Less common gynecologic malignancies

Less common gynecologic malignancies

Seminars in Oneology Nursing, Vol 18, No 3 (August), 2002: pp 207-222 207 LESS COMMON GYNECOLOGIC MALIGNANCIES AMBER DOOR W OMEN diagnosed with vu...

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Seminars in Oneology Nursing, Vol 18, No 3 (August), 2002: pp 207-222

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OMEN diagnosed with vulvar carcinoma, vaginal carcinoma, sex eord-stromal tumors of the ovary, and gestational trophoblastic tumors constitute 5% or less of malignant diagnoses. Often, these w o m e n are treated for symptoms of the disease without an accurate diagnosis because the incidence of these less c o m m o n malignancies is not frequent. The treatments that m a y be required are often multimodal and will cause acute, as well as potentially chronic physical and emotional changes. Education of health professionals and w o m e n to the signs and symptoms that should be evaluated promptly, the disease processes, t r e a t m e n t options, clinical trials, potential long-term sequela, and resources available to these women and their support system is critical. Each of these u n c o m m o n malignancies is highly curable if diagnosed early. VULVAR AND VAGINAL CANCERS arcinoma of the vulva is a rare gynecologic t u m o r constituting approximately 4% to 5% of all gynecologic malignancies.i, 2 Primary vaginal malignancies are the rarest of the malignant processes, as the vaginal tissues are relatively i m m u n e to malign a n t change. 3,4 Prognosis, as with other malignancies, is influenced primarily by stage of disease at diagnosis. The primary t r e a t m e n t modalities used for vulvar and vaginal cancers are surgery and radiation therapy.

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Incidence and Mortality Vulvar c a n c e r is ranked fourth among gynecologic malignancies, with an estimated 3,800 new cases expected in 2002. 2 The ineidence of vulvar carcinoma is thought to be rising secondary to the aging population. Vaginal cancers are the least c o m m o n gynecologic malignancy, with an expected 2,000 cases in 2002. 5 Both vaginal and vulvar c a n c e r are estimated to cause 800 deaths each in 2002. 2 Cancers of the vulva and vagina are most prevalent in women over the age of 60,1 but can occur in younger women.

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Vulvar c a n c e r is a highly curable disease when diagnosed early. In 1997 the National Cancer Database reported a 5-year survival of 93% for stage I vulvar c a n c e r and 87% for stage II. s If there were positive nodes and the p r i m a r y lesion was -< 2 era, survival was 62%. 5 Survival fell to 43% if the lesion was greater than 2 em with positive nodes. 5 Fiveyear SUlwival in w o m e n with any size primary t u m o r with three or more unilateral or two or more bilateral nodes had a 29% 5-year survival. 6 Published survival data for vaginal c a n c e r in the last 20 years is based on small patient populations accrued from as early as the 1950s with mixed t u m o r histologies. Overall survival for all stages ranged from 8% to 56%. 3,7,8 Most recently the National Cancer Database report on c a n c e r of the vagina published 5-year survival data on 792 women, showing survivals of 73% for stage I vaginal e a n e e r and 58% each for stage II to IV. 9

Etiology The exact etiologies of vulvar and vaginal malignancies remain unknown. T h e r e continues to be m u c h debate over the role of the h u m a n papilloma virus, bacterial and viral infectious processes, vulvar dystrophy, genetic eofactors, and chemical exposures. Unlike the role of h u m a n papilloma virus as a precursor in the development of cervix cancer, its role in the d e v e l o p m e n t of vulvar and vaginal cancers has not been clearly demonstrated. H u m a n papilloma virus DNA has b e e n found more often in vulvar cancers of younger w o m e n with a history of tobacco use. ~° The incidence of in situ, or preinvasive disease of the vulva has doubled in the past two decades, whereas the rate of invasive squamous cell carcin o m a of the vulva has r e m a i n e d stable, n Vulvar c a n c e r is associated with multiple risks factors and is c o m m o n in the poor and elderly in most parts of the world (See Table 1). 10-13 Vaginal intraepithelial neoplasia has b e e n the subject of increasing attention as a p r e c u r s o r for vaginal cancer, although the true malignant potential of vaginal intraepithelial neoplasia is not known. ~4 T r e a t m e n t of vaginal intraepithelial neoplasia m a y potentially reduce the c h a n c e of developing invasire c a r c i n o m a of the vagina, but this remains unproven.IS The most frequent histologic type of malign a n c y of the vulva and vagina is squamous cell carcinoma. Other malignancies sueh as malignant melanomas; sarcomas; adenoeareinomas arising in the Bartholin gland, sweat glands, or eetopie

HypeRension

Syphilis

Data from Barakat et al. 13

breast tissue on the vulva or in adenosis of the vagina; basal cell carcinomas; and invasive Paget's disease of the vulva can arise, but are rare. A great deal of attention has been focused on the d e v e l o p m e n t of clear cell adenoeareinomas of the vagina and cervix in w o m e n exposed to diethylstilbesterol (DES) in utero. Primary adenoeareinomas are rare and occur most frequently in postmenopausal women, but in a series of 519 women with primary adenoeareinomas of the vagina exposed to DES in utero, 91% were diagnosed between the ages of 15 and 27.16 It has been suggested that DES exposure m a y be teratogenie with increased adenosis and other uterine anomalies, but data do not substantiate that DES intranterine exposure is a carcinogenic event. 3,16 The ineidenee of this has decreased markedly since 19753 and should continue to decrease as the cohort of w o m e n exposed to DES in utero continues to age.3, iv Thus far, w o m e n exposed to DES in utero have shown no increased c a n e e r risk, except for clear cell adenocareinomas of the vagina and cervix. ~ s

Prevention and Detection The most frequently noted s y m p t o m of vulvar c a r c i n o m a is a long history of pruritus. Other reported symptoms are burning, bleeding, pain, or an enlarging mass. Symptoms are often noted for 6 to 12 m o n t h s before diagnosis. During this time w o m e n often self-treat with over the c o u n t e r reed-

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ieation or receive topical treatments from their medical professional based on symptoms without benefit of a vulvar examination or biopsy. Vulvar malignancies can present as benign-appearing warty, eondylomatous lesions, fiat ulcerative lesions, or pigmented lesions. Vulvar carcinomas are usually well demarcated in early stages and are most frequently unilateral. Visual examination of the vulva with a biopsy of any visible lesion at the onset of symptoms is critical to early detection and treatment. Vaginal malignancies often present with abnormal vaginal bleeding and/or watery or discolored vaginal discharge that is painless in early stage disease. Dyspaerurlia and changes in bowel and bladder function as well as pain may be present in more advanced disease. Visual inspection of the entire vaginal canal is critical to detect abnormalities. Education is a key factor in early detection of vaginal cancer. Women must be educated, particularly after hysterectomy for benign disease, that speculum examinations and PAP smears should still be performed despite the laek of their uterus/ cervix. It has been suggested that this be performed every 2 to 3 years based on the assumption that the natural history of vaginal cancer is similar to squamous cell carcinoma of the cervix, a

Diagnostic Techniques All clinically evident lesions on the vulva should be biopsied. In women with preinvasive changes

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on the vulva or dystrophies of the vulva, colposcopie examination of the vulva using a 3% acetic acid wash to the area may be helpful to the clinician in choosing a biopsy site. The biopsy should include, if possible, adjacent normal skin and the underlying dermis so that the pathologist can address depth of invasion. A punch biopsy of the lesion is preferred to excision of the lesion for establishing a diagnosis so that the gynecologic oneologist can tailor surgical margins based on the size and location of the primary tumor. The diagnosis of vaginal malignancies must include a thorough examination of the cervix, vulva, and vagina, visually, as well as by palpation with biopsies of any abnormal areas to identify not only the primary site, but the histology of the lesion. PAP smears may be helpful in the diagnosis of early vaginal cancer, but will not detect a submucosal malignancy, as with adenocareinomas. The use of eolposeopy can be helpful in identifying areas of abnormality of the vaginal mucosa.

Staging and Prognostic Indicators In 1988 the International Federation of Gynecology and Obstetrics established a surgical staging system for carcinoma of the vulva. This system was modified in 1994 to subdivide stage I disease to A or B based on depth of invasion (Table 2). 19 Before 1988, vulvar carcinoma was staged clinically based on evaluation of the primary tumor, regional lymph nodes, and a limited search for

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T A B L E 3. International Federation of Gynecology and Obstetrics Staging for Vaginal Cancer Stage 0 Stage I Stage t Stage III Stage tV

IVA IVB

"]'is T1 T2

T3 T~

Carcinoma in situ, intraep the a carc noma Carcinoma is limiied to the vaginal wal Carcinoma has involved the subvaginal tissue, but has not extended onto the pe v c wall Carcinoma has extended onto the pelvic wall Carcinoma has extended beyond tile true pelvis or has invo ved the mucosa of the bladder or rectum bullous edema or tumor bulge into the bladder or rectum is not acceptable evidence of invasion Spread of the growth to adjacent organs and/or direct extens on beyond the true pe v s Any d stanl metastas s

American Joint Commission on Cancer. 19

distant metastasis. Microscopic lymph node metastasis are not clinically palpable, and inflammation may cause enlarged lymph nodes in the absence of metastatic disease. Compared with surgical staging of vulvar carcinoma, the percentage of error in clinical staging increases from 18% for stage I disease to 44% in stage IV disease. 6 The only risk factors associated with prognosis in vulvar cancer are the diameter of the primary lesion and the status of the lymph nodes at diagnosis. 6 The age and underlying medical condition of the patient have an impact on prognosis if they preclude the surgical resection of the primary lesion and lymph nodes. Staging of vaginal cancer according to the International Federation of Gynecology and Obstetries is performed clinically not surgically (Table 3). 19 Vaginal cancer is staged using physical examination, chest x-ray, intravenous pyelogram, eystoscopy, proetoseopy, and (when indicated) barium enema and lymphangiogram. Further studies such as computed tomography or magnetic resonance imaging may be used to individualize treatment, but are not used for staging. The primary prognostic indicator in vaginal cancer is the stage of disease at the time of diagnosis. Other factors that correlate with a poorer prognosis are: age over 60 years; any symptoms at diagnosis; a lesion in the middle or lower third of the vagina; or a poorly differentiated tumor. 7,2° Also, in squamous cell carcinoma, which initially spreads along the vaginal wall before invading the paravaginal tissue, the length of the vaginal wall involvement of the tumor has been found to correlate with survival and stage of disease. 21

Primary Treatment Early stage disease.

The primary treatment for invasive vulvar malignancies in operable patients has been a radical vulveetomy with groin dissections. This aggressive surgical approach has been associated with an operative mortality rate that approached 20% in early series. 22 In the last two decades this has been reduced to 1% to 2%. 12 The most frequently encountered complication of surgery is wound breakdown, which in most series occurs in over 50%12 of patients, with impaired primary wound healing in a series from the Mayo Clinic seen in 85%.23 The trend in the last two decades is toward a more eonservative surgical approach for early vulvar malignancies to cause less disfigurement of the genitals and fewer changes in sexual function and body image. Postoperative morbidity and long hospitalizations that were associated with en bloc radical dissections, an increased number of younger women with smaller lesions, and an increased awareness of the psychosexual consequences of radical vulveetomy, are all factors that have led to this change in praetie. 24 The use of radical or modified radical vulveetomy with separate groin incisions (tripleincision approach) has been associated with decreased complications and similar survival and recurrence rates to en bloc radical vulveetomy.25, 26 Management of vulvar eaneer should be individualized with each woman. The goal of treatment is for the most conservative surgical intervention that optimizes cure. The factors that need to be considered are size of the lesion, location on the vulva, depth of invasion, risk of groin node in-

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volvement, condition of the remaining vulva, and the patients overall medieal eondition. The use of intraoperative lymphatic mapping and lymphoseintigraphy may assist the surgeon in tailoring treatment. Early results of lymphatic mapping for vulvar cancer have shown that it has the ability to deteet sentinel lymph nodes in 86% of patients; in no ease was a nonsentinel lymph node found to be positive if the sentinel node was n e g a t i v e s Careful patient selection and experience can permit sentinel node identifieation with blue dye alone in more than 95% of patients with vulvar cancer. 2s Planning primary treatment for vaginal cancer is dependent on the stage at presentation, location of the lesion, and the presence or absence of the uterus. The maintenanee of a functional vagina is an important factor to consider when planning treatment. Cases of squamous cell carcinoma reported in the gynecologic literature have been treated most commonly by radiotherapy, primarily because of the difficulty in attaining adequate surgieal margins short of exenteration. 3 For stage 1 disease with lesions located on the upper vagina, recommended treatment is radical surgieal resection with pelvie lymph node disseetion and vaginal reconstruction, if possible/feasible. This is followed by radiation therapy if reseetion margins are close or involved.8, 29 For early lesions in the lower third of the vagina, the inguinal lymph nodes must be eneompassed in the treatment field as well. Radiation therapy is also used in place of radical surgery in early stage vaginal cancer.3,s,3° In stage II vaginal cancer, combined external beam radiation therapy and braehytherapy is the standard treatment.3,30 A d v a n c e d or recurrent disease. As with early vulvar caneer, treatment in advanced and recurrent disease must be individualized taking into account the overall medical eondition of the patient and the size and location of the tumor. Treatment for stage III/IV disease is most often surgery eombined with external beam radiation therapy. 31,32 Surgical resection with adequate margins may require fecal or urinary diversion. The use of chemotherapy concurrently with radiation therapy using 5-fluorouraeil or 5-fluorouraeil and cisplatin has resulted in a 53% to 59% complete response rate in patients with primary unreseetable disease or for those who would have had to undergo an exenterative procedure to resect the tumor. 23 There have been no adequate prospective studies comparing various therapies

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or eombinations of therapies that are available for analysis .3 The treatment for advanced and recurrent vaginal carcinomas remains external radiation therapy and braehytherapy, both intracavitary and interstitial therapy with consideration for tailored surgery. 3°,33 Chemotherapy for advanced or recurrent disease does not have a significant role in disease management at this time. 3,3°,34 Nursing Im pl i cat i ons The nursing care of women with vulvar and vaginal carcinomas present particular challenges to nurses. The rarity of both vulvar and vaginal cancer present the first challenge. Many women do not know that they earl develop cancers of the vulva or vagina. Edueation regarding these malignaneies is erueial to improve early detection and increase cure rates. Nurses must educate women about the risk faetors for both diseases, teach self-vulvar examination, encourage women to continue to have pelvic examinations even after hystereetomy, and encourage them to seek medical attention for a persistent sore, itch, rash, or change in the vulva. Once the diagnosis of malignancy is made, education of the patient regarding the disease, treatment options, and potential complications is eritieal (Table 4). Written information regarding postoperative care given preoperatively is an important tool for preparing the patient for what is expected of her and her earegivers after discharge. Postoperatively, the primary concern is for wound healing. Over 50% of patients will experienee wound breakdown following a radieal vulveetomy with groin dissection. 12 Vulvectomy wounds are under tremendous stress because of multiple factors, but primarily by virtue of loeation. Both the groin and vulvar ineisions are difficult to immobilize, thus placing an undue amount of tension on them. In addition, the groin node disseetion undermines the skin, leaving a pocket in which lymphatic fluid can collect, ealled a lymphoeyst. This is a frequent oceurrenee, despite the use of postoperative drains. This lack of tissue adherenee to the underlying tissue delays wound healing and increases the risk of infection. Finally, the location of the vulvar and groin incisions in proximity to the urethra and the reetum increases the risk of infectionY Meticulous perineal care is required postoperatively and is often difficult in the older population affected by vulvar cancer. An early assessment of the patient's functional and eogni-

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.......... TABLE 4. Nursing Aspect of Vulvar and Vaginal Cancem

Preoperat ve

Postoperative

Rad ation therapy/chemotherapy

Rehabilitation/long term

genitals Education about disease, treatment, and p an of care Education on appropriate skin care of lesion and skin care pestoperat vely Provide emotional support to pat ent and fam y Thrombolic prophylaxis Assess for pu monary embo and deep ve n thrombos s Activity as ordered Pedneal care, sitz baths, and drying of perineum as ordered Instruction of patient and careg vet w th return demonstrat ons of perineal care Wound care of open wounds until healed by secondary intent Nutritional assessment Initiate early viewing of incision by patient and caregiver Educate for signs and symptoms of infection Education of drain management and drainage record f d scharge planned with groin drains in place Teach appropriate skin care of perineum (sitz bath, blow dryer) Pain medication as necessary Antiemetics as necessary with chemotherapy Education regarding management of vulvitus during radiation (iced Burrows solution, saline) Educate regarding peripheral edema; support hose, leg elevation, activity. compression sleeves Sexual dysfunction: discuss alteration in sexual activity ~ith patient and significant other if patient desires lubrication issues, vaginal dilation, positioning, change n genital appearance, referral for counseling if necessary Urinary changes (change in urinary stream direction, conduit) Disfigurement: provide ongoing emotional support, referral for psychological counSeling/assistance if necessary Education for long-term follow-up and signs and symptoms of recurrent disease

tive ability to care for her wounds will facilitate interventions to assist in wound healing. bymphedema is a potential long-term complication of surgical resection of inguinal lymph nodes or radiation to the lymph nodes. Patients should be edueated to the possibility of lymphedema preoperatively and be given instructions as to the management of lymphedema if it oeeurs. Prevention instructions include wearing loose clothing with avoidanee of tight bands around the groin, knee or anMe, the use of exercise to maintain muscle tone, the use of support stockings when standing for a long period, and not sitting with knees and hips bent for long periods of time. If

lymphedema does oeeur, patients need to be edueated in the use of eompression stockings, sequential eompression sleeves, and/or manual lymph drainage. Referral to a lymphedema specialist ean be made for a plan of eare. Cellulitis or lymphangitis are potential problems, particularly in patients who develop lymphedema. Patients need to be edueated to the signs and symptoms of both, which may inelude redness aeross the lower abdomen, groin, thigh or vulva, fever, and pain. Prompt treatment with antibioties is neeessary. A long-term, low-dose, prophylaetie antibiotie may be preseribed to deerease the ehanee of reeurrenee in the future. Education to

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avoid infections to the lower extremities include avoid going barefoot, wear shoes that fit properly, use an electric razor to shave legs, avoid cuts and serapes to legs, anMes, and feet, and avoid cutting toenails too short. For women receiving radiation therapy to the pelvis for vulvar or vaginal cancer, the major adverse effects are vaginal fibrosis and scarring with loss of blood supply and elasticity) 6 Currently, the general recommendation is for the use of a vaginal dilator or vaginal intercourse with the use of a water-soluble lubricant or estrogen cream, if necessary, two to three times per week for life. To date there has been no prospective randomized trials regarding the use of vaginal dilators to optimize vaginal length and caliber, although efforts are currently underway in the Gynecologic Oneology Group to address this issue to optimize the care of women undergoing radiation therapy to the pelvis, vagina, and/or cervix. Another potential adverse effect from radiation therapy when it is given to the vulva and groin area is desquamation of the skin, 36 although this is not life-threatening or permanent, it is distressing to the patient and may cause treatment delays. Educating the patient and her earegivers regarding meticulous skin care is essential during radiation therapy. The area must be kept clean and dry, which is often difficult, using vigilant peri-eare with mild soaps, warm water sitz baths, blow dryers, and if necessary eortieosteroid and antibiotic creams to decrease or prevent skin infections.

Conclusion Vulvar and vaginal cancers are rare malignancies that have the high possibility of cure if detected early. Because treatment is multimodal, it is often aggressive and radical to improve longterm survival. For this reason, women with vulvar and vaginal cancer should be treated at tertiary care centers. Radiation and surgery to the genital area for vulvar and vaginal cancer can cause longterm physical changes to the appearance of the vulva, functional changes to the bladder and bowel, lymphedema, and a change in sexual function. These issues must be addressed, and education of the patient and family should begin at the time of diagnosis. Communication across all diseiplines of health care is necessary for the complete care that women with these uncommon malignancies require. A nurse educated in the treatment of these rare diseases and the management of the sequelae of treatment will aid the

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patient and her family in adapting to the changes that may occur. SEX CORD-STROMAL TUMORS cord-stromal tumors are rare ovarian tuk J m o r s that comprise approximately 5% to 8% of ovarian malignancies, but account for nearly 90% of all functioning ovarian neoplasms, a7-4° These ovarian tumors are more prevalent in women under the age of 40, but are seen in women from infancy to the ninth decade. The tumors are most frequently of low malignant potential and associated with very favorable long-term prognosis. Because these tumors have a propensity for indolent growth, they tend to recur late. On average, they can recur between 5 and 10 years after the original diagnosis or as late as 20 years. 41 Unlike epithelial ovarian malignancies the presentation of women with sex eord-stromal tumors is frequently governed by the clinical manifestations resulting from the endocrine abnormalities and are predominately diagnosed at an early stage. 42

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Etiology Sex eord-stromal tumors arise from the sex cords or the ovarian stroma. This group of tumors includes granulosa cell tumors (adult and juvenile type), tumors containing theca cells and luteinized derivatives, signet ring cell stromal tumors, Sertoli cells, Leydig cells, and fibroblasts originating from gonadal stroma. 42 The most frequently seen sex cord-stromal tumors are granulosa cell tumors (adult type). Prevention and Detection There is currently no known means of preventing sex cord-stromal tumors. This group of tumors is usually diagnosed early because patients develop symptoms secondary to the endocrine abnormalities produced by the tumor. Granulosa cell, theea cell, and Sertoli cell tumors are generally considered estrogenic tumors. Sertoli-Leydig cell and steroid cell tumors are predominately androgenic, but may also have an estrogenic effect. 4°,41 When found in prepubital patients they cause sexual pseudopreeocity in 75% to 80% of girls. 43,44 Women in their reproductive years may experience menstrual irregularities or seeondary amenorrhea and cystic hyperplasia of the endometrium. In postmenopausal women, abnormal uterine bleeding is a frequent presenting corn-

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plaint. Endometrial cancer can occur simultaneously with granulosa cell tumors in 5% of eases. 4s Endometrial hyperplasia has been reported to be associated in 25% to 50% of cases. 37,4s-47

Diagnostic Technique A careful preoperative clinical and physical assessment for promontory symptoms such as amenorrhca or menstrual irregularity, abdominal pain, androgenic changes, or breast tenderness may prompt preoperative blood studies to help assess for sex cord-stromal tumors. Serum inhibin has been shown to be seven times above the normal follicular phase levels preoperatively in granulosa cell tumors and following surgery may become elevated for up to 2 years before further surgery is undertaken for a palpable mass. 4s Plasma testosterone levels may be elevated in assoeiation with Sertoli-Leydig cell tumors, though typically the diagnosis of a sex eord-stromal tumor is made postoperatively with the lesion removed intaet without the benefit of preoperative tumor markers.

Staging and Prognostic Indicators Staging of sex cord-stromal tumors is surgical. In the premenopausal patient, lesions are adequately managed by removing the involved ovary and ipsilateral tube. In the perimenopausal and postmenopausal patient, the uterus and both the involved and the uninvolved ovary should be removed. 41 Sex eord-stromal tumors are referred to as low-grade malignancies and carry a similar prognosis as epithelial borderline tumors of the ovary.

Primary Treatment The primary treatment for sex eord-stromal tumors of the ovary is surgical resection of the primary tumor with staging to assess for extra ovarian disease. If the patient is interested in maintaining fertility, the uterus and uninvolved ovary is preserved. Surgical resection alone is acceptable treatment for patients with early stage sex eord-stromal tumors because no standard therapy exists. 39,41

Chemotherapy is used to treat women with advanced and recurrent disease, but the optimal chemotherapeutic regimen has not yet been determined. Most recently the use of bleomyein, etoposide, and cisplatin has shown a 37% response rate in a study completed by the Gynecologic Ontology Group. 49 Other agents that have been reported to have responses are alkylating agents, doxorubiein, daetinomyein, and vinblastine in multiple combinations, but most reports are in cohorts of less than 15 patients. 49 To date, the role of radiation therapy is undefined. It has been used in both the adjuvant and recurrent disease setting with clinically observed responses and palliation of symptoms. ~9

Nursing Implications When caring for patients with sex cord-stromal tumors the nurse must have adequate knowledge of the disease, treatment, and prognosis. Longterm management is different than the more frequently seen epithelial ovarian malignancies. Education and emotional support are critical for the patient and family in understanding these rare tumors and treatment strategies. If eligible, patients with these rare tumors should be enrolled in a clinical trial. Following diagnosis, patients and their families must be educated regarding the details of the recommended long-term follow-up. This is particularly important for children diagnosed with these rare tumors. Follow-up will include physical examinations (to include a pelvic exam, blood marker assay testing when appropriate, and radiologic testing as indicated). Ongoing emotional support will be needed because follow-up may continue longer than 5 years because of the risk of late recurrences. The issue of fertility and sexuality should be discussed preoperatively, but must be readdressed postoperatively because of the potential for late recurrence. Open communication between the patient, nurse, and physician is critical. Fertility options should be discussed, with the possible need for referral to a reproductive endocrinologist to monitor hormone replacement and to discuss fertility options, s°

Advanced or Recurrent Disease Although the majority of sex cord-stromal tumors are diagnosed early, advanced and recurrent disease may be encountered. Granulosa cell tumors can recur 5 to 30 years after diagnosis with metastasis to the lung, liver, and brain. 47,4s

Conclusion Sex eord-stromal tumors are rare gynecologic tumors that are diagnosed most frequently in early stages and are generally considered low-grade malignancies. Like many other malignaneies, the eause

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of sex eord-stromal tumors is unknown. To date there is no specific marker or radiologie presentation that can discern a sex eord-stromal tumor from another ovarian process. Primary treatment is often surgery alone with the ability to preserve fertility in the young women that are frequently diagnosed with these tumors. There is no standard therapy recommended in the adjuvant or recurrent setting; although the combination of bleomyein, etoposide, and eisplatin has shown response in a recent Gynecologic Ontology Group study. Because of the rarity of these tumors, enrollment onto a clinical trial when eligible should be encouraged, as it is unlikely in the near future that a standard treatment will be found for sex eord-stromal tumors. Education of the patient regarding their diagnosis, options, treatment, and follow-up, along with emotional support for what likely will be a long journey, is critical GESTATIONAL TROPHOBLASTIC NEOPLASIA estational trophoblastie neoplasia (GTN) is among the rare malignancies that are curable, even in face of widespread metastasis.S1, s2 Gestational trophoblastic neoplasia broadly encompasses a spectrum of diseases originating from the ehorionie portion of the placenta and can occur following any gestational event. These tumors include complete hydatidiform mole, partial hydatidiform mole, invasive moles, ehoriocareinoma, and placental site trophoblastie tumors. Each tumor is a unique disease and varies in its ability to locally invade tissue and metastasize. Before the use of chemotherapy for GTN, the prognosis for advanced disease was dismal. This is no longer the ease for GTN, except for placental site trophoblastie tumors, for several reasons: (1) a sensitive tumor marker is produced by the tumors called human ehorionie gonadotropin (hCG). The level of the marker is directly related to the number of viable tumor cells; (2) this malignancy is extremely sensitive to various chemotherapeutic agents; (3) one can identify high-risk factors in this disease to individualize treatment; and (4) the aggressive use of multiple modalities is possible, such as single and multiagent chemotherapy regimens, radiation, and surgery. 53 The probability of cure, type of treatment, and follow-up is dependent on multiple factors. It is critical that health care providers be knowledgeable regarding GTN to enable them to provide

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timely and adequate treatment for these potentially highly curable women.

Etiology and Risk Factors Gestational trophoblastic neoplasia is a pregnancy-related event. A complete mole results from a fertilized ovum that either loses or has the maternal genetic material deactivated. In 90% of cases this results in a genetic karotype of 46, XX, caused by the duplication of a single 23, X sperm, s4 The remaining 10% are 46, XY and probably 46, XX from the result of fertilization by two sperm, s4,Ss Partial moles are triploid and arise from two sets of paternal chromosomes and a single set of maternal chromosomes. There can also be histologie evidence of fetal tissue associated with partial moles, s6,s7 Epidemiologie patterns for complete and partial molar pregnancies appear to differ. The incidence of GTN varies dramatically in different regions of the world. Asian countries have a reported incidence that is seven to ten times greater than North America and Europe. Variations in these rates may partly result from difference between hospital-based reporting versus population-based data. 5s,s9 The incidence of GTN is estimated to be 0.2 to 1.96 per 1,000 pregnancies. 6°,61 There may be a two- to four-fold increased incidence in women from Japan and Saudi Arabia when compared with other populations. 6°,61 Chorioearcinoma is much less common and estimates of incidence are highly variable. The most significant known risk factors for developing a molar pregnancy and ehorioeareinoma are a history of prior molar pregnancy and maternal age. 59 It has been estimated that women with a previous mole have over 10 times the risk of having another mole compared with women who have never had one. This risk continues to increase with each subsequent molar pregnancy a woman has. s3 Women 15 years old and younger are at increased risk and women over 40 may have a five- to 10-fold increase risk of developing a complete mole.S3,6o The risk of developing a partial mole is associated with reproductive factors such as irregular menstrnal cycles, pregnancy histories including only male infants among prior live births, and oral contraceptive use for more than 4 years. 59 Other risk factors that may play a role in the development of moles, but are less dear, are dietary intake of protein, fat, vitamin A, or carotene, socioeconomic class, genetics, professional oceu-

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pation, history of spontaneous abortions, and number of months since last pregnancy.S3,62

Prevention and Detection Essentially all women with complete hydatidiform moles have delayed menses and are thought to be pregnant. Vaginal bleeding usually occurs in the first trimester. Historically, other clinical features may include excessive uterine size, pre eelampsia, hyperemesis gravidarum, hyperthyroidism, trophoblastic embolization causing respiratory distress, and theea lutein ovarian cysts. 63 In recent years the diagnosis of complete mole is made more often in the first trimester before the classical clinieal signs and symptoms develop. However, despite earlier diagnosis, the incidence of post molar GTN has not decreased significantly.S7, 64 Partial hydatidiform moles generally present with signs and symptoms of an incomplete or missed abortion. Symptoms include vaginal bleeding and the absence of a fetal heart beat, although in rare eases a fetus may eoexist with a mole. 65

Diagnostic Techniques The use of ultrasonography is a reliable and sensitive technique for the diagnosis of a complete molar pregnancy. This is because the ehorionie villi exhibit diffuse swelling that produces a characteristic sonographie pattern that is usually referred to as a "snowstorm" pattern. However, it may not be able to identify small molar villi in the early first trimester. The specificity of sonographic findings in complete moles may be enhanced when used with the concurrent hCG level, s9 Ultrasonography may also be helpful in the diagnosis of a partial molar pregnancy. Sonographic changes associated with partial moles are cystic changes in the placenta and a ratio of transverse to anteroposterior dimension of the gestational sac greater than 1.5 eln. s7 However, beeause partial moles are frequently initially thought to be a missed abortion, the diagnosis is most often made after histologic evaluation of the curettings. 66 Human chorionie gonadotropin is a sensitive marker for gestational trophoblastie tumors, excluding placental site trophoblastic tumors. Patients with complete moles commonly have markedly elevated pre-evacuation levels. A quantitative pregnancy test greater than 1,000,000 IU/L, when combined with an enlarged uterus and vaginal bleeding, suggest the diagnosis of hydatidiform mole, even in the absence of pathologic material. 53

After making the diagnosis of GTN, the patient must be earefully assessed for any factors that eould eomplieate surgical evacuation (ie, pre eelampsia, electrolyte imbalances, hyperthyroidism, and anemia). 67 Suction curettage is the preferred method of evacuation, s3,67 Hysterectomy is an option for women no longer desirous of fertility. Although removal of the uterus eliminates the risks of local invasion, it does not prevent metastasis or the need for follow-up in the same manner as a patient that did not have a hysterectomy. 53,67 At the time of hysterectomy, if thecaqutein cysts are encountered, the ovaries should be left in situ because the cysts will regress to normal as the hCG normalizesY

Staging and Prognostic Indicators To predict the potential for chemotherapy resistance, gestational trophoblastic disease is both staged and scored based on prognostic indicators. There are currently three classification systems for metastatic gestational tumors, but lack of uniformity exists in the use of these staging and scoring systems. Different investigators not only define risk groups differently from the World Health Organization recommendations, but also modify the World Health Organization's scoring system in novel, individualistic ways that ehange the total score and outcome assessment. 6s The International Federation of Gynecology and Obstetrics uses an anatomie staging system for GTN. In 1992, the International Federation of Gynecology and Obstetries system was modified by adding two prognostic factors: (1) hCG greater than 100,000 mU/mL, and (2) duration of disease greater than 6 months since antecedent pregnancy. 69 These prognostic factors have been added as substages(Table 5). In addition to the clinical stage of GTN, a seoring system of prognostie variables, proposed by Bagshawe in 1976, 7° was modified and adopted by the World Health Organization to help clinicians define high- and low-risk patients and individualize treatment (Table 6). 7°'71 The most popular method of assessing trophoblastic tumors in the United States was advocated by Hammond et al, 72 and now frequently designated as the National Caneer Institute Classification, divides patients into nonmetastatic and metastatic groups, with the latter being further classified into low risk and high risk depending on certain prognostic factors (Table 7). s6,6s,72 A patient is considered to have a high risk of chemotherapy-resistant disease if the prognostie score is

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treated initially with combination chemotherapy. s7

higher than 7. The distinction between low- and high-risk disease applies mainly to stage II and stage III disease. High-risk scores are more likely indicative of tumors that are resistant to singleagent chemotherapy and should therefore be

Immediate staging and treatment planning on a somewhat emergent basis should be started on any woman with documented persistent hydatidiform mole, ehorioearcinoma following a term pregnancy, evidence of GTN after a therapeutic abortion or tubal pregnancy, or a remote pregnaney. 65 A thorough history and physical examination, hCG levels, hepatic, thyroid and renal rune-

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tion tests, and a chest radiograph is warranted. If there is evidence of vaginal involvement and/or choriocareinoma, computed tomography or magnetic resonance imaging should be performed to exelude liver and brain involvement.67,73 Primary Treatment

The primary treatment for stage I placental site trophoblastie tumor is hysterectomy because of the inherent resistance to chemotherapy, ss,62 The role of prophylactic chemotherapy, given concurrent or subsequent to molar evacuation, remains controversial, with the primary concern being exposing patients to potentially toxic treatment when only 20% are at risk for developing persistent GTN.62,r2 Prophylactic chemotherapy may benefit patients with high-risk complete moles when the likelihood of persistent disease is as high as 40% to 50% and there is a greater risk of developing metastases because chemotherapy prophylaxis may reduce the risk of post molar tumor by 10% to 15%.sl It may also be beneficial when hormonal follow-up is unavailable or unreliable.67,72 All other gestational trophoblastic tumors are highly sensitive to ehemotherapy. In stage I malignant gestational trophoblastic disease, singleagent chemotherapy is preferred for women who wish to maintain fertility,ss The agents of choiee are methotrexate and daetinomycin, which have resulted in high and similar remission rates in nonmetastatic disease, as well as in low- or moderate-risk metastatic disease if the duration of disease is short and the tumor burden is small.SZ,74,7s Single-agent chemotherapy with methotrexate and/or dactinomycin induced remission in 99% of patients in a study by Roberts and Lurain. 76 Both agents ean be administered by several different regimens (Table 8). Etoposide has also been shown to be effective in the treatment of low-risk gestational trophoblastic tumors resistant to methotrexate but, because of the increased risk of secondary tumors, including myeloid leukemia, colon and breast cancer, etoposide should be reserved for tumors that are likely to be resistant to single-agent therapy and in women with high-risk metastatic diseas. 77,7s The Gynecologic Oneology Group is currently investigating the use of weekly parenteral methotrexate versus every other week (pulsed) intravenous dactinomyein for the primary management of lowrisk gestational trophoblastie disease. These regimens purportedly are less costly and require fewer

treatment-related contaets than the methotrexate/folinic acid or daily dactinomycin regimens. Advanced or Recurrent Disease

Advanced and recurrent gestational trophoblastie tumors require aggressive multimodal treatment. All patients should be treated with combination chemotherapy and the selective use of radiation and surgery. 6a Triple chemotherapy regimens consisting of methotrexate, daetinomyein, and eyelophosphamide or chlorambueil were previously the combination drugs of choice. 79-81 In the 1980s etoposide, when used as primary treatment, proved to be a highly effective agent, ss Subsequently, a new combination was developed consisting of etoposide, methotrexate, daetinomytin, cyelophosphamide and vineristine (EMA-CO) (Table 9). This regimen has induced remission in 70% to 75% of patients with high-risk metastatic disease and as high as 87% of patients with cerebral metastases. Ts,s2,s3 EMA-CO has now beeome the treatment of choice for advanced gestational trophoblastic tumors, ss,62,s4 If the tumor is resistant to this regimen, eisplatin and etoposide have been shown to be active agents for resistant disease and ean be substituted for eyclophosphamide and vineristine on day 8 (EMA-EP). ss,s2,ss,s6 Combination chemotherapy is administered as frequently as toxicity allows. Treatment should be given several cycles past normalization of hCG levels to reduce the risk of relapse. 53,ss,62 Metastatic tumors are highly vaseular and friable and may cause aeute hemorrhage requiring surgical intervention. If cerebral metastases are diagnosed, whole brain irradiation (3,000 eGy in

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Follow-up surveillance with hCG testing and physieal examinations assists the practitioner with detection of reeurrenee (Table 10). Patients should be instructed to seek medical care early with future pregnancies and have an ultrasound early in the first trimester to confirm a viable fetus. The plaeenta should be examined with all subsequent pregnancies, regardless of the pregnancy outcome, and serum hCG should be monitored postpartum to exclude ehorioeareinoma. 61

Nursing ImpUcations Women who present with GTN have a broad spectrum of physical, emotional, spiritual, social, and educational needs. They are faced with a potentially lethal disease process that is directly related to their reproductive desires. The patient, her significant other, and/or family are faced with not only a pregnancy loss, but also a disease that requires prompt treatment and months of follow-up. The physical problems that may arise with GTN are bleeding, hyperemesis gravidarum, pre eelampsia, respiratory distress, hyperthyroidism, pelvic pain secondary to theea lutein ovarian cysts, and/or neurologie changes associated with brain metastases. Physical needs associated with GTN should be continually assessed and changes should be promptly reported. Chemotherapy poses yet another set of physical problems that may include nausea and vomiting, stomatitis, myelosuppression, alopeeia, and fatigue. Treatment, particularly in women with persistent disease, often causes more side effects than the disease itself. Symptom management, emotional support, and education during this time are critical to assist the patient in eompleting the prescribed therapy. The nurse must routinely asses for both treatment- and disease-related side effeets, establish 10 fractions) should be promptly instituted. 62 For vaginal metastases, the use of angiographie embolization of the hypogastric arteries have recently been used with success.62, sr

Follow-Up Women who had a complete or partial molar pregnancy can anticipate a normal reproductive outcome of subsequent pregnancies. However, there is a small chance (1%) that a mole will reoccur. Even with a history of persistent tumor requiring ehemotherapy, women can have subsequent normal pregnancies at about the same rate as the average American. There does not seem to be any increased risk of spontaneous abortion, congenital anomalies, or need for cesarean section, ss

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and educate the patient regarding interventions to prevent and manage side effects, and evaluate the outcome of those interventions. The psychological needs that may arise are fear and anxiety, grief over pregnancy loss, guilt, sexuality concerns, spiritual distress, and body image disturbance. It is important to address these issues throughout the treatment and follow-up period and to assure the patient that these feelings are normal, s9,9° If needed, referrals should be arranged with a pregnancy loss support group and for psychiatric or sexual counseling. Conclusion The educational needs for the patient and her support network are eritieal for patients with

GTN. They must be edueated regarding the diagnosis, treatment, potential toxieities, long-term follow-up, and potential long-term sequelae (secondary malignancies), if applieable. This education may help reduee anxiety and fear and promote eoping, thereby promoting eomplianee with treatment and follow-up. Although GTN are rare gynecologie malignaneies, knowledge of the signs and symptoms of this disease is eritieal for early diagnosis. With prompt aggressive treatment, even women who present with advaneed disease ean be cured. Physieal, emotional, and psychologieal support for the patient throughout disease continuum is erueial from the health eare team to maintain complianee with treatment and follow-up.

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