Ioannis Gounaris and Christine Parkinson
Case history
A 47-year-old pre-menopausal woman presented with a few-week history of feeling excessively tired and unwell. She denied any abdominal symptoms and she had a past medical history of endometriosis and benign liver cysts. Clinical examination showed a palpable mass arising from the pelvis. Routine blood tests were normal. CA-125 was 54U/L (normal range 0–30). She underwent a CT scan of her abdomen and pelvis (Fig. 19.1).
Fig. 19.1
Questions
1. What does the CT scan in Fig. 19.1 show?
2. Is the history of endometriosis relevant?
3. What is your next management decision?
Answers
1. What does the CT scan in Fig. 19.1 show?
The CT scan shows a large mass arising from the pelvis and extending into the abdomen. The mass appears complex, with cystic and solid components and septae (A, B). The ovaries cannot be seen separately from the mass. These features are suggestive of malignancy. Imaging does not show any peritoneal deposits (C). There are two hypodense lesions in the liver (D), and the larger one is well circumscribed while the smaller one has indistinct borders suspicious of a metastasis.
This patient had multiple prior CT and MRI scans of her liver to monitor her cystic disease, which confirmed the two lesions as cysts. If that had not been the case, further investigation with liver US and MRI scans would be warranted.
2. Is the history of endometriosis relevant?
Malignant transformation of endometriosis occurs in 0.5–1% of patients. However, this risk is restricted to specific histological subtypes, namely clear cell (CCC), endometrioid (EC), and low-grade serous (LGS) cancers. The odds ratios for these subtypes in women with self-reported endometriosis range between 2 and 3. There is no increased risk for the common ovarian cancer subtypes, high-grade serous (HGS), or mucinous and borderline tumours. In this patient, the history of endometriosis and the presence of a large pelvic mass with no upper abdominal spread make CCC or EC likely.
3. What is your next management decision?
The scans and the raised CA-125 are highly suggestive of malignancy.Therefore she should be reviewed by a gynaecological oncology surgeon, with the aim of undergoing a complete macroscopic removal of all tumour and comprehensive surgical staging, which includes total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO), infracolic omentectomy, peritoneal washings, and systematic peritoneal inspection and biopsies. The role of pelvic and retroperitoneal lymphadenectomy in women with normal-looking lymph nodes is debatable. When the decision is to proceed with primary surgery, pre-operative biopsy to confirm malignancy is not necessary.
For women staged initially with ultrasound, the risk of malignancy index (RMI), that takes into account ultrasound features, menopausal status, and CA-125 levels, can be calculated. A RMI score of >200 has a positive predictive value for malignancy of 80% with specificity of 89–92%.
At laparotomy, a large cystic mass arising from the right ovary was seen and removed. Unfortunately, the cyst ruptured during removal. There was no spread of the tumour beyond the ovary and no residual disease at the end of surgery. Histological examination revealed CCC of the right ovary (Fig. 19.2). Peritoneal biopsies were negative for malignancy. The final pathological staging was stage IC (rupture) clear cell ovarian cancer.
Fig. 19.2 (See also colour plate section)
Questions
4. What is the importance of histological subtypes in ovarian cancer?
5. What is your estimate of prognosis in this case?
6. Do you advise further treatment?
7. If you advise adjuvant chemotherapy, is there a preferred regimen?
8. Is there a role for radiotherapy in early stage CCC?
Answers
4. What is the importance of histological subtypes in ovarian cancer?
For many decades all epithelial ovarian cancers (EOCs) have been treated as a single disease entity. However, current understanding is that the five subtypes of EOC, namely HGS, CCC, EC, mucinous, and LGS, are distinct diseases. HGS cancers commonly present with advanced disease while most CCCs remain confined to the ovary at presentation and are surgically curable. CCC is characterized by increased incidence of thrombocytosis, hypercalcaemia, and venous thromboembolism, features that the clinician should keep in mind, especially during the perioperative period. CA-125 levels tend to be lower in CCC, a fact that can limit its utility in the diagnosis and monitoring of this disease. The effect of chemotherapy greatly differs between HGS and CCC tumours (see the answer to Question 6). Furthermore, whereas HGS cancers are molecularly characterized by ubiquitous TP53 mutations and frequent DNA repair defects (including BRCA1/2 mutations), these features are exceedingly rare in CCC. The latter show predominantly mutations in the chromatin remodelling gene ARID1A, activating PIK3CAmutations, and almost universal overexpression of the transcription factor HNF1B. The absence of BRCA1/2 mutations in CCC has obvious implications for the genetic counselling of these patients.
5. What is your estimate of prognosis in this case?
There has been considerable debate as to the prognosis of early stage CCC. In a series with contemporary pathology review from the British Columbia Cancer Agency (BCCA), patients with stage I–II CCC had better OS than patients with HGS (HR 0.55, 95% CI 0.37–0.79) (Anglesio et al. 2011). A meta-analysis of all published series again showed better OS for stage I–II CCC compared with HGS (HR 0.87, 95% CI 0.75–1.02) (Lee et al. 2011). Cyst rupture, either pre- or intraoperatively, has long been considered an adverse prognostic factor, and results in upstaging of stage IA/B disease to IC. However, at least three case series agree that, in CCC, cyst rupture does not influence prognosis; these patients have identical survival to stage IA patients (Hoskins et al. 2012). Therefore, the best estimate is that this patient’s 5-year OS is around 90%, based on similar patients who underwent comprehensive surgical staging and received adjuvant chemotherapy.
6. Do you advise further treatment?
Adjuvant platinum-based chemotherapy is recommended for all but the lowest risk (stage IA/B, low grade) early stage EOC. This is based on the results of the ICON-1/ACTION combined analysis that showed an 8% 5-year OS advantage for platinum-based chemotherapy compared with observation (Trimbos et al. 2003). Paclitaxel is commonly added to carboplatin based on improved patient outcomes in studies that mostly enrolled patients with advanced HGS. Adjuvant chemotherapy with carboplatin and paclitaxel is recommended in all patients with CCC as this is considered a high-risk subtype. This recommendation is supported by the fact that the 130 patients with CCC enrolled in ICON-1/ACTION showed a similar benefit from chemotherapy to the whole trial population (albeit with wide confidence intervals). Nevertheless, there is extensive evidence from the advanced disease setting that CCC is comparatively resistant to chemotherapy. From the published case series, the median response to single-agent platinum and to a carboplatin–paclitaxel combination in advanced CCC is 20% and 40%, compared with >70% and >80%, respectively, in HGS. This fact, in addition to the excellent reported outcomes in stage IA/IC (rupture only) CCC, tempers enthusiasm for chemotherapy. It is not possible, at present, to be certain as to the exact contribution of chemotherapy to the reported 90% 5-year OS rate for these patients. It should be noted that two small case series from Japan, including 225 patients with stage IA/C CCC who received adjuvant chemotherapy and 67 who did not, failed to show any benefit from adjuvant chemotherapy (Takano et al. 2010, Takada et al.2012). To summarize, current best practice is to offer adjuvant chemotherapy to all patients with early stage CCC in the absence of contraindications. However, more clinical trials in this area are clearly required.
7. If you advise adjuvant chemotherapy, is there a preferred regimen?
The standard adjuvant chemotherapy for early stage CCC is carboplatin and paclitaxel (see answer to Question 6). However, the absolute survival benefit from chemotherapy is probably small, and therefore single-agent carboplatin is a reasonable choice in patients with comorbidities or those who wish to avoid the alopecia and peripheral neuropathy of taxane treatment. The combination of cisplatin and irinotecan is being compared with the standard carboplatin–paclitaxel doublet for the first-line treatment of CCC in an ongoing phase III study in Japan (JGOG 3017).
8. Is there a role for radiotherapy in early stage CCC?
Whole abdominal radiotherapy (WART) with a pelvic boost was used in the treatment of ovarian cancer in the 1960s and 1970s. However, it fell out of favour due to its long-term toxicities and the development of effective chemotherapy regimens. Adjuvant WART (22.5Gy to the pelvis in 10 fractions followed by 22.5Gy to the whole abdomen and pelvis in 22 fractions) has been a standard policy of the BCCA following surgery and adjuvant chemotherapy. In a recent report by this group the use of adjuvant radiotherapy was associated with a 20% absolute 5-year PFS advantage in high-risk (defined as stage IC (non-rupture)/II) CCC (Hoskins et al. 2012). A prospective trial is planned but, at present, there is no indication for the routine use of adjuvant radiotherapy in early stage CCC.
Treatment and follow-up
This patient received four cycles of adjuvant chemotherapy with carboplatin-paclitaxel cycles without any unexpected toxicities.
Further reading
Anglesio MS, Carey MS, Kobel M, et al. Clear cell carcinoma of the ovary: a report from the first Ovarian Clear Cell Symposium, June 24th, 2010. Gynecologic Oncology 2011; 121: 407–415.
Hoskins PJ, Le N, Gilks B, et al. Low-stage ovarian clear cell carcinoma: population-based outcomes in British Columbia, Canada, with evidence for a survival benefit as a result of irradiation. Journal of Clinical Oncology 2012; 30: 1656–1662.
Lee Y-Y, Kim T-J, Lim M-J, et al. Prognosis of ovarian clear cell carcinoma compared to other histological subtypes: a meta-analysis. Gynecologic Oncology 2011; 122: 541–547.
Prat J. Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Archiv 2012; 460: 237–249.
Takada T, Iwase H, Iitsuka C, et al. Adjuvant chemotherapy for stage i clear cell carcinoma of the ovary: an analysis of fully staged patients. International Journal of Gynecological Cancer 2012; 22: 573–578.
Takano M, Sugiyama T, Yaegashi N, et al. Less impact of adjuvant chemotherapy for stage I clear cell carcinoma of the ovary: a retrospective Japan clear cell carcinoma study. International Journal of Gynecological Cancer2010; 20: 1506–1510.
Trimbos JB, Parmar M, Vergote I, et al. International Collaborative Ovarian Neoplasm Trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. Journal of the National Cancer Institute 2003; 95: 105–112.