Germ Cell and Sex Cord-Stromal Ovarian Cancers
Germ Cell Tumors
Germ cell tumors of the ovary comprise fewer than 5% of all malignant ovarian tumors. Germ cell tumors arise from the primordial germ cells and sex cord-stromal derivatives; they are exceedingly common in that they account for approximately one-quarter of all ovarian tumors, yet only 1% to 5% of germ cell tumors are malignant.1–5 This disease is characterized by a young age at diagnosis. Survival is excellent due to the typically early stage at diagnosis and the relative chemosensitivity of even advanced disease, especially in comparison with epithelial ovarian, tubal, and peritoneal cancers.
EPIDEMIOLOGY
Key Points
1. The peak incidence of these tumors occurs in the 15- to 19-year-old age range.
2. Germ cell tumors may occur in setting of dysgenetic gonads, so karyotype testing may be warranted.
Within the United States, the incidence (age-adjusted) of malignant germ cell tumors is estimated at between 0.34 to 0.41 per 100,000, and rates appear to have declined over the last 30 years.1,2 Risk factors are not well understood, but include younger age; the 15- to 19-year-old age group has by far the highest incidence rates. Studies have not consistently confirmed other specific demographic characteristics, such as in utero exposures (hormones, pesticides, smoking, or alcohol), maternal reproductive history, parental occupation, or congenital abnormalities as associated risk factors for germ cell tumors.6–8 Racial differences exist in that dysgerminoma occurs twice as often in whites and other nonwhites as compared with blacks, and teratoma incidence is increased for blacks and other nonwhites as compared with whites; there appear to be no significant differences for the remainder of types.2,9
As opposed to some epithelial and stromal ovarian malignancies, germ cell tumors in females do not appear to be related to any yet-identified inherited cancer susceptibility syndromes (eg, BRCA mutations for epithelial ovarian, tubal, and peritoneal cancers and Peutz-Jegher syndrome for certain ovarian stromal tumors).10 Surprisingly, in a recent review of pediatric germ cell tumors, a family history of testicular cancer was correlated with an increased risk of male germ cell tumors; however, a family history of ovarian or uterine cancer was inversely correlated with female germ cell tumors.10 In contrast, there have been several case reports of familial clustering of germ cell tumors, and authors have hypothesized that a fraction of ovarian germ cell tumors could be a rare manifestation of a familial gonadal tumor syndrome.11
Of particular note, however, is that women with gonadal dysgenesis are at very high risk for the development of germ cell tumors. Gonadal dysgenesis is defined as a defect in development that causes abnormal sex steroid production and subsequent clinical manifestations such as delayed puberty or primary amenorrhea. In general, Turner syndrome (normally 45 X, or rarely a mosaic form of 45 X with a partial Y fragment) accounts for approximately two-thirds of diagnosed dysgenetic gonads. The majority of patients with Turner syndrome who develop tumors have the mosaic karyotype. Gonadal dysgenesis may also occur in 46 XX or 46 XY individuals. The greatest risk for germ cell tumors, especially dysgerminomas, is found in patients with Swyer syndrome (complete gonadal dysgenesis with 46 XY, but a female phenotype) and may affect more than 30% of patients12; prophylactic removal of both gonads should be strongly considered as soon as one of these syndromes is diagnosed.13
DIAGNOSIS
Key Points
1. Pelvic pain or mass is the most common presenting symptom of women with germ cell tumors.
2. The majority of germ cell tumors are stage IA at diagnosis.
3. Malignant germ cell tumors characteristically appear solid on imaging ultrasonography.
Most women with germ cell tumors present during the reproductive years, with a mean age in the early 20s. The most frequent symptoms are pelvic pain and/or mass (up to 85% of patients) followed by abdominal distension (30%), fever (10%), vaginal bleeding (10%), or ovarian torsion.1,3,5 Of note, in ovarian torsion cases, up to 10% of adult cases but fewer than 2% of pediatric cases are ultimately proven to be caused by a malignant process. 5,14,15
As part of the initial work-up for a pelvic mass in a young woman, ultrasound is the preferred radiographic modality due to the information gleaned regarding ovarian morphology and the lack of radiation. The majority of germ cell tumors are also unilateral. Only dysgerminomas are observed to be bilateral in 10% to 15% of cases.3,5
In addition, the majority of the malignant germ cell tumors will be predominantly solid (Figure 14-1).16,17 Ultrasound alone may be able to raise the suspicion for an immature teratoma (or other malignant germ cell tumor) as opposed to its far more common benign counterpart, a mature cystic teratoma. A recent study from Canada evaluating ultrasound characteristics in teratomas found that benign cystic teratomas were more commonly predominantly cystic (77% vs. 18%), and the entirely solid tumors were all immature teratomas.17 Another recent study in the pediatric population also observed that the benign ovarian germ cell tumors were smaller (7.65 cm vs. 16.9 cm; P < .001) and more often cystic compared with their malignant counterparts.16 For evaluation of extraovarian disease, magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) may be used, but due to the relatively low likelihood of malignancy and incidence of extraovarian metastases in germ cell tumors, this is often omitted during the initial mass evaluation.
FIGURE 14-1. Ultrasound demonstrating a dysgerminoma of the ovary (white solid arrow) with the adjacent normal ovarian tissue with follicles (white dashed arrow).
Diagnostic testing should include preoperative evaluation of tumor markers and should include quantitative human chorionic gonadotropin (hCG), lactate dehydrogenase, α-fetoprotein (AFP), CA-125, and baseline blood work for surgery.1,3,5,18,19 The most commonly abnormal tumor markers are hCG and AFP, and elevations are virtually diagnostic of a malignant germ cell tumor; specific patterns of tumor markers vary by tumor types (Table 14-1). Newer tumor markers may help differentiate malignant from benign masses; for example, the newly US Food and Drug Administration–approved OVA1 test (representing a combination of 5 immunoassays, including CA-125, transthyretin, apolipoprotein A1, β-2 microglobulin, and transferrin) demonstrated a 78% sensitivity for malignant nonepithelial ovarian cancers. Further research is needed, however, before applying the OVA1 test to these rare tumor types.20 For patients with suspected gonadal dysgenesis, a karyotype should be performed before surgery, if possible, to ensure both ovaries are removed if indicated.
Table 14-1 Tumor Markers in Germ Cell Tumors
Definitive diagnosis is via surgical removal using a method that allows full surgical staging if necessary and can be done via laparotomy or laparoscopy, depending on patient and mass characteristics, as well as surgeon preference. The ovary should be removed intact (ie, no intra-abdominal morcellation). Frozen section can confirm the diagnosis and further surgical management undertaken as appropriate (see Treatment section).
PATHOLOGY
Key Points
1. Dysgerminoma and immature teratoma are most common malignant types of germ cell tumors.
2. Immature teratomas are defined by the presence of immature neural elements.
3. The hallmark histopathologic feature of endodermal sinus tumors is the Schiller-Duval body.
In the latest World Health Organization (WHO) classification, germ cell tumors are categorized into 3 broad categories (Table 14-2) that include (1) primitive germ cell tumors, (2) biphasic or triphasic teratoma, and (3) monodermal teratomas (including somatic tumors arising within teratomas). Malignant germ cell tumors include immature teratomas, dysgerminomas, and endodermal sinus tumors, along with the less common types. A recent Surveillance, Epidemiology, and End Results (SEER) data review of malignant germ cell tumors found that the most frequently diagnosed subtypes were immature teratoma (36%), dysgerminoma (33%), endodermal sinus tumor (15%), mixed non-dysgerminoma types (5%), embryonal (4%), mature teratoma with malignant degeneration (3%), and choriocarcinoma (2%).2
Table 14-2 Categories of Germ Cell Tumors
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II. Biphasic or triphasic teratoma |
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III. Monodermal teratoma and somatic-type tumors associated with group II (above) |
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Adapted from World Health Organization classification of tumors: Tavassoli FA, Deville P. Pathology and Genetics of Tumors of the Breast and Female Genital Organs. Lyon, France: International Agency for Research on Cancer; 2003.
Grossly and histologically, several tumor types have distinctive appearances. Dysgerminomas are primarily solid tumors with a gray/white appearance and microscopically have sheets of vesicular cells with large nuclei with a fibrous stroma separating them (Figure 14-2). Immature teratomas are usually more solid than cystic and may contain hair or sebaceous material in a similar manner to mature teratomas; there is often extensive necrosis and hemorrhage. The immature components are comprised of neural tissue (required for diagnosis; Figure 14-3); they may also include glands, bone, or muscle.20 Endodermal sinus tumors may be both solid and cystic with soft, friable tissue that may often be either hemorrhagic or necrotic (Figure 14-4). The hallmark histologic feature associated with endodermal sinus tumors is the Schiller-Duval body, which most closely resembles a renal glomerulus. Embryonal carcinomas maybe histologically solid (with diffuse sheets of ana-plastic cells), tubular, or papillary; frequently there is a combination of these patterns (Figure 14-5). There is commonly foci of coagulative necrosis, and spindle cell stroma around tumor nests.
FIGURE 14-2. Dysgerminoma. A. Gross picture of dysgerminoma. B. Micrograph of dysgerminoma. (Image contributed by Dr. Kristen Atkins, Department of Pathology, University of Virginia Health System.)
FIGURE 14-3. Micrograph of immature teratoma. (Image contributed by Dr. Kristen Atkins, Department of Pathology, University of Virginia Health System.)
FIGURE 14-4. Endodermal sinus tumor. A. Micrograph of endodermal sinus tumor with typical vitelline growth pattern. (Image contributed by Dr. Kristen Atkins, Department of Pathology, University of Virginia Health System.) B. Micrograph of endodermal sinus tumor with associated Schiller-Duval body.
FIGURE 14-5. Micrograph of embryonal carcinoma.
TREATMENT
Key Points
1. Complete surgical resection is critical in the management of germ cell tumors.
2. Controversy exists regarding the need for comprehensive surgical staging in the pediatric population.
3. Adjuvant platinum-based chemotherapy has been recommended for treatment of all malignant germ cell tumors except stage I dysgerminoma and stage I, grade 1 immature teratomas.
4. In general, germ cell tumors are both chemo- and radiosensitive, even in advanced or recurrent disease.
Surgery
The mainstay of treatment for malignant germ cell tumors is surgery, as approximately 60% of all germ cell tumors will be confined to the ovary, and most (except dysgerminomas) are unilateral.3,5 Although ovarian cystectomy is not recommended if the diagnosis is known intraoperatively, excellent survival rates after cystectomy for immature teratoma have been reported, but notably, most patients received adjuvant chemotherapy.21 Few dispute the necessity of removal of the involved ovary, but there are divergent opinions regarding the extent (or necessity) of comprehensive surgical staging. In the gynecologiconcology community, the standard recommended surgery has included a unilateral salpingo-oophorectomy (and bilateral salpingo-oophorectomy with hysterectomy if future fertility is not desired), peritoneal cytology, peritoneal biopsies, omentectomy, and retroperitoneal lymphadenectomy, including removal of bilateral pelvic and para-aortic nodes and any abnormal tissue. Because of the extremely chemosensitive nature of the disease, extensive and aggressive surgical resection procedures may not be advised if they increase morbidity or would delay chemotherapy.
In one of the largest reviews of lymph node metastasis, Kumar et al4 found that approximately half of all patients with germ cell tumor in the SEER database diagnosed between 1988 and 2004 did not have lymph node dissection done as part of their surgery. Of the patients who did undergo lymph node dissection, overall 18% had positive nodes, and women with dysgerminoma had the highest rate of node metastases at 28%. Positive lymph nodes, not surprisingly, were an independent negative predictor of survival. Another study by Palenzuela et al22 noted that only approximately half of the malignant germ cell tumors underwent comprehensive staging; none of the stage IA patients who underwent complete surgical staging experienced recurrence during observation without adjuvant chemotherapy, and none of the stage I patients who received adjuvant chemotherapy experienced recurrence, whereas approximately 40% of the patients with presumed (but not fully staged) stage I disease had recurrence.
In the pediatric oncology and surgery community, there has been a potential shift toward even more minimal surgery (unilateral salpingo-oophorectomy, washings, directed peritoneal biopsies, and careful abdominal inspection without retroperitoneal lymphadenectomy or omentectomy unless abnormalities are detected/palpated).23 This change has occurred, in large part, from a study by Billmire et al24 that reviewed the role and outcomes of surgical staging in germ cell tumors in children and adolescents enrolled in 2 large intergroup trials that involved postoperative chemotherapy treatment (bleomycin, etoposide, and cisplatin [BEP] or high-dose cisplatin with etoposide and bleomycin). They found that deviations from standard surgical guidelines were the norm (most often the omission of lymphadenectomy), but that survival was excellent regardless of the extent of staging. They concluded that surgery should include washings, excision of any abnormal peritoneal surfaces, biopsy of any abnormal nodes or an abnormal contralateral ovary, and removal of the tumor-containing ovary. 23,24 However, all of the participants in this study received adjuvant platinum-based chemotherapy, which may have minimized any benefit of surgical staging in this very chemosensitive group of tumors.24,25
Most recently, a large Children’s Oncology Group (COG) study examining surveillance of patients with stage I germ cell tumors who did not undergo chemotherapy closed to accrual in 2010; however, these data are not yet available. Of note, the COG uses a modified staging system (not the standard International Federation of Gynecology and Obstetrics [FIGO] staging26) in which lymphadenectomy and omentectomy are not routinely performed, tumor markers and radiographic imaging are employed as part of the staging assignment process, and patients who have positive washings/cytology/ascites are classified as having a stage III tumor25(Table 14-3, COG staging; Table 14-4, FIGO staging).
Table 14-3 Children’s Oncology Group Staging for Ovarian Germ Cell Tumor
Table 14-4 FIGO Staging for Ovarian Tumors
In summary, in adult women, full staging including lymphadenectomy allows better counseling regarding the need for postoperative adjuvant therapy; however, gynecologic oncologists need to be aware that this may not be the standard practice in pediatric patients who undergo surgery with other specialists.
Chemotherapy
Postoperative chemotherapy has been generally recommended for all malignant germ cell tumors with the exception of stage I dysgerminomas and stage I immature teratomas (low grade). There has been a recent trend toward the consideration of surveillance in all stage I germ cell tumors, as many contend that recurrences are almost always successfully treated with salvage therapy; this would obviate the need for initial adjuvant chemotherapy and eliminate chemotherapy-associated short- and long-term adverse sequelae.1,3,27 Given the rarity of this disease and the overall excellent prognosis of patients with stage I disease, no randomized trial comparing surveillance with adjuvant therapy in adults will likely ever be undertaken, although a surveillance study has been completed (but not reported) in the COG for all stage I malignant germ cell tumors.
To evaluate the strategy of surveillance after surgery for all stage IA germ cell patients, Patterson et al27 reported a recurrence rate of 22% in dysgerminomas and a 36% recurrence rate for the other types. Additionally, they reported a salvage/cure rate of 90% in patients with recurrent disease. The authors concluded that all patients with stage I disease may be safely observed; however, their recurrence rates are much higher than those reported for stage I patients receiving adjuvant treatment, and not all recurrences were cured. Further, this was a small study with 37 patients (some previously reported), and this limits the conclusions.27 In other studies reported in the late 1990s and early 2000s, 3 groups evaluated surveillance alone in stage I germ cell tumors (83 patients), with an overall survival rate of 97%; 92% (12 of 13) of those patients who experienced disease recurrence were subsequently cured with chemotherapy.3,28–31 A recent study by Vicus et al32 of pure dysgerminomas found that the recurrence rate for stage IA patients without adjuvant therapy was 22% compared with 0 for those who received adjuvant treatment; again, all patients who experienced recurrence were cured. Of note, only 4 patients of the entire 65 patients in that study underwent full surgical staging (including lymphadenectomy and omentectomy).
Ultimately, the choice of adjuvant chemotherapy for stage I germ cell malignancy remains controversial and is influenced by both patient and physician preferences. Chemotherapy may be overtreatment for many women, whereas surveillance may represent undertreatment for others who might not be cured at the time of recurrence. Especially, in the absence of full surgical staging, the recurrence rates for presumed stage I malignant germ cell tumors will be approximately 20% to 40%.
Historically, the cure rate for malignant germ cell tumors has been exceedingly poor, as all women with advanced-stage disease died, and a minority of even patients with presumed stage I disease survived before the advent of chemotherapy.3 Initially, vincristine, actinomycin D, and cyclophosphamide (VAC) was used, and cure rates improved. With the advent of platinum agents, cure for this disease, even in advanced stages, is the rule rather than the exception. The mainstay of platinum-based regimens for this disease is currently BEP, and this is the recommended primary adjuvant therapy according to several large Gynecologic Oncology Group studies as well as the National Comprehensive Cancer Network guidelines.1,3,5,18,25 A common adult regimen is bleomycin 30 units/wk, etoposide 100 mg/m2/d for 5 days, and cisplatin 20 mg/m2/d for 5 days on a 4-week schedule, but multiple other dosing schemes are reported. For other patients for whom toxicity concerns are a priority, an alternate regimen is etoposide (120 mg/m2/d for 3 days) and carboplatin (400 mg/m2 on day 1) for 3 cycles on a 4-week schedule or EP (BEP regimen without the bleomycin). Other active regimens that have been used include cisplatin, vincristine, methotrexate, and bleomycin (POMB); vinblastine, bleomycin, and cisplatin; actinomycin D, cyclophosphamide, and etoposide (ACE); or vincristine, ifosfamide, and cisplatin (VIP).
Most women who present with advanced-stage disease at diagnosis still undergo surgical staging and/or debulking followed by chemotherapy. Given the extremely chemosensitive nature of the disease, however, there have been recent reports advocating the possible use of neoadjuvant chemotherapy (where chemotherapy is given before surgical resection) and fertility preservation. Raveendran et al33 reported 2 patients with advanced germ cell tumors who underwent neoadjuvant chemotherapy (BEP) and had no viable tumor at interval surgery with excellent survival.
Radiation
Germ cell tumors are also very radiosensitive, with excellent responses after radiation therapy. Since the advent of effective chemotherapy, however, the use of radiation in the adjuvant setting for germ cell tumors has been largely abandoned due to the detrimental effects on future fertility and the potential for late side effects. In the past, women with dysgerminomas were treated with either pelvic and para-aortic radiation or whole abdominal radiation with cure rates approaching 100% for early stage and approximately 60% for advanced disease.5,32
SURVIVAL AND PROGNOSIS
Key Points
1. In general, survival for germ cell tumors is excellent, and most women are cured with surgery and chemotherapy.
2. Advanced stage remains the most important negative prognostic factor.
3. Elevated initial tumor markers may portend worse prognosis.
The overall survival for malignant ovarian germ cell tumors remains excellent, and the reported 5-year survival rates range from 80% to 97% and vary according to well-established prognostic factors, particularly stage.2,4,9,14,24,27,34–36 Since the advent of platinum-based chemotherapy, cure rates for stage I disease are almost 100%, and even in advanced disease, cure rates approach 75%.3
Stage remains the most important prognostic factor in determining both recurrence risk and overall survival.1,3,5,35–37 Almost all stage I/II cancers are cured, but patients with advanced-stage disease are more likely to experience recurrence. For example, Chan et al36 reported a significant survival difference (97.6% for stage I/II vs. 85.5% for stage III/IV); 
) for all germ cell tumors in a recent SEER analysis. All advanced-stage tumors were treated with adjuvant chemotherapy as described previously. Similarly, the presence of lymph node involvement (denoting advanced stage) in a recent SEER analysis conferred a 3-fold increase risk of death compared with women without lymph node involvement.4
Tumor marker elevation (primarily hCG and AFP) at diagnosis has been relatively consistently linked to increased recurrence rates (3- to 4-fold relative risk), but although this finding has been consistent, it is not necessarily universal.5,37,38 Failure to normalize tumor markers indicates persistent disease and mandates further treatment.
Histologic type has also been found to be indicative of recurrence. Dysgerminomas have a better prognosis than the other types and have less recurrence risk.3,5,35,36 In a comparison of the impact of the 3 main histologic types, dysgerminomas appear to have the best 5-year survival rates, followed by immature teratomas and then endodermal sinus tumors (99.5% vs. 94.3% vs. 85.5%; 
).36 Lai et al35 found a 100% 5-year overall survival rate for the dysgerminoma and immature teratoma patients compared with 80% other types combined 
. Data on endodermal sinus tumors are limited to case series from single institutions or SEER data but indicate a 5-year survival rate of 72% to 90%.36,39–41 Of note, these tumors may more often be late stage; in one series, 31% of patients with endodermal sinus tumors experienced recurrence (all within 8 months), and only 1 patient was cured.39
Racial disparities have also been documented, with black and white women having lower survival rates compared with other nonwhites; it has been hypothesized that this discrepancy for black women may represent diminished access to treatment.2 Another study found a difference in survival for white compared with blacks (92% vs. 86%; P = .02) . However, on multivariate analysis that controlled for complete surgical staging, stage, and histologic type, this difference was no longer significant.9
MANAGEMENT OF RECURRENT DISEASE
Key Points
1. The majority of women with recurrent disease naïve to chemotherapy can be treated and cured.
2. Most recurrences are diagnosed within a year and very rarely after 2 years. Options for platinum-resistant disease are limited.
Most recurrences of germ cell tumors occur within the first year, and almost none is ever reported after 2 years of follow-up.1,3,5,35,37,38 Recurrences are most often detected by tumor markers but also are detected on physical or radiographic imaging. For those patients who did not receive initial chemotherapy and then experience recurrence during surveillance, BEP remains the drug regimen of choice, with an almost 100% cure rate. When including all patients with recurrent germ cell tumors, the overall salvage rate for recurrence, however, is approximately 50%.3 The optimal treatment of recurrent cancer in those women previously treated with BEP is less clear, in part due to the paucity of patients, and regimens have been adopted based on the testicular germ cell trials. Some small studies suggest a role for high-dose salvage chemotherapy with stem cell transplant, with successful long-term cures documented, but most data on this modality are from the testicular germ cell tumors.35,42 Other options that have been reported with varying success include all the previously mentioned chemotherapeutic combinations in upfront therapy (eg, BEP, VIP, PVB, POMB, ACE) as well as some new regimens undergoing evaluation, including paclitaxel/carboplatin/ifosfamide, gemcitabine, oxaliplatin/paclitaxel, and targeted therapies including bevacizumab, sunitinib, and flavopiridol.
Data supporting a role for surgical resection for chemotherapy-refractory recurrent disease are limited. In one of the only case series reported, Munkarah et al43 demonstrated limited efficacy and suggested that the role of secondary cytoreductive surgery might be limited to immature teratoma.
SPECIAL MANAGEMENT ISSUES
Fertility Preservation
Because most women with germ cell tumors are of reproductive age, fertility-sparing surgery has become the standard of care and does not adversely affect clinical outcomes.1,3,5,14,18,22–24,27,36,37,44 Fertility-sparing surgery is defined as preserving the uterus at a minimum and usually preserving the normal contralateral ovary as well. A recent SEER database review found that the median age of patients with germ cell tumors in the United States was 23 years, and the vast majority of patients had stage I or II disease. In this review, 41% received fertility-preserving surgery; this percentage increased over the time period studied, with almost half (48.4%) having fertility preservation for the most recent time period examined (1998-2001).36 There were no significant survival differences observed between women treated with fertility-preserving surgery compared with those undergoing hysterectomy and bilateral salpingo-oophorectomy.
For those young women who undergo fertility preservation, several studies have documented that most will return or attain normal menstrual function, even after chemotherapy administration.14,44,45 Yoo et al45 found that 89% of prepubertal girls and 94% of adolescents treated with chemotherapy (primarily BEP), subsequently experienced normal menses; similarly, Biswajit14 reported 100% resumption of normal menses after treatment with chemotherapy. Gershenson et al44 surveyed 132 women who had undergone treatment for germ cell malignancies and found that approximately 54% had fertility preservation and 87% of those still reported normal menstrual function; successful pregnancies were reported in approximately a third of the fertile women (of note, almost 40% were using birth control at the time of the survey). Several other authors have also reported that women can achieve pregnancy after treatment for germ cell tumors: Tangir et al46 reported 76%, Zanetta et al47 reported 86%, and de La Motte Rouge40 reported that 75% of women who attempted pregnancy were able to conceive.
Long-Term Sequelae of Treatment
Given the young age at diagnosis, women undergoing treatment for germ cell tumors also can develop late effects relating to therapy (primarily chemotherapy). In addition to the hormonal and reproductive factors addressed previously, women can develop from delayed puberty, irregular menses, and premature menopause. Of note, germ cell cancer survivors who were younger at diagnosis and report fewer gynecologic symptoms have associated better physical functioning.48 Additionally, women may develop neurotoxicity due to chemotherapy, and this finding is the most highly predictable for decreased physical quality of life.48 In comparing germ cell survivors with controls, survivors were more likely to report high blood pressure, high cholesterol, and chronic functional problems, including numbness, tinnitus, or nausea, but were less likely to report joint pain or muscle cramps.49 Most survivors have a quality of life comparable to that of controls with these minimal exceptions.
One of the most devastating potential late toxicities is the development of a secondary malignancy; this is most commonly attributed to etoposide and/or cisplatin and may approach 1% of all patients.5
FUTURE DIRECTIONS
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