Precancer diseases of the female sexual organs. Female cancer.
preapeared by Korda I.
Epidemiology. Cervical carcinoma is a common gynecologic malignancy. The average age of diagnosis for invasive cervical cancer is approximately 50. During the last years a tendency to increasing incidence of cervical carcinoma in young women is maked. Women relating to early sexual intercourse with multiple partners have this disease more frequent. Squamous cell carcinoma is practically never encountered in virgins. it is caused by the carcinogen or promoting factor that is sexually transmitted.
For about 500 000 of women which are affected by cancer diseases are found annually in the world. This disease is an important medical and social problem in all the economically developed countries.
The highest morbidity and mortality is in African and Latin American countries, especially among the native population.
Etiology. Sexually-transmitted diseases are infected by herpes simplex viruses of 2-serotype (HSV-2) or by human papillomavirus (HPV-16/18, 29/31, 35), that can stay for a long time in the latent form. They are the causes of cervical cancer. The virus is inherited by sexual way through smegma. Pseudoerosions, leukoplakias, cervical polyps are the precursors for its development most frequently. Dysplasia of the epithelium belongs to precancer states. A carcinomatous process begins on the squamo-columnar junction.
Cervical carcinoma may be intraepithelial (preinvasive), microinvasive (growth of the process into stroma on the depth up to 0,5 cm beneath from basal membrane) and invasive one.
Histologically there have been distinguished:
l squamous cell keratinous carcinoma
l squamous cell nonkeratinous carcinoma
l clear cell adenocarcinoma
l dimorphic adeno-squamous cell carcinoma
Highly-differentiated, moderate-differentiated and low- differentiated (or undifferentiated) cancers have been distinguished according to the potential malignancy.
Forms of tumor growth are: endophytic, exophytic, mixed.
At exophytic form a tumor grows into vagina (fig. 124), resembling a cauliflower and is able to fill into vagina. The endophytic form is characterized by tumor growing into the muscular layer of the cervix. As a result of this cervix enlarges and consolidates. During tumor disintegration a crater ulcer is formed. A mixed pattern of cervical carcinoma growth has signs of both endophytic and exophytic ones. Cervical carcinoma can be spread on the uterine body, parametrium and vagina (fig. 125).
Regional lymphatic nodes are situated around the cervix (obturator lymph nodes, general iliac, sacral, parasacral ones). Hematogenous metastasing of cervical carcinoma occurs rarely. Distant metastases to organs even in agonizing patients occur in less than 25-40 % cases.
Clinic. It depends on the process stage. The duration of preinvasive and microinvasive cancer is without any symptoms (preclinical stage).
Serous or serous-bloody discharge, contact bleeding after sexual intercourse, vaginal examination, speculum examination may be used in the first stage. Pain in the hypogastrium and back, serous-purulent discharge, resembling meat slops with unpleasant smell (caused by lymph and blood effluence during tumor disintegration) on the second and third stage appears. Patients’ general state is suffered. fast tiredness and irritability can appear. The tumor can erode urinary bladder and rectum due to growing inside of them. Constipation and urinary disorders can occur in the result of this.
Diagnosis. The diagnosis is made after the speculum examination. The form of vaginal part of the cervix, its dimensions and anatomic state is determined. In the initial stages of cervical carcinoma one can see changes typical to pseudoerosion. contact bleeding is an important symptom of cancer. If cancer is found only by cytological method, there can be no clinical signs. The bimanual vaginal examination in the initial stages of cancer is not informative. The cervix is dense or chondroid; crater and infiltration are available in patients with the expressed clinical process. Patients with suspicion of cervical carcinoma should be obligatory examined per rectum. These examinations are called as rectovaginal and rectoabdominal. It allows to estimate the state of lateral and back parametria and uterine cervix better.
The cytological examination of the cervical canal and uterine secretion is the method of early diagnosis of the cervical carcinoma. It provides rapid evalution of clinical state of the cervix, to diagnose preclinical forms of cervical cancer. Sampling of the material for cytological research is made before the bimanual examination of the patient. In healthy women the material is taken with a single-use wooden spatula from the vaginal part of the cervix and lateral fornices. Also one can use a brush to take the material from the cervical canal and squamo-columnar junction with a brush. Local sampling of material is performed in patients with suspicion on cervical cancer. Material is carried on the glass and thinly smeared on its surface.
Microscopic evaluation of smears is made by Papanicolau method (Pap smear screening) (see part IV):
l I type — unaltered epithelium
l II-a type — inflammatory process
l II-b type — proliferation, metaplasia, hyperkeratosis, (at suitable clinical picture they are interpreted as polyp, simple leuloplakia, endocervicosis)
l III-a type — mild, moderate dyplasia on the background of benign process and unaltered epithelium
l III-b type — severe dysplasia of squamosus epithelium on the background of benign process and in the region of unaltered epithelium
l IV type — suspicion of malignization intraepithelial cancer
l V type — cancer
l VI type — the smear is uninformative (the material was taken wrongly)
For the patients with III-V types of smears for confirmation of diagnosis simple and broadened colposcopy, and histological research must be held. Patients with III type of smears undergo regular medical monitoring.
This method of diagnosis cervical cancer is sufficiently exact, histological and cytological conclusion coincides in 95% of patients. Cytological diagnosis is not referred to the definitive one, because it does not determine the depth of invasion process.
Colposcopy (simple and broadened) is used for the early diagnosis. But it is necessary to mention, that it is impossible to make a diagnosis of cervical carcinoma only thanks to colposcopic examination, because this method is additional and allows to choose the most altered cervical area for taking biopsy. A definitive diagnosis is made on the histological results of the material, which has been obtained during the biopsy. Biopsy in majority of cases allows also to determine the depth of the invasion.
EXOPHYTIC FORM OF CERVICAL CARCINOMA
ENDOPHYTIC FORM OF CERVICAL CARCINOMA
Treatment is performed by oncogynecologysts according to the process’ invasion. The intraepithelial and microinvasive cancer in young women undergo surgical treatment by cervical conization (fig. 123) or its amputation. In the middle-aged or elderly women with uterine myoma, or ovarian cyst presence it is expedient to perform total hysterectomy with adnexa. The I-b – II stage of cancer are treated by combined (radiation + surgery) or combined-radical method (if contraindications for surgical intervention are present). Surgical intervention foresees the total hysterectomy or Wertheim’s operation (removal of the uterus with its adnexa, the upper third of vagina and cellular tissue with regional lymphatic nodes). Treatment of cervical carcinoma at the III stage is performed by combined-radical method: distant irradiation of the initial focus and parametria followed by intracavitary curie-therapy (fig. 127). Patients with stage IV are treated individually, the therapy is usually symptomatic.
Sometimes the patients with cervical carcinoma require urgent care because of the presenting accident and rather considerable bleeding.
In such case it is necessary to perform speculum examination to inspect cervix for excluding the trauma of vagina and protruding myoma. If bleeding from crater ulcer or tumor which looks like a cauliflower is present, it is necessary to insert into vagina a hemostatic sponge. For its absence one should make a dense tamponade of vagina by gauze tampon, previously moistened by 10% calcium chloride solution, hydrogen peroxide or aminocapronic acid and to hospitalize the patient (transport by ambulance, in accompaniment of health care worker).
Prognosis depends on the process stage, histological structure and clinical form of tumor growth. A 5-year patients’ survival at first stage of cervical carcinoma is observed in 75-85%, at II-a stage — in 55-65%, at III-a stage — in 20-30% of cases.
patients with cervical carcinoma period of treatment need special attendance, full-value balanced feeding. Individual treatment is a basic element of medical rehabilitation. Treatment of radical therapy complications (proctitis, cystitis and others) is especially hard. Instillations and microclysters with herbal infusions, sea-buckthorn oil are used. After the combined treatment the patients are considered to be able to work depending on profession: with mental activity — after 6-7 months, with physical work — after a year. If there are the expressed complications or treatment has proved to be ineffective, patients are transferred on the disablement.
Prevention. Diagnosis and treatment of diseases predisposing to cervical carcinoma, benign and precancer states are the main ones in the prevention of cervical carcinoma. Interm diagnosis and treatment of benign and precancerous cervical lesions are indicated. All women during all their life time should be regularly encouraged to avail themselves of annual health care checkups to include the Pap smear.
Although endometrial neoplasia may appear at any time during reproductive and menopausal age, it is found primarily in women who have experienced cessation of menses at the age of 50-60 years. There are 4-5 cases of this disease for 100000 of population in Ukraine.
Endometrial carcinoma belongs to hormone-sensitive diseases. Continuously increased estrogen production leads to excessive endometrial proliferation with transformation into malignant tumor. Immune status of organism, virus infection, genetic disorders play an important role in the development of this disease. Obesity, diabetes mellitus are classically associated with endometrial carcinoma and, therefore, qualified as risk factors.
There is another type of cancer — autonomous which doesn’t depend on the hormone’s level. All of these disorders are absent in this type.
At first pathogenetical type the disease occurrs on the background of endometrial hyperplasia and is accompanied by ovarian theca tissue hyperplasia. The second type is characterised by ovarian stroma fibrosis and endometrial atrophy.
At first type the tumor is well-differentiated and has some signs which are typical for primary tissue and is hormone-active. Poorly differentiated tumours belong to the second pathogenetical type.
Well-differentiated types of endometrial carcinoma are characterised by slow growing and extending into surrounding tissues. They increase sensitivity to progestins, have low potention to lymphogenic metastases and more favourable prognosis.
Morphologically: adenocarcinoma, adenoacanthoma, clear cell mesonephroid adenocarcinoma, adenosquamous carcinoma, undifferentiated cancer are the subtypes.
According to International classification, adenocarcinoma is classified into well, moderate and poorly differentiated tumors. Advanced grade is associated with the higher risk of deep myometrial invasion and lymph node involvement.
Malignant tumor arises primarily in the area of uterine fundus and fallopian tubes angles, it is very difficult to determine primary tumor location during its growing. In most cases, there is an exophyte type of growing, sometimes they look like polyps. Endophyte type of growing is an exception, thus ulcerative-infiltrative type of endometrial carcinoma is rare.
Depth of the tumor invasion plays an important role for clinical duration of disease. It is absent in 8% of patients. Such tumors should be removed at uterine curettage.
Lymphogenous and hematogenous ways of metastases are common. At the beginning general iliac, external iliac and aortic lymph nodes involvement is common. Inguinal and supraclavicular lymph nodes invasion is present at the late stages. In 10 % of patients hematogenous way of metastases is present (lungs, liver, uterus, brain). Invasion of vagina may occur by lympho-hematogenous way or direct implantation.
MALIGNISATION OF FIBROID
Clinic. Abnormal uterine bleeding is the most important symptom of endometrial cancer. Women in menopause may have abnormal bleeding or watery discharge (lymphorhea) from vagina. Pain is the late symptom of endometrial cancer. At first it is the result of excretions accumulation in the uterine cavity. It is dull in case of peritoneal, adjacent organs or nervous nodes involvement. If the pathological process is extended into adjacent organs following symptoms would be present: revealing of mucus and blood in the feces, coprostasis — in case of rectal tumor; hematuria — in case of urinary bladder involvement; hydronephrosis as a result of uterher’s compression.
There are three types of cancer clinical course.
Slow, rather favourable clinical course. This form is observed in patients with significant hyperestrogenemia and lipids and carbohydrates dysmetabolism impairment. Continuous uterine bleeding as a result of endometrial hyperplasia is the most common symptom. Lymphatic way of metastasing is absent. Histologycally, it is well-differentiated cancer with superficial invasion of the myometrium.
Unfavourable clinical course. Metabolism disorder is absent. The course of the disease is rather short. Endometrial carcinoma involves all layers of myometrium, extends to cervix, parametrium and vagina. It is a poorly differentiated tumor.
Acute, extremely unfavourable clinical course. It is characterised by unfavourable factors combination, such as deep extension of tumor, lymph nodes and peritoneal metastases. “Ovarian” type of metastases would be present. It is characterised by ascitis and omentum metastases.
Diagnosis is made basing on history, clinics, physical and pelvic examination.
Other additional examinations should be performed, including ultrasonography (fig. 160), cytological sampling of the endometrial cavity, hysteroscopy (fig. 161), hysterography (fig. 159 a, b), fractional curettage with the cytological examination.
In history it is very important to pay attention to reproductive period duration, menstrual dysfunction, especially to presence of acyclic uterine bleeding, climacterium and menopausal course peculiarities.
The overall accuracy of cytological sampling research of the endometrial cavity approaches 90 %. Hysterocervicography or hysteroscopy gives a possibility to reveal tumor location, extension of invasion.
Combination of hysterography and gases pelviography is the best method for diagnosis of the depth of endometrial carcinoma invasion — tumor extension into myometrium and out of uterine borders. These methods help to make a special management of patient’s treatment that is accompanied by clinical and morhological signs.
Biopsy curettage of the endometrial cavity after hysterocervicography should be performed. Histological structure peculiarities and level of tumor differentiation should be revealed. Fractional curettage should be performed.
Ultrasound examination of female internal organs is indicated for diagnosis of metastases.
Investigation of adjacent organs, such as cystoscopy, chromocystoscopy, excretory urography, rectoromanoscopy, colonoscopy is recommended. Plain film of breast and X-ray examination of skeleton is indicated in case of distant metastases. Patient’s examination is finished by radioizotope lymphography which can reveal lymph nodes metastases. Combination with hysterocervicography gives a possibility to reveal the level of tumor extension.
Treatment. Surgical, combined treatment, combining of radiation and hormones should be used.
Surgical treatment is the method of choice in the patients with tumor localized near uterine fundus without deep invasion, without lymph nodes involvement, mainly at the first pathogenetical type of tumor. Vertgeum-Gubarev operation is the cornerstone of surgical treatment. total abdominal hysterectomy with bilateral salpingoophorectomy is performed, but it is contraindicated for the patients with concomitant extragenital pathology. Therefore, J.V.Bochman (1964) has offered his modification.
Endometrial cancer classification
Stage (T) Tumor (N) Nodulus (M) Metastases
0 T1S (preinvasive carcinoma) N0 M0
IA T1A (tumor limited to endometrium, N0 M0
the uterine cavity lengh is 8 cm)
IB T1A (tumor limited to endometrium, N0 M0
the uterine cavity length is more than 8 cm)
II T2 (cervical involvement only ) N0 M0
III T1-T3 (tumor invades serosa N1 (Metastases M0
or adnexa or positive peritoneal to pelvic
cytology) or paraaortic
IVA T4 (Tumor invasion of adjacent Any N MO
organs — bladder, bowel mucosa)
IVB Any T (distant metastases including Any N M1
intra-aabdominal and/or inguinal
Difference between these two operations is that the author abstains from the removal of the upper third part of vagina, wide excision of transverse and sacrouterine ligaments, paravaginal fat, that let to avoid separation of ureters. Such variant of operation is possible in case when tumor doesn’t reach the internal cervical ostium and when the ability of its growing into vagina and parametrium is insignificant.
Combined treatment (operation+radiation, operation+hormones, operations+radiation+hormones) should be recommended for the patient with deeply invasive cancer, those with cervical involvement, poorly differentiated tumors with regional lymph node metastases or for the patients with the second pathogenetical type of endometrial carcinoma (without hormonal, carbohydrates and lipids dysmethabolism).
In case of combining radiative therapy intrauterine radiation with a-radiation should be applied. Application of cobalt inside uterine cavity is also recommended (fig. 127).
Hormonotherapy is the method of choice in the patients with contraindications to operative and radiative treatment. Oxyprogesterone acetate should be prescribed for these patients in a dose of 250 mg every day during 4 month, every second day during the next 4 months, then — every week in a dose of 500 mg during lifetime.
The efficiency of this treatment is considerably increased in case of its combination with chemotherapeutic agents, such as Ftoruracil, cyclophospan and adriamycin.
(prognosis). Patient with endometrial tumor that doesn’t invade the myometrium has
95% 5-year survival rate, whereas patient with
a poorly differentiated tumour with deep myometrial invasia may have 5-year survival rate only 20%.
Prevention. Interm treatment of endometrial hyperplasia and menstrual dysfunction.
All not epithelial malignant tumors belong to sarcomas.
Presence of uterine myoma in pre- and postmenopausal women, especially during its fast growing belong to the risk factors of uterine sarcomas.
There are four histological types of uterine sarcomas:
l endometrial stromal sarcoma
l carcinosarcoma (malignant mixed homologous mesodermal tumor)
l mixed heterologous mesodermal tumor
l other types of sarcomas
Clinical findings. Uterine bleeding and pelvic pain are the most common presenting symptoms.
General weakness, weight loss, subfebril temperature for a long period of time are the symptoms of uterine sarcoma presence for a long period of time.
Metastasis. The preferential way of spread is via the bloodstream. other less frequent ways of spread are via the lymph nodes and by contiguity.
Diagnosis. In many cases, the diagnosis is an unexpected finding at the time of hysterectomy done for other indications (fig. 163). Sampling research of the endometrial cavity either by biopsy and curettage can assist in diagnosis less than 50% of cases owing to the fact that many of these tumors are intramural and thus without endometrial extension. Hysterography or hysterocervicography should be performed. Investigation of the adjacent organs should be recommended in all types of uterine sarcomas.
Plain film of breast, liver and X-ray examination of skeleton should be prescribed for diagnostics of distant metastases.
Treatment. The preferred treatment is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Careful intraperitoneal and retroperitoneal revision is performed. Radiation therapy and chemotherapy are indicated for palliation of patients with distant metastases or recurrences. Adriamycin and Karminozine are used.
Last Updated: May 19, 2006
Synonyms and related keywords: uterine cancer, carcinosarcoma, endometrial cancer, endometrial stromal sarcoma, ESS, mixed mьllerian tumors, MMT, uterine leiomyosarcoma, LMS, uterine sarcoma, postmenopausal vaginal bleeding, adenocarcinoma, adenosquamous carcinoma, clear cell carcinoma, uterine papillary serous carcinoma, UPSC, sarcoma, carcinosarcoma, mixed homologous mьllerian tumor, endometrial stromal sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, invasive neoplasm of the uterine corpus, postmenopausal vaginal bleeding, Papanicolaou test, Pap smear
Author: William E Winter III, MD, Director of Gynecology Tumor Board, Assistant Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Brooke Army Medical Center
Coauthor(s): Jim A Gosewehr, MD, Clinical Assistant Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Northwest Medical Specialists
William E Winter III, MD, is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Society for Clinical Oncology, and Society of Gynecologic Oncologists
Editor(s): John J Kavanagh, Jr, MD, Chief, Professor, Department of Internal Medicine, Section of Gynecological and Medical Therapeutics, MD Anderson Cancer Center, University of Texas College of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Antonio V Sison, MD, FACOG, Program Director, Department of Obstetrics and Gynecology, Robert Wood Johnson University Hospital Hamilton; Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Assumption Community Hospital; and Lee P Shulman, MD, Professor of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University; Chief, Division of Reproductive Genetics, Department of Obstetrics and Gynecology, Prentice Women's Hospital, Northwestern Memorial Hospital
Invasive neoplasms of the female pelvic organs account for almost 15% of all cancers in women. In 2005, approximately 80,000 women in the United States were predicted to receive a diagnosis of pelvic gynecologic malignancy.
The most common of these malignancies is uterine cancer, specifically, endometrial cancer. Endometrial cancer is the fourth most common cancer in women, following breast, lung, and colorectal cancer, in that order. However, it is only the eighth most common cause of cancer deaths because it is usually detected in early stages.
Of the 40,880 cases of uterine cancer predicted for 2005, only 7,310 cancer deaths were predicted for the year. Ovarian cancer accounts for the largest number and highest frequency of cancer deaths from pelvic gynecologic malignancies, with 22,220 new cases and 16,210 deaths predicted for 2005.
History of the Procedure: Cancer of the uterine corpus is the most common pelvic gynecologic malignancy in the United States and in most developed countries with access to sufficient health care. Approximately 95% of these malignancies are carcinomas of the endometrium. The most common symptom in up to 90% of women is postmenopausal (PMP) bleeding. Most women recognize the need for prompt evaluation, although only 10-20% of women with PMP vaginal bleeding have a gynecologic malignancy. Because of this prompt evaluation, 70-75% of women are diagnosed with surgical stage I disease.
Currently, no screening tests for cancer of the uterus are recommended for asymptomatic women. No evidence suggests that routine endometrial sampling or transvaginal sonography to evaluate the endometrial stripe in asymptomatic women has a role in early detection of uterine cancer, even in women who take tamoxifen after breast cancer. The early detection, presenting symptoms, and higher survival rate make it unlikely that screening will have a successful impact on earlier detection and increased survival rate.
Sixty percent of endometrial carcinomas are adenocarcinomas. Other histologic subtypes include adenosquamous, clear cell, and papillary serous carcinomas. Sarcomas make up about 4% of uterine corpus malignancies, including carcinosarcomas or mixed homologous mьllerian tumors (48-50%), leiomyosarcomas ([LMS] 38-40%), and endometrial stromal sarcomas ([EES] 8-10%). The remaining sarcomas are made up of heterologous tumors—tumors that contain histologic components foreign to the uterus, such as rhabdomyosarcomas, osteosarcomas, and chondrosarcomas. This article discusses endometrial cancer but briefly addresses uterine sarcomas.
Problem: Uterine cancer is defined as any invasive neoplasm of the uterine corpus.
Frequency: Approximately 40,880 women were predicted to develop this form of malignancy in 2005 in the United States. After doubling in the early 1970s, the incidence of uterine cancer has remained fairly constant. In 2005, 7,310 deaths were predicted.
Endometrial cancer is primarily a disease of postmenopausal women. The average age at diagnosis is approximately 60 years. Women diagnosed with endometrial cancer when they are younger than 40 years make up only 5% of the total cases. These women invariably have specific risk factors such as morbid obesity, chronic anovulation, and hereditary syndromes. Endometrial cancer is more common in white women when compared to black women.
Uterine sarcomas, regardless of the histologic subtype, are more common in black women. LMS tends to occur more often in women aged 30-50 years, as compared to carcinosarcomas and EES, which have much higher incidence in women older than 50 years.
- Risk factors for endometrial cancer
- Obesity (relative risk of 2-11) - Relative risk of 3.0 in women 21-50 lb overweight and 10 in women more than 50 lb overweight
- Nulliparity (relative risk of 2-3)
- Late menopause, ie, occurring in women older than 52 years (relative risk of 2.4)
- Exogenous unopposed estrogen (relative risk of 1.6-12)
- Tamoxifen (relative risk of 1.7-2.5)
- Diabetes (relative risk of 1.3-2.7)
- Hypertension (relative risk of 1.2-2.1)
- High dietary fat consumption
- Radiation therapy (relative risk of 8)
- Miscellaneous risk factors
- Risk factors for uterine LMS include early menarche, late menopause, African American race, and a history of induced abortions.
- Women with a history of pelvic radiation are at greatest risk for carcinosarcomas and, to a lesser extent, LMS.
- Nulliparous women are at greater risk for both types of sarcomas.
- Factors that reduce risk
- Protective effects are noted with combination oral contraceptives. Past or current use of oral contraceptives prevents about 2000 cases of endometrial cancer each year. For these patients, the relative risk for developing endometrial cancer is approximately 0.5.
- Although smoking decreases the risk of endometrial cancer, the increased risk of lung cancer and other major morbidities far outweighs this benefit.
- While unopposed estrogens have an adverse effect in terms of risk, progestins have a well-known protective effect on the endometrium even when administered in combination with estrogen replacement. The other risks of combined hormone replacement therapy (eg, myocardial infarction, stroke, breast cancer) are an entirely separate discussion.
Pathophysiology: Endometrial cancer may originate in a small area (eg, within an endometrial polyp) or in a diffuse multifocal pattern. Early tumor growth is characterized by an exophytic and spreading pattern. As noted in Clinical, this growth is characterized by friability and spontaneous bleeding, even at early stages. Later tumor growth is characterized by myometrial invasion and growth toward the cervix. Four routes of spread occur beyond the uterus:
- Direct/local spread accounts for the majority of local extension beyond the uterus.
- Lymphatic spread accounts for spread to pelvic, para-aortic, and, rarely, inguinal lymph nodes.
- Hematologic spread is responsible for metastases to the lungs, liver, bone, and brain (rare).
- Peritoneal/transtubal spread results in intraperitoneal implants, particularly with uterine papillary serous carcinoma (UPSC), similar to the pattern observed in ovarian cancer.
Adenocarcinoma of the endometrium, the most common histology, is usually preceded by adenomatous hyperplasia with atypia. If left untreated, simple and complex endometrial hyperplasia with atypia progress to adenocarcinoma in 8% and 29% of cases, respectively. Without atypia, simple and complex hyperplasia progress to cancer in only 1% and 3% of cases, respectively.
Endometrial adenocarcinoma is histologically characterized by cribriform glands (or glandular crowding) with little, if any, stromal tissue between the glands. Nuclear atypia, variation in gland size, and increased mitoses are common in adenocarcinoma. Well-differentiated tumors may be confused with complex hyperplasia with atypia histologically. Likewise, poorly differentiated tumors might be confused with sarcomas histologically. The differentiation of endometrial cancers is one of the most important prognostic factors. Grade 1, 2, and 3 tumors make up approximately 45%, 35%, and 20%, respectively, of adenocarcinomas of the endometrium. The 5-year survival rate of clinical stage I cancers is 94%, 88%, and 79% for grade 1, 2, and 3 tumors, respectively. The degree of histologic differentiation of adenocarcinoma of the endometrium as defined by the International Federation of Gynecology and Obstetrics (FIGO) is as follows:
- FIGO grade 1 - Five percent or less of solid/nonglandular areas
- FIGO grade 2 - Six percent to 50% of solid/nonglandular areas
- FIGO grade 3 - More than 50% of solid/nonglandular areas
Less histologic differentiation is associated with higher incidence of deep (ie, greater than one half) myometrial invasion and lymph node metastases. Subsequently, the depth of myometrial invasion and presence of tumor in the lymph nodes is directly related to recurrence rates and 5-year survival rates.
Other histologic variants of endometrial carcinoma exist. Some tumors have more than one histologic variant. An element of malignant squamous differentiation occurs in 5-6% of endometrial cancers. These tumors are adenosquamous carcinomas. When corrected for grade, however, the presence of squamous components has not been demonstrated to cause a significant difference in prognosis compared to pure adenocarcinomas.
UPSC is an aggressive variant of endometrial cancer found in 5% of cases. A higher incidence of deep myometrial invasion, lymphvascular space involvement, lymph node metastases, extrauterine disease, and positive peritoneal cytology and implants is characteristic. Even with surgical stage I cancer, the 5-year survival rate is 60%. UPSC resembles papillary serous carcinoma of the ovary histologically. Although adjuvant chemotherapy is helpful, UPSC does not have the same duration of response to cytotoxic agents (eg, paclitaxel, carboplatin) as its ovarian counterpart. Often, elements of clear cell carcinoma are associated with UPSC.
Clear cell carcinoma is another variant of endometrial carcinoma characterized by its aggressive behavior. It makes up about 3-6% of all endometrial carcinomas. The 5-year survival rate associated with these tumors is 45-60%. Nuclear grade adds no prognostic information in terms of survival.
In regards to uterine sarcomas, specifically LMS, the histopathologic diagnosis can be unclear until the time of definitive surgery. Diagnosis of LMS is believed to depend on the number of mitoses (or mitotic count) and the degree of cellular atypia. The diagnosis of LMS versus leiomyoma and leiomyoma with high mitotic activity or uncertain malignant potential is based on the metastatic potential of the tumor. The mitotic count and cellular atypia correlates to this metastatic potential.
Although controversy continues to exist regarding the diagnosis of LMS, several studies support the theory that if the mitotic count is less than 5 per 10 high-powered fields (HPF), the tumor is a leiomyoma with negligible metastatic potential regardless of the presence of any cellular atypia. Likewise, the tumor has a high metastatic potential and is considered an LMS, regardless of the degree of cellular atypia, if the mitotic count is greater than 10 per 10 HPF. Some believe that mitotic count alone is not a good indicator of metastatic potential.
Carcinosarcomas or homologous mixed mьllerian tumors (MMT) typically have an endometrioid carcinoma, usually a higher grade, and an undifferentiated spindle cell sarcoma. The sarcomatous portion of the tumor may exhibit an ESS pattern, if differentiated. MMTs are termed heterologous only if identifiable extrauterine histology is demonstrated. MMTs are characterized by early extrauterine spread and lymph node metastases. Extrauterine disease and lymph node metastases are directly related to depth of myometrial invasion and the presence of cervical disease. The presence of heterologous elements does not seem to affect prognosis in terms of the initial extent of disease. New evidence points to a substantial expression of c-kit receptors in MMTs.
ESS can be divided into 2 categories: low-grade ESS (LGESS) and high-grade ESS (HGESS). LGESS is characterized by fewer than 5-10 mitoses per 10 HPF and minimal cellular atypia. These tumors can have a recurrence rate of up to 50% but demonstrate indolent growth and late recurrences. HGESS have a greater mitotic count and degree of cellular atypia. Risk of recurrence in both LGESS and HGESS is determined not only by histological characteristics but also by surgical stage and extent of disease. Interestingly, some authors believe that true HGESS does not exist.
Clinical: The most common symptom is PMP bleeding. Only 10-20% of women with PMP vaginal bleeding have a gynecologic malignancy. Endometrial cancer is diagnosed in 12-16% of women with PMP bleeding. The differential diagnosis must include breakthrough bleeding with estrogen replacement therapy, atrophic endometrium, atrophic vaginitis, endometrial/cervical polyps, and submucosal leiomyomas. In developing countries, the most common cause of PMP is cervical cancer. As the patient's age and number of risk factors (see Etiology) increase, the etiology of the PMP bleeding is more likely to be endometrial cancer. Women with premenopausal bleeding due to endometrial cancer are usually older than 40 years. However, the diagnosis of endometrial cancer needs to be considered in younger women with a history of anovulatory bleeding and obesity.
Other presenting symptoms may include purulent genital discharge, pain, weight loss, and a change in bladder or bowel habits. These are symptoms of advanced disease. Fortunately, most cases of endometrial cancer are diagnosed prior to this clinical presentation because of the recognition of PMP bleeding as a possible early symptom of cancer. Less than 5% of the cases of endometrial cancer are diagnosed incidentally when the patient is asymptomatic. The finding of atypical glandular cells on Papanicolaou test (Pap smear) in a woman after menopause is strongly suggestive of uterine malignancy.
Uterine sarcomas can present in a similar fashion to endometrial carcinomas. LMS may present in women early in the sixth decade of life with irregular menses or PMP bleeding. Other symptoms include pain, pelvic pressure, and a rapidly enlarging pelvic mass. Unfortunately, the diagnosis is rarely made prior to definitive surgery. ESS usually presents with PMP bleeding, pelvic pain, and an enlarging mass. Like MMT, ESS typically presents in the seventh decade of life. Irregular and PMP bleeding are the most common symptoms of MMT also. Weight loss, anorexia, and change in bowel or bladder habits are signs of advanced disease all cases of uterine cancer.
The 2 mainstays of primary treatment in endometrial cancer and uterine sarcomas are surgery and radiotherapy. Chemotherapy plays a role in adjuvant therapy for high-grade uterine sarcomas, in addition to recurrent or metastatic endometrial cancer and adjuvant therapy for UPSC. Hormonal therapy also has a role in adjuvant therapy in receptor-positive endometrial cancers. Details regarding all of these therapies are discussed later in this article.
Knowledge of the surgicopathologic, as well as clinical, staging of cancer of the uterine corpus (FIGO 1988) is crucial in developing an appropriate management plan for endometrial cancer and uterine sarcomas. The staging classification is as follows (see Pathophysiology for a discussion of grading classification):
Table 1. Staging of Cancer of the Uterine Corpus
Stage I (grade 1, 2, or 3)*
Limited to the endometrium
Invasion of less than one half of the myometrium
Invasion of one half or more than one half of the myometrium
Stage II (grade 1, 2, or 3)
Endocervical glandular involvement only
Cervical stromal invasion
Stage III (grade 1, 2, or 3)
Invades serosa and/or adnexa and/or positive peritoneal cytology
Metastases to pelvic and/or para-aortic lymph nodes
Stage IV (grade 1, 2, or 3)
Invasion of bladder and/or bowel mucosa
Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes
*Tumor confined to the uterine corpus
Most endometrial cancers are diagnosed as stage I tumors. In fact, most endometrial cancer can be cured with surgery alone, and relatively few patients need adjuvant radiotherapy. In the past, surgery and radiation therapy were both used as primary therapy. Now, survival rates with surgery are known to be 15-20% better than with primary radiation therapy. Thus, primary radiation therapy is reserved only for patients who are poor surgical candidates or for those with unresectable disease.
Like endometrial cancer, primary surgical therapy is the first step in treatment of uterine sarcomas. In fact, these tumors are often found at the time of surgery for benign indications such as uterine leiomyomata and dysfunctional uterine bleeding, or they are found postoperatively. Approximately 1 of every 2000 women older than 40 years who are undergoing a hysterectomy for uterine leiomyomata have LMS on final pathologic diagnosis.
Malignant ovarian neoplasms
Most of the malignant neoplasms that arise in the ovary fall into three categories: primary cancer (neoplasms derived from the ovarian surface epithelium, i.e. epithelial tumors), secondary (neoplasms derived from papillary or pseudomucinous cystadenomas), metastatic (intestinal and breasts’ metastasis).
Ovarian cancer is the fourth most common of all cancers of women having the frequency of 15-20%. The risk increases with age. More often it occurs in women at the age of 45-50. Rarely it is found in women of ealier age. There is considerable worldwide variation in the incidence of the ovarian cancer. There is a higher incidence of ovarian cancer in Sweden 15,1 per 100.00 women, Estonia — 14,2 per 100.00 of population, in Ukraine — 7,3 per 100.000 women.
Etiology. Ovarian tumors belong to hormonal active tumors. Epidemiologic and experimental investigations of ovarian cancer reveal impairment of menstrual function in these tumors.
The certain epidemiologic factors associated with the development of ovarian cancer include low parity, decreased fertility and delayed childbearing. All of these factors lead to hormonal disbalance in the organism.
Recently, demonstration of the genetic inheritance of ovarian cancer has revealed an important information regarding the possible etiology of the disease
The relationship between the benign ovarian neoplasm and its malignant counterpart is clinically important. If the benign counterpart is found in the patient the removal of both ovaries is necessary, because of the possibility of future malignant transformation in the remaining ovary. The decision concerning the removal of one or both ovaries, however, must be individual and is based on the age, type of tumor, and future risks. Some investigators have suggested that a bilateral oophorectomy in the patients over 40 years should be performed. It gives a possibility to decrease the ovarian cancer development. There is a connection between breast cancer and ovarian tumors. The incidence of ovarian cancer in these women is in 10 times higher than in healthy women. There is dependence between endometrial hyperplastic processes and ovarian cancer.
One should remember that unblastomatic unproliferative processes (follicle, luteal cysts) are the results of pituitary and ovarian hormones disbalance. The observation that patients with breast cancer have a two fold increase in the risk of developing of ovarian cancer supports the concept that hormones play an important role in the cause of ovarian cancer.
Malignant ovarian neoplasms are usually categorized according to the origin of the cell and are similar to their deign counterparts:
l malignant epithelial cell tumors, which are the most common type, 46-48%
l malignant germ cell tumors, 10-14%
l malignant stromal cell tumors, 4,7%
There are malignant tumors with inside and outside growing. Mixed tumors are also common.
Epithelial cell ovarian carcinoma may reach both small and large sizes, they are typically multiloculated and often have external excrescencies on otherwise smooth capsular surface. The walls of malignant cysts have different thickness, and, as a rule, have papillary injections on the inner surface (fig. 176). Epithelial tumors haven’t cysts, they are soft. They are small in sizes, with smooth surface and grow in the direction of the adjacent organs.
Sometimes the metastatic cancer can appear in the ovaries. The term Krukenberg tumor (fig. 174) describes the ovarian tumor that is metastatic from other sites such as the gastrointestinal tract (80% from stomach, remainder from colon, breast, and endometrium). Most of these tumors are characterized as infiltrative, mucinous carcinoma of predominantly signet-ring cell type and as bilateral and associated with the widespread metastatic disease.
Ways of spread of ovarian cancer. Ovarian cancer can spread by means of several pathways. The neoplasm can directly invade adjacent organs such as the small intestine, rectosigmoid, colon, peritoneum, omentum, uterus, fallopian tubes, and broad ligament. Spread can occur by means of the peritoneal fluid and malignant cells can be implanted throughout the pelvis and abdominal cavity, including the omentum, posterior cul-de-sac, infundibulopelvic ligaments, paracolic gutters, right diaphragm and capsule of the liver. Ascites can often develop with peritoneal metasteses.
Dissemination may also occur through lymphatics to the uterine tube, uterus, pelvic and paraaortic lymph nodes (fig. 175). Metastases occasionally are detected in distal sites such as the supraclavicular or inguinal lymph nodes.
The least common way of spread is hematogenous dissemination. Hematogenous metastases occur in the liver parenchyma, skin, and lungs.
Clinic. Early diagnosis of ovarian cancer is difficult, because symptoms are often absent or vague until the neoplasm has attained a large size and metastasized. Even large tumors usually produce nonspecific symptoms. Early symptoms include vague sensations of pelvic or abdominal discomfort, urinary frequency, and alterations in gastrointestinal function. When the neoplasm attains a diameter of about 15 cm, it rises into abdominal cavity, which leads to feelings of abdominal fullness or distension and early safety. Abdominal enlargement can also be secondary to ascites. General weakness, weight loss, continuos dull pain in the lower part of abdomen are common. In 15% of patients they experience abnormal vaginal bleeding.
Hemorrhage into the tumor or torsion of the ovary containing neoplasm can produce sudden pain and other symptoms of acute abdomen.
The physical findings in patients with ovarian neoplasms in early stages are similar to benign ovarian cystadenomas. Usually, they are of small sizes, painless, movable, with firm consistency. They are palpated on the back from the uterus. The tumor may be palpated by means of rectal examination. One can feel the mass within the cul-de-sac. The tumor may be fixed because it can fill the available space in the pelvis or because the pedicle is very short (it looks like uterine myoma). The tumor reaches large sizes and rises out of the pelvis. It is palpated in the abdomen. The surface of tumor is nodular. there may be irregularities or even solid portions. it is immobile. There is a high temperature as a result of products’ disintegration absorption in the case of tumor destruction. Anemia, leukocytosis and increased ESR are common symptoms in early stages of tumor. If the tumor reaches large sizes the symptoms of intestinal obstruction may be present. The dyspnoe may be present at ascites. Bilaterality or fixation arouse the suspicion of malignancy.
Diagnosis. Pelvic examination is the main one in diagnostics of ovarian cancer neoplasms. Physical findings in patients are absent if a tumor is of small sizes. Bilateral tumors may be palpated on the sides of the pelvis, sometimes in the back of the uterus. Malignant ovarian tumors are similarly irregular with nodular surface and have the firm consistency. Ultrasonography should determine tumor location, its internal surface. Ultrasonography is especially useful for uncertain physical findings in case of obesity.
Percutaneous fine-needle aspiration is an accurate method of diagnosing of the variety of tumors. It should not be used for the initial diagnosis of the ovarian tumor, because the neoplasm should be treated by surgical excision. There is some risk that a cystic neoplasm may rupture when aspirated.
Laparoscopy with diagnostic purposes should be indicated for the patients for revealing external peculiarities of the tumor, presence of dissemination and metastases. It is contrindicated for the patients that were previously operated, with excessive weight, with large tumors.
Sometimes diagnostic laparotomy is necessary in the evaluation of ovarian cancer. After skin incision a detailed inspection of pelvis and abdominal cavity must be held. smears for cytologic evaluation and biopsy should be performed. The final diagnosis is made after cytologic and hystologic investigation.
Radiographic examination is valuable in the diagnosis of chest and abdominal cavity revealing. X-ray examination of stomach and intestine is obligatory for exception of metastatic ovarian cancer. Fibrogastroscopy and biopsy, pneumopelviography may be useful for diagnosis.
Lymphography is of value in the diagnosis of dysgerminoma when lymphogenic way of spread is the main one. In 30% of patients sacral metastases are present.
Treatment. All histologic types of ovarian carcinoma are threated in the same way. The standard surgical procedure for carcinoma of the ovary is total abdominal hysterectomy and bilateral salpingoophorectomy. A partial or complete omentectomy should be performed, and in the advanced disease, an attempt should be made to resect as much metastatic tumor as possible. The contralateral ovary and fallopian tube are removed unless the conservation of fertility is important. The contralateral ovary is resected because it has been shown to contain an occult metastasis or primary carcinoma in 5% of patients.
It is a radical method of treatment for the patients with ovarian carcinoma in the I-II stages. In the cases of advanced cancer (III-IV stages) the surgeon must determine the appropriate treatment after exploring the patient’s abdomen. Some patients have unrespectable cancer. In this case the surgeon should attempt to establish the diagnosis by excising the involved ovary. if this is not feasible, a biopsy should be obtained from the ovary or metastases. Several studies have revealed that survival of the patients with stage III-IV ovarian cancer is improved. Radiation therapy is uneffective when there are large residual tumor masses, and treatment with many chemotherapeutic regimens is also the most successful when residual tumor volume is minimized. This type of surgery is referred to as cytoreductive surgery.
The patient whose neoplasm has spread beyond the ovary is initially a candidate for chemotherapy even if all tumor has been resected. Chemotherapy is usually advocated for women with all stages of disease. A variety of drugs are active against the ovarian cancer. Such of them as Methotrexate, cyclophosphan, sarcolizine are emerhed as drugs for chemotherapy. Combination chemotherapy may be more effective than single-agent chemotherapy in patients with bulky residual tumor, but it is also more toxic. Combination of such agents as cyclophosphane+phtoruracil; cyclophosphane+methotrexate+phtoruracil; cyclophosphane+adriablastine+cisplatin should be prescribed. Tiotef and cisplatin should be administrated intraperitoneally.
There is no difference between single-agent and combination therapy in the cases of advanced cancer. You should remember that cisplatin has nephrotoxic effects, and adryamicin and phtoruracil have cardiotoxic effects.
Prognosis. The overall survival rate for stage IA is 90-98%; for stage IB — it is less than 68%, for stage II — 50%, for stage III — 10-15%. The overall survival rate for ovarian cancer at 5 years is 28-30%.
Dysgerminoma is the most common malignant germ cell tumor which is arising from undifferenting gonades that are present in the ovarian sinus.
Clinic. The tumor is common in the infantile patients of 30 years of age. Patients generally can observe pelvic or abdominal mass, abdominal enlargement or pain. The duration of symptoms ranges from 1 month to 2 years with a median of 4 months. The metastases are present in lungs.
Diagnosis is difficult and it is based on the results of clinical findings, laparoscopy and histologic investigation results.
Treatment is surgical with the following radiation therapy and chemotherapy.
Ovarian teratoblastoma is a rare malignant tumor which is found in childhood in juvenile period.
Clinic. Pain in the lower part of the abdomen and general weakness are common. In the advanced cases ascites is present. Metastatses arise very quickly.
Diagnosis is based on the histologic results.
Treatment is surgical with the following radiation therapy.
of the fallopian tube
Adenocarcinoma of the fallopian tube is one of the rarest malignancies of the female genital tract. It may developed primarily (from uterine tube) secondary, or metastatically (from lesions arising in the adjacent organs such as uterus and ovaries). primarily the disease affects the older women. the average age is 40-55 years that had chronic tubal inflammation for a long period of time. The process is always unilateral.
Adenocarcinoma of the fallopian tube has pappilary, glandular-papillarty, papillary-solid and solid structure. The process can quickly metastase inside the pelvis. Ascites is a rare associated finding. Distant metastases are relatively more important for tubal carcinoma than for ovarian carcinoma. More than 50% of the recurrences with tubal carcinoma appear outside the peritoneal cavity, although they usually associated with intraperitoneal metastases.
Clinic. Most patients with tubal carcinoma are asymptomatic, and diagnosis is made only after the patient has undergone surgical exploration for a pelvic mass. A few patients have symptoms such as vaginal bleeding or discharge, lower abdominal pain, abdominal distension and pressure. In many cases these symptoms are vague and nonspecific. Postmenopausal bleeding or discharge may be a symptom. The most common finding at examination is a pelvic or abdominal mass.
Diagnosis. Ultrasonography and laparoscopy, cytologic investigation of the uterine aspirate can prove the diagnosis.
Treatment is surgical. total abdominal hysterectomy and bilateral salpingo-ophorectomy with the following radiation and chemotherapy are used.
Malignant Lesions of the Ovaries
Last Updated: October 5, 2005
Synonyms and related keywords: carcinoma of the ovary, ovarian carcinoma, ovary cancer, ovary carcinoma, cancer of the ovary, ovarian cancer, ovarian malignancy, epithelial ovarian cancer, EOC, gynecological cancer, gynecological carcinoma, gynecologic cancer, gynecologic carcinoma, female genital tract malignancy, gynecological tumor, gynecologic tumor, low malignant potential tumor, LMP tumor, malignant germ cell tumor, malignant GCT, dysgerminoma, immature teratoma, teratoma, granulosa cell tumor, sex-cord stromal tumor, sex cord stromal tumor, Sertoli-Leydig cell tumor
Malignant lesions of the ovaries include primary lesions arising from normal structures within the ovary and secondary lesions from cancers arising elsewhere in the body. Primary lesions include epithelial ovarian carcinoma (70% of all ovarian malignancies), germ-cell tumors, sex-cord stromal tumors, and other more rare types. Metastases to the ovaries are relatively frequent, with the most common being from the endometrium, breast, colon, stomach, and cervix. For more information on ovarian cancer, see Ovarian Cancer.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Ovarian Cancer.
Epithelial ovarian cancer
Epithelial ovarian cancer (EOC) is the sixth most common cancer in women and the second most common female genital tract malignancy after endometrial cancer. In the United States, EOC is diagnosed in approximately 22,000 women each year with 16,000 women dying from the disease. The lifetime risk of a woman developing EOC is 1 in 70.
EOC can occur in females as young as 15 years, but the mean age is 56 years. Incidence of ovarian carcinoma is approximately 15 cases per 100,000 women per year for women aged 50-54 years, rising to 35 cases per 100,000 women for women aged 70-74 years in the United States. EOC occurs most commonly in white women in the industrialized countries of northern and western Europe and North America and least commonly in India and Asia.
The risk of EOC is increased in women who have not had children and possibly those with early menarche or late menopause. Two theories attempt to explain this. The incessant ovulation theory suggests that repeated ovarian epithelial trauma caused by follicular rupture and subsequent epithelial repair results in genetic alterations within the surface epithelium. The gonadotropin theory proposes that persistent stimulation of the ovaries by gonadotropins, coupled with local effects of endogenous hormones, increases surface epithelial proliferation and subsequent mitotic activity.
Although treatment with agents that induce ovulation in women with infertility has been suggested to increase the incidence of EOC, this is unproven.
Women with a history of breast cancer have an increased risk of EOC. Lactose consumption and the use of talcum powder on the vulva and perineum may be associated with increased risk. A steady decreased risk is observed with increasing parity and with use of the combined oral contraceptive pill.
Familial and hereditary ovarian cancer
From 5-10% of cases of ovarian cancer occur in an individual with a family history of the disease. Only a small percentage of these patients have an inherited genetic abnormality, and the risk of this occurrence increases with the strength of the family history. Hereditary EOC occurs at a younger age (approximately 10 y younger), but the prognosis may be somewhat better.
Assessment of women for their risk of ovarian cancer necessitates obtaining a careful family history of both male and female relatives, including those relatives without cancer. If possible, obtain verification of the histologic diagnoses. The counsel of a trained geneticist is ideal. Significant problems are involved in the counseling of women and their families with regard to genetic testing and its implications. Carriers of mutations may be detected through laboratory analysis of the genetic structure of white blood cells.
Disorders of the genes associated with breast cancer, BRCA1 and BRCA2, and more rarely, genes within the Lynch II syndrome complex, are associated with ovarian cancer. Mutations in these genes are inherited in an autosomal dominant pattern, with the mutated gene coming from either parent.
Approximately 1 person in 4000 in the general population carries a mutation of BRCA1. Some populations have a much higher rate of BRCA1 and BRCA2 mutations, especially Ashkenazi Jews. In families with 2 first-degree relatives (mother, sister, or daughter) with premenopausal EOC, the likelihood of a female relative having an affected BRCA1 or BRCA2 gene is as high as 40%. The probability is much lower when the disease occurs in relatives postmenopausally. Individuals with a mutation of the BRCA1 gene have a 50-85% lifetime risk of developing breast cancer and a 15-45% risk of developing EOC. Individuals with a mutation of the BRCA2 gene have a 50-85% lifetime risk of developing breast cancer and a 10-20% risk of developing EOC. Families with mutations in BRCA2 are at risk for developing cancer of the prostate, larynx, pancreas, and male breast.
Individuals with Lynch II syndrome (hereditary nonpolyposis colorectal cancer syndrome) have a higher incidence of ovarian, endometrial, breast, and other malignancies, including ureter, kidney, pancreas, small bowel, and stomach. Mutations have been demonstrated in mismatch repair genes MSH2, MLH1, PMS1, and PMS2.
EPITHELIAL OVARIAN CANCER - PREVENTION AND SCREENING
Ovarian cancer does not lend itself to screening because it has a relatively low prevalence within the general population and no proven precursor lesion exists that can be detected and treated to prevent the cancer from occurring.
Currently, the National Cancer Institute (NCI) recommends that women considered to be at high risk should seek advice from their physician and consider having annual ultrasound examination, annual cancer antigen 125 (CA125) testing, and be considered for oophorectomy or participation in a clinical trial. The NCI recommends no screening methodology for women at normal risk for EOC, but these women also should be considered for research protocols seeking improved detection methods.
Cancer antigen 125 and other tumor markers
CA125 is a glycoprotein antigen detected by using mouse monoclonal antibody OC125 raised from an ovarian cancer cell line. CA125 is not specific for EOC and is elevated in other benign and malignant conditions, including menstruation; endometriosis; pelvic inflammation; liver, renal, and lung disease; and cancer of the endometrium, breast, colon, pancreas, lung, stomach, and liver. It also is elevated in 6% of women who do not have EOC. Although CA125 is elevated in 83% of women with EOC, it is elevated in only 50% of those with stage I disease.
CA125 is not useful when used alone as a single one-time test for ovarian cancer screening, but it may have increased value when serial measurements are performed over time and if it is incorporated into a risk of ovarian cancer algorithm. Other markers have been investigated, including lysophosphatidic acid, tumor-associated glycoprotein 72 (TAG 72), OVX1, and macrophage colony-stimulating factor (M-CSF). Still, other markers are undergoing active investigation.
Ultrasonography is a noninvasive technology that can detect abnormalities in ovarian size and morphology. For screening, transvaginal ultrasonography gives better views than the transabdominal approach because the probe can be positioned closer to the ovaries and the examination can be performed with an empty bladder.
Several scoring systems have been developed to differentiate benign from malignant lesions based on ovarian volume and the complexity of the cyst, including thickness of the cyst wall, number of cysts, papillary projections into the cyst, thickness of septa, surface excrescences, and presence of ascitic fluid.
Clinical trials of screening
Currently, studies are trying to improve the accuracy of screening for early-stage ovarian cancer. Most are targeting perimenopausal or postmenopausal women or those with a family history of EOC.
Many studies are using a combination of ultrasound, serum CA125 testing, and other tumor markers. Large prospective trials include the United Kingdom Collaborative Trial of Ovarian Cancer Screening, a European trial of ovarian cancer screening, and the National Institutes of Health Prostatic, Lung, Colorectal and Ovarian (NIH-PLCO) cancer study. The primary outcome measure of the latter study is mortality from ovarian and fallopian tube cancer on 10-year follow-up.
Considerable interest has developed in the characterization of computer-analyzed protein patterns in the blood as a way of improving screening for ovarian cancer. Such methods are currently undergoing intensive research and clinical validation, and they may hold hope for the future.
The risk of developing EOC is significantly reduced by bearing children, using the combined oral contraceptive pill, undergoing tubal ligation, and undergoing bilateral oophorectomy.
Evidence suggests that taking the oral contraceptive pill for at least 5 years reduces the relative risk of developing EOC to 50% of the risk for a woman who has never taken it.
The epithelial lining of the ovaries is embryologically identical with the lining of the peritoneal cavity, and similar cancers can develop from the peritoneum. Thus, while oophorectomy prevents a pure EOC from developing, a small risk still exists for developing carcinoma of the peritoneum, a disease that behaves similarly to EOC.
For patients who are known carriers of BRCA1 or BRCA2 mutations, bilateral oophorectomy may be performed as soon as childbearing is complete, and probably before the patient is aged 35 years. This reduces the chance of developing EOC, but it does not prevent carcinoma of the peritoneum.
For women with BRCA1 and BRCA2 mutations who opt to not undergo early oophorectomy, the task force of the Cancer Genetics Studies Consortium recommends transvaginal ultrasound, timed to avoid the middle of the menstrual cycle, together with serum CA125 levels performed every 6-12 months in women aged 25-35 years. Use of the oral contraceptive pill is associated with lower risk of EOC in these women.
EPITHELIAL OVARIAN CANCER - PRESENTING FEATURES AND DIAGNOSIS
EOC presents with a wide variety of vague and nonspecific symptoms, including bloating, abdominal distension or discomfort, pressure effects on the bladder and rectum, constipation, vaginal bleeding, indigestion and acid reflux, shortness of breath, tiredness, weight loss, and early satiety. The patient may feel an abdominal mass. Presentation with swelling of a leg due to venous thrombosis is not uncommon. Paraneoplastic syndromes due to tumor-mediated factors lead to a variety of presentations.
Presence of advanced ovarian cancer is often suspected on clinical grounds but can be confirmed only pathologically by removal of the ovaries or, when disease is advanced, by sampling tissue or ascitic fluid.
Ultrasonography is the most useful initial investigation in a patient found to have a pelvic mass. This may define the morphology of the pelvic tumor. In addition, it can determine whether large masses are present in other parts of the abdomen, including in the liver. This technique can also be used to evaluate the kidneys for evidence of ureteric obstruction and to detect ascites.
CT scan with oral and intravenous contrast is generally not as good as ultrasonography for helping characterize pelvic masses, but it can detect intra-abdominal disease, including liver metastases, and help evaluate for pelvic sidewall disease. Some have suggested that this modality plays a role in assessing operability of the tumor.
Tumor markers such as CA125 are not good discriminators of benign lesions from malignant lesions in premenopausal women but have better accuracy in postmenopausal women.
Positron emission tomography (PET) scanning does not have an established role in the diagnosis of primary ovarian malignancy. Its use is still being evaluated, but the PET scan plays a useful role in some patients by detecting the pattern and sites of recurrent disease. PET scanning is not very useful for patients with mucinous cancers.
EOC tumors are found as partially cystic lesions with solid components. The surface may be smooth or covered in papillary projections (see Image 1), and the cysts contain fluid ranging from straw-colored to opaque brown or hemorrhagic.
EOC is thought to arise from epithelium covering the ovaries, which is derived from the coelomic epithelium in fetal development. This coelomic epithelium also is involved in formation of the mьllerian ducts, from which the Fallopian tubes, uterus, cervix, and upper vagina develop.
Five main histologic subtypes, which are similar to carcinoma, arise in the epithelial lining of the cervix, uterus, and fallopian tube: (1) serous (from fallopian tube), (2) endometrioid (endometrium), (3) mucinous (cervix), (4) clear cell (mesonephros), and (5) Brenner. Some variation is observed in the patterns of spread and disease distribution within the various histologic subtypes.
EOC most often spreads initially within the peritoneal cavity (see Image 2, Image 3). Metastatic disease often is found on the peritoneal surfaces, particularly on the undersurface of the diaphragms, the paracolic gutters, the bladder, and the cul-de-sac. Other common sites are the surface of the liver, the mesentery and serosa of the large and small bowel, in the omentum, the uterus, and para-aortic and pelvic lymph nodes. Outside the peritoneal cavity, EOC may spread to the pleural cavity, lungs, and groin lymph nodes. Presence of pleural effusion does not necessarily indicate disease in the chest, and malignancy can be diagnosed only cytologically. Mucinous tumors tend to form large dominant masses, while papillary serous tumors have a more diffuse distribution and are more commonly bilateral. Endometrioid and clear-cell variants more commonly exhibit local invasion and retroperitoneal disease.
EOC is staged according to Federation International de Gynecologie et Obstetrique (FIGO) (ie, International Federation of Gynecology and Obstetrics) rules as follows:
- Stage I - Growth limited to the ovaries
- IA - Growth limited to 1 ovary, no ascites present containing malignant cells, no tumor on the external surface, capsule intact
- IB - Growth limited to both ovaries, no ascites present containing malignant cells, no tumor on the external surfaces, capsules intact
- IC* - Tumor either stage IA or IB, but with tumor on surface of 1 or both ovaries with capsule ruptured, with ascites present containing malignant cells, or with positive peritoneal washings
- Stage II - Growth involving 1 or both ovaries with pelvic extension
- IIA - Extension and/or metastases to the uterus and/or tubes
- IIB - Extension to other pelvic tissues
- IIC* - Tumor either stage IIA or IIB, but with tumor on surface of 1 or both ovaries, with capsule(s) ruptured, with ascites present containing malignant ovaries, or with positive peritoneal washings
- Stage III - Tumor involving 1 or both ovaries with histologically confirmed peritoneal implants outside pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastasis equals stage III; tumor limited to true pelvis, but with histologically proven malignant extension to small bowel and omentum
- IIIA - 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 mesentery
- IIIB - Tumor of 1 or both ovaries with histologically confirmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative
- IIIC - Peritoneal metastasis beyond the pelvis larger than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes
- Stage IV - Growth involving 1 or both ovaries with distant metastases; if pleural effusion is present, positive cytology must be apparent to allot a case to stage IV; parenchymal liver metastasis qualifies as stage IV disease
*In order to evaluate the prognostic impact of the different criteria for allotting cases to stage IC or IIC, knowing if rupture of the capsule was spontaneous or caused by the surgeon is of value. Also of value is knowing if the source of malignant cells detected was peritoneal washings or ascites.
Hydatidiform mole is one of the forms of trophoblastic disease (pathology of conceptus) which is characterised by abnormal proliferation of syncytiotrophoblast and replacement of normal placental trophoblastic tissue by hydropic placental villi.
It is displayed by sharp increasing of villuses dimensions and their hydropic degeneration which have been containing light fluid. Hydropic villi are up to 3 cm in diameter and look like a mass of grape-like vesicles (fig. 141).
The ethiology and pathogenesis of trophoblastic disease is unknown. It has been observed that molar pregnancy is developed from unnucleated ovum’s fertilization. It is more common in very young women and in women at the end of their reproductive age.
Molar pregnancy may be divided into complete mole and incomplete (partial) hydatidiform mole. Complete hydatidiform mole is identified macroscopically by edema and swelling of virtually all chorionic villi with a lack of fetus or amniotic membranes. It is developed during the first weeks of pregnancy. Incomplete (partial) hydatidiform mole is often associated with the identifiable fetus or with amniotic membranes. Grossly, placenta has a mixture of normal and hydropic villi that look like mosaic (fig. 142, 143).
The diagnosis of invasive mole (also called chorioidcarcinoma detruens) rests on the demonstration of complete hydatidiform mole. Hydropic villi invade into the myometrium on different distances destroying muscle elements and vessels. It is similar to tumor growing.
Clinic. Hydatidiform mole is characterised by such main symptoms as:
l uterine size/dates discrepancy (uterine enlargement greater than expected for gestational dates)
l tigh-elastic uterine consistancy
l numerous painless spotting with the fragments of edematous trophoblast (absolute sign)
l other signs and symptoms, including visual disturbances, severe nausea, vomiting, marked pregnancy-induced hypertension (preeclampsia), proteinuria
l absence of positive signs of pregnancy (fetus is not found by ultrasound and physical examination, heart tones of the fetus are absent)
l “snowstorm” appearance of hydatidiform mole during the ultrasound examination
l great increasing of hormones in urine (fig. 142)
l presence of large adnexal masses (theca lutein cysts) as the result of high levels of ChGT
Characteristic sign of hydatidiform mole is extremely high level of ChGT that reflects a degree of trophoblast enlargement.
In pregnant women with normal duration of pregnancy the concentration of ChGT in urine provides the positive test on pregnancy only with undiluted urine. In patients with Hydatidiform mole the reaction will be positive in urine diluted 1:50 and even 1:100.
Invasive mole is the potential for extensive bleeding that is dangerous for life (fig. 145). Patients with this pathology have a high incidence of malignant sequel — choriocarcinoma. It is characterised by extremely rapid growth. Common sites are uterus, adjacent pelvic structures, lungs, brain. Chest radiography should be performed in all the patients with hydatidiform mole for diagnosis of probable complications.
Treatment. In most cases of molar pregnancy the definite treatment is removal of intrauterine contents. Uterine curettage is do by dilation of the cervix followed by suction curettage (large danger for perforation), vacuum aspiration, digital removal of mole (in the case if cervical canal passes 1-2 fingers) with the following curettage.
With cases involving 24 weeks’ gestational size, an alternative to suction evacuation is induction of labor by prostaglandin and oxytocin. Hysterectomy should be performed in case of excessive bleeding. All removed tissues should undergo histologic examination.
After reception of histological research results, that confirm the diagnosis, the woman is sent to oncologist’s consultation where they will decide whether chemotherapy (Methotrexatum) is necessary. Such patients demand careful medical supervision during 1,5-2 years because they have a risk of choriocarcinoma development. During the first year the patient is examined monthly with definition of ChGT. During the second year she is examined every three months. At normal pregnancy the level of ChGT is reduced to normal in 20 days, at molar pregnacy — in 4 months. If the reaction on ChGT has appeared positive in later terms, it testifies to preserving of trophoblast activity, then the patient should be re-examined and cured. Pregnancy is contraindicated for 2 years.
Choriocarcinoma (malignant gestational trophoblastic neoplasia) is a malignant transformation of epithelial elements of chorion. It appears mainly after molar pregnancy, but it may be also present after labor or abortions. Most often the disease is found in women aged 28-32. The incidence of choriocarcinoma among all malignant neoplasms of female reproductive system is 2-2,3%.
The ethiology of this disease have been investigated insufficiently. There is a scientific data about excessive immunodeficiency in the patients with choriocarcinoma.
Morphology. In spite of localization choriocarcinoma has characteristic signs: cyanotic or dark red nodules. On recently formed focus section a tissue which has been impregnated with blood is revealed; focuses which have been formed during the long period have grey-brown color in the result of tissual distruction in the center of the focus.
The tumor arises in the place of conceptus’ implantation. These units are small, not bigger than a cherry up to 3-4 cm in diameter, have mild consistency and indistinct borders. On microscopic sample it consists of syncytial elements such as protoplasmic dark-colored globules with numerous nuclei and light-colored epithelial cells. It has no stroma and vessels.
Choriocarcinoma has been called a metastatic disease because during the early stages it forms metastases. Histologically, metastatic sites don’t differ from the primary tumor.
Clinic. Irregular uterine bleeding with different duration after labor or abortion is the main complaint of the patients with choriocarcinoma. Uterine curettage is not effective in this case. it may increase the bleeding in the result of traumatization. Intraabdominal hemorrhage may be present if tumor has grown through all uterine layers. The diagnosis of ectopic pregnancy is made in these cases and choriocarcinoma has been diagnosed during the surgical intervention or after tumor’s histologic research.
Fever, abdominal pain, general weakness, weight loss, serous and later purulent vaginal discharge are common symptoms in these patients. This tumor grows and gives metastases very quickly and leads to severe anemia, but antianemic drugs are not effective in this situation.
The most common metastatic sites of chorioncarcinoma are: lungs — 40%, brain — 17%, liver — 16%, kidneys — 13%, vagina (fig. 146), parametrium, adnexa, uterine cervix, bones (fig. 147). All symptoms depend on metastatic sites. Hemoptysis, chest pain, cough are present in case of lung metastases, loss of consciousness and coma are common at brain metastases, pain in right upper quadrant of abdomen present in case of liver metastases.
The diagnosis is made on the data of clinical, histological, X-ray and laboratory investigation (determination of ChGT and trophoblastic b-globulin). It is very important to take the patient’s history which gives a possibility to reveal the connection of the disease with the previous pregnancy, labor, abortion or molar pregnancy. Bimanual research reveals 8-9 gestational week enlarged uterus, bilateral theca lutein cysts in ovaries. Speculum examination allows to observe vaginal or uterine cervix metastases which look like cyanotic “powder burns”.
The purpose of ChGT level surveillance is an early detection of trophoblastic neoplasia. This level is extremely high in choriocarcinoma and requires dynamical detection. Chest X-ray examination is the obligatory method of investigation of these patients because it allows to reveal metastatic sites in lungs. Cytological examination of uterine discharge is the additional histological method of investigation. It allows to reveal atypical cells in vaginal smears.
Treatment is surgical. Hysterectomy with the following chemotherapy or just chemotherapy is used which allow to cure the disease and to protect the patient’s childbearing capacity. Indication to surgical intervention is bleeding which lead to patient’s anemia, tumor growing through all uterine layers, more than 12- gestational week enlarged uterus, tumor resistance to chemotherapy.
Metotrexate, Rubomocin, Actinomycin-D as chemotherapeutic drugs should be prescribed by oncologist. Menstrual and childbearing function is restored in the majority of the women.
Radial therapy should be indicated for the patients with parametrial metastases.
Criteria of convalescence is negative reaction on serum ChGT and a-globulin, decreasing of uterine size, renewing of menstrual function.
One or three courses of repetitive chemotherapy are indicated for the patients after the first course of treatment.
Women who have been treated successfully for gestational trophoblastic neoplasia should be monitored for 5 years of serum ChGT level surveillance after the therapy.
Prognosis of choriocarcinoma depends on the general state of the organism, therefore immunoactive and antianemic drugs should be prescribed for these patients.
The convalescence comes in 100% of case if the process has been circumscribed to the uterus and in 65% of cases if there are distant metastases.
Prophylactics consists in in-therm diagnostics and treatment of molar pregnancy. ChGT level surveillance and histological research of uterine discharge must be held in case when after abortion the patients have prolonged bleeding which doesn’t stop with the prescribed treatment.
Presence of adhesions inside uterine cavity is called as intrauterine adhesions (fig. 149, 150). They arise after the careful uterine curettage, especially after the repeated ones. Frequently they are the cause of infertility and spontaneous abortions (miscarriage).
Diagnosis is based on the data of gysteroscopy, gysterography and sounding of uterine cavity (fig. 151).
Treatment is surgical. endoscopic intervention consists of cutting of adhesions.
Precancerous uterine diseases
(uterine carcinoma precursors)
According to international classification (1982), such processes as glandular endometrial hyperplasia, cystic glandular endometrial hyperplasia, endometrial polyps belong to benign endometrial diseases.
Glandular endometrial hyperplasia with cellular proliferation, adenomatous hyperplasia and adenomatous polyps are precancerous uterine diseases.
Cystic glandular hyperplasia, which is found in postmenopausal women or in reproductive period belongs to precancerous uterine lesions (fig. 152).
Glandular endometrial hyperplasia and cystic glandular endometrial hyperplasia are different stages of the same process. Difference between them is presence or absence of cysts in endometrial hyperplasia. Atypical cellular signs at these diseases are not present. The common endometrial polyp is made up of endometrial tissue.
Atypical adenomatous hyperplasia is characterized by structural rearrangement and more intensive proliferation of glandular elements comparing with other types of hyperplasia (fig. 153). Glandular cylindrical epithelium is multinucleated. It forms projections inside the glands, nuclei are enlarged. There is plenty of pathological mitosis amount. At the expressed form of adenomatosis glands are closely connected with each other, there is no stroma between them. There is polymorphism in multilayer glandular epithelium. Some forms of this pathology belong to uterine carcinoma potentialities.
Ethiology. The main causes of endometrial hyperplastic processes are different hormonal disorders at hypothalamic-pituitary-ovarian levels. The correlation between estrogen production and endometrial growth is direct. Endometrial proliferation represents a normal part of the menstrual cycle and occurs during the follicular or estrogen — dominant phase of the cycle with the continued estrogen stimulation through either endogenous mechanisms (hyperglycemia, obesity, conversion of androstenedione) or by exogenous administration (medications). Simple endometrial proliferation will become endometrial hyperplasia.
Factors affecting the risk of endometrial hyperplasia are diabetes mellitus, late menopause, women who have never childbeared.
Clinic. The precancerous processes manifest with acyclic uterine bleeding which can be either appreciable or insignificant, but they are continuous. More often these bleedings arise after some weeks or months delay of menses. Cyclic bleedings which appear during menses and last for a long period of time may be also present. Reproductive age women complain of infertility as a result of anovulation.
Diagnosis. Bimanual examination doesn’t find out abnormalities. Sometimes, insignificant enlargement of uterus may be revealed at the examination.
Ultrasound examination of uterine cavity determines the endometrial depth. At glandular-cystic hyperplasia echogenic inclusions are up to 1cm in size, in adenomatosis — up to 2-3 cm. Endometrial heterogenity, presence of small amount of inclusions are the characteristic signs for endometrial processes. Endometrial polyp is characterised by legible contours and distinct borders between the formation in uterine cavity and its walls. Hysteroscopy, hysterography can also be used for diagnosis that gives a possibility to research uterine cavity, determine the location of pathological process (fig. 154, 155).
Hysteroscopic characteristics depend on the type of hyperplasia, patient’s age, phase of reproductive cycle. in case of diffuse hyperplasia endometrium is pink or red-coloured with the large amount of folds and crests on its surface. Polypoid hyperplasia looks like a local gross of mucous membrane, its vascular network is more expressed. Adenomatous hyperplasia has a sign of “melting snow”. endometrium is rough and of a dirty red colour. During the contact endometrium can easily bleed.
One of the diagnosis methods is the cytological research of the smears from uterine cavity.
The diagnosis of endometrial hyperplasia can be made by taking a sample of the endometrium for histological evaluation during uterine and cervical curettage. Cystic glandular endometrial hyperplasia is characterised by the increased number of glands, some of which look like cysts.
It is necessary to start the treatment from the uterine curettage. Indication to hormonal therapy is histological confirmation of uterine hyperplasia. Progestins are the medications of choice because of hyperestrogenemia. Oxyprogesterone acetate should be taken on the 12-14 days of reproductive cycle once per month during 5-6 cycles at reproductive age. In case of polyposis it should be taken twice per month at 12 and 19 days of reproductive cycle. In menopausal women it should be prescribed once or twice per week during 5-6 months, then the dose is gradually reduced. Androgens may be prescribed these menopausal patients. Surgical intervention should be performed in case of no efficiency from hormonal therapy, its contraindications.
All the patients with endometrial hyperplasia should be monitored during 5 years. In-therm treatment of precancerous endometrial lesions is the main factor in cancer’s prevention.
What is a molar pregnancy?
In a molar pregnancy, the early placenta develops into a mass of cysts (called a hydatidiform mole) that resemble a bunch of white grapes. The embryo either does not form at all or is malformed and cannot survive. About one in 1,000 pregnancies is molar. Women who are over age 40 or who have had two or more miscarriages are at increased risk of molar pregnancy.
There actually are two types of molar pregnancy, complete and partial. With a complete mole, there is no embryo and no normal placental tissue. With a partial mole, there may be some normal placenta and the embryo, which is abnormal, begins to develop.Both types of molar pregnancy arise from an abnormal fertilized egg. In a complete mole, all of the fertilized egg’s chromosomes (tiny thread-like structures in cells that carry our genes) come from the father. Normally, half come from the father, and half from the mother. Shortly after fertilization, the chromosomes from the mother’s egg are lost or inactivated, and those from the father are duplicated. In most cases of partial mole, the mother’s 23 chromosomes remain, but there are two sets of chromosomes from the father (so the embryo has 69 chromosomes instead of the normal 46). One way this happens is fertilization of an egg by two sperm cells.
Molar pregnancy poses a threat to the pregnant woman when the mole penetrates deep into the uterine wall, which can result in heavy bleeding. Occasionally, a mole can turn into a choriocarcinoma, a rare pregnancy-related form of cancer.
What are the symptoms of a molar pregnancy?
A molar pregnancy may start off like a normal pregnancy. Then, around the 10th week of pregnancy, vaginal bleeding, which often is dark brown in color, usually occurs. Other common symptoms include: severe nausea and vomiting, abdominal cramps (from a uterus that is too large due to the increasing number of cysts), and high blood pressure.
How is a molar pregnancy diagnosed?
An ultrasound examination can diagnose a molar pregnancy. The doctor also will measure the levels of hCG, which often are higher than normal with a complete mole, and lower than normal with a partial mole.
How is a molar pregnancy treated?
A molar pregnancy is a very frightening experience. Not only does the woman lose a pregnancy, she learns that she has a slight risk of developing cancer. In order to protect the woman, all molar tissue must be removed from the uterus. This usually is done using a procedure called suction curettage, under general anesthesia. Occasionally, when the mole is extensive and the woman has decided against future pregnancies, a hysterectomy may be done.
After the procedure, the doctor will again measure the level of hCG. If it has dropped to zero, the woman generally needs no additional treatment. However, the doctor will continue to monitor hCG levels for one year to be sure there is no remaining molar tissue. A woman who has had a molar pregnancy should not become pregnant for one year, because a pregnancy would make it difficult to monitor hCG levels.
How often do moles become cancerous?
After the uterus is emptied, about 20 percent of complete moles and 2 percent of partial moles persist and the remaining abnormal tissue may continue to grow. This is called persistent gestational trophoblastic disease (GTD). Treatment with one or more cancer drugs cures GTD nearly 100 percent of the time. Rarely, a cancerous form of GTD called choriocarcinoma develops that spreads to other organs. Treatment with multiple cancer drugs also is very successful at treating this cancer.
What is the outlook for future pregnancies after a molar pregnancy?
If a woman has a molar pregnancy, her outlook for a future pregnancy is good. The risk that a mole will develop in a future pregnancy is only one to two percent.
Both ectopic and molar pregnancies are medical emergencies. As she undergoes diagnosis and treatment, the pregnant woman may be concerned mainly about her own health. Afterwards, the woman and her partner feel relief that she has come through the ordeal. Then grief over the loss of the pregnancy may hit them. As with any couple who has lost a pregnancy, they need time to grieve and to recover emotionally. This is a difficult time, and it may be helpful for the couple to speak with a counselor who is experienced in dealing with pregnancy loss.
TREATMENT OF THE ONCOLOGICAL PATIENTS
Surgery and radiation therapy are the two primary therapeutic modalities most commonly used to treat invasive cervical carcinoma. In general, primary surgical management is limited to patients with stage I and IIA disease, while radiation therapy can be applied to patients with all stages of disease. For patients with early-stage disease, multiple factors should be considered in selecting the most appropriate treatment program. Age is not a contraindication to surgical management, provided the patient does not have significant medical comorbidity. Young patients desiring ovarian preservation and sexually active patients are preferentially managed surgically. Other reasons for the selection of radical surgery over radiation include concomitant inflammatory bowel disease, previous radiation for other disease, and the presence of a coexistent adnexal neoplasm.
Surgery provides the opportunity to perform a thorough pelvic and abdominal exploration, which can identify patients with a disparity between the clinical and surgicopathologic stages. Such patients can then be offered an individualized treatment plan based on their precise disease status. The primary surgical management of cervical cancer generally consists of hysterectomy. For patients with stage IA1 lesions who desire fertility preservation, cervical conization with clear surgical margins is acceptable treatment. The safety and efficacy of surgery to preserve fertility (e.g., radical trachelectomy) for patients with larger stage I lesions however has yet to be fully evaluated. There are five distinct variations or types of hysterectomy used in the treatment of cervical cancer.
Types of Hysterectomy
Type I A type I hysterectomy refers to the standard extrafascial total abdominal hysterectomy. This procedure ensures complete removal of the cervix with minimal disruption to surrounding structures and is appropriate treatment for stage IA1 disease.
Type II A type II hysterectomy is also referred to as a modified radical hysterectomy ( Fig. 52.5, Fig. 52.6 and Fig. 52.7). This procedure involves dissection of the ureters from the parametrial and paracervical tissues down to the ureterovesical junction. This permits removal of all parametrial tissue medial to the ureters, as well as the medial half of the uterosacral ligament and proximal 1 to 2 cm of vagina. This operation is usually performed in conjunction with pelvic lymphadenectomy.
Type III In a type III or radical abdominal hysterectomy, the ureters are completely dissected from within the paracervical tunnel, and the bladder and rectum are extensively mobilized ( Fig. 52.5, Fig. 52.6 and Fig. 52.7). Establishing the paravesical and pararectal spaces facilitates removal of all the parametrial tissue out to the pelvic sidewall, complete resection of the uterosacral ligaments, and excision of the upper one-third to one-half of the vagina. Bilateral pelvic lymphadenectomy is performed with this procedure, removing all lymph-bearing tissue between the mid-common iliac vessels distally to the circumflex iliac vessels and from within the obturator fossa ventral to the obturator nerve.
Type IV/Type V A type IV or extended radical hysterectomy includes removal of the superior vesical artery, periureteral tissue, and up to three fourths of the vagina. In a type V or partial exenteration operation, the distal ureters and a portion of the bladder are resected. Type IV and type V procedures are rarely performed today because most patients with disease extensive enough to require these operations can be more adequately treated with primary radiation therapy.
Complications of Radical Abdominal Hysterectomy Modern surgical techniques and anesthesia have reduced the operative mortality associated with radical hysterectomy to 0.6%. Potentially fatal pulmonary embolism occurs in 1% to 2% of patients. Urinary and bowel fistula formation and incisional complications related to surgical treatment tend to occur early in the postoperative period and are usually amenable to surgical repair. Ureterovaginal and vesicovaginal fistulae occur in 2% and 0.9% of patients, respectively. The most commonly observed complication after radical hysterectomy is urinary dysfunction resulting from partial denervation of the detrusor muscle during excision of the paracervical and paravaginal tissue. Radical hysterectomy results in vaginal shortening; however, with sexual activity gradual lengthening will occur. Pelvic lymphocyst formation occurs in 2% to 6.7% of patients following radical hysterectomy and pelvic lymphadenectomy. The incidence is somewhat lower when the retroperitoneal spaces are left open. Most lymphocysts are asymptomatic and do not require intervention; however, lymphocysts may occasionally produce pelvic pain, ureteral obstruction, or partial venous obstruction with thrombosis.
Primary Radiation Therapy
Radiation therapy can be used for all stages of disease and for most patients regardless of age, body habitus, or coexistent medical conditions. The recommended nomenclature for measurement of absorbed radiation dose is the gray (Gy); 1 Gy is equal to one joule (J) of energy absorbed per kilogram of substance. Radiation dose is also commonly expressed as centi-gray (cGy), with 100 cGy equal to 1Gy. By convention, the irradiation dose used in the treatment of cervical cancer is described relative to two anatomic landmarks within the pelvis. Point A is defined as a point 2 cm above the lateral vaginal fornix and 2 cm lateral to the uterine canal corresponding to the paracervical triangle. Point B reflects the dose delivered to the pelvic sidewall and is located 3 cm lateral to point A.
The technical treatment modalities used in modern radiation therapy for cervical cancer consist of a combination of external irradiation and local irradiation. External irradiation is delivered from a source remote from the body (e.g., linear accelerator, cobalt-60) and is used to treat the regional lymph nodes, decrease tumor volume, and reduce the anatomic distortion produced by larger tumor masses. External beam irradiation treatment for cervical cancer is usually delivered using a four-field technique (anterior, posterior, and lateral fields). The precise treatment volume is determined according to individual patient anatomy, but usually measures 15 cm × 15 cm to 18 cm × 18 cm. The pelvic radiation field extends 1 to 2 cm beyond the lateral borders of the bony pelvis and inferiorly beyond the border of the obturator foramen. The cephalad margin may be extended to 18 cm in length to treat the common iliac lymph nodes or even higher if paraaortic lymph node coverage is necessary.
Brachytherapy, refers to a radiation source in direct proximity to the target tissue and may be delivered using a variety of intracavitary applicator devices, but the intrauterine tandem and vaginal colpostats are used most frequently for primary treatment ( Fig. 52.9). Once adequate placement is assured, the device is after-loaded with radioactive isotope (e.g., radium-226, cesium-137, iridium-192). Alternatively, vaginal cylinders or interstitial needle implants may be used to deliver local radiation therapy, depending on patient anatomy and tumor distribution.
The total dose delivered to point A is determined by the volume of disease to be treated and ranges from 6,500 to 7,000 cGy for small stage IB lesions to 8,500 to 9,000 cGy for bulky stage IIB and stage III lesions. For patients with documented paraaortic node metastasis, or those at high risk, 4,500 cGy of extended field irradiation is delivered to the paraaortic region. Cure rates with irradiation therapy are stage-dependent, with 5-year survival rates averaging 70% to 85% for stage I, 60% for stage II, 45% for stage III, and 18% to 20% for stage IV disease.
Concurrent Chemotherapy and Radiation Therapy In 1999, five multi-institutional, randomized controlled trials reported a survival advantage associated with the concurrent administration of chemotherapy and radiation therapy in the management of cervical cancer. Although these trials differed in their inclusion criteria, chemotherapy schedules, and prescribed radiation treatment, all demonstrated a similar improvement in progression-free survival (10%–27%) and overall survival (10%–17%). Many centers now administer concurrent treatment with chemotherapy and radiation therapy as standard practice for patients with locally advanced cervical cancer. Cisplatin (Platinol), 5-fluorouracil (Adrucil), and hydroxyurea (Hydrea) have been the chemotherapeutic agents most extensively studied as part of a combined modality treatment program. A commonly used contemporary regimen is cisplatin 40 mg per m 2 administered intravenously on a weekly basis during the radiation treatment interval.
Complications of Radiation Therapy Radiation therapy is associated with both acute and chronic complications. Perforation of the uterus may occur at the time of intracavitary insertion and, if unrecognized, may result in significant blood loss, radiation damage, and peritonitis. Appropriate management consists of removal of the implant and broad-spectrum antibiotic coverage if signs of infection are present. Vaginal fibrosis and stenosis is the most common chronic complication of radiation therapy for cervical cancer and is seen in up to 70% of cases. Ovarian function is lost in virtually all patients undergoing radiation therapy to the pelvis. Proctosigmoiditis occurs in up to 8% of patients undergoing radiation therapy for cervical cancer. Symptoms include abdominal pain, diarrhea, and nausea. An antispasmodic agent, a low-gluten and low-lactose diet, and steroid enemas may be useful; however, severe cases may require hyperalimentation and a diverting colostomy. Hemorrhagic cystitis is seen in approximately 3% of patients undergoing radiation therapy for cervical cancer. In contrast to surgical therapy, fistulous complications associated with radiation therapy tend to occur late and are more difficult to repair secondary to poorly vascularized tissues from radiation fibrosis and vasculitis. Rectovaginal and vesicovaginal fistulae each occur in approximately 1% of cervical cancer patients treated with irradiation. In such cases, biopsy specimens should be obtained from the edge of the fistula to rule out recurrent cancer. Diversion of the fecal (colostomy) or urinary (percutaneous nephrostomy) stream is usually required to allow adequate healing (3–6 months) prior to surgical repair. Two percent of patients experience small bowel obstruction as a consequence of radiation therapy; it is more common in those patients with vascular disease or a history of previous abdominal surgery. The most common site of small bowel obstruction is the terminal ileum, which is relatively fixed within the radiation field by the cecum. Complete small bowel obstruction or cases recalcitrant to conservative management require surgical intervention.
Chemotherapy as the sole mode of treating cervical cancer is indicated for patients with extrapelvic metastases (stage IVB) or those with recurrent disease who are not candidates for radiation therapy or exenterative surgery. Cisplatin has been the most extensively studied agent and has demonstrated the most consistent clinical response rates. Complete clinical responses have been observed in 24% of patients, with an additional 16% demonstrating a partial response. Unfortunately, in most series, responses to cisplatin are short-lived (3–6 months). Other agents demonstrating at least partial activity against cervical cancer include carboplatin (Paraplatin), ifosfamide (Ifex), doxorubicin hydrochloride (Adriamycin), vinblastine sulfate (Velban), vincristine sulfate (Oncovin), 5-fluorouracil, methotrexate, and altretamine (Hexalen). There is little objective evidence to suggest that combination chemotherapy is superior to single-agent cisplatin treatment in improving the overall survival of patients with advanced or recurrent cervical cancer.
GENERAL MANAGEMENT BY STAGE
The 5-year survival rate of these patients approaches 100% with primary surgical therapy. Extrafascial hysterectomy is adequate treatment for this group of patients. Conization may be used selectively if preservation of fertility is desired, provided the surgical margins are free of disease. In the absence of lymph–vascular invasion, the incidence of pelvic lymph node metastasis is 0.3%, and lymphadenectomy is not indicated. In the presence of lymph–vascular involvement, the risk of pelvic node metastasis increases to 2.6%. Pelvic lymphadenectomy and extrafascial hysterectomy should be performed in these cases. In patients who are medically inoperable, stage IA1 carcinoma can be effectively treated with intracavitary radiation.
Microinvasive carcinoma with stromal invasion of 3.1 to 5.0 mm is associated with positive pelvic lymph nodes in 6.2% of patients. The preferred treatment for these lesions is modified radical (type II) hysterectomy with pelvic lymphadenectomy. Radiation therapy is equally effective from a survival standpoint but may carry a greater risk of post-treatment morbidity compared to modified radical hysterectomy.
Stages IB1, IB2, IIA
Both radical surgery and radiation therapy are equally effective in treating stages IB and IIA carcinoma of the cervix. Numerous uncontrolled studies support the merits of each modality, with no significant differences in pelvic tumor control or overall survival. Zander and colleagues reported on 1,092 patients with stages IB and II cervical cancer treated with radical (type III) hysterectomy and pelvic lymphadenectomy. Five-year survival rates were 84.5% for stage IB and 71.1% for stage II disease. Similar survival rates are obtained with primary radiation therapy. In one series, Perez and associates reported 5-year survival rates of 85% for 312 patients with stage IB disease and 70% for 98 patients with stage IIA disease treated with primary radiation therapy.
Treatment should be individualized for patients with bulky stage I (IB2) tumors. Tumor expansion of the upper endocervix and lower uterine segment can distort cervical anatomy and lead to suboptimal placement of intracavitary radiation sources. Consequently, the central failure rate has been reported as high as 17.5% in patients with cervical lesions greater than 6 cm treated with radiation alone. In such situations, a “completion” extrafascial hysterectomy is usually performed following radiation therapy. While many clinicians limit the use of radical hysterectomy to patients with small stage IB (<3–4 cm) or stage IIA lesions, there is evidence that acceptable survival rates can be obtained with primary surgical treatment in patients with bulky disease confined to the cervix. Five-year survival rates range from 73.6% to 82% after radical hysterectomy and pelvic lymphadenectomy for cervical lesions greater than 4 cm. Survival decreases to 66% at 5 years for lesions greater than 6 cm.
An alternative management plan for patients with bulky local disease is to administer chemotherapy in order to reduce the primary tumor volume prior to attempting radical hysterectomy. This approach has been termed neoadjuvant chemotherapy. Cisplatin, bleomycin sulfate (Blenoxane), and vinblastine has been the most extensively used drug combination. When chemotherapy is administered prior to surgery, complete clinical response rates range from 17% to 44%, with overall response rates of 80% to 90%. In addition to increasing surgical resectability, preoperative chemotherapy also decreases the number of positive pelvic lymph nodes and, in some studies, has seemingly improved 2- and 3-year survival rates.
Adjuvant Therapy Following Surgery Data are limited concerning the efficacy of postoperative pelvic irradiation in patients at high risk of recurrence after radical hysterectomy and pelvic lymphadenectomy. High-risk prognostic factors include positive pelvic lymph nodes, microscopic parametrial invasion, pelvic lymph node metastases, deep cervical invasion, and positive or close surgical margins. Sedlis and co-workers report results of a randomized, prospective trial of the Gynecologic Oncology Group comparing postoperative pelvic radiation therapy versus no further therapy for patients with high-risk stage IB cervical cancer following radical hysterectomy and pelvic lymphadenectomy. High- risk factors included large tumor diameter, deep stromal invasion, and the presence of tumor in capillary lymphatic spaces. For patients with these risk factors and negative pelvic lymph nodes, adjuvant pelvic radiation was associated with a statistically significant 47% reduction in the risk of disease recurrence. Survival analysis for this study however awaits additional data maturation.
Grossly Positive Lymph Nodes Encountered at Radical Hysterectomy The management of patients with grossly positive lymph nodes encountered at the time of radical hysterectomy has been controversial. Although there are no controlled studies, radiation therapy is commonly administered in such circumstances. In order to minimize postoperative radiation-related complications and preserve cervical anatomy for brachytherapy radiation placement, some clinicians advocate abandoning the surgical procedure once metastatic disease is confirmed by intraoperative histologic frozen section. Conversely, retrospective data suggest that postoperative irradiation after resection of all gross nodal disease and radical hysterectomy is associated with a lower rate of local recurrence and may provide a modest gain in survival, particularly for patients with three or more positive pelvic lymph nodes. Hacker and colleagues report their experience with patients undergoing complete resection of grossly positive lymph nodes in conjunction with radical hysterectomy and postoperative radiation therapy. The 5-year survival rates were 80% for patients with positive pelvic nodes and 48% for patients with positive paraaortic nodes; however, serious morbidity occurred in 18% of patients in this series. In addition, lower-extremity lymphedema has been reported in up to 23.4% of patients receiving combined modality therapy.
Stages IIB, III, IVA, and IVB
Radiation therapy is the treatment of choice for patients with stage IIB and more advanced disease. Radiation therapy for invasive cervical cancer is given as a combination of external and intracavitary treatments as described earlier. Long-term survival rates are approximately 60% for stage II, 45% for stage III, and 18% for stage IV disease. Patients with stage IVB disease are usually treated with chemotherapy alone or chemotherapy in combination with local irradiation for palliation of symptoms. These patients have a uniformly poor prognosis regardless of treatment modality.
Among patients with recurrent cervical cancer, recurrence is detected within 1 year in 50% of patients and within 2 years in more than 80%. Pelvic examination and lymph node evaluation, including supraclavicular nodes, should be performed every 3 months for 2 years and then every 6 months for an additional 3 years. As many as 70% of patients with recurrent cervical cancer in the pelvis will have abnormal cervical or vaginal cytology; therefore, appropriate cytologic smears should be obtained at the time of each routine examination. Any palpable pelvic mass should be evaluated by CT with fine-needle aspiration cytology if possible. A chest x-ray should be obtained annually to detect pulmonary metastases.
TREATMENT OF RECURRENT CERVICAL CANCER
Cervical cancer detected within the first 6 months after primary therapy is often termed persistent cancer, while that diagnosed later is referred to as recurrent disease. Appropriate treatment of recurrent cervical cancer is dictated by both the site of recurrence and the modality of primary therapy. In general, patients in whom locally recurrent disease develops following primary surgery should be considered for salvage radiation therapy. Conversely, surgical treatment should be considered for those patients with recurrent central disease who initially received irradiation. Distantly metastatic recurrent tumor is not amenable to either modality alone and is an indication for palliative chemotherapy and possibly radiation therapy for local control.
Surgical Treatment of Recurrent Cervical Cancer
Only patients with recurrent tumor confined to the central pelvis are candidates for surgical intervention. Total hysterectomy is inadequate treatment for centrally recurrent cervical cancer. Additionally, when radical hysterectomy is performed following maximum-dose radiation therapy, 20% to 50% of patients will experience ureteral strictures, urinary fistulae, or other serious complications. Therefore, pelvic exenteration is usually the procedure of choice for centrally recurrent cervical cancer.
Prior to exenterative surgery, a thorough investigation should be undertaken to rule out extrapelvic metastases. The clinical triad of unilateral leg edema, sciatic pain, and ureteral obstruction heralds tumor extension to the pelvic sidewall and is a contraindication to surgery. In most series, approximately 25% of patients with recurrent cervical cancer are deemed satisfactory candidates for exenterative surgery.
Anterior exenteration is indicated for treatment of recurrent cervical cancer limited to the cervix, anterior vagina, or bladder. The procedure combines radical cystectomy with radical hysterectomy and vaginectomy. Posterior exenteration combines abdominal perineal resection of the rectum with radical hysterectomy and vaginectomy and is indicated for lesions confined to the posterior fornix and rectovaginal septum. Total pelvic exenteration is most often required for recurrent cervical cancer. The procedure involves the en-bloc excision of the bladder, uterus, rectum, and vagina.
Using current surgical stapling devices, low-rectal reanastomosis can be performed in approximately 70% of cases. Reconstruction of the urinary system is accomplished using either an intestinal urinary conduit or one of the many techniques of continent urinary diversion (Miami pouch, Indiana pouch). A neovagina can be created by a variety of techniques using myocutaneous flaps (e.g., bulbocavernosus, gracilis, transverse rectus abdominus) or an omental flap with split-thickness skin graft. Modern surgical techniques and intensive care unit support have reduced the perioperative mortality to less than 7% in recent series. With proper patient selection and sound surgical judgment, 5-year survival rates after pelvic exenteration range from 45% to 61%.
GLANDULAR LESIONS OF THE CERVIX
Adenocarcinoma In Situ
Adenocarcinoma in situ (AIS) is characterized by replacement of the endocervical glandular cells by tall columnar cells with nuclear stratification, hyperchromatism, irregularity, and increased mitotic activity ( Fig. 52.11). About 50% of women with AIS also have coexistent squamous cervical intraepithelial neoplasia (CIN). A diagnosis of AIS may be detected incidentally at the time of conization performed for CIN. Historically, a point of major concern regarding AIS is that these lesions were multifocal, so that conization margins were thought to be unreliable in predicting the presence of residual disease. In one study, Poyner and associates report on 28 patients with AIS in which 4 of 10 patients with negative conization margins had residual AIS in hysterectomy or repeat conization specimens. In contrast, studies using careful histologic sectioning indicate that cervical AIS lesions are usually located within the transformation zone and that true multifocality occurs in fewer than 15% of cases. A retrospective study from Shin and co-workers found only one case of residual or recurrent AIS among 98 patients undergoing conization with negative surgical margins and followed with conservative surveillance. As additional data accumulate, it appears that negative conization margins may be a more reliable indicator of disease clearance than previously thought. For young patients desiring to maintain reproductive capacity, AIS appears to be safely managed by cold knife conization and diligent surveillance. Clear surgical margins however are an absolute prerequisite to conservative management. For patients who have completed their childbearing, a simple hysterectomy should be performed because of the risk of recurrence, even in the presence of negative margins. Patients with unreliable follow-up and those with persistently positive conization margins should be offered simple hysterectomy as definitive therapy.
Cervical adenocarcinoma in situ showing tall columnar cells with nuclear stratification, hyperchromatism, and irregularity.
CERVICAL CANCER IN PREGNANCY
Cervical cancer is one of the most common malignancies in pregnancy, with an estimated incidence ranging from 1 in 1,200 to 1 in 2,200 pregnancies (1.6–10.6 cases per 10,000 pregnancies). Conversely, 1 of every 34 women diagnosed with cervical cancer is pregnant at the time of diagnosis. The most common complaint of pregnant patients with cervical cancer is abnormal bleeding. However, confusion between the symptoms of early cervical cancer and those of normal pregnancy frequently leads to a delay in diagnosis. Pathologic confirmation of the presence of invasive cervical cancer should be obtained by directed biopsy in the presence of a grossly visible lesion. Conization is only indicated for those patients with apparent microinvasive disease on directed biopsy or for patients with persistent cytologic evidence of invasive cancer in the absence of a colposcopically visible lesion. Diagnostic conization should only be considered when a diagnosis of invasive cancer will result in a modification of treatment recommendations, timing, or mode of delivery. From an obstetric standpoint, the optimal time to perform conization is between 14 and 20 weeks gestational age or after the time of fetal viability has been reached.
The same clinical staging system of cervical cancer is employed for both nonpregnant and pregnant patients alike. For pregnant patients with cervical cancer, the use of MRI may be an appropriate substitute for intravenous pyelogram (IVP) or CT if minimizing fetal exposure to ionizing radiation is desirable. Once the diagnosis of cervical cancer has been established, treatment recommendations are individualized and are dependent on the stage of disease, gestational age at the time of diagnosis, and the desires of the patient regarding continuation of the pregnancy. Patients with well-documented stage IA1 disease (conization with negative surgical margins) may be managed with vaginal delivery and reevaluation postpartum. If the patient has completed childbearing, a simple extrafascial hysterectomy would be appropriate, otherwise close clinical follow-up is required. For patients with stage IA2 disease, a modified radical cesarean hysterectomy with pelvic lymph node dissection is the preferred treatment. Patients with stage IB or IIA disease may be treated with surgery in the form of radical hysterectomy and pelvic lymph node dissection, either in conjunction with cesarean section or with the fetus in situ, depending on the gestational age. Radiation therapy is the treatment of choice for patients with stage IIB to IVA disease or those with stage IB and IIA disease who are not favorable candidates for radical hysterectomy. Radiation therapy may be initiated with the fetus in situ for nonviable pregnancies, with spontaneous abortion occurring 4 to 5 weeks after starting treatment. For more advanced gestations, classic cesarean delivery is performed initially, with radiation therapy commencing 2 to 3 weeks following delivery. The issue of delaying treatment in order to reach a gestational age consistent with fetal viability has been controversial. Although the data are limited and retrospective in nature, it appears that a treatment delay of 6 to 12 weeks is not detrimental for patients with localized (stage I) disease. Treatment delays are not recommended for patients with more advanced disease.
· Regular cervical cytologic screening with the Pap smear is the single most effective means of reducing the incidence and mortality of invasive cervical cancer.
· By convention, cervical cancer is a clinically staged disease; however, ancillary tests and surgical staging may provide useful information and facilitate a treatment approach tailored to the true extent of disease.
· Surgery (radical hysterectomy with pelvic lymphadenectomy) and radiation therapy are associated with equivalent survival outcomes for patients with early-stage (I–IIA) cervical cancer.
· Patients with advanced-stage disease (IIB–IVA) should receive radiation therapy with curative intent, preferably in combination with concurrent chemotherapy.
The primary management for endometrial cancer is surgery, consisting of removal of the uterus, cervix, and adnexal structures. Surgical staging procedures, including careful exploration of the abdomen and pelvis and lymphadenectomy, often are done at the same time, as described above. As soon as the uterus has been removed, it should be sent to the pathology laboratory for frozen section to determine tumor grade and depth of invasion, as well as to obtain tissue for estrogen and progesterone receptor levels and other studies, as indicated. For patients in whom lymph node sampling is indicated (see Table 54.12), representative samples of lymph node–bearing tissue from the lower aorta and vena cava are removed. Pelvic lymph node sampling should remove nodes from common and external iliac and obturator regions. An omental biopsy may be performed and is indicated for patients with papillary serous and clear cell cancers. In patients who are very poor candidates for exploratory laparotomy (e.g., morbidly obese), vaginal hysterectomy or laparoscopically assisted vaginal hysterectomy should be considered. Every effort should be made to remove the adnexal structures; therefore, laparoscopically assisted vaginal hysterectomy may be preferable. If appropriate surgical expertise is available, the full surgical staging, including pelvic and periaortic lymphadenectomy, can be performed through the laparoscope. Until additional information is obtained, vaginal hysterectomy should be limited to very select patients who otherwise might be given radiation therapy only. In patients with clinically apparent cervical involvement, radical hysterectomy with bilateral salpingo-oophorectomy and lymph node dissection may be considered.
Following surgery and review of the final pathology report, patients may be divided into risk groups based on the many prognostic factors discussed above. This classification can then be used to individualize the recommended postoperative therapy, if needed. Because formal surgical staging has been utilized widely for less than 10 years, most of the information on recommendations for postoperative radiation therapy are based on clinically staged patients. The risk of pelvic recurrence in patients with high-risk factors but negative surgical staging is largely unknown. The GOG study based on surgicopathologic correlation found that even when sampled lymph nodes were negative, patients with deep myometrial invasion and poorly differentiated cancers were still at a higher risk of recurrence. Even though the surgical staging procedures failed to document extrauterine pelvic disease, postoperative pelvic irradiation was associated with a decreased risk of local recurrence. It is not yet clear whether surgical staging can define a subgroup of stage I patients, other than the already identified low-risk patients, who can be treated without adjuvant radiation therapy.
Treatment for patients with stage II disease remains somewhat controversial. Most studies suggest that patients with cervical involvement are at a higher risk for vaginal vault recurrence, and often recommend adjuvant vaginal cuff irradiation. Whether or not those patients with otherwise negative surgical staging also need pelvic irradiation remains to be confirmed. With clinically apparent cervical involvement, treatment recommendations include either radical hysterectomy or preoperative irradiation followed by extrafascial hysterectomy.
Treatment for patients with documented extrauterine disease (stages III and IV) should be individualized to encompass the true extent of the disease. Therapeutic options include pelvic irradiation, extended-field irradiation to cover the periaortic lymph nodes, whole-abdomen irradiation, and systemic hormone therapy or chemotherapy. In most cases, management of distant metastasis with either high-dose progestins or chemotherapy is palliative only, with little expectation for long-term control of disease. The most widely used chemotherapy agents include doxorubicin hydrochloride (Adriamycin) and cisplatin (Platinol) or carboplatin (Paraplatin).
Progestins have been used for many years in the management of recurrent endometrial carcinoma, with approximately one third of patients having a favorable response. Patients with well-differentiated tumors have a higher response rate than those with moderately or poorly differentiated cancers. Although the role of estrogen and progesterone receptors in endometrial cancer therapy has not yet been accepted widely, it does appear that the responsiveness of recurrent tumor to progestin therapy is related to the content of both estrogen and progesterone receptors. If both receptors are present, the likelihood of a favorable response is good, regardless of tumor grade or other high-risk factors. If the concentration of receptors is low, it is unlikely that the recurrent tumor will respond to progestins, and other chemotherapy should be considered.
Endometrial cancer in approximately 10% to 15% of patients is inoperable, usually because of morbid obesity or severe intercurrent disease. In these patients, primary radiation therapy should be considered. In most cases, a combination of external beam and intracavitary irradiation should be used, and with definitive therapy approximately 85% to 90% of patients with early-stage disease will have control of uterine disease. The overall risk of recurrence in these patients with stage I disease correlates with tumor grade, with a 5-year survival of 94% for grade 1, 92% for grade 2, and 78% for grade 3 tumors.
Many studies have confirmed that after treatment of endometrial cancer, most recurrences will occur within 3 years. Approximately one half of these recurrences will be asymptomatic and, thus, the traditional recommendation has been to follow patients with physical examination and vaginal cytology every 3 to 4 months for the first 2 to 3 years, and then at 6-month intervals for at least 5 years. Serial serum CA-125 measurements also have been suggested for surveillance of patients who have been treated for endometrial cancer, although the level may be normal in patients with early recurrent disease. Because treated endometrial cancer will not recur in the great majority of patients, however, several studies have addressed the cost effectiveness of this traditional recommendation. In a study from the M.D. Anderson Cancer Center, 59% of patients with recurrence were asymptomatic, with over one half being picked up on physical examination, 26% by an elevated CA-125, and only 4% by vaginal cytologic examination. Because of these findings, these authors recommended that physical examination, serum CA-125 assay, and vaginal cytology be performed only every 6 to 12 months on asymptomatic patients. A Canadian study reported that only one recurrence was documented during more than 200 routine follow-up visits after treatment for endometrial cancer, using a schedule of examinations of every 3 months for the first year, every 4 months for the second year, and every 6 months thereafter. There was no difference in the salvage rates of recurrent disease picked up during routine surveillance compared with recurrent disease documented in symptomatic patients. In this study, no recurrence was picked up by vaginal cytology alone. In a third study from Duke University, an analysis of various follow-up techniques demonstrated that routine vaginal cytology and chest radiograph were not cost effective. The recommendation of these investigators is to follow patients every 6 months with examination alone, using additional testing to evaluate any symptoms.
Estrogen Replacement Therapy After Treatment
For many years, it has been thought that a history of endometrial cancer, even successfully treated, was an absolute contraindication to estrogen replacement therapy (ERT), because adenocarcinoma of the endometrium is considered an estrogen-dependent neoplasm. Because no scientific data support the contention that ERT is dangerous for patients who have had a hysterectomy for endometrial cancer and because the body of evidence is increasing in supporting the value of ERT in decreasing morbidity and mortality from heart disease, strokes, and osteoporosis, many physicians and patients are questioning the earlier proscription. During the last decade, there have been several small retrospective studies of patients given ERT following treatment for early-stage endometrial cancer ( Table 54.13). In 1986, Creasman and coworkers reported on 221 patients with stage I endometrial cancer, of whom 47 (21%) were given postoperative estrogen replacement for a median of 26 months. Statistical analysis revealed no increased risk of recurrence or death between those who received ERT and those who did not when adjustments were made for tumor grade, myometrial invasion, nodal metastasis, peritoneal cytology, and age. In fact, the risk of recurrence was significantly higher in the untreated group (15% vs. 2%), as was the risk of dying of intercurrent disease. Similar study design and conclusions were reported 3 years later by Lee and others. In both of these studies, selection bias may have contributed to the results, but it does appear that a low-risk group of patients can be selected who can safely take estrogen replacement. Chapman and colleagues retrospectively reviewed information on 123 patients with stages I and II endometrial cancer, of whom 62 received ERT, and again documented no increase in recurrences or deaths from this malignancy. In a Committee Opinion in August 1993, the American College of Obstetricians and Gynecologists concluded that there are no definitive data to support specific recommendations regarding ERT for women previously treated for endometrial cancer. The opinion states that estrogens could be used for the same indications as for any other woman, except that the selection of appropriate candidates should be based on prognostic indicators and the risk that a patient is willing to assume. The gynecologic practice committee, due to the paucity of data, could not evaluate the need for progestational agents in addition to estrogens. A large GOG trial is underway to assess the risk of hormonal replacement in these patients.
Classifications of uterine sarcomas
· Endometrial stromal sarcoma
· Mixed homologous müllerian sarcoma (carcinosarcoma)
· Mixed heterologous müllerian sarcoma (mixed mesodermal sarcoma)
Endometrial stromal sarcoma has a much more aggressive course, with frequent and widespread metastases and a very poor prognosis. As with leiomyosarcoma, the diagnosis of stromal sarcoma versus low-grade stromal sarcoma depends on the number of mitoses per 10 HPF, with 10 mitoses being the cutoff to categorize the tumor as an endometrial stromal sarcoma ( Fig. 54.9). Despite this distinction, controversy still exists as to the prognostic significance of the number of mitoses seen. A study from the Mayo Clinic failed to identify this feature as an independent prognostic variable. As with most sarcomas, irradiation may control local disease but has little effect on overall survival. These tumors often exhibit high concentrations of both estrogen and progesterone receptors, and occasional responses have been seen when high-dose progesterone therapy is administered.
Endometrial stromal sarcoma. Nests of bland endometrial stromal cells diffusely infiltrate the myometrium.
Total abdominal hysterectomy with bilateral salpingo-oophorectomy is the treatment of choice for almost all uterine sarcomas. Because there is no formal staging system for sarcomas, most authorities feel that the endometrial staging system should be used. Local spread of a sarcoma can be treated with radiation therapy. This may not improve overall survival but will control local disease and diminish the likelihood of the morbidity of a pelvic recurrence. Unfortunately, there are no good prospective randomized trials evaluating the efficacy of postoperative radiation therapy on overall survival. The retrospective studies that do exist show only a benefit for local control. The largest study to address this issue by Salazar comprised more than 900 patients and failed to show a statistically significant survival benefit with postoperative radiation therapy, only a benefit of local control. One can argue that one must obtain control of microscopic local disease before one can cure the cancer. Typically 5,000 to 6,000 cGy is given with or without adjuvant brachytherapy. Investigators from the Mallinckrodt Institute of Radiology noted fewer pelvic recurrences when more than 5,000 cGy were used.
Some patients with leiomyosarcoma may experience an isolated pulmonary metastasis. These sometimes can be resected for cure. Significant 5-year survivals have been recorded in these rare situations. Recurrences of low-grade tumors should be considered for resection no matter where they are.
Recurrences also can be treated with chemotherapy. Many agents have shown activity ( Table 54.16). Unfortunately, no therapy has shown a significant increase in overall survival.
Uterine cancers comprise a wide variety of histologic types that carry a wide range of metastatic potential and survival.
Endometrial hyperplasia is a premalignant precursor to endometrioid adenocarcinoma. Simple hyperplasia has a low propensity to progress to a cancer (less than 1%), whereas complex hyperplasia with atypia has a 30% chance of developing into a cancer.
Endometrial cancer is the most common gynecologic cancer. Type I endometrial cancers are associated with relative estrogen excess. This can be endogenous, as in obese women who have significant conversion of steroids to estrone, or it can be exogenous, as in women who take unopposed estrogen replacement therapy.
Type II endometrial cancers are not associated with estrogen and are comprised of more aggressive histologic types, such as poorly differentiated endometrioid, papillary serous, and clear cell cancers. These later types have a survival rate as poor as 60%, compared with a greater than 80% survival in the other histologic types.
Management of endometrial cancers consists of comprehensive staging, including a total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic washings, pelvic and paraaortic lymph node dissection, and careful abdominal exploration. Management may also include postoperative radiation therapy.
Postoperative surveillance should include regular examination with Pap smear. The most common site of recurrence is at the vaginal cuff. Radiation treatment of an isolated cuff recurrence has a cure rate of 50% with external radiation therapy.
Endometrial cancer is the most common inherited form of gynecologic cancer and is associated with HNPCC or Lynch II syndrome. It is important to take a careful family history to assess if the risk is high, and formal genetic counseling and genetic testing may be appropriate.
Sarcomas are the most lethal of the uterine malignancies, with an overall survival of around 50%. There are several histologic types of sarcomas. The most common is the malignant mixed müllerian tumor, followed by the leiomyosarcoma, and finally by the endometrial stromal sarcomas. Therapy consists of exploratory laparotomy and staging procedure as outlined for endometrial cancers. Postoperative radiation therapy may be recommended, but this is associated only with decreased pelvic recurrence and not improved survival.
FALLOPIAN TUBE CARCINOMA
Surgery is the most important aspect in the initial care of patients with epithelial ovarian cancer. Surgery alone is curative for many patients with early-stage ovarian carcinoma. For more advanced disease, surgery establishes the diagnosis and allows appropriate staging and cytoreduction, optimally to less than 1 cm of residual disease. Conservative surgical management of young women who desire to preserve fertility with a unilateral salpingo-oophorectomy with a full staging procedure may be appropriate for stage Ia disease. The contralateral ovary should be evaluated carefully, because there is a 5% chance of occult metastasis or a separate primary carcinoma. Biopsy of the contralateral ovary is no longer recommended unless there are grossly apparent abnormalities. Such patients also must have strict follow-up. Although a hysterectomy and removal of remaining adnexae is recommended for women who have completed childbearing, this recommendation is not based on randomized clinical trials. Primary cytoreduction of ovarian carcinoma has been recommended for almost 30 years. The theory is that removal of large tumor nodules allows better penetration of chemotherapeutic agents and removes potential foci of chemoresistance. Optimal cytoreduction is defined as residual disease smaller than 1 cm. Several reports over the last 25 years have shown that the diameter of the largest residual disease correlates with response rate, progression-free interval, and overall survival. The GOG evaluated survival by maximal diameter of residual disease (data from protocols 52 and 97) and found that the survival rate for patients with residual disease of 2 cm or greater is about 20% after 4 years, compared with a 60% survival rate after 4 years in those with only microscopic residual disease. For patients with residual disease less than 2 cm, the survival rate was 40% after 4 years ( Fig. 55.33). Median survival of patients who have received optimal cytoreduction was approximately twice that of patients with suboptimal cytoreduction.
There has been great debate in the literature regarding the relative importance of surgical cytoreduction as compared with the inherent tumor biology of the cancer as determinants of patient survival. Patient age, the number and size of tumor nodules at time of diagnosis, and tumor grade have been cited as significant predictors of outcome. Other series have found that optimal surgical cytoreduction did not equate the survival benefit experienced by patients who initially had small-volume disease. Some investigators have suggested that platinum-based therapy has had a larger impact on survival than surgical debulking. Data, including a large meta-analysis, have demonstrated that maximal initial surgical cytoreduction was the most powerful predictor of patient survival. Patients with ovarian cancer are more likely to have optimal cytoreduction under the care of a gynecologic oncologist than with general surgeons or general gynecologists. Despite the benefit of improved survival, most patients with ovarian cancer in the United States never see a gynecologic oncologist. Ongoing efforts to educate physicians and patients regarding appropriate referral to specialized centers are needed. At the end of chemotherapy, patients who are clinically in complete remission may be offered second-look evaluation to determine the success of therapy, as measured by the presence of any residual tumor cells. The reasons for second-look evaluation are as follows: (a) to determine disease presence, thus allowing continued therapy in an attempt to improve survival, (b) to debulk any residual carcinoma, and (c) a prognostic tool for patient survival. Most second-look evaluations can be completed successfully via the laparoscope among surgeons with adequate expertise, and second-look laparoscopy has equivalent rates of detection of residual disease when compared with laparotomy. A laparoscopic approach reduces the length of hospital stay (frequently done as outpatient surgery) and patient recovery time. Older studies have shown that survival rates for those who underwent second-look surgery, as compared with those who did not, were essentially the same, suggesting no benefit for the procedure. However, these studies have not evaluated the effect of newer chemotherapy and more effective salvage therapies. Although second-look surgery should not be considered standard of care, it should be performed in patients enrolled in clinical trials to evaluate the efficacy of newer first-line therapies and the efficacy of better salvage therapies in improving survival. Secondary cytoreduction at the time of second-look laparotomy also has been examined in several studies that revealed a benefit in a select group of patients with gross disease that is reduced successfully to microscopic disease. However, only a minority of patients will have gross residual disease after clinical response to platinum-based chemotherapy. More recent data suggest that the presence or absence of residual disease at second-look surgery is one of the most significant prognostic factors for patient survival. Therefore, until more accurate diagnostic tests can be identified to determine residual disease after standard treatment, second-look surgery may be offered to patients with advanced stage disease in clinical remission to help determine prognosis, with the caveat that the procedure has prognostic value but no impact on survival. Interval debulking surgery is performed after neoadjuvant chemotherapy in patients with advanced ovarian cancer. Although it remains a controversial subject, the Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer conducted a large randomized study documenting the benefit of interval debulking surgery. All patients received three cycles of cyclophosphamide and cisplatin followed by randomization to debulking versus no debulking surgery, and all patients then received three more cycles of chemotherapy. The study revealed that interval debulking surgery resulted in significantly better progression-free and overall survival ( Fig. 55.34). Although the 6-month improvement in median overall survival is relatively small, interval debulking surgery may be considered in patients in whom cytoreduction was not optimal during initial surgery, yet who have responded to neoadjuvant chemotherapy.
Secondary cytoreductive surgery in patients with recurrent epithelial ovarian carcinoma has also been evaluated in several studies. Most of these reports show a statistically significant survival benefit for patients whose cytoreduction was optimal during secondary surgery. The likelihood of successful secondary cytoreduction and improved patient survival increases for patients with a longer disease-free interval (>12 months), unifocal disease, and initial optimal cytoreduction.
Following surgery, most patients will require chemotherapy. However, for patients with completely staged Ia or Ib grade 1 or 2 ovarian cancers, no survival benefit has been demonstrated with adjuvant chemotherapy. The studies have shown clear benefit to adjuvant chemotherapy in select patients with stage Ia or Ib grade 3 and stage Ic disease compared with observation. The GOG and the Gruppo Italiano Collaborativo in Oncologia Ginecologica studies found that patients with stage Ia or Ib grade 1 or 2 disease had comparable survival with observation and melphalan. In contrast, high-risk patients with stages Ia, Ib, Ic and II disease had improved disease-free intervals with cisplatin-containing regimens compared with observation, intraperitoneal phosphorus-32, or melphalan (Alkeran). The optimal number of cycles of chemotherapy for early-stage disease remains unclear, and it is the objective of a current prospective trial to compare the efficacy of three versus six cycles of paclitaxel and cisplatin in patients with early-stage ovarian cancer. Various chemotherapeutic agents are active against ovarian cancer. Platinum-based therapy has been the mainstay of treatment for ovarian cancer for over 25 years. Combination platinum-based regimens have demonstrated superior response rates to those obtained with single-agent platinum, although there is insufficient evidence to suggest longer overall survival in these patients. The lack of survival benefit in some trials may relate to the high crossover treatment of patients who failed on one treatment arm and received other study treatments, as well as the varied length of patient follow-up in these studies. Paclitaxel, a microtubule stabilizer, was found to have significant activity in many cancers, including epithelial ovarian carcinoma. In 1996, the GOG published a study comparing the efficacy of paclitaxel and cisplatin with cyclophosphamide and cisplatin as first-line adjuvant therapy in patients with suboptimally debulked epithelial ovarian carcinoma (stages III or IV). Disease-free survival and overall survival for the paclitaxel-cisplatin group was statistically longer than for the cyclophosphamide-cisplatin group (median survival 38 to 24 months). Paclitaxel-cisplatin was also more effective in patients with advanced stage ovarian cancer after optimal cytoreduction. Substitution of carboplatin for cisplatin and decreased paclitaxel infusion times have reduced cost and patient side effects compared with the paclitaxel-cisplatin regimen. A subsequent prospective randomized trial replaced paclitaxel with docetaxel (Taxotere), another microtubule stabilizing agent, and found comparable response rates with less peripheral neuropathy. During the last 5 years, many new drugs have been found to be active second-line agents for epithelial ovarian cancer including topotecan, etoposide, altretamine (Hexalen), docetaxel (Taxotere), gemcitabine hydrochloride (Gemzar), vinorelbine tartrate (Navelbine), and doxorubicin hydrochloride liposomal injection (Doxil). Both topotecan, a topoisomerase inhibitor, and doxorubicin have shown promising activity in patients with recurrent, platinum-resistant disease with response rates of 20% to 30%. A large, prospective trial is randomizing patients to one of several combination multiagent chemotherapy regimens using gemcitabine, doxorubicin, or topotecan with paclitaxel-carboplatin as the control arm, to better define the best first-line regimen for patients with advanced stage ovarian cancer. Neoadjuvant chemotherapy to reduce the tumor load before performing a laparotomy is being investigated. Based on available noninvasive testing, it is difficult to predict accurately which patients will not be candidates for a successful cytoreduction. Furthermore, neoadjuvant therapy has been employed only in small retrospective observational series. Although neoadjuvant chemotherapy has resulted in less morbidity from subsequent cytoreductive surgery, this approach has not translated into higher survival rates in the limited number of patients studied. Intraperitoneal therapy allows direct exposure of a tumor to a drug concentration that may be 10-fold to 1,000-fold higher than that achieved with systemic therapy. In theory, this approach may have value for epithelial ovarian cancer, but its superiority has not yet been demonstrated despite extensive study. The clinical situations in which intraperitoneal therapy may be considered include salvage therapy for patients with disease of 5 mm or less, consolidation therapy for patients with surgically documented complete chemotherapeutic response, initial therapy for patients with high-grade early-stage tumors, or combination intraperitoneal therapy with systemic infusion. A randomized trial of intraperitoneal cisplatin and intravenous cyclophosphamide chemotherapy as first-line therapy showed promising survival rates with much less toxicity than older standard intravenous cisplatin-cyclophosphamide regimens. This study suggests that combination intraperitoneal cisplatin with an intravenous agent as primary therapy may be advantageous. However, optimal intraperitoneal regimens remain to be defined and will require randomized trials comparing intraperitoneal infusion with other approaches.
Abdominopelvic radiation therapy has been used postoperatively in selected patients who have microscopic or small-volume residual disease; however, with more effective chemotherapy, radiation therapy is an infrequently used adjuvant therapy for ovarian cancer. One of the largest series, compiled by investigators in Toronto, treated patients with stage II and III disease with abdominopelvic radiation and showed a 10-year disease-free survival of 38% (n = 91) for patients with residual smaller than 2 cm and 6% (n = 91) for patients with residual larger than 2 cm. Further studies on the usefulness of radiation therapy for ovarian cancer are warranted.
With the addition of improved chemotherapeutic regimens and aggressive surgical cytoreduction, survival has improved in patients with advanced stage ovarian cancer. The overall 5-year survival is approximately 50%. Further strides in the management of ovarian cancer will require more knowledge of the molecular alterations that cause it. Advances in molecular biology indicate that ovarian tumorigenesis results from an accumulation of sequential genetic mutations. With a better understanding of the neoplastic transformation of ovarian epithelium, targeted therapies may be directed against the specific genetic aberrations in an individual cancer to improve patient outcome. Several innovative trials have combined gene therapy or immunotherapy and standard chemotherapy with promising early results. Ongoing efforts in both basic and clinical research are critical for the development of prevention strategies, screening for early detection, and better therapies.
FALLOPIAN TUBE CARCINOMA
Primary Fallopian Tube Epithelial Carcinoma
Fallopian tube carcinoma accounts for approximately 0.1% to 0.5% of all gynecologic malignancies. Peak incidence occurs at ages 60 to 64 years. Epidemiologic data suggest that age and nulliparity are associated with fallopian tube carcinoma, similar to endometrial and ovarian carcinomas. The constellation of symptoms including pelvic pain, a pelvic mass, and serosanguinous vaginal discharge (Latzko's triad) occur in the minority of cases. The most common symptom is vaginal staining or bleeding. Hydrops tubae profluens is characterized by colicky lower abdominal pain relieved by a profuse, serous, watery, yellow, intermittent vaginal discharge. The most common physical sign is a pelvic or abdominal mass. This mass often is thought to be an ovarian mass, with the correct diagnosis made only during surgery. Occasionally, a Pap smear revealing abnormal glandular cells with negative cervical or endometrial findings may lead the clinician to the diagnosis of fallopian tube cancer. Serum CA-125 levels often are elevated in advanced disease, as is noted in patients with ovarian carcinoma. Fallopian tube carcinoma is staged according to the FIGO. In contrast to ovarian cancer, most patients are diagnosed with early-stage disease: stage I, 37%; stage II, 21%; stage III, 31%; stage IV, 10%.
Fallopian tube carcinoma usually is characterized by swollen tubes secondary to intraluminal growth. Most fallopian tube adenocarcinomas are serous and histologically identical to ovarian serous carcinoma ( Fig. 55.35). Other types of epithelial fallopian tube carcinoma have been reported but are very rare. Several diagnostic criteria have been established to differentiate fallopian tube malignancy from ovarian and other primary tumors. Microscopically, the tumor must arise from the endosalpinx, with a histologic pattern consistent with tubal mucosal epithelium. The transition from benign to malignant epithelium is helpful for diagnosis. The ovaries and endometrium are either normal or have tumor smaller than that in the tube. As in epithelial ovarian carcinoma, fallopian tube epithelial tumors commonly spread by exfoliation and implantation throughout the peritoneal cavity. The extensive lymphatic channels within the fallopian tube facilitate lymphatic dissemination of tumor, and paraaortic lymph node metastases are common.
Surgery remains the principal treatment, including a total abdominal hysterectomy, bilateral salpingo-oophorectomy, tumor debulking, and a full staging, as with ovarian cancer (see Table 55.3). Treatment of primary fallopian tube epithelial tumors is based on the standard management for ovarian carcinoma, due to the lack of large-scale studies for this rare tumor. Platinum-based therapies are recommended following cytoreductive surgery, based on several series showing superior response rates and survival compared with those obtained with other agents.
Due to the rarity of fallopian tube cancer, paclitaxel has not yet been widely studied in this disease. However, based on data from ovarian cancer, platinum-taxane chemotherapy is used for patients with fallopian tube cancer. As in ovarian carcinoma, the prognosis is dependent upon the extent of disease and the amount of residual tumor at the end of surgery. Second-look surgery may be helpful in determining treatment efficacy and persistent disease but, as in ovarian carcinoma, it is not considered standard therapy.
HEREDITARY OVARIAN CANCER
Hereditary Forms of Ovarian Cancer
Approximately 5% to 10% of patients with ovarian cancer are thought to have an inherited genetic predisposition. Although this represents a small percentage of patients with ovarian cancer, great emphasis has been placed on these genetic mutations, given their clinical, social, and ethical implications.
Hereditary ovarian cancer syndromes are linked to dominantly inherited genetic mutations. A detailed family history from both maternal and paternal sides of the family must be obtained to determine the genetic susceptibility for the women at risk. Average age at diagnosis for this group of patients is often younger than for the general population, and most tumors are of serous histology.
The breast-ovarian cancer syndrome accounts for up to 85% of all hereditary ovarian cancer cases and is associated most frequently with mutations in the BRCA1 or BRCA2 genes. The BRCA1 and BRCA2 genes were identified and linked to hereditary breast and ovarian cancer in the 1990s. BRCA1 is located on chromosome 17q12-21, and BRCA2 is located on chromosome 13q12-13. Although the precise function of the BRCA genes is unknown, they appear to be involved in the recognition and repair of DNA damage. A sample pedigree of a breast-ovarian cancer syndrome family is illustrated in Fig. 55.36. The presence of a BRCA-associated syndrome is suspected whenever a pedigree reveals three or more affected relatives in two generations, bilateral or premenopausal breast cancers, a relative with breast and ovarian cancer, or a male with breast cancer in the pedigree
Many mutations have been described, located throughout the BRCA1 and BRCA2 genes, with nonsense mutations or frameshift mutations being predominant. Nonsense mutation occurs when a single nucleotide substitution results in a stop codon, and frameshift mutation occurs when one or more nucleotides are deleted to produce a downstream stop codon. Certain ethnic groups have higher carrier frequencies of founder BRCA mutations. Three specific founder mutations, 185delAG and 5382insC on BRCA1 and 6174delT on BRCA2, have been seen in approximately 2% to 2.4% of the Ashkenazi Jewish population. Studies have found that 40% to 60% of Jewish patients with ovarian cancer have a mutation in BRCA1 or BRCA2, in contrast to 5% of non-Jewish women with ovarian cancer.
Data have also demonstrated that fallopian tube carcinoma can occur in patients with an inherited genetic predisposition to ovarian cancer by virtue of germline mutations in the BRCA genes. A large population-based series of patients with fallopian tube cancer found that 16% of patients had inherited mutations in BRCA1 or BRCA2. Based upon these data, fallopian tube carcinoma should be considered a clinical component of the BRCA-associated breast-ovary cancer syndrome. Patients with germline BRCA mutations who elect to have prophylactic surgery should have both ovaries and fallopian tubes removed, with careful histologic evaluation to eliminate occult fallopian tube carcinoma. It is unknown whether hysterectomy is necessary, in addition to salpingo-oophorectomy, in order to remove the cornual portion of the fallopian tube as surgical prophylaxis for these patients.
Hereditary nonpolyposis colorectal cancer (HNPCC) syndrome accounts for approximately 10% of all hereditary ovarian cancer cases. It is an autosomal dominant genetic syndrome characterized by three or more first-degree relatives with colon cancer (over 70% in the proximal colon) or endometrial cancer, where one is a first-degree relative of the other two, and two of them must be diagnosed with cancer before age 50 years. Four genes that are part of the DNA mismatch repair (MMR) pathway have been identified as being responsible for the HNPCC phenotype: hMSH2 (chromosome 2p), hMLH1 (chromosome 3p), hPMS1 (chromosome 2q), and hPMS2 (chromosome 7p). Most affected patients are found to have defects in either hMSH2 or hMLH1. An inherited defect in any one of these genes increases an individual's risk of developing cancer because of an impaired ability to repair somatic genetic mutations. Family members with HNPCC syndrome are at risk for cancer at other gastrointestinal sites, the urologic tract, and the ovary. The risk of endometrial cancer among women in the HNPCC syndrome is estimated to be 40% to 60% by the age of 70 compared with 1.5% in the general population. Limited studies have reported a 3.5-fold increase in the risk of ovarian cancer in members of these families (see Table 55.8).
Genetic Testing Although hereditary cancers account for only 10% of ovarian malignancies, individual risk assessment and appropriate genetic testing can identify those individuals with significant lifetime risk. The first concern in genetic testing is the scientific and technical utility of the tests: the reliability of tests, their predictive value, their interpretation, and ultimately their ability to prevent cancer in patients who have positive test results. The second major concern relates to the ethical, legal, and social implications of gene testing. The proper selection of patients for testing is very important. Genetic counseling is imperative. As testing for these genes becomes more available to the public in both commercial and academic settings, clinicians and patients must work together to ensure that the results are used in a fashion that will consider carefully the ethical, legal, and psychosocial issues that may arise from genetic testing. Multidisciplinary services that include pretest and posttest counseling, screening, treatment, and psychosocial sessions have been established in the major referral centers. Patients must be counseled regarding the potential advantages and disadvantages of genetic testing, as well as the utility of screening and prophylactic measures that are available. American Society of Clinical Oncology guidelines recommend offering testing to anyone with a greater than 10% risk of carrying a mutation based on pedigree analysis, and only if the test result will influence medical management. First- and second-degree relatives of an affected individual from a family with breast-ovarian cancer syndrome should be offered genetic testing if they carry a mutation of the BRCA1 or BRCA2 gene. Certain ethnic groups, such as Ashkenazi Jews, are at increased risk for carrying a BRCA mutation, and a lower threshold for genetic testing may be appropriate in these individuals. Genetic testing for the MMR genes should be considered when there is a first-degree relative with a known mutation and when the patient meets the Amsterdam or the Bethesda Criteria for HNPCC syndrome (see Table 55.7). A comprehensive family history can provide an estimate of an individual's risk of carrying a genetic mutation; however, genetic testing provides more accurate information regarding the chance that an individual patient will develop cancer. The best way to determine if a cancer-associated mutation is present in a family is to test an affected family member, who is usually the most likely proband to carry a deleterious mutation. The first family member often will need comprehensive gene sequencing, and subsequent individuals can then be tested for the identified mutation, which may be unique to the particular family. In the Ashkenazi Jewish population, genetic testing for the three founder mutations is required because of the high carrier frequency in this population and occasional reports of individuals carrying both BRCA1 and BRCA2 mutations. Test results may come back positive or negative for an identifiable mutation or may report a mutation of indeterminate clinical significance. When a test result returns negative, interpretation will depend on the patient's family history. If an affected family member has tested positive for a mutation, then the patient has likely not inherited the deleterious mutation, and her cancer risk approximates that of the general population. If there is no documented positive mutation in the family, it is still possible that the patient has a cancer-associated mutation that is not detectable with testing. Approximately 12% of testing results are genetic variants or polymorphisms, reported as indeterminate clinical significance. Further study of these genetic variants and associated cancer risks in large populations will help reduce the number of indeterminate reports.
Follow-up and Management
Follow-up and treatment of patients with an inherited genetic predisposition to ovarian cancer is complex due to the variable penetrance of genetic alterations and the lack of effective early detection methods. Serum CA-125 levels and transvaginal ultrasonography with color Doppler flow are the two modalities that have shown potential usefulness in surveying these patients. CA-125 levels may be elevated in other benign diseases and may not be elevated in early stage I ovarian cancer; thus, it lacks sufficient sensitivity. Transvaginal ultrasonography is very sensitive in detecting adnexal masses; however, it cannot differentiate between malignant and benign masses, resulting in a high false-positive result rate and unnecessary surgery, especially in premenopausal women. Consequently, screening of the general population is not warranted with the currently available technology. There is no conclusive evidence to support screening patients with higher risk of ovarian cancer. Ovarian surveillance modalities have not improved significantly the detection of early-stage invasive epithelial ovarian cancers, with minimal impact on the survival among the screened patients. One prospective study of high-risk women demonstrated enhanced survival among the screened population versus historic controls; however, conclusions are limited by small patient numbers. Despite the available data, the National Institute of Health Consensus Statement on Ovarian Cancer and the Cancer Genetic Studies Consortium recommend screening starting at ages 25 to 35 years as part of the annual or semiannual routine examination for women with germline BRCA1 or BRCA2 mutations. The benefit, however, is not proven, because the evidence is based on expert opinion only. Table 55.9 lists the provisional recommendations for cancer surveillance for the carriers of BRCA1 and BRCA2 mutations. Screening and prophylactic surgery for patients with HNPCC-associated mutations is also based on expert opinion, although colonoscopy and stool occult blood testing have been shown in randomized clinical trials to reduce the incidence of and mortality from colon cancer
Prevention Chemoprophylaxis with oral contraceptive pills (OCP) for 5 years decreases ovarian cancer risk by 50% in the both general population and in high-risk women. A case-controlled study of 207 known BRCA mutation carriers and their sister controls found a 60% reduction of ovarian cancer risk with OCP use. Other risk-reducing strategies such as tubal ligation and hysterectomy have also demonstrated reduced incidence of ovarian cancer among many high-risk women.
Prophylactic bilateral salpingo-oophorectomy (PBSO) is another preventive strategy for patients with BRCA mutations to reduce cancer risk. Given that most hereditary ovarian cancer occurs after the age of 35 to 40, prophylactic oophorectomy is an option in carefully selected patients at unequivocally high risk for ovarian cancer who have completed their childbearing. This procedure can be performed laparoscopically, and the decision for concomitant hysterectomy is individualized. The surgical pathologist must be alerted to perform a careful examination of the high-risk patient's ovaries and fallopian tubes given the reports of occult ovarian and tubal carcinoma in these specimens ranging in frequency from 2% to 15%. The efficacy of PBSO in hereditary breast-ovarian cancer syndrome has been evaluated in several studies. Prospective studies have documented a significant reduction in both ovarian, peritoneal, and breast carcinoma among BRCA mutation carriers following PBSO, one study of 248 patients found a 98% decrease of ovarian and primary peritoneal cancers, and a 50% reduction in subsequent breast cancer compared with age-matched controls. This supports the findings of another prospective study that documented a 50% reduction of breast cancer with PBSO among premenopausal and postmenopausal BRCA mutation carriers that persisted irrespective of the use of hormone replacement therapy. Despite oophorectomies, primary peritoneal cancer has been reported in 0.4% to 10.7% of high-risk patients, and patients must be counseled regarding this disease. It is believed that that all coelomic epithelium, including the peritoneal covering of the entire abdominal pelvic cavity, is prone to malignant transformation in BRCA mutation carriers. Several other significant issues remain unresolved regarding the physiologic adjustments to premature surgical menopause and the safety of hormone replacement therapy in this group, especially in those at high risk for breast cancer. Recommendations from other agencies or groups are as follows:
American College of Obstetricians and Gynecologists (1992). Women with familial ovarian or hereditary breast-ovarian cancer syndromes who do not wish to maintain their reproductive capacity may be offered PBSO. Such women should have a documented familial syndrome, preferably established via a full pedigree analysis by a geneticist. These women should be informed that removal of the tubes and ovaries does not provide 100% protection; primary peritoneal carcinoma has been reported after bilateral salpingo-oophorectomy in some cases.
National Institutes of Health Consensus Statement on Ovarian Cancer (1994). The probability of a hereditary ovarian cancer syndrome in a family pedigree increases with the number of affected relatives, with the number of affected generations, and with young age of onset of disease. Therefore, prophylactic oophorectomy should be considered in these patients after careful weighing of the risks and potential benefits. The risk of ovarian cancer in women from families with hereditary ovarian cancer syndrome is sufficiently high to recommend prophylactic oophorectomy at age 35 years or after completion of childbearing.
· Germ cell tumors are the most common gynecologic malignancy in young women. The cure rate is 90% due to the significant advancement of chemotherapeutic regimens. The most commonly used regimen is BEP. The risk of secondary malignancy, especially hematologic, with the use of etoposide must always be considered when this regimen is administered.
· Sex cord–stromal tumors, such as granulosa cell and Sertoli-Leydig cell tumors, have the potential for steroid hormone secretion, with estrogen being the most frequently produced hormone. Aside from juvenile granulosa cell tumors, sex cord–stromal tumors rarely occur in women under 20 years. Primary treatment usually entails primary tumor resection and staging. When the pathology is malignant, the need for chemotherapy must be individualized, because no standard treatment regimen has been established.
· Tumors of LMP account for approximately 15% of epithelial ovarian cancers and have an earlier age of onset, around 40 years. All epithelial histologic subtypes of LMP tumors exist, with serous being the most common. Pseudomyxoma peritonei, characterized by extracellular gelatinous material in the peritoneal cavity, may accompany mucinous LMP tumors. Therapy for LMP tumors is surgical excision and appropriate tumor staging and, when necessary, debulking.
· Although significant strides have been made in the treatment of epithelial ovarian cancer, the 5-year survival rate remains approximately 50%. Continued efforts are needed to understand the etiology of these tumors, which ultimately will result in the development of prevention strategies, early detection, and improved therapies. Optimal cytoreductive surgery followed by platinum-taxane combination chemotherapy is the current standard treatment for advanced stage disease.
· Identification of the genes that are responsible for several familial ovarian cancer syndromes, especially BRCA1 and BRCA2, has opened up new areas of investigation and provided valuable information for understanding the development of both hereditary and sporadic ovarian carcinomas. Although there is no level I evidence to support the use of screening and prophylactic surgery in patients who are at high risk for ovarian cancer, these modalities may be considered to reduce the chance of disease development. Oral contraceptive pill use may also decrease ovarian cancer incidence in these high-risk women.