Timothy J. Duncan, BM, BS, BMedSci, Department of Gynaecological Oncology, Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. Email: firstname.lastname@example.org
Sex cord–stromal tumors (SCSTs) of the ovary are uncommon. Their behavior is unpredictable, often with late recurrence, making counseling, management, and prediction of prognosis challenging. A 65-year-old woman presenting with a SCST underwent a bilateral oophorectomy, the histology was unusual but likely to be a luteinized thecoma with suspicious features for invasion. Two years later following a gastrointestinal bleed, a metastasis within the small bowel mucosa was detected. This represents probable isolated hematogenous or lymphatic spread, which is highly unusual especially in the absence of concurrent peritoneal disease. This is the first reported case of a SCST recurring in small bowel mucosa, mimicking a primary colorectal tumor. This highlights the diverse nature and behavior of these tumors.
Sex cord–stromal tumors (SCSTs) of the ovary are uncommon neoplasms that account for 5–8% of all ovarian malignancies(1). Their histopathologic appearance and malignant potential are highly variable, making the optimum treatment of these tumors difficult to establish. The group includes granulosa–stromal tumors, fibroma–thecoma, Sertoli–stromal cell tumors, steroid cell tumors, and SCSTs of mixed or unclassifiable type. The unpredictable behavior and often late recurrence of these tumors make counseling of patients with regard to subsequent management and prognosis a major challenge.
In keeping with the variable behavior of these tumors, we present an unusual case of a SCST that was difficult to classify, which recurred in the small bowel extending through into the lumen as a polyp.
A 65-year-old woman, gravida 6, para 6, presented with a short history of lower abdominal pain. She had not experienced any postmenopausal bleeding and had no bowel or urinary symptoms. She was a nonsmoker and was not on any medication.
A pelvic ultrasound 2 years earlier, to locate a misplaced intrauterine contraceptive device, demonstrated that the right ovary was of normal appearance and the left ovary was not seen. There was no other significant past medical history and no sign of virilization.
Examination revealed a smooth cystic mass lying posterior to the uterus. A transvaginal and transabdominal pelvic ultrasound demonstrated a 9- × 7- × 7-cm heterogeneous mass in the right adnexa. There was no vascular flow seen, and the ovaries were not seen separate to the mass. There were three small intramural fibroids noted and no ascites. A chest x-ray was normal. Her serum CA-125 level was 6 IU/mL. Renal, liver, and hematologic parameters were all in the normal range.
She underwent a midline laparotomy, having expressed a desire to retain her uterus if at all possible, although hysterectomy was strongly recommended due to the possibility of malignancy. At laparotomy, a large torted left ovarian cyst was discovered with small bowel adhesions to its surface. The right ovary appeared normal but was adherent to the small bowel; an 8-week-sized fibroid uterus was noted. The liver and omentum appeared normal and there was no pelvic or abdominal lymphadenopathy. There was a small amount of ascites that was sent for cytology. Bilateral oophorectomies were performed with no macroscopic residual disease. An omental biopsy was taken.
The histology showed a tumor in the ovary of sex cord–stromal type, which was difficult to classify further (Fig. 1). The main component comprised dense spindle cells interspersed with small groups of cells with prominent eosinophilic cytoplasm. Crystals of Reinke, a marker of Leydig cell differentiation, were not identified within the majority of these cells, but there was a group at the hilum at the edge of the tumor. In the absence of unequivocal Reinke’s crystals, the tumor was reported as a luteinized thecoma. There were features such as the mitotic rate, which were regarded as worrying and the tumor could not be regarded as being benign. No vascular invasion was identified. Immunohistochemistry showed the tumor was positive for inhibin and vimentin. There was no evidence of metastasis in the other specimens received.
She made an uncomplicated recovery and was followed up every 6 months for 2 years before being discharged.
The patient, soon after being discharged, represented with a short history of fresh rectal bleeding and melena. She had not experienced any weight loss or change in bowel habit and was otherwise asymptomatic.
Initial examination was unremarkable. The patient was noted to have a mild microcytic hypochromic anemia (10.2 g/dL). Renal and liver function was normal.
Upper and lower gastrointestinal endoscopies were performed and with the exception of mild gastritis, no abnormality was detected.
A further emergency admission occurred following a heavier rectal bleed from which her hemoglobin dropped to 5.4 g/dL. She was given a blood transfusion.
An abdominal and pelvic ultrasound was performed; the previously noted fibroid uterus was seen with an 8- × 6- × 6-cm mass superior to this, the nature of which was unclear. A computed tomography of the abdomen and pelvis confirmed the mass to be within a loop of small bowel with some dilatation of the bowel proximal to this (Fig. 2). A barium follow-through study demonstrated a filling defect in the lumen of the distal ileum, consistent with a small bowel tumor.
At laparotomy, a soft intraluminal mass was identified within the ileum. There was no defect in the serosa of the bowel and no evidence of peritoneal or pelvic deposits. A recurrence of the ovarian tumor seemed unlikely.
Histology of the lesion showed very similar appearances to the previous ovarian tumor except that the endocrine component was more prominent (Fig. 3). The gross appearances were very unusual in that there was transmural involvement of the small bowel with an ulcerated polypoid mass protruding into the lumen.
This was an unusual metastatic recurrence of a SCST. It appeared to be an isolated recurrence within the small bowel.
The treatment of such an unusual tumor recurrence is challenging due to the limited evidence available. The patient, however, expressed a strong wish to be managed conservatively and did not want to consider chemotherapy. The patient has remained asymptomatic with no clinical evidence of recurrence 14 months after the small bowel resection.
SCSTs vary greatly in prognosis and behavior, depending on subtype. Deciding on methods of management for recurrence can therefore be difficult, especially when it is at an unusual site, as in this case.
Since transcoelomic spread is the most common mode of metastasis in ovarian cancer, the gastrointestinal tract is frequently involved. In some advanced cases, determining whether the origin of the tumor is bowel or ovarian can be difficult. The use of immunohistochemical markers such as CK7 and CK20 can assist in the differentiation. The question of tumor origin did not present a problem with this case as the histologic morphology clearly demonstrated a recurrent SCST as opposed to an adenocarcinoma, which could be of ovarian or colonic origin.
The majority of gastrointestinal recurrences from ovarian tumors occur via direct transcoelomic spread and invasion of the serosal surface in a centripetal direction. Rose et al. demonstrated metastasis relating to small bowel in 43% of autopsies performed for ovarian cancer. However, it is likely that these mainly had serosal involvement and there were no SCSTs in this series(2). Most tumors involving the mucosa of the bowel will show evidence of associated serosal involvement. Reed et al.(3), in their review of 77 autopsy records of ovarian cancer, discovered bowel serosal involvement in 86% and mucosal involvement in 36%. This case is unusual in that the metastasis appears to have arisen in the mucosa alone, suggesting hematogenous or lymphatic spread. It has been suggested that this spread occurs in epithelial ovarian tumors along bowel wall lymphatic channels, displaying a “buckshot” distribution in which multiple separate foci were seen along a length of bowel mucosa. This lymphatic spread only occurs when there is a high level of intraperitoneal disease, which was not seen in our case(4).
Some SCSTs are considered to be of low malignant potential, having a low proliferation rate similar to that of borderline tumors of the ovary. As they are slow growing, they tend to present at an earlier stage compared with epithelial tumors and have an excellent prognosis, with overall 5-year survival of 79%. Recurrence and metastasis are rare and often late. More than 50% of recurrences occur after more than 5 years and 25% after 10 years(5). Others such as thecomas and fibromas generally behave in a benign fashion, although features such as mitotic rate, hemorrhage, and necrosis should be regarded with caution as these may better be regarded as fibrosarcomas.
Both luteinized thecomas and stromal Leydig cell tumors are usually regarded as benign, but in our case, there were worrying features that were identified on the initial histology. Zhang et al.(6) reported a series of 50 ovarian stromal tumors in which luteinized or Leydig cells were present, four appeared malignant histologically. One patient died rapidly, one was alive and well at 5 years, and there was insufficient follow-up on the other two cases. They make the comment that luteinized thecomas and stromal Leydig cells are only distinguished by the presence of crystals of Reinke, and due to the difficulty in identifying these structures, some luteinized thecomas may well be unrecognized stromal Leydig cell tumors(6). Virilization may act as a flag to search harder for Reinke‘s crystals. Very few cases of stromal Leydig cell tumors have been reported in the literature. In addition to Zhang’s series, two have been reported in young women(7,8).
Surgical intervention is generally adopted as the primary mode of treatment; this is often conservative in young women wishing to retain their fertility. Age, large tumor size, lymph node involvement, and residual disease are all predictors of poor prognosis(5).
While surgery is likely to remain the foundation for treatment of SCSTs, chemotherapy has been used as an adjunct in particular cases. Various authors have used chemotherapy in selected cases with advanced stage, significant residual disease, metastasis, or recurrence. While it is likely that chemotherapy provides improved survival in such cases, the optimum regime is still unclear. As SCSTs are variable in their histologic appearance, many chemotherapy regimes are assessed using the most common subgroup, the granulosa cell tumor, with extrapolation of the findings to all SCSTs. In addition, due to the indolent nature of these tumors, long-term follow-up of any proposed treatment is needed to observe the full effects. Hence, optimizing chemotherapy treatment in these cases is a challenge. A number of regimes have been used in the past including vincristine, doxorubicin, and cyclophosphamide, bleomycin, etoposide, and cisplatin (BEP), and most recently taxanes (paclitaxel or docetaxel)(9). A Gynecologic Oncology Group trial used BEP in the treatment of incompletely resected stages II–IV or recurrent SCSTs and found 69% of primary advanced and 51% of recurrences remained progression free following treatment, although there were problems of bleomycin-related pulmonary toxicity in a minority of cases(10). The use of taxanes with or without platinum has been shown to be as effective as BEP with regard to disease-free survival and overall survival. The taxane group experienced less major toxicity (14% mainly hematologic) compared with the BEP group (24% mainly pulmonary fibrosis or neutropenia). It should be noted that in all the aforementioned studies, the majority of tumors were adult granulosa cell tumors and so the findings may not be directly applicable to other SCSTs.
We believe this to be the first reported case of an ovarian stromal tumor containing lutein or Leydig cells that recurred in the small bowel mimicking a primary tumor in its mode of presentation. This further highlights the diverse nature and behavior of this group of tumors. This case demonstrates the difficulty in adopting an evidence-based approach to the treatment and follow-up in these rare cases. The need for careful discussion with the patient regarding additional treatment, if any, is of paramount importance.