Educational Perspective
Radiology’s Role in the Battle against Pediatric Cancers Richard B. Gunderman, MD, PhD, Darren L. Transue, MD
If you would understand anything, observe its history and development. —Aristotle Like most medical disciplines, radiology is relentlessly forward looking, always tending to focus on the latest innovations. Journal articles and continuing medical education courses are replete with the latest developments in imaging science and technology, outlining their implications for the daily practice of radiology. This is both natural and good. However, there are risks in gazing only in the forward direction and never pausing to reflect on where we have been. For one thing, we cannot draw lessons from our mistakes and successes unless we reflect on our past. Moreover, understanding the contributions of predecessors can enhance our appreciation for the value of the capabilities we currently enjoy, ensuring that we do not take them for granted. Above all, we cannot see our current location and trajectory unless we understand where we have come from. One of the most remarkable stories in medicine in the latter half of the 20th century was the successful battle against many pediatric cancers. For example, about 3000 children each year are diagnosed with acute lymphoblastic leukemia. In the 1950s as today, a child 3 to 5 years of age would present to a physician’s office with complaints of pallor, shortness of breath, bruising, headaches, and lack of appetite. A blood smear would show a large number of lymphocytic blasts. In 1950, effective treatments were unavailable, and the question was not whether the patient would die, but how soon. Today, patients diagnosed with acute lymphoblastic leukemia enjoy a 90% survival rate. Happily, such progress has not been restricted to leukemias, and the overall survival rate of US children diagnosed with cancers of all types has risen from approximately 10% in 1950 to >80% today. Cancer in childhood is relatively uncommon, accounting for only 13,000 of the 1.3 million new US cancer diagnoses each year. This being said, however, children’s cancers have served as important models for the management of cancers
Acad Radiol 2012; 19:1300–1303 From the Department of Radiology, Indiana University, 702 North Barnhill Drive, Room 1053, Indianapolis, IN 46202. Received June 14, 2012; accepted June 23, 2012. Address correspondence to: R.B.G. e-mail:
[email protected] ªAUR, 2012 http://dx.doi.org/10.1016/j.acra.2012.06.003
1300
in patients of all ages. Pediatric oncologists were pioneers in the use of multi-institutional trials to develop and evaluate diagnostic and therapeutic protocols, through such initiatives as the National Wilms Tumor Study Group, the Children’s Cancer Research Group, and the Pediatric Oncology Group. Many of the findings of these groups, such as the value of multimodality therapy, were first identified in children. By treating the care of every patient as a learning opportunity and widely sharing the lessons learned, pediatric oncology opened up new pathways in the treatment of all cancer patients. Radiology has been privileged to play a vital role in the battle against pediatric cancers. This battle coincided with the introduction of a number of new mainstays in clinical imaging, such as sonography, computed tomography (CT), magnetic resonance (MR) imaging, and nuclear medicine. Without the abilities these new imaging modalities provided to diagnose, stage, assess treatment response, and maintain surveillance for recurrence, many advances in pediatric oncology would not have been possible. Many radiologists who trained in the past few decades may not appreciate the magnitude of the difference radiology has made. The purpose of this article is to survey the nature of radiology’s contribution to the care of pediatric cancer patients. To do so, we focus on three illustrative pediatric cancers: primary central nervous system (CNS) malignancies, Hodgkin’s lymphoma, and Wilms tumor.
CENTRAL NERVOUS SYSTEM MALIGNANCIES Primary CNS malignancies include a variety of neoplasms with varying biologies, prognoses, and treatments (1). They also represent the second most frequent form of pediatric cancer. Common types include astrocytoma, brain stem glioma, ependymoma, and medulloblastoma. Craniopharyngiomas are also usually included. Overall, the 5-year survival rate between 1975 and 2000 increased from 15% to 70%. Prior to the early 1970s, the diagnosis of these lesions typically required a number of relatively invasive procedures, such as pneumoencephalography, ventriculography, and arteriography. In 1971, the pioneering pediatric neuroradiologist Derek Harwood Nash reported that Sick Children’s Hospital in Toronto had performed 1200 special neuroradiologic procedures, 80% of which consisted of one of these three examinations.
Academic Radiology, Vol 19, No 10, October 2012
Initially pioneered by Walter Dandy (of Dandy-Walker malformations), pneumoencephalography involved the injection of air during lumbar puncture, then ‘‘tumbling the patient head over heels,’’ sometimes using a gyroscopic device of the sort used to induce motion sickness in astronauts, to get the air to rise into the cerebral ventricles. If the results of pneumoencephalography were unsatisfactory, ventriculography could be performed. This involved opening the cranial vault and dura and then injecting air using a needle directly into the ventricles. In the 1972 textbook Pediatric Neuroradiology, Harwood Nash described catheter angiography as ‘‘the initial procedure in the evaluation of cerebral neoplasms,’’ ‘‘requiring bilateral internal and external carotid injections in order to characterize the primary lesions and assess for dural involvement.’’ Such procedures involved significant risks and adverse effects. Although cerebral angiography is generally a safe procedure, any time a catheter is passed up the aorta and into the carotid arteries, there are risks of bleeding, dissection, and thromboembolism. Pneumoencephalography required the violation of one of the routine precautions of lumbar puncture; namely, keeping patients supine for a period of $6 hours to prevent spinal headaches. Patients who underwent this procedure often reported the severest headache, nausea, and vomiting they had ever experienced. And ventriculography carried all the risks associated with craniotomy, including infection and bleeding. If the needle was passed through the tumor, it increased the risk for bleeding even further. Today’s patients, to say nothing of contemporary radiologists, are extraordinarily fortunate to live in the era of CT and MR. To be sure, the quality of the initial computed tomographic scans in the early 1970s was, by today’s standards, little short of appalling. Moreover, the very earliest scanners required that the patient’s head be placed in a water bath to provide a ‘‘zero-base coefficient for imaging.’’ And the actual scan took $30 minutes to complete, with the computers of the day laboring for hours before images were available. Nevertheless, the ability to peer inside the skull noninvasively represented a new and glorious age in neuroimaging. In 1983, Sweet wrote in Clinical Radiology that ‘‘CT has truly revolutionized the work of the pediatric neuroradiologist, for whom invasive techniques.have become occasional, rather than daily tasks.’’ We should not leave the subject of pediatric CNS malignancies without pausing to remark on the changing role of irradiation in their treatment. During this same time period, physicians also began to recognize the deleterious effects of therapeutic doses of ionizing radiation on the brain. Whole-brain irradiation was shown to be associated with median IQ scores in the 60 to 65 range 5 to 7 years after therapy. Radiation therapy of the spine was associated with hypoplasia of the vertebral column and spinal cord. Finally, the relative risk for secondary CNS or thyroid malignancies proved to be increased approximately threefold to sixfold. This has led to a shift, wherever possible, away from
RADIOLOGY’S ROLE IN PEDIATRIC CANCER
whole-brain radiotherapy and toward a more targeted approach. It has also increased reliance on chemotherapy, which generally does not affect the developing CNS so severely. HODGKIN’S LYMPHOMA Hodgkin’s lymphoma accounts for approximately 10% of lymphomas diagnosed in the United States each year, representing approximately 8200 cases (2). It has a bimodal distribution, with peaks occurring at 15 to 20 years of age and again in patients aged > 55 years. When the disease was first identified in the 19th century, it was considered highly lethal, with a 3-year mortality rate of 90% and virtually no survivors at 5 years. Today, however, the cure rate of Hodgkin’s lymphoma is >90%. A famous survivor of the disease is Paul Allen, cofounder of Microsoft, who was diagnosed and successfully treated in 1983. In 2009, however, Allen was diagnosed with non-Hodgkin’s lymphoma. Second malignancies are a known long-term risk of treatment for Hodgkin’s lymphoma. Other famous Hodgkin’s survivors include former Pennsylvania senator Arlen Specter and Pittsburgh Penguins hockey star Mario Lemieux. The disease is named after Dr Thomas Hodgkin, a British physician who first described it in a paper published in 1832 (3). He noted that the disease seemed to spread along continuous lymph node chains and, in advanced cases, often involved the spleen. However, he did not investigate the disease using a microscope. It was at the turn of the 20th century that Dorothy Reed at Johns Hopkins and Carl Sternberg in Germany independently described the characteristic histologic finding in the disease, the ‘‘owl’s eyes–like’’ giant cells known as Reed-Sternberg cells. In the 1930s, investigators noticed that soldiers exposed to mustard gases in World War I suffered from bone marrow depression, and by the 1940s, nitrogen mustard had become the first effective chemotherapy agent. In the 1960s, a combination of chemotherapy agents called MOPP (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone) was introduced as the first combination chemotherapy, improving the remission rate by more than 4 times. A key component in the prognosis and treatment of Hodgkin’s disease is accurate staging. Decades ago, a mainstay of staging was exploratory laparotomy, an operation in which the surgeon examines organs such as the spleen and looks for enlarged lymph nodes. Although it is relatively straightforward to remove the spleen, the surgical examination of lymph node chains requires extensive surgical dissection. In an effort to achieve a less invasive form of staging, in the 1950s, Kinmonth developed lymphangiography (4). This involved injecting methylene blue dye between the toes, making the lymphatic vessels visible underneath the skin of the foot. A radiologist could then inject oily contrast material into the vessels. Because the lymphatic vessels are so small and fragile, contrast could be injected at the rate of only about 1 mL every 1301
GUNDERMAN AND TRANSUE
10 minutes. Radiographs of the lower extremities, pelvis, abdomen, and chest could then be used to determine whether any of the lymph node chains were involved. Today, the staging for Hodgkin’s lymphoma is dramatically improved. It includes nonradiologic studies, including blood tests, biopsy of enlarged lymph nodes, and bone marrow biopsy. In addition, patients undergo a variety of imaging examinations, including chest radiography and CT or MR imaging of the neck, chest, abdomen, and pelvis. To determine whether organs such as the spleen and groups of lymph nodes are involved, CT and MR rely on anatomic criteria, especially abnormal enlargement. By contrast, positron emission tomographic scanning is able to assess the metabolic activity of tissue, thereby increasing both sensitivity and specificity of imaging. Thanks to these and other imaging examinations, suspicious masses can be needlebiopsied percutaneously, avoiding more invasive open surgical biopsy. As a result, many patients no longer need to undergo exploratory laparotomies and other invasive surgical procedures to diagnose and stage their disease. WILMS TUMOR Wilms tumor is the most common primary malignant renal tumor of childhood (5). Initially known as embryoma, it was described by the German physician Max Wilms in a classic 1899 article. In fact, William Osler had described the signs and symptoms associated with the lesion some 20 years earlier. The earliest known specimen of the tumor extends even further back in history, having been placed on display in the museum of the Royal College of Surgeons in London by John Hunter, who died in 1793. Today, about 500 new cases of Wilms tumor are diagnosed each year in the United States. It has served as the paradigm for multimodality treatment of a pediatric solid neoplasm. Again, it is one of the success stories of pediatric oncology, the 5-year survival rate having increased from 10% in 1920 to >90% today. For most of the first half of the 20th century, the diagnosis of Wilms tumor relied primarily on physical examination and exploratory laparotomy. A large abdominal mass would be palpated, and surgery would be scheduled to determine its site of origin and histologic diagnosis. Plain radiography played a role, but it was often not possible to do more than estimate the tumor’s approximate location and size. In some cases, plain radiography of other parts of the body could be helpful. For example, the presence of multiple pulmonary nodules, present in 20% of patients with Wilms tumor at diagnosis, suggested Wilms tumor, while if the patient had multiple skeletal metastases, neuroblastoma would be favored. Angiography could be used to determine the organ of origin, blood supply, and shape of the tumor, but final diagnosis and staging were a surgical matter. In the 1950s and 1960s, the mainstay of diagnostic imaging in pediatric abdominal masses was intravenous urography, often referred to as intravenous pyelography. Contrast was injected intravenously, and serial radiographs were 1302
Academic Radiology, Vol 19, No 10, October 2012
obtained to visualize the kidneys and their excretion of the contrast material. Key parameters to be evaluated included the position of the kidneys, their contours, and the characterization of calyceal abnormalities. The typical finding in a Wilms tumor was a large renal mass that displaces and distorts the collecting system. Wilms tumors have a propensity to invade the renal vein and inferior vena cava, so aortography or cavography was often performed, to better characterize the extent of vascular invasion. Such information was important not only for diagnosis and staging, but also for surgical planning. With the advent of ultrasound, it became possible to image the kidneys noninvasively. Sonography has become the most appropriate initial imaging exam in an infant or small child with an abdominal mass. It is also excellent at assessing for tumor invasion of the renal vein and inferior vena cava. CT can provide even more information about the site of origin, tissue characteristics, and extent of the lesion. In addition, CT enables accurate, noninvasive staging of the lesion, to determine the extent of its spread. Intravenous urography simply could not provide this information, and ultrasound generally does not perform as well. Compared to CT, MR does an equally good and perhaps even better job of characterizing and staging the tumor and does not require ionizing radiation. MR is also better than ultrasound and CT at identifying small cancerous and precancerous lesions in the opposite kidney. However, MR is clearly inferior to CT when it comes to assessing for pulmonary metastatic disease. CONCLUSIONS There have been extraordinary advances in the diagnosis and treatment of pediatric cancers, but there are major obstacles to further progress (6). Despite the fact that one in 300 children in the United States will be diagnosed with cancer by the age of 20 years, the annual US incidence of pediatric cancer of only 13,000 cases per year means that the number of cases of each specific pediatric cancer type is small. The high costs and low odds of ever bringing a drug to market make pharmacologic research in this area an economically unattractive proposition. Another problem is the fact that children do not vote, and research into children’s cancers often does not receive the same level of political support as adult diseases such as breast cancer. Moreover, children are not small adults, and their cancers often behave differently from adult cancers, limiting the ability to piggyback on research in adults. Finally, the ethical considerations of cancer research differ in children, and standards for approving new studies are often both higher and less well formulated. Despite these obstacles, the future of radiology as a vital contributor to the care of pediatric cancer patients appears bright. Radiology will continue to play a vital role in identifying and diagnosing tumors, assessing their size and extent, monitoring response to therapy, diagnosing complications related to therapy, and providing surveillance for recurrence.
Academic Radiology, Vol 19, No 10, October 2012
Immediate prospects for additional contributions include improved image quality and speed of imaging, decreased reliance on sedation and anesthesia, reductions in the risks and costs of imaging, and the introduction of new molecular imaging techniques. To continue to build on this impressive foundation, radiologists involved in the care of pediatric cancer patients need to learn from and work collaboratively with pediatric oncologists and surgeons. Pediatric oncologists were pioneers in collaborative clinical investigation, and radiologists would be well advised to continue to emulate their example.
RADIOLOGY’S ROLE IN PEDIATRIC CANCER
REFERENCES 1. Gupta N, Banerjee A, Haas-Kogan D. Pediatric CNS Tumors. New York: Springer, 2009. 2. Hoppe RT, Mauch PT, Armitage JO, et al. Hodgkin Lymphoma. Philadelphia, PA: Wolters Kluwever, 2007. 3. Hellman S. Thomas Hodgkin and Hodgkin’s disease: two paradigms appropriate to medicine today. JAMA 1991; 265:1007–1010. 4. Gouch MH. Lymphangiography in children. Arch Dis Child 1964; 39: 177–181. 5. Geller E, Kochan PS. Renal neoplasms of childhood. Radiol Clin North Am 2011; 49:689–709. 6. Boklan J. Little patients, losing patience: pediatric cancer drug development. Mol Cancer Ther 2006; 5:1905.
1303