PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
In addition to an anatomic stage, a substage—A (low risk) or B (high risk)—is assigned based on nonanatomic factors.
PERSPECTIVE AND PATTERNS OF SPREAD
The spectrum of gestational trophoblastic tumors (GTTs) can include molar pregnancy, invasive hydatiform mole to the neoplastic placental-derived trophoblastic tumor, and the very aggressive choriocarcinoma (Table 45.1; Fig. 45.1A,B). A history of molar gestation is a major risk factor that is somewhat higher among black women. At one time GTTs were incurable, but with chemotherapy complete regression and ablation are readily achievable. In fact, the eradication of GTTs was among the first chemotherapeutic successes and provided a major stimulus to pursue other malignancies with drug therapy. Human chorionic gonadotropin (hCG) is a marker for persistent tumor. If hCG levels remain elevated after delivery of a molar pregnancy with dilation and curettage, then persistent disease remains to be treated. Methotrexate is effective as single-agent therapy.
Figure 45.1 | A. Partial hydatidiform mole. Two populations of chorionic villi are evident. Some are normal; others are conspicuously swollen. Trophoblastic proliferation is focal and less conspicuous than in a complete mole. B: Choriocarcinoma. Malignant cytotrophoblast and syncytiotrophoblast (arrows) are present.
The staging system has evolved over time, recognizing that anatomic extent and histopathology were elegant but limited in their ability to prognosticate. In the 1990s, the International Federation of Gynecology and Obstetrics introduced a Prognosis Scoring Index, which includes age, antecedent pregnancy, interval months from index pregnancy, largest tumor size, size of metastases, number of metastases identified, and response to chemotherapy. In addition to an anatomic stage, a substage—A (low risk) or B (high risk)—is assigned based on nonanatomic factors. The prognostic scores are ≥0, 1, 2, or 4 for individual risk factors. A score of ≤7 is A (low risk) and one of ≥8 is B (high risk).
PATHOLOGY
This highly invasive malignancy is illustrated by the patterns of spread in Fig. 45.2 and Table 45.2. Once this cancer spreads to extrauterine sites (Fig. 45.2B) it behaves aggressively, invading surrounding tissues. Common sites invaded include cervix, vagina, and ovary; these cancers behave similar to primary cancers at these sites.
Figure 45.2 | Patterns of spread. A. Coronal. B. Sagittal. The cancer is color coded for stage: T0, yellow; T1, green; T2, blue. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern, i.e., SIMLAP, Table 45.2.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The highly malignant choriocarcinoma has access to the rich vascular blood supply of a failed placenta and can rapidly invade hematogenously. Presentations of metastatic disease may be encountered before recognition of the local regional manifestations of GTT. As noted, the serum tumor marker β-hCG is an important diagnostic as well as a staging prognostic aid.
After surgical removal by dilation and curettage or hysterectomy, myometrial invasion may be evident (T1). Nodal metastases are uncommon. Local spread to cervix, ovary, or vagina (stage T2) is common, and lung is a favored metastatic site. Dissemination to liver often occurs, but such remote sites as the kidney, gastrointestinal tract, spleen, bone, and brain also may be involved.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
The definitions of TNM and the Stage Grouping for this chapter have not changed from the Sixth Edition (Fig. 45.3).
The “Risk Factors” (7) portion of the stage groups has been revised as Table 45.3A into A Low Risk (score 7 or less); B High Risk (score 8 or more).
The TNM Staging Matrix allows for identification of stage group once T and N stages are determined (Table 45.3A).
GESTATIONAL TROPHOBLASTIC TUMORS
Figure 45.3 | TNM staging diagram arranged vertically with T definitions on the left and stage groupings on the right. Gestational trophoblastic tumors are highly metastatic but highly curable with chemotherapy. There are four main stages, each with two or three substages. Color bars are coded for stage: stage 0, yellow; I, green; II, blue; III, purple; IV, red; metastatic disease to viscera and nodes, black.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR T-ONCOANATOMY
The isocenter for the uterus is at the S4 level but can vary from S2 to S5, depending on the degree of anteflexion or retroflexion (Fig. 45.4).
T-oncoanatomy
The T-oncoanatomy is displayed in three planar views in Fig. 45.5:
• Coronal: The upper two thirds of the uterus above the level of the internal cervical os is called the “corpus uteri.” The fallopian tubes enter at the upper lateral corners of its pear-shaped body. The portion of the muscular organ positioned above the line joining the tubouterine orifices is called the “fundus.”
• Sagittal: The body of the uterus sits in the peritoneal cavity. Although it is juxtaposed to these structures, it is separated by the peritoneal lining, making direct invasion rare.
• Transverse: The relationship of the uterus to other pelvic tissues is important, particularly to the rectum and bladder. The rectovaginal or the vesicovaginal septum can be invaded. Note that the juxtaposition of the vaginal wall directly to the bladder and the rectum makes these organs directly accessible.
Figure 45.4 | Orientation of oncoanatomy of gestational trophoblastic tumor. The anatomic isocenter is at the midline and at the S3 to S4 level inside the true pelvis. A. Coronal. B. Sagittal.
Figure 45.5 | T-oncoanatomy. A. Coronal. B. Sagittal. C. Transverse. The color code for the anatomic sites correlates with the color code for the stage group (Fig. 45.3), patterns of spread (Fig. 45.2), and SIMLAP table (Table 45.2). Connecting the dots in similar colors will provide an appreciation for the 3D oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
Lymphatic invasion is uncommon. When the cervix is invaded, extension into bladder and rectum can be due to the major lymphatic trunks, the utero-ovarian (infundibulopelvic), parametrial, and presacral nodes that drain into the hypogastric, external iliac, common iliac, presacral, and para-aortic nodes. However, the fundus also drains via ovarian lymphatics to retroperitoneal lymph nodes. The sentinel node could be either an obturator node or a para-aortic lymph node (Fig. 45.6A, Table 45.4).
M-ONCOANATOMY
The major venous drainage is via uterine veins or ovarian veins into the vena cava (see Fig. 45.6B). Pulmonary metastases are more common (90%), followed by liver, which is reflected in the staging system. Choriocarcinoma invades primarily through venous sinuses in the myometrium. It metastasizes widely by the hematogenous route, especially lungs (>90%), brain, and gastrointestinal tract, liver, and vagina (Table 45.3B).
Figure 45.6 | A. N-oncoanatomy. The sentinel nodes for gestational trophoblastic tumors into the internal iliac and to paraaortic nodes. With invasion of the cervix (T2) the cancer behaves like cancer of the cervix and can spread to hypogastric or obturator nodes. B. M-oncoanatomy.
518STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
The initial diagnostic procedures are the staging criteria. Both clinical and pathologic criteria establish the primary tumor anatomic extent; however, specific criteria suggest persistent and/or metastatic GTT and require chemotherapy.
Imaging recommendations apply to the metastatic workup, and are similar to those for the uterine fundus as to primary site and pelvic nodes (Table 45.6, Fig. 45.7).
Clinical Staging
With few exceptions, hysterectomy and bilateral salpingooophorectomy are performed for both staging and diagnosis. Uterine enlargement can be assessed, but myometrial and serosal invasion is difficult to determine on pelvic examination. The International Federation of Gynecology and Obstetrics mandates surgical staging, cautioning that aggressive and wide lymph node sampling may be too risky because pelvic and para-aortic nodes are at risk. Imaging is utilized when available, especially for high-grade cancer and enlarged uteri preoperatively.
Surgical-pathologic Staging
The completely resected specimen, including the primary site and regional lymph nodes, which must be thoroughly analyzed, are pTNM designated. Radical hysterectomy and bilateral salpingo-oophorectomy with pelvic lymph node resection is the usual procedure for pathologic evaluation.
Although the staging has remained unchanged at most gynecologic primary sites, the rules for classification still do not allow for sophisticated imaging, which includes computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US) to alter staging. The multidisciplinary approach to decision making is truly interdisciplinary, most often involving a gynecologic oncologist and a dedicated radiation oncologist. Over the decades, diagnostic and therapeutic protocols in national cooperative groups have provided a scientific basis for introducing combined modalities and innovations into clinical practice.
Oncoimaging with CT is commonly applied to staging cancers, often combined with positron emission tomography to determine the true extent of primary cancer and involved lymph nodes.
Oncoimaging Annotations
• Chest CT with helical techniques allow for detection of pulmonary metastases of 5 to 10 mm.
• CT is preferred over US for pathologic confirmation of liver metastases.
• MRI is superior to CT for detecting peritoneal metastases.
Imaging Modalities for Staging Gestational Trophoblastic Cancer TABLE 45.5
PROGNOSIS AND CANCER SURVIVAL
PROGNOSIS
Patients with molar gestations can be stratified into low- and high-risk categories on the basis of clinical and laboratory parameters. Those who have large-for-dates uteri or a preevacuation serum hCG level higher than 100,000 mIU/mL (high-risk molar pregnancy) have about a 50% risk of developing invasive mole. Patients without these and other highrisk features have less than a 5% risk.
Follow-up
Surveillance of patients treated for gestational trophoblastic disease is mandatory. Fortunately, these tumors produce large amounts of hCG (with the exception of placental-site tumors), which can be measured accurately in the serum and is close to an ideal tumor marker. Patients with either a complete or partial mole should undergo weekly serum β-hCG measurement until a normal level is reached. After three normal levels, serum hCG measurements may be obtained at longer intervals. The follow-up for patients with invasive mole or choriocarcinoma is similar to that for patients with molar pregnancy. However, in cases in which remission was difficult to achieve (requiring more than three or four courses of chemotherapy), the period of serum hCG follow-up should be extended to 2 years because late recurrences are possible.
Survival
Currently, patients undergoing evacuation of a molar pregnancy have an excellent prognosis, both in terms of their outlook for future fertility and with respect to the available treatment should an invasive mole or choriocarcinoma develop. Most patients (80%) with a molar pregnancy have no further sequelae after evacuation of the mole; the remaining 20% develop either nonmetastatic or metastatic gestational trophoblastic neoplasia (GTN) that requires chemotherapy. However, virtually all patients with nonmetastatic disease are cured, although some (5%) may require hysterectomy or uterine resection to remove a focus of resistant tumor. Patients with low-risk metastatic GTN also have an excellent prognosis.
Figure 45.7 | Axial CTs of female pelvis correlate with the T-oncoanatomy transverse section (Fig. 45.5C). (1) Left ovary. (2) Physiologic fluid in pelvis (normal in menstruatingage female). (3) Uterine fundus. (4) Endometrial cavity. (5) Iliopsoas muscle. (6) Gluteus minimus muscle. (7) Gluteus medius muscle. (8) Gluteus maximus muscle.
Currently, about 5% of patients with high-risk metastatic GTN die of the disease. Poor prognostic factors have been identified, such as the presence of liver or brain metastases, or both, an interval of more than 24 months since the antecedent pregnancy, patient age, and previous inadequate chemotherapy. In patients with two or more poor prognostic factors, the survival rates are 82% and 43%, respectively. Of some concern, a small but significant increase in the risk of secondary malignant tumors has been reported following treatment with sequential or combination therapy.
