A 10-year-old, overweight girl presents to the clinic with 3 weeks of fever. She was in her usual state of health until 21 days before presentation, when she developed a fever in the setting of cough, congestion, abdominal pain, and myalgias. Her symptoms subsided within 5 days of onset, but she continued to have waxing and waning fevers, ranging between 102°F and 104°F (38.9°C–40.0°C), lasting for several days at a time, with occasional defervescence for up to 48 hours. She was seen in the pediatric clinic on day 7, where she was afebrile with normal examination findings. Respiratory viral polymerase chain reaction panel revealed a positive reaction to rhinovirus/enterovirus. She was diagnosed as having a viral illness and sent home with supportive care instructions regarding pyrexia management, optimizing hydration status, expected clinical course, and primary care follow-up as needed. For the next 2 weeks she had daily fevers and was seen in the emergency department several times, with documented examination findings suggesting no focal abnormalities and serial laboratory evaluations showing increasing values of inflammatory markers (white blood cell count, from 10,200/µL [10.2 × 109/L] to 15,300/µL [15.3 × 109/L]; C-reactive protein level, from 14 mg/dL [140 mg/L] to 21 mg/dL [210 mg/L]; and erythrocyte sedimentation rate, from 35 mm/hr to 51 mm/hr), with negative serial blood and urine cultures. She was seen again in the clinic during week 3 of illness with review of systems at that time noting 3 days of nausea as well as mild, intermittent abdominal bloating and discomfort. Vital signs at this visit show tachycardia (heart rate, 127 beats/min) and tachypnea (respiratory rate, 36 breaths/min), with normal pulse oximetry (99%) and blood pressure (105/68 mm Hg). Weight and height are both greater than the 99th percentile (Fig 1). Examination reveals an ill- and anxious-appearing young lady. She demonstrates rapid but nonlabored breathing and has a slightly distended, nontender abdomen without peritoneal signs, palpable mass, or hepatosplenomegaly. Her abdominal examination was functionally challenging due to baseline developmental delays, resulting in difficulty achieving a relaxed complete examination. A genitourinary examination was declined by the family.Her medical history is significant for idiopathic tall stature; chronic, presumed functional constipation; and a diagnosis of level 1 autism made at age 3 years with normal genetic testing. She is verbal with friends and family with an age-appropriate IQ but primarily communicates to providers through her parents. Historically, compliance with examinations has been limited due to communication delays. Nine months earlier her developmental pediatrician commented that she “appears much older than her stated age” and referred her to women’s health due to recent onset of menarche, which occurred shortly after her 10th birthday. Her periods at that time were listed as infrequent and irregular, lasting for 3 to 4 days on average and occurring every 4 to 8 weeks, with an estimated 2 and 3 pads per day needed to control flow on her heaviest days. Her parents reported that thelarche occurred between 6 and 7 years of age, with adrenarche concurrently appearing around this same time. A diagnostic evaluation for precocious puberty, including bone age, had not yet been pursued.The differential diagnosis at the time of her current evaluation in the clinic included infectious, connective tissue, and malignant pathologies. Specifically, there were concerns for secondary bacteremia after initial viral insult, an occult localized bacterial infection (urinary tract infection, intra-abdominal or pelvic abscess, pneumonia), a less typical bacterial process (mycobacterial, salmonellosis, toxoplasmosis) although no overt suggestive exposures were identified, or a protracted viral illness (cytomegalovirus, Epstein-Barr virus, adenovirus, enteroviruses). Primary vasculitis (immunoglobulin A vasculitis, polyarteritis nodosa), early manifestations of systemic lupus erythematosus, and inflammatory bowel disease were also considered. The presence of presumed precocious puberty and abdominal swelling increased concern for a hormonally active neoplastic process such as a gonadal tumor, adrenocortical carcinoma, or hepatoblastoma.Repeated inflammatory markers at this time were significantly elevated (white blood cell count, 23,800/µL [23.8 × 109/L]; C-reactive protein level, 302.1 mg/dL [3,021 mg/L]; erythrocyte sedimentation rate, 54 mm/hr). Radiographs of her chest and abdomen revealed a gasless abdomen and lingular atelectasis with a left-sided pleural effusion. A computed tomographic (CT) scan of the abdomen and pelvis showed ascites and a large, left-sided, complex pelvic mass that appeared adnexal in origin. Her serum α-fetoprotein (AFP) level was markedly elevated at 4,710 ng/mL (4,710 µg/L) (reference range, <8 ng/mL [<8 µg/L]), and her cancer antigen 125 (CA-125) level was high at 951 U/mL (951 kU/L) (reference range, <35 U/mL [<35 kU/L]). Based on these elevated tumor markers, presence of systemic symptoms, and abnormal chest radiographs, a CT scan of the chest was obtained and showed masses in the mediastinum with large, bilateral pleural effusions. She was diagnosed as having suspected metastatic primary ovarian malignancy. Surgical resection of her ovarian mass revealed a 30-cm, 4.59-kg mixed germ cell tumor consisting of 90% immature teratoma and 10% yolk sac tumor (Fig 2).Ovarian and other adnexal tumors are rare in the pediatric population, with an estimated incidence of 2.6 cases per 100,000 girls per year. (1) Most of these masses are benign, with approximately 10% demonstrating malignant potential. (2) In contrast to the adult population, the age-adjusted incidence of ovarian malignancy is 0.1 per 100,000 per year in girls and adolescent females compared with 11.4 per 100,000 per year in women older than 20 years. (3) Despite their infrequency, ovarian tumors are among the most common neoplasms of the genital tract in childhood and account for approximately 1% of all malignancies in females younger than 17 years. (4) These tumors thus represent an important component of pediatric oncology and often present a diagnostic dilemma for the general pediatrician because their clinical manifestations are nonspecific and often subtle.The most common presenting symptom of ovarian cancer is abdominal pain (57%), followed by a palpable abdominal or pelvic mass (46%). A small case series showed fever present in only 12% of patients, with nausea, vomiting, poor appetite, weight loss, constipation, precocious puberty, and urinary symptoms also occasionally noted on presentation. (5) Approximately 18% of cases are asymptomatic, with tumor being detected incidentally on routine physical examination or during diagnostic imaging for another purpose. There is tremendous overlap regarding the clinical manifestations of the various ovarian tumors, and distinguishing between tumor types often requires histopathologic determination. However, there are a few key features that can help distinguish benign from malignant neoplasms and may help direct the diagnostic evaluation and surgical approach. Children with a palpable mass or precocious puberty have a reportedly higher likelihood of malignancy. (6) Systemic inflammatory response syndrome, and pyrexia in particular (as described in this case), is an uncommon feature of ovarian tumors and, if present, suggests malignancy with metastatic spread. Ovarian torsion, although more commonly associated with no underlying pathologic lesion, seems to be a more frequent symptom of benign rather than malignant tumors. (7) Although not specific to ovarian malignancy, delays and errors in cancer diagnosis have been linked to cancers for which there is an atypical or nonspecific presentation, for which there is a very low prevalence of disease burden in the general population, and in children with comorbidities that may mask, alter, or add to the complexity of the presentation and examination. (8)Primary pediatric ovarian tumors generally fall into 1 of 3 categories based on their cell origins: germ cell tumors, epithelial-stromal tumors, and sex cord–stromal tumors (Table 1).Unlike in the adult population, where epithelial-stromal tumors predominate, germ cell tumors are by far the most common ovarian neoplasm discovered in children, accounting for 60% to 80% of cases. Although germ cell tumors are predominantly benign in adults, up to one-third of ovarian germ cell tumors are malignant in children. (9) In the category of germ cell tumors, 3 histologic subtypes predominate: teratomas, dysgerminomas, and yolk sac tumors. Teratomas include both immature (malignant) and mature (benign, predominantly cystic) forms. Dysgerminomas occur almost exclusively in patients with gonadal dysgenesis and thus have a proclivity for chromosomal conditions where this is a feature (eg, Turner syndrome). Yolk sac tumors, also known as endodermal sinus tumors, are rare and tend to be the most aggressive, malignant, and rapidly growing of the germ cell tumors. These tumors often present with extensive abdominopelvic cavity spread. Sex cord–stromal tumors arise from granulosa, theca, Leydig, or Sertoli cells and are unique in their proclivity to be hormonally active. Specifically, tumors with granulosa or theca cells typically produce estrogen, resulting in isosexual precocity. Sertoli-Leydig cell tumors have a tendency to produce androgen analogues, resulting in phenotypic androgen excess. Epithelial-stromal tumors are extremely uncommon before menarche because hormonal stimulation is typically required to activate their growth. (13)The stages of diagnostic evaluation depend on the clinical features evident at the onset of evaluation. Well-appearing females with a palpable abdominal mass suspected to be adnexal in origin should undergo imaging to determine whether the finding is more likely physiologic (eg, simple ovarian cyst) or neoplastic. Transabdominal ultrasonography is the imaging modality of choice in this case. If features concerning for malignancy are present, CT or magnetic resonance imaging should be pursued to elucidate the nature and extent of the tumor. Although it is difficult to distinguish between benign and malignant ovarian tumors purely from imaging, findings that suggest malignancy can be found in Table 2. (11)Once an ovarian tumor is discovered, assay of targeted tumor markers is the recommended next step to help facilitate diagnosis, dictate preoperative planning, and follow postoperatively for response to therapy. The most commonly cited serologic markers are serum AFP, β-human chorionic gonadotropin (β-hCG), CA-125, and inhibin. Serum AFP levels are primarily elevated in patients with malignant germ cell tumors, including yolk sac tumors, immature teratomas, and embryonal carcinomas. Although it is uncommon, AFP level can also be elevated in sex cord–stromal tumors. β-hCG levels are primarily linked to embryonal carcinomas and mixed germ cell tumors. CA-125 levels are commonly more elevated in patients with epithelial ovarian tumors than with germ cell tumors. This tumor marker, however, has low sensitivity and specificity for detection of ovarian malignancy in the pediatric population and can be elevated for a variety of benign reasons in postpubertal patients (endometriosis, ovarian torsion, menses). It thus has limited clinical utility in evaluation of pediatric ovarian tumors. Lactate dehydrogenase level is commonly elevated in dysgerminomas, and inhibin is a sensitive marker of tumor activity in sex cord–stromal tumors. Although tumor markers can be helpful, it is important to note that up to 46% of malignant tumors have no detectable elevations in tumor markers. (13) The ultimate nature of the tumor, malignant or benign, cannot be confirmed until histologic analysis is performed. Absence of metastases also does not exclude malignant histology.Contemporary management of ovarian germ cell tumors is evolving as collaboration among pediatric, genitourinary, and gynecologic oncologists continues to better characterize effective risk classifications, adjuvant therapy candidates, and surveillance strategies. (14) Surgical resection is the primary therapeutic modality for ovarian germ cell tumors, with oophorectomy or salpingo-oophorectomy serving as the definitive treatment for most cases. Adjuvant chemotherapy is considered for patients based on tumor stage, histologic findings, and risk stratification at the time of diagnosis but is typically reserved for children with metastasis beyond the ovary, residual disease, or failure of serum markers to normalize after resection (Table 3). (14) Candidates for postoperative chemotherapy are recommended to receive a platinum-based regimen, traditionally consisting of bleomycin, etoposide, and cisplatin. (14) A fertility-sparing surgical approach is considered the standard of care in pediatric patients with ovarian germ cell tumors, although surgical planning must take into account the unique clinical manifestations, presence of serum tumor markers, distinctive imaging features, and population-based tumor characteristics to generate an optimal approach. (12) Although cryopreservation of the nonaffected ovary may be considered, patients undergoing fertility-sparing unilateral salpingo-oophorectomy, even those requiring postoperative chemotherapy, have favorable fertility outcomes. Case series have shown that regular menstrual cycles return in 87% to 97% of women who had complete response to treatment (consisting of fertility-sparing surgery and platinum-based chemotherapy). (17)(18) Of those attempting conception after treatment, 75% were able to successfully achieve pregnancy. (18) Prognosis, including event-free and overall survival rates, depend primarily on age (<11 years old is considered a positive prognostic indicator), histopathologic tumor type, as well as the tumor stage at diagnosis but are generally favorable (Table 4). (19)(20) Of note, in children with hormonally active tumors resulting in precocious puberty, pediatric endocrinology plays a critical role in the initial evaluation and postoperative surveillance. Treatment of the primary malignancy with fertility-sparing techniques resolves or diminishes pubertal findings in almost all surviving patients with an intact hypothalamic-pituitary-gonadal axis. (21)The patient was diagnosed as having a rapidly growing mixed germ cell tumor with metastatic spread to the omentum and spread beyond the abdomen to the mediastinal lymph nodes (Children's Oncology Group stage IV). After salpingo-oophorectomy and greater oomenectomy she was started on chemotherapy with bleomycin, etoposide, and cisplatin. Her pleural effusions resolved shortly after tumor resection, and cytologic analysis showed transudative fluid with absent tumor burden. At the time of this writing, the patient tolerated her first round of chemotherapy well, with excellent response to interventions. Her most recent AFP levels were within normal limits.