Hong-Ru Chen, Medical Student, University of Hawaii John A. Burns School of Medicine, Honolulu, HI; Sarah Fryberger, Staff, Pediatric Hematology and Oncology, Kapiolani Medical Center, Honolulu, HI; Jeffrey D. Lee, Associate Clinical Professor of Surgery, University of Hawaii John A. Burns School of Medicine, Honolulu, HI; Linda L. Wong, Professor of Surgery, University of Hawaii John A. Burns School of Medicine, Honolulu, HI
Hong-Ru Chen, BA
University of Hawaii
John A. Burns School
Sarah Fryberger, MD
Jeffrey D. Lee, MD
Professor of Surgery
University of Hawaii
John A. Burns School
Linda L.Wong, MD
Professor of Surgery
University of Hawaii
John A. Burns School
Primitive neuroectodermal tumors (PNETs) of the kidneys are extremely rare and generally occur in young adults. These tumors are often large and patients present with abdominal or flank pain and hematuria. Treatment usually includes radical nephrectomy and postoperative chemotherapy. PNETs are aggressive and prognosis varies. Long-term survivors have been reported, but few centers have much experience with these tumors. We report the case of a successfully resected PNET of the kidney that extended to the renal vein, inferior vena cava, right atrium, and hepatic veins in a patient with Budd-Chiari syndrome.
A previously healthy 17-year-old Filipina girl came to our institution reporting fatigue and increased abdominal girth of 3 months' duration. She attributed the swelling to weight gain and began exercising more. She noted that exercise resulted in an asymmetrical loss of her abdominal swelling and observed greater protuberance on the right side. She reported becoming fatigued easily, dyspnea, and palpitations upon minimal physical activity. One week before admission to the hospital, the patient experienced fever and chills. She reported no nausea, vomiting, anorexia, abdominal pain, hematuria, or changes in her bowel habits. She had no major medical history, but her family history was notable for gastric carcinoma, diabetes mellitus, and hypertension.
Physical examination revealed abdominal distension with a fluid wave, massive bilateral lower extremity edema, and pleural effusions. Her weight gain was 65 pounds from baseline. A computed tomography (CT) scan showed a large retroperitoneal mass that involved the right kidney and extended into the renal vein, inferior vena cava, right atrium, and hepatic veins (Figure 1). She had Budd-Chiari syndrome, hepatomegaly, ascites, and a bilirubin of 15 mg/dL (Figure 2). An open biopsy of the renal mass yielded a diagnosis of PNET of the right kidney with extension into the inferior vena cava and right atrium. Fluorescent in situ hybridization (FISH) of the tumor showed EWSR gene translocation, consistent with PNET/Ewing sarcoma.
The patient was placed on an aggressive neoadjuvant chemotherapeutic regimen of vincristine, doxorubicin, and cyclophosphamide. After completing three cycles, she developed a febrile syndrome of unclear etiology. CT scans demonstrated several new lesions in her left lung. An abdominal CT scan showed the mass in the retroperitoneum had only a minimal radiographic response. There was continued involvement of the inferior vena cava and right atrium, although the liver was not as enlarged and the ascites had resolved.
Resection of the pulmonary lesions showed only chronic inflammation and fibrosis, with evidence of . No malignancy, granulomas, or were identified. Acid-fast staining was negative.
Because of the opportunistic infection, chemotherapy was stopped and the patient was given systemic antifungal therapy. Five months after the initial diagnosis, she underwent exploratory laparotomy and median sternotomy with curative intent. Preoperatively, her laboratory findings included total bilirubin, 7.9 mg/dL; prothrombin time, 14 seconds; serum albumin, 3.1 g/dL; hemoglobin, 14.6 g/dL; and creatinine, 1.3 mg/dL. During the operation, a massive, 20 x 20-cm renal mass with palpable extension into the renal vein, inferior vena cava, and right atrium was found. After the mass was mobilized, the patient underwent cardiopulmonary bypass through the femoral vein and superior vena caval cannulas. Hypothermic circulatory arrest was then initiated to avoid the risk of tumor embolization. After obtaining vascular control, the lower inferior vena cava, renal vein, and right atrium were opened simultaneously and the tumor's intravascular portions were removed. Transesophageal echocardiography (TEE) was used to guide complete excision of the tumor from the retrohepatic inferior vena cava and hepatic veins (Figure 3). After reversing the cardiopulmonary bypass and heparinization, the right kidney and mass were removed using radical nephrectomy.
Pathology revealed PNET/Ewing sarcoma involving the kidney and perinephric fat with invasion into the renal vein (Figure 4). All margins were clear and there was no nodal involvement. The resected vena caval tumor contained a blood clot and fibrous tissue revealing viable PNET/Ewing sarcoma with necrosis (Figure 5). The patient's postoperative course was notable for mild coagulopathy and pancreatitis, which resolved with conservative treatment. She was discharged from the hospital on postoperative day 16 and continues her course to recovery. Her bilirubin levels and abdominal girth are normal, and there is no evidence of metastatic disease. Additional courses of chemotherapy are planned.
PNETs, in association with peripheral nerves, were first described by Arthur Purdy Stout in 1918 in a case report that involved an ulnar nerve tumor.1 These tumors commonly occur in the soft tissues of the trunk, head, neck, and extremities. PNETs of the kidneys are exceedingly rare. The exact number of cases is difficult to determine because these tumors are sometimes not clearly differentiated from extraskeletal Ewing's sarcomas.2
Macroscopically, PNETs are large, bulky tumors. They tend to be a grayish color, encapsulated, and contain focal areas of hemorrhage, necrosis, or both. The tumor can be sharply demarcated from a normal kidney and can present with rupture. PNETs are categorized as small round cell tumors because, histologically, they contain small round cells with rounded nuclei and scant cytoplasm (Figure 4). They often exhibit different patterns of rosettes, perivascular rosettes, and spindle cell elements. A Homer Wright rosette formation suggests the presence of immature neural tumor cells such as neuroblastomas, which are also seen in PNETs. Special stains and neural markers such as CD99, neuron-specific enolase (NSE), and monoclonal antibodies can be helpful in making the correct diagnosis. CD99 is detected in PNETs and Ewing's sarcomas. NSE, S100 neurofilaments, and chromogranin-A can exclude typical and atypical extraosseal Ewing's sarcomas. Should these prove insufficient for establishing a diagnosis, electron microscopy, DNA image cytometry, FISH, and molecular pathology?such as reciprocal translocation of chromosomes 11 and 22 [t(11;22)(q24;q12)]?can be used as confirmatory tests.3,4
Because PNETs are uncommon, the literature consists mostly of case reports, which currently includes 38 cases. PNETs are found equally in both sexes and tend to occur in relatively young patients. The literature shows an age range from 4 to 69 years, with 33 of the 38 reported cases occurring in patients younger than 42 years. Patients present with flank and abdominal pain, hematuria, or a palpable mass. Tumors ranged from 4 to 21 cm and exceeded 10 cm in 60% of cases.2-14
In the 22 reported cases that included treatment data, all patients underwent nephrectomy or radical nephrectomy, and 16 received adjuvant chemotherapy (Table). There were no consistent protocols, and treatment included various combinations of vincristine, ifosfamide, doxorubicin, VP16 cyclophosphamide, carboplatin, paclitaxel, interferon, estramustine, and etoposide. Four patients received adjuvant radiation therapy, one underwent radiation for bone metastases, and one had a bone marrow transplant after chemotherapy.2-13
Ten patients were reported to have PNETs of the kidneys that involved a major renal vessel, four of whom had tumors that extended into both the renal vein and inferior vena cava.3,5-9 One of those four patients had extension into the right atrium. A 23-year-old patient from Japan had pulmonary metastases at the time of her radical nephrectomy and resection of her inferior vena cava thrombus.6 These metastases apparently regressed after surgery, and she was alive and disease-free at 12-month follow-up. A 28-year-old patient underwent radical nephrectomy and inferior vena cava thrombectomy for a 13-cm mass and received adjuvant vincristine, cyclophosphamide, doxorubicin, and etoposide.7 He was alive without recurrence at 12-month follow-up. The third patient with venal caval involvement was a 55-year-old woman whose 5.7-cm mass extended into the right atrium.3 The mass was resected with radical nephrectomy, inferior vena caval and right atrial thrombectomy, cardiopulmonary bypass, and deep hypothermic circulatory arrest. She received adjuvant ifosfamide, cyclophosphamide, and doxorubicin and was alive 5 months after treatment. The only reported case to mention Budd-Chiari syndrome involved a 17-year-old girl with a 14-cm mass extending into the renal vein and inferior vena cava.9 A radical nephrectomy was performed, but the caval thrombus, which extended from the left renal vein to the retrohepatic segment of the inferior vena cava, was left behind. The patient died of Budd-Chiari syndrome and liver failure approximately 5 months after surgery.
In our case, Budd-Chiari syndrome was identified at the time of diagnosis. Neoadjuvant therapy with vincristine, doxorubicin, and cyclophosphamide was used to reduce the size of the tumor, and the patient subsequently underwent a complete surgical resection. Early removal of the intravascular tumor component was deemed essential to avoid tumor embolization. This also served to markedly relieve liver congestion, which facilitated the radical nephrectomy. Intraoperative TEE was helpful to ensure complete removal and coring out of the intravascular tumor from the less accessible retrohepatic inferior vena cava and hepatic veins. Our patient was alive and disease-free 7 months after her condition was initially diagnosed.
The literature leaves the prognosis for patients with PNETs difficult to determine. Many studies suggest PNETs are aggressive, but most of these are case reports with only limited follow-up. Of the 28 patients whose outcomes were reported, 15 were alive 5 to 64 months after diagnosis and 9 were eventually rendered disease-free. Recurrences were both local and distant. Although large studies are not possible for PNETs, aggressive management with both surgery and chemotherapy may allow long-term survival.
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