The treatment of early-stage (stages I–IIA) ovarian carcinoma is predominantly surgical, and the surgical staging is the most relevant step in the treatment of this disease. The significance of surgical staging is twofold. First, proper staging distinguishes between ‘real’ early-stage ovarian carcinoma and ‘perhaps’ early-stage disease. The latter carries an appreciable likelihood of unappreciated residual disease in 16–42% of cases. Second, there is solid proof that proper surgical staging is an independent prognostic factor for improved disease-free and overall survival in early-stage ovarian carcinoma. In this chapter, the relevance of various staging steps is discussed and surgical guidelines are given.
The indication for adjuvant chemotherapy after surgery is closely related to the adequacy of surgical staging. Adjuvant chemotherapy only works in patients in whom surgical staging was inadequate and who, thus, remain with a certain risk of unnoticed residual intraperitoneal or retroperitoneal tumour spread. Moreover, there is no indication that adjuvant chemotherapy is of any value after an adequate, comprehensive staging procedure. Controversies and misunderstandings on this important issue are discussed.
Highlights
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Early-stage (I–IIA) epithelial ovarian cancer has to be defined by a complete surgical staging.
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The completeness of surgical staging predicts survival and disease-free survival in early-stage ovarian carcinoma.
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The effectiveness of adjuvant chemotherapy in properly staged early-stage ovarian carcinoma is questionable.
Introduction
Early-stage ovarian carcinoma relates to the disease stage with extension not further than the internal gonads in the small pelvis. This concurs with stages I–IIA by the FIGO system . The revised version of the FIGO stages in 2014 describes different sub-stages for stage IC: IC1 = surgical spill; IC2 = capsule rupture before surgery or tumour on the ovarian or fallopian tube surface; IC3 = malignant cells in the ascites or peritoneal washings .
The global rate of ovarian cancer is assumed to be 6.3 per 100,000 women and approximately 9.3 per 100,000 women in high-resource countries . Early-stage ovarian carcinoma is estimated to account for 25–30% of the total number of cases .
By the nature of its location, early-stage ovarian carcinoma should be amenable to complete surgical resection of disease by removing the internal genitals. Unfortunately, this is not the case. The 10-year recurrence-free survival varies from 56% to 78% depending on the type of surgery . The explanation for these sobering low figures is that at the time of primary surgery, unnoticed and subclinical metastases might already be present. These metastases will remain unnoticed unless a comprehensive staging procedure rules out or minimizes the likelyhood of their presence. It has been demonstrated that by doing so in approximately one-quarter to one-third of cases (range 16–42%), proper surgical staging can detect intraperitoneal or retroperitoneal spread that would have been left unnoticed when only removal of the internal genitals had been performed (see also ‘History of surgical staging’). Therefore, ‘early-stage ovarian carcinoma’ without adequate surgical staging cannot be considered real early-stage ovarian carcinoma. It is a blend of two-thirds or less real early-stage ovarian carcinoma and one-third or higher more advanced disease. Thus, surgical staging of early-stage ovarian carcinoma remains the cornerstone of treatment of this disease, and it will be addressed from various angles in this chapter. It is stated here that this chapter is entirely devoted to invasive disease.
History of surgical staging
The concept of staging early-stage ovarian carcinoma was developed when more understanding and knowledge of the natural course of the disease was gained in the 1970s and 1980s. At that time, the incidence of occult intraperitoneal and retroperitoneal disease was defined in several studies . Piver described microscopic metastasis at different sites such as the right hemidiaphragm in 11% of cases, the omentum in 35% of cases and malignant cells in peritoneal washings in up to 33% of cases . Peritoneal seeding is considered to occur by the fact that peritoneal fluid circulates continuously from the small pelvis along the paracolic gutters and across the omentum to the diaphragm where it is absorbed into small lymph vessels at the peritoneal side of the diaphragm . This circulation of peritoneal fluid provides the most common pathway for peritoneal seeding of tumour implants throughout the abdominal cavity.
Another important route for metastasis is through the lymphatic system. Lymphatic vessels run parallel to the ovarian vessel in the infundibulo-pelvic ligament and enter the para-aortic and paracaval nodes, especially in the area between the inferior mesenteric artery and the left renal vein. Another lymphatic pathway enters the obturator and external and common iliac nodes. Infrequently, ovarian lymphatic channels follow the round ligament to drain into the inguinal nodes. Involvement of para-aortic nodes has been reported in 5–24% in early-stage disease and involvement of iliac pelvic nodes has been reported in 8–15% of cases .
These data led to several staging recommendations and guidelines by different organizations such as the FIGO , EORTC , GOG and the Norwegian Radium Hospital . These guidelines differ in detail, but they all share the most relevant staging steps ( Table 1 ; Figure 1 ).
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a In case of stage I disease and the wish to preserve fertility, unilateral salpingo-oophorectomy is permitted (see ‘Fertility-sparing surgery’).
b Upgrading to stage IIB by the presence of adhesions to the ovarian tumour is still controversial. Dense adhesions that need sharp dissection or adhesions that result in tumour rupture at dissection, result in outcomes equivalent to stage II disease in some studies but not in others . Histologic proof of tumour cell ingrowth into adhesions, however, should always be considered as stage IIB disease.
History of surgical staging
The concept of staging early-stage ovarian carcinoma was developed when more understanding and knowledge of the natural course of the disease was gained in the 1970s and 1980s. At that time, the incidence of occult intraperitoneal and retroperitoneal disease was defined in several studies . Piver described microscopic metastasis at different sites such as the right hemidiaphragm in 11% of cases, the omentum in 35% of cases and malignant cells in peritoneal washings in up to 33% of cases . Peritoneal seeding is considered to occur by the fact that peritoneal fluid circulates continuously from the small pelvis along the paracolic gutters and across the omentum to the diaphragm where it is absorbed into small lymph vessels at the peritoneal side of the diaphragm . This circulation of peritoneal fluid provides the most common pathway for peritoneal seeding of tumour implants throughout the abdominal cavity.
Another important route for metastasis is through the lymphatic system. Lymphatic vessels run parallel to the ovarian vessel in the infundibulo-pelvic ligament and enter the para-aortic and paracaval nodes, especially in the area between the inferior mesenteric artery and the left renal vein. Another lymphatic pathway enters the obturator and external and common iliac nodes. Infrequently, ovarian lymphatic channels follow the round ligament to drain into the inguinal nodes. Involvement of para-aortic nodes has been reported in 5–24% in early-stage disease and involvement of iliac pelvic nodes has been reported in 8–15% of cases .
These data led to several staging recommendations and guidelines by different organizations such as the FIGO , EORTC , GOG and the Norwegian Radium Hospital . These guidelines differ in detail, but they all share the most relevant staging steps ( Table 1 ; Figure 1 ).
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a In case of stage I disease and the wish to preserve fertility, unilateral salpingo-oophorectomy is permitted (see ‘Fertility-sparing surgery’).
b Upgrading to stage IIB by the presence of adhesions to the ovarian tumour is still controversial. Dense adhesions that need sharp dissection or adhesions that result in tumour rupture at dissection, result in outcomes equivalent to stage II disease in some studies but not in others . Histologic proof of tumour cell ingrowth into adhesions, however, should always be considered as stage IIB disease.
Fertility-sparing surgery
Early-stage ovarian carcinoma can be found in young premenopausal women. The median age of patients in a large randomized trial was 54, but with a range from 18 to 84 . Zannetta and co-workers have emphasized that it is permittable and safe to leave the uterus and contralateral ovary in situ in stage I early-stage ovarian cancer . This was confirmed by French investigators a few years later . The FIGO staging guideline of 2000 advised to restrict this policy to grade I disease . The EORTC favoured conservative surgery in all grades of stage I early-stage ovarian carcinoma . The latter policy also seems to be the most practical as definite information on tumour grade is sometimes difficult to obtain at the time of surgery because of sampling errors at the frozen section, especially in large (mucinous) cysts. In the past, wedge resection of the contralateral ovary was advised in case of conservative surgery to preserve fertility, but this approach has been abandoned because of the low predictive value of this procedure and the catastrophic effect of post-operative peri-ovarian adhesions on fertility.
Some remarks on individual staging steps
Peritoneal washing with saline should be performed at the start of the staging procedure before any actual surgery has begun, to prevent contamination of the washing fluid with blood. It is recommended to perform the washing with a sufficient amount of fluid (> 500 ml) and to change the position of the operating table from Trendelenburg to anti-Trendelenburg in order to allow the washing fluid to reach all the peritoneal areas.
The next step is the careful inspection and palpation of all the peritoneal surfaces, including the small pelvis, omentum, paracolic gutters and the diaphragm. Furthermore, the serosa of the entire digestive tract should be inspected and palpated together with the bowel mesentery. This procedure should be performed comprehensively and precisely as tumour seeding deposits can be small and have no preference to a particular site on the bowel surface. Running the bowel should be performed before any dissection in the pelvis because the detection of macroscopic disease in the upper abdomen alters the staging surgery in the sense that stage III(B) disease is already established and the design of the surgery changes from a staging procedure to cytoreduction.
The removal of the primary tumour will typically involve the dissection of a cystic ovarian mass. When the mass is large or fixed, there is a risk of cystic rupture that should be avoided. Cystic rupture before surgery with slow spillage of the cystic fluid has been known for a long time to be associated with an adverse prognosis . In a retrospective analysis of >1500 patients with stage I early-stage ovarian carcinoma, Vergote and co-workers showed that besides rupture before surgery, surgical spill at the time of tumour removal is also associated with a lower overall survival . These considerations are also relevant when considering laparoscopic surgery because the risk of spill during removal of a laparoscopic cyst is significantly higher than at open surgery.
The performing of blind peritoneal biopsies has been discussed in relationship to its significance for the procedure of staging . It has been reported that blind peritoneal biopsies in clinically early-stage ovarian carcinoma harbour malignant cells in 3–17% of cases . In the textbook, Clinical Gynecologic Oncology, Disaia and Creasman reviewed 14 studies on upstaging rates in presumed early-stage ovarian carcinoma. They summarized the frequency of microscopic metastases after comprehensive surgical staging as follows: pelvic peritoneum 9% (range 6–10%), abdominal peritoneum 8% (range 7–9%) and bowel mesentery – serosa 6% (range 3–13%) . A recent study from Korea demonstrated positive blind biopsies of the peritoneum in 7.1% of 127 patients with apparent early-stage ovarian cancer . Ayhan et al. described that random peritoneal biopsies or appendectomy showed microscopic metastases of clinical early-stage ovarian carcinoma in 12 of 169 patients (7%) . It has been argued that another important benefit of the procedure of performing blind peritoneal biopsies is that it provides practical proof that careful inspection and evaluation of the peritoneal area concerned has actually been performed.
By nature of the lymphogenic tissue in the omentum (milky spots), this ‘policeman of the abdomen’ has been considered a high-risk site for metastases of various tumours. The reported incidence of metastatic disease in the omentum ranges from 0 to 11% of cases . Despite these findings, it should be noted that the removal of a grossly normal omentum will rule out the possibility to use it for future surgical purposes .
Lymph node dissection is technically the most challenging part of the surgical staging procedure of apparent early-stage ovarian carcinoma. Lymph node involvement can be found in approximately 14% of cases . A recent literature review confirms this figure, ranging from 2.9% in grade I tumours to 20% in grade III tumours . In this review, only contralateral lymph node metastases of a unilateral tumour was found in 16% of positive pelvic nodes and 11% of positive para-aortic nodes . These findings provide a strong argument against an ipsilateral node dissection alone. The incidence of lymph node metastases in grade I mucinous early-stage ovarian carcinoma is so low that lymph node dissection in these cases can safely be omitted .
The minimum number of lymph nodes to be removed is a matter of debate. Nodal count depends on various factors such as the comprehensiveness of pathologic analysis and individual anatomical variations. Relying on studies in high-risk endometrial cancer, the MD Anderson group has proposed a selective lymph node dissection for retroperitoneal staging procedures in gynaecological oncology . They recommend a minimum of 10 nodes originating from specific, different retroperitoneal sites: para-aortic above the inferior mesenteric artery, common iliac, external iliac, hypogastric and obturator . The reliability of this approach to cover various high-risk areas by node sampling has been confirmed by investigators from the University of Tokyo . The concept of at least 10 nodes from different, well-defined sites has been adopted in various guidelines for surgical staging .
A retrospective analysis of the US SEER (Surveillance, Epidemiology and End Results) cancer registry of the National Cancer Institute of 6686 patients with stage I ovarian cancer showed that the extent of node resection (0, fewer than 10, 10 or more) increased the survival of patients with IC disease from 72.8% to 86.7% to 90.1% (p < 0.001) . Kleppe and co-authors analysed 3658 early-stage ovarian carcinoma patients from the Dutch Cancer Registry. They found a positive correlation between the number of removed lymph nodes and overall survival . These authors regarded 10 nodes as the minimum number of an adequate lymph node dissection, but they advised a number of 20 nodes or more .
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