Pituitary adenomas in childhood
http://www.100md.com
《美国医学杂志》
Department of Endocrinology & Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
Abstract
Pituitary adenomas are common tumors composed of adenohypophysial cells.Although they usually arise in the sella turcica, they may occasionally be ectopic. Pituitary adenomas are rarely diagnosed in childhood and adolescence, but their mass effect and endocrine abnormalities can compromise both quality and length of life. Many signs or symptoms of pituitary adenoma, complained of in adulthood, not became evident during adolescence, suggesting true prevalence of this tumor in teenagers is higher than expected. Pititury adenoma occuring during adolescence are associated with features or therapeutic needs sometimes different from those occuring in adulthood. At the onset of disease, delay in growth was rarely observed in teenagers with pituitary adenomas. Many girls complain of oligoamenorrhoea and galactorrhoea, while headache and delay in pubertal development are the most commons features in boys. Hypopituitarism is occasionally encountered in adolescence. Early diagnosis and appropriate choice of therapy are necessary to avoid permanent endocrine complications of disease and its treatment.
Keywords: Pituitary adenoma; Hypopituitarism; Adolescence
Pituitary adenomas are common tumors composed of adenohypophysial cells commonly arising in the sella turcica but occasionally ectopic. Pituitary adenomas are the most common cause of pituitary disease in adults but less common in children, becoming increasingly more frequent during adolescent years.[1]
The estimated incidence of pituitary adenoma in children is still unknown since most published series included patients with onset of symptoms before the age of 20 years as pediatric patients.[2] Pituitary adenomas constitute less than 3% of supratentorial tumors in children[3] and 2.3-6% of all pituitary tumors treated surgically.[4] The average annual incidence of pituitary adenoma in children has been estimated to be 0.1/million.[5] Among all supratentorial tumors treated during a 25-year period, pituitary adenoma was diagnosed in only 1.2% of children.[6] Pituitary carcinomas are rare in adults and extremely rare in children.[7]
Experience at our centre, which is a tertiary care hospital, cases of pituitary adenoma in childhood and adolescent are limited. This is largely on account of lack of early diagnosis and late presentation to the neurosurgical of our hospital.
Majority of the cases with presentation of non-functioning pituitary adenoma were craniophyrangioma. They presented with headache, delayed growth and puberty and occasionally with polyuria and polydipsia suggestive of diabetes inspidius. Six patients had hamartomas on MRI in pituitary stalk Figure1. One male and two females presented with features of isosexual precocious puberty before eight years of age. We had five patients of ACTH producing Cushing disease. All patients presented with typical centripetal obesity, weight gain, moon facies, proximal weakness and amenorrhoea. Basal cortisol and dexamethasone suppression test revealed Cushing's disease. MRI of putuitary was normal. Three patients treated with ketoconazole and hydrocortisone (Block Replace therapy) and referred to higher institute for dynamic MRI and inferior petrosal sinus sampling. Two patients underwent bilateral adrenalectomy and pituitary external radiation as patients couldn't afford specific test and treatment. One patient presented with pituitary mass and gigantism. No case of prolactinoma was seen.
There is no consensus on the alleged greater invasiness cases of pituitary adenoma in children than in adults, while a slightly greater prevalence in females has been reported.[8] Gender distribution reflects the relative contribution of the two main groups, prolactin and ACTH secreting adenomas which predominate in most series reported. However, the evidence that many signs or symptoms of pituitary adenomas, complained of in adulthood, became evident during adolescence, suggests that the true prevalence of these tumors in teenagers is higher than expected. Moreover, despite the fact that pituitary adenomas occurring during adolescence are associated with clinical features or therapeutic needs sometimes different from those occurring in childhood, depending on the hormone hypersecretion and on the size of the tumor, few data are available on their outcome.
Prolactinoma is indeed the most frequent adenoma histotype in children, followed by the corticotropinoma and the somatotropinoma. Non-functioning pituitary adenomas, TSH-secreting, and gonadotropin-secreting adenomas are very rare in children accounting for only 3-6% of all pituitary tumors.[8] ACTH secreting adenomas have earlier onset and predominate in the pre-pubertal period,[4] while GH secreting adenomas are very rare before puberty. Similar to adults, presenting symptoms are generally related to the endocrine dysfunction rather than to mass effect.[9]
Pathogenesis
The pathogenesis of pituitary tumors continues to be an enigma in the field of endocrine oncology. Despite their prevalence and potential for significant morbidity, the etiologies of most pituitary tumors remain unknown. Hypothesis of pituitary oncogenesis has vacillated in the last two decades, moving from one milestone to the next. Like other differentiated neuroendocrine cells, the anterior pituitary displays remarkable plasticity in response to physiological demands, as exemplified by the lactotroph differentiation and proliferation during pregnancy or the thyrotroph hyperplasia of primary hypothyroidism.[10] Subsequently, the early years of molecular biology applications permitted clonality assessment based on the X-chromosome inactivation principle. The majority of these studies suggested a clonal pattern, providing the basis for assignment of pituitary adenomas to the list of monoclonal neoplasms Figure2.
Role of hypothalamus
Hypothalamic releasing and inhibiting polypeptides selectively regulate gene expression and secretion of the pituitary trophic hormones.[11] Recently evidences suggest that the hypothalamic hormones may in fact be expressed both within anterior pituitary gland as well as within pituitary tumor.[12] One of the first candidate factors to emerge was the G-protein a stimulating activity polypeptide (gsp). The gsp mutation results in GTPase inactivation with subsequently elevated cAMP levels and growth hormone hypersecretion. Thus constitutive activation of the GHRH g-protein signaling unit, allows ligand independent induction of growth hormone gene expression. Phosphorylation of the CREB-Pit-1 signaling unit may also be impaired as suggested by excessive serine phosphorylation of CREB observed in a subset of growth hormone secreting cell adenomas.[13]
Intrinsic pituitary lesions
Virtually all functional and non-functional pituitary tumors arise from a single cell. This monoclonality implies that intrinsic genetic alterations account for the initiating events in pituitary tumorigenesis. Recent reports are in consonance with earlier clinical evidence suggesting that resection of small well-circumscribed adenomas may result in a surgical cure for non-functioning growth hormone secreting, and corticotrophin (ACTH) secreting adenomas.[14] Furthermore, the adenohypophyseal tissue surrounding the pituitary adenoma is usually normal, reflecting the notion that multiple independent cellular events ( e.g., generalized hyperplasia) do not necessarily precede adenoma formation.
Oncogene mutations
The multistep development of neoplasia involves a spectrum of successive genetic alterations. Dysregulation of cell proliferation, differentiation, and specific hormone production may occur by activation of oncogene function or inactivation of tumor suppressor genes. Oncogene activation may occur as a result of excessive gene expression, activating single point mutations, or dysregulated promoter-driven oncogene activity.
Candidate genes in human pituitary tumors inactivating mutations
Several chromosomal lesions and gene mutations have been observed in sporadic pituitary tumors table1. Loss of heterozygosity involving chromosomes 11q13, 13, and9 occurs in as many as 20% of sporadic pituitary tumors.[15] Despite the location of gene for MEN-1 on chromosome 11, analysis of this gene in non-MEN-1 patients with sporadic pituitary tumors harboring 11q loss of heterozygosity detected intact coding and intronic sequences, with appropriately expressed MEN-1 mRNA.[16] Thus another tumor suppressor gene distinct from MEN-1 may, in fact, be present on this locus in these sporadic tumors. Lesions in chromosome 13 and 9 are also more prevalent in invasive or larger adenomas.[17] Frequent chromosome 13q loss of heterozygosity occurs in proximity to the RB locus and has been found in 13 aggressive pituitary tumors; however, immunoreactive RB protein was detected in these tumors. This suggests that another tumor suppressor gene located close to RB on chromosome 13 may be involved in controlling the propensity for tumor invasion in these patients.
Frequent loss of heterozygosity of 9p21 is also encountered in pituitary tumors.[15] The CDKN2A gene maps to this locus, and its protein product, p16, a cell cycle regulator that is frequently disrupted in several human neoplasms. In the absence of p16, CDK4 phosphorylates and inactivates RB. Gene silencing by methylation has been implicated as a possible mechanism for the observed decreased p16 mRNA expression in some pituitary tumors.[18]
Activating mutations
Stimulatory G (GS) proteins that activate adenyl cyclase and cAMP accumulation are inactivated by GTPase. Missense mutations replacing residue 201 (ArgCys or His) or 227 (GlnArg or leu) are termed gsp and result in persistently elevated Gs activity. This results in ligand independent constitutionally elevated cAMP and growth hormone hypersecretion.[19]
Recently, a novel pituitary tumor transforming gene (PTTG) cDNA by differential display PCR using mRNA derived from rat pituitary tumor cells and normal pituitary tissue was isolated.[20] The nucleotide sequence of the human homologous shares 89% identifies with rat PTTG. Three homologous genes in human PTTG family have now been classified. PTTG1 is located on chromosome 5q33, a locus associated with recurrent neoplastic abnormalities of the lung and acute myelogenous leukemias while PTTG2 is on chromosome 4p12 and PTTG 3 on 8q22. PTTG expression is low in most normal adult tissues, including colon, small intestine, brain and pancreas, modest in thymus and abundant in testis, where it appears necessary for normal spermatogenesis.
The PTTG was characterized as a member of the securin family that functions in regulating chromatid separation. Highest expression of PTTG was observed in hormone secreting pituitary tumors which had invaded the sphenoid bone compared to tumors confined to pituitary fossa. The significant increase in PTTG expression was seen in all subtypes of secreting and nonfunctioning tumors.
The PTTG protein contains an SH-3 docking motif, suggesting that it is involved in intracellular signaling.[21] In fact, PTTG induces the expression of fibroblast growth factor (FGF), a known mediator of cell growth and angiogenesis. Mutations of the PTTG molecule within the SH3-binding motif prevent in vitro cell transformation, in vivo tumorigenesis, and FGF induction.
FGF-2 (basic FGF, 146 AA) is a potent angiogenic factor expressed in normal pituitary tissues. Human pituitary adenomas express FGF-2, and patients with MEN-1 with untreated pituitary adenoma have increased circulating levels of pituitary derived FGF-2.[22] FGF-4, a 206 AA protein encoded by the heparin-binding secretory transforming gene (hst), is expressed in prolactinomas and also possesses potent angiogenic activity. The transfected hst oncogene, or FGF4 protein itself, enhances prolactin secretion, and its overexpression is associated with experimental tumor cell aggressiveness.[23] Nevertheless, the recent observation that PTTG induces FGF expression suggests a paracrine loop whereby a transforming gene, PTTG, induces this growth factor. Thus, enhanced PTTG expression in most pituitary tumors implies that PTTG is an early molecular requirement for pituitary tumor formation.
Classification of pituitary adenoma
Pituitary adenomas are classified by various groups of investigators in different ways. Endocrinologists use a functional classification based on their hormonal activity in vivo. Radiologists and neurosurgeons prefer an anatomic or radiographic classification based on tumor size and degree of local invasion. Morphological classifications of pituitary adenomas include the conventional histologic criteria of cytoplasmic staining, immunohistochemical staining based on the detection of antigens in tissue, and ultrastructural classification based on subcellular features of cell differentiation table2.
Currently, there are no accepted markers to predict invasive behavior and possible recurrence of a pituitary adenoma. Cytologic features are not valid, and aneuploidy does not correlate with recurrence. Some investigators have suggested that the proliferation markers Ki-67, PCNA, or p105 may be useful. Other indicators of potential prognostic significance include growth factors and receptor expression and alterations of oncogenes and tumor suppressor genes. As these characteristics prove to be reliable predictors of tumor behaviour, such as invasive growth, recurrence, or metastasis, they can be added to the immuno-histochemical analysis of these tumors table2. The clinical characteristic of various pituitary tumors in children and adolescent are summarized in table3.
Prolactin secreting adenomas
Prolactinomas are the most frequent tumors both in childhood and in adulthood, and their frequency varies with age and sex, occurring more frequently in females.[24] In a study by Cannavo S et al, they found prolactinoma in 68% of teenagers.[25] Partington MD et al found prolactinoma in 41.7% of children at mayo clinic clinical presentation and diagnosis.[9]
Prolactinomas are usually diagnosed at the time of puberty or in the postpubertal period and clinical manifestations vary in keeping with the age and sex of the child.[4],[12] Pre-pubertal children generally present with a combination of headache, visual disturbances, growth failure, and amenorrhoea. However, growth failure is not a common symptom. Impairment of other pituitary hormone secretion was found only in a minority of patients (27%). Spontaneous or provoked galactorrhea is seen in 50% of children. Macroadenomas at presentation are more likely in boys than in girls.[26] Hyperprolactinemic patients have a decrease of bone mineral density and progressive bone loss. Young hyperprolactinemic men were shown to have a more severe impairment of BMD than patients in whom hyperprolactinemia occurred at an older age. In another series of patients, occurrence of hyperprolactinemia during adolescence has a lower BMD than those having adult onset tumors.[27] The use of drugs to increase bone mass, such as aminobisphosphonates has not been investigated. A single measurement of PRL levels is unreliable since PRL secretion is markedly influenced by physical and emotional stress. In order to obtain a diagnostic value of PRL concentration, at least 3-6 samples are necessary and the average value are taken into consideration.
Treatment strategy
In the absence of complications needing immediate surgery, such as visual loss, hydrocephalus or cerebrospinal fluid leak, pharmacotherapy with dopamine agonists should be considered the first treatment approach. In children, bromocriptine (BRC) has been used successfully by several investigators.[28] In one series, BRC at doses ranging from 2.5-20 mg/day orally, induced normoprolactinemia in 38.5% of patients.[26]
Both quinagolide (CV), at doses starting at 0.075 mg/day and ranging from 0.075-0.6 mg/day, or cabergoline (CAB), at doses starting at 0.25 mg twice weekly and ranging from 0.5-3.5 mg/week orally, two selective DA receptor subtype-2 selective agonists, have been reported to be effective in reducing PRL secretion.[29] CAB has a longer half-life then BRC, needs to be administered only once or twice a week and causes normalization of serum PRL levels and restoration of gonadal functions. The easily weekly administration makes CAB an excellent therapeutic approach to children.
ACTH-secreting adenomas
Between 11 and 15 years of age, ACTH secreting adenomas are the most frequent cause of adrenal hyperfunction and the second most frequent pituitary adenoma after prolactinomas.[30] A macroadenoma is rarely the cause of Cushing's disease (CD) in children.[31]
Clinical presentation and diagnosis
The clinical manifestations of CD are mostly the consequence of excessive cortisol production. The clinical presentation is highly variable, with signs and symptoms that can range form subtle to obvious. The diagnosis is generally delayed since a decrease in growth rate may be the only symptom for a long time. Growth failure in CD may be due to a decrease of free IGF1 levels and/or a direct negative effect of cortisol on the growth plate. In a series of 50 children with CD, Magiakou et al found that obesity and growth retardation were the most frequent symptoms (in 90 and 83% respectively).[32] The skin of face is plethoric, and atrophic striae can be found in the abdomen, legs and arms. Results on BMD or bone metabolism in children with CD have been reported only in some patients in a few studies.[33] The bone loss is more evident in trabecular than in cortical bone. In children with CD, the direct negative effect of hypercortisolism on bone formation is further worsened by concomitant hypogonadism and GH deficiency, both of which are associated with decreased BMD. Children with CD may have impaired carbohydrate tolerance, while overt diabetes mellitus is uncommon. Excessive adrenal androgens may cause acne and excessive hair growth, or premature sexual development in the first decade of life. On the other hand, hypercortisolism may cause pubertal delay in adolescent patients. Peculiarly, young patients with CD may present neuropsychiatric symptoms which differ form those of adult patients. Frequently they tend to be obsessive and are high performers at school.
The differential diagnosis of CD includes adrenal tumors, ectopic ACTH production, and ectopic CRH producing tumors. However, ectopic ACTH secretion is extremely rare in the pediatric age. Among a large series including 306 cases with pediatric and adult Cushing's syndrome investigated at the St. Bartholomew's Hospital in London, 32 had ectopic ACTH syndrome of whom only 1 was in pediatric age.[31]
Diagnosis is based on measurement of basal and stimulated levels of cortisol as outlined Figure3 and for localization MRI pituitary and bilateral inferior petrosal sinus sampling can be done.
Treatment strategy
Trans sphenoidal adenomectomy is the treatment of choice for ACTH secreting adenomas. Surgical remission is successful in the majority of children, with initial remission rates of 70-98% and long term cure of 50-98% in most studies.[34]
Surgery is usually followed by adrenal insufficiency and patients require hydrocortisone replacement for 6-12 months. After normalization of cortisol levels, resumption of normal growth or even catch up growth can be observed. Generally, final height is compromised compared to target weight. Labrathon et al demonstrated that early hGH replacement may contribute to a favorable outcome on final outcome.[35] The treatment modality in patients who have relapses is still controversial. Some authors recommend repeated surgery while others favor radiotherapy. Radiotherapy with or without concomitant mitotane treatment may be indicated in patients with macro adenoma. Bilateral adrenalectomy may be the last therapeutic option in case of failure of both surgery and radiotherapy.
Growth hormone secreting adenomas
GH excess derives from a GH-secreting adenoma in over 98% of cases. In adulthood, these adenomas are relatively rare with a prevalence of 50-80 cases/million, and an incidence of 3-4 new cases/million per year,[36] while gigantism is extremely rare with approximately 100 reported cases to date.[37] In childhood, GH-secreting adenomas account for 5-15% of all pituitary adenomas. In less than 2% of the cases excessive GH secretion may depend on a hypothalamic or ectopic GH releasing hormone (GHRH) - producing tumor (gangliocytoma, bronchial or pancreatic carcinoid), which causes somatotroph hyperplasia or a well-defined adenoma.
Clinical presentation
In adult, chronic GH hyper secretion causes acromegaly which is characterized by local bone overgrowth, while in children and adolescents it leads to gigantism because of the associated secondary hypogonadism which delays epiphyseal closure, thus allowing continued bone growth. However, the two disorders may be considered along a spectrum of GH excess, with principal manifestations determined by the developmental stage during which such excess originates. 10% of acromegalics exhibiting tall stature,[38] and the majority of giants eventually demonstrating features of acromegaly. In contrast with adults where there is an increased prevalence of large bowel polyps and cancer, central or obstructive sleep apnea and cardiomyopathy which are considered major morbidity and mortality factors, there is no reports of similar complications in childhood. All growth parameters are affected although not necessarily symmetrically, mild to moderate obesity occurs frequently, and macrocephaly has been reported.[37] In girls, menstrual irregularity can be present while glucose intolerance and diabetes mellitus are rare. Only one case of ketoacidosis has been reported so far.[39]
Diagnosis
The diagnosis is usually clinical, and can be readily confirmed by measuring GH levels, which in more than 90% of patients are above 10 mg/l.[36] The OGTT is the simplest and most specific dynamic test for both the diagnosis and the evaluation of the optimal control of GH excess. Evaluation of circulating IGF-1 concentrations, which are considered stable and correlate with the integrated 24 hr GH secretion, has been recently proposed to replace the OGTT. The assay of circulating IGF binding protein-3 (IGFBP-3), the main circulating carrier protein for IGF-1, as well as of free IGF-1 does not have a higher diagnostic sensitivity than total IGF-1 measurement, while the labile subunit of the ternary complex of IGF-1 seems to be a promising diagnostic tool.[40]
Treatment
The objectives of treatment of GH excess are tumor removal with resolution of its eventual mass effect, restoration of normal basal and stimulated GH secretion, relief of symptoms directly caused by GH secretion, relief of symptoms directly caused by GH excess and prevention of progressive disfigurement, bone expansion, osteoarthritis and cardiomyopathy which are disabling long-term consequences, as well as prevention of hypertension, insulin resistance, lipid abnormalities that are risk factors for vascular damage. Surgery, radiotherapy and pharmacological suppression of GH levels are the currently available treatment options.
Transphenoidal adenomectomy remains the first treatment for GH-secreting tumors. Currently, cure criteria are serum GH levels below 2.5 mg/l, glucose suppressed GH levels below 1 mg/l together with age-normalized IGF-1 levels. Treatment with somatostatin analogs is very effective in patients with GH hypersecretion, although few data in adolescent patients have been reported. The long term treatment octreotide plus bromocriptine was tested in one child and was proven to be safe. In another case of a 15-year-old-girl with a mixed GH/PRL secreting adenoma, octreotide-landostatin combined with cabergoline normalized GH and IGF-1 levels, and decreased growth rate from 12 cm/year to nearly 2.5 cm/year.[41] Promising new therapeutic agents have recently emerged in the form of competitive GHRH and GH antagonists which have been shown to effectively suppress GH and/or IGF-1 levels.
TSH-secreting adenomas
This tumor type is rare in adulthood and even rarer in childhood and adolescence with only a few cases reported so far. It is frequently a macroadenoma presenting with mass effect symptoms such as headache, visual disturbances, together with variable signs and symptoms of hyperthyroidism. It must be differentiated from the syndrome of thyroid hormone resistance.[42]
Treatment strategy
TSS is the first treatment approach to these tumors. In adults, radiotherapy is recommended as routine adjunctive therapy. However, due to high frequency of post-radiotherapy hypopituitarism, in children pharmacotherapy is the preferred second choice. Chronic treatment with SR-lanreotide reduced plasma TSH and normalized fT4 and fT3 levels, suggesting its use in the long-term medical treatment of these adenomas.[43]
Nonfunctioning adenomas:
FSH and LH-secreting tumors with a clinical picture of hormone hypersecretion are very rare.[44] The majority of FSH/LH-producing adenomas are clinically asymptomatic. In adults, they represent 33-50% of all pituitary tumors, while in pediatric patients they account for less than 4-6% of cases.[45] In a recent study, 5 out of 2288 patients treated at the Hamburg University between 1970-1996 were diagnosed to bear a clinically nonfunctioning adenoma. The clinical presentation included visual field defects, headache and some degree of pituitary insufficiency since invariably all patients had macroadenoma. In the pediatric population, these adenomas need to be differentiated from other sellar/parasellar masses such as cysts, craniopharyngioma and dysgerminoma. Therefore, the MRI of the sella and parasellar structure is the basic step in the diagnosis.
Treatment
The first approach to these adenomas is trans sphenoidal surgery (TSS) to remove tumor mass and decompress parasellar structures. After surgery, these patients partially recover from hypopituitarism. Postoperative radiotherapy is applied in patients with subtotal tumor removal to prevent tumor regrowth and reduce residual tumors, but is burdened by high prevalence of panhypopituitarism. Very recently, positive effects of cabergoline were observed in some patients with a subunit secreting adenomas, mostly in patients with tumor expressing high number of dopamine D2 receptors.[46]
Conclusion
Pituitary adenomas are rare constituting less than 3% of supra-tentorial tumors. The most frequent tumor histiotypes are prolactin secreting and ACTH secreting adenomas, while GH, TSH secreting and clinical nonfunctioning adenomas are very rare. The clinical presentation varies according to the tumor histiotype, but stunted growth is a frequent sign of macroadenomas. Surgery is the treatment of choice for most adenomas, with exception of prolactin secreting adenomas. Radiotherapy should be reserved to very aggressive tumors due to the very high incidence of subsequent hypopituitarism.
References
1. Odom GL, Davis CH, Woodhall B. Brain tumors in children. Clinical analysis in 164 cases. Pediatrics 1956;18:856-869.
2. Colao A, Boche S, Cappabianca P, de Divitiis E, Lombardi G. Pituitary adenomas in children and adolescents. Clinical Presentation, diagnosis and therapeutic strategies. The Endocrinologist 2000; 10: 314-320.
3. Mindermann T, Wilson CB. Pediatric pituitary adenomas. Neurosurgery 1995; 36: 259-269.
4. Abe T, Tara LA, Ludecke DK. Growth hormone-secreting pituitary adenomas in childhood and adolescence: features and results of transnasal surgery. Neurosurgery 1999; 45:1-10.
5. Ludecke DK, Herrmann HD, Schulte FJ. Special problems with neurosurgical treatment of hormone-secreting pituitary adenomas in children. Prog Exp Tumor Res 1987; 30: 362-370.
6. Gold EB. Epidemiology of pituitary adenomas. Epidemiol Rev 1981; 3: 163-183.
7. Haddad SF, VanGilder JC, Menezes AH. Pediatric pituitary tumors. Neurosurgery 1991; 29: 509-514.
8. Lafferty AR, Chrousos GP. Pituitary tumors in children and adolescents. J Clin Endocrinol Metab 1999; 84: 4317-4323.
9. Partington MD, Dudley HD, Laws ER, Scheithauer BW. Pituitary adenomas in childhood and adolescence. Results of transsphenoidal surgery. J Neurosurg 1994; 80: 209-216.
10. Ezzat S. The role of hormones, growth factors and their receptors in pituitary tumorigenesis. Brain Pathol 2001; 11: 356-370.
11. Melmed S. Pituitary function and neoplasia. In Jameson L, ed. Principles of Molecular Medicine Textbook. Totowa; NJ; Humana Press, 1998; 443-449.
12. Shimon I, Melmed S. Pituitary tumor pathogenesis. J Clin Endocrinol Metab 1997; 82: 1675-1681.
13. Bertherat J, Chanson P, Montminy M. The cyclic adenosine 3',5'-monophosphate responsive factor CREB is constitutively activated in human somatotroph adenomas. Mol Endocrinol 1995; 9: 777-783.
14. Wilson CB. Role of surgery in the management of pituitary tumors. Neurosurg Clin North Am 1990; 1: 139-159.
15. Farrell WE, Simpson DJ, Bicknell JE et al. Chromosome 9p deletions in invasive and non-invasive nonfunctional pituitary adenomas: The deleted region involves markers outside of the MTS1 and MTS2 genes. Cancer Res 1997; 57: 2703-2709.
16. Prezant T, Levine J, Melmed S. Molecular characterization of the MEN1 tumor suppressor gene in sporadic pituitary tumors. J Clin Endocrinol Metab 1998; 83: 1388-1391.(Singh SK, Aggarwal Rohit)
Abstract
Pituitary adenomas are common tumors composed of adenohypophysial cells.Although they usually arise in the sella turcica, they may occasionally be ectopic. Pituitary adenomas are rarely diagnosed in childhood and adolescence, but their mass effect and endocrine abnormalities can compromise both quality and length of life. Many signs or symptoms of pituitary adenoma, complained of in adulthood, not became evident during adolescence, suggesting true prevalence of this tumor in teenagers is higher than expected. Pititury adenoma occuring during adolescence are associated with features or therapeutic needs sometimes different from those occuring in adulthood. At the onset of disease, delay in growth was rarely observed in teenagers with pituitary adenomas. Many girls complain of oligoamenorrhoea and galactorrhoea, while headache and delay in pubertal development are the most commons features in boys. Hypopituitarism is occasionally encountered in adolescence. Early diagnosis and appropriate choice of therapy are necessary to avoid permanent endocrine complications of disease and its treatment.
Keywords: Pituitary adenoma; Hypopituitarism; Adolescence
Pituitary adenomas are common tumors composed of adenohypophysial cells commonly arising in the sella turcica but occasionally ectopic. Pituitary adenomas are the most common cause of pituitary disease in adults but less common in children, becoming increasingly more frequent during adolescent years.[1]
The estimated incidence of pituitary adenoma in children is still unknown since most published series included patients with onset of symptoms before the age of 20 years as pediatric patients.[2] Pituitary adenomas constitute less than 3% of supratentorial tumors in children[3] and 2.3-6% of all pituitary tumors treated surgically.[4] The average annual incidence of pituitary adenoma in children has been estimated to be 0.1/million.[5] Among all supratentorial tumors treated during a 25-year period, pituitary adenoma was diagnosed in only 1.2% of children.[6] Pituitary carcinomas are rare in adults and extremely rare in children.[7]
Experience at our centre, which is a tertiary care hospital, cases of pituitary adenoma in childhood and adolescent are limited. This is largely on account of lack of early diagnosis and late presentation to the neurosurgical of our hospital.
Majority of the cases with presentation of non-functioning pituitary adenoma were craniophyrangioma. They presented with headache, delayed growth and puberty and occasionally with polyuria and polydipsia suggestive of diabetes inspidius. Six patients had hamartomas on MRI in pituitary stalk Figure1. One male and two females presented with features of isosexual precocious puberty before eight years of age. We had five patients of ACTH producing Cushing disease. All patients presented with typical centripetal obesity, weight gain, moon facies, proximal weakness and amenorrhoea. Basal cortisol and dexamethasone suppression test revealed Cushing's disease. MRI of putuitary was normal. Three patients treated with ketoconazole and hydrocortisone (Block Replace therapy) and referred to higher institute for dynamic MRI and inferior petrosal sinus sampling. Two patients underwent bilateral adrenalectomy and pituitary external radiation as patients couldn't afford specific test and treatment. One patient presented with pituitary mass and gigantism. No case of prolactinoma was seen.
There is no consensus on the alleged greater invasiness cases of pituitary adenoma in children than in adults, while a slightly greater prevalence in females has been reported.[8] Gender distribution reflects the relative contribution of the two main groups, prolactin and ACTH secreting adenomas which predominate in most series reported. However, the evidence that many signs or symptoms of pituitary adenomas, complained of in adulthood, became evident during adolescence, suggests that the true prevalence of these tumors in teenagers is higher than expected. Moreover, despite the fact that pituitary adenomas occurring during adolescence are associated with clinical features or therapeutic needs sometimes different from those occurring in childhood, depending on the hormone hypersecretion and on the size of the tumor, few data are available on their outcome.
Prolactinoma is indeed the most frequent adenoma histotype in children, followed by the corticotropinoma and the somatotropinoma. Non-functioning pituitary adenomas, TSH-secreting, and gonadotropin-secreting adenomas are very rare in children accounting for only 3-6% of all pituitary tumors.[8] ACTH secreting adenomas have earlier onset and predominate in the pre-pubertal period,[4] while GH secreting adenomas are very rare before puberty. Similar to adults, presenting symptoms are generally related to the endocrine dysfunction rather than to mass effect.[9]
Pathogenesis
The pathogenesis of pituitary tumors continues to be an enigma in the field of endocrine oncology. Despite their prevalence and potential for significant morbidity, the etiologies of most pituitary tumors remain unknown. Hypothesis of pituitary oncogenesis has vacillated in the last two decades, moving from one milestone to the next. Like other differentiated neuroendocrine cells, the anterior pituitary displays remarkable plasticity in response to physiological demands, as exemplified by the lactotroph differentiation and proliferation during pregnancy or the thyrotroph hyperplasia of primary hypothyroidism.[10] Subsequently, the early years of molecular biology applications permitted clonality assessment based on the X-chromosome inactivation principle. The majority of these studies suggested a clonal pattern, providing the basis for assignment of pituitary adenomas to the list of monoclonal neoplasms Figure2.
Role of hypothalamus
Hypothalamic releasing and inhibiting polypeptides selectively regulate gene expression and secretion of the pituitary trophic hormones.[11] Recently evidences suggest that the hypothalamic hormones may in fact be expressed both within anterior pituitary gland as well as within pituitary tumor.[12] One of the first candidate factors to emerge was the G-protein a stimulating activity polypeptide (gsp). The gsp mutation results in GTPase inactivation with subsequently elevated cAMP levels and growth hormone hypersecretion. Thus constitutive activation of the GHRH g-protein signaling unit, allows ligand independent induction of growth hormone gene expression. Phosphorylation of the CREB-Pit-1 signaling unit may also be impaired as suggested by excessive serine phosphorylation of CREB observed in a subset of growth hormone secreting cell adenomas.[13]
Intrinsic pituitary lesions
Virtually all functional and non-functional pituitary tumors arise from a single cell. This monoclonality implies that intrinsic genetic alterations account for the initiating events in pituitary tumorigenesis. Recent reports are in consonance with earlier clinical evidence suggesting that resection of small well-circumscribed adenomas may result in a surgical cure for non-functioning growth hormone secreting, and corticotrophin (ACTH) secreting adenomas.[14] Furthermore, the adenohypophyseal tissue surrounding the pituitary adenoma is usually normal, reflecting the notion that multiple independent cellular events ( e.g., generalized hyperplasia) do not necessarily precede adenoma formation.
Oncogene mutations
The multistep development of neoplasia involves a spectrum of successive genetic alterations. Dysregulation of cell proliferation, differentiation, and specific hormone production may occur by activation of oncogene function or inactivation of tumor suppressor genes. Oncogene activation may occur as a result of excessive gene expression, activating single point mutations, or dysregulated promoter-driven oncogene activity.
Candidate genes in human pituitary tumors inactivating mutations
Several chromosomal lesions and gene mutations have been observed in sporadic pituitary tumors table1. Loss of heterozygosity involving chromosomes 11q13, 13, and9 occurs in as many as 20% of sporadic pituitary tumors.[15] Despite the location of gene for MEN-1 on chromosome 11, analysis of this gene in non-MEN-1 patients with sporadic pituitary tumors harboring 11q loss of heterozygosity detected intact coding and intronic sequences, with appropriately expressed MEN-1 mRNA.[16] Thus another tumor suppressor gene distinct from MEN-1 may, in fact, be present on this locus in these sporadic tumors. Lesions in chromosome 13 and 9 are also more prevalent in invasive or larger adenomas.[17] Frequent chromosome 13q loss of heterozygosity occurs in proximity to the RB locus and has been found in 13 aggressive pituitary tumors; however, immunoreactive RB protein was detected in these tumors. This suggests that another tumor suppressor gene located close to RB on chromosome 13 may be involved in controlling the propensity for tumor invasion in these patients.
Frequent loss of heterozygosity of 9p21 is also encountered in pituitary tumors.[15] The CDKN2A gene maps to this locus, and its protein product, p16, a cell cycle regulator that is frequently disrupted in several human neoplasms. In the absence of p16, CDK4 phosphorylates and inactivates RB. Gene silencing by methylation has been implicated as a possible mechanism for the observed decreased p16 mRNA expression in some pituitary tumors.[18]
Activating mutations
Stimulatory G (GS) proteins that activate adenyl cyclase and cAMP accumulation are inactivated by GTPase. Missense mutations replacing residue 201 (ArgCys or His) or 227 (GlnArg or leu) are termed gsp and result in persistently elevated Gs activity. This results in ligand independent constitutionally elevated cAMP and growth hormone hypersecretion.[19]
Recently, a novel pituitary tumor transforming gene (PTTG) cDNA by differential display PCR using mRNA derived from rat pituitary tumor cells and normal pituitary tissue was isolated.[20] The nucleotide sequence of the human homologous shares 89% identifies with rat PTTG. Three homologous genes in human PTTG family have now been classified. PTTG1 is located on chromosome 5q33, a locus associated with recurrent neoplastic abnormalities of the lung and acute myelogenous leukemias while PTTG2 is on chromosome 4p12 and PTTG 3 on 8q22. PTTG expression is low in most normal adult tissues, including colon, small intestine, brain and pancreas, modest in thymus and abundant in testis, where it appears necessary for normal spermatogenesis.
The PTTG was characterized as a member of the securin family that functions in regulating chromatid separation. Highest expression of PTTG was observed in hormone secreting pituitary tumors which had invaded the sphenoid bone compared to tumors confined to pituitary fossa. The significant increase in PTTG expression was seen in all subtypes of secreting and nonfunctioning tumors.
The PTTG protein contains an SH-3 docking motif, suggesting that it is involved in intracellular signaling.[21] In fact, PTTG induces the expression of fibroblast growth factor (FGF), a known mediator of cell growth and angiogenesis. Mutations of the PTTG molecule within the SH3-binding motif prevent in vitro cell transformation, in vivo tumorigenesis, and FGF induction.
FGF-2 (basic FGF, 146 AA) is a potent angiogenic factor expressed in normal pituitary tissues. Human pituitary adenomas express FGF-2, and patients with MEN-1 with untreated pituitary adenoma have increased circulating levels of pituitary derived FGF-2.[22] FGF-4, a 206 AA protein encoded by the heparin-binding secretory transforming gene (hst), is expressed in prolactinomas and also possesses potent angiogenic activity. The transfected hst oncogene, or FGF4 protein itself, enhances prolactin secretion, and its overexpression is associated with experimental tumor cell aggressiveness.[23] Nevertheless, the recent observation that PTTG induces FGF expression suggests a paracrine loop whereby a transforming gene, PTTG, induces this growth factor. Thus, enhanced PTTG expression in most pituitary tumors implies that PTTG is an early molecular requirement for pituitary tumor formation.
Classification of pituitary adenoma
Pituitary adenomas are classified by various groups of investigators in different ways. Endocrinologists use a functional classification based on their hormonal activity in vivo. Radiologists and neurosurgeons prefer an anatomic or radiographic classification based on tumor size and degree of local invasion. Morphological classifications of pituitary adenomas include the conventional histologic criteria of cytoplasmic staining, immunohistochemical staining based on the detection of antigens in tissue, and ultrastructural classification based on subcellular features of cell differentiation table2.
Currently, there are no accepted markers to predict invasive behavior and possible recurrence of a pituitary adenoma. Cytologic features are not valid, and aneuploidy does not correlate with recurrence. Some investigators have suggested that the proliferation markers Ki-67, PCNA, or p105 may be useful. Other indicators of potential prognostic significance include growth factors and receptor expression and alterations of oncogenes and tumor suppressor genes. As these characteristics prove to be reliable predictors of tumor behaviour, such as invasive growth, recurrence, or metastasis, they can be added to the immuno-histochemical analysis of these tumors table2. The clinical characteristic of various pituitary tumors in children and adolescent are summarized in table3.
Prolactin secreting adenomas
Prolactinomas are the most frequent tumors both in childhood and in adulthood, and their frequency varies with age and sex, occurring more frequently in females.[24] In a study by Cannavo S et al, they found prolactinoma in 68% of teenagers.[25] Partington MD et al found prolactinoma in 41.7% of children at mayo clinic clinical presentation and diagnosis.[9]
Prolactinomas are usually diagnosed at the time of puberty or in the postpubertal period and clinical manifestations vary in keeping with the age and sex of the child.[4],[12] Pre-pubertal children generally present with a combination of headache, visual disturbances, growth failure, and amenorrhoea. However, growth failure is not a common symptom. Impairment of other pituitary hormone secretion was found only in a minority of patients (27%). Spontaneous or provoked galactorrhea is seen in 50% of children. Macroadenomas at presentation are more likely in boys than in girls.[26] Hyperprolactinemic patients have a decrease of bone mineral density and progressive bone loss. Young hyperprolactinemic men were shown to have a more severe impairment of BMD than patients in whom hyperprolactinemia occurred at an older age. In another series of patients, occurrence of hyperprolactinemia during adolescence has a lower BMD than those having adult onset tumors.[27] The use of drugs to increase bone mass, such as aminobisphosphonates has not been investigated. A single measurement of PRL levels is unreliable since PRL secretion is markedly influenced by physical and emotional stress. In order to obtain a diagnostic value of PRL concentration, at least 3-6 samples are necessary and the average value are taken into consideration.
Treatment strategy
In the absence of complications needing immediate surgery, such as visual loss, hydrocephalus or cerebrospinal fluid leak, pharmacotherapy with dopamine agonists should be considered the first treatment approach. In children, bromocriptine (BRC) has been used successfully by several investigators.[28] In one series, BRC at doses ranging from 2.5-20 mg/day orally, induced normoprolactinemia in 38.5% of patients.[26]
Both quinagolide (CV), at doses starting at 0.075 mg/day and ranging from 0.075-0.6 mg/day, or cabergoline (CAB), at doses starting at 0.25 mg twice weekly and ranging from 0.5-3.5 mg/week orally, two selective DA receptor subtype-2 selective agonists, have been reported to be effective in reducing PRL secretion.[29] CAB has a longer half-life then BRC, needs to be administered only once or twice a week and causes normalization of serum PRL levels and restoration of gonadal functions. The easily weekly administration makes CAB an excellent therapeutic approach to children.
ACTH-secreting adenomas
Between 11 and 15 years of age, ACTH secreting adenomas are the most frequent cause of adrenal hyperfunction and the second most frequent pituitary adenoma after prolactinomas.[30] A macroadenoma is rarely the cause of Cushing's disease (CD) in children.[31]
Clinical presentation and diagnosis
The clinical manifestations of CD are mostly the consequence of excessive cortisol production. The clinical presentation is highly variable, with signs and symptoms that can range form subtle to obvious. The diagnosis is generally delayed since a decrease in growth rate may be the only symptom for a long time. Growth failure in CD may be due to a decrease of free IGF1 levels and/or a direct negative effect of cortisol on the growth plate. In a series of 50 children with CD, Magiakou et al found that obesity and growth retardation were the most frequent symptoms (in 90 and 83% respectively).[32] The skin of face is plethoric, and atrophic striae can be found in the abdomen, legs and arms. Results on BMD or bone metabolism in children with CD have been reported only in some patients in a few studies.[33] The bone loss is more evident in trabecular than in cortical bone. In children with CD, the direct negative effect of hypercortisolism on bone formation is further worsened by concomitant hypogonadism and GH deficiency, both of which are associated with decreased BMD. Children with CD may have impaired carbohydrate tolerance, while overt diabetes mellitus is uncommon. Excessive adrenal androgens may cause acne and excessive hair growth, or premature sexual development in the first decade of life. On the other hand, hypercortisolism may cause pubertal delay in adolescent patients. Peculiarly, young patients with CD may present neuropsychiatric symptoms which differ form those of adult patients. Frequently they tend to be obsessive and are high performers at school.
The differential diagnosis of CD includes adrenal tumors, ectopic ACTH production, and ectopic CRH producing tumors. However, ectopic ACTH secretion is extremely rare in the pediatric age. Among a large series including 306 cases with pediatric and adult Cushing's syndrome investigated at the St. Bartholomew's Hospital in London, 32 had ectopic ACTH syndrome of whom only 1 was in pediatric age.[31]
Diagnosis is based on measurement of basal and stimulated levels of cortisol as outlined Figure3 and for localization MRI pituitary and bilateral inferior petrosal sinus sampling can be done.
Treatment strategy
Trans sphenoidal adenomectomy is the treatment of choice for ACTH secreting adenomas. Surgical remission is successful in the majority of children, with initial remission rates of 70-98% and long term cure of 50-98% in most studies.[34]
Surgery is usually followed by adrenal insufficiency and patients require hydrocortisone replacement for 6-12 months. After normalization of cortisol levels, resumption of normal growth or even catch up growth can be observed. Generally, final height is compromised compared to target weight. Labrathon et al demonstrated that early hGH replacement may contribute to a favorable outcome on final outcome.[35] The treatment modality in patients who have relapses is still controversial. Some authors recommend repeated surgery while others favor radiotherapy. Radiotherapy with or without concomitant mitotane treatment may be indicated in patients with macro adenoma. Bilateral adrenalectomy may be the last therapeutic option in case of failure of both surgery and radiotherapy.
Growth hormone secreting adenomas
GH excess derives from a GH-secreting adenoma in over 98% of cases. In adulthood, these adenomas are relatively rare with a prevalence of 50-80 cases/million, and an incidence of 3-4 new cases/million per year,[36] while gigantism is extremely rare with approximately 100 reported cases to date.[37] In childhood, GH-secreting adenomas account for 5-15% of all pituitary adenomas. In less than 2% of the cases excessive GH secretion may depend on a hypothalamic or ectopic GH releasing hormone (GHRH) - producing tumor (gangliocytoma, bronchial or pancreatic carcinoid), which causes somatotroph hyperplasia or a well-defined adenoma.
Clinical presentation
In adult, chronic GH hyper secretion causes acromegaly which is characterized by local bone overgrowth, while in children and adolescents it leads to gigantism because of the associated secondary hypogonadism which delays epiphyseal closure, thus allowing continued bone growth. However, the two disorders may be considered along a spectrum of GH excess, with principal manifestations determined by the developmental stage during which such excess originates. 10% of acromegalics exhibiting tall stature,[38] and the majority of giants eventually demonstrating features of acromegaly. In contrast with adults where there is an increased prevalence of large bowel polyps and cancer, central or obstructive sleep apnea and cardiomyopathy which are considered major morbidity and mortality factors, there is no reports of similar complications in childhood. All growth parameters are affected although not necessarily symmetrically, mild to moderate obesity occurs frequently, and macrocephaly has been reported.[37] In girls, menstrual irregularity can be present while glucose intolerance and diabetes mellitus are rare. Only one case of ketoacidosis has been reported so far.[39]
Diagnosis
The diagnosis is usually clinical, and can be readily confirmed by measuring GH levels, which in more than 90% of patients are above 10 mg/l.[36] The OGTT is the simplest and most specific dynamic test for both the diagnosis and the evaluation of the optimal control of GH excess. Evaluation of circulating IGF-1 concentrations, which are considered stable and correlate with the integrated 24 hr GH secretion, has been recently proposed to replace the OGTT. The assay of circulating IGF binding protein-3 (IGFBP-3), the main circulating carrier protein for IGF-1, as well as of free IGF-1 does not have a higher diagnostic sensitivity than total IGF-1 measurement, while the labile subunit of the ternary complex of IGF-1 seems to be a promising diagnostic tool.[40]
Treatment
The objectives of treatment of GH excess are tumor removal with resolution of its eventual mass effect, restoration of normal basal and stimulated GH secretion, relief of symptoms directly caused by GH secretion, relief of symptoms directly caused by GH excess and prevention of progressive disfigurement, bone expansion, osteoarthritis and cardiomyopathy which are disabling long-term consequences, as well as prevention of hypertension, insulin resistance, lipid abnormalities that are risk factors for vascular damage. Surgery, radiotherapy and pharmacological suppression of GH levels are the currently available treatment options.
Transphenoidal adenomectomy remains the first treatment for GH-secreting tumors. Currently, cure criteria are serum GH levels below 2.5 mg/l, glucose suppressed GH levels below 1 mg/l together with age-normalized IGF-1 levels. Treatment with somatostatin analogs is very effective in patients with GH hypersecretion, although few data in adolescent patients have been reported. The long term treatment octreotide plus bromocriptine was tested in one child and was proven to be safe. In another case of a 15-year-old-girl with a mixed GH/PRL secreting adenoma, octreotide-landostatin combined with cabergoline normalized GH and IGF-1 levels, and decreased growth rate from 12 cm/year to nearly 2.5 cm/year.[41] Promising new therapeutic agents have recently emerged in the form of competitive GHRH and GH antagonists which have been shown to effectively suppress GH and/or IGF-1 levels.
TSH-secreting adenomas
This tumor type is rare in adulthood and even rarer in childhood and adolescence with only a few cases reported so far. It is frequently a macroadenoma presenting with mass effect symptoms such as headache, visual disturbances, together with variable signs and symptoms of hyperthyroidism. It must be differentiated from the syndrome of thyroid hormone resistance.[42]
Treatment strategy
TSS is the first treatment approach to these tumors. In adults, radiotherapy is recommended as routine adjunctive therapy. However, due to high frequency of post-radiotherapy hypopituitarism, in children pharmacotherapy is the preferred second choice. Chronic treatment with SR-lanreotide reduced plasma TSH and normalized fT4 and fT3 levels, suggesting its use in the long-term medical treatment of these adenomas.[43]
Nonfunctioning adenomas:
FSH and LH-secreting tumors with a clinical picture of hormone hypersecretion are very rare.[44] The majority of FSH/LH-producing adenomas are clinically asymptomatic. In adults, they represent 33-50% of all pituitary tumors, while in pediatric patients they account for less than 4-6% of cases.[45] In a recent study, 5 out of 2288 patients treated at the Hamburg University between 1970-1996 were diagnosed to bear a clinically nonfunctioning adenoma. The clinical presentation included visual field defects, headache and some degree of pituitary insufficiency since invariably all patients had macroadenoma. In the pediatric population, these adenomas need to be differentiated from other sellar/parasellar masses such as cysts, craniopharyngioma and dysgerminoma. Therefore, the MRI of the sella and parasellar structure is the basic step in the diagnosis.
Treatment
The first approach to these adenomas is trans sphenoidal surgery (TSS) to remove tumor mass and decompress parasellar structures. After surgery, these patients partially recover from hypopituitarism. Postoperative radiotherapy is applied in patients with subtotal tumor removal to prevent tumor regrowth and reduce residual tumors, but is burdened by high prevalence of panhypopituitarism. Very recently, positive effects of cabergoline were observed in some patients with a subunit secreting adenomas, mostly in patients with tumor expressing high number of dopamine D2 receptors.[46]
Conclusion
Pituitary adenomas are rare constituting less than 3% of supra-tentorial tumors. The most frequent tumor histiotypes are prolactin secreting and ACTH secreting adenomas, while GH, TSH secreting and clinical nonfunctioning adenomas are very rare. The clinical presentation varies according to the tumor histiotype, but stunted growth is a frequent sign of macroadenomas. Surgery is the treatment of choice for most adenomas, with exception of prolactin secreting adenomas. Radiotherapy should be reserved to very aggressive tumors due to the very high incidence of subsequent hypopituitarism.
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