CHAPTER 45 Carcinoma of the ovary and fallopian tube
Carcinoma of the Ovary
Epidemiology
The incidence of ovarian carcinoma varies around the world, with lower rates recorded in Japan (3/100,000 women) and some of the highest rates recorded in the Nordic countries (20/100,000 women). Variations are also noted within Europe, with lower rates occurring in Mediterranean countries (Figure 45.1). In the UK, approximately 7000 cases are reported each year, with a mortality rate of 4500. As such, ovarian cancer remains the most lethal of the gynaecological cancers, and the fourth most common malignant cause of death in women. The majority of women present with disease spread outside the ovaries, normally stage III–IV disease (Table 45.1), and this has a 5-year survival rate of approximately 40%. Ovarian cancer is mainly a disease of postmenopausal women, with the bulk of cases occurring in women aged 50–75 years. The main histological tumours are epithelial in origin, accounting for 90% of cases. Serous tumours are the most common, and as tubal tumours are also serous, accurate identification of the true primary site of disease can be difficult.
Figure 45.1 Age-standardized incidence and mortality rates for ovarian cancer, European Union, 2002 estimates.
Table 45.1 FIGO staging for ovarian cancer
| Stage I | Growth limited to the ovaries |
| Stage IA | Growth limited to one ovary, no ascites, no tumour on external surface, capsule intact |
| Stage IB | Growth limited to both ovaries, no ascites, no tumour on external surface, capsule intact |
| Stage IC | Tumour as for stage IA or B, but tumour on surface of one or both ovaries or capsule ruptured or positive ascites/peritoneal washings |
| Stage II | Tumour as for stage IC, but growth involving one or both ovaries with pelvic extension |
| Stage IIA | Extension and/or metastases to the uterus and/or tubes |
| Stage IIB | Extension to other pelvic tissue |
| Stage IIC | Tumour as for stage IIA or B, but tumour on surface of one or both ovaries or capsule ruptured or positive ascites/peritoneal washings |
| Stage III | Tumour involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Includes superficial liver metastases or histologically proven malignant extension to small bowel/omentum |
| Stage IIIA | Tumour grossly limited to true pelvis with negative nodes, but histologically confirmed microscopic seeding of abdominal peritoneal surfaces |
| Stage IIIB | Tumour involving one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter |
| Stage IIIC | Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes |
| Stage IV | Growth of one or both ovaries with distant metastases, e.g. parenchymal liver metastases, or cytologically proven pleural effusion |
Aetiology
The main theory recounted for many years, called the ‘incessant ovulation theory’, is derived from the association between a woman’s number of lifetime ovulations and the risk of ovarian cancer. The greater the number of ovulations, the greater the risk of ovarian cancer. Prevention of ovulation by either pregnancy or use of the combined contraceptive pill should reduce the risk of ovarian cancer, and this has indeed been noted. Some of the proposed explanations for this theory are that the milieu of rapid cellular turnover (in the development of the ovum), the injury caused with release of the ovum and stromal invagination (which occurs at ovulation) contribute to the risk of malignancy. However, more complex factors are likely to be involved. For example, the progesterone in the contraceptive pill is known to cause apoptosis of ovarian cells, and this is being investigated in a phase II trial by the Gynecologic Oncology Group in high-risk patients to determine the apoptotic effect on ovarian tissues. This may potentially become a preventative therapy in the future.
Infertility
For many years, it has been recognized that there may be an association between infertility and risk of ovarian cancer. The relationship has never been absolutely clarified, and there are many conflicting reports in the literature (Mahdavi et al 2006, Jensen et al 2009). The difficulties mainly relate to the information available, as the types of drugs used, their duration of use and the outcome of pregnancies were not well recorded in many reports. One proposal associating the use of drug-induced ovulation and potential malignant transformation was seen in the increased ovarian cellular dyplasia in ovaries removed from women with a history of in-vitro fertilization treatment (Chene et al 2009). However, further larger longitudinal studies are needed to confirm the situation regarding infertility and ovarian cancer.
Endometriosis
Endometriosis affects approximately one in eight women. The notable tumours associated with endometriosis are ovarian clear cell carcinomas. Endometrioid tumours are also known to have a relationship with endometriosis, but this association is weaker. An interesting fact is that clear cell tumours are most prevalent in Japan, despite the fact that Japan has the lowest incidence of ovarian cancer in the world. The concept that endometriosis is a premalignant condition has been proposed, based on the ability of endometriosis to metastasize, and also as it is found in association with ovarian malignancies. There is a need for further work in this area, but it is interesting to note that women with endometriosis also have a higher relative risk of developing other cancers (Melin et al 2007).
Genetic factors
It is estimated that approximately 10% of all ovarian malignancies are hereditary, and the potential genetic factors in tubal malignancies are becoming increasingly recognized. The latter are rare, but represent sufficient reason to recommend removal of the fallopian tubes when undertaking prophylactic surgery. The two main mutations are BRCA1 and BRCA2. These mutations interfere with the efficacy of p53, and thus permit progression of the malignant process. The greater risk is in women with BRCA1 who have up to a 40% lifetime risk, compared with 20–25% in those with BRCA2. When considering prophylactic surgery, this should be performed before 40 years of age to gain a real benefit. Understandably, if the familial pattern is for a younger age group to develop the disease, siblings will often wish for earlier intervention. The only other familial association is with Lynch type 2 syndrome, with mutations on chromosome 5. In these patients, the family history mainly relates to bowel carcinoma, although the incidence of ovarian cancer is approximately 12% compared with a lifetime risk of approximately 2%. These patients do have a high risk for endometrial cancer, and thus will require the uterus to be removed at the same time if prophylactic surgery is deemed appropriate.
Molecular biology
One aspect of ovarian cancer is the somewhat limited understanding of the tumour biology and the natural history of the condition itself. Most patients present with advanced disease and it is often considered that ovarian cancer has a rapid growth phase, hence the late presentation with a short history of symptoms. Some work on symptoms in ovarian cancer suggests that these may be present some time prior to diagnosis (Goff et al 2007), and the natural progression of the disease may be different to previous assumptions. However, this requires further research before becoming acceptable.
In ovarian cancer, molecular markers have been researched although there is a lack of true understanding of tumour biology. Tumour vascular proteins (Buckanovich et al 2007) have been shown to have different expression in ovarian malignancies compared with normal, and with the development of antivascular endothelial growth factor therapies with a spectrum of tumour vascular proteins now recognized, further therapies may be developed. Serum mesothelin level is another marker noted to be elevated in ovarian cancer and to have a direct correlation with disease stage, and this could have potential use in screening (Huang et al 2006). Proteomic studies are used increasingly and should yield some valuable information to facilitate the understanding of ovarian cancer (Boyce and Kohn 2005).
Classification of ovarian tumours
Ovarian tumours can be solid or cystic. They may be benign or malignant. In addition, there are those which, while having some features of malignancy, lack any evidence of stromal invasion. These are called ‘borderline tumours’.
The most commonly used classification of ovarian tumours was defined by the World Health Organization (Scully 1999). This is a morphological classification that attempts to relate the cell types and patterns of the tumour to tissues normally present in the ovary. The primary tumours are thus divided into those that are of epithelial type (implying an origin from surface epithelium and the adjacent ovarian stroma), those that are of sex cord gonadal type (also known as sex cord stromal type or sex cord mesenchymal type, and originating from sex cord mesenchymal elements) and those that are of germ cell type (originating from germ cells). A simplified classification is given in Table 45.2.
Table 45.2 Simplified classification of ovarian cancers
| Epithelial origin | |
| Germ cell origin | |
| Others |
Pathology of epithelial tumours
Epithelial tumours are derived from the ovarian surface epithelium, which is a modified mesothelium with a similar origin and behaviour to the Müllerian duct epithelium, and from the adjacent distinctive ovarian stroma. They are subclassified according to epithelial cell type (serous, mucinous, endometrioid, clear, transitional, squamous); the relative amount of epithelial and stromal component (when the stromal is larger than the cystic epithelial component, the suffix ‘fibroma’ is added); and the macroscopic appearance (solid, cystic, papillary). They account for 50–55% of all ovarian tumours, but their malignant forms represent approximately 90% of all ovarian cancers in the Western world (Koonings et al 1989). Well-differentiated epithelial carcinomas are more often associated with early-stage disease, but the degree of differentiation does correlate with survival, except in the most advanced stages. Diploid tumours tend to be associated with earlier stage disease and a better prognosis. Histological cell type is not in itself prognostically significant.
Serous carcinoma
Gross features
The majority of serous carcinomas show a mixture of solid and cystic elements, although a significant minority are predominantly cystic. Serous carcinomas have a propensity to bilaterality, ranging from 50% to 90%, but in only 25–30% of stage I cases.
Microscopic features
The better differentiated tumours have an obvious papillary pattern with unequivocal stromal invasion, and psammoma bodies (calcospherules) are often present. A highly differentiated form of serous papillary carcinoma called ‘psammocarcinoma’ contains large numbers of psammoma bodies surrounded by no more than 15 well to moderately differentiated serous cells, and has a favourable prognosis despite the fact that most lesions are found in stage III. None of these features are diagnostic of serous tumours alone. Endometrioid and clear cell carcinomas and, to a lesser extent, mucinous carcinomas may all form papillary structures. The term ‘papillary carcinoma of the ovary’ should not, therefore, be used as a diagnosis.
At the other end of the spectrum is the anaplastic tumour composed of sheets of undifferentiated neoplastic cells in masses within a fibrous stroma. Occasional glandular structures may be present to enable a diagnosis of adenocarcinoma. All gradations between these two are seen, sometimes in the same tumour.
Mucinous carcinoma
Gross features
Malignant mucinous tumours comprise approximately 12% of malignant tumours of the ovary. They are typically multilocular, thin-walled cysts with a smooth external surface and contain mucinous fluid. The locules vary in size and the tumour is often composed of one major cavity with many smaller daughter cysts apparently within its wall. Mucinous tumours are amongst the largest tumours of the ovary and may reach enormous dimensions; a cyst diameter of 25 cm is quite commonplace.
A mucinous cystadenocarcinoma may look the same as a benign tumour. Some malignant tumours may exhibit obvious solid areas, perhaps with necrosis and haemorrhage. The more advanced carcinomas will show the stigmata of ovarian malignancy, with adhesions to adjacent viscera and malignant ascites.
Microscopic features
Mucinous adenocarcinomas present a variety of histological appearances. They may contain endocervical-like cells alone, intestinal-type cells alone or a combination of the two, but are more often composed of mucinous cells without distinguishing features. The better differentiated examples are composed of cells that retain a resemblance to the tall, picket-fence cells of the benign tumour, although stromal invasion is present. As differentiation is lost, the cells become less easily recognizable as being of mucinous type and their mucin content diminishes.
Endometrioid carcinoma
Endometrioid carcinomas are ovarian tumours that resemble the malignant neoplasia of epithelial, stromal and mixed origin that are found in the endometrium (Czernobilsky et al 1970). They account for 2–4% of all ovarian tumours. They are accompanied by ovarian or pelvic endometriosis in 11–42% of cases, and a transition to endometriotic epithelium can be seen in up to 30% of cases. The pathologist must distinguish metaplastic and reactive changes in endometriosis from true neoplastic changes.
Gross features
There is little to characterize an ovarian tumour as being of endometrioid type by naked-eye examination. Most are cystic, often unilocular and contain turbid brown fluid. The internal surface of the cyst is usually rough with rounded, polypoid projections and solid areas, the appearances of which are usually distinct from those of the papillary excrescences seen in serous tumours.
Microscopic features
Endometrioid carcinomas resemble the endometrioid carcinomas of the endometrium. The pattern is predominantly tubular and may resemble proliferative endometrium. The epithelium is tall and columnar, with a high nuclear : cytoplasmic ratio. Endometrioid carcinomas of the ovary are more likely to be papillary than primary endometrial carcinomas. Five to 10% of cases are seen in continuity with recognizable endometriosis. Ovarian adenoacanthoma, with benign-appearing squamous elements, account for almost 50% in some series of endometrioid tumours.
Associated endometrial carcinoma
It is important to note that 15% of endometrioid carcinomas of the ovary are associated with endometrial carcinoma in the body of the uterus. Although this is sometimes due to a primary tumour in one site and a secondary tumour at the other, these are usually two separate primary tumours.
Clear cell carcinoma
Clear cell carcinomas are the least common of the malignant epithelial tumours of the ovary, accounting for 5–10% of ovarian carcinomas (Anderson and Langley 1970).
Gross features
There is nothing characteristic about the gross appearance of clear cell tumours to distinguish them from other cystadenocarcinomas of the ovary. Most are thick-walled, unilocular cysts containing turbid brown or bloodstained fluid, with solid, polypoid projections arising from the internal surface. Approximately 10% are bilateral.
Microscopic features
Clear cell carcinomas of the ovary are characterized by the variety of architectural patterns, which may be found alone or in combination in any individual tumour. The appearance from which the tumours derive their name is the clear cell pattern but, in addition, some areas show a tubulocystic pattern with the characteristic ‘hob-nail’ appearance of the lining epithelium. The third major pattern is papillary.
Full access? Get Clinical Tree
