Mucinous cystadenocarcinoma of ovary: Changing treatment paradigms

Abstract

Traditionally, all carcinomas arising from the surface epithelial layer of the ovary have been grouped together. This grouping has led to a single therapeutic strategy that is used for all epithelial ovarian cancers. However mucinous cancers appear to be distinct from serous cancers in their clinical behaviour and molecular signatures. In comparison to serous tumours, early stage mucinous tumours tend to be localised at diagnosis with a higher overall survival. But when metastatic at presentation or after recurrence, the outcome of mucinous tumours is far inferior to serous tumours. With standard platinum based chemotherapy the response rate and survival is far worse in mucinous cancers. The precise biological and molecular explanation for this difference remains unanswered. There is urgent need for testing and adoption of therapeutic approaches tailored to molecular characteristics of mucinous carcinomas so that patient survival can be optimised.

Key Words: Ovary; Carcinoma; Mucinous

INTRODUCTION

Traditionally, all carcinomas arising from the surface epithelial layer of the ovary have been grouped together. This grouping has led to a single therapeutic strategy that is used for all epithelial ovarian cancers. With the emergence of more robust clinicopathologic, molecular, and genetic data over the past decade, we are clearly in the midst of an exciting paradigm shift that challenges the status quo of treating all women with a diagnosis of epithelial ovarian cancer similarly, regardless of cell type or histological grade. Specifically, mucinous carcinoma appears to have a distinct clinical behaviour and molecular profile[1]. In the year 2004, as noted by Hess et al[2] advanced stage mucinous ovarian cancer had a worse outcome than women with non mucinous type, with advanced stage non mucinous living three times longer than those with mucinous pathology. If we are going to preach about tailored oncology care, we need to walk the talk; it is time to get it right. The purpose of this review is to examine the differences between mucinous cystadenocarcinoma of ovary from other histological subtypes, and to discuss strategies for better management of this tumor.

INCIDENCE

Mucinous carcinomas appear to comprise approximately 2%-5% of ovarian epithelial neoplasms[3]. The incidence of mucinous histology in various large trials ranged from 1.6%-4.4%[4,5], and the standard treatment in these tumors was based on these large studies with very limited histological subtype of mucinous tumor. Hence behaviour and natural history of mucinous carcinoma per se remained an unresolved issue so long.

PRIMARY VS METASTATIC MUCINOUS CARCINOMA OF THE OVARY

Primary mucinous carcinomas of the ovary are distinct from other ovarian carcinoma types, but they can pose a particular challenge for correct diagnosis from metastases, which most usually originate from the colorectum. The question also arises whether the survival of women with advanced stage primary mucinous carcinoma of the ovary differs significantly from that of women with mucinous carcinoma metastatic to the ovary.

These quandaries were looked into by the Gynaecologic Oncology Group Study conducted by Richard J Zaino[6]. Using the Lee and Young study[7], they classified tumor as metastatic or primary tumor based on 12 parameters.

Metastatic tumors pathologically had a diameter less than 13 cm, were bilateral, and had surface involvement, hilar involvement and nodularity. These tumors were associated with infiltrative patterns of invasion, signet ring cells, small glands/tubules and single neoplastic cells. Primary mucinous carcinoma of the ovary were usually larger, unilateral, had an expansile growth pattern with complex papillae and necrotic luminal debris. Most primary ovarian mucinous tumors are of surface epithelial-stromal origin and exhibit diffuse expression of cytokeratin 7 combined with variable expression of cytokeratin 20 (CK20); this immunoprofile distinguishes them from most lower gastrointestinal tract tumors secondarily involving the ovaries, but this last difference was not used in the above study.

The median survival did not differ significantly between the groups interpreted as primary or metastatic. Longer survival was possibly seen with the absence of- signet ring cells, an infiltrative pattern of invasion, and small neoplastic glands. The study highlighted that the overall survival for women with advanced stage mucinous carcinomas (whether the ovary was the primary or metastatic site) is significantly less than that for women with advanced stage serous carcinoma (median survival of 14 mo vs

42 mo, respectively P < 0.001).

SEROUS VS MUCINOUS CANCERS OF THE OVARY

Natural history

Clinically most primary mucinous carcinoma of ovary are confined to ovary at time of diagnosis; an advanced stage mucinous carcinoma involving the ovary at first diagnosis should be evaluated as possible metastasis from other site, particularly the gastrointestinal tract. In comparison to serous tumors, mucinous tumors of the ovary are usually early stage at diagnosis (early stage: 4% serous vs 83% mucinous)[3], with no evidence of occult lymph node metastasis (10% serous vs 0% mucinous)[8] and have a higher overall survival (34 mo vs 70 mo)[9]. However in advanced stages, the outcome of mucinous tumor is far inferior (Table 1)[2,10].

Table 1 outcome of advanced stage mucinous tumor compared to other histological subtypes.

Advanced stage	Mucinous subtype	Other histology
Hess et al[2]	Mucinous	Non mucinous
Progression free survival	5.7 mo	14.1 mo
Overall survival	12 mo	36.7 mo
Winter et al[10]	Mucinous	Serous
Progression free survival	10.5 mo	16.9 mo
Overall survival	14.8 mo	45.2 mo

OUTCOME WITH TREATMENT

Early stage disease

The primary treatment for early stage mucinous neoplasm is surgical- that is total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging as with serous tumors. In patients who have undergone a thorough staging laparotomy and in whom there is no evidence of spread beyond the ovary, the uterus and contra lateral ovary can be retained in women who wish to preserve fertility. Early stage mucinous tumors originate from a genetically stable precursor lesion, frequently from a borderline tumor and have an indolent course. In contrast high grade early stage serous tumors arise from a precursor lesion in distal fallopian tube, called STIC (serous tubal intraepithelial carcinoma)[11] and have poorer outcome due to cytogenetic instability[12]. Hence there is a questionable role of adjuvant chemotherapy or radiotherapy in early stage (1A-B) mucinous tumors.

Advanced disease

Response to platinum based chemotherapy-first line setting: In one of the earliest study in 2004 by Hess et al[2], where the outcome of advanced mucinous tumor was compared with non mucinous ovarian tumor with standard platinum based chemotherapy, the response rate and survival was far worse in advanced mucinous group. In their study the outcome of eighty-one patients (27 mucinous, 54 non mucinous) treated with platinum-based regimens was analyzed. The response rates for mucinous and non mucinous tumors were 26.3% and 64.9%, respectively. Median progression-free survival was 5.7 mo vs 14.1 mo and overall survival was 12.0 mo vs 36.7 mo for mucinous and non mucinous tumors, respectively. Other studies also showed poor response rate of mucinous tumors to platinum based chemotherapy, and the response rate was inferior to serous tumors (Shimada et al[13]: mucinous 12.5% vs serous 67.7% and Pectasides et al[14]: mucinous 38.5% vs serous 70%).

Response to platinum in the recurrent setting: The Study of an Ovarian Cancer cohort Recurred After first-line Treatment: a retrospective Survey[15] showed that mucinous ovarian carcinoma have a poorer prognosis compared with other histological subtypes with platinum based chemotherapy in recurrent platinum sensitive setting, with lower response rate (36.4% vs 62.6%), median progression free survival (4.5 mo vs 8 mo) and overall survival (17.9 mo vs 28.8 mo) in recurrent setting. Other studies[16] also showed poor response of mucinous ovarian cancer to chemotherapy both in the first-line and in the recurrence settings. No response was observed to platinum/paclitaxel retreatment in patients with very late recurrence and no response to liposomal doxorubicin or topotecan was observed in platinum-refractory/resistant patients treated as second- or third-line chemotherapy.

MOLECULAR BIOLOGY

The differences in the natural history and outcome with treatment between mucinous and serous cancers may be due to the differences in the molecular biology of the tumors. About 50% of mucinous ovarian carcinomas had KRAS mutations, compared to only 5% of serous ovarian carcinomas. BRCA1 and BRCA2 mutations are thought to play a significant role in the development of serous ovarian carcinomas but not mucinous ovarian carcinomas. Mutations in p53 have been found in almost 60% of serous tumors but only 16% of mucinous tumors. With better understanding of molecular pathways, ovarian tumors are classified into two subtypes: type I tumors which typically involve mutation in genes such as KRAS, BRAF, PTEN and PI3K pathway and type II tumors which involve mutation in genes such as p53 and BRAC1 and BRAC2. Mucinous tumor and low grade serous tumor are classified under type I tumor, whereas high grade serous tumors are classified under type II tumor. These differences are also seen in the immunohistochemical studies where mucinous tumors are more likely to express E-cadherin (62% vs 4%) and less likely to stain positive for N-cadherin (8% vs 68%). Carcinoembryonic antigen which is a well known marker for gastrointestinal malignancy is expressed as a serum marker in mucinous tumors (CEA: 88% mucinous vs 19% non mucinous) whereas CA 125 is less likely to be expressed[3]. Interestingly the KRAS/BRAF pathway which is involved in pathogenesis of mucinous tumors is also involved in pathogenesis of colorectal malignancies.

CHANGING PARADIGM

Both mucinous carcinomas of the ovary and colorectum have led to the same dilemma. Hence there is an urgent need for considering testing and adoption of therapeutic approaches tailored to molecular characteristics of mucinous carcinomas, irrespective of organ site, so that patient survival can be optimised.

Hess et al[2] in his study had highlighted the need for specific alternative therapeutic approaches for mucinous tumors, perhaps involving fluorouracil-based chemotherapy. The role and benefit from 5-flourouracil and its oral analogue has been shown by Sato et al[17] in advanced or recurrent mucinous ovarian cancer.

Based on in vitro sensitivity of these tumors to irinotecan[18], Shimizu et al[19] conducted a phase II trial in platinum refractory mucinous carcinoma and showed a response rate of 52% and median overall survival of 15.3 mo with irinotecan and mitomycin.

In a prospective phase II study of heavily pretreated patients with ovarian cancer, 5-fluorouracil and oxaliplatin was found to have a clinical efficacy rate of 58% (overall response rate of 29% and stable disease of 29% by Response Evaluation Criteria in Solid Tumors criteria)[20]. This regimen also has been evaluated in ovarian cancer cell lines (MN-1, OMC-1, RMUG-L, RMUG-S, TU-OM-1) and was found to be additive or synergistic[17].

CONCLUSION

In the past the standard treatment for all advanced stage epithelial ovarian cancer was cytoreductive surgery followed by standard postoperative treatment with platinum based chemotherapy.

Unfortunately, recent data have confirmed what many clinicians have long suspected: that mucinous ovarian cancers do not respond to the standard platinum based chemotherapy routinely employed in the malignancy and both progression- free and overall survival are substantially shorter for mucinous subtypes compared to other epithelial ovarian morphologies.

Of interest, the majority of documented mucinous ovarian cancers appear to be localized to the ovary at diagnosis and surgically resectable, but when revealed to be metastatic at presentation, or if recurrence is experienced, the prognosis is very poor. Molecular explanation involving difference in oncogenes and tumor suppressor gene expression and mutation may account for this discrepancy. In advanced mucinous ovarian cancers (metastatic/recurrent), an argument can be made to use a chemotherapy regimen known to be active in colon cancer (e.g., 5 flourouracil with oxaliplatin- or irinotecan), although unfortunately there is currently a paucity of evidence suggesting such an approach will be beneficial in advanced stage mucinous cystadenocarcinoma.