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Cancers of the Endocrine Glands and Endocrinopathies Faced by Pediatric Cancer Survivors

Maya B. Lodish, MD
  • Joan C. Han, MD, Head, Unit on Metabolism and Neuroendocrinology
  • Urania Dagalakis, BA, Postbaccalaureate Fellow
  • Kelsey B. Lokie, NIH Summer Student Program

Our primary goal is to investigate endocrine-related complications faced by survivors of pediatric cancers. In addition, we are involved in several studies aimed at improving the clinical care of pediatric patients with many types of endocrine cancers, including pheochromocytoma, Cushing's syndrome, and thyroid cancer. In conjunction with the National Cancer Institute, we are also focusing on the endocrine-related manifestations of neurofibromatosis type 1 in children with plexiform neurofibromas.

Detection and treatment of endocrine abnormalities in childhood cancer survivors and hematopoitic stem cell–transplant recipients

Although the survival rate of children with malignancies is improving, survivors of childhood cancer have a high rate of illness secondary to chronic health conditions. The types of endocrine-related conditions faced by childhood cancer survivors include hypothalamic-pituitary dysfunction and associated precocious or delayed puberty, growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Pediatric cancer survivors are also at higher risk for primary thyroid dysfunction, primary gonadal dysfunction, and associated infertility, as well as decreased bone mineral density. Gaining a better understanding of the long-term medical consequences of childhood malignancies and their treatment is essential to meet the health care needs of childhood cancer survivors. Our goal is to optimize the early detection of potential problems that may arise as a result of past cancer therapy. Many of the endocrine-related side effects are treatable, and early intervention may increase quality of life by limiting the impact of these complications on the patient's health.

In conjunction with the National Cancer Institute, we initiated an IRB-approved protocol to treat the long-term endocrine conditions faced by pediatric cancer survivors at the NIH. Our protocol, entitled "Detection and Treatment of Endocrine Abnormalities in Childhood Cancer Survivors, 07-CH-0192" has been actively accruing patients since June, 2007. The study determines the prevalence of endocrine-related side effects in children who have been treated for cancer and establishes a database and registry organized according to cancer diagnosis, treatments, and endocrine side effects. Over the past year, we expanded our protocol through collaboration with the NHLBI to include not only survivors of pediatric malignancies, but all children seen at the NIH who underwent bone marrow transplants. In addition, as pediatric cancer survivors are at high risk for metabolic syndrome and cardiovascular mortality, we recently added to our protocol assessment of early signs of cardiovascular dysfunction in our patients, using carotid MRI measurements.

Endocrine-related manifestations of neurofibromatosis type 1

Neurofibromatosis type 1 (NF-1) is one of the most common autosomal dominantly inherited disorders, with an incidence of about 1 in 3500. NF-1 is characterized by the development of benign tumors of the nervous system as well a predisposition to malignancy. NF-1 patients are at greater risk for various endocrine disorders, including short stature, precocious puberty, hypothalamic-pituitary dysfunction, diminished bone mineral density (BMD), and pheochromocytoma. The pathophysiology of impaired bone mineral density in these patients is not well understood, and further studies are needed to determine the molecular basis of these abnormalities. In collaboration with Brigitte Widemann, we are conducting endocrine evaluations of pediatric patients enrolled in the NF-1 natural history study. We aim to measure the true prevalence of diminished BMD in pediatric patients with NF-1 while correcting for patient stature. We are analyzing risk factors for BMD deficits, including vitamin D deficiency, history of chemotherapy, size and location of neurofibromas, and other heath conditions that may contribute to impaired BMD. We are also conducting an analysis of the relationship between pubertal stage, hormonal levels, and growth of plexiform neurofibromas in these patients.

Tyrosine kinase inhibitors and medullary thyroid cancer

Hereditary medullary thyroid carcinoma (MTC) is a rare calcitonin-producing tumor that arises from the parafollicular C cells of the thyroid gland. MTC represents a promising model for targeted cancer therapy, as the oncogenic event responsible for initiating malignancy has been well characterized and results from autosomal dominant gain-of-function mutations in the RET proto-oncogene. Tyrosine kinase inhibitors targeting activated RET are currently in clinical trials for the treatment of patients with MTC. We have an interest in the role of tyrosine kinase inhibition in pediatric thyroid cancer and collaborate with the NCI through a protocol studying the use of these agents in pediatric patients with medullary thyroid cancer; the protocol is entitled "Phase I/II Trial of Vandetanib (ZD6474, ZACTIMA) in Children and Adolescents with Hereditary Medullary Thyroid Carcinoma (MTC)." Since the initiation of this protocol in July of 2007, we have been undertaking endocrine evaluations in these patients when admitted to the study and during regular follow-up visits. The patients require close endocrinologic follow up for hypothyroidism, hypoparathyroidism, pheochromocytoma, and other aspects of care related to their underlying neuroendocrine tumor. Currently, we are examining the utility of Octreotide Scintigraphy in the evaluation of metastatic disease. Little is known about the effects of tyrosine kinase inhibitors on endocrine function in children. We are also evaluating the endocrine-related side effects of tyrosine kinase inhibitors in children, including alterations in thyroid hormone balance, calcium balance, and bone health.

Additional Funding

  • NICHD intramural ACI program


  • Lodish MB, Hsiao H, Sermpis A, Sinaii N, Rothenbuhler A, Keil M, Boikos S, Reynolds J, Stratakis C. Bone Mineral Density in Pediatric Patients with Cushing Disease Before and After Surgical Cure. J Pediatr 2010;156:1001-1005.
  • Lodish MB, Adams KT, Huynh TT, Prodanov T, Ling A, Chen C, Shusterman S, Jimenez C, Merino M, Hughes M, Cradic KW, Milosevic D, Singh RJ, Stratakis CA, Pacak K. Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl. Endocr Relat Cancer 2010;17:581-8.
  • Lodish M, Stratakis CA. Endocrine side effects of broad-acting kinase inhibitors. Endocr Relat Cancer 2010;17:233-44.
  • Lodish MB, Stratakis CA. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. Best Pract Res Clin Endocrinol Metab 2010;24:439-49.
  • Janeway KA, Kim SY, Lodish M, Nosé V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M, Lai AH, Kelly L, Hornick JL; NIH Pediatric and Wild-Type GIST Clinic, O'Sullivan M, de Krijger RR, Dinjens WN, Demetri GD, Antonescu CR, Fletcher JA, Helman L, Stratakis CA. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA 2010;108:314-318.


  • Aerang Kim, MD, Pediatric Oncology Branch, NCI, Bethesda, MD
  • Crystal Mackall, MD, Pediatric Oncology Branch, NCI, Bethesda, MD
  • Lawrence Nelson, MD, Program on Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
  • Karel Pacak, MD, PhD, DSci, Program on Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
  • Kathy Warren, MD, PhD, DSci, Pediatric Oncology Branch, NCI, Bethesda, MD
  • Alan Wayne, MD, PhD, DSci, Pediatric Oncology Branch, NCI, Bethesda, MD
  • Brigitte Widemann, MD, PhD, DSci, Pediatric Oncology Branch, NCI, Bethesda, MD

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