PERSPECTIVE, PATTERNS OR SPREAD, AND PATHOLOGY
The ovary is as much a structure of the whole peritoneal cavity as it is of the pelvis.
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PERSPECTIVE AND PATTERNS OF SPREAD
Ovarian cancer is the most lethal cancer of the female genital tract. Deaths from this cancer surpass deaths attributed to gynecologic cancers at all other sites combined. The total loss of life in 2010 was 21,880, compared with 13,000 for all other gynecologic sites. The estimated incidence is 25,000 new cases annually. The common symptom and sign is the insidious accumulation of ascitic fluid masquerading as weight gain and increase in abdominal girth. Unlike the other common gynecologic cancers, in this case vaginal bleeding is rare. Clinical detection is most often due to routine physical and pelvic examination coupled with pursuit of imaging and serum markers in high-risk patients with familial histories or those testing positive for both BRCA-1 and -2 oncogene mutations.
The staging of these cancers demands surgical laparotomy exploration of both the pelvic and peritoneal cavity, including the omentum, the mesentery, the liver, and the diaphragm, because abdominal seeding is the dominant pattern of spread (Fig. 43.1, Table 43.1). The ovary is as much a structure of the whole peritoneal cavity as it is of the pelvis. This is particularly true once it has become subject to malignant transformation. The ovary is positioned essentially at the bottom of the peritoneal cavity. Its blood supply reflects its abdominal origin that is, ovarian arteries arise from the aorta, and ovarian veins drain directly to the inferior vena cava, unlike uterine vessels that arise from the pelvic internal iliac artery and drain into pelvic internal iliac veins.
When cancer forms in the ovary, it invades through its capsule and forms excrescences. Tumor cells are released and seed the peritoneal surface, often invading the gynecologic tract in the manner of an ovum or filling the cul-de-sac. Because there is no true separation between the pelvic and abdominal cavities, this cancer often seeds the omentum, mesentery, and intestine. The diaphragm may act as a “blotter” for these dispersed tumor cells in the peritoneal cavity. Ascites and pleural effusion are common in advanced stages.
Molecular markers such as CA-125 can be elevated at diagnosis and are useful for following response versus relapse. Germ cell tumors can have elevated serum markers, such as α-fetoprotein (AFP) and human chorionic gonadotropin (β-HCG), which can be used to assess treatment.
Figure 43.1 | Patterns of spread. A. Coronal. B. Sagittal. The cancer is color coded for stage: T0, yellow; T1, green; T2, blue; T3, purple. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern, i.e., SIMLAP Table 43.1.
Histopathology
The coelomic cavity mesothelial lining specializes when it encapsulates the ovary, forming a simple cuboidal epithelial cell wrap. With repetitive oocyte ejection and rupture of this layer, transformation of the epithelium-stroma into a benign proliferation, then borderline changes, and finally into malignant carcinom occurs. The dedifferentiation into serous, endometroid, mucinous histologies relates to the Müllerian epithelial anlage. The World Health Organization list of histopathologies is endorsed by the American Joint Committee on Cancer/International Union Against Cancer (Table 43.2). Between 80% and 90% are epithelial cancers; 5% to 10% are bilateral. Serous carcinomas are the most common subtype, microscopically containing papillary and glandular elements. T o understand the full range of diversity of histopathologic types of ovarian tumors, one must recapitulate the embryogenesis of the ovary and its unique relationship to the peritoneal cavity (Table 43.2, Fig. 43.2).
• Serous cancers are similar to fallopian tube epithelia (Fig. 43.2A).
• Mucinous cancers are similar to endocervix epithelia (Fig. 43.2B).
• Endometroid cancers are similar to endometrial epithelia (Fig. 43.2C).
The specialized tumors of the ovary are derived from germ cells and their supporting cells, which, during their differentiation, can result in a genetic error and mutate into a variety of cancers unique to the ovary.
• Dysgerminomas resemble oogonia of the fetal ovary and are the female counterpart of seminomas (Fig. 43.2D).
• Endodermal sinus (yolk sac) tumors resemble the mesenchyme of primitive yolk sac (Fig. 43.2E).
• Granulosa cell tumors occur in adults, often in menopause (Fig. 43.2F).
• Krukenberg tumors are metastatic cancers from gastrointestinal primaries—mainly stomach and colon—that can seed and grow into bilateral symmetric ovarian masses, which is the converse of ovarian cancers seeding into the peritoneal cavity (Fig. 43.2G).
• Peritoneal mesotheliomas that minimally involve the ovary are considered primary peritoneal carcinomas (Fig. 43.2H).
Figure 43.2 | A. Serous cystadenocarcinoma. (1) The ovary is enlarged by a solid tumor that exhibits extensive necrosis (N). (2) Microscopic examination shows a papillary cancer invading the ovarian stroma. Several psammoma bodies are present (arrows). (3) A higher-power view shows the laminated structure of a psammoma body. B. Mucinous cystadenocarcinoma. The malignant glands are arranged in a cribriform pattern and are composed of mucin-producing columnar cells. C. Endometriod tumors. D. Dysgerminoma. The neoplastic germ cells have clear, glycogen-filled cytoplasm and central nuclei. Fibrous septa containing lymphocytes traverse the tumor. E. Yolk sac carcinoma of ovary. The tumor cells are arrayed in a reticular pattern. A Schiller-Duval body (center) resembles the endodermal sinuses of the rodent placenta and consists of a papilla protruding into a space lined by tumor cells. F. Granulosa cell tumor of the ovary. (1) Cross section of the enlarged ovary shows a variegated solid tumor with focal hemorrhages. The yellow areas represent collections of lipid-laden luteinized granulosa cells. (2) The orientation of tumor cells about central spaces results in the characteristic follicular pattern (Call-Exner bodies). G. Krukenberg tumor. (1) The ovary is enlarged and partially hemorrhagic. (2) A microscopic section of panel (1) reveals mucinous (signet-ring) cells infiltrating the ovary. H. Well-differentiated peritoneal mesothelioma. Cuboidal epithelium lines papilla.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The evolution of ovarian cancer staging criteria has rested on careful exploratory laparotomy and gradually required multiple sampling of a variety of peritoneal sites such as omentum, mesentery, liver, and the diaphragm. By the fourth edition, the three stages of each had three subcategories. The pattern of spread in the earliest stages is limited to the ovary (stage T1a); if both ovaries are involved, stage is T1b, and with positive washings or ascites it is T1c. Once extension occurs to pelvic organs or implants on uterus or tubes, it is T2a; onto pelvic wall or bladder, T2b; and with positive washings or ascites, T2c. Once peritoneal metastatic seeding occurs into the abdominal peritoneal cavity but is microscopic tumor, it is stage T3a; macroscopic tumor 2 cm, T3b; and macroscopic tumor >2 cm, T3c (Fig. 43.3A).
Important clarifications include the following: Only malignant ascites affect staging, and liver capsule metastases are T3, but liver parenchyma metastases are M1. Pleural effusion must have positive cytology to be M1 stage. Patients with only intraperitoneal carcinoma without ovarian involvement or minimally involved should be labeled as having “extraovarian” peritoneal carcinoma and by definition are stage T3 o M1.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• The definition of TNM and the Stage Grouping for this chapter have not changed from the Sixth Edition (Fig. 43.3A).
• Primary peritoneal carcinoma has been included in this chapter.
The TNM staging matrix allows for identification of stag group once T and N stages are determined (Table 43.3).
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Figure 43.3A | TNM staging diagram arranged vertically with T definitions on the left and stage groupings on the right. Ovaria cancers are cancers of the pelvis and peritoneal cavity. Resectability depends on the number and size of peritoneal implants. Color bars are coded for stage: stage I, green; II, blue; III, purple; IV, red; and metastatic disease to viscera and nodes, black.
FALLOPIAN TUBES
The basis for staging carcinomas of the fallopian tube clearly parallels that for ovarian cancer.
PERSPECTIVE AND PATTERNS OF SPREAD
Carcinoma of the fallopian tube (FT) is rare and most often simulates ovarian cancers in presentation as an adnexal mass (Fig. 43.2G). Often, FT cancers are associated with two symptoms: vaginal bleeding and abdominal pelvic pain, often spasmodic in nature. This is an uncommon female malignant cancer, representing 1% of all female cancers.
Histopathologically, FT cancers are serous adenocarcinomas. The majority are identified at surger, and the basis of this staging system is surgical-pathologic. The histopathology is similar to that of ovarian cancers (Table 43.2).
EPIDEMIOLOGY AND ETIOLOGY*
Carcinoma of the fallopian tube is an uncommon malignancy that accounts for 0.3% to 1.1% of all female genital tract cancers. The most common form of this cancer is a papillary serous carcinoma, but only about 300 cases of this are reported each year in the United States. The paucity of information makes its natural history and management unfamiliar. In most series, the median patient age at diagnosis is between 55 and 60 years. The clinical course of fallopian tube carcinoma is often similar to that of epithelial ovarian carcinoma, although there are several significant differences.
DETECTION AND DIAGNOSIS
Unlike epithelial ovarian carcinoma, fallopian tube carcinoma is often symptomatic. The three most common symptoms and signs are abnormal vaginal bleeding, a pelvic mass, and abdominal or pelvic pain. Pelvic pain is more common in tubal carcinoma than in ovarian carcinoma; as the tumor in the fallopian tube enlarges, pain results from the peristaltic contractions of a hollow viscus. The lack of specificity of these finings and the rarity of tubal carcinoma make accurate preoperative diagnosis very difficult.
Fallopian tube carcinoma often may be mistaken for an ovarian neoplasm, uterine leiomyomata, hydrosalpinx, or a tubo-ovarian abscess—all of which are more common than tubal carcinoma. Therefore, the diagnosis of fallopian tube carcinoma is considered before surgery in only 0% to 15% of patients. The majority are identified during surgery or b pathologic examination.
• Rarely, fallopian tube carcinoma is detected on Pap smear, but in general the positivity of this method is only 25% to 50%. Cytologic findings play the greatest role in staging.
• Pelvic ultrasound may demonstrate tubal carcinoma, but it is often mistaken for an ovarian tumor because tubal carcinoma appears frequently as a complex fusiform mass on ultrasound. A number of studies have shown that contrast-enhanced magnetic resonance imaging (MRI) demonstrates superior characterization and differentiation compared to ultrasound.
• Although laparotomy is necessary for definitive diagnosis o primary tubal carcinoma, there still can be uncertainty on gross examination.*
HISTOPATHOLOGY
Histopathology is similar to ovarian cancer but largely to serous cytadenocarcinoma (refer to Fig. 43.2A).
TNM STAGING CRITERIA
The basis for staging carcinomas of the FT clearly parallels that for ovarian cancer. The patterns of spread are similar, with invasion into the uterus and female genital tract versus seeding into the peritoneal cavity. The American Joint Committee on Cancer introduced the TNM staging in the fifth edition and left it unchanged in the sixth edition (Fig. 43.3B). Laparotomy and resection of tubal masses, as well as hysterectomy and suspicious sites, require biopsy and histology for confirmation
SUMMARY OF CHANGES SEVENTH EDITION AJCC
The definitions of TNM and the Stage Groupings for thi chapter have not changed from the Sixth Edition.
Oncoimaging Annotations
• Hydrosalpinx with solid nodulation suggests FT carcinoma.
• Computed tomography (CT) is the recommended imaging modality for staging. MRI is reserved for patients with contraindications to iodinated contrast media (essential for diagnostic CT study) and for questions unanswered by CT.
• CT with intravenous contrast, helical technique, provides excellent cross-sectional imaging for detecting signs of malignancy such as varied morphology of cystic/solid walls or internal septa, lobulated papillary mass, implants 1 to 3 cm in size, and coarse calcifications
• MRI is highly accurate in determining the origin of an adnexal mass and in characterizing ovarian masses as benign, malignant, or nonneoplastic. Intravenous gadolinium should be used because it improves lesion characterization.
• CT is useful for detecting small or large bowel invasion, mesenteric and omental “cake” masses, adenopathy, liver involvement, and ascites.
*Rubin P, Williams J, eds. Clinical Oncology: A Multidisciplinary Approach for Physicians and Students. 8th ed. Philadelphia: Elsevier, 2001:489.
FALLOPIAN TUBE
Figure 43.3B | TNM staging diagram arranged vertically with T definitions on the left and stage groupings on the right Fallopian tube cancers are quite rare and are resectable as stage II (blue) and are borderline resectable in stage IIIA. Color bars are coded for stage: stage 0, yellow; I, green; II, blue; III, purple; IV, red; and metastatic disease to viscera and nodes, black.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The isocenter of the ovary is at the roof of the female genital system at the S2, S3 level, 5 to 10 cm lateral to the midline (Fig. 43.4).
The FT is an appendage that extends from the posterior superior aspect of the uterus and opens to the peritoneal cavity and the ovary. It has a length of 10 cm.
T-oncoanatomy
The T-oncoanatomy is displayed in three planar views in Fig. 43.5:
• Coronal: The ovaries are a pair of solid, flattened ovoids 2. to 4.0 cm in diameter in premenopausal women. They are connected by a peritoneal fold to the broad ligament and by the suspensory ligament of the ovary to the lateral wall of the pelvis.
• Sagittal: The ovary is also connected by the broad ligament and the ovarian ligament to the pelvic brim. During its functioning years, the menstrual cycle is regulated by ovulation and is divided into a proliferative (follicular) and a secretory (luteal) phase. It is in the postmenopausal state that neoplasia occurs. Rather than becoming atrophic and cystic, mitotic activity occurs.
• Transverse: The uterus is usually asymmetrically placed; in this example, it leans to the left. The round ligament of the female takes the same subperitoneal course as the deferent duct of the male. The free edge of the medial four fifths o the broad ligament contains the uterine tube, and that of the lateral one fifth, the ovarian vessels in the suspensory ligament of the ovary.
Figure 43.4 | Orientation of oncoanatomy of the ovary and fallopian tube. The anatomic isocenter is off the midline on each side at the true pelvis inlet estimated at the transverse S1 to S3 level. A. Coronal. B. Sagittal.
Figure 43.5 | T-oncoanatomy. A. Coronal. B. Sagittal. C. Transverse axial. Connecting the dots: Structures are color coded for cancer stage progression. The color code for the anatomic sites correlates with the color code for the stage group (Fig. 43.3) and patterns of spread (Fig. 43.1) and SIMLAP table (Table 43.1). Connecting the dots in similar colors will provide an appreciation for the three-dimensional oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
Ovarian cancers, by the nature of their peritoneal dissemination, alter normal lymphatic drainage of the ovary to that of the entire abdominal cavity and its contents.
The lymphatic drainage occurs via the ovarian ligament and round ligament trunks and an external iliac accessory route into the following regional nodes: The para-aortic nodes are the major regional nodes followed by the external iliac, common iliac, hypogastric, lateral sacral, and, rarely, to the inguinal nodes (Fig. 43.6A, Tables 43.4A, 43.4B). Although the ovary is pelvic in location, its lymphatic drainage recapitulates its abdominal or homologous origin—the para-aortic lymph nodes. Its vestigial relationship via the round ligament to the labia reaffirms its similarity to the testes in its intimat scrotal location, which makes drainage to inguinal nodes possible. Although an inguinal node can be considered a first station node, most oncologists regard an extrapelvic node as metastatic.
M-ONCOANATOMY
The ovarian veins drain into the inferior vena cava and targets the right side of the heart and then the lungs (see Fig. 43.6B, Table 43.4C). However, peritoneal seeding, as mentioned, is a predominant metastatic pattern involving the abdominal cavity, liver, and diaphragm. Malignant ascites is the predominant death pattern.
The internal and external iliac veins drain the female reproductive organs, and metastatic dissemination is via the inferior vena cava to lung, which is the favored target organ.
• Ovarian cancers arise from the epithelial surface, which, during embryogenesis, is derived from the coelomic cavity lined by mesothelial cells, which become specialized to form a serosal covering of the gonadal ridge. As ovarian cancers shed their cells into the peritoneal cavity, they behave like peritoneal mesotheliomas, studding the omentum, the intestinal tissues, liver, and diaphragm, resulting in ascites.
• Distant metastases ultimately occur in 38% of patients who were originally limited to the peritoneal cavity and their length of survival.
• Significant risk factors for developing metastases are malignant ascites, peritoneal implants, paraortic lymph nodes, and aneuploid tumors.
Figure 43.6 | A. N-oncoanatomy. Although the ovary drains to the high para-aortic nodes, most ovarian cancers spread initially in the pelvis, placing both the internal and external iliac nodes at risk. B. M-oncoanatomy.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging
Physical and pelvic examinations are limited in their assessment. Reliance on imaging is essential and includes transvaginal ultrasound (TVUS), magnetic resonance imaging (MRI), enhanced computed tomography (CT), and positron emission tomography (PET). All are of value for patients with advanced cancer (see Table 43.5, Fig. 43.7). Laparotomy and histologic confirmation of spread are required for accurate staging. Imaging can guide the determination of which pelvic and peritoneal areas to assess.
Surgical-pathologic Staging
Ovarian cancer is surgically/pathologically staged. Laparotomy and resection of the ovarian mass and biopsy sampling of peritoneal sites include any suspicious peritoneal nodules or implants on omentum, mesentery, diaphragm, pelvic, and para-aortic lymph nodes. Peritoneal washing with cytospins as well as for ascites can establish positive cells. Suspicious pulmonary nodules or supraclavicular nodes require pathologic confirmation. A detailed operative report with precise measurements in centimeters for mass lesions is mandatory before any other treatment. To stage a patient IA, multiple biopsies are required to be negative, as mentioned. Second-look laparotomies may be useful after chemotherapy and debulking surgery but do not change the original staging. The use of imaging procedures to guide surgery is highly recommended.
Oncoimaging Annotations
• TVUS is the optimal imaging procedure for early detection and evaluation of any adnexal mass irregularities.
• Color Doppler aids in diagnosis of malignancy if active neovascularization is identified with vessels that have a characteristic waveform shift.
• MRI is preferred to CT for adnexal mass imaging for malignancy criteria with gadolinium contrast. Criteria for malignancy include mass size >4 cm and wall and septa thickness >3 mm with heterogeneous densities.
• Fluorine-18–labeled deoxy-D-glucose PET reliably images tumors >1 cm. In pilot studies, the sensitivity of PET appears higher than that of MRI or CT (not significant) with equivalent specificit. Large-scale studies are needed to determine the role of PET in assessing ovarian cancer.
• Cross-sectional imaging is used as an alternative to second-look laparotomy, which is no longer performed routinely.
• Significant criteria of malignancy of ovarian mass include the following: size >4 cm; solid more than cystic; wall thickness >3 cm; septa >3 mm; heterogeneous appearance of nodulation; and vegetations.
• Omental cakes, especially of calcified scattered deposits indicate advanced abdominal disease.
• Bilateral symmetric adnexal masses suggests Krukenberg tumors secondary to the gastrointestinal tract.
• Ascites, especially with internal fluid–fluid level, is consitent with cancer and is referred to as “complex ascites.”
With advances in imaging technologies, most gynecologic oncologists have utilized both CT and MRI to assess the stage of uterine fundus and cervix carcinomas. MRI is preferred for evaluating primary tumor size, depth of invasion and extra-uterine invasion and extensions. For lymph node metastases, both CT and MRI are useful. The addition of PET scans are added to CT to validate the presence of metastases. In staging ovarian cancers, MRI is more accurate than CT. With the addition of gadolinium, metastatic foci are more readily identified. CT enhancement with contrast is often utilized and the addition of PET improves the assessment of stage.
PROGNOSIS AND CANCER SURVIVAL
CANCER STATISTICS AND SURVIVAL AND PROGNOSIS
Prognostic Factors
In ovarian cancers, histopathology and cancer grade are equally important in determining prognosis as in the staging of cancer. Tumor markers are emerging as important indicators of cancer control and recurrence. CA-125 is commonly used to gauge treatment effectiveness for epithelial cancers but is not as reliable as prostate-specific antigen in prostate cance. Germ cell cancers may have increases in serum tumor α-fetoprotein (AFP) and human chorionic gonadotropin (β-HCG). Possible future genetic markers are noted in Table.
In most series, about 60% of patients with tubal carcinoma present with disease confined to the pelvis (stage I or II), wit only 40% in stage III or IV; with ovarian cancer the ratio is reversed. On a univariate analysis, a number of prognostic factors have emerged:
• Postoperative adjuvant therapy
• Optimal debulking surgery
• Absence of closure of the fimbriated end of the tub
• Age
• Aneuploid cancers
Figure 43.7 | Axial CTs of pelvis correlate with the Toncoanatomy transverse section (Fig. 43.5C). Oncoimaging with CT is commonly applied to staging cancers, often combined with PET to determine the true extent of primary cancer and involved lymph nodes. (1) Right ovary. (2) Sigmoid colon. (3) Pirifornis muscle. (4) Iliacus muscle. (5) Psoas muscle. UT, uterus (fundus). The CT/MRI transverse section can be correlated with the anatomy in Fig. 43.5Cas an assist to staging.
• Stage, particularly stage I versus II/III/IV
• Tumor differentiation
However, in the few studies with sufficient numbers to allo for a multivariate analysis, stage at presentation is the only consistent factor. In addition, the presence of vascular or lymphatic invasion with early-stage disease has been shown in one study to decrease 5-year survival rates to 29% versus 83% for those who do not have such invasion.
Survival Rates
The survival rate gains in both cervix uteri and fundus uteri have been incremental. Given that invasive cancers of the gynecologic tract have had a higher baseline—greater than 50% in the 1950s—the gains for all stages are only 15%, or 2% to 3% per decade. As noted, mortality rates have plummeted owing to early detection, especially of cancer of the cervix, because it is most often detected in its noninvasive stage. Localized uterine cancers are more than 90% curable (see Fig. 43.8).
The observed survival rates are similar for both ovarian and fallopian tube cancers. The localized early stage I cancers offer excellent survival rates as compared to more advanced stage II cancers. Stage III A/B/C has a 5-year survival rate of 50% to 40%.
Figure 43.8 | Five-year observed survival rates for (A) ovarian epithelial cancer and (B) carcinoma of the fallopian tube. (Data from Edge SB, Byrd DR, and Compton CC, et al., AJCC Cancer Staging Manual. 7th ed. New York, Springer; 2010; p. 422 and p. 431.)