Evaluation and Management of Childhood Hypothalamic And Pituitary Tumors

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Chapter 13

Evaluation and Management of Childhood Hypothalamic And Pituitary Tumors

Cristina Traggiai and Richard Stanhope

Intracranial and spinal cord tumors are the most frequent type of childhood cancer after leukemia. Tumors in the pediatric age group differ from adults in the types and location of tumors, the value of extensive surgical resection of malignant tumors, the importance of chemotherapy, improved prognosis, and the delay in using radiotherapy. The relationship between tumor location and tumor type is close. Advances in the therapy of malignant brain tumors in children have led to a significant improvement in survival rates over the last few years. Radiation therapy still plays a major role in the management of intracranial malignancies. Together with surgical resection and, more recently, chemotherapy, this has led to improvement in the outcomes of several tumor types. Endocrine symptoms are well recognized as sequelae of the treatment of intracranial tumors. Much less commonly, hypothalamic tumors can result in children presenting with growth failure and/or endocrine dysfunction. Endocrinopathies are significant consequences of childhood intracranial tumors and their treatment. The risk of developing these adverse events is related to the underlying tumor, as well as surgery, chemotherapy, and irradiation therapy.

Epidemiology

Intracranial and spinal cord tumors are the second most frequent type of childhood malignancy after leukemia, accounting for approximately 20% of cases.¹ While much is known about the epidemiology of malignant intracranial tumors in childhood, there is a paucity of information about benign tumors. The incidence of brain tumors in childhood is 3 per 100,000. The highest age-adjusted incidence, 31.4 per million, was observed in the Nordic countries, and rates between 24 and 27 per million were found in most other predominantly white populations. In the United States, the age-adjusted incidence rate was 36% higher in males and 68% higher in females than the rate based on malignant tumors alone. Black children had a significantly lower incidence than white children. Lower rates were seen in South America, Africa, and Asia; the lowest rates were for Chinese populations and for blacks in Africa, both below 15 per million. Among white populations, astrocytoma was the most common histologic type, often with an incidence of at least 10 per million, followed by medulloblastoma, 5 to 6 per million, and ependymoma, 2 to 4 per million. In other regions with lower incidence rates, these three types accounted for similar proportions of the total. Black children in the United States had a higher incidence of craniopharyngioma than white children, and there was an unusually high incidence of pineal tumors in Japan, 0.9 per million compared with 0.3 to 0.4 in many other countries. An incidence rate of 2.76 per 100,000 people younger than 18 years of age was found. Tumors in the suprasellar/hypothalamic region are unusual, the most common being craniopharyngiomas, which are approximately 9% of childhood intracranial tumors; other tumors are much rarer. The incidence of intracranial germinoma is only 0.26 cases per million children per year.¹^,² Considerable progress has been made toward improving survival for children with brain tumors, and yet there is still relatively little known regarding the molecular genetic events that contribute to tumor initiation or progression. Nonrandom patterns of chromosomal deletions in several types of childhood brain tumors suggest that the loss or inactivation of tumor suppressor genes is a critical event in tumorigenesis. Deletions of chromosomal regions 10q, 11, and 17p, for example, are frequent events in medulloblastoma, whereas loss of a region within 22q11.2, which contains the INI1 gene, is involved in the development of atypical teratoid and rhabdoid tumors.

Classification

Intracranial tumors are most commonly situated in the posterior fossa in 70% of cases, in the supratentorial region in 30%, and can occur at any age, although the most frequent age is between 2 and 5 years. The classification can be made either on the basis of histology or on the location of tumor site (Table 13-1). Many sellar and suprasellar tumors in childhood, such as craniopharyngiomas and Rathke’s cysts, do not originate from the central nervous system and are not “brain tumors.” Hypothalamic tumors are usually hypothalamic hamartoma, low-grade astrocytoma, Langerhans’ cell histiocytosis (LCH), and dermoid and epidermoid tumors. Tumors such as craniopharyngiomas and germinomas tend to affect the hypothalamus indirectly, originating in the peripituitary or pituitary region and extending upward. The pituitary stalk is typically affected from lesions such as germinomas, LCH, and craniopharyngiomas. LCH commonly affects the middle of the pituitary stalk, in a similar appearance to tuberculosis and sarcoidosis, which may be related to LCH cells involving the cerebrospinal fluid. The anterior pituitary is frequently affected by benign pituitary adenoma, whereas the posterior pituitary is the common location of pilocytic astrocytoma and LCH. Malignant glioma, meningioma, Schwann cell, and pituitary tumors, as well as metastases (which are the most common intracranial tumors in adults), are comparatively uncommon in children.³ In contrast, benign glioma, primitive neuroectodermal tumors, and craniopharyngiomas account for a substantially higher percentage of intracranial tumors in children than in adults.⁴^,⁵ Classification of primitive neuroepithelial cells is based on appearance of the tumor as determined by light microscopy, immunocytochemical techniques, and ultrastructural features without consideration for site of origin.⁶

Table 13-1

Histologic Classification of Intracranial Tumors

Supratentorial midline tumors	Low-grade glioma
	Craniopharyngioma
	Germ cell tumor
	Pineal cell tumors (pineocytoma/pineoblastoma)
Supratentorial hemispheric tumors
Infratentorial tumors

Symptoms and Signs

The mode of presentation depends on the age of the child and the location of the tumor. Symptoms and signs can be usefully divided into those from raised intracranial pressure, focal neurologic signs, and endocrinopathy. Nonspecific symptoms of increased intracranial pressure are repeated and frequent headaches, especially if they are worsening and associated with nausea or vomiting, often occurring in the early morning; irritability; listlessness; vomiting; failure to thrive; macrocephaly; and loss of developmental milestones.⁷ Epilepsy may be the initial presenting feature of an intracranial tumor. This may be due to the structural abnormality caused by the space-occupying lesion but may be secondary to the associated endocrinopathies of hypoglycemia (secondary to growth hormone and/or cortisol insufficiency) or hyponatremia (from the syndrome of inappropriate antidiuretic hormone secretion). Although young children are more likely than infants to manifest localizing neurologic abnormalities, these are by no means uniformly present. In older children, a larger percentage of tumors manifest with localizing symptoms and signs that often suggest the location as well as the histologic identity of the tumor. Midline tumors often present in an insidious onset with various symptoms and signs: visual defects such as nystagmus, complete loss of vision, and diplopia because of paralysis of the lateral rectus muscles due to a sixth nerve palsy or due to raised intracranial pressure because of obstruction of the cerebrospinal fluid pathways; neuroendocrine dysfunction, behavioral and appetite disturbances, and regression of motor skills; or they may reflect the compression or infiltration of adjacent structures. Pineal region tumors typically manifest with eye movement abnormalities, such as Parinaud’s syndrome or hydrocephalus and alteration of consciousness.⁸

Endocrine Dysfunction

For both benign and malignant tumors, presenting symptoms usually reflect the age of the child and the position of the tumor. Growth failure in children with occult intracranial tumors is characteristic. In idiopathic (congenital) growth hormone deficiency (GHD), birth length is relatively short, but growth rate is normal until approximately 18 months of age, when a gradual deceleration occurs. Idiopathic GHD is usually easily distinguished from the growth failure associated with an occult intracranial tumor, in which growth is initially normal and height is appropriate for the parental percentiles, followed by a marked growth deceleration. This is usually due to GHD but may exceptionally be due to the presence of the intracranial tumor with normal endocrine function. Absence of puberty of more than 2 standard deviations (SD) will require neuroradiologic imaging, but delayed puberty with growth deceleration is usually due to constitutional delay of growth and puberty. Even a child with suspected constitutional delay who does not respond to sex-steroid therapy should be investigated endocrinologically and neuroradiologically. Craniopharyngiomas commonly present with failure to enter puberty or arrested puberty associated with an abnormal growth spurt; they usually demonstrate an absence of the normal consonance of puberty.⁹

The idiopathic form of central precocious puberty (CPP) occurs in 74% of affected girls, and in 60% of affected boys, who are more likely to have an occult intracranial tumor than girls.¹⁰^,¹¹ Although it is commonly recognized that gonadotropin-dependent precocious puberty (or CPP) in boys is usually caused by an intracranial lesion, it used to be believed that girls had an idiopathic etiology and did not require neuroradiologic imaging. Recent large series of girls with gonadotropin-dependent precocious puberty have shown that both girls and boys should have neuroradiologic imaging. Although in girls with CPP, hypothalamic hamartoma is the most common lesion, other tumors such as astrocytomas may present in this fashion; it is important not to miss the opportunity for an early diagnosis. Intracranial tumors causing CPP in girls are histologically specific, despite being in the same anatomic site involving the hypothalamus between the mamillary bodies and the median eminence, and may be related to the secretion of specific local growth factors. CPP may be caused by hypothalamic hamartomas, astrocytomas, optic gliomas, pineal tumors, and arachnoid cysts. Interestingly, some other suprasellar tumors such as craniopharyngiomas, germinomas, and LCH are only rarely associated with the development of gonadotropin-dependent precocious puberty, despite the lesion being in the same anatomic site. High-risk factors for the presence of an intracranial tumor in children with CPP are: a young age of onset (under age 3), high serum luteinizing hormone concentrations not associated with the development of a luteinizing hormone surge, and high serum leptin concentrations. However, it is impossible to exclude an intracranial lesion in a child with CPP without performing a magnetic resonance imaging (MRI) scan.¹²^,¹³ Diencephalic syndrome is a rare cause of failure to thrive in infancy and early childhood. The syndrome is characterized by profound emaciation despite normal or increased caloric intake, absence of cutaneous adipose tissue, locomotor hyperactivity, euphoria, and alertness. It commonly occurs in association with chiasmatic and hypothalamic gliomas. It has also been described in association with other lesions, such as midline cerebellar astrocytomas, suprasellar ependymomas, suprasellar spongioblastomas, and thalamic tumors.¹⁴ Such children may even present to an eating disorder clinic, their growth failure attributed to an anorexic illness.¹⁵

The onset of diabetes insipidus (DI) with or without an evolving anterior pituitary endocrinopathy is suspicious of a space-occupying lesion. DI followed by an evolving anterior pituitary deficiency, including growth failure from GHD, is usually due to a sella/suprasellar tumor. Although DI is also common in midline cerebral malformations (such as septo-optic dysplasia), this usually follows or is contemporaneous with anterior pituitary failure.¹⁶

The term Cushing’s disease describes the symptoms and signs of hypercortisolism due to a pituitary overproduction of adrenocorticotropic hormone. It must be distinguished from Cushing’s syndrome, which results from any etiology causing glucocorticoid excess. Symptoms and signs of childhood Cushing’s disease are similar to those of adults and have often been present for many years prior to the diagnosis: obesity, hirsutism, acne, moon facies, hypertension, buffalo hump on the back of the neck, muscular weakness, psychiatric disturbance, depression, and osteoporosis. However, the initial and most characteristic symptom in childhood is growth arrest; this combined with rapid weight gain should point to the diagnosis. In young children, Cushing’s syndrome is usually of adrenal etiology, including McCune-Albright syndrome. However, in older children and adolescents, it is more likely to be Cushing’s disease with excessive adrenocorticotropic hormone production from a tumor of the anterior pituitary.

Pituitary gigantism is a rare disorder due to growth hormone (GH) hypersecretion, usually secondary to an adenoma of the anterior pituitary. Overproduction of GH secretion is responsible for gigantism in a patient with open epiphyses and for acromegaly in a patient with closed epiphyses. The physical signs of GH excess are common to both disorders, but the signs in pituitary gigantism are usually less obvious because of the shorter duration of the endocrinopathy. From what data are available, surprisingly, such children appear to continue to grow for many years even after epiphyseal closure. GH-secreting tumors may occur in multiple endocrine neoplasia type 1 and McCune-Albright syndrome. Pituitary gigantism is a rare component of McCune-Albright syndrome, whereas the more usual manifestations are characteristic cutaneous pigmentation, polyostotic fibrous dysplasia, and gonadotropin-independent precocious puberty. Rarely, endocrine manifestations are adrenal dependent, Cushing’s syndrome, thyrotoxicosis, and hyperparathyroidism.

The most common endocrine presentation of macroprolactinoma (more common in children and adolescents than microprolactinoma) is delayed/absent puberty due to prolactin (PRL) suppression of gonadotropin pulsatility, combined with gynecomastia in boys and galactorrhea in girls. The presentation may be part of multiple endocrine neoplasia type 1. Macroprolactinomas usually extend upward and encroach on the visual pathway and are often accompanied by visual field defects. It is important to measure the serum PRL in every child with pituitary enlargement, particularly before any surgery is contemplated.¹⁷

Isolated adrenocorticotropic hormone insufficiency may occur in lymphocytic hypophysitis, although this condition is not a malignant tumor but presents as the differential diagnosis of a central pituitary mass. This tumor usually occurs in the puerperium and is extremely rare in childhood.¹⁸

Patients with arachnoid cyst tended to be older at initial diagnosis than those with craniopharyngioma or Rathke’s cleft cyst. Patients with craniopharyngioma generally present with a long duration of symptoms, especially visual symptoms. Mass effects, such as visual problems and headaches, are common symptoms of all three cystic lesions, but psychiatric symptoms, eating disorders, and calcification of solid tumor components on neuroimaging are characteristic of craniopharyngioma. Children are more likely to present with neurologic symptoms than adults.

Diagnosis

MRI scans have become the preferred diagnostic study for pediatric intracranial tumors. MRI is preferred under most circumstances, providing superior resolution and multiplanar imaging capabilities and avoiding the “spray” artifact from the petrous ridge that may obscure computed tomographic images of the base of the brain, without a radiation burden to the child. The administration of gadolinium diethylenetriamine-pentaacetic acid appears to be a safe and effective contrast agent for MRI and provides a more accurate method of imaging in the follow-up of brain tumors in pediatric patients. Where clinical suspicion remains (normal neuroradiologic imaging in patients with DI), scans reported as normal should be sent for expert review and consideration of repeat imaging with time. The intervals for scanning should also be guided clinically, since any set interval is empirical. MRI scan should be performed at a minimum of yearly intervals.¹⁹ For lesions with a high frequency of cerebrospinal fluid dissemination, such as primitive neuroectodermal tumors and germ cell tumors, a neuraxis staging evaluation by spinal MRI, if not obtained preoperatively, should be performed approximately 2 weeks after surgery. In children with pineal region tumors, measurement of α-fetoprotein and β–human chorionic gonadotropin in the blood is useful for the diagnosis of malignant germ cell tumors (pineoblastomas); however, cerebrospinal fluid markers are of limited assistance. Placental alkaline phosphatase is a clinically useful tumor marker for primary intracranial germinoma.²⁰

Thyroid function tests (as well as serum PRL concentration) are always required prior to surgery of a suspected pituitary tumor.¹⁷ An elevated serum PRL concentration requires the distinction between stalk compression with moderate rise in PRL from the very high PRL concentrations associated with a PRL-secreting tumor. Macroprolactinomas usually have very high PRL secretion, and there is little ambiguity about the diagnosis. It is important to distinguish thyroid-stimulating hormone–secreting adenomas, which are extremely rare, from the pituitary hyperplasia associated with longstanding primary hypothyroidism. After prolonged, severe primary hypothyroidism with increased secretion of thyroid-stimulating hormone, the pituitary gland is usually increased in size and may attain a suprasellar extension and compression of the optic chiasm/nerves. This may be accompanied by a gonadal form of premature sexual maturation which is not true puberty (isolated breast development in girls and large testicular volumes with minimal virilization in boys).²¹ These signs of premature maturation and pituitary enlargement decrease or resolve following the decrease in secretion of thyroid-stimulating hormone within 6 months of commencing appropriate thyroxin replacement.