Ovarian Cancer Staging

Ovarian Cancer Staging Liz Y. Han, MD, and Robert L. Coleman, MD

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rimary malignancy of the ovary is fortunately a relatively uncommon condition. In 2007, an estimated 22,430 new cases and 15,280 deaths are expected.1 However, the number of women who succumb to this disease eclipses the total contribution of all other distinct gynecologic cancers combined, distinguishing it as the most lethal. Histologically, the most common form of the disease is epithelial, accounting for more than 80% of primary malignant diagnoses. However, ovarian cancer may also arise from the germ cells, ovarian stroma, and other supporting tissues. In addition, a sizeable proportion of younger women with ovarian cancer will have a proliferative, but noninvasive element designated as “low malignant potential” or “borderline” epithelial ovarian tumor. Individual risk factors and therapeutic options for these subtypes are important to clearly distinguish given their occurrence in women of reproductive potential and unique natural history. The focus of this contribution will center on the management and care of patients with epithelial ovarian cancer; however, surgical approaches to staging of these rarer ovarian cancers are similar in the absence of desired fertility preservation. A brief outline of these considerations appears at the end of this discussion. Although the incidence of ovarian carcinoma ranks second in all malignancies of the female reproductive tract, it remains the most deadly. Risk factors for epithelial ovarian carcinoma are well established. Although pregnancies and oral contraceptive use are protective, age is the strongest patient-related risk factor. Overall, it is estimated that 1 in 70 women will develop ovarian cancer in their lifetime with age-specific incidence peaking at 75 to 80 years of age.2 This is especially startling considering the aging population of the United States. Furthermore, a family history of ovarian cancer, breast cancer, or both, is the second strongest risk factor. Women who are heterozygous for mutations of either BRCA 1 or BRCA 2 have an estimated lifetime risk of 16% to 60%.3 Other risk factors may also include nulliparity, involuntary infertility, early menarche, and late menopause.2 Failure of early detection is the principle reason behind ovarian carcinoma’s high mortality. More than 90% of From the Department of Gynecologic Oncology, The University of TexasM.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Robert L. Coleman, MD, Professor, Director of Clinical Research, The University of Texas-M.D. Anderson Cancer Center, Department of Gynecologic Oncology, 1155 Herman Pressler, CPB6.3244, Unit 1362, Houston, TX 77030. E-mail: RColeman@ mdanderson.org.

1524-153X/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.optechgensurg.2007.08.002

women diagnosed with ovarian cancer have symptoms antedating the diagnosis by several months, however, these are often vague (abdominal bloating, pelvic pressure, urinary dysfunction, etc.) contributing to a delayed diagnosis.4 CA125 has proven to be an excellent marker of surveillance for treatment response; however, its diagnostic value is yet to be proven. Seventy-five percent of this malignancy is diagnosed in advanced stages when the disease has spread beyond the pelvis.1,5 The 5-year survival for these patients is only 30% to 40%.6 These factors underlie the importance of not only early detection, but also proper surgical staging and optimal disease debulking with subsequent adjuvant chemotherapy to maximize survival potential. In general, the surgical principium of ovarian cancer is accurate staging for limited disease and cytoreduction for advanced or metastatic disease. Surgical staging in the absence of visible metastatic spread requires broad and directed sampling of “at-risk” tissues sufficient to assign an appropriate stage in accordance with FIGO guidelines (Table 1). In the presence of more advanced disease, surgical extirpation is undertaken to remove the primary site of disease and levy the greatest impact on tumor burden. Frequently this is referred to as performing an “optimal cytoreduction” procedure. The definition of optimal cytoreduction in ovarian carcinoma remains controversial, although the most widely accepted is residual disease less than 1 cm.7 The survival advantage gained from debulking was first described by Meigs in 1934,8 and explored in a systematic fashion by Griffiths in 1975 where longer survival is associated with lesser residual disease.9 Since then, the survival advantage of optimal debulking is further proven retrospectively by various authors; in fact, Bristow and co-workers demonstrated that for each 10% decrease in residual tumor volume, there is a 5.5% increase in median survival.10,11 Currently, there is a trend to establish optimal cytoreduction as no visible residual disease. Published studies have demonstrated that prognosis is directly related to number of residual implants as well as volume of residual disease.12,13 Various series reflect optimal cytoreduction is obtainable in approximately 20% to 25% of patients presenting with advanced ovarian cancer.14,15 Furthermore, in GOG trials examining primary cytoreduction and adjuvant chemotherapy, patients with no visible residual disease had the best prognosis for survival.6,16,17 Therefore, some authors have concluded that all efforts including resection, ablation, aspiration of all visible disease as allowed by medical status and 53

54 Table 1 Ovarian Cancer Staging by FIGO Criteria (1986) I. Growth limited to the ovaries IA. Tumor limited to one ovary; capsule intact, no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings IB. Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings IC. Tumor limited to one or both ovaries with any of the following: capsule ruptured, tumor on ovarian surface; malignant cells in ascites or peritoneal washings II. Tumor involves one or both ovaries with pelvic extensions IIA. Extension and/or implants on uterus and/or tube(s); no malignant cells in ascites or peritoneal washings IIB. Extension to other pelvic tissues; no malignant cells in ascites or peritoneal washings IIC. Pelvic extension with malignant cells in ascites or peritoneal washings III. Tumor involves one or both ovaries with peritoneal metastasis outside the pelvis and/or retroperitoneal or inguinal node metastasis IIIA. Microscopic peritoneal metastasis beyond pelvis IIIB. Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension IIIC. Peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension and/or regional lymph node metastasis IV. Distant metastasis (excludes peritoneal metastasis) to liver parenchyma or malignant pleural effusion

intraoperative patient stability should be performed to achieve complete cytoreduction.18

Ovarian Carcinoma Staging Preoperative Evaluation and Considerations Preoperative imaging with computed tomography (CT) scan is most helpful in initial evaluation of disease spread. In addition, CT findings such as diffuse disease sites and peritoneal thickenings may be predictors of suboptimal debulking.19-22 Other predictors for suboptimal debulking include preoperative CA-125 level greater than 500.23 In patients with extensive disease and elevated CA-125 with multiple comorbidities, neoadjuvant chemotherapy may be another option. Published retrospective data revealed that up-front chemotherapy can reduce morbidity and mortality while offering higher rates of optimal interval cytoreduction without survival compromise.24,25

Ovarian Carcinoma Staging After appropriate preoperative medical and anesthesia assessment, patients requiring formal staging or cytoreduction should undergo exploration with laparotomy. Incidental early stage ovarian cancers discovered during laparoscopic evaluation of an adnexal or pelvic mass may be staged via laparoscopy as long as the same procedure and staging biopsies can be obtained including retroperitoneal lymph nodes.

L.Y. Han and R.L. Coleman The debulking procedure begins generally with a midline vertical skin incision from the level of the pubic symphysis extending cephalad around the umbilicus to a point felt sufficient to evaluate the upper abdomen and diaphragmatic peritoneum. We generally prefer extension around the right side umbilicus or directly through the umbilicus, in case a diverting colostomy is necessary as part of the cytoreduction procedure. The abdomen is then opened to the peritoneum with care exercised inferiorly to avoid injury to the bladder. If a patient has massive ascites, drainage at the most ventral aspect of the abdomen before opening is prudent. In the absence of ascites, 100 to 150 mL of sterile saline is used to obtain washings from the pelvis, paracolic gutters, and diaphragm bilaterally. This fluid should be sent for permanent cytological evaluation. At this point, a survey of the abdomen and pelvis is performed to evaluate the disease extent. A methodical and thorough system should be adopted in this evaluation to encompass the following: upper abdomen including the liver surface, gall bladder, dome of the diaphragm bilaterally, the stomach, pancreas, and retroperitoneally, the kidneys. The small bowel is examined from the cecum to the ligament of Treitz, paying attention to both serosal disease as well as mesenteric involvement, and same technique is applied to the large bowel survey. The entirety of the peritoneal surface, including the paracolic gutters should be palpated for disease presence. The omentum is fanned out for visual inspection. Next, the pelvic organs such as ovaries, fallopian tubes and uterus, including the anterior and posterior cul-de-sacs, rectosigmoid, are evaluated. What appears to be early stage ovarian carcinoma (ie, stages I and II) by initial abdominal and pelvic survey merit additional peritoneal and lymph node biopsies as information gained may upstage the diagnosis in 25% of cases.26 Random peritoneal biopsies should be performed in the pelvis and abdomen, including the paracolic gutters. The most manageable approach is completed using pickups and Metzenbaum scissors to excise the peritoneum in the locations listed and applying electrocautery for hemostasis (Fig 1). Lymph node biopsies are obtained from the pelvis as well as the para-aortic regions. Pelvic lymphectomy begins with adequate exposure of the external iliac vessels (Fig 2). The nodal bundle straddling the vessels can be peeled away using a combination of sharp dissection with the Metzenbaum scissors and hemo-clips to occlude the arterioles and venules to achieve hemostasis. The external iliac vein is then retracted laterally with exposure of the obturator space that allow for collection of additional nodal tissue whereas carefully dissecting the obturator nerve. The retroperitoneum dissection is then extended superior and medially with electrocautery, carefully avoiding the ureter as it courses over the common iliac vessels, and retracted laterally to allow for adequate visualization (Fig 3 A, B). The inferior mesenteric artery is then isolated approximately 3 cm superior to the aortic bifurcation and the nodal bundle around the aorta is retrieved in a similar fashion. The superior border of this dissection is the renal vein. Routine appendectomy is not indicated in ovarian staging. However, if frozen section returns with a diagnosis of mucinous tumor of the ovaries, 8% of the appendices are involved; therefore, appendectomy should be performed.27 Liver resection and splenectomy are not part of ovarian cancer staging;

Ovarian cancer staging

Figure 1 (A, B) Suggested location of tissue biopsies required for systematic evaluation for metastatic disease, based on theorized flow of metastatic cells in abdominal cavity.

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Figure 2 Adequate sampling of lymphatic tissues in the pelvis should include four areas: obturator, external iliac, junctional, and common iliac nodes.

therefore, should only be performed as part of a radical debulking with a feasible aim for optimal cytoreduction.

Total Abdominal Hysterectomy With Bilateral Salphino-Ophorectomy and Omentectomy The core of ovarian carcinoma staging involves total abdominal hysterectomy and bilateral salphino-ophorectomy, followed by omentectomy (see “Hysterectomy” elsewhere in this issue). As tumors often distort the anatomy and generate dense adhesions, restoration of normal anatomy is paramount before starting any procedure. Furthermore, careful isolation of the ureter from the beginning provides tremendous advantage. Once adequate exposure of the pelvis is obtained, Kelly clamps are then placed on the uterine cornua bilaterally to apply traction during the procedure. The round ligaments are identified and suture ligated with absorbable sutures and transected. This step allows the division of the anterior and posterior leaflets of the broad ligament that provides an entry into the retroperitoneal space where on clearance of the areolar tissues, the ureter is found along the medial surface of the broad ligament. A small window is made in an avascular space of the broad ligament to isolate the infundibular pelvic (IP) ligaments encompassing the ovarian vessels. The IP ligaments then are double clamped, suture ligated and transected. The anterior leaflet of the broad ligament is then incised inferiorly along the uterine contour then the bladder reflection to construct a bladder flap. The bladder is then gently dissected off the lower uterine segment as well as the cervix. Cephalad traction on the uterus facilitates this process. The uterine vessels are skeletonized, clamped, transected, and

ligated. The cardinal and uterosacral ligaments are sequentially clamped, transected, and stitched followed by the complete amputation of the uterus with intact cervix using Jorgensen scissors. The vaginal cuff is then reapproximated using a series of figure-of-eights. Vaginal cuff hemostasis is vital as it is one of the most common site of postoperative hemorrhage.28 Occasionally, the pelvis structures present as a diffuse amalgamation incorporating bladder peritoneum, uterus, fallopian tubes, and ovaries as well as the sigmoid colon. This may be effectively accomplished through modified posterior exenteration procedure described below.29 The omentum is then fanned out and its attachments to the transverse colon are identified (Fig 4 A-C). The posterior leaflet of the omentum is then incised with electrocautery, and an avascular space between the omentum and the transverse mesocolon is developed superiorly to the level of the lesser sac by finger dissection. Along the greater curvature of the stomach, the omental side of the gastroepiploic and its anastomotic short gastric vessels are isolated and transected with linear dissecting stapler to free the entire omentum.

Special Surgical Considerations The abdominal and pelvic survey renders a diagnosis of stage. In advanced ovarian carcinoma (ie, stages III and IV), what ensues this evaluation is the decision making process to determine whether an optimal cytoreduction can be achieved. Optimal cytoreduction rates are varied and dependent on tumor volume and location.30 The possible morbidity incurred from a radical debulking procedure should be balanced against the survival benefits gained from an optimal debulking; however, if optimal disease resection cannot be achieved, then radical surgery fails to be justified as prognosis is uninfluenced by residual disease greater than 2 cm.11

Ovarian cancer staging

Figure 3 (A, B) Paraortic node sampling should include tissue from below and above the level of the inferior mesenteric artery bilaterally.

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Figure 4 (A-C) The omentum can contain a substantial amount of metastatic disease. In cases of no visible disease, it represents a large surface area for early implantation underscoring its importance in surgical staging. Supracolic resection is often necessary for bulky omental disease.

Many have commented on the radicality of ovarian cancer debulking to achieve optimal cytoreduction, especially in bulky stage IIIC and IV diseases. Patients may require extensive upper abdominal organ resections such as diaphragm peritonectomy or full-thickness resection, splenectomy with or without distal pancreatectomy, cholecystectomy for gallbladder surface tumor or resection of parenchymal liver or porta hepatic disease in addition to possible ablative upper abdominal procedures using electrocautery, Cavitron ultrasonic aspirator (CUSA) or argon-beam coagulator (ABC).31 Moreover, patients may also exhibit extensive tumor spread in the pelvis, often involving the rectosigmoid and the cul-de-sac where a modified posterior exenteration and low rectal anastomosis must be performed.29 Isolated diaphragmatic tumors can often to be ablated. However, extensive diaphragmatic disease can be removed by stripping the peritoneum away from the muscle, and more invasive implants often require full thickness resection with

repair. Postoperative complications often include pneumothorax and symptomatic pleural effusion that necessitate medical interventions (see “Surgical Management of Diaphragm Disease in Ovarian Cancer” elsewhere in this issue).32 Superficial splenic metastasis can be ablated, and splenectomy is performed for the following indications: (1) involvement of the splenic surface, hilum, and/or vasculature with bulky disease contiguous with omental metastases; (2) isolated or confluent hilar and/or capsular metastases that could not be resected, ablated, or aspirated; and (3) parenchymal metastases.33 The gastrosplenic and splenorenal ligaments are divided and separated from the spleen at the level of the splenic flexure of the colon, and its vessels are clamped, cut and ligated with absorbable sutures. If disease is involved in the hilum and the pancreatic tail, the distal pancreas is mobilized with electrocautery as well. The splenic artery and vein are then dissected away from the pancreas and clamped, cut and ligated. The pancreas is then divided with a linear stapler.33

Ovarian cancer staging

59 the paravesical and pararectal spaces. The lateral ligaments can then be serially ligated close to the pelvic sidewall with the specimen on cephalad traction. The vagina and rectum are transected at the level of the levator muscle and above the levator sling, respectively. The rectum can then be processed for anastomosis with a mobilized descending colon using an automatic surgical stapler.34 A diverting ileostomy may be indicated if the anastomotic suture line is felt to be tenuous.

Nonepithelial and Low Malignant Potential Tumors Approximately 15% of ovarian malignancies occur in women of reproductive age, therefore, special consideration must be given to fertility sparing surgical approaches such as unilateral cystectomy and oophorectomy in the setting of proper staging with cytology and multiple pelvic and abdominal biopsies.35 Ovarian germ cell tumors (with the exception of dysgerminomas) are almost always unilateral, therefore, preservation of the contra-lateral ovary and uterus is often feasible.36 Approximately 80% of juvenile granulose cell tumors, a subset of sex cord stromal ovarian carcinoma, is diagnosed in women under 20 years of age.35 Considering that 95% of this type of tumor is unilateral, and confined to the ovaries at time of diagnosis, this tumor type can be appropriately treated with conservative measures as well. Low malignant potential (LMP) tumors of the ovary typically is found in younger women when compared with their epithelial ovarian carcinoma counterparts, and account for 15% of all epithelial ovarian carcinoma, and has a 10-year survival of 90%.37 For both serous and mucinous LMP tumors, 60% and 90% of cases are confined to one ovary, therefore, affording the opportunity for fertility sparing surgeries.35 However, because LMP tumors are often diagnosed on permanent sections for pathological evaluation, a management dilemma arises as to the clinical relevance of restaging. Retrospective data have shown that patients with provisional stage IA disease are upstaged 7% to 15% when re-operated for complete diagnosis, and current recommendations remains conflicting.38,39 However, serous histology and initial cystectomy are two risk factors that contribute to upstaging and patients with these risk factors should be considered for re-exploration. Figure 5 Pelvic disease may be extensive, including the cul-de-sac and recto-sigmoid. A modified posterior exenteration and rectosigmoidectomy may be necessary.

Conclusion

For contiguous tumor involvement of the cul-de-sac and the rectosigmoid, a modified posterior exenteration and low rectal anastomosis may be necessary (Fig 5 A, B).33 The procedure begins with bilateral opening the peritoneum covering the rectosigmoid colon to mobilize the colon. Care is taken to preserve the ureters. A linear stapler is then applied to the rectosigmoid colon slightly below the sacral promontory. The rectum is then dissected away from the sacrum to the coccyx, and the rectal stalk is sequentially ligated and transected from its lateral attachments. The hysterectomy is performed as previously described with the exception that the ureters are cleared from the cardinal web bilaterally, and the combination of the uterine and rectal dissections allows for opening of

Proper ovarian staging provides vital information in terms of patient diagnosis and prognosis. Published studies have demonstrated that survival of women with advanced ovarian carcinoma is improved when the primary surgery is performed by gynecologic oncologists versus general gynecologists or surgeons.40-42 A recently published study examined proper staging techniques for early stage ovarian carcinoma, and found that significantly more gynecologic oncologists are likely to perform lymph node dissection than general gynecologists and surgeons. Furthermore, patients treated by gynecologic oncologists had better outcomes compared with their counterparts treated by generalists.43 Nonetheless, hospital and surgeon specific procedure volumes are not strong predictors of survival outcomes after surgery for ovarian cancer among older women.44 As cytoreduction is intimately

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60 intertwined in this surgical staging process, appropriate referral to a gynecologic oncologist is often indicated.

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