Metachronous Ovarian Metastases in a Patient with Primary Colorectal Cancer. A Case Report and Review of the Literature

Background

Worldwide, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer mortality [1]. At the time of diagnosis, about 20% of patients with CRC have already developed metastatic disease, with the liver, lungs, bones, and brain being the most affected organs [2,3]. Less frequent metastatic sites include intraabdominal organs (pancreas, spleen, kidneys or ovaries) and non-abdominal organs (thyroid or breast).

Between 15–20% of all malignant ovarian tumors are metastatic, with the most common primary tumor sites reported to be the large intestine, the breast, the uterine corpus, the uterine cervix, and the stomach [4]. Metastases originating from primary gastrointestinal tumors are also known as Krukenberg tumors, named after Friedrich Ernst Krukenberg (1871–1946) who described five cases of in 1896 while he was a student in Germany [5,6].

Ovarian metastases usually present with pain and abdominal distention, which are attributed either to ascites or to the abdominal mass. In most cases, ovarian metastases present without specific symptoms or signs and are usually diagnosed during follow-up imaging [4]. A rare case is presented of metachronous ovarian metastasis from primary CRC, diagnosed on follow-up by computed tomography (CT) and magnetic resonance imaging (MRI), and includes a review of the literature.

Case Report

A 66-year-old woman was admitted to our department with a diagnosis of a cystic lesion in her right ovary, which was identified at follow-up computed tomography (CT) scan, three years following a left hemicolectomy for adenocarcinoma of the sigmoid colon. Magnetic resonance imaging (MRI) of the pelvis (Figure 1A, 1B) was performed to characterize the mass further, and showed an 8.6×5.6 cm cystic tumor of the right ovary. The tumor had clear margins, and there was no invasion into the uterus or bladder. The patient was asymptomatic, and there were no significant findings at previous routine follow-up visits, and no tumor recurrence or metastatic disease had previously been identified.

On this admission, her blood tests were normal, with serum carcinoembryonic antigen (CEA) level of 3.74 ng/ml (normal, <3.3 ng/ml), and a serum CA-125 of 27.87 μ/ml (normal range, 0–35 μ/ml). Clinical examination of the cardiovascular and respiratory systems was normal. Three years previously, she underwent a left hemicolectomy for adenocarcinoma of the sigmoid colon, and the diagnosis was confirmed with histopathology, and the tumor was staged as a pT3, N0, M0 adenocarcinoma. After the case was discussed at the multidisciplinary team meeting, no adjuvant therapy was given to the patient at that time.

On the current admission, the patient underwent an exploratory laparotomy through a midline incision. A cystic lesion of the right ovary was found intra-operatively with macroscopic characteristics consistent with malignancy. Total hysterectomy and bilateral salpingo-oophorectomy were performed, and no residual tumor was found within the abdominal cavity. The macroscopic appearance of the tumor showed cystic, solid, and papillary areas with foci of hemorrhage (Figure 2). The histology showed a mainly papillary tumor with few glands that were covered by a layer of neoplastic epithelial cells (Figure 3A, 3B). The glands within the tumor contained necrotic debris (Figure 3C). The neoplastic cells were columnar with eosinophilic cytoplasm, atypical nuclei and nucleoli (Figure 3D). The mitotic index was high. Immunohistochemistry showed that the malignant cells were positive for CDX2 (Figure 4A) and cytokeratin 20 (CK20) (Figure 4B), and negative for cytokeratin 7 (CK7), estrogen receptor (ER), and progesterone receptor (PR), which supported the origin of the tumor in the right ovary from the colon. The patient recovered well, and the postoperative course was uneventful. She was further referred to the oncology department, and adjuvant treatment was commenced.

Discussion

Metachronous metastasis is defined as occurring more than three months after the diagnosis of malignancy at another site. This report is of a rare case of metachronous ovarian metastasis from a primary colorectal carcinoma (CRC), or Krukenberg tumor, in a 66-year-old woman, diagnosed three years after surgical resection. The ovarian tumor was diagnosed at follow-up by computed tomography (CT) and magnetic resonance imaging (MRI). Previous studies from single centers have reported the incidence of synchronous ovarian metastases in 0–9% of women with colorectal cancer (CRC), and metachronous ovarian metastasis in 0.9–7% [4,9,10]. A Swedish population-based study estimated the incidence of metachronous ovarian metastasis as 0.8% in women treated for CRC [11]. Metachronous ovarian metastases were identified at a median of 16 months after resection of the primary tumor [11]. This previous study also showed that there was a significant difference between the incidence of metachronous ovarian metastases in women with primary adenocarcinoma of the colon (1.1%) compared with women with primary adenocarcinoma of the rectum (0.1%) (P<0.001) [11]. Adenocarcinoma of the rectum was less likely to present with metastases, as the diagnosis was usually made at an early stage, and was more likely to be treated with radiotherapy, which prevents micrometastases [11]. Also, radiotherapy may induce ovarian atrophy and impair the ovarian blood supply, which reduces the risk of hematogenous tumor spread to the ovaries [11]. Also, in this previous study, women with metachronous ovarian metastases were younger than women who did not develop metastatic disease, indicating that reduced hematogenous spread may occur in older women with ovarian atrophy [11].

In a study by Ojo et al., the incidence of metachronous ovarian metastases from CRC was similar was 0.76%, with the diagnosis made at a median of 23.5 months after the primary tumor diagnosis [12]. In 75% of the cases of metachronous ovarian metastasis, the primary tumor was located in the proximal colon [12]. Unlike the case described in this report, none of the patients with metachronous tumors had isolated ovarian metastases at the time of presentation, and they were younger, with a median age of 49 years [12]. Tan et al. reported the incidence of metachronous ovarian metastases from CRC as 0.4%, with the diagnosis made at a median of 15 months after the primary diagnosis of CRC [13]. Bilateral ovarian metastatic disease, synchronous or metachronous, was more common, while 44% of patients had only unilateral ovarian involvement [13]. Further studies have confirmed the low incidence of metachronous ovarian metastases originating from CRC, and the higher prevalence of ovarian metastases from CRC in women of younger age [4,5,14–18].

The routes of metastatic spread of CRC may include hematogenous, lymphatic, direct, and transperitoneal spread. However, for CRC and spread to the ovary, the hematogenous route is most likely. Peritoneal involvement is usually absent at the time of diagnosis, and the external surface of the ovaries often lack tumor seedings, or adhesions [19]. Vascular imaging studies have shown vascular communication between both ovaries through the fundic arterial branches [20], which also explains why ovarian metastases from CRC tends to be bilateral, and even when unilateral, there is a high probability that the contralateral ovary, if not removed, will develop metastases [4,5,13,16]. The reduced risk of ovarian metastases in post-menopausal women indicates the protective role of reduced ovarian vascularity [11]. However, retrograde lymphatic spread after malignant obstruction of the lymphatics, or the direct implantation of malignant cells may still occur.

Abdominal pain is the most common symptom in patients presenting with ovarian metastases from CRC, followed by a change in bowel habit, and abdominal distension due to ascites or an abdominal mass [4]. Measurement of serum tumor markers, including carcinoembryonic antigen (CEA) and CA-125, are commonly used in the diagnosis of in CRC and ovarian cancer. CA-125 levels are commonly increased in epithelial ovarian cancer, and serum CA-125 is a useful prognostic marker in patients with ovarian metastases from the gastrointestinal tract (Krukenberg tumors), and levels >75 IU/ml are associated with a reduced 5-year survival rate [14]. Also, a preoperative increase in serum CA-125 usually decreases after re-section of the tumor, which makes it a useful marker for successful tumor resection, and tumor recurrence [20–22]. Also, in patients with an ovarian mass who present with raised serum CA-125 levels, clinicians should always exclude a primary CRC and other gastrointestinal malignancy before diagnosing a primary ovarian cancer, as ovarian metastases have been reported as the initial manifestation in 51% of these patients [22]. There may also be a role in using both serum CEA and CA-125 in postoperative follow-up of female patients with CRC who have not had bilateral oophorectomy [13]. However, further studies are needed to support the benefit of this management approach.

The imaging characteristics of ovarian masses on computed tomography (CT), a smooth margin and cystic elements, similar to the current case, favors the presence of colonic metastases rather than a primary ovarian neoplasm [23]. Also, the presence of calcification may be associated with a metastatic mucinous carcinoma [23]. The difficulty in differentiating between primary and metastatic tumors of the ovary has been well described by Herrera et al. [20], and Skirnisdottir et al. [22]. Both studies concluded that there is still difficulty in diagnosing metastatic ovarian tumors, which continue to be misdiagnosed as primary ovarian tumors [20,22]. To distinguish between ovarian metastases due to CRC and primary ovarian carcinoma, immunohistochemical staining can support a definitive diagnosis. Positive immunostaining for cytokeratin 20 (CK20) and negative immunostaining for cytokeratin 7 (CK7) support a diagnosis of ovarian metastases from primary CRC [5,24,25].

The ovary has been described as a sanctuary for metastatic cells, as metastatic ovarian tumors do not respond favorably to chemotherapy [4,5,12]. Therefore, the only realistic option for the treatment of ovarian metastases remains oophorectomy, although the outcome remains poor. The presence of ovarian metastases indicates that the primary malignant disease has progressed, and poor prognosis can be expected [15]. Surgery may improve survival in selected patients who are younger (<50 years) and those who have only ovarian metastases [14]. Even in these cases, the 5-year survival has been estimated at around 9%, with a median survival of between 19 and 29.6 months [12]. For patients with disseminated disease, optimal cytoreduction, when feasible, offers a significant survival advantage compared with patients who have residual malignancy [4]. However, most patients die within one year from the diagnosis of ovarian metastases [26].

Finally, in female patients with primary CRC, or other gastrointestinal malignancy, there has been interest in the use of prophylactic oophorectomy, which could be easily performed at the time of primary surgery, without additional morbidity or mortality, to reduce the likelihood of ovarian metastases. However, given that metastatic ovarian cancer has a higher incidence in premenopausal women, oophorectomy may not be an option. Therefore, clinicians should offer female patients with primary gastrointestinal malignancy a range of options explaining in detail the advantages, limitations, and consequences of the procedure, because, currently, there are no consensus guidelines or recommendation regarding the use of prophylactic oophorectomy in CRC [11,13,15,16,22].

Conclusions

Newly-diagnosed ovarian metastasis from primary colorectal cancer (CRC) is challenging to diagnose and manage, and may be initially incorrectly diagnosed as malignancy of primary ovarian origin. This case demonstrated that it is important to confirm the diagnosis with imaging, histology, and the appropriate use of tumor markers. Because ovarian metastases do not respond favorably to chemotherapy, the treatment of choice is surgery. However, for women who are treated for CRC, the use of prophylactic oophorectomy remains controversial.