PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The uterine cancers and sarcomas are related to the essential components of the uterus—a pear-shaped organ lined by simple columnar epithelium and tubular glands that extend to the myometrium.
PERSPECTIVE AND PATTERNS OF SPREAD
Endometrial cancers are among the most curable gynecologic cancers and may relate to the normal physiologic functions of menstruation and pregnancy with shedding of the lining and the placenta. In addition, pregnancy, with its invasive placenta, is limited to myometrial extensions. With the continual stimulus of hormones, it is not surprising that these are the most common gynecologic cancers in the United States and Western Europe. With approximately 43,470 cases, deaths are limited to 18%, or 2% of all cancer deaths in women. The postmenopausal woman presenting with unexpected menstruation or vaginal bleeding should have early referral. Diagnosis is readily made on histologic examination of the fractional dilation and curettage. Risk factors include obesity, diabetes mellitus, and hypertension. Unopposed estrogen replacement and tamoxifen therapy have been cited as reasons to abandon such treatment for postmenopausal women owing to increased risk of inducing endometrial cancers.
The pattern of spread is reflected in the basic anatomy o the uterine fundus (Table 44.2, Fig. 44.2), anteriorly or posteriorly into its muscle wall. Inferiorly, it invades the cervix and vagina. With further advance, it can enter rectum and/or bladder once the cervix is invaded. The serosa, once penetrated, allows for speed into the peritoneal cavity and bowel. The uterus is a pear-shaped organ lined by simple columnar epithelium and tubular glands that extend to the myometrium. The endometrium consists of two layers—the functionalis, a superficial layer sloughed with menstruation; and the basalis, which is a deep, narrow layer whose glands regenerate the functionalis. The uterine cancers and sarcomas are related to the essential components of the uterus (Fig. 44.1A–C). The dominant malignancy is endometrial carcinoma (90%), mesenchymal tumors (stromal sarcomas and leiomyosarcomas [5%]), and mixed tumors (carcino sarcoma & adenocarcinoma [3%]).
Figure 44.1A–C | Grading of endometrial adenocarcinoma. The grade depends primarily on the architectural pattern, but significant nuclear atypia changes a grade 1 tumor to grade 2, and a grade 2 tumor to grade 3. Nuclear atypia is characterized by round nuclei; variation in shape, size, and staining; hyperchromasia; coarsely clumped chromatin; prominent nucleoli; and frequent and abnormal mitoses. Significant nuclear atypia, if present, increases the tumor grade. Gland percentage: A. Greater than 5%. B. Greater than 50%. C. Less than or equal to 50%. Solid growth percentage: A. Less than or equal to 5% B. Less than or euqal to 50%. C. Greater than 50%.
Figure 44.2 | 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 44.2.
PATHOLOGY
These cancers are predominantly adenocarcinomas; however, they can be serous, endometrioid, or mucinous, similar to the ovarian cancers. This reflects the embryonic mesonephro anlage. The current, seventh edition of the AJCC Cancer Staging Manual expands the histopathologic malignancies to be classified and staged. The most common form remains endometrial carcinoma, which is induced by estrogen excess exposure exogenously or due to diabetes and obesity. Increased risk occurs with granulosa cell carcinoma (Table 44.1, Fig. 44.1A).
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The T staging criteria are similar to those for a hollow organ, with minor modification (Fig. 44.3A). The criteria for corpu uteri have remained the same; however, the clinical examination has been supplanted by surgical pathologic assessment. In the early editions, stage I was confined to the corpus and classified according to its enlargement: stage IA, ≤8 cm, and stage IB, ≤8 cm in greatest length. With the fourth edition, stage I was limited to endometrium (IA); with myometrial invasion, stage IB penetrates less than half the thickness of the myometrium, and IC, more than half the thickness. In earlier editions, stage II was gross clinical involvement of the cervix, but this was changed and now requires specific histopatho logic verification. Stage IIA is surface endocervical involve ment; deeper stomal invasions signify stage IIB. Stage III is extension beyond the uterus, spreading into serosa or adnexa. Stage IIIA is vaginal involvement; IIIB is invasion of other genital sites but remaining in the true pelvis. Stage IV was divided into IVA, which is similar to the cervix with invasion of the rectum and bladder, and stage IVB, metastatic spread to distant organs. These criteria did not change in the sixth edition. Lymph node invasion was relegated to stage III, and more recently advanced and categorized to stage IIIC.
The rules for classification were noted in the fourth edition Uterine enlargement could be due to fibroids and other disorders, such as adenomyosis. These argued for dilation and curettage to establish the diagnosis, with emphasis on fractional curettage beginning with scraping the cervix. In the sixth edition, that fractional curettage requires histopathologic evidence of stromal invasion or hysterectomy with microscopic verification
The importance of surgical-pathologic evaluation applies to regional lymph nodes, as well as to the primary sites.
Adenocarcinomas include three more histopathologies:
• Endometroid Carcinomas arising in endometriosis. Simultaneous cancers of uterine corpus and ovary in association with pelvic endometriosis are classified as separate independent primaries.
• Squamous Cell Cancers mixed with Adenocarcinomas are due and arise in islands of squamous cell metaplasia.
• Carcinosarcomas in which both elements are malignant.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• The definition of TNM and the Stage Grouping for thi chapter have changed from the Sixth Edition and reflec new staging adopted by the International Federation of Gynecology and Obstetrics (FIGO) (2008).
• Three new separate staging schemas for uterine sarcomas adopted by FIGO have been added.
The TNM Staging Matrix allows for identification of stag group once the T and N stages are determined (Table 44.3).
FUNDUS UTERI ADENOCARCINOMA: ENDOMETROID CARCINOMA, MIXED SQUAMOUS CELL AND ADENOCARCINOMA, AND CARCINOSARCOMA
Figure 44.3A | TNM staging diagram for (A) fundus uteri adenocarcinoma, (B) uterine fundus leiomyosarcoma/endometrial stromal sarcoma, and (C) uterine fundus adenosarcoma arranged vertically with T definitions on the left and stage groupings o the right. Uterine fundus cancers are most often detected early and are readily resectable at stage I and II with excellent cure rates. 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; and metastatic disease to viscera and nodes, black.
UTERINE FUNDUS LEIOMYOSARCOMA/ENDOMETRIAL STROMAL SARCOMA
STAGING HISTOPATHOLOGY
Uterine sarcomas constitute less than 1% of gynecologic malignancies and only 1% to 3% of malignant tumors of the uterus. The TNM staging is new and is illustrated in Fig. 44.3B. Size and extensions are the key criteria. To understand the new staging systems proposed, reference to the Uterine Sarcoma Classification of the Gynecologic Oncology Group i helpful, which divides sarcomas into two major groups as the basis for the new staging systems:
• Mesenchymal tumors having an overlapping benign epithelial lining, where the malignant element is the underlying fibrous stroma.
• Mixed epithelial–stromal elements combining adenocarcinoma and stromal sarcoma.
These are discussed later.
Histology is an important prognostic factor in uterine sarcoma, and mitotic activity and grade strongly influence th natural history of the tumor (Fig. 44.1D–F). The histologic classification used most often is that of the Gynecologic Oncology Group. Note that the uterine neoplasm classification of the International Society of Gynecologic Pathologists uses the term carcinoma for all primary uterine neoplasms containing malignant elements of both epithelial and stromal light-microscopic appearance, regardless of whether malignant heterologous elements are present.
• Pure leiomyosarcomas constitute about 20% to 50% of uterine sarcomas. These tumors often occur in premenopausal women and are not associated with prior pelvic irradiation. The leiomyosarcoma frequently is diagnosed after a hysterectomy is performed for a presumed leiomyomatous uterus. Histologically, the smooth muscle cells have increased atypia, pleomorphism, and cellularity. The degree of atypia and mitotic activity are used to differentiate leiomyosarcomas from benign smooth muscle tumors. Leiomyosarcomas that have more than 10 mitoses per 10 high-power fields are classified as malignant
• Mixed mesodermal tumors represent about 30% to 50% of all uterine sarcomas. These tumors are composed of an admixture of a sarcomatous stromal component and malignant epithelium. The epithelial component frequently is adenocarcinoma; however, squamous carcinoma also may be present. The mesenchymal component may be fibrosarcoma rhabdomyosarcoma, or an endometrial stromal sarcoma component. Carcinosarcoma (malignant mixed Müllerian tumor, homologous type) is the most common type.
• Endometrial stromal sarcoma occurs in about 15% to 20% of patients with uterine sarcomas. Histologically, increased numbers of endometrial stromal cells are seen with varying degrees of atypia and pleomorphism. High-grade stromal sarcomas have 10 or more mitotic figures per 10 high power fields, whereas low-grade stromal sarcomas have fewer than 10. Low-grade tumors were formerly termed endolymphatic stromal myosis, which is descriptive of their predilection to extend into lymphatic or vascular channels within the uterus. These low-grade sarcomas have a protracted natural history and may recur many years after the initial diagnosis. High-grade tumors have a poor prognosis.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• The definition of TNM and the Stage Grouping for this are new in the seventh edition and reflect new staging adopted by the International Federation of Gynecology and Obstetrics (FIGO) (2008).
• A separate staging schema adopted by FIGO for uterine sarcoma has been added.
Figure 44.1D–F | D. The uterus has been opened to reveal a large, soft leiomyosarcoma (LS) that has irregular borders (horizontal arrows) and invades the surrounding myometrium. By comparison, a small, firm leiomyoma (vertical arrow) with a hemorrhagic center is sharply demarcated. E. At low magnification, areas of necrosis are sharply demarcated from the viabl tumor. F. The malignant cells are moderately disorganized in arrangement; they are irregular in shape and display numerous mitoses (arrows).
UTERINE FUNDUS LEIOMYOSARCOMA AND ENDOMETRIAL STROMAL SARCOMA
Figure 44.3B | TNM staging diagram for uterine fundus leiomyosarcoma endometrial stromal sarcoma. Uterine fundus cancers are most often detected early and are readily resectable at stage I and II with excellent cure rates. 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; and metastatic disease to viscera and nodes, black.
UTERINE FUNDUS ADENOSARCOMA
STAGING AND PATTERNS OF SPREAD
Carcinosarcomas need to be distinguished from adenosarcomas (Fig. 44.1G). The latter sarcomas have an overlying benign epithelial lining and a malignant fibrous stroma, whereas carcinosarcomas have both carcinoma and sarcomatous elements.
SARCOMAS OF THE UTERUS
Sarcomas constitute less than 1% of gynecologic malignancies and represent about 1% to 3% of all malignant tumors of the uterus. These tumors are derived from pure mesenchymal tissue or mixtures of epithelial and mesenchymal tissue (Table 44.4). The mean patient age at diagnosis is about 60 years; women with endometrial stromal sarcomas and leiomyosarcomas tend to be younger than those with mixed mesodermal tumors. Some studies also have demonstrated the possibility of a racial component.
The etiology of uterine sarcomas is often attributed to previous pelvic irradiation:
• Previous pelvic irradiation, often administered for benign uterine bleeding 5 to 25 years earlier, is one of the few known etiologic factors for uterine sarcomas; about 2.4% to 17% of women with uterine sarcomas have a history of previous pelvic irradiation. Of the different types of uterine sarcomas, mixed mesodermal tumors are most often associated with previous irradiation.
• As with endometrial carcinomas, at least one study has shown an association between uterine sarcomas and endogenous estrogen use and marital status, but it is not known to be associated with nulliparity or obesity.
Figure 44.1G | A benign epithelial lining covers a malignant stroma.
DETECTION AND DIAGNOSIS
• Common presenting symptoms and signs are abnormal uterine bleeding, abdominal pain, tumor prolapse through the cervical ox, or a pelvis mass; the diagnostic evaluation of patients for uterine sarcomas is the same as that for endometrial carcinoma.
• The Pap smear is rarely diagnostic, and an endometrial biopsy or dilation and curettage is performed for diagnosis.
• It is not uncommon for the dilation and curettage to reveal copious amounts of tissue from the endometrial cavity, and this material is often diagnostic. When small amounts of tissue are obtained or only an endometrial biopsy is performed, only 4% of stromal sarcomas and leiomyosarcomas are identified correctl, compared with 91% of mixed mesodermal tumors.
STAGING
Uterine adenosarcomas are a new TNM system. Depth of invasion and extensions are key criteria (Fig. 44.3C). A thorough abdominal exploration, including inspection of peritoneal surfaces and pelvic and para-aortic lymph node sampling, is an important determinant of the exact disease extent. In stage I and II disease, lymph node metastases occur in 15% to 45%; tumor extent at initial diagnosis is the most important predictor of prognosis, and patients with lymph node metastases have a poor outlook.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• The definition of TNM and the Stage Grouping for thi chapter are new in the seventh edition and reflect new staging adopted by the International Federation of Gynecology and Obstetrics (FIGO) (2008).
• A separate staging schema adopted by FIGO for uterine sarcoma has been added.
UTERINE FUNDUS ADENOSARCOMA
Figure 44.3C | TNM staging diagram for uterine fundus adenosarcoma. Uterine fundus cancers are most often detected early and are readily resectable at stage I and II with excellent cure rates. 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; and 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 retrofle ion (Fig. 44.4).
T-oncoanatomy
The T-oncoanatomy is displayed in three planar views in Fig. 44.5:
• 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 th “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 rectouterine or the vesicouterine septum becomes invaded. Note that the juxtaposition of the vaginal wall directly to the bladder and the rectum makes these organs directly accessible (Fig. 44.5).
Figure 44.4 | Orientation of oncoanatomy of uterine fundus. The anatomic isocenter is at the midline and at the S3 to S4 level inside the true pelvis. A. Coronal. B. Sagittal.
Figure 44.5 | 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. 44.3), patterns of spread (Fig. 44.2), and SIMLAP table (Table 44.2). Connecting the dots in similar colors will provide an appreciation for the three-dimensional oncoanatomy.
Note: The foregoing applies only to adenocarcinomas, not sarcomas.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
When the cervix is invaded, extension into bladder and rectum can be due to the major lymphatic trunks—the utero-ovarian, parametrial, and presacral—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. 44.6A, Table 44.5).
REGIONAL LYMPH NODES
For adequate evaluation of the regional lymph nodes, a representative evaluation of bilateral para-aortic and pelvic lymph nodes (including external iliac, internal iliac, and obturator nodes) should be documented in the operative and surgical pathology reports. Parametrial nodes are not commonly detected unless a radical hysterectomy is performed for cases with gross cervical stromal invasion.
For pN, histologic examination of regional lymphadenectomy specimens will ordinarily include six or more lymph nodes. For TNM staging, cases of fewer than six resected nodes should be classified using the TNM pathologic classifcation according to the status of those nodes (e.g., pN0, pN1) as per the general rules of TNM. The number of resected and positive nodes should be recorded (note that FIGO classifie cases with fewer than six nodes resected as pNX).*
M-ONCOANATOMY
The major venous drainage is via uterine veins or ovarian veins into the vena cava (see Fig. 44.6B). Lung is the common metastatic site.
METASTATIC SITES
The lung and vagina are the common metastatic sites. V agina is next-most-common site due to retroflow of an invaded lymphatic and venous drainage of the uterine wall. Intra-abdominal metastases to peritoneal surfaces of the omentum are seen particularly with serous and clear cell tumors.
*Preceding passage from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, pp. 404–405.
Figure 44.6 | A. N-oncoanatomy. The sentinel nodes for confined uterine fundal (stage T1) adenocarcinomas are into the interna iliac and to para-aortic 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.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
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. FIGO mandates surgical staging, cautioning that aggressive 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 (Table 44.6). Both computed tomography and magnetic resonance imaging are useful for defining tumo invasion and extension (Fig. 44.7).
Surgical-pathologic Staging
The completely resected specimen, including the primary site and regional lymph nodes, must be thoroughly analyzed and 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 allo for sophisticated imaging, which includes computed tomography, magnetic resonance imaging, and ultrasonography 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 combine modalities and introducing innovations into clinical practice.
Oncoimaging with computed tomography is commonly applied to staging cancers, often combined with positron emission tomography to determine the true extent of primary cancer and involved lymph nodes.
Figure 44.7 | MRI Sagittal section of female pelvis. 1. Rectus abdominis m. 2. Levator ani (pubococcygeus) m. 3. Sphincter ani externus m. 4. Pubis 5. Vertebral body (L5) 6. Sacrum (S1) 7. Coccyx 8. Urinary bladder 9. Urethra 10. Vagina 11. Posterior fornix of the vagina 12. Fundus uterus 13. Corpus uterus 14. Endometrium 15. Junctional zone 16. Myometrium 17. Internal os cervix 18. Endocervical canal 19. External os cervix 20. Cervical stroma 21. Rectum 22. Anal canal
PROGNOSIS AND CANCER SURVIVAL
Oncoimaging Annotations
• Magnetic resonance imaging (MRI) is preferred for detecting tumors that are hyperintense on T2-weighted and gadolinium-enhanced images and helps to distinguish between lesions versus fluid and necrosis in heterogeneous uterine masses
• MRI after gadolinium is best for determining myometrial invasion.
• MRI best demonstrates cervical stromal invasion on sagittal gadolinium-enhanced views but still needs pathologic confirmation
• MRI is a useful adjunct to clinical staging and is between 84% and 94% accurate overall.
• Computed tomography is useful for guiding needle biopsies.
• Ultrasonography has its advocates for determining the depth of myometrial invasion and is recommended for screening postmenopausal bleeders: An endometrial stripe of ≤7 mm is within normal range, and ≤4 mm virtually excludes carcinoma.
• MRI for staging: Sagittal and axial images assess spread to uterus, bladder, rectum, and pelvic sidewall.
• Positron emission tomography with18 F-fluorodeoxyglucose can detect 1-cm nodules with 80% accuracy for peritoneal metastases.
• Ultrasonography has been used to evaluate depth of myometrial invasion.
• Gadolinium is useful for differentiating tumor infiltrat (enhanced) versus debris (nonenhanced) in enlarged uterus.
PROGNOSIS
The majority of the identified prognostic factors are related t histologic features (Table 44.7).
• In a large study of 310 cases of uterine sarcomas of mixed pathology, survival was found to be best in those patients with either leiomyosarcomas or endometrial stromal sarcomas and worst with carcinosarcomas or mixed mesodermal sarcomas.
• Larson and coworkers studied 143 patients with uterine leiomyosarcomas and demonstrated that the 5-year survival rate was 65% for cases with a low mitotic rate (>10 mitotic figures per 10 high-power fields), compared with 17% for those with a higher mitotic rate. (Fig. 44.1F).
• Major and coworkers evaluated 453 cases of stage I and stage II uterine sarcomas and demonstrated that the recurrence rates were 53% for mixed Müllerian tumors and 71% for leiomyosarcomas.
Other reported factors are similar to those identified wit endometrial carcinomas (i.e., deep myometrial invasion, lymphatic or vascular space invasion, involvement of the isthmus or cervix, and high-grade, serous, and clear cell carcinomatous components).
CANCER STATISTICS AND SURVIVAL
Survival rates have been excellent for uterine fundus, improving over five decades from 78% to 86%, an increase of 14% For stage IA, the 5-year results are outstanding, rising to almost 90% (Fig. 44.8).
Then decrement to 50% survival as stage progresses from stage II to stage III.
Prognostic Factors (Site-Specific Factors) (Recommended for Collection for Carcinomas and Sarcomas)
Figure 44.8 | Five-year observed survival for carcinoma of the uterus fundus. (Data from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 408.)