Nearly 25% cases of pyrexia of unknown origin (PUO) may be associated with malignancies but this fever can be attributed to a multitude of causes. In contrast, neoplastic fever by definition is a diagnosis of exclusion and a rarely reported presenting symptom of cancer. We share our experience of yolk sac tumour in an 18 year old unmarried girl who presented with high grade fever as the chief complaint. No cause could be found for her fever even after extensive workup and she failed to respond to empirical antibiotics. Response to oral Naproxen (Naproxen test) suggested the diagnosis of neoplastic fever in this patient. The patient was taken up for staging laparotomy after resolution of fever and unilateral salpingoophorectomy and omectectomy was done. The patient stayed afebrile following appropriate surgical management which further corroborated our diagnosis of neoplastic fever. This unsual presentation should be further studied and considered early on incases of malignancies to avoid delay in diagnosis and management.
An 18-year-old unmarried girl presented to our emergency with a history of high-grade fever for two weeks associated with abdominal lump which was insidious in onset and rapidly increased in size over a period of one week. The fever was sudden in onset, not associated with chills and rigors without other localizing signs or symptoms. It was temporarily relieved with paracetamol only to recur again and was not responsive to over the counter antibiotics.
At the time of presentation, the patient had an Eastern
Cooperative Oncology Group (ECOG) performance score
of 3, high-grade fever (104 °F), tachycardia (106 bpm), and
severe anemia. She had decreased breath sounds in right
basal zone on chest examination with no added sounds, and
abdominal examination revealed a large abdominopelvic
lump corresponding to 32 weeks size gravid uterus which
was occupying all the quadrants, firm, immobile, non-tender
with irregular margins, and overlying normal skin.
The patient was evaluated for fever and empirically started on injectable broad-spectrum antibiotics in view of raised leucocyte count (20,000/mm3, DLC-N86, L8, M5, E1B0). She had a hemoglobin of 5.8 gm% (MCV-111.4, MCH-34.7 AND MCHC-31.2) with normal liver and kidney function tests. All her body fluid samples were sent for culture and sensitivity before the institution of antibiotics, which came back negative. CECT chest showed a right pleural effusion of 3.2 mm with collapse of underlying lung, athletic bands, and few enlarged supraclavicular lymph nodes (up to 12 mm). Pleural fluid cytology was negative for malignant cells and tuberculosis.
The CECT abdomen was suggestive of large abdominopelvic mass (19 × 11 × 18cm) arising from right adnexa with vascular solid component and enhancing internal septations (Fig. 1). Tumor markers showed raised alpha fetoprotein (AFP) levels (> 3000 ng/ml) and LDH (899 IU/l). These findings were highly suggestive of a malignant ovarian yolk sac tumor.
After discussion with the tumor board, the patient was planned for primary cytoreductive surgery but declared unfit in view of persistent high-grade fever and severe anemia. Antibiotics were stepped up. Since the fever was not responding to antibiotics and the TLC was persistently high, empirical antitubercular treatment (ATT) was started on the basis of chest findings, despite a negative tuberculosis screen. The diagnosis of neoplastic fever was considered after the patient failed to respond even to empirical ATT. Subsequently, naproxen test was administered (375 mg of naproxen twice a day for 2 days). Her pleural fluid culture report showed a growth of acinetobacter sensitive to levofloxacin, and patient was started on levofloxacin on the same day as naproxen. The fever of the patient abated, and she was given blood transfusions to build her up for surgery. After 48 h of stopping naproxen, the patient developed fever again. And there was no change in her TLC while still being on levofloxacin which confirmed that the fever had responded to naproxen and not levofloxacin. Naproxen was given again to the patient to settle fever, and she was taken up for staging laparotomy. Right salpingoophorectomy with removal of solid cystic mass with bilateral pelvic lymphadenectomy with infracolic omentectomy was done (Fig. 2). The histopathology report confirmed a malignant yolk sac tumor, stage pT1aN0Mx limited to the ovary with negative lymph nodes, and omentum. In the post-operative period, the patient was afebrile, her AFP levels declined, and leucocyte counts drastically decreased (HB-8.7, TLC-11,690, DLC-N73.9, L13.9). The continued afebrile state of the patient post-surgery further corroborated our diagnosis of neoplastic fever. Her ATT was stopped, and she was planned for 4 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy in consultation with the medical oncology department and discharged in satisfactory condition. On follow-up, patient tolerated first cycle of chemotherapy well and her AFP after first cycle was 109 ng/ml.
Fever in malignancy patients can be attributed to a wide
spectrum of causes, but it is important for clinicians to consider
the diagnosis of neoplastic fever as a part of the paraneoplastic
syndrome, if other causes are ruled out.
The exact etiology is elusive, but it has been attributed
to release of pyrogenic cytokines (interleukin-1, interleukin-
6, and tumor necrosis factor) from tumor cells or macrophages
responding to these tumor cells. These cytokines
induce prostaglandin E2 synthesis which acts on the preoptic
nuclei of hypothalamus to reset the thermostatic set point.
Unfortunately, there is no fever pattern specific to neoplastic
fever. Some authors have reported features like low
incidence of chills and rigors, no or minimal tachycardia,
mental changes, less response to acetaminophen, and more
dramatic defervescence with NSAIDS such as naproxen. In
our case, the tachycardia was continuous, irrespective of
fever, and can be attributed to severe anemia. In another case reported by Kansara et al. [1], the patient reported with
high-grade fever and overt hypothyroidism. As in our case,
fever was persistent, with no other identifiable cause and
resistant to empirical antibiotic therapy. In their case also,
fever disappeared after cytoreductive surgery.
Conflict of interest The authors declare that they have no conflict of interest.
Informed Consent An informed consent was taken from the patient for the publication.
