STAGING OF GYNECOLOGIC MALIGNANCIES

GYNECOLOGIC ONCOLOGY

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STAGING OF GYNECOLOGIC MALIGNANCIES F. Odicino, MD, PhD, G. Favalli, MD, L. Zigliani, BA, and Sergio Pecorelli, MD, PhD

The staging of patients with gynecologic malignancies is one of the fundamental aspects of their diagnostic path leading to the most appropriate treatment. Incomplete or inadequate staging often leads to an imprecise understanding of the clinical conditions of the patient and hence to inappropriate or incomplete therapeutic planning. The natural history of the tumor essentially defines the staging system, which is designed in steps (stages) to be usefully adopted by clinicians who are in charge of making the final decision in managing a patient with cancer; however, planning treatment for a given patient depends not only on the staging of the tumor, but also on the patient’s characteristics to determine which treatment modalities will be best suited for that particular patient. By staging a tumor, the clinician makes fundamental basic evaluations that can be drawn from the clinical, surgical, and imaging results obtained. Cancer staging needs to be clinically relevant, user friendly, evidence based, internationally agreed on, precise in the information provided, consistent with the current clinical practice, and provide prognostic information to achieve definition of The local extent of the tumor and the anatomical site of the primary tumor, as well as the extent of possible local invasion of adjacent tissues Extent of regional spread Extent of distant metastases The accuracy of investigation reflects the precision of the staging, thus investing those scientific committees in charge of cancer staging classifications with the responsibility of providing the medical community with the standard practice guidelines to adequately perform staging. Cancer staging should be based on the best available knowledge, which can

From the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Brescia, Brescia (FO, GF, SP); and the International Federation of Gynecology and Obstetrics (FIGO) Annual Report Editorial Office, European Institute of Oncology, Milan (FO, LZ, SP), Italy

SURGICAL CLINICS OF NORTH AMERICA VOLUME 81 * NUMBER 4 AUGUST 2001

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be subject to changes deriving from new knowledge. Knowledge is achieved through the integration of new data and clinical research and needs to be spread by means of a common language and teaching. The Committee on Gynecologic Oncology of the International Federation of Gynecology and Obstetrics (FIGO) is the internationally recognized official advisory body in charge of the definition of the staging criteria of all gynecologic malignancies. Since 1976 the FIGO classifications have been adopted by the American Joint Committee on Cancer, which has adopted the format used in the Annual Report on the Results of Treatment in Gynecologic Cancer (based on statistics provided by several institutions throughout the world on a voluntary basis), published every 3 years. The present membership of the FIGO Committee on Gynecologic Oncology includes:

J. Lou Benedet, Chair, Vancouver, Canada Hans Bender, Diisseldorf, Germany Howard Jones 111, Nashville, TN, United States Hextan Y. S. Ngan, Hong Kong, People’s Republic of China Sergio Pecorelli, Editor of the FIGO Annual Report, Milan, Italy In clinical practice the FIGO nomenclature has replaced the TNM (T = extent of primary tumor; N = nodal metastasis status; M = distant metastasis status) modality of staging gynecologic malignancies. The American Joint Committee on Cancer and the Union Internationale Contre le Cancer, which formerly adopted the TNM system, agreed on working in close cooperation with FIGO to provide the medical community with a specific staging classification of cancer at gynecologic sites. Nevertheless, FIGO and TNM staging of malignant tumors are essentially the same with regard to categories and details (see relevant tables for each tumor site).

STAGING VULVAR CANCER

The vulva is a morphologic and functional unit comprising all female external genital organs, including the labia, clitoris, and vaginal opening. The mean age of patients diagnosed with invasive vulvar cancer is between 60 and 70 years, with preinvasive cancer occurring 10 to 15 years before. Like most cancers, vulvar cancer is best treated if early diagnosed. The diagnostic and staging workup includes the definition of the primary site disease and the potential spread to adjacent and/or distant organs. To diagnose the malignant nature of the disease, it is necessary to obtain a tissue sample from the suspicious area(s) by an excisional or punch biopsy, preferably obtained with magnifying lenses (vulvoscopy). Special attention should be paid to the lymph nodes, particularly to the regional ones in the groin area. A complete physical and gynecologic examination is mandatory to rule out clinical evidence of distant metastasis (chest radiography included) and the potential synchronous presence of a cervical cancer. Cystoscopy and proctoscopy are recommended to rule out urethral, bladder, and rectal involvement. CT scanning and MR imaging, although useful for a thorough general diagnostic workup, are not considered mandatory. In 1969 FIGO adopted a clinical staging system based on TNM findings. This staging was based on the clinical evaluation of the primary tumor and regional lymph nodes and on a limited workup of distant metastases. Micro-

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Table 1. FlGO NOMENCLATURE FOR VULVAR CANCER (1994) Stage

Stage 0 Stage I Stage IA Stage IB Stage I1 Stage I11 Stage IV Stage IVA Stage IVB

Description

Carcinoma in situ, intraepithelial neoplasia grade I11 Lesions 2 cm in size, confined to the vulva or perineum, no nodal metastasis Lesions 2 cm confined to the vulva or perineum and with stromal invasion 1.0 mm,* no nodal metastasis Lesions 2 cm confined to the vulva or perineum and with stromal invasion > 1.0 mm,* no nodal metastasis Tumor confined to the vulva or perineum; > 2 cm in greatest dimension; no nodal metastasis Tumor of any size with adjacent spread to the lower urethra or the vagina, or the anus, or unilateral regional lymph node metastasis Tumor invades any of the following: upper urethra, bladder mucosa, rectal mucosa, pelvic bone, or bilateral regional node metastases Any distant metastasis, including pelvic lymph nodes

*The depth of invasion is defined as the measurement of the tumor from the epithelial-stromal junction of the adjacent most superficial dermal papilla, to the deepest point of invasion.

scopic metastases may be present in clinically nonsuspicious nodes, whereas suspicious lymph nodes may be enlarged because of inflammatory reactions. Compared with surgical staging of vulvar cancer, the percentage of clinical inadequacy in staging ranges from 18% in stage I to 44% in stage IV disease. So far, vulvar cancer has been surgically staged (1988). The final diagnosis is dependent on thorough histopathologic evaluation of the surgical specimen (vulva and lymph nodes). Some modifications were made with a subdivision of stage I in 1994 (Tables 1 and 2). A more precise prognostic definition can be provided through the surgical

Table 2. STAGE GROUPING FOR VULVAR CANCER

UICC FlGO Stage

0 IA IB I1 111

IVA

IVB

T

N

M

Tis Tla Tlb T2 T1 T2 T3 T3 T1 T2 T3 T4 Any T

NO NO NO NO N1 N1 NO N1 N2 N2 N2 AnY N Any N

MO MO MO MO MO MO MO MO MO MO MO MO M1

FIG0 = International Federation of Gynecology and Obstetrics; UICC = International Union Against Cancer.

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staging system: patients with negative lymph nodes have a good prognosis independently of the diameter of the primary tumor, with a survival rate of more than 80% for stage I and I1 disease; survival is influenced by the number of positive lymph nodes. Therefore, stage I11 represents a heterogeneous group of patients varying from those with negative lymph nodes and urethral or vaginal involvement, with an excellent prognosis, to those with multiple inguinal lymph nodes, with a very poor prognosis. Patients should be classified as affected by vulvar cancer when the primary site of growth is in the vulva. If the tumor simultaneously presents in the vulva and vagina, it should considered as a vulvar cancer. Regional lymph nodal stations are the femoral and inguinal nodes. All other stations (external, hypogastric obturator, and common iliac) should be considered distant metastases. There are different histopathologic types in the vulvar cancer. According to the classification of the International Society of Gynecological Pathology (ISGP), squamous cell carcinoma is the most common type. Following is the complete list of all histopathologic types of vulvar cancer. Vulvar intraepithelial neoplasia, grade 111, squamous cell carcinoma in situ Squamous cell carcinoma Verrucous carcinoma Paget’s disease of vulva Adenocarcinoma not otherwise specified Basal cell carcinoma not otherwise specified Bartholin gland cancer As for vulvar melanoma, which accounts for approximately 10% of all malignant tumors of the vulva, the FIGO and TNM staging system has not been shown to adequately correlate with the clinical behavior of the disease and the survival of this group of patients. Therefore, the Breslow’s classification system is accepted worldwide as a reproducible and reliable staging method. As mentioned earlier, the FIGO staging of vulvar cancer is based on the surgical pathologic findings of the primary site tumor and of the lymph nodes. The most important independent prognostic factors related to survival are the lesion size and the presence of metastatic disease to lymph nodes, with the latter being a highly significant predictor of survival. This new classification incorporates these accepted prognostic variables. Compared with the clinical staging system (TNM), the new FIGO surgical classification system has been shown to better correlate with the survival data.3

STAGING VAGINAL CANCER The vagina extends from the vulva upward to the uterine cervix. Primary vaginal cancer is an uncommon disease, accounting for less than 2% of gynecologic malignancies. Most cancers occurring in the vagina are synchronous to cervical or vulvar cancers; such cases should be classified as cervical or vulvar cancers with secondary vaginal involvement. Less commonly, the vagina is involved by extragenital cancers (bladder, urethra, rectum), but these cases cannot be classified as primary vaginal tumors. Therefore, patients should be diagnosed with vaginal cancer when the primary site of the growth is the vagina and there is no evidence of cancer(s) in either adjacent genital or extragenital sites. There must be always histologic confirmation of the malignant neoplastic nature of the disease.

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Table 3. FlGO NOMENCLATURE FOR VAGINAL CANCER (1994) Stage

Stage 0 Stage I Stage I1 Stage I11 Stage IV Stage IVA Stage IVB

Description

Carcinoma in situ; intraepithelial neoplasia grade 111 The carcinoma is limited to the vaginal wall The carcinoma has involved the subvaginal tissue, but has not extended to the pelvic wall The carcinoma has extended to the pelvic wall The carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum; bullous edema as such does not permit a case to be allotted to stage IV Tumor invades bladder and/or rectal mucosa and/or direct extension beyond the true pelvis Spread to distant organs

The FIGO staging of vaginal cancer is clinical. The staging classification is similar to that of the cervix uteri because they both present similar spread patterns. The most common sites of distant spread include the lungs, liver, and bony skeleton. The vagina is drained by lymphatics to the pelvic nodes in its upper two thirds and to the inguinal nodes in the lower third. For this reason, lesions in the upper vagina often are treated with radical surgery or radiation therapy as well as in the carcinoma of the cervix. Similarly, lesions of the lower third of the vagina are often treated like vulvar cancer. Tumor location does not represent an independent prognostic variable, however. The staging of vaginal cancer has been extensively debated on, and several alternative methods have been proposed. Nevertheless, the FIGO clinical staging system is the most widely accepted and adopted (Tables 3 and 4). There are different histopathologic types of vaginal cancer. Squamous cell carcinoma is the most common type, but infrequently an adenocarcinoma may occur. Other extremely rare tumors affecting the vagina are: malignant melanoma, clear cell carcinoma (diethylstilbestrol [DESI-related), endodermal sinus tumor, primary vaginal lymphoma, and the very rare sarcoma botryoides.

Table 4. STAGE GROUPING FOR VAGINAL CANCER

UICC FlGO Stage

0 I I1 I11

IVA IVB

T

N

M

Tis T1 T2 T1 T2 T3 T3 T4 Any T

NO NO NO N1 N1 NO N1 AnY N Any N

MO MO MO MO MO MO MO

FIG0 = International Federation of Gynecologic Oncologists; UICC Against Cancer.

MO M1 =

International Union

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For clinical staging purposes, the FIGO Committee on Gynecologic Oncology recommends the following examination methods: Clinical examination (preferably performed by an experienced physician and eventually with the patient under general anesthesia) Colposcopy (hysteroscopy) cyst0sc0py Proctoscopy Intravenous urography Chest and bone radiography Suspicious bladder or rectal involvement must be histologically confirmed. STAGING CERVICAL CANCER Cancer of the cervix is the second most common malignancy affecting women worldwide (450,000 new cases per year). An important feature of the epidemiology of this cancer is the much higher incidence in developing countries compared with the relatively low number of cases in developed countries (75% of cases occur in developing countries). In 1929 a group of experts, replying to a request of the Radiological Subcommission of the Cancer commission of the League of Nations, provided a set of recommendations and guidelines to classify the disease of patients with cervical cancer into different stages to produce statistical information in a uniform and consistent manner. This was one of the first attempts at having an international staging system for this disease. This classification is still the basis of the modem staging system, identifying stages I and I1 as the local spread of the disease in the cervix and vagina, respectively; stage 111, as the infiltration of the parametria or metastases in the lower vagina or pelvic lymph nodes; and stage IV, as the spread to the bladder or rectum or distant metastases. Eight years after that, the first Annual Report was published and contained statements to promote more uniform grouping of cases. In 1938 the second annual report contained changes in the definitions for the various stages of cervical cancer, and no further changes were made until 1950. Since then, several changes have been made, the most recent being in 1994. Most of these changes regard the stages of preclinical and early invasive cervical cancer. Cervical cancer is the primary gynecologic cancer subject to "clinical" staging as opposed to surgical staging. It is generally agreed that the most experienced clinician involved in the case should stage the lesion, and if there is a doubt as to which stage applies, the earlier stage is mandatory. Among patients referred for surgery, the anatomopathologic evaluation may show that the cancer has spread more than the initial clinical assessment had revealed. Clinicians should take into account this information for treatment decisions, although this information does not change the initial FIGO stage allocation. Cervical cancers are staged worldwide almost exclusively according to the FIGO classification. Recommended staging modalities for clinical examination are: Inspection Palpation Biopsy Hysteroscopy Cystoscopy Rectosigmoidoscopy

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Intravenous urography Chest and skeleton radiography Other imaging or minimally invasive surgical techniques are of undoubted value for therapeutic planning, but because they are more expensive and not generally available, and because the interpretation of their findings is variable, they should not alter the definition of the clinical stage. The inaccuracy of this clinical staging, approaching 40% to 60% in different series, is well recognized. The most common errors in staging cervical cancer include the assessment of parametrial and lymph nodal involvement and vary from 15% to 20% in stage IA, to 40% to 45% in stages I1 and 111, according to the data published in the latest volume of the FIGO annual report. Clinical-Diagnostic Staging

Staging of cervical cancer is based on clinical evaluation; therefore, careful clinical examination should be performed in all cases, preferably by an experienced examiner and with the patient under general anesthesia. Clinical staging must not be changed because of subsequent findings. In cases of doubt as to which stage a particular cancer should be allocated, the earlier stage is mandatory. Suspicious bladder or rectal involvement should be confirmed by biopsy and histologic evidence. Conization or amputation of the cervix is regarded as a clinical examination. In patients treated with surgical procedures, the pathologist’s findings in the removed tissues are the basis for accurate statements on the extent of disease. These findings do not change the clinical staging, however, but they should be recorded for clinical research. The pathologic TNM nomenclature is appropriate for this purpose. Uncommonly, hysterectomy is carried out in the presence of nonsuspicious extensive invasive cervical cancer. Because such cases cannot be clinically staged, they should not be included in therapeutic statistics. Stage 0 comprises those cases with full-thickness involvement of the epithelium with atypical cells, but with no signs of invasion into the stroma. In 1988 as a result of several studies and suggestions deriving from other scientific bodies, FIGO subclassified stage IA into two subcategories, stage IA1 (minimal immeasurable microscopic invasion) and IA2 (depth of invasion 5 5 mm), both not wider in horizontal spread than 7 mm. It was the first time that microscopic dimensions were included in a FIGO staging nomenclature. In 1994 two major changes were inserted in the classification of stage I. Stage IA1 and IA2 were redefined, and stage IB was subclassified into two subcategories. The diagnosis of stages IA1 and IA2 should be based on microscopic examination of the removed tissue, preferably a cone biopsy, which must include the entire lesion. The depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates. The second dimension, the horizontal spread, should be less than 7 mm. Vascular space involvement, either venous or lymphatic, should not alter the staging but should be specifically recorded because it may affect treatment decisions in the future. Larger lesions should be staged as IB. In 1994 this stage was subclassified into two subcategories, with a cutoff of the maximum visible diameter of the 4-cm lesion (Table 5). As a rule, it is impossible to clinically determine whether a cancer of the

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Table 5. FIG0 NOMENCLATURE FOR CERVICAL CANCER (1994) ~

Description

Stage 0 Stage I Stage IA

Stage IA1 Stage IA2 Stage IB Stage IB1 Stage IB2 Stage I1 Stage IIA Stage IIB Stage I11

Stage IIIA Stage IIIB Stage IV Stage IVA Stage IVB

Carcinoma in situ, cervical intraepithelial neoplasia grade I11 The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded) Invasive carcinoma which can be diagnosed only by microscopy. All macroscopically visible lesions-ven with superficial invasion-are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.0 mm and a horizontal extension of not > 7.0 mm. Depth of invasion should not be > 5.0 mm taken from the base of the epithelium of the original tissue-superficial or glandular. The involvement of vascular spaces-venous or lymphatic-should not change the stage allotment. Measured stromal invasion of not > 3.0 mm in depth and extension of not > 7.0 mm Measured stromal invasion of > 3.0 mm and not > 5.0 mm with an extension of not > 7.0 mm Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IA Clinically visible lesions not > 4.0 cm Clinically visible lesions > 4.0 cm Cervical carcinoma invades beyond the uterus but not to the pelvic wall or to the lower third of the vagina No obvious parametrial involvement Obvious parametrial involvement The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydronephrosis or nonfunctioning kidney are included, unless they are known to be due to other causes. Tumor involves lower third of the vagina, with no extension to the pelvic wall Extension to the pelvic wall or hydronephrosis or nonfunctioning kidney The carcinoma has extended beyond the true pelvis, or has involved (biopsy proved) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to stage IV Spread of the growth to adjacent organs Spread to distant organs

cervix has extended to the corpus. Extension to the corpus should therefore be disregarded for staging purposes. Patients with a growth fixed to the pelvic wall by a short and indurated, but not nodular, parametrium should be allotted to stage IIB. It is impossible, at clinical examination, to determine whether a smooth and indurated parametrium is truly cancerous or only inflammatory. Therefore, this disease should be classified as stage I11 only if the parametrium is nodular to the pelvic wall or if the growth extends to the pelvic wall. The presence of hydronephrosis or nonfunctioning kidney resulting from stenosis of the ureter by cancer permits a case to be allotted to stage I11 even if there is no obvious involvement of the parametrium to the pelvic wall. The presence of bullous edema of the bladder should not permit a disease

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to be classified as stage IVA. Finding malignant cells in cytologic washings from the urinary bladder requires further histologic confirmation to be considered for stage IVA. Cases should be classified as cervical cancer if the primary growth is in the cervix (esocervix or endocervix). Squamous cell cancers and adenocarcinomas account for approximately 80% and lo%, respectively. Histologic grading by any of the suggested methods has not shown an independent impact on prognosis yet; therefore, although encouraged, it is not a basis for modifying the stage groupings. When surgery is the primary treatment, histologic findings permit the case to have pathologic staging. In this case, the TNM nomenclature may be used (Table 6). All tumors are to be microscopically verified. The different histopathologic types of tumors that can arise in cervical cancer include: Squamous cell carcinoma (keratinizing, nonkeratinizing, verrucous) Endocervical adenocarcinoma Endometrioid adenocarcinoma Clear cell adenocarcinoma Adenosquamous carcinoma Adenoid cystic carcinoma Small cell carcinoma Adenoma malignum Undifferentiated carcinoma STAGING ENDOMETRIAL CANCER

The upper two-thirds of the uterus superior to the level of the internal cervical 0 s is called the corpus. The fallopian tubes enter at the upper lateral corners of this pear-shaped body. The portion of the muscular organ that is superior to a line joining the tubouterine orifices is often referred to as thefimdus.

Table 6. STAGE GROUPING FOR CERVICAL CANCER UICC FIG0 Stage

0 IA1 IA2 IB1 IB2 IIA IIB IIIA IIIB

IVA IVB

T

N

M

Tis Tlal Tla2 Tlbl Tlb2 T2a T2b T3a T1 T2 T3a T3b T4 Any T

NO NO NO NO NO NO NO NO N1 N1 N1 Any N Any N Any N

MO MO MO MO MO MO MO MO MO MO MO MO MO

FIG0 = International Federation of Gynecologic Oncologists; UICC Against Cancer.

M1 =

International Union

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Cancer of the corpus uteri is the most common genital cancer after menopause in the West and is most commonly diagnosed in women aged 60 to 70 years. As many as 20% of women with endometrial cancer have no symptoms at diagnosis. The most common symptom in patients with invasive disease is an abnormal vaginal bleeding, even if the duration and amount of bleeding does not reflect the extent of the disease. The risk for being affected by endometrial cancer in patients with postmenopausal vaginal bleeding increases with the interval between menopause and the onset of the bleeding. Uncommon symptoms, usually occurring in advanced-stage disease, are represented by purulent or blood-tinged vaginal discharge, pelvic pain or mass, and weight loss. In premenopausal women, the most common symptom is irregular vaginal bleeding, which also can be the symptom of benign conditions or precursors of endometrial cancer. Today there are no recommended screening tests or examinations that can reliably detect most endometrial cancer in asymptomatic women because the numerous efforts in developing screening methods are far from acceptable specificity and sensitivity. Obesity, endocrine disorders ( e g , chronic anovulation, insufficiency of the corpus luteum, endogenous hyperestrogenism, and polycystic ovarian disease), and exogenous factors (e.g., unbalanced hormonal replacement therapy, tamoxifen intake) are clinical conditions for which the same screening techniques showed reliable results. The major efferent lymphatic channels from the uterus run the ovarian ligament to the infundibulopelvic ligament to the para-aortic nodes from the fundus, and the parametrial and presacral channels which drain from the remaining myometrium into the hypogastric, external iliac, common iliac, and presacral. Spread to the vagina occurs in approximately 7% of patients. Peritoneal metastases are found in 10% of patients and are the result of lymphatic or direct spread. Distant metastases are uncommon, with the most common sites being the lungs, liver, and bones. Endometrial cancer has been staged by several systems. The first classification, developed in 1925, classified disease as clinically operable, technically operable, or inoperable. In 1950 FIGO proposed its first classification based on the extent of the disease and operability. Classifications that were subsequently put forward were sometimes surgical-pathologic and sometimes clinical until 1972, when the revised FIGO classification found greater acceptance. Following its meeting in 1988, the FIGO Committee on Gynecologic Oncology recommended that endometrial cancer be surgically staged (Tables 7 and 8). This new classification had to include not only the extent of the tumor but also the histologic differentiation for all stages. Depth of myometrial invasion and lymph nodal involvement, important prognostic factors, were taken into account, together with the pathologic evaluation of cervical involvement. The diagnostic preoperative workup comprises the sampling of endometrial tissue obtained with endometrial biopsy (with or without hysteroscopy) or with dilation and curettage. Other tests to detect spread of endometrial cancer are: Cystoscopy and proctoscopy (to rule out the involvement of the bladder or rectum) CA 125 blood test (elevated levels suggest that endometrial cancer has probably spread beyond the uterus) CT scanning MR imaging Intravenous pyelography

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Table 7. FlGO NOMENCLATURE FOR ENDOMETRIAL CANCER (1988) Stage

Description

Stage IA G1, G2, G3 Stage IB G1, G2, G3 Stage IC G1, G2, G3 Stage IIA G1, G2, G3 Stage IIB G1, G2, G3 Stage IIIA G1, G2, G3 Stage IIIB G1, G2, G3 Stage IIIC G1, G2, G3 Stage IVA G1, G2, G3 Stage IVB G1, G2, G3

Tumor limited to the endometrium Invasion to less than half of the myometrium Invasion equal to or more than half of the myometrium Endocervical glandular involvement only Cervical stromal invasion Tumor invades the serosa of the corpus uteri or adnexae and/ or positive cytological findings Vaginal metastases Metastases to pelvic and/or para-aortic lymph nodes Tumor invasion of bladder and/or bowel mucosa Distant metastases, including intra-abdominal metastasis or inguinal lymph nodes

The gross inaccuracy of clinical staging for endometrial cancer is theoretically overcome by the latest FIGO classification. Stage 0 includes all preinvasive lesions of the malignant endometrium, together with the controversial pathological entity, the carcinoma in situ. In stage I, the presence and depth of myometrial invasion (expressed as greater or less than half) are the main prognostic factors, the importance of which must be combined with the degree of differentiation. Intraoperative assessment of peritoneal cytology, lymph nodal status, and the pelvic and abdominal surfaces is conclusive for diagnostic and staging purposes. Patients should be diagnosed as affected by cancer of the corpus uteri if the primary growth of the tumor is the endometrium. All tumors are to be

Table 8. STAGE GROUPING FOR ENDOMETRIAL CANCER UICC

FlGO Stage

0 IA IB IC IIA IIB IIIA IIIB IIIC

IVA IVB FIGO Cancer.

=

T

N

M

Tis Tla Tlb Tlc T2a T2b T3a T3b T1 T2 T3a T3b T4 Any T

NO NO NO NO NO NO NO NO N1 N1 N1 N1 AnY N AnY N

MO MO MO MO MO MO MO MO MO MO MO MO MO M1

International Federation of Gynecologic Oncology; UICC

=

International Union Against

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microscopically verified. Malignant mesenchymal tumors of the uterus (uterine sarcomas) are staged according to the same rules for classification. The different histopathologic types of tumors that can arise from the endometrium, according to the World Health Organization (WHO)/International Society of Gynecological Pathology (ISGP) classification system, include: Endometrioid carcinoma Adenocarcinoma Adenoacanthoma (adenocarcinoma with squamous metaplasia) Adenosquamous carcinoma (mixed adenocarcinoma and squamous cell carcinoma) Mucinous adenocarcinoma Papillary serous adenocarcinoma Clear cell adenocarcinoma Adenosquamous carcinoma Undifferentiated carcinoma Mixed carcinoma The universal recognition of the importance of grade in the prognosis of endometrial cancer is reflected in the inclusion of the histopathologic grading criteria in the FIGO staging system. Cases of corpus uteri cancer should be grouped with regard to the degree of differentiation of the adenocarcinoma, as follows:

G1: 5% of a nonsquamous or nonmorular solid growth pattern G2: 6% to 50% of a nonsquamous or nonmorular solid growth pattern G3: more than 50% of a nonsquamous or nonmorular solid growth pattern Notes on pathologic grading: Notable nuclear atypia, inappropriate for the architectural grade, raises the grade of a grade 1 or grade 2 tumor by 1. In serous and clear cell adenocarcinomas, nuclear grading takes precedent. Adenocarcinomas with squamous differentiation are graded according to the nuclear grade of the glandular component. Notes related to staging: Corpus cancer is now surgically staged, therefore procedures previously used for determination of stages are no longer applicable (e.g., the findings of fractional curettage to differentiate between stage I and 11). It is appreciated that there may be a small number of patients with corpus cancer who will be treated primarily with radiation therapy. In these cases, the clinical staging adopted by FIGO in 1971 would still apply, but designation of that staging system would be noted. Ideally, width of the myometrium should be measured along with the depth of tumor invasion. STAGING OVARIAN CANCER The ovaries are a pair of solid, oval-shaped organs, 2 to 4 cm in diameter, connected by a peritoneal fold to the broad ligament of the uterus and by the infundibulopelvic ligament (in which ovarian vessels run) to the lateral wall of the pelvis. Several malignancies arise from the ovary and can be subclassified into two

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main groups: epithelial and nonepithelial cancers, depending on their histogenesis. In the West, epithelial ovarian cancers are the female genital tract neoplasia with the lowest incidence and the highest mortality rate (twofold that of cervical cancer and threefold that of endometrial cancer). Between the clearly benign and the unequivocal epithelial malignant, invasive neoplasia of the ovary lies an intermediate group in which some histological characteristics show similarity with the frankly invasive carcinoma, but they are characterized by a clinical behavior closer to that of benign tumors. These tumors have become known as cystadenocarcinomas of low malignant potential (borderline tumors). The highest incidence of invasive ovarian cancer is among patients aged 40 to 70 years, whereas for borderline tumors (10-20% of all malignant tumors), the incidence remains stable among patients aged 15 to 70 years. Today there are no blood tests or imaging studies recommended for ovarian cancer screening of women who do not have an increased risk for disease. Women with a higher risk for ovarian cancer are those with very strong family history. Approximately 5% to 10% of ovarian cancers are familiar, and three distinct hereditary patterns have been identified: (1)ovarian cancer alone, (2) ovarian and breast cancer, and (3) ovarian and colon cancer. These patients may be screened with transabdominal and transvaginal sonography and the CA-125 blood test. There are no tests recommended for screening women for nonepithelial ovarian tumors. Ovarian cancer does not cause specific symptoms; most symptoms that accompany this cancer may be caused by benign diseases of the ovary or cancers of other organs. Swelling of the abdomen, aspecific digestive problems, pelvic or abdominal pain and, rarely, abnormal vaginal bleeding are the most common symptoms reported by patients. Ovarian cancer usually spreads into the peritoneal cavity by local seeding and after the peritoneal fluid circulation implants on all peritoneal surfaces in the lower and upper abdomen, including the omentum, diaphragm, and liver. The lymphatic drainage occurs by the utero-ovarian and round ligament channels and an external iliac accessory route into the following regional nodes: external iliac, common iliac, hypogastric, lateral sacral, para-aortic nodes and, occasionally, inguinal nodes. Rarely, ovarian cancer locally invades the surface of other organs by local invasion (i.e., bowel or bladder). Pulmonary and pleural involvement is common by transdiaphragmatic spread. Staging of ovarian cancer has always been based on the findings of laparotomy. As for other gynecologic cancers, the first classification was based on the resectability of the tumor. According to the best knowledge of the natural history of this disease, in 1988 FIGO defined the new classification distinguishing four stages and numerous substages (Tables 9 and 10). Surgical pathologic staging of ovarian cancer is an integral part of the management of this disease. The FIGO staging criteria are based on surgical findings at the opening of the abdomen before tumor resection. This can be achieved through accurate inspection and palpation of the entire abdominal cavity by a midline incision of the abdomen. If bulky disease is found, cytoreduction is needed to optimize therapy and outcome. If there is no clinically obvious evidence of disease outside of the ovary, the clinical inspection alone results in mis-staging in as many as 30% of cases. In these patients, an accurate and systematic sampling of all possible sites of microscopic seeding should be obtained (biopsy of pelvic and abdominal peritoneum, multiple peritoneal cytology specimens, infracolic omentectomy, appendectomy, and biopsy of the pelvic and paraortic lymph nodes). There should be histologic confirmation of the ovarian origin of the disease, and all the specimens sampled should be evaluated. Operative findings, before

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Table 9. FlGO NOMENCLATURE FOR OVARIAN CANCER (1988) Stage

Description

Stage I Stage IA Stage IB Stage IC* Stage I1 Stage IIA Stage IIB Stage IIC* Stage 111

Stage IIIA

Stage IIIB Stage IIIC Stage IV

Growth limited to the ovaries Growth limited to one ovary; no ascites present containing malignant cells; no tumor on the external surface; capsule intact Growth limited to both ovaries; no ascites present containing malignant cells; no tumor on the external surfaces; capsules intact Tumor either stage IA or IB, but with tumor on surface of one or both ovaries, or with capsule ruptured, or with ascites present containing malignant cells, or with positive peritoneal washings Growth involving one or both ovaries with pelvic extension Extension and/or metastases to the uterus or tubes Extension to other pelvic tissues Tumor either stage IIA or IIB, but with tumor on surface of one or both ovaries; or with capsule(s) ruptured; or with ascites present containing malignant cells or with positive peritoneal washings Tumor involving one or both ovaries with histologically confirmed peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastases equal stage 111. Tumor is limited to the true pelvis, but with histologically proven malignant extension to small bowel or omentum Tumor grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces, or histologically proven extension to small bowel or mesentery Tumor of one or both ovaries with histologically confirmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative Peritoneal metastasis beyond the pelvis > 2 cm in diameter and/or positive retroperitoneal or inguinal nodes Growth involving one or both ovaries with distant metastases; if pleural effusion is present, there must be positive cytology to allot a case to stage IV; parenchymal liver metastasis equals stage IV

‘To evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it would be of value to know whether rupture of the capsule was spontaneous or caused by the

surgeon and whether the source of malignant cells detected was peritoneal washings or ascites.

Table 10. STAGE GROUPING FOR OVARIAN CANCER FlGO Stage

IA IB IC IIA IIB IIC IIIA IIIB IIIC IV FIG0 Cancer.

=

UICC T

N

M

Tla Tlb Tlc T2a T2b T2c T3a T3b T3c hYT Any T

NO NO NO NO NO NO NO NO NO N1 Any N

MO MO MO MO MO MO MO MO MO MO M1

International Federation of Gynecologic Oncology; UICC

=

International Union Against

STAGING OF GYNECOLOGIC MALIGNANCIES

767

tumor debulking, determine stage, which may be modified by histopathologic and clinical or radiologic evaluation. The final histologic findings after surgery (and cytologic ones when available) are to be considered in the staging. Preoperative clinical studies include routine chest radiography (pleural effusions should be aspirated for cytology), gastroscopy, and proctosigmoidoscopy if needed. Imaging studies (i.e., CT scanning and MR imaging) and serum tumor markers may be helpful in initial treatment planning and follow-up of these tumors. The task forces of FIGO recommend that all ovarian epithelial tumors be subclassified according to a simplified version of the WHO classification. The types of tumors classified are as follows: Serous tumors Benign serous cystadenomas Of borderline malignancy: serous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities, but with no infiltrative destructive growth (carcinomas of low potential malignancy) Serous cystadenocarcinomas Mucinous tumors Benign mucinous cystadenomas Of borderline malignancy: mucinous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities, but with no infiltrative destructive growth (carcinomas of low potential malignancy) Mucinous cystadenocarcinomas Endometrioid tumors Benign endometrioid cystadenomas Of borderline malignancy: endometrioid tumors with proliferating activity of the epithelial cells and nuclear abnormalities, but with no infiltrative destructive growth (carcinomas of low potential malignancy) Endometrioid adenocarcinomas Clear cell tumors Benign clear cell tumors Of borderline malignancy: clear cell tumors with proliferating activity of the epithelial cells and nuclear abnormalities, but with no infiltrative destructive growth (low potential malignancy) Clear cell cystadenocarcinomas Brenner Benign Brenner Borderline malignancy Malignant Transitional cell Undifferentiated carcinomas: a malignant tumor of epithelial structure that is too poorly differentiated to be placed in any other group Mixed epithelial tumors: these tumors are composed of two or more of the five major cell types of common epithelial tumors (types should be specified) Cases with intraperitoneal carcinoma in which the ovaries appear to be incidentally involved and not the primary origin should be labeled as extra-ovarian peritoneal carcinoma Studies on the prognostic role of the histologic differentiation in ovarian cancer showed a significant survival advantage in the group of patients with well-differentiated tumors, stage by stage. These data are confirmed in the last FIGO Annual Report (volume 24, 2001) both in initial stages (1-11) and in advanced stages (111-IV), with a significant different prognostic impact when

768

ODICINO et a1

comparing well-differentiated to moderately or poorly differentiated tumors. Although such prognostic factors do not alter the stage, it is highly recommended to record them for their important clinical impact. Following are the histopathologic grades (G): Gx G1 G2 G3

Grade cannot be assessed Well differentiated Moderately differentiated Poorly or undifferentiated

STAGING CANCER OF THE FALLOPIAN TUBES

The fallopian tube extends from the posterior superior surface of the uterine fundus laterally and anteriorly to the ovary. Its length is approximately 10 cm. The lateral end opens to the peritoneal cavity. Primary cancer of the fallopian tube is a very rare cancer, accounting for less than 0.5% of female genital tumors. The peak incidence of the disease is 50 to 70 years of age, with 80% of patients being older than 50 years at diagnosis, as reported in the FIGO Annual Report? No demographic or personal characteristics allow for the identification of individuals at high risk for this malignancy. Onset symptoms are not specific to the cancer of the fallopian tube and comprise vaginal bleeding or discharge, abdominal discomfort, and swelling, similar to those of ovarian cancer. Because of the similarity to ovarian cancer, the diagnostic workup is similar to that adopted for ovarian cancer, and surgical staging is used as in ovarian cancer. The spread patterns of tubal cancer closely resemble those of ovarian cancer, with the main difference being that this tumor is more commonly diagnosed when confined to the pelvis (60% stage 1-11 compared with 25% stage 1-11 in epithelial ovarian cancer). Cancer of the fallopian tube must be surgically staged following the guidelines provided for ovarian cancers. The FIGO surgical classification is similar to that of the ovary, although presenting some peculiarities because of the anatomic differences in the primary site (Table 11). The staging classification of this tumor is based on the findings at the time of the opening of the abdominal cavity (Table 12). Carcinoma in situ of the fallopian tube is a defined entity; therefore, it is included in the staging under stage 0. Primary fallopian tubal cancer originates from the epithelium of the mucosa, and the tumor extension into the submucosa or muscularis and to the serosa must be defined (a concept similar to that of Duke’s classification for colon cancer). These observations are the basis for allotting cases as stage IA, IB, and IC, in addition to laterality and the presence or absence of ascites. As in ovarian cancer, peritoneal washings positive for malignant cells or malignant ascites are included in stage IC. As with ovarian cancer, pleural effusion must have malignant cells to be called stage IV. Laparotomy and resection of tubal masses and hysterectomy form the basis for staging and debulking procedures. Biopsies of all suspicious sites, such as the omentum, mesentery, liver, diaphragm, and pelvic and para-aortic nodes, are required. The final histologic and cytologic findings after surgery are to be considered when staging.

STAGING OF GYNECOLOGIC MALIGNANCIES

769

Table 11. FlGO NOMENCLATURE FOR CANCER OF THE FALLOPIAN TUBE (1991) Description

Stage

Stage 0 Stage I Stage IA Stage IB Stage IC Stage I1 Stage IIA Stage IIB Stage IIC Stage 111

Stage IIIA Stage IIIB

Stage IV

Carcinoma in situ (limited to tubal mucosa) Growth limited to the fallopian tubes Growth is limited to one tube, with extension into the submucosa and/or muscularis, but not penetrating the serosal surface; no ascites Growth is limited to both tubes, with extension into the submucosa and/or muscularis, but not penetrating the serosal surface; no ascites Tumor either Stage IA or IB, but with tumor extension through or onto the tubal serosa, or with ascites present containing malignant cells, or with positive peritoneal washings Growth involving one or both fallopian tubes with pelvic extension Extension or metastasis to the uterus and/or ovaries Extension to other pelvic tissues Tumor either stage IIA or IIB and with ascites present containing malignant cells or with positive peritoneal washings Tumor involves one or both fallopian tubes, with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastasis equals stage 111; tumor appears limited to the true pelvis, but with histologically proven malignant extension to the small bowel or omentum Tumor is grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces Tumor involving one or both tubes, with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; lymph nodes are negative IIIC; abdominal implants > 2 cm in diameter or positive retroperitoneal or inguinal nodes Growth involving one or both fallopian tubes with distant metastases; if pleural effusion is present, there must be positive cytology to be stage IV; parenchymal liver metastases equal stage IV

Table 12. STAGE GROUPING FOR CANCER OF THE FALLOPIAN TUBE

UICC FlGO Stage

IA IB

IC IIA IIB IIC IIIA IIIB IIIC

IV FIG0 Cancer.

=

T

N

M

Tla Tlb Tlc T2a T2b T2c T3a T3b T3c h Y T Any T

NO NO NO NO NO NO NO NO NO N1 Any N

MO MO MO MO MO MO MO MO MO MO M1

International Federation of Gynecologic Oncology; UICC = International Union Against

770

ODICINO et a1

Among histopathologic types, adenocarcinoma is the most common. Sarcomas are rare. Among the subhistotypes, serous and endometrioid adenocarcinoma are those most commonly reported. Following is a list of histopathologic types. Serous adenocarcinoma Mucinous adenocarcinoma Endometrioid adenocarcinoma Clear cell adenocarcinoma Adenoacanthoma Adenosquamous carcinoma Undifferentiated adenocarcinoma

References 1. Benedet JL, Bender H, Jones H, et al: FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. Int J Gynecol Obstet 70209-262, 2000 2. Twenty-third Volume of the FIGO Annual Report on the Results of Treatment in Gynecological Cancer. J Epidemiol Biostat, Vol. 3, No 1, 1998 3. Twenty-fourth Volume of the FIGO Annual Report on the Results of Treatment in Gynecological Cancer. J Epidemiol Biostat, Vol. 6, No 1, 2001 4. Pecorelli S, Benedet JL, Creasman WT, et a1 FIGO Staging of Gynecologic Cancer. 1994-1997 FIGO Committee on Gynecologic Oncology. International Federation of Gynecology and Obstetrics. Int J Gynaecol Obstet 645-10, 1999 5. Pecorelli S, Benedet JL, Creasman WT, et al: FIGO Staging of Gynecologic Cancer. 1994-1997 FIGO Committee on Gynecologic Oncology. International Federation of Gynecology and Obstetrics. Int J Gynaecol Obstet 65243249, 1999

Address reprint requests to Sergio Pecorelli, MD, PhD European Institute of Oncology Via Ripamonti 435 20141 Milano Italy e-mail: sergio.pecorelliQieo.it