Introduction

Dysgerminoma is a germ cell tumor (GCT) which comprises 2–15% of ovarian tumors in the dog.^1–4 In humans, ovarian dysgerminoma most commonly affects females <20 yr old and is typically treated with a combination of surgery/chemotherapy and/or salvage radiation.⁵ Radiation is most often used either postoperatively, adjunctive to chemotherapy, or at relapse when definitive surgical options are lacking as this can impair future fertility.⁵ The prognosis is generally excellent regardless of metastatic disease or disease burden.⁶ Previous veterinary studies have included surgical treatment but with limited follow-up and without adjunctive therapy.^1,3 This highlights the significance of the following report, which describes the associated diagnostic evaluation, as well as outcome following the use of combination palliative radiation therapy (RT) and chemotherapy for recurrent and metastatic dysgerminoma in a dog.

Case Report

An ∼8 yr old female spayed (3.4kg) poodle/terrier mixed-breed dog was referred to the University of California, Davis, Veterinary Medical Teaching Hospital (UCD-VMTH) for evaluation of an abdominal mass noted on examination by the primary veterinarian. For 2–3 mo prior to presentation, decreased muscle mass was noted with concurrent progressive abdominal distention. Increased respiratory rate and effort as well as a reduced appetite were also noted within the prior 1–2 wk. Historically, an 11 cm abdominal mass was identified and resected via ovariohysterectomy 425 days prior to presentation to the UCD-VMTH. Histopathology of the mass revealed a left ovarian dysgerminoma with evidence of vascular invasion, a mitotic index of >30, moderate anisocytosis/anisokaryosis, as well as right ovarian involvement.

Physical examination at UCD-VMTH revealed decreased bronchovesicular sounds ventrally bilaterally, increased respiratory rate/effort, and a firm ∼10 cm caudal abdominal mass. Body condition score was noted to be 3/9 with muscle wasting along the dorsum as well as symmetric truncal alopecia.⁷ Previous bloodwork (within 2 wk of presentation), including a complete blood count (CBC) and biochemical profile, were unremarkable. Thoracic radiographs demonstrated a large cranial mediastinal mass causing dorsal displacement of the trachea, severe widening of the cranial mediastinum, and border effacement of the cranial cardiac silhouette margin. Abdominal ultrasound revealed a lobular heterogeneously hyperechoic retroperitoneal mass spanning from portal hepatis to the urinary bladder. The mass enveloped the aorta from the mesenteric root to the external iliac artery branching. There was severe hydronephrosis of the kidneys bilaterally. Ultrasound-guided fine-needle aspirates from both the retroperitoneal and mediastinal masses, read by board-certified clinical pathologists, revealed malignant neoplasia compatible with dysgerminoma.

Pre- and postcontrast computed tomography (CT) was performed using a 16-slice multidetector CT^a at 120 kVp, 150 mA, 5.62 mm/rotation, 10 mm detector collimation (0.625 mm × 16 detectors), 0.625 mm slice thickness, 0.562 pitch, and 17.8 × 17.8 cm field of view with a standard soft tissue kernel in ventral recumbency. Nonionic iodinated intravenous contrast media^b (740 mg I/kg) was administered, and images were acquired with a standard soft-tissue kernel. The study was reviewed on DICOM dedicated stations using Eizo 24 in. color LCD monitors^c with 1920 × 1200 resolution pixel size of 0.27 and a contrast ratio of 1200:1. Viewing software used was efilm^d, and the window and level could be manually altered.

CT images identified a 6.8 × 5.5 × 5.3 cm, lobular, soft tissue attenuating, mildly contrast-enhancing cranial mediastinal mass (Figure 1). The mass displaced the trachea dorsally, heart caudally, and cranial vena cava to the right. The left cranial lung lobe was markedly displaced caudally and laterally, and the bronchus was compressed. Additionally, an 11 × 10.6 × 6.8 cm lobular, soft tissue attenuating, mildly heterogeneously contrast-enhancing retroperitoneal mass was identified (Figure 1). It encircled and ventrally displaced the aorta and caudal vena cava with central soft tissue attenuating material noted in the vena cava. Severe bilateral hydronephrosis was confirmed on CT and compatible with bilateral ureteral obstruction.

View Figure

• Download as Powerpoint
• Download Figure

The dog was anesthetized and positioned in a moldable bag^e prior to CT for RT planning.⁸ An intensity modulated radiation therapy (IMRT) plan was created^f. Organs at risk (OAR) were contoured, including spinal cord, lungs, heart, liver, kidneys, bladder, small intestines, and rectum. The gross tumor volume (GTV) included all identifiable abnormal tissue within the thorax and abdomen. Because the GTV was large and directly adjacent to multiple OAR, the planning target volume (PTV) was equivalent to the GTV (478.5 cm³ based on the contoured volume) (Supplementary Table I).

A total PTV dose of 20Gy was prescribed such that 95% of the volume received full dose. A 6 MV sliding-window IMRT plan was designed with a single isocenter placed between the thorax and abdominal PTV, 11 equidistant fields, and using heterogeneity correction (Figure 2). Volumes of and doses to the PTV and OAR are presented in Supplementary Table I. Verification of the treatment plan was performed for quality assurance using a diode array^g with Gamma analysis having a 98% pass rate with a 3 mm distance-to-agreement and 3% difference in dose.

View Figure

• Download as Powerpoint
• Download Figure

Eleven days post-CT, 6 MV photons from a linear accelerator with a 2.5 mm leaf, high-definition, multileaf collimator were used to deliver 5 consecutive daily RT fractions of 4 Gy^h. Anesthesia for RT was induced with propofolⁱ IV given to effect, followed by endotracheal intubation, and maintained using isoflurane^j. A cone-beam CT image set was used daily to verify positioning (X-ray tube current 20 mA, voltage 100 kV, exposure 149 mAs, time 7.47 s). The retroperitoneal mass was smaller by day 4 of treatment causing incidental inclusion of kidneys, bladder, and small intestine within the PTV margin. On treatment day 5, CBC/chemistry were performed with grade 1 neutropenia, grade 2 anemia, and grade 1 elevation in blood urea nitrogen identified.⁹ Twenty-four hours after RT completion, grade 2 vomiting and diarrhea were reported, which responded within 36 hr to oral supportive medications (metronidazole 10mg/kg per os q 12 hr^k and maropitant citrate^l 1–2 mg/kg per os q 24 hr). The neutrophil nadir (grade 1 [1757/uL]) was identified 5 days after RT, which normalized within 11 days, and the anemia/elevated blood urea nitrogen resolved 18 days postradiation.⁹

Cell counts were considered adequate for chemotherapy 11 days after completing RT (UCD-VMTH cut-off = ≥2000 neutrophils/uL). Abdominal ultrasound and thoracic radiographs performed at this visit, 11 days post-RT, showed a partial response assessing longest diameter in the retroperitoneal and mediastinal masses with size reductions of 64 and 46%, respectively.¹⁰ Clinically, the dog’s quality of life had also improved, with recovered appetite and respiratory rate/effort. Alternating bleomycin/carboplatin was initiated based on chemotherapeutic approaches for human ovarian dysgerminoma.^11,12 The protocol commenced with bleomycin^m administered subcutaneously at 0.3 mg/kg.¹³ Carboplatin was administered 1 wk later following a normal CBC, and the owners were instructed to obtain a CBC 1 and 2 wk following this dose. With bilateral hydronephrosis, pretreatment with IV fluids (at 56 mL/kg/d for 2–3 hr) and a reduced dose of carboplatinⁿ at 5 mg/kg was administered intravenously.¹⁴ The recommended CBCs were not pursued, but no adverse events were reported. Three weeks after the carboplatin, another CBC was performed and confirmed normal cell counts prior to the next dose of bleomycin. Forty-one days following radiation completion and after one dose of each agent, complete radiographic remission of the mediastinal mass was documented. Continued alternation in this manner and progressive, mild dose escalation of carboplatin, in 0.1 mg/kg increments up to 7 mg/kg, was successfully achieved without complication. No adverse events were noted by the owners or on repeat diagnostics and no dose delays were necessary.

Ninety-three days after initiating chemotherapy (after three doses each of bleomycin/carboplatin), ultrasonographic remission of the retroperitoneal mass was noted as well as resolution of the alopecia. However, new hepatic nodules were identified, and cytology confirmed metastatic malignant neoplasia, compatible with dysgerminoma. One additional dose of bleomycin was attempted, but continued progression of the hepatic nodules was identified ultrasonographically. With progressive disease, single-agent doxorubicin^o was initiated at a dose of 1mg/kg intravenously every 3 wk. Ultrasonographic resolution of hepatic involvement was noted 3 wk postdoxorubicin initiation and maintained after seven doses (median 0.95 mg/kg). Remission was cytologically confirmed 81 days after the last chemotherapy dose. No hematologic, gastrointestinal (GI) adverse events, or dose delays were noted, but following the seventh dose of doxorubicin (119 mg/m² lifetime dose), a reduced systolic dysfunction was identified compared with a prior echocardiogram (60% versus 36.5%), which in conjunction with the complete response, prompted discontinuation of the drug. The dog remained in remission at last follow-up, 524 days after presentation and 501 days after completing radiation.

Discussion

To the authors’ knowledge, this is the first report characterizing the use of RT and subsequent chemotherapy for ovarian dysgerminoma in the dog. GCTs in humans are exquisitely sensitive to chemotherapy and radiation, but response rates in veterinary patients are largely unknown. One report described radiotherapy for dogs with metastatic seminoma, another GCT, which in combination with the human literature, prompted its use herein.¹⁵ For this case, surgical resection was not feasible, and quality of life was poor at presentation. Given the unknown response to chemotherapy and extensive disease present, adjunctive radiation was offered as a salvage therapy. A palliative course of radiation was chosen given the significant tumor burden, respiratory, as well as renal compromise, and unknown expectations for outcome.

IMRT was elected to spare regional organs with a high degree of precision and accuracy.¹⁶ Prevention of long-term damage to the lungs and kidneys were of particular interest, whereas the dose to the GI tract was minimized to reduce acute side effects. Minor early GI side effects 24 hr post-RT likely indicate some inclusion of GI tract within the radiation field but were responsive to supportive medications. Similarly, inclusion of bone marrow likely occurred given the large PTV but resulted in tolerable hematologic effects.¹⁷ Adaptive RT may have ameliorated this, where additional radiation plans are created during treatment courses with tumor shrinkage.¹⁸ Tumor size was reduced on cone-beam CT after 4 days of treatment, but adaptive RT was not feasible because of protocol duration; however, it could be beneficial for longer courses. At publication, 524 days post-RT, no late-term side effects had been noted.¹⁹

Given the sequential administration of the palliative radiation and chemotherapy, it is difficult to know the benefit of and response to each modality individually but was recommended given the recurrent and metastatic nature in this case. Adjunct chemotherapy is used in humans for recurrent dysgerminoma and, as in this dog, has been effective in controlling disease.²⁰ Although an initial response was noted following palliative radiation and alternating carboplatin/bleomycin, subsequent hepatic involvement prompted initiation of rescue doxorubicin therapy. This regimen was elected based on reported use of doxorubicin-based protocols in platinum-refractory cases in people as well as client preference.²¹

Conclusion

In conclusion, this report suggests use of combined RT and chemotherapy for this rare tumor type and illustrates the potential benefits of IMRT for the avoidance of critical structures. Despite extensive disease, quality of life was greatly improved secondary to multimodal therapy with minimal acute side effects, and remission maintained 524 days after presentation.