In the last decades, the 5-year survival rate of patients with childhood cancer has improved. However, the long-term survival of these patients is prevented by factors such as tumor recurrence, second primary cancer, circulatory diseases, and respiratory diseases1. Wilms tumor (WT) is a pediatric-specific cancer, with a 5-year survival rate of >90%2,3. Since the 1970s, treatment for WT has been chemotherapy, radiation therapy (RT), and operation. Although the British Childhood Cancer Survivor Study (BCCSS) has reported that the mortality risk of circulatory disorders in patients with childhood cancer increases with age1, the actual mechanism underlying the development of these complications remains unclear. We report the case of a man, who was diagnosed with WT at 3 years of age, which was treated. However, he died at 48 years of age due to circulatory disorders due to RT, and we present his clinical course, therapeutic regimens and autopsy findings in this report.
We report the caution of the treatment against for long-term pediatric cancer survivors and provide appropriate advice and information regarding their condition.
A 48-year-old man was diagnosed with WT at 3 years of age, for which he underwent nephrectomy, chemotherapy, and RT. We could not determine the details of his therapy from his chart or from his family. He developed ileus at 5 years of age, for which he underwent multiple abdominal surgeries.
At adulthood, he became a smoker. Because his bowel adhesion was very strong, he was told that he could not be operated upon anymore. He complained of abdominal pain several times and could not eat solid food because strong bowel adhesion gradually prevented foods from passing through his small intestine and colon (Figs. 1A, B). He consumed only water and an amino acid-rich elemental diet. At 34 years of age, he complained of intermittent claudication and was diagnosed with arteriosclerosis obliterans. Contrast-enhanced computed tomography showed that his abdominal aorta and left iliac artery were narrowing due to atherosclerosis and that the superior mesenteric artery was occluded (Figs. 1C, D). He complained of severe abdominal pain and diarrhea, for which he was started on central venous nutrition from 42 years of age. At 47 years of age, he underwent interventional radiology (IVR) (Fig. 2). Following this intervention, the frequency of abdominal pain increased from once a month to once a week, and he had to be admitted in the hospital. A skin ulcer developed on his left knee, and his left iliac artery was occluded again because of stent thrombosis. Although he received another IVR on the same side, his left iliac artery was occluded again. Once the skin ulcer on his left knee was cured after IVR, the left knee deteriorated and skin ulcers and necrosis developed on other parts of the body, such as left toes, buttocks, and perineum (Fig. 3).
Initially, analgesia was provided for his abdominal and leg pain by the administration of acetaminophen, tramadol, and nonsteroidal anti-inflammatory agents. However, his pain could not be controlled, and he was started on fentanyl by continuous intravenous infusion at 0.3 μg/kg/h and flurbiprofen at 150 mg/d. Despite all these medications, the pain could not be completely controlled. He developed urinary retention, for which a urethral catheter was inserted, but the perineum became necrotic. Consequently, septic shock occurred due to urinary tract or bacterial infection from bedsore lesions, and he subsequently died.
An autopsy showed that his bowels and abdominal wall had strongly adhered and that stents from the abdominal aorta to the left iliac artery were completely occluded (Fig. 4). Two major infectious lesions were noted at the perineum and buttocks. Gross and microscopic images showed multiple septic changes in the lungs, heart, and spleen, which were observed as diffuse alveolar damage, dilatation of the right ventricle, and white suppurative nodules on the splenic surface, respectively. There was no evidence of malignancy.
Currently, the health care transition for childhood cancers is a complex and challenging concern. In Japan, some adult patients are still examined by pediatric consultants or pediatric surgeons. Although there are long-term WT survivors, their long-term outcomes have not been reported. The BCCSS and other European countries have reported that the causes of death for long-term WT survivors are subsequent malignant neoplasms, cardiac diseases, end-stage renal diseases, and pulmonary diseases. However, these causes have not been researched in depth.
Although RT for WT has improved the 5-year survival rate, this therapy also has late side-effects4. Whole abdominal irradiation causes both radiation enteropathy and peripheral artery diseases5,6. Jurado et al6 reported that balloon angioplasty with or without stenting should be considered as a treatment of choice in patients with radiation-induced carotid artery disease. However, in our patient, we presume the irradiation range in his therapy was not limited and vascular damage became fatal in a short period of time. His abdominal pain originated from superior mesenteric artery obstruction, insufficient collateral circulation for his bowels, and bowel obstruction. Bowel obstruction is reported a common complication of RT of the gastrointestinal tract5. In the present case, RT and repeated abdominal surgery caused bowel obstruction. After he received IVR, his intestinal blood stream changed and abdominal pain frequently occurred. Gillbert and Byard7 have reported that fatal ischemic enteritis is a late complication in WT survirvors. Therefore, we recommend that long-term variable hemodynamics must be carefully treated. The irradiation-induced enteropathy and peripheral artery disease in some cases can cause fatal conditions. In addition to RT, we believe that our patient’s smoking worsened his iliac artery atherosclerosis. Many studies have reported smoking is a major risk of peripheral artery disease8. Smoking induces oxidative stress, vascular inflammation and platelet coagulation. Patients who have received treatment during childhood have less health-related knowledge, and such patients and their lifestyles should be carefully monitored, and they should receive regular health advice.
Although we cannot determine the number of patients who suffer from vascular complications after RT, some patients may complain of abdominal or foot pain. Initially, we used acetaminophen and loxoprofen as analgesics for our patient. However, the pain could not be controlled after his stents were occluded. Finally, we started narcotics for analgesia and achieved a good control in the beginning. However, some adverse events related to narcotics occurred—one of them being urinary retention9. Because of this complication, we had to insert a urethral catheter that led to perineum necrosis, urinary tract infection, and sepsis.
In conclusion, long-term pediatric cancer survivors should be monitored and treated by multidisciplinary teams, and their health should be carefully managed according to their age. The incidence of cardiovascular disorders is bound to increase, and patients with such risks should be provided appropriate advice and information regarding their condition.
Our study is according acceptable research standards.
Sources of funding
The authors did not receive any funding.
The authors would like to thank Makoto Urano, Sayumi Tahara, and Makoto Kuroda for the autopsy findings. The other authors were responsible for his treatment.
Conflicts of interest disclosure
The authors declare that they have no financial conflict of interest with regard to the content of this report.
Research registration unique identifying number (UIN)
This study does not have any unique identifying number.
There are no guarantor in this study.
The authors would like to thank the patient and his family. The patient wanted his treatment progress to be reported in his lifetime, and, therefore, he consented to having his pictures taken and provided permission to dissect. His family cooperated for the interviews and provided all the required information.
1. Reulen RC, Winter DL, Frobisher C, et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA 2010;304:172–9.
2. Termuhlen AM, Tersak JM, Liu Q, et al. Twenty-five year follow-up of childhood Wilms tumor
: a report from the childhood Cancer Survivor Study. Pediatr Blood Cancer 2011;57:1210–6.
3. Cotton CA, Peterson S, Norkool PA, et al. Early and late mortality after diagnosis of wilms tumor
. J Clin Oncol 2009;27:1304–9.
4. Paulino AC, Wen BC, Brown CK, et al. Late effects in children treated with radiation therapy
for Wilms’ tumor. Int J Radiat Oncol Biol Phys 2000;46:1239–46.
5. Wang J, Boerma M, Fu Q, et al. Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy. World J Gastroenterol 2007;13:3047–55.
6. Jurado JA, Bashir R, Burket MW. Radiation-induced peripheral artery disease. Catheter Cardiovasc Interv 2008;72:563–8.
7. Gilbert JD, Byard RW. Fatal ischemic enteritis with hemorrhage—a late complication of treated Wilms tumor
. J Forensic Sci 2013;58:234–6.
8. National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. The health consequences of smoking-50 years of progresss: a report of the surgeon general. Atlanta, GA: Centers for Disease Control and Prevention (US); 2014.
9. de Boer HD, Detriche O, Forget P. Opioid-related side effects: postoperative ileus, urinary retention, nausea and vomiting, and shivering. A review of the literature. Best Pract Res Clin Anaesthesiol 2017;31:494–504.