2 served as nuclear markers to identify gastrointestinal and colorectal differentiation, and PAX8 was used as a nuclear marker to delineate Müllerian lineages.