PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The patterns of cancer spread are determined by the anatomy and the central position of the cervix in the female genital system.
PERSPECTIVE AND PATTERNS OF SPREAD
The success in conquering cancer of the uterine cervix is due to widespread and highly effective screening using the Papanicolaou (Pap) smear of exfoliative cytology. There are 65,000 cases new cases each year of noninvasive carcinoma in situ, compared with 13,000 new cases of invasive cancer, usually early stages. There are fewer than 5,000 deaths annually. Most are of elderly, postmenopausal women who are less active sexually and are not being screened, or women in low socioeconomic groups, Latinos, and African Americans. The low incidence among Jewish women suggests that male circumcision may be a factor.
The patterns of cancer spread are determined by the anatomy and the central position of the cervix in the female genital system: First, within the cervix, then (i) inferiorly into the vagina, (ii) laterally into the parametrium, or (iii) anteriorly into the bladder or posteriorly into the rectum (Fig. 46.2; Table 46.2).
PATHOLOGY
The cervix is the terminal end of the uterus that protrudes into the vagina, and its lumen is lined with a mucus-secreting, simple columnar epithelium. However, when the cervix protrudes into the vagina, the epithelium is stratified squamous and i nonkeratinized (Fig. 46.1A–D). It is not surprising that of the several histopathologic types, 80% to 90% are squamous cell cancers and only 5% to 10% are adenocarcinomas. Table 46.1 lists the variations and subtypes, as well as the grading of cervical cancers.
Figure 46.1A | Squamous cell cancer.
Interrelations of naming systems in Premalignant Cervical Cancer interepithelial neoplasia (CIN) is a spectrum of cellular changes that begins as atypia and then progresses to invasive cancer. The grades progress to cancer have corresponding cytologic changes that are shed and graded as squamous intraepithelial lesions (SIL).
Figure 46.1B–C | Comparison of (B) standard Papanicolaou smear with (C) mono-layer preparation. There has been rapid adoption of liquid based cytology (LBC) for cervical screening over the past decade. Most cervical smears in the United States are taken into solution despite the lack of large randomized studies. Recent technological improvements in automation of processing and assessment of LBC specimens, particularly the use of an automated imager, are likely to increase this utilization. The ability to test LBC specimens for HPV DNA and other sexually transmitted organisms further enhances the clinical appeal of this technology.
Figure 46.1D | Interrelations of naming systems in premalignant cervical disease. This complex chart integrates multiple aspects of the disease complex. It lists the qualitative and quantitative features that become increasingly abnormal as the premalignant disease advances in severity. It also illustrates the changes in progressively more abnormal disease states and provides translation nomenclature for the dysplasia/carcinoma in situ (CIS) system, cervical intraepithelial neoplasia (CIN) system, and Bethesda system. Finally, the scheme illustrates the corresponding cytologic smear resulting from exfoliation of the most superficial cells, indicating that even in the mildest disease state, abnormal cells reach the surface and are shed. SIL = squamous intraepithelial lesion.
Figure 46.2 | Patterns of spread. A. Coronal. B. Sagittal. The cancer is color coded for stage: Tis, yellow; T1, green; T2, blue; T3, purple; and T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern, i.e., SIMLAP, Table 46.2.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
Cancer of the cervix is the archetype for staging cancer. Review of the first six editions of the AJCC Cancer Staging Manual shows that the main stages I, II, III, and IV have consistently reflected the progression of the primary cance. As cervical cancer was detected earlier due to the Pap smear being applied universally, microinvasion was defined and T1 wa divided into multiple subgroups, but stage I remained confine to the cervix. Other stages also have been divided into A and B to reflect different vectors and degrees of spread. These eigh substages encompass the numerous T, N, and M combinations and subgroups; with stage 0 added for Tis, the total becomes 9.
The cervix is at the anatomic isocenter of the female pelvis. The TNM staging criteria have been established and reflec cancer spread patterns. Cervical cancer is the archetype as the first cancer staged more than 70 years ago. Since 1937, the International Federation of Gynecology and Obstetrics (FIGO) has collected data on cervical cancer survival and outcomes from numerous institutions. The pooled results have become the international gold standard on reporting cancer survival results.
The TNM introduced by Pierre Denoix simply adapted their categories to fit the FIGO stages. Although the basic def initions have been stable, the increasing success of findin preinvasive cancers has led to expanding the subcategories of stage I because of conization techniques. Thus, in early versions of the American Joint Committee on Cancer/International Union Against Cancer system, stage I was simply a cancer confined to the cervix, without any size or specific measuremen requirements. The staging preferably was a bimanual examination under anesthesia. With the fourth edition (1992), microscopic sizing of invasion was introduced as subcategory IA and further defined in the fifth edition with the subcatego IB, with ≤4.0 cm designated as IB1 and >4.0 cm as IB2. The stage IA microinvasive lesions are defined as a maximum depth of 5.0 mm for the favorable category, which implies that there will be few instances of lymphatic or capillary infiltration, which, even if present, does not change this criterion. Stage IB are visible lesions or microinvasion beyond 5.0 mm. As noted, 4.0 cm divides stage IB1 and IB2 cancers (Fig. 46.3).
Spread patterns beyond the cervix lead to stage II. Superior invasion into the uterus is ignored for staging. Inferior invasion into the vagina is T2a, and lateral spread into the parametrium is T2b. Stage III cancers extend to the pelvic wall (T3b) or lower third of the vagina (T3a), which alters lymph nodes at risk. Stage T4a is designated for anterior spread into the bladder, which requires biopsy proof; T4b is rectal invasion, which occurs only from vaginal extension because the posterior lip of the cervix is separated from the rectum by the rectouterine pouch of Douglas.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
The definitions of TNM and the Stage Grouping for this chapter have changed from the Sixth Edition and reflect new staging adopted by the International Federation of Gynecology and Obstetrics (FIGO) (2008) (Fig. 46.3).
The 2008 FIGO staging classification has adopted T sub classifications based on tumor size ≤4 cm (T2a1) and >4 cm (T2a2) for cervical carcinoma spreading beyond the cervix but not to the pelvic side wall or lower one third of the vagina (T2 lesions).
The TNM Staging Matrix allows for identification of stag group once T and N stages are determined (Table 46.3).
UTERINE CERVIX
Figure 46.3 | TNM staging diagram arranged vertically with T definitions on the left and stage groupings on the right. Uterin cervix cancers are often detected in microinvasive stages and are most resectable in stage IA or IB cancers. With further invasion, chemoradiation treatment is effective. There are four main stages, each with two or three substages. Color bars are coded for stage: stage 0 and IA, yellow; IB, 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 cervix is the central structure in the female pelvis. It is retropubic at the level of the coccyx and midway between the ovaries and vulva (Fig. 46.4).
T-oncoanatomy
The T-oncoanatomy is displayed in three planar views in Fig. 46.5:
• Coronal: The cervix comprises the lower third of the uterus. It is roughly cylindrical in shape, projecting through the upper vaginal wall. It communicates with the vagina through an orifice called the “external os.” Cancer of the cervix may originate on the vaginal surface or in the cervical canal.
• Sagittal: There is invasion of the bladder trigone from a cancer in the anterior lip of the cervix and fornix of the vagina. Vaginal extension into its posterior fornix and wall precedes rectal wall invasion.
• Transverse: The mesometrium or the broad ligament of the uterus contains a number of very important structures that determine the course of events in a number of oncologic presentations and complications. The course of the ureter, which is a critical normal structure, passes from its lateral position in the abdomen to its medial location in the pelvis by moving horizontally to insert into the bladder. It is crossed superiorly and medially by the uterine artery. The long transverse course of the ureter makes it particularly vulnerable to entrapment by cancer spread from the cervix because it lies juxtaposed to the cervix before its entry to the bladder. Uncontrolled stage IV cancer blocks both ureters, resulting in hydronephrosis and renal failure, leading to uremic death. Along the sidewall of the pelvis, the obturator nerve and vessel enter into the obturator foramen.
Figure 46.4 | Orientation of oncoanatomy of uterine fundus. The anatomic isocenter is at the midline at the floor of the tru pelvis at the S4/S5 level. A. Coronal. B. Sagittal.
Figure 46.5 | T-oncoanatomy. A. Coronal, B. Sagittal, C. Transverse axial. The color code for the anatomic sites correlates with the color code for the stage group (Fig. 46.3), patterns of spread (Fig. 46.2), and SIMLAP table (Table 46.2). Connecting the dots in similar colors will provide an appreciation for the three-dimensional oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
The cervix is drained by preureteral, postureteral, and uterosacral lymphatics. Cancers confined to the cervix drain fir to obturator nodes, then to hypogastric or internal iliac nodes. These are the first station lymph nodes and are on the lateral wal of the true pelvis, where the internal obturator artery and vein penetrate the levator ani muscle. The lymphatics follow the uterine vein, which drains into the internal and not the external iliac (Fig. 46.6A; Table 46.4A). As the cancer invades more deeply and extensively, the lymph nodes beyond the true pelvis are at risk. When the cancer invades the parametrium and is fixed t the sidewall of the pelvis, lymphatic anastomoses to the external iliac nodes may lead to their involvement. With vaginal invasions up to its lower third, inguinal nodes are at risk. Rectal invasions may lead to the inferior mesenteric nodes being at risk.
The cervical cancer sentinel node is the obturator node, placing the internal iliac chain at risk when the cancer is stage I or II. With more extensive infiltration of the cance, second and third stations or echelons of nodes are at risk.
The distribution and incidence of pelvic lymph node metastases is illustrated for early stage cervical cancer (stage I and IIA) (Fig. 46.7A).
As the stage advances the incidence increases but can be modified and decreases with both radiation and neoadjuvant chemotherapy prior to lymph adenectomy (Fig. 46.7B).
Para-ortic lymph nodes generally increase with stage advancement (Table 46.4B).
M-ONCOANATOMY
The arterial and venous blood supply and drainage are via the uterine vessels, and hematogenous spread is via the internal iliac to the common iliacs and inferior vena cava (Fig. 46.6B). The lung is the target metastatic organ. Skeletal invasion of the lateral cortex of the true pelvis or vertebrae is due to lymphatic and lymph node metastatic cancer penetrating the nodal capsule and directly invading the juxtaposed bone. Once this occurs, the cancer spreads beyond the confines of the lymp nodes, and it often savagely destroys the pelvic bone and/or vertebrae crossing and eradicating intervertebral discs.
The incidence and distribution of distant metastases by anatomic site of first metastases is shown in table 46.4C
Figure 46.6 | A. N-oncoanatomy. The sentinel nodes are the obturator nodes of the internal iliac chain. Para-aortic nodes are juxtaregional. B. M-oncoanatomy.
Figure 46.7 | A. Distribution of pelvic node metastases in 14 patients with stage IB to IIA cervical cancer, tumor size 4 cm, and (B) 38 patients with locally advanced cervical cancer treated with neoadjuvant chemotherapy. (From Benedetti-Panici P, Maneschi F, Scambia G, et al. Lymphatic spread of cervical cancer: an anatomical and pathological study based on 225 radical hysterectomies with systematic pelvic and aortic lymphadenectomy. Gynecol Oncol1996;62:19–24, with permission.)
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging and Imaging
The sine qua non of clinical staging occurs before treatment, preferably performed by a multidisciplinary team consisting of a gynecologic oncologist and a radiation oncologist with the patient under anesthesia. Imaging is advisable but cannot be used to alter staging; however, there is little doubt that newer modalities such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography (US), and positron emission tomography are more accurate than clinical palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, or cystoscopy. Suspected bladder and rectal invasion must be confirmed on biops. Fine-needle aspiration should be used to determine enlarged node status (Table 46.5; Fig. 46.8).
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 no allow for sophisticated imaging, which includes CT, MRI, and 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 introducin combined modalities and innovations into clinical practice.
Oncoimaging Annotations
• CT is most useful for advanced stages greater than stage III and is worthwhile in assessing cervix size. Because cancers are isodense on CT, cervical cancer dimensions are not as accurate but are excellent for staging purposes.
• CT is not reliable for early parametrial invasion but is accurate in determining advanced disease with pelvic sidewall fixation
• CT suggests parametrial, bladder, and rectal invasion when fat planes exist between cervix and structure or they show irregular thickening.
• MRI identifies cancer on T2-weighted images as an intens signal, increasing its accuracy to detect cancer size and lymph nodes involved.
• Gadolinium-enhanced MRI allows for identification of sof tissue invasion in vagina and parametria.
• CT: Early parametrial invasion is not as reliably predicted as advanced parametrial extension to the pelvic wall.
• MRI: More accurate for assessing parametrial invasion and tumor size.
PROGNOSIS AND CANCER SURVIVAL
• MRI can demonstrate intact normal fibrous rim aroun cervix cancer and has high negative predictive value (95%) for parametrial invasion.
• MRI provides a more accurate assessment of cancer infiltration of rectum and bladder.
PROGNOSIS
The limited number of prognostic factors are listed in Table 46.6.
CANCER STATISTICS AND SURVIVAL
Female genital system cancers collectively account for 80,000 new cases a year, with uterine corpus exceeding cervix cancer by a factor of four. Both are highly curable, and deaths are relatively low. The major gynecologic killer is ovarian cancer, with 16,000 deaths annually, which exceeds the other six primary sites combined.
Survival Rates
The survival rate gains in both cervix uteri and fundus uteri cancer 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 >90% curable.
Figure 46.8 | Axial CTs of uterine cervix correlate with the T-oncoanatomy transverse section (Fig. 46.5C). 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. (1) Rectum. (2) Uterine cervix. (3) Iliopsoas muscle. (4) Obturator internus muscle. (5) Acetabular roof. UB, urinary bladder.
The cancer survival rates indicate that the gain in survival for uterine corpus and cervix cancer have been modest (14%) over the last five decades. Howeve, most uterine cervix cancers are detected as cancer in situ, and this is not reflected in the figure Ovarian cancer survival has improved by 22% and, as stated, remains lethal because most cases are detected late owing to its insidious onset and the inaccessibility of ovarian nodules to early diagnosis. Brighter notes are the high cure and 5-year survival rates for stage I patients with cervical cancer (92%), uterine corpus cancer (96%), and ovarian cancer (95%) (Fig. 46.9).
Survival rates for cancer of the cervix have improved from 1950 to 2000 for all stages, rising from 59% to 67%, an increment of 18%. For stage I localized cancers, the cure rate exceeds 90% (Fig. 46.9).
Figure 46.9 | Five-year observed survival for carcinoma of the cervix. (Edge SB, Byrd DR, and Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York: Springer, 2010, p. 398.)