Pediatric Pituitary Adenomas: Early and Long-Term Surgical Outcome in a Series of 85 Consecutive Patients

Pediatric Pituitary Adenomas: Early and Long-Term Surgical Outcome in a Series of 85 Consecutive... Abstract BACKGROUND Young age has been reported as a negative prognostic factor for pituitary adenomas (PAs). They are very uncommon in children and adolescents; therefore, surgical outcomes are poorly described. OBJECTIVE To report results of microsurgical transsphenoidal approach (MTSA) in pediatric PAs. METHODS The study retrospectively analyzed 3040 PAs treated in our institute, according to the adenoma subtype and then divided into pediatric (≤18 yr) and adult groups (>18 yr). The average follow-up after surgery was 58 mo (n = 2906). RESULTS In the pediatric group, the majority of adenomas were hormone-secreting (89.5%) with a female sex prevalence (78%) in prolactinomas and nonfunctioning pituitary adenomas (NFPAs); the maximum diameter of growth hormone (GH)-secreting adenomas was greater (28.1 ± 4.1 mm) than in adults (18 ± 0.3 mm, P = .002). Surgical remission rate at 6 mo was similar in both groups for all adenoma subtypes: 72.1% and 76% in pediatric and adult Cushing's disease, 69.3% and 59.3% in prolactinomas, 55.6% and 61% in gigantism or acromegaly, 55.6% and 61.5% in NFPAs. Recurrences after remission occurred more frequently in pediatric GH-secreting adenomas compared to adults (40.0% vs 5.3%, P = .028) despite similar follow-up (38 ± 17 and 48.1 ± 2.2 mo, P = .7). Mortality was zero in the pediatric and 0.2% in the adult group (P = .7); major morbidity was 2.4% and 2.2%, respectively (P = .8). CONCLUSION MTSA was safe and effective in children and adolescents as in adults, with the only exception of higher recurrence rate in pediatric GH-secreting adenomas. No complications related to young age appeared. Pediatric pituitary adenomas, Pituitary tumors, Transsphenoidal surgery ABBREVIATIONS ABBREVIATIONS ACTH adrenocorticotropic hormone BIPSS bilateral inferior petrosal sinus sampling CD Cushing's disease DA dopamine agonist GH growth hormone GKRS Gamma Knife stereotactic-radiosurgery MRI magnetic resonance imaging MTSA microsurgical transsphenoidal approach NFPAs nonfunctioning pituitary adenomas PAs pituitary adenomas PRL prolactin TSS transsphenoidal surgery In pediatric age, pituitary adenomas (PAs) are the most common sellar tumors after craniopharyngiomas. They are rare in children, becoming increasingly more frequent in adolescents and adults; only 2% to 10% of surgically treated PAs presents during the first 2 decades of life.1-9 The annual incidence is 0.1 case/1000 000 and they account approximately for 3% of all pediatric brain tumors.10,11 PAs are benign and slow growing tumors, but they can extend into and infiltrate the parasellar areas, although the morphological markers of tumor aggressiveness correlate poorly with clinical behavior.12-14 Invasive adenomas are defined as tumors infiltrating the cavernous or sphenoidal sinus and the dura or the bone, whereas the term atypical adenoma is characterized by atypical morphology, increased mitotic activity, Ki-67 labeling index higher than 3%, and extensive p53 immunoreactivity.15,16 Clinically, PAs can be divided into endocrine-active and inactive tumors. Unlike adults, young patients have secreting-adenomas much more frequently than nonfunctioning pituitary adenomas (NFPAs). Pediatric series of PAs have been previously reported, and the clinical presentation, slightly different from that in adulthood, is well characterized.2-9,17 Conversely, the natural history and the long-term outcome after surgery are less clearly defined. Some papers suggested that PAs are more aggressive in adolescents than in adults,18-24 reporting a very high incidence of invasive growth pattern during puberty (up to 77.7%-100%),18,20 data not confirmed by other authors.3,4,25,26 However, PAs invasiveness is not synonymous of aggressive behavior and analysis of the outcomes after surgery must be made to correlate morphological and clinical features. About this, data on age as risk factor for recurrence are contradictory: a meta-analysis, published in 2012, demonstrated that age was unrelated to recurrence, although it has a prognostic significance in a certain amount of studies.27 Conversely, in a more recent series of 410 PAs, young age was a poor prognostic factor for recurrence and progression free survival 8 yr after surgery.16 We report our experience in the surgical treatment of pediatric PAs by focusing specifically on the remission and recurrence rates as well as on the safety of surgery. The study also describes the long-term disease control after surgery plus adjuvant therapies. METHODS Patient Selection and Data Collection Between January 1990 and December 2016, a total of 3040 consecutive patients with PA were treated in our department. Clinical and biochemical data, as well as complications, were prospectively recorded and retrospectively analyzed in 3002 cases. Patients were subdivided into 2 groups: 2917 adults (>18 yr old; 97.2%) and 85 pediatric patients (≤18 yr old; 2.8%). Hormonal, visual, and clinical data as well as magnetic resonance imaging (MRI) were evaluated 6 mo after surgery (early surgical remission) and then yearly (recurrence rate) in 2906 patients (84 pediatric and 2822 adult), excluding 75 thyrotropin-secreting adenomas and 21 patients lost to follow-up. In 15 other adults, long-term information were incomplete so final disease control, after surgery plus adjuvant treatments, was calculated on 2891 patients (84 pediatric and 2807 adult). Surgical Technique All patients underwent sublabial transseptal microsurgical transsphenoidal approach (MTSA), as previously described.28 Wide drilling of the sphenoidal bone, including the tuberculum sellae, was done to remove large suprasellar or subfrontal PAs. In these cases, a final inspection by a rigid endoscope 4 mm in diameter with 0° and 30° lenses (Karl Storz-Endoskope, Tuttlingen, Germany) was performed. Considering the size of nares in children, a shorter and smaller self-retracting Cushing-Landolt speculum was required and a high-speed drill was used to open the sellar floor in conchal type or poorly pneumatized sphenoid sinuses. Histopathological diagnosis was based on hematoxylin-eosin stained sections and immunocytochemical characterization of secretory activity. All the procedures respected the standards of the institutional Research Ethics Committee and the 1964 Helsinki Declaration. Informed consent was obtained in all the cases by the patients or their parents. Early Surgical Remission Six months after surgery we applied the following criteria to define the early surgical remission: - Growth hormone (GH)-secreting adenoma: basal or oral glucose tolerance test-GH levels below 1 μg/L and normalization of age- and sex-adjusted insulin growth factor-1 levels. - Prolactin (PRL)-secreting adenoma: normalization of basal PRL levels (<20μg/L in women and <15μg/L in men) without dopaminergic therapy for at least 6 mo. - Adrenocorticotropic hormone (ACTH)-secreting adenoma: presence of hypocortisolism requiring glucocorticoid substitution therapy, or, in case of normal serum and urinary cortisol levels, normal suppression of serum cortisol level after an overnight low-dose dexamethasone test. - NFPA: absence on the first postoperative MRI of residual adenomatous tissue (complete surgical removal). Long-Term Outcome During follow-up in early cured patients, recurrence was defined as reappearance of hormone hypersecretion in hormone-active PAs and as evidence of new tumor on MRI in NFPAs. In patients not cured by primary surgery or with recurrent disease, Gamma Knife stereotactic-radiosurgery (GKSRS, Leksell Gamma Knife®, Elekta, Stockholm, Sweden), radiotherapy, drugs, and/or repeated surgery, either transcranial or transsphenoidal, were applied to achieve disease control. Radiotherapy was used when residual tumor extended extensively into the skull base, whereas GKSRS in small unresectable PAs, usually located within the cavernous sinus. Surgery was repeated if tumor was accessible. Therefore, the final disease control rate included all patients cured by initial surgery plus those in remission after adjuvant therapies. Statistical Analysis Continuous data were expressed as mean ± standard error. Student's t-test for unpaired data was used to compare continuous variables among groups. Categorical variables were compared with the Pearson's chi-square test or with the Fisher exact test when appropriate. Recurrence-free survival was calculated using Kaplan–Meier survival function. A P value of less than .05 was considered to indicate statistical significance. All calculations were performed using the IBM SPSS Statistics package (IBM Corporation, Released 2011, SPSS Statistics for Macintosh, Version 20.0, Armonk, New York). RESULTS General Results NFPAs and hormone-secreting adenomas, respectively, occurred in 10.5% and 89.5% of 85 pediatric patients, as compared to 39% and 61% of 2917 adults (Figure 1). There was a female prevalence in both adult and pediatric prolactinomas (Figure 2), in adult but not in pediatric Cushing's disease (CD; P < .001) and in pediatric NFPAs (P = .03). Macroadenomas occurred more frequently in pediatric prolactinomas (Table 1; P = .007) and GH-secreting adenomas (P = .048), while the tumor invasiveness was similar in adult and pediatric groups. FIGURE 1. View largeDownload slide Adenoma type distribution in a series of 3002 PAs treated by TSS. The pediatric group comprised 85 cases: 43 CD, 23 prolactinomas, 9 gigantism/acromegaly, 9 NFPAs, and 1 TSH-sa. In 2917 adults, there was a prevalence of NFPAs (1142 cases), followed by acromegaly (786 cases), CD (647 cases), prolactinomas (268 cases), and TSH-sa (74 cases). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; TSH-sa, thyrotropin-secreting adenoma, NFPA, nonfunctioning pituitary adenoma. FIGURE 1. View largeDownload slide Adenoma type distribution in a series of 3002 PAs treated by TSS. The pediatric group comprised 85 cases: 43 CD, 23 prolactinomas, 9 gigantism/acromegaly, 9 NFPAs, and 1 TSH-sa. In 2917 adults, there was a prevalence of NFPAs (1142 cases), followed by acromegaly (786 cases), CD (647 cases), prolactinomas (268 cases), and TSH-sa (74 cases). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; TSH-sa, thyrotropin-secreting adenoma, NFPA, nonfunctioning pituitary adenoma. FIGURE 2. View largeDownload slide Female prevalence in a series of 2927 PAs; considering the only case of thyrotropin-secreting adenoma in pediatric group, this adenoma type (75 cases) was excluded from comparison between adults and pediatric population. Pearson's chi-square with Fisher exact test shows female prevalence in both adult and pediatric prolactinomas, in adult CD (P < .001) and in nonfunctioning pituitary pediatric adenomas (P = .03). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; NFPA, nonfunctioning pituitary adenoma. FIGURE 2. View largeDownload slide Female prevalence in a series of 2927 PAs; considering the only case of thyrotropin-secreting adenoma in pediatric group, this adenoma type (75 cases) was excluded from comparison between adults and pediatric population. Pearson's chi-square with Fisher exact test shows female prevalence in both adult and pediatric prolactinomas, in adult CD (P < .001) and in nonfunctioning pituitary pediatric adenomas (P = .03). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; NFPA, nonfunctioning pituitary adenoma. TABLE 1. Size and invasiveness in 2927 pituitary adenomas ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Macroadenomas, n 148/647 8/43 142/268 20/23 638/786 8/9 1136/1142 9/9 % 22.9% 18.6% 53% 87% 81.2% 88.9% 99.5% 100% P = .6 = .007 = .048 = .9 Greatest diameter, mm 8.6 ± 0.3 7.1 ± 1 14.9 ± 0.7 16.2 ± 1.1 18 ± 0.3 28.1 ± 4.1 27.8 ± 0.3 25.6 ± 2.8 (mean ± SE, range) 2-41 2-34 3-65 7-26 4-72 10-50 7-80 15-40 P = .2 = .6 = .002 = .5 CS invasion, n 36/647 1/43 49/268 2/23 178/786 2/9 394/1142 2/9 % 5.6% 2.3% 18.3% 8.7% 22.6% 22.2% 34.5% 22.2% P = .7 = .4 = .2 = .7 SS invasion, n 49/647 1/43 23/268 1/23 82/786 3/9 115/1142 1/9 % 7.6% 2.3% 8.6% 4.3% 10.4% 33.3% 10.1% 11.1% P = .3 = .7 = .07 = 1 ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Macroadenomas, n 148/647 8/43 142/268 20/23 638/786 8/9 1136/1142 9/9 % 22.9% 18.6% 53% 87% 81.2% 88.9% 99.5% 100% P = .6 = .007 = .048 = .9 Greatest diameter, mm 8.6 ± 0.3 7.1 ± 1 14.9 ± 0.7 16.2 ± 1.1 18 ± 0.3 28.1 ± 4.1 27.8 ± 0.3 25.6 ± 2.8 (mean ± SE, range) 2-41 2-34 3-65 7-26 4-72 10-50 7-80 15-40 P = .2 = .6 = .002 = .5 CS invasion, n 36/647 1/43 49/268 2/23 178/786 2/9 394/1142 2/9 % 5.6% 2.3% 18.3% 8.7% 22.6% 22.2% 34.5% 22.2% P = .7 = .4 = .2 = .7 SS invasion, n 49/647 1/43 23/268 1/23 82/786 3/9 115/1142 1/9 % 7.6% 2.3% 8.6% 4.3% 10.4% 33.3% 10.1% 11.1% P = .3 = .7 = .07 = 1 ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone; CS, cavernous sinus; SS, sphenoidal sinus Pearson's chi-square with Fisher exact test Seventy-five thyrotropin-secreting adenoma was excluded because comparison between adults and patients younger than 18 yr was not appropriate (only 1 case in pediatric age). View Large TABLE 1. Size and invasiveness in 2927 pituitary adenomas ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Macroadenomas, n 148/647 8/43 142/268 20/23 638/786 8/9 1136/1142 9/9 % 22.9% 18.6% 53% 87% 81.2% 88.9% 99.5% 100% P = .6 = .007 = .048 = .9 Greatest diameter, mm 8.6 ± 0.3 7.1 ± 1 14.9 ± 0.7 16.2 ± 1.1 18 ± 0.3 28.1 ± 4.1 27.8 ± 0.3 25.6 ± 2.8 (mean ± SE, range) 2-41 2-34 3-65 7-26 4-72 10-50 7-80 15-40 P = .2 = .6 = .002 = .5 CS invasion, n 36/647 1/43 49/268 2/23 178/786 2/9 394/1142 2/9 % 5.6% 2.3% 18.3% 8.7% 22.6% 22.2% 34.5% 22.2% P = .7 = .4 = .2 = .7 SS invasion, n 49/647 1/43 23/268 1/23 82/786 3/9 115/1142 1/9 % 7.6% 2.3% 8.6% 4.3% 10.4% 33.3% 10.1% 11.1% P = .3 = .7 = .07 = 1 ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Macroadenomas, n 148/647 8/43 142/268 20/23 638/786 8/9 1136/1142 9/9 % 22.9% 18.6% 53% 87% 81.2% 88.9% 99.5% 100% P = .6 = .007 = .048 = .9 Greatest diameter, mm 8.6 ± 0.3 7.1 ± 1 14.9 ± 0.7 16.2 ± 1.1 18 ± 0.3 28.1 ± 4.1 27.8 ± 0.3 25.6 ± 2.8 (mean ± SE, range) 2-41 2-34 3-65 7-26 4-72 10-50 7-80 15-40 P = .2 = .6 = .002 = .5 CS invasion, n 36/647 1/43 49/268 2/23 178/786 2/9 394/1142 2/9 % 5.6% 2.3% 18.3% 8.7% 22.6% 22.2% 34.5% 22.2% P = .7 = .4 = .2 = .7 SS invasion, n 49/647 1/43 23/268 1/23 82/786 3/9 115/1142 1/9 % 7.6% 2.3% 8.6% 4.3% 10.4% 33.3% 10.1% 11.1% P = .3 = .7 = .07 = 1 ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone; CS, cavernous sinus; SS, sphenoidal sinus Pearson's chi-square with Fisher exact test Seventy-five thyrotropin-secreting adenoma was excluded because comparison between adults and patients younger than 18 yr was not appropriate (only 1 case in pediatric age). View Large Because clinical characteristics of PAs are well known and beyond the purpose of the study, we reported symptoms and pituitary function before surgery, as well as recovery after surgery, only in pediatric patients (Table 2). Figure 3 shows the mean age at diagnosis in pediatric population. TABLE 2. Clinical Manifestations, Pituitary Dysfunction Before Surgery and Recovery After Surgery in 84a Pediatric PAs ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas n 43 23 9 9 Females/Males 23/20 18/5 4/5 7/2 Clinical Manifestation Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Weight gain 36/43 (83.7%) 36/36 (100%) – – – Growth failure 14/43 (32.6%) 14/14 (100%) – – 1/9 (11.1%) Linear growth° – – 9/9° (100%) – Visual defect – 1/23 (4.3%) 1/1 (100%) 4/8 (50%) 3/4b (75%) 6/9 (66.7%) 3/6b (50%) Headache 30/43 (69.8%) 27/30 (90%) 9/23 (39.1%) 9/9 (100%) 3/9 (33.3%) 3/3 (100%) 4/9 (44.4%) 4/4 (100%) Menstrual irregularities (postpubertal females) 10/21 (47.6%) 9/10 (90%) 16/17 (94.1%) 15/17 (88.2%) 3/3 (100%) 1/3 (33.3%) 6/6 (100%) 0/6 (0%) Precocious puberty 2/43 (4.7%) 0/23 (0%) 0/9 (0%) 0/9 (0%) Delayed puberty – – – 1/9 (11.1%) Depression 15/43 (34.9%) 8/15§(53.3%) – – – Hypertension 13/43 (30.2%) 10/13 (76.9%) – 0/9 (0%) – Diabetes mellitus 1/43 (2.4%) 1/1 (100%) – 0/9 (0%) – Hypogonadism (postpubertal patients) 17/32 (53.1%) 13/17 (76.5%) 20/21 (95.2%) 17/20 (85%) 7/7 (100%) 2/7 (28.6%) 5/7 (71.4%) 1/5 (20%) Hypothyroidism 1/42 (2.4%) 0/1 (0%) 0/23 (0%) – 2/8 (25%) 1/2 (50%) 3/9 (33.3%) 0/3 (0%) Adrenal deficiency – 1/23 (4.3%) 1/1 (100%) 1/9 (11.1%) 0/1 (0%) 1/9 (11.1%) 0/9 (0%) Diabetes insipidus 0/43 (0%) 0/23 (0%) 0/9 (0%) 0/9 (0%) ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas n 43 23 9 9 Females/Males 23/20 18/5 4/5 7/2 Clinical Manifestation Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Weight gain 36/43 (83.7%) 36/36 (100%) – – – Growth failure 14/43 (32.6%) 14/14 (100%) – – 1/9 (11.1%) Linear growth° – – 9/9° (100%) – Visual defect – 1/23 (4.3%) 1/1 (100%) 4/8 (50%) 3/4b (75%) 6/9 (66.7%) 3/6b (50%) Headache 30/43 (69.8%) 27/30 (90%) 9/23 (39.1%) 9/9 (100%) 3/9 (33.3%) 3/3 (100%) 4/9 (44.4%) 4/4 (100%) Menstrual irregularities (postpubertal females) 10/21 (47.6%) 9/10 (90%) 16/17 (94.1%) 15/17 (88.2%) 3/3 (100%) 1/3 (33.3%) 6/6 (100%) 0/6 (0%) Precocious puberty 2/43 (4.7%) 0/23 (0%) 0/9 (0%) 0/9 (0%) Delayed puberty – – – 1/9 (11.1%) Depression 15/43 (34.9%) 8/15§(53.3%) – – – Hypertension 13/43 (30.2%) 10/13 (76.9%) – 0/9 (0%) – Diabetes mellitus 1/43 (2.4%) 1/1 (100%) – 0/9 (0%) – Hypogonadism (postpubertal patients) 17/32 (53.1%) 13/17 (76.5%) 20/21 (95.2%) 17/20 (85%) 7/7 (100%) 2/7 (28.6%) 5/7 (71.4%) 1/5 (20%) Hypothyroidism 1/42 (2.4%) 0/1 (0%) 0/23 (0%) – 2/8 (25%) 1/2 (50%) 3/9 (33.3%) 0/3 (0%) Adrenal deficiency – 1/23 (4.3%) 1/1 (100%) 1/9 (11.1%) 0/1 (0%) 1/9 (11.1%) 0/9 (0%) Diabetes insipidus 0/43 (0%) 0/23 (0%) 0/9 (0%) 0/9 (0%) ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone aOne patient with Thyrotropin hormone-secreting adenoma reported only in the text. §Depression in all cases improved. °All cases presented with linear growth, associated with acral enlargement in five patients (55.5%). bAll cases improved after surgery. View Large TABLE 2. Clinical Manifestations, Pituitary Dysfunction Before Surgery and Recovery After Surgery in 84a Pediatric PAs ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas n 43 23 9 9 Females/Males 23/20 18/5 4/5 7/2 Clinical Manifestation Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Weight gain 36/43 (83.7%) 36/36 (100%) – – – Growth failure 14/43 (32.6%) 14/14 (100%) – – 1/9 (11.1%) Linear growth° – – 9/9° (100%) – Visual defect – 1/23 (4.3%) 1/1 (100%) 4/8 (50%) 3/4b (75%) 6/9 (66.7%) 3/6b (50%) Headache 30/43 (69.8%) 27/30 (90%) 9/23 (39.1%) 9/9 (100%) 3/9 (33.3%) 3/3 (100%) 4/9 (44.4%) 4/4 (100%) Menstrual irregularities (postpubertal females) 10/21 (47.6%) 9/10 (90%) 16/17 (94.1%) 15/17 (88.2%) 3/3 (100%) 1/3 (33.3%) 6/6 (100%) 0/6 (0%) Precocious puberty 2/43 (4.7%) 0/23 (0%) 0/9 (0%) 0/9 (0%) Delayed puberty – – – 1/9 (11.1%) Depression 15/43 (34.9%) 8/15§(53.3%) – – – Hypertension 13/43 (30.2%) 10/13 (76.9%) – 0/9 (0%) – Diabetes mellitus 1/43 (2.4%) 1/1 (100%) – 0/9 (0%) – Hypogonadism (postpubertal patients) 17/32 (53.1%) 13/17 (76.5%) 20/21 (95.2%) 17/20 (85%) 7/7 (100%) 2/7 (28.6%) 5/7 (71.4%) 1/5 (20%) Hypothyroidism 1/42 (2.4%) 0/1 (0%) 0/23 (0%) – 2/8 (25%) 1/2 (50%) 3/9 (33.3%) 0/3 (0%) Adrenal deficiency – 1/23 (4.3%) 1/1 (100%) 1/9 (11.1%) 0/1 (0%) 1/9 (11.1%) 0/9 (0%) Diabetes insipidus 0/43 (0%) 0/23 (0%) 0/9 (0%) 0/9 (0%) ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas n 43 23 9 9 Females/Males 23/20 18/5 4/5 7/2 Clinical Manifestation Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Weight gain 36/43 (83.7%) 36/36 (100%) – – – Growth failure 14/43 (32.6%) 14/14 (100%) – – 1/9 (11.1%) Linear growth° – – 9/9° (100%) – Visual defect – 1/23 (4.3%) 1/1 (100%) 4/8 (50%) 3/4b (75%) 6/9 (66.7%) 3/6b (50%) Headache 30/43 (69.8%) 27/30 (90%) 9/23 (39.1%) 9/9 (100%) 3/9 (33.3%) 3/3 (100%) 4/9 (44.4%) 4/4 (100%) Menstrual irregularities (postpubertal females) 10/21 (47.6%) 9/10 (90%) 16/17 (94.1%) 15/17 (88.2%) 3/3 (100%) 1/3 (33.3%) 6/6 (100%) 0/6 (0%) Precocious puberty 2/43 (4.7%) 0/23 (0%) 0/9 (0%) 0/9 (0%) Delayed puberty – – – 1/9 (11.1%) Depression 15/43 (34.9%) 8/15§(53.3%) – – – Hypertension 13/43 (30.2%) 10/13 (76.9%) – 0/9 (0%) – Diabetes mellitus 1/43 (2.4%) 1/1 (100%) – 0/9 (0%) – Hypogonadism (postpubertal patients) 17/32 (53.1%) 13/17 (76.5%) 20/21 (95.2%) 17/20 (85%) 7/7 (100%) 2/7 (28.6%) 5/7 (71.4%) 1/5 (20%) Hypothyroidism 1/42 (2.4%) 0/1 (0%) 0/23 (0%) – 2/8 (25%) 1/2 (50%) 3/9 (33.3%) 0/3 (0%) Adrenal deficiency – 1/23 (4.3%) 1/1 (100%) 1/9 (11.1%) 0/1 (0%) 1/9 (11.1%) 0/9 (0%) Diabetes insipidus 0/43 (0%) 0/23 (0%) 0/9 (0%) 0/9 (0%) ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone aOne patient with Thyrotropin hormone-secreting adenoma reported only in the text. §Depression in all cases improved. °All cases presented with linear growth, associated with acral enlargement in five patients (55.5%). bAll cases improved after surgery. View Large FIGURE 3. View largeDownload slide Mean age at surgery ± standard error and range in a series of 84 pediatric PAs (1 patient with thyrotropin hormone-secreting adenoma was 14 yr old). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; NFPA, nonfunctioning pituitary adenoma. FIGURE 3. View largeDownload slide Mean age at surgery ± standard error and range in a series of 84 pediatric PAs (1 patient with thyrotropin hormone-secreting adenoma was 14 yr old). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; NFPA, nonfunctioning pituitary adenoma. ACTH-Secreting Adenomas Among the 690 patients who underwent surgery for CD, MRI was positive or doubtful in 30/43 pediatric cases (69.8%) and in 448/647 adults (69.2%; P = .9). Bilateral inferior petrosal sinus sampling (BIPSS) was carried out in 13 (30.2%) and 221 patients (30.1%; P = .9) of the 2 groups, respectively. Remission of CD after surgery was achieved in 31/43 patients (72.1%). Positive histology was found in 25 of the 31 cured patients (80.6%) and was negative in the other 6 (19.4%; P = .001), proving its favorable significance on surgical outcome. The mean follow-up after surgery in cured patients was 48.1 ± 9.7 mo. Two patients (6.4%) had recurrence of disease 71 and 73 mo after surgery. Patients with persistent or recurrent hypercortisolism required a multimodality approach: drugs (5), repeat surgery (3), GKSRS (2), surgery plus radiotherapy or GKSRS combined with (2 cases), or without medical therapy (2 cases). At the last follow-up (64.4 ± 10.6 mo) 40 of 43 patients (93%) achieved the CD control. Surgical remission, recurrence rates, and final CD control were not different between adult and pediatric population as well as the follow-up time (Table 3). The 10-yr recurrence-free survival rate was 81.8% (95% confidence interval [CI], 70%-93%) in pediatric CD and 75.4% (95% CI, 72%-79%, P = . 3) in adults (Figure 4). TABLE 3. Surgical Remission and Recurrence in 2906 PAs According to Age Group; Final Cure/Growth Tumor Control After Surgery and Adjuvant Therapies in 2891 PAs. Outcome ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Surgical remission/complete removal 6 months after surgery (n = 2906) 491/646 31/43 159/268 16/23 473/776 5/9 696/1132 5/9 76% 72.1% 59.3% 69.3% 61% 55.6% 61.5% 55.6% P = .3 = .2 = .7 = .7 Recurrence after remission/complete removal at last follow-up (n = 1876) 57/491 2/31 26/159 3/16 25/473 2/5 110/696 0/5 11.6% 6.4% 16.3% 18.7% 5.3% 40% 15.8% 0% P = .5 = .5 = .028 = .3 Follow-up after surgical remission (mean ± SE) 50.4 ± 2.3 48.1 ± 9.7 46.3 ± 5.2 61.4 ± 25 48.1 ± 2.2 38 ± 17 54.9 ± 2.2 67.8 ± 30.3 6-237 6-204 6-183 6-190 6-276 6-92 6-242 6-184 P = .4 = .1 = .7 = .7 Final cure/Growth tumor control at last follow-up (n = 2891) 537/646 40/43 201/268 18/23 639/761 7/9 890/1132 7/9 83.1% 93% 75% 78.3% 84% 77.8% 78.6% 77.8% P = .5 = .8 = .8 = .6 Follow-up after surgery ± adjuvant therapies (mean ± SE) 56.8 ± 2.2 64.4 ± 10.6 63 ± 2.3 58.9 ± 12.3 63 ± 2.3 79.1 ± 21.1 71.2 ± 2.1 71.8 ± 23.9 6-289 6-221 6-297 6-204 6-286 6-216 6-309 6-211 P = .4 = .4 = .4 = .9 Outcome ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Surgical remission/complete removal 6 months after surgery (n = 2906) 491/646 31/43 159/268 16/23 473/776 5/9 696/1132 5/9 76% 72.1% 59.3% 69.3% 61% 55.6% 61.5% 55.6% P = .3 = .2 = .7 = .7 Recurrence after remission/complete removal at last follow-up (n = 1876) 57/491 2/31 26/159 3/16 25/473 2/5 110/696 0/5 11.6% 6.4% 16.3% 18.7% 5.3% 40% 15.8% 0% P = .5 = .5 = .028 = .3 Follow-up after surgical remission (mean ± SE) 50.4 ± 2.3 48.1 ± 9.7 46.3 ± 5.2 61.4 ± 25 48.1 ± 2.2 38 ± 17 54.9 ± 2.2 67.8 ± 30.3 6-237 6-204 6-183 6-190 6-276 6-92 6-242 6-184 P = .4 = .1 = .7 = .7 Final cure/Growth tumor control at last follow-up (n = 2891) 537/646 40/43 201/268 18/23 639/761 7/9 890/1132 7/9 83.1% 93% 75% 78.3% 84% 77.8% 78.6% 77.8% P = .5 = .8 = .8 = .6 Follow-up after surgery ± adjuvant therapies (mean ± SE) 56.8 ± 2.2 64.4 ± 10.6 63 ± 2.3 58.9 ± 12.3 63 ± 2.3 79.1 ± 21.1 71.2 ± 2.1 71.8 ± 23.9 6-289 6-221 6-297 6-204 6-286 6-216 6-309 6-211 P = .4 = .4 = .4 = .9 ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone View Large TABLE 3. Surgical Remission and Recurrence in 2906 PAs According to Age Group; Final Cure/Growth Tumor Control After Surgery and Adjuvant Therapies in 2891 PAs. Outcome ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Surgical remission/complete removal 6 months after surgery (n = 2906) 491/646 31/43 159/268 16/23 473/776 5/9 696/1132 5/9 76% 72.1% 59.3% 69.3% 61% 55.6% 61.5% 55.6% P = .3 = .2 = .7 = .7 Recurrence after remission/complete removal at last follow-up (n = 1876) 57/491 2/31 26/159 3/16 25/473 2/5 110/696 0/5 11.6% 6.4% 16.3% 18.7% 5.3% 40% 15.8% 0% P = .5 = .5 = .028 = .3 Follow-up after surgical remission (mean ± SE) 50.4 ± 2.3 48.1 ± 9.7 46.3 ± 5.2 61.4 ± 25 48.1 ± 2.2 38 ± 17 54.9 ± 2.2 67.8 ± 30.3 6-237 6-204 6-183 6-190 6-276 6-92 6-242 6-184 P = .4 = .1 = .7 = .7 Final cure/Growth tumor control at last follow-up (n = 2891) 537/646 40/43 201/268 18/23 639/761 7/9 890/1132 7/9 83.1% 93% 75% 78.3% 84% 77.8% 78.6% 77.8% P = .5 = .8 = .8 = .6 Follow-up after surgery ± adjuvant therapies (mean ± SE) 56.8 ± 2.2 64.4 ± 10.6 63 ± 2.3 58.9 ± 12.3 63 ± 2.3 79.1 ± 21.1 71.2 ± 2.1 71.8 ± 23.9 6-289 6-221 6-297 6-204 6-286 6-216 6-309 6-211 P = .4 = .4 = .4 = .9 Outcome ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Surgical remission/complete removal 6 months after surgery (n = 2906) 491/646 31/43 159/268 16/23 473/776 5/9 696/1132 5/9 76% 72.1% 59.3% 69.3% 61% 55.6% 61.5% 55.6% P = .3 = .2 = .7 = .7 Recurrence after remission/complete removal at last follow-up (n = 1876) 57/491 2/31 26/159 3/16 25/473 2/5 110/696 0/5 11.6% 6.4% 16.3% 18.7% 5.3% 40% 15.8% 0% P = .5 = .5 = .028 = .3 Follow-up after surgical remission (mean ± SE) 50.4 ± 2.3 48.1 ± 9.7 46.3 ± 5.2 61.4 ± 25 48.1 ± 2.2 38 ± 17 54.9 ± 2.2 67.8 ± 30.3 6-237 6-204 6-183 6-190 6-276 6-92 6-242 6-184 P = .4 = .1 = .7 = .7 Final cure/Growth tumor control at last follow-up (n = 2891) 537/646 40/43 201/268 18/23 639/761 7/9 890/1132 7/9 83.1% 93% 75% 78.3% 84% 77.8% 78.6% 77.8% P = .5 = .8 = .8 = .6 Follow-up after surgery ± adjuvant therapies (mean ± SE) 56.8 ± 2.2 64.4 ± 10.6 63 ± 2.3 58.9 ± 12.3 63 ± 2.3 79.1 ± 21.1 71.2 ± 2.1 71.8 ± 23.9 6-289 6-221 6-297 6-204 6-286 6-216 6-309 6-211 P = .4 = .4 = .4 = .9 ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone View Large FIGURE 4. View largeDownload slide Recurrence-free cumulative survival in CD after surgical remission. Comparison between adult (continuous line) and pediatric (dotted line) groups does not show any statistical difference (Kaplan–Meier, Log-Rank P = .47). FIGURE 4. View largeDownload slide Recurrence-free cumulative survival in CD after surgical remission. Comparison between adult (continuous line) and pediatric (dotted line) groups does not show any statistical difference (Kaplan–Meier, Log-Rank P = .47). PRL-Secreting Adenomas The tumor size significantly differed between pediatric and adult patients because of a higher prevalence of macroadenomas in the first group (87% vs 53%, respectively; P = .007); however, the maximum tumor diameter was similar (Table 1; P = .6) as well as the invasiveness into the cavernous (P = .4) and sphenoidal sinuses (P = .7). The early surgical remission rate was 69.6%. During a mean follow-up of 61.4 ± 25.0 mo, 3 of the 16 cured patients (18.7%) had recurrence of hyperprolactinemia, 28, 70, and 96 mo after surgery. Recurrent or persistent hyperprolactinemia was treated in 6 patients with dopamine agonist (DA); 1 patient underwent GKSRS, 2 patients GKSRS plus DA, and 1 radiation therapy plus surgery and DA. At the last follow-up (68 ± 12.3 mo), 18 of the 23 patients (78.3%) had normal PRL levels. Surgical remission rate, frequency of recurrence, final hormonal control, and follow-up were similar in the adult and pediatric population (Table 3). GH-Secreting Adenomas Only 1 child had a microadenoma whereas the other 8 pediatric patients had a macroadenoma with suprasellar extension (88.9%), so the frequency of macroadenomas was higher compared to adults (Table 1; P = .048). The maximum tumor diameter was greater in pediatric patients (28.1 ± 4.1 mm) than in adults (18 ± 0.3 mm; P = .002), whereas the invasiveness into the cavernous and sphenoidal sinuses was similar (Table 1; P = .2 and P = .07, respectively). The surgical remission rate was 55.6% (5/9). During a mean follow-up of 38.4 ± 17.0 mo, 2 patients (40.0%) had recurrence of GH-hypersecretion, 79 and 86 mo after surgery. Patients with persistent or recurring acromegaly received medical therapy (2 cases), GKSRS plus medical therapy (1 case), and radiation plus medical therapy (1 case); finally, 2 patients did not receive any treatment. Disease control at the last follow-up (mean 79.1 ± 21.1 mo) was achieved in 7 of 9 patients (77.8%). Surgical remission rate, final hormonal control, and follow-up were similar in adult and pediatric population (Table 3), whereas frequency of recurrence was significantly higher in pediatric compared to adult patients (40.0% vs 5.3%, P = .028). The risk of recurrence in both groups combined was higher in macroadenomas (7.1%) than in microadenomas (1.6%, P = .023). Nonfunctioning Pituitary Adenomas Radical removal of the tumor was achieved in 5 of 9 patients (55.6%). During a mean follow-up of 71.8 ± 23.8 mo, no recurrence of disease was observed. Second-line treatments, for partially removed tumors with skull base invasion, included radiation therapy in 2 cases and repeated surgery plus radiotherapy in the other 2 cases. At the last follow-up (71.8 ± 23.8 mo), tumor control occurred in 7 of 9 patients (77.8%). Early complete surgical removal, frequency of recurrence, final growth control, and follow-up were similar in adult and pediatric population (Table 3). TSH-Secreting Adenomas The only case of pediatric TSH-secreting macroadenoma has already been described in detail elsewhere.29 Preoperative treatment with somatostatin analogues for 1 yr caused a significant shrinkage of the irregularly shaped suprasellar portion of the tumor, which allowed performing MTSA. Postoperative MRI showed a small residual tumor and the patient continued medical therapy. Complications Major surgical complications occurred in 2 cases (2.4%), consisting of meningitis without neurological sequels in 1 patient and epistaxis requiring nasal dressing and blood transfusion 10 d after surgery in the other patient. Endocrinological morbidity consisted of new onset partial hypopituitarism in 2 patients (2.4%), permanent diabetes insipidus in 1 case (1.2%), and delayed hyponatremia in 5 cases (6.1%). There was no significant difference between adult and pediatric groups in surgical mortality (0.2% and 0%, respectively; P = .8) and major morbidity (2.2% and 2.4%; P = .7). Surgical complications in 2917 adults were: cerebrospinal fluid rhinorrhea requiring surgical repair in 6 cases (0.2%), meningitis in 6 (0.2%), intracranial/sellar hemorrhage in 32 (1.1%), visual deterioration in 3 (0.1%) and oro-rhino-sinusal complications in 20 (0.7%). DISCUSSION It is well known that children develop PAs uncommonly and their frequency slightly increases in the postpubertal age.1,3,6 Most pediatric PAs appear to be endocrine-active and prolactinomas are the most common subtype.4,6,9 On the other hand, many prolactinomas respond satisfactorily to DA and do not need surgery, explaining why in surgical series prolactinomas are not the leading diagnosis, as confirmed in the present series.2,3,5 Pediatric PAs usually occur more frequently in females but different gender distribution according to age has been described.4,6,9 Patients with CD show a male preponderance during prepubertal age, while toward puberty the sex distribution equalizes and then reverts to the female prevalence, typical of adulthood.31 Consequently, the gender distribution may differ according to the cut-off of age adopted and the caseload of prepubertal patients; our findings, including 18-yr-old or younger patients, confirmed that females were significantly more represented than males, though only in prolactinomas and NFPAs. ACTH-Secreting Adenomas The usual CD features encountered in pediatric population are different from those in adults and include rapid weight gain, generalized rather than centripetal, associated with decreased linear growth in prepubertal cases.5,30 Obesity was the first and most frequent symptom to appear in our series, followed by headache and menstrual irregularities. Growth retardation, psychiatric disorders, and hypertension were present in one-third of our cohort. Selective adenomectomy is the first line treatment of pediatric CD.31,32 The main difficulty may be the correct localization of the pituitary tumor, since most ACTH-secreting adenomas are tiny microadenomas. When MRI is negative and/or hormonal data are inconsistent, the BIPSS is the most sensitive test (99%) for the exclusion of ectopic ACTH production.31 Even though technically more demanding in children than in adults, BIPSS is very safe in experienced hands.31,32 In our series, MRI showed a PA in 69.8% of cases and BIPSS was performed in the remnant 30.2% without any complication. A meticulous exploration of the pituitary gland, including the posterior lobe, should be performed even when BIPSS shows a lateralizing side, because its accuracy is only partial, ranging from 70% to 91%.30,31 Removal of half or two-thirds of the gland is indicated when the exploration is negative.5,33 Oliveira and colleagues34 reported a surgical remission rate of CD in 70.5% of pediatric patients (mean of previously published cases), a value very close to ours. However, the range in the literature varies from 40% to 100%, probably because of different hormonal criteria, neurosurgeon experience, and technical improvement in the last 25 yr.31,34,35 Recognized factors associated with CD remission are identification of adenoma at surgery and histological confirmation. Young age, small tumor size, and absence of dural invasion are associated with long-term remission of CD, suggesting that the earlier is the diagnosis the better is the prognosis.31 We calculated a 10-yr recurrence-free survival rate of 81.8% and documented a recurrence frequency of 6.4% during a follow-up of more than 5 yr. Reported recurrence frequency in literature varies, ranging between 0% and 25%.2,3,6,8,21,31,32 Early and late surgical results were similar in our pediatric and adult population. In recurrent or residual CD, we suggest repeated surgery or GKSRS, whereas medical therapy or bilateral adrenalectomy should be reserved in rare circumstances. Second transsphenoidal surgery (TSS) may be successful in about 60% of cases, especially in patients with a positive MRI, being aware of the adenoma location based on the previous surgical report and positive histology.31 The presence of residual adenoma within the cavernous sinus favors the choice of GKSRS. PRL-Secreting Adenomas Clinical signs and symptoms of prolactinomas vary according to age, sex, tumor size, and PRL levels.36,37 Prepubertal children usually present with headache, visual disturbances, and growth failure. During adolescence in females delayed puberty or amenorrhea and galactorrhea are reported as the major presenting symptoms, whereas in males headache and mass effect related symptoms are common manifestations.37 In our experience, almost all girls (94%) complained of menstrual irregularities. Visual impairment occurred in only 1 case (4.3%) despite the high prevalence of large adenomas. Indeed, macroprolactinomas were more frequent in pediatric age compared to adults, as previously described,38 although there was a female prevalence in both groups (Figure 2). Nevertheless, cavernous and sphenoidal sinus invasion was similar in the 2 groups, suggesting that the bigger size in pediatric patients could be explained only by delayed diagnosis rather than invasiveness. Treatment with DA is the first therapeutic option in adults as well as in children and it has been reported to be adequate even in the presence of visual field defects,36-39 leading to normalization of PRL levels and tumor shrinkage in 85% of patients.39 Surgery might be regarded as a second therapeutic option in cases of drug resistance, intolerance, or poor compliance. On the other hand, if the diagnosis is uncertain or the patient presents with tumor apoplexy, surgery is a first-choice option. TSS is often deemed as poorly effective,40 as suggested by remission rates of hyperprolactinemia ranging from 33.3% to 66.7% in small surgical series.2,3,41 In our series, remission of hyperprolactinemia occurred in 70% of cases, confirming that, especially in patients with intrasellar adenomas and PRL levels less than 200 μg/L, surgery may have a high cure rate.2,5,41 A well-known caveat of TSS for prolactinomas is the disease recurrence.40,41 Indeed, we found a recurrence rate of 18.7%, similar to that in adults. Despite adjuvant therapies, the long-term control of hyperprolactinemia was obtained in only 78.3% of pediatric patients, probably reflecting the high prevalence of resistance to DA in our cases. Similar results were observed in the adult group, suggesting that it is not an age-specific problem. GH-Secreting Adenomas GH hypersecretion in pediatric patients is characterized by excessive linear growth causing gigantism, followed by menstrual irregularities and visual defects.24 In our series, pituitary deficiency was more frequent than in other hormone-secreting adenomas, probably because most patients had a macroadenoma (88.9%). Indeed, maximum tumor diameter was greater in pediatric patients than in adults. These results partially overlap with previous data, despite the small number of cases.23 In a series of 15 patients aged 20 yr or less reported by Abe et al,23 the 73.3% of GH-secreting adenomas were macroadenomas and cavernous sinus invasion was detected in the 40%, more frequently compared to the 26.8% in adults. Incidence of invasiveness is very variable in the literature, ranging from 20% to 60%, probably because of different modalities used to define it, but similar to that in adults at least in our series (22.2% and 22.6%).2,6,36,20,21,23 The hormonal remission rate reported by Abe et al23 was 46.7% after surgery and 60% after surgery and adjuvant therapy, lower than in adults (78%), suggesting that GH-secreting adenomas were more likely to be aggressive in adolescents, as described also in other studies.2,6,20,21,23 In our experience, the surgical remission rate was 55.6%, similar to that in adults, and both age ≤18 yr and macroadenoma size are negative prognostic factors for recurrence, despite similar follow-up between the groups. A similar trend was also noted by Abe and colleagues23 that described recurrence in 13.3% of pediatric patients as compared to 1% in adults. These data are probably best explained by the presence of larger tumors in pediatric patients as compared to adults. An alternative explanation, suggested in a recent retrospective case series of pituitary gigantism, demonstrating a successful surgical outcome in only 25% of pediatric patients, might be a different tumor pathogenesis between children and adults.42 Nonfunctioning Pituitary Adenomas NFPAs in pediatric age are very uncommon.2,3,6,43 As in other series, the most frequent symptoms were pubertal delay or primary amenorrhea in pre- or peripubertal patients and menstrual irregularities in postpubertal female patients. Growth failure occurred only in a minority of prepubertal patients. As expected, visual defects were present in most patients, while anterior pituitary deficiency was unexpectedly frequent (71.4%), at variance with other series showing pituitary deficiency in only 26.1% of patients.43 In a review by Abe and colleagues,23 complete tumor removal, judged by intraoperative findings, was detected in 64% of cases, which is comparable to our data. It is worth noting that postoperative MRI was used to verify the tumor removal in our patients. Recurrence of NFPA after surgery, followed or not by adjuvant therapy, has been detected uncommonly in pediatric patients. During a mean follow-up of 7 yr, only one patient out of 16 had tumor regrowth in the series of Abe et al,43 while no case occurred in our surgically cured patients with similar follow-up. Complications Confirming other major pediatric surgical series,31,32 MTSA was safe in our experience with no mortality and a low risk of major morbidity (2.4%). Particularly, no complications specific to pediatric patients emerged. Moreover, we have not found any intraoperative limitation due to the nasal, sphenoid, and sellar anatomy typical of pediatric patients. In younger patients, drilling of an incompletely pneumatized sphenoid sinus to reach the sella may be necessary2,3,43 but this anatomic characteristic cannot be considered a contraindication to TSS. Limitations Some inherent limitations of this retrospective single center study should be kept in mind. The long study interval may raise concerns because of the changing definitions of surgical remission and the different methodologies to measure hormone concentrations. To reduce the risk of misclassification, diagnostic cut-off values were adjusted and a single endocrinologist analyzed all hormonal results. On the whole, the strength of this study is its single center nature, which allowed for homogenous indications and surgical techniques, and the relatively long follow-up, which was essential to analyze the data on recurrences and final disease control. Another limitation is the lack of Ki67 analysis and histological diagnosis according to the last WHO classification, due to the very long inclusion period of the study. No case of atypical adenomas was recorded in our pediatric population. Even though our series is one of the largest in the literature, the number of patients in each subtype of pediatric PA is quite small. Therefore, our results must be interpreted with great caution. Interpretation Our results demonstrate similar outcomes and complications in patients aged 18 yr or less and adults with the only exception for recurrences in GH-secreting adenomas. The last result, even with the above-mentioned limitation, is to notice for further investigation. Our data seem to suggest that pediatric GH-secreting adenomas tend to be bigger than in adults but not more invasive, consequently the reason for higher recurrence rate in gigantism is not completely clear. It could just be the result of delayed discovery, when the tumor is larger, or due to a different adenoma growth in young patients, explaining both the size and the recurrence. Generalizability The paper focused on remission/removal and recurrence of PA after surgery in adult and pediatric population, all treated by microsurgical approach. Comparison with more recent techniques, like pure endoscopic procedures, is beside our scope and therefore the results here presented might be not extended to all pituitary surgeries. However, the considerations about the recurrence risk after surgery, in adults and children or adolescents, should be related to tumor biology, precisely because the applied technique was always the same, and so these may be of interest regardless the surgical approach. CONCLUSION MTSA achieves hormonal remission or complete tumor removal with preservation of pituitary function in the majority of pediatric patients, with very low morbidity and without any complications specific to this age. Regular and long follow-up is important, especially in GH-secreting adenomas, as well as early diagnosis. 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Results of transsphenoidal surgery in a large series of patients with pituitary adenoma . Neurosurgery . 2005 ; 56 ( 6 ): 1222 - 1233 ; discussion 1233 . Google Scholar CrossRef Search ADS PubMed 29. Rabbiosi S , Peroni E , Tronconi GM , Chiumello G , Losa M , Weber G . Asymptomatic thyrotropin-secreting pituitary macroadenoma in a 13-year-old girl: successful first-line treatment with somatostatin analogs . Thyroid . 2012 ; 22 ( 10 ): 1076 - 1079 . Google Scholar CrossRef Search ADS PubMed 30. Magiakou MA , Mastorakos G , Oldfield EH et al. Cushing's syndrome in children and adolescents. Presentation, diagnosis, and therapy . N Engl J Med . 1994 ; 331 ( 10 ): 629 - 636 . Google Scholar CrossRef Search ADS PubMed 31. Lonser RR , Wind JJ , Nieman LK , Weil RJ , DeVroom HL , Oldfield EH . Outcome of surgical treatment of 200 children with Cushing's disease . J Clin Endocrinol Metab . 2013 ; 98 ( 3 ): 892 - 901 . Google Scholar CrossRef Search ADS PubMed 32. Storr HL , Savage MO . Management of endocrine disease: paediatric Cushing's disease . Eur J Endocrinol . 2015 ; 173 ( 1 ): R35 - R45 . Google Scholar CrossRef Search ADS PubMed 33. Oldfield EH . Surgical management of Cushing's disease: a personal perspective . Neurosurgery . 2011 ; 58 (Suppl 1) : 13 - 26 . Google Scholar CrossRef Search ADS 34. Oliveira RS , Castro M , Antonini SR , Martinelli CE Jr , Moreira AC , Machado HR . Surgical management of pediatric Cushing's disease: an analysis of 15 consecutive cases at a specialized neurosurgical center . Arq Bras Endocrinol Metab . 2010 ; 54 ( 1 ): 17 - 23 . Google Scholar CrossRef Search ADS 35. Storr HL , Drake WM , Evanson J et al. Endonasal endoscopic transsphenoidal pituitary surgery: early experience and outcome in paediatric Cushing's disease . Clin Endocrinol . 2014 ; 80 ( 2 ): 270 - 276 . Google Scholar CrossRef Search ADS 36. Fideleff HL. Are there any regional differences in the clinical presentation of adult growth hormone deficient patients? J Postgrad Med . 2008 ; 54 ( 2 ): 84 - 85 . Google Scholar CrossRef Search ADS PubMed 37. Lafferty AR , Chrousos GP . Pituitary tumors in children and adolescents . J Clin Endocrinol Metab . 1999 ; 84 ( 12 ): 4317 - 4323 . Google Scholar CrossRef Search ADS PubMed 38. Fideleff HL. Are there any regional differences in the clinical presentation of adult growth hormone deficient patients? J Postgrad Med . 2008 ; 54 ( 2 ): 84 - 85 . Google Scholar CrossRef Search ADS PubMed 39. Colao A , Loche S , Cappa M et al. Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up . J Clin Endocrinol Metab . 1998 ; 83 ( 8 ): 2777 - 2780 . Google Scholar CrossRef Search ADS PubMed 40. Eren E , Yapici S , Cakir ED , Ceylan LA , Saglam H , Tarim O . Clinical course of hyperprolactinemia in children and adolescents: a review of 21 cases . J Clin Res Pediatr Endocrinol . 2011 ; 3 ( 2 ): 65 - 69 . Google Scholar CrossRef Search ADS PubMed 41. Abe T , Ludecke DK . Transnasal surgery for prolactin-secreting pituitary adenomas in childhood and adolescence . Surg Neurol . 2002 ; 57 ( 6 ): 369 - 378 ; discussion 378-369 . Google Scholar CrossRef Search ADS PubMed 42. Creo AL , Lteif AN . Pituitary gigantism: a retrospective case series . J Pediatr Endocrinol Metab . 2016 ; 29 ( 5 ): 597 - 602 . Google Scholar CrossRef Search ADS PubMed 43. Abe T , Ludecke DK , Saeger W . Clinically nonsecreting pituitary adenomas in childhood and adolescence . Neurosurgery . 1998 ; 42 ( 4 ): 744 - 749 ; discussion 750-741 Google Scholar CrossRef Search ADS PubMed Acknowledgment We are grateful to Prof Massimo Giovanelli who, since 1990, created in our Department a multidisciplinary team to evaluate and manage any PA adopting a multimodality strategy. COMMENTS The authors present a series of pediatric patients with pituitary adenomas treated at a single institution and compare it to a contemporaneous cohort of adult patients. Immediate and long-term outcomes are described for secreting and non-secreting tumors. The authors highlight important differences between pediatric and adult PAs, including the higher frequency of secreting tumors in children, and outline the existing literature on the natural history of these tumors in the pediatric population. They report on 85 children compared to 2917 adults over a 26-year period treated by a microscopic sublabial technique with occasional endoscopic assistance for larger tumors. In their series, the authors re-demonstrate the higher frequency of secreting tumors in children (89.5% vs 61% in adults), as well as more frequently occurring secreting macroadenomas in children. They achieve similar hormonal remission rates between children and adults for Cushing's Disease, Acromegaly and Prolactinoma, and non-secreting tumors were completely removed at a similar rate in children as in adults. Complications were uncommon, 2.4%, and consisted of 1 case of meningitis and 1 epistaxis. These and endocrine morbidities occurred at similar rates to the adult comparison cohort. This report adds to the growing literature on the safety and efficacy of ventral approaches to pediatric sellar and parasellar pathology. Previously thought to be limited by small anatomy, it has been repeatedly demonstrated now that these tumors can be removed with minimally invasive approaches with success rates and risk profiles comparable to adult patients. One criticism of this study is that it fails to assess the state-of-the-art of these approaches, using conventional microscopic techniques as the primary surgical tools, rather than endoscopic endonasal exposure. Additionally, the follow-up periods may be too brief to accurately report recurrence rates. For example, in the Cushing's group, recurrence occurred in 2 patients at >70 months, but the average follow-up was 48 months. Perhaps longer follow-up would show that their recurrence rate is not as low as it seems. Nonetheless, the comprehensive nature of their follow-up and delineation of secreting and non-secreting tumors in both children and adults warrants reporting. Theodore H. Schwartz New York, New York This paper presents a case series of 85 pediatric pituitary cases, including meticulous endocrine outcomes. There is significant value for the literature in this series and it helps to establish a gold standard for microscopic transsphenoidal approach (MTSA) for such tumors. In addition, the paper provides valuable insight into presentation and long-term control. Finally, it includes a comparison with the same group's adult series helping to demonstrate the differences in these populations. The results presented in this paper are very impressive, with the exception of nonfunctioning adenomas and GH-secreting adenomas, both of which had complete resection in only 55.6%. The addition of radiation for 4/9 NFPAs is concerning for a pediatric series, but the use of radiosurgery later in the series has become standard for cavernous sinus residual. Consideration should be given in the future to options such as ‘expanded’ endoscopic endonasal approaches which have been shown to provide improved access and resection rates for tumors with cavernous invasion (yet to show significantly improved outcomes for functional tumors). The authors do add that endoscopes were used for inspection, but this was only presumably later in the series and not throughout the entire series. Indeed, there are several aspects of the surgical technique used that could explain some of the limitations. The addition of image guidance, endoscopy, and otolaryngology for greater exposure and more lateral access could potentially improve outcomes, especially for the tumors with which they had most difficulty; namely larger tumors, such as the NFPAs and GH-secreting tumors. Certainly, the lack of sinus pneumatization in children leads to a smaller natural corridor and the addition of the above adjuvant techniques does provide greater access. The use of a sublabial approach in this series may have offset some of these challenges which would be more evident with a transnasal approach. Paul A. Gardner Pittsburgh, Pennsylvania This is a careful study of a relatively large number of pediatric patients having surgery for pituitary adenomas at a single institution over a 36-year interval. The results reinforce in many respects the observations from previous retrospective analyses on this topic. Based on the existing literature, there remains an unresolved contention that pediatric pituitary adenomas may exhibit faster growth and more aggressive features compared to their adult counterparts. Although this manuscript does not definitively answer this question, for the great majority of adenoma subtypes in the current study there did not appear to be any significant prognostic difference between pediatric and adult tumors. Also importantly, surgical remission for hormonally-active tumors was achieved at rates comparable to generally accepted rates for adult tumors in the literature. In the current analysis, the observed differences in outcome between adults and children for somatotropic adenomas should be viewed with caution, as the pediatric cohort in this study was very small (n = 5). The limitations for this type of retrospective analysis are notable, including bias related to case selection, patient referral, follow-up, non-adjudicated assessments of outcome, and variations in diagnostic and treatment protocols over the 36-year study interval, especially regarding endocrinologic criteria for surgical remission. Nevertheless, this manuscript is an important addition to the body of evidence concerning the clinical behavior of pediatric pituitary adenomas. Ultimately the questions regarding the differences between pediatric and adult pituitary adenomas will likely require a thorough genotypic and phenotypic comparison of these tumors to resolve the issue of differences in biologic behavior. Marc R. Mayberg Seattle, Washington Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Pediatric Pituitary Adenomas: Early and Long-Term Surgical Outcome in a Series of 85 Consecutive Patients

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Congress of Neurological Surgeons
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Copyright © 2018 by the Congress of Neurological Surgeons
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0148-396X
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1524-4040
D.O.I.
10.1093/neuros/nyy204
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Abstract

Abstract BACKGROUND Young age has been reported as a negative prognostic factor for pituitary adenomas (PAs). They are very uncommon in children and adolescents; therefore, surgical outcomes are poorly described. OBJECTIVE To report results of microsurgical transsphenoidal approach (MTSA) in pediatric PAs. METHODS The study retrospectively analyzed 3040 PAs treated in our institute, according to the adenoma subtype and then divided into pediatric (≤18 yr) and adult groups (>18 yr). The average follow-up after surgery was 58 mo (n = 2906). RESULTS In the pediatric group, the majority of adenomas were hormone-secreting (89.5%) with a female sex prevalence (78%) in prolactinomas and nonfunctioning pituitary adenomas (NFPAs); the maximum diameter of growth hormone (GH)-secreting adenomas was greater (28.1 ± 4.1 mm) than in adults (18 ± 0.3 mm, P = .002). Surgical remission rate at 6 mo was similar in both groups for all adenoma subtypes: 72.1% and 76% in pediatric and adult Cushing's disease, 69.3% and 59.3% in prolactinomas, 55.6% and 61% in gigantism or acromegaly, 55.6% and 61.5% in NFPAs. Recurrences after remission occurred more frequently in pediatric GH-secreting adenomas compared to adults (40.0% vs 5.3%, P = .028) despite similar follow-up (38 ± 17 and 48.1 ± 2.2 mo, P = .7). Mortality was zero in the pediatric and 0.2% in the adult group (P = .7); major morbidity was 2.4% and 2.2%, respectively (P = .8). CONCLUSION MTSA was safe and effective in children and adolescents as in adults, with the only exception of higher recurrence rate in pediatric GH-secreting adenomas. No complications related to young age appeared. Pediatric pituitary adenomas, Pituitary tumors, Transsphenoidal surgery ABBREVIATIONS ABBREVIATIONS ACTH adrenocorticotropic hormone BIPSS bilateral inferior petrosal sinus sampling CD Cushing's disease DA dopamine agonist GH growth hormone GKRS Gamma Knife stereotactic-radiosurgery MRI magnetic resonance imaging MTSA microsurgical transsphenoidal approach NFPAs nonfunctioning pituitary adenomas PAs pituitary adenomas PRL prolactin TSS transsphenoidal surgery In pediatric age, pituitary adenomas (PAs) are the most common sellar tumors after craniopharyngiomas. They are rare in children, becoming increasingly more frequent in adolescents and adults; only 2% to 10% of surgically treated PAs presents during the first 2 decades of life.1-9 The annual incidence is 0.1 case/1000 000 and they account approximately for 3% of all pediatric brain tumors.10,11 PAs are benign and slow growing tumors, but they can extend into and infiltrate the parasellar areas, although the morphological markers of tumor aggressiveness correlate poorly with clinical behavior.12-14 Invasive adenomas are defined as tumors infiltrating the cavernous or sphenoidal sinus and the dura or the bone, whereas the term atypical adenoma is characterized by atypical morphology, increased mitotic activity, Ki-67 labeling index higher than 3%, and extensive p53 immunoreactivity.15,16 Clinically, PAs can be divided into endocrine-active and inactive tumors. Unlike adults, young patients have secreting-adenomas much more frequently than nonfunctioning pituitary adenomas (NFPAs). Pediatric series of PAs have been previously reported, and the clinical presentation, slightly different from that in adulthood, is well characterized.2-9,17 Conversely, the natural history and the long-term outcome after surgery are less clearly defined. Some papers suggested that PAs are more aggressive in adolescents than in adults,18-24 reporting a very high incidence of invasive growth pattern during puberty (up to 77.7%-100%),18,20 data not confirmed by other authors.3,4,25,26 However, PAs invasiveness is not synonymous of aggressive behavior and analysis of the outcomes after surgery must be made to correlate morphological and clinical features. About this, data on age as risk factor for recurrence are contradictory: a meta-analysis, published in 2012, demonstrated that age was unrelated to recurrence, although it has a prognostic significance in a certain amount of studies.27 Conversely, in a more recent series of 410 PAs, young age was a poor prognostic factor for recurrence and progression free survival 8 yr after surgery.16 We report our experience in the surgical treatment of pediatric PAs by focusing specifically on the remission and recurrence rates as well as on the safety of surgery. The study also describes the long-term disease control after surgery plus adjuvant therapies. METHODS Patient Selection and Data Collection Between January 1990 and December 2016, a total of 3040 consecutive patients with PA were treated in our department. Clinical and biochemical data, as well as complications, were prospectively recorded and retrospectively analyzed in 3002 cases. Patients were subdivided into 2 groups: 2917 adults (>18 yr old; 97.2%) and 85 pediatric patients (≤18 yr old; 2.8%). Hormonal, visual, and clinical data as well as magnetic resonance imaging (MRI) were evaluated 6 mo after surgery (early surgical remission) and then yearly (recurrence rate) in 2906 patients (84 pediatric and 2822 adult), excluding 75 thyrotropin-secreting adenomas and 21 patients lost to follow-up. In 15 other adults, long-term information were incomplete so final disease control, after surgery plus adjuvant treatments, was calculated on 2891 patients (84 pediatric and 2807 adult). Surgical Technique All patients underwent sublabial transseptal microsurgical transsphenoidal approach (MTSA), as previously described.28 Wide drilling of the sphenoidal bone, including the tuberculum sellae, was done to remove large suprasellar or subfrontal PAs. In these cases, a final inspection by a rigid endoscope 4 mm in diameter with 0° and 30° lenses (Karl Storz-Endoskope, Tuttlingen, Germany) was performed. Considering the size of nares in children, a shorter and smaller self-retracting Cushing-Landolt speculum was required and a high-speed drill was used to open the sellar floor in conchal type or poorly pneumatized sphenoid sinuses. Histopathological diagnosis was based on hematoxylin-eosin stained sections and immunocytochemical characterization of secretory activity. All the procedures respected the standards of the institutional Research Ethics Committee and the 1964 Helsinki Declaration. Informed consent was obtained in all the cases by the patients or their parents. Early Surgical Remission Six months after surgery we applied the following criteria to define the early surgical remission: - Growth hormone (GH)-secreting adenoma: basal or oral glucose tolerance test-GH levels below 1 μg/L and normalization of age- and sex-adjusted insulin growth factor-1 levels. - Prolactin (PRL)-secreting adenoma: normalization of basal PRL levels (<20μg/L in women and <15μg/L in men) without dopaminergic therapy for at least 6 mo. - Adrenocorticotropic hormone (ACTH)-secreting adenoma: presence of hypocortisolism requiring glucocorticoid substitution therapy, or, in case of normal serum and urinary cortisol levels, normal suppression of serum cortisol level after an overnight low-dose dexamethasone test. - NFPA: absence on the first postoperative MRI of residual adenomatous tissue (complete surgical removal). Long-Term Outcome During follow-up in early cured patients, recurrence was defined as reappearance of hormone hypersecretion in hormone-active PAs and as evidence of new tumor on MRI in NFPAs. In patients not cured by primary surgery or with recurrent disease, Gamma Knife stereotactic-radiosurgery (GKSRS, Leksell Gamma Knife®, Elekta, Stockholm, Sweden), radiotherapy, drugs, and/or repeated surgery, either transcranial or transsphenoidal, were applied to achieve disease control. Radiotherapy was used when residual tumor extended extensively into the skull base, whereas GKSRS in small unresectable PAs, usually located within the cavernous sinus. Surgery was repeated if tumor was accessible. Therefore, the final disease control rate included all patients cured by initial surgery plus those in remission after adjuvant therapies. Statistical Analysis Continuous data were expressed as mean ± standard error. Student's t-test for unpaired data was used to compare continuous variables among groups. Categorical variables were compared with the Pearson's chi-square test or with the Fisher exact test when appropriate. Recurrence-free survival was calculated using Kaplan–Meier survival function. A P value of less than .05 was considered to indicate statistical significance. All calculations were performed using the IBM SPSS Statistics package (IBM Corporation, Released 2011, SPSS Statistics for Macintosh, Version 20.0, Armonk, New York). RESULTS General Results NFPAs and hormone-secreting adenomas, respectively, occurred in 10.5% and 89.5% of 85 pediatric patients, as compared to 39% and 61% of 2917 adults (Figure 1). There was a female prevalence in both adult and pediatric prolactinomas (Figure 2), in adult but not in pediatric Cushing's disease (CD; P < .001) and in pediatric NFPAs (P = .03). Macroadenomas occurred more frequently in pediatric prolactinomas (Table 1; P = .007) and GH-secreting adenomas (P = .048), while the tumor invasiveness was similar in adult and pediatric groups. FIGURE 1. View largeDownload slide Adenoma type distribution in a series of 3002 PAs treated by TSS. The pediatric group comprised 85 cases: 43 CD, 23 prolactinomas, 9 gigantism/acromegaly, 9 NFPAs, and 1 TSH-sa. In 2917 adults, there was a prevalence of NFPAs (1142 cases), followed by acromegaly (786 cases), CD (647 cases), prolactinomas (268 cases), and TSH-sa (74 cases). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; TSH-sa, thyrotropin-secreting adenoma, NFPA, nonfunctioning pituitary adenoma. FIGURE 1. View largeDownload slide Adenoma type distribution in a series of 3002 PAs treated by TSS. The pediatric group comprised 85 cases: 43 CD, 23 prolactinomas, 9 gigantism/acromegaly, 9 NFPAs, and 1 TSH-sa. In 2917 adults, there was a prevalence of NFPAs (1142 cases), followed by acromegaly (786 cases), CD (647 cases), prolactinomas (268 cases), and TSH-sa (74 cases). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; TSH-sa, thyrotropin-secreting adenoma, NFPA, nonfunctioning pituitary adenoma. FIGURE 2. View largeDownload slide Female prevalence in a series of 2927 PAs; considering the only case of thyrotropin-secreting adenoma in pediatric group, this adenoma type (75 cases) was excluded from comparison between adults and pediatric population. Pearson's chi-square with Fisher exact test shows female prevalence in both adult and pediatric prolactinomas, in adult CD (P < .001) and in nonfunctioning pituitary pediatric adenomas (P = .03). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; NFPA, nonfunctioning pituitary adenoma. FIGURE 2. View largeDownload slide Female prevalence in a series of 2927 PAs; considering the only case of thyrotropin-secreting adenoma in pediatric group, this adenoma type (75 cases) was excluded from comparison between adults and pediatric population. Pearson's chi-square with Fisher exact test shows female prevalence in both adult and pediatric prolactinomas, in adult CD (P < .001) and in nonfunctioning pituitary pediatric adenomas (P = .03). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; NFPA, nonfunctioning pituitary adenoma. TABLE 1. Size and invasiveness in 2927 pituitary adenomas ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Macroadenomas, n 148/647 8/43 142/268 20/23 638/786 8/9 1136/1142 9/9 % 22.9% 18.6% 53% 87% 81.2% 88.9% 99.5% 100% P = .6 = .007 = .048 = .9 Greatest diameter, mm 8.6 ± 0.3 7.1 ± 1 14.9 ± 0.7 16.2 ± 1.1 18 ± 0.3 28.1 ± 4.1 27.8 ± 0.3 25.6 ± 2.8 (mean ± SE, range) 2-41 2-34 3-65 7-26 4-72 10-50 7-80 15-40 P = .2 = .6 = .002 = .5 CS invasion, n 36/647 1/43 49/268 2/23 178/786 2/9 394/1142 2/9 % 5.6% 2.3% 18.3% 8.7% 22.6% 22.2% 34.5% 22.2% P = .7 = .4 = .2 = .7 SS invasion, n 49/647 1/43 23/268 1/23 82/786 3/9 115/1142 1/9 % 7.6% 2.3% 8.6% 4.3% 10.4% 33.3% 10.1% 11.1% P = .3 = .7 = .07 = 1 ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Macroadenomas, n 148/647 8/43 142/268 20/23 638/786 8/9 1136/1142 9/9 % 22.9% 18.6% 53% 87% 81.2% 88.9% 99.5% 100% P = .6 = .007 = .048 = .9 Greatest diameter, mm 8.6 ± 0.3 7.1 ± 1 14.9 ± 0.7 16.2 ± 1.1 18 ± 0.3 28.1 ± 4.1 27.8 ± 0.3 25.6 ± 2.8 (mean ± SE, range) 2-41 2-34 3-65 7-26 4-72 10-50 7-80 15-40 P = .2 = .6 = .002 = .5 CS invasion, n 36/647 1/43 49/268 2/23 178/786 2/9 394/1142 2/9 % 5.6% 2.3% 18.3% 8.7% 22.6% 22.2% 34.5% 22.2% P = .7 = .4 = .2 = .7 SS invasion, n 49/647 1/43 23/268 1/23 82/786 3/9 115/1142 1/9 % 7.6% 2.3% 8.6% 4.3% 10.4% 33.3% 10.1% 11.1% P = .3 = .7 = .07 = 1 ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone; CS, cavernous sinus; SS, sphenoidal sinus Pearson's chi-square with Fisher exact test Seventy-five thyrotropin-secreting adenoma was excluded because comparison between adults and patients younger than 18 yr was not appropriate (only 1 case in pediatric age). View Large TABLE 1. Size and invasiveness in 2927 pituitary adenomas ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Macroadenomas, n 148/647 8/43 142/268 20/23 638/786 8/9 1136/1142 9/9 % 22.9% 18.6% 53% 87% 81.2% 88.9% 99.5% 100% P = .6 = .007 = .048 = .9 Greatest diameter, mm 8.6 ± 0.3 7.1 ± 1 14.9 ± 0.7 16.2 ± 1.1 18 ± 0.3 28.1 ± 4.1 27.8 ± 0.3 25.6 ± 2.8 (mean ± SE, range) 2-41 2-34 3-65 7-26 4-72 10-50 7-80 15-40 P = .2 = .6 = .002 = .5 CS invasion, n 36/647 1/43 49/268 2/23 178/786 2/9 394/1142 2/9 % 5.6% 2.3% 18.3% 8.7% 22.6% 22.2% 34.5% 22.2% P = .7 = .4 = .2 = .7 SS invasion, n 49/647 1/43 23/268 1/23 82/786 3/9 115/1142 1/9 % 7.6% 2.3% 8.6% 4.3% 10.4% 33.3% 10.1% 11.1% P = .3 = .7 = .07 = 1 ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Macroadenomas, n 148/647 8/43 142/268 20/23 638/786 8/9 1136/1142 9/9 % 22.9% 18.6% 53% 87% 81.2% 88.9% 99.5% 100% P = .6 = .007 = .048 = .9 Greatest diameter, mm 8.6 ± 0.3 7.1 ± 1 14.9 ± 0.7 16.2 ± 1.1 18 ± 0.3 28.1 ± 4.1 27.8 ± 0.3 25.6 ± 2.8 (mean ± SE, range) 2-41 2-34 3-65 7-26 4-72 10-50 7-80 15-40 P = .2 = .6 = .002 = .5 CS invasion, n 36/647 1/43 49/268 2/23 178/786 2/9 394/1142 2/9 % 5.6% 2.3% 18.3% 8.7% 22.6% 22.2% 34.5% 22.2% P = .7 = .4 = .2 = .7 SS invasion, n 49/647 1/43 23/268 1/23 82/786 3/9 115/1142 1/9 % 7.6% 2.3% 8.6% 4.3% 10.4% 33.3% 10.1% 11.1% P = .3 = .7 = .07 = 1 ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone; CS, cavernous sinus; SS, sphenoidal sinus Pearson's chi-square with Fisher exact test Seventy-five thyrotropin-secreting adenoma was excluded because comparison between adults and patients younger than 18 yr was not appropriate (only 1 case in pediatric age). View Large Because clinical characteristics of PAs are well known and beyond the purpose of the study, we reported symptoms and pituitary function before surgery, as well as recovery after surgery, only in pediatric patients (Table 2). Figure 3 shows the mean age at diagnosis in pediatric population. TABLE 2. Clinical Manifestations, Pituitary Dysfunction Before Surgery and Recovery After Surgery in 84a Pediatric PAs ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas n 43 23 9 9 Females/Males 23/20 18/5 4/5 7/2 Clinical Manifestation Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Weight gain 36/43 (83.7%) 36/36 (100%) – – – Growth failure 14/43 (32.6%) 14/14 (100%) – – 1/9 (11.1%) Linear growth° – – 9/9° (100%) – Visual defect – 1/23 (4.3%) 1/1 (100%) 4/8 (50%) 3/4b (75%) 6/9 (66.7%) 3/6b (50%) Headache 30/43 (69.8%) 27/30 (90%) 9/23 (39.1%) 9/9 (100%) 3/9 (33.3%) 3/3 (100%) 4/9 (44.4%) 4/4 (100%) Menstrual irregularities (postpubertal females) 10/21 (47.6%) 9/10 (90%) 16/17 (94.1%) 15/17 (88.2%) 3/3 (100%) 1/3 (33.3%) 6/6 (100%) 0/6 (0%) Precocious puberty 2/43 (4.7%) 0/23 (0%) 0/9 (0%) 0/9 (0%) Delayed puberty – – – 1/9 (11.1%) Depression 15/43 (34.9%) 8/15§(53.3%) – – – Hypertension 13/43 (30.2%) 10/13 (76.9%) – 0/9 (0%) – Diabetes mellitus 1/43 (2.4%) 1/1 (100%) – 0/9 (0%) – Hypogonadism (postpubertal patients) 17/32 (53.1%) 13/17 (76.5%) 20/21 (95.2%) 17/20 (85%) 7/7 (100%) 2/7 (28.6%) 5/7 (71.4%) 1/5 (20%) Hypothyroidism 1/42 (2.4%) 0/1 (0%) 0/23 (0%) – 2/8 (25%) 1/2 (50%) 3/9 (33.3%) 0/3 (0%) Adrenal deficiency – 1/23 (4.3%) 1/1 (100%) 1/9 (11.1%) 0/1 (0%) 1/9 (11.1%) 0/9 (0%) Diabetes insipidus 0/43 (0%) 0/23 (0%) 0/9 (0%) 0/9 (0%) ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas n 43 23 9 9 Females/Males 23/20 18/5 4/5 7/2 Clinical Manifestation Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Weight gain 36/43 (83.7%) 36/36 (100%) – – – Growth failure 14/43 (32.6%) 14/14 (100%) – – 1/9 (11.1%) Linear growth° – – 9/9° (100%) – Visual defect – 1/23 (4.3%) 1/1 (100%) 4/8 (50%) 3/4b (75%) 6/9 (66.7%) 3/6b (50%) Headache 30/43 (69.8%) 27/30 (90%) 9/23 (39.1%) 9/9 (100%) 3/9 (33.3%) 3/3 (100%) 4/9 (44.4%) 4/4 (100%) Menstrual irregularities (postpubertal females) 10/21 (47.6%) 9/10 (90%) 16/17 (94.1%) 15/17 (88.2%) 3/3 (100%) 1/3 (33.3%) 6/6 (100%) 0/6 (0%) Precocious puberty 2/43 (4.7%) 0/23 (0%) 0/9 (0%) 0/9 (0%) Delayed puberty – – – 1/9 (11.1%) Depression 15/43 (34.9%) 8/15§(53.3%) – – – Hypertension 13/43 (30.2%) 10/13 (76.9%) – 0/9 (0%) – Diabetes mellitus 1/43 (2.4%) 1/1 (100%) – 0/9 (0%) – Hypogonadism (postpubertal patients) 17/32 (53.1%) 13/17 (76.5%) 20/21 (95.2%) 17/20 (85%) 7/7 (100%) 2/7 (28.6%) 5/7 (71.4%) 1/5 (20%) Hypothyroidism 1/42 (2.4%) 0/1 (0%) 0/23 (0%) – 2/8 (25%) 1/2 (50%) 3/9 (33.3%) 0/3 (0%) Adrenal deficiency – 1/23 (4.3%) 1/1 (100%) 1/9 (11.1%) 0/1 (0%) 1/9 (11.1%) 0/9 (0%) Diabetes insipidus 0/43 (0%) 0/23 (0%) 0/9 (0%) 0/9 (0%) ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone aOne patient with Thyrotropin hormone-secreting adenoma reported only in the text. §Depression in all cases improved. °All cases presented with linear growth, associated with acral enlargement in five patients (55.5%). bAll cases improved after surgery. View Large TABLE 2. Clinical Manifestations, Pituitary Dysfunction Before Surgery and Recovery After Surgery in 84a Pediatric PAs ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas n 43 23 9 9 Females/Males 23/20 18/5 4/5 7/2 Clinical Manifestation Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Weight gain 36/43 (83.7%) 36/36 (100%) – – – Growth failure 14/43 (32.6%) 14/14 (100%) – – 1/9 (11.1%) Linear growth° – – 9/9° (100%) – Visual defect – 1/23 (4.3%) 1/1 (100%) 4/8 (50%) 3/4b (75%) 6/9 (66.7%) 3/6b (50%) Headache 30/43 (69.8%) 27/30 (90%) 9/23 (39.1%) 9/9 (100%) 3/9 (33.3%) 3/3 (100%) 4/9 (44.4%) 4/4 (100%) Menstrual irregularities (postpubertal females) 10/21 (47.6%) 9/10 (90%) 16/17 (94.1%) 15/17 (88.2%) 3/3 (100%) 1/3 (33.3%) 6/6 (100%) 0/6 (0%) Precocious puberty 2/43 (4.7%) 0/23 (0%) 0/9 (0%) 0/9 (0%) Delayed puberty – – – 1/9 (11.1%) Depression 15/43 (34.9%) 8/15§(53.3%) – – – Hypertension 13/43 (30.2%) 10/13 (76.9%) – 0/9 (0%) – Diabetes mellitus 1/43 (2.4%) 1/1 (100%) – 0/9 (0%) – Hypogonadism (postpubertal patients) 17/32 (53.1%) 13/17 (76.5%) 20/21 (95.2%) 17/20 (85%) 7/7 (100%) 2/7 (28.6%) 5/7 (71.4%) 1/5 (20%) Hypothyroidism 1/42 (2.4%) 0/1 (0%) 0/23 (0%) – 2/8 (25%) 1/2 (50%) 3/9 (33.3%) 0/3 (0%) Adrenal deficiency – 1/23 (4.3%) 1/1 (100%) 1/9 (11.1%) 0/1 (0%) 1/9 (11.1%) 0/9 (0%) Diabetes insipidus 0/43 (0%) 0/23 (0%) 0/9 (0%) 0/9 (0%) ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas n 43 23 9 9 Females/Males 23/20 18/5 4/5 7/2 Clinical Manifestation Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Frequency before surgery Recovery after surgery Weight gain 36/43 (83.7%) 36/36 (100%) – – – Growth failure 14/43 (32.6%) 14/14 (100%) – – 1/9 (11.1%) Linear growth° – – 9/9° (100%) – Visual defect – 1/23 (4.3%) 1/1 (100%) 4/8 (50%) 3/4b (75%) 6/9 (66.7%) 3/6b (50%) Headache 30/43 (69.8%) 27/30 (90%) 9/23 (39.1%) 9/9 (100%) 3/9 (33.3%) 3/3 (100%) 4/9 (44.4%) 4/4 (100%) Menstrual irregularities (postpubertal females) 10/21 (47.6%) 9/10 (90%) 16/17 (94.1%) 15/17 (88.2%) 3/3 (100%) 1/3 (33.3%) 6/6 (100%) 0/6 (0%) Precocious puberty 2/43 (4.7%) 0/23 (0%) 0/9 (0%) 0/9 (0%) Delayed puberty – – – 1/9 (11.1%) Depression 15/43 (34.9%) 8/15§(53.3%) – – – Hypertension 13/43 (30.2%) 10/13 (76.9%) – 0/9 (0%) – Diabetes mellitus 1/43 (2.4%) 1/1 (100%) – 0/9 (0%) – Hypogonadism (postpubertal patients) 17/32 (53.1%) 13/17 (76.5%) 20/21 (95.2%) 17/20 (85%) 7/7 (100%) 2/7 (28.6%) 5/7 (71.4%) 1/5 (20%) Hypothyroidism 1/42 (2.4%) 0/1 (0%) 0/23 (0%) – 2/8 (25%) 1/2 (50%) 3/9 (33.3%) 0/3 (0%) Adrenal deficiency – 1/23 (4.3%) 1/1 (100%) 1/9 (11.1%) 0/1 (0%) 1/9 (11.1%) 0/9 (0%) Diabetes insipidus 0/43 (0%) 0/23 (0%) 0/9 (0%) 0/9 (0%) ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone aOne patient with Thyrotropin hormone-secreting adenoma reported only in the text. §Depression in all cases improved. °All cases presented with linear growth, associated with acral enlargement in five patients (55.5%). bAll cases improved after surgery. View Large FIGURE 3. View largeDownload slide Mean age at surgery ± standard error and range in a series of 84 pediatric PAs (1 patient with thyrotropin hormone-secreting adenoma was 14 yr old). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; NFPA, nonfunctioning pituitary adenoma. FIGURE 3. View largeDownload slide Mean age at surgery ± standard error and range in a series of 84 pediatric PAs (1 patient with thyrotropin hormone-secreting adenoma was 14 yr old). ACTH-sa, adrenocorticotropic hormone-secreting adenoma; PRL-sa, prolactin-secreting adenoma; GH-sa, growth hormone-secreting adenoma; NFPA, nonfunctioning pituitary adenoma. ACTH-Secreting Adenomas Among the 690 patients who underwent surgery for CD, MRI was positive or doubtful in 30/43 pediatric cases (69.8%) and in 448/647 adults (69.2%; P = .9). Bilateral inferior petrosal sinus sampling (BIPSS) was carried out in 13 (30.2%) and 221 patients (30.1%; P = .9) of the 2 groups, respectively. Remission of CD after surgery was achieved in 31/43 patients (72.1%). Positive histology was found in 25 of the 31 cured patients (80.6%) and was negative in the other 6 (19.4%; P = .001), proving its favorable significance on surgical outcome. The mean follow-up after surgery in cured patients was 48.1 ± 9.7 mo. Two patients (6.4%) had recurrence of disease 71 and 73 mo after surgery. Patients with persistent or recurrent hypercortisolism required a multimodality approach: drugs (5), repeat surgery (3), GKSRS (2), surgery plus radiotherapy or GKSRS combined with (2 cases), or without medical therapy (2 cases). At the last follow-up (64.4 ± 10.6 mo) 40 of 43 patients (93%) achieved the CD control. Surgical remission, recurrence rates, and final CD control were not different between adult and pediatric population as well as the follow-up time (Table 3). The 10-yr recurrence-free survival rate was 81.8% (95% confidence interval [CI], 70%-93%) in pediatric CD and 75.4% (95% CI, 72%-79%, P = . 3) in adults (Figure 4). TABLE 3. Surgical Remission and Recurrence in 2906 PAs According to Age Group; Final Cure/Growth Tumor Control After Surgery and Adjuvant Therapies in 2891 PAs. Outcome ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Surgical remission/complete removal 6 months after surgery (n = 2906) 491/646 31/43 159/268 16/23 473/776 5/9 696/1132 5/9 76% 72.1% 59.3% 69.3% 61% 55.6% 61.5% 55.6% P = .3 = .2 = .7 = .7 Recurrence after remission/complete removal at last follow-up (n = 1876) 57/491 2/31 26/159 3/16 25/473 2/5 110/696 0/5 11.6% 6.4% 16.3% 18.7% 5.3% 40% 15.8% 0% P = .5 = .5 = .028 = .3 Follow-up after surgical remission (mean ± SE) 50.4 ± 2.3 48.1 ± 9.7 46.3 ± 5.2 61.4 ± 25 48.1 ± 2.2 38 ± 17 54.9 ± 2.2 67.8 ± 30.3 6-237 6-204 6-183 6-190 6-276 6-92 6-242 6-184 P = .4 = .1 = .7 = .7 Final cure/Growth tumor control at last follow-up (n = 2891) 537/646 40/43 201/268 18/23 639/761 7/9 890/1132 7/9 83.1% 93% 75% 78.3% 84% 77.8% 78.6% 77.8% P = .5 = .8 = .8 = .6 Follow-up after surgery ± adjuvant therapies (mean ± SE) 56.8 ± 2.2 64.4 ± 10.6 63 ± 2.3 58.9 ± 12.3 63 ± 2.3 79.1 ± 21.1 71.2 ± 2.1 71.8 ± 23.9 6-289 6-221 6-297 6-204 6-286 6-216 6-309 6-211 P = .4 = .4 = .4 = .9 Outcome ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Surgical remission/complete removal 6 months after surgery (n = 2906) 491/646 31/43 159/268 16/23 473/776 5/9 696/1132 5/9 76% 72.1% 59.3% 69.3% 61% 55.6% 61.5% 55.6% P = .3 = .2 = .7 = .7 Recurrence after remission/complete removal at last follow-up (n = 1876) 57/491 2/31 26/159 3/16 25/473 2/5 110/696 0/5 11.6% 6.4% 16.3% 18.7% 5.3% 40% 15.8% 0% P = .5 = .5 = .028 = .3 Follow-up after surgical remission (mean ± SE) 50.4 ± 2.3 48.1 ± 9.7 46.3 ± 5.2 61.4 ± 25 48.1 ± 2.2 38 ± 17 54.9 ± 2.2 67.8 ± 30.3 6-237 6-204 6-183 6-190 6-276 6-92 6-242 6-184 P = .4 = .1 = .7 = .7 Final cure/Growth tumor control at last follow-up (n = 2891) 537/646 40/43 201/268 18/23 639/761 7/9 890/1132 7/9 83.1% 93% 75% 78.3% 84% 77.8% 78.6% 77.8% P = .5 = .8 = .8 = .6 Follow-up after surgery ± adjuvant therapies (mean ± SE) 56.8 ± 2.2 64.4 ± 10.6 63 ± 2.3 58.9 ± 12.3 63 ± 2.3 79.1 ± 21.1 71.2 ± 2.1 71.8 ± 23.9 6-289 6-221 6-297 6-204 6-286 6-216 6-309 6-211 P = .4 = .4 = .4 = .9 ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone View Large TABLE 3. Surgical Remission and Recurrence in 2906 PAs According to Age Group; Final Cure/Growth Tumor Control After Surgery and Adjuvant Therapies in 2891 PAs. Outcome ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Surgical remission/complete removal 6 months after surgery (n = 2906) 491/646 31/43 159/268 16/23 473/776 5/9 696/1132 5/9 76% 72.1% 59.3% 69.3% 61% 55.6% 61.5% 55.6% P = .3 = .2 = .7 = .7 Recurrence after remission/complete removal at last follow-up (n = 1876) 57/491 2/31 26/159 3/16 25/473 2/5 110/696 0/5 11.6% 6.4% 16.3% 18.7% 5.3% 40% 15.8% 0% P = .5 = .5 = .028 = .3 Follow-up after surgical remission (mean ± SE) 50.4 ± 2.3 48.1 ± 9.7 46.3 ± 5.2 61.4 ± 25 48.1 ± 2.2 38 ± 17 54.9 ± 2.2 67.8 ± 30.3 6-237 6-204 6-183 6-190 6-276 6-92 6-242 6-184 P = .4 = .1 = .7 = .7 Final cure/Growth tumor control at last follow-up (n = 2891) 537/646 40/43 201/268 18/23 639/761 7/9 890/1132 7/9 83.1% 93% 75% 78.3% 84% 77.8% 78.6% 77.8% P = .5 = .8 = .8 = .6 Follow-up after surgery ± adjuvant therapies (mean ± SE) 56.8 ± 2.2 64.4 ± 10.6 63 ± 2.3 58.9 ± 12.3 63 ± 2.3 79.1 ± 21.1 71.2 ± 2.1 71.8 ± 23.9 6-289 6-221 6-297 6-204 6-286 6-216 6-309 6-211 P = .4 = .4 = .4 = .9 Outcome ACTH-secreting adenomas PRL-secreting adenomas GH-secreting adenomas Nonfunctioning adenomas Adult Pediatric Adult Pediatric Adult Pediatric Adult Pediatric Surgical remission/complete removal 6 months after surgery (n = 2906) 491/646 31/43 159/268 16/23 473/776 5/9 696/1132 5/9 76% 72.1% 59.3% 69.3% 61% 55.6% 61.5% 55.6% P = .3 = .2 = .7 = .7 Recurrence after remission/complete removal at last follow-up (n = 1876) 57/491 2/31 26/159 3/16 25/473 2/5 110/696 0/5 11.6% 6.4% 16.3% 18.7% 5.3% 40% 15.8% 0% P = .5 = .5 = .028 = .3 Follow-up after surgical remission (mean ± SE) 50.4 ± 2.3 48.1 ± 9.7 46.3 ± 5.2 61.4 ± 25 48.1 ± 2.2 38 ± 17 54.9 ± 2.2 67.8 ± 30.3 6-237 6-204 6-183 6-190 6-276 6-92 6-242 6-184 P = .4 = .1 = .7 = .7 Final cure/Growth tumor control at last follow-up (n = 2891) 537/646 40/43 201/268 18/23 639/761 7/9 890/1132 7/9 83.1% 93% 75% 78.3% 84% 77.8% 78.6% 77.8% P = .5 = .8 = .8 = .6 Follow-up after surgery ± adjuvant therapies (mean ± SE) 56.8 ± 2.2 64.4 ± 10.6 63 ± 2.3 58.9 ± 12.3 63 ± 2.3 79.1 ± 21.1 71.2 ± 2.1 71.8 ± 23.9 6-289 6-221 6-297 6-204 6-286 6-216 6-309 6-211 P = .4 = .4 = .4 = .9 ACTH, adrenocorticotropic hormone; PRL, prolactin; GH, growth hormone View Large FIGURE 4. View largeDownload slide Recurrence-free cumulative survival in CD after surgical remission. Comparison between adult (continuous line) and pediatric (dotted line) groups does not show any statistical difference (Kaplan–Meier, Log-Rank P = .47). FIGURE 4. View largeDownload slide Recurrence-free cumulative survival in CD after surgical remission. Comparison between adult (continuous line) and pediatric (dotted line) groups does not show any statistical difference (Kaplan–Meier, Log-Rank P = .47). PRL-Secreting Adenomas The tumor size significantly differed between pediatric and adult patients because of a higher prevalence of macroadenomas in the first group (87% vs 53%, respectively; P = .007); however, the maximum tumor diameter was similar (Table 1; P = .6) as well as the invasiveness into the cavernous (P = .4) and sphenoidal sinuses (P = .7). The early surgical remission rate was 69.6%. During a mean follow-up of 61.4 ± 25.0 mo, 3 of the 16 cured patients (18.7%) had recurrence of hyperprolactinemia, 28, 70, and 96 mo after surgery. Recurrent or persistent hyperprolactinemia was treated in 6 patients with dopamine agonist (DA); 1 patient underwent GKSRS, 2 patients GKSRS plus DA, and 1 radiation therapy plus surgery and DA. At the last follow-up (68 ± 12.3 mo), 18 of the 23 patients (78.3%) had normal PRL levels. Surgical remission rate, frequency of recurrence, final hormonal control, and follow-up were similar in the adult and pediatric population (Table 3). GH-Secreting Adenomas Only 1 child had a microadenoma whereas the other 8 pediatric patients had a macroadenoma with suprasellar extension (88.9%), so the frequency of macroadenomas was higher compared to adults (Table 1; P = .048). The maximum tumor diameter was greater in pediatric patients (28.1 ± 4.1 mm) than in adults (18 ± 0.3 mm; P = .002), whereas the invasiveness into the cavernous and sphenoidal sinuses was similar (Table 1; P = .2 and P = .07, respectively). The surgical remission rate was 55.6% (5/9). During a mean follow-up of 38.4 ± 17.0 mo, 2 patients (40.0%) had recurrence of GH-hypersecretion, 79 and 86 mo after surgery. Patients with persistent or recurring acromegaly received medical therapy (2 cases), GKSRS plus medical therapy (1 case), and radiation plus medical therapy (1 case); finally, 2 patients did not receive any treatment. Disease control at the last follow-up (mean 79.1 ± 21.1 mo) was achieved in 7 of 9 patients (77.8%). Surgical remission rate, final hormonal control, and follow-up were similar in adult and pediatric population (Table 3), whereas frequency of recurrence was significantly higher in pediatric compared to adult patients (40.0% vs 5.3%, P = .028). The risk of recurrence in both groups combined was higher in macroadenomas (7.1%) than in microadenomas (1.6%, P = .023). Nonfunctioning Pituitary Adenomas Radical removal of the tumor was achieved in 5 of 9 patients (55.6%). During a mean follow-up of 71.8 ± 23.8 mo, no recurrence of disease was observed. Second-line treatments, for partially removed tumors with skull base invasion, included radiation therapy in 2 cases and repeated surgery plus radiotherapy in the other 2 cases. At the last follow-up (71.8 ± 23.8 mo), tumor control occurred in 7 of 9 patients (77.8%). Early complete surgical removal, frequency of recurrence, final growth control, and follow-up were similar in adult and pediatric population (Table 3). TSH-Secreting Adenomas The only case of pediatric TSH-secreting macroadenoma has already been described in detail elsewhere.29 Preoperative treatment with somatostatin analogues for 1 yr caused a significant shrinkage of the irregularly shaped suprasellar portion of the tumor, which allowed performing MTSA. Postoperative MRI showed a small residual tumor and the patient continued medical therapy. Complications Major surgical complications occurred in 2 cases (2.4%), consisting of meningitis without neurological sequels in 1 patient and epistaxis requiring nasal dressing and blood transfusion 10 d after surgery in the other patient. Endocrinological morbidity consisted of new onset partial hypopituitarism in 2 patients (2.4%), permanent diabetes insipidus in 1 case (1.2%), and delayed hyponatremia in 5 cases (6.1%). There was no significant difference between adult and pediatric groups in surgical mortality (0.2% and 0%, respectively; P = .8) and major morbidity (2.2% and 2.4%; P = .7). Surgical complications in 2917 adults were: cerebrospinal fluid rhinorrhea requiring surgical repair in 6 cases (0.2%), meningitis in 6 (0.2%), intracranial/sellar hemorrhage in 32 (1.1%), visual deterioration in 3 (0.1%) and oro-rhino-sinusal complications in 20 (0.7%). DISCUSSION It is well known that children develop PAs uncommonly and their frequency slightly increases in the postpubertal age.1,3,6 Most pediatric PAs appear to be endocrine-active and prolactinomas are the most common subtype.4,6,9 On the other hand, many prolactinomas respond satisfactorily to DA and do not need surgery, explaining why in surgical series prolactinomas are not the leading diagnosis, as confirmed in the present series.2,3,5 Pediatric PAs usually occur more frequently in females but different gender distribution according to age has been described.4,6,9 Patients with CD show a male preponderance during prepubertal age, while toward puberty the sex distribution equalizes and then reverts to the female prevalence, typical of adulthood.31 Consequently, the gender distribution may differ according to the cut-off of age adopted and the caseload of prepubertal patients; our findings, including 18-yr-old or younger patients, confirmed that females were significantly more represented than males, though only in prolactinomas and NFPAs. ACTH-Secreting Adenomas The usual CD features encountered in pediatric population are different from those in adults and include rapid weight gain, generalized rather than centripetal, associated with decreased linear growth in prepubertal cases.5,30 Obesity was the first and most frequent symptom to appear in our series, followed by headache and menstrual irregularities. Growth retardation, psychiatric disorders, and hypertension were present in one-third of our cohort. Selective adenomectomy is the first line treatment of pediatric CD.31,32 The main difficulty may be the correct localization of the pituitary tumor, since most ACTH-secreting adenomas are tiny microadenomas. When MRI is negative and/or hormonal data are inconsistent, the BIPSS is the most sensitive test (99%) for the exclusion of ectopic ACTH production.31 Even though technically more demanding in children than in adults, BIPSS is very safe in experienced hands.31,32 In our series, MRI showed a PA in 69.8% of cases and BIPSS was performed in the remnant 30.2% without any complication. A meticulous exploration of the pituitary gland, including the posterior lobe, should be performed even when BIPSS shows a lateralizing side, because its accuracy is only partial, ranging from 70% to 91%.30,31 Removal of half or two-thirds of the gland is indicated when the exploration is negative.5,33 Oliveira and colleagues34 reported a surgical remission rate of CD in 70.5% of pediatric patients (mean of previously published cases), a value very close to ours. However, the range in the literature varies from 40% to 100%, probably because of different hormonal criteria, neurosurgeon experience, and technical improvement in the last 25 yr.31,34,35 Recognized factors associated with CD remission are identification of adenoma at surgery and histological confirmation. Young age, small tumor size, and absence of dural invasion are associated with long-term remission of CD, suggesting that the earlier is the diagnosis the better is the prognosis.31 We calculated a 10-yr recurrence-free survival rate of 81.8% and documented a recurrence frequency of 6.4% during a follow-up of more than 5 yr. Reported recurrence frequency in literature varies, ranging between 0% and 25%.2,3,6,8,21,31,32 Early and late surgical results were similar in our pediatric and adult population. In recurrent or residual CD, we suggest repeated surgery or GKSRS, whereas medical therapy or bilateral adrenalectomy should be reserved in rare circumstances. Second transsphenoidal surgery (TSS) may be successful in about 60% of cases, especially in patients with a positive MRI, being aware of the adenoma location based on the previous surgical report and positive histology.31 The presence of residual adenoma within the cavernous sinus favors the choice of GKSRS. PRL-Secreting Adenomas Clinical signs and symptoms of prolactinomas vary according to age, sex, tumor size, and PRL levels.36,37 Prepubertal children usually present with headache, visual disturbances, and growth failure. During adolescence in females delayed puberty or amenorrhea and galactorrhea are reported as the major presenting symptoms, whereas in males headache and mass effect related symptoms are common manifestations.37 In our experience, almost all girls (94%) complained of menstrual irregularities. Visual impairment occurred in only 1 case (4.3%) despite the high prevalence of large adenomas. Indeed, macroprolactinomas were more frequent in pediatric age compared to adults, as previously described,38 although there was a female prevalence in both groups (Figure 2). Nevertheless, cavernous and sphenoidal sinus invasion was similar in the 2 groups, suggesting that the bigger size in pediatric patients could be explained only by delayed diagnosis rather than invasiveness. Treatment with DA is the first therapeutic option in adults as well as in children and it has been reported to be adequate even in the presence of visual field defects,36-39 leading to normalization of PRL levels and tumor shrinkage in 85% of patients.39 Surgery might be regarded as a second therapeutic option in cases of drug resistance, intolerance, or poor compliance. On the other hand, if the diagnosis is uncertain or the patient presents with tumor apoplexy, surgery is a first-choice option. TSS is often deemed as poorly effective,40 as suggested by remission rates of hyperprolactinemia ranging from 33.3% to 66.7% in small surgical series.2,3,41 In our series, remission of hyperprolactinemia occurred in 70% of cases, confirming that, especially in patients with intrasellar adenomas and PRL levels less than 200 μg/L, surgery may have a high cure rate.2,5,41 A well-known caveat of TSS for prolactinomas is the disease recurrence.40,41 Indeed, we found a recurrence rate of 18.7%, similar to that in adults. Despite adjuvant therapies, the long-term control of hyperprolactinemia was obtained in only 78.3% of pediatric patients, probably reflecting the high prevalence of resistance to DA in our cases. Similar results were observed in the adult group, suggesting that it is not an age-specific problem. GH-Secreting Adenomas GH hypersecretion in pediatric patients is characterized by excessive linear growth causing gigantism, followed by menstrual irregularities and visual defects.24 In our series, pituitary deficiency was more frequent than in other hormone-secreting adenomas, probably because most patients had a macroadenoma (88.9%). Indeed, maximum tumor diameter was greater in pediatric patients than in adults. These results partially overlap with previous data, despite the small number of cases.23 In a series of 15 patients aged 20 yr or less reported by Abe et al,23 the 73.3% of GH-secreting adenomas were macroadenomas and cavernous sinus invasion was detected in the 40%, more frequently compared to the 26.8% in adults. Incidence of invasiveness is very variable in the literature, ranging from 20% to 60%, probably because of different modalities used to define it, but similar to that in adults at least in our series (22.2% and 22.6%).2,6,36,20,21,23 The hormonal remission rate reported by Abe et al23 was 46.7% after surgery and 60% after surgery and adjuvant therapy, lower than in adults (78%), suggesting that GH-secreting adenomas were more likely to be aggressive in adolescents, as described also in other studies.2,6,20,21,23 In our experience, the surgical remission rate was 55.6%, similar to that in adults, and both age ≤18 yr and macroadenoma size are negative prognostic factors for recurrence, despite similar follow-up between the groups. A similar trend was also noted by Abe and colleagues23 that described recurrence in 13.3% of pediatric patients as compared to 1% in adults. These data are probably best explained by the presence of larger tumors in pediatric patients as compared to adults. An alternative explanation, suggested in a recent retrospective case series of pituitary gigantism, demonstrating a successful surgical outcome in only 25% of pediatric patients, might be a different tumor pathogenesis between children and adults.42 Nonfunctioning Pituitary Adenomas NFPAs in pediatric age are very uncommon.2,3,6,43 As in other series, the most frequent symptoms were pubertal delay or primary amenorrhea in pre- or peripubertal patients and menstrual irregularities in postpubertal female patients. Growth failure occurred only in a minority of prepubertal patients. As expected, visual defects were present in most patients, while anterior pituitary deficiency was unexpectedly frequent (71.4%), at variance with other series showing pituitary deficiency in only 26.1% of patients.43 In a review by Abe and colleagues,23 complete tumor removal, judged by intraoperative findings, was detected in 64% of cases, which is comparable to our data. It is worth noting that postoperative MRI was used to verify the tumor removal in our patients. Recurrence of NFPA after surgery, followed or not by adjuvant therapy, has been detected uncommonly in pediatric patients. During a mean follow-up of 7 yr, only one patient out of 16 had tumor regrowth in the series of Abe et al,43 while no case occurred in our surgically cured patients with similar follow-up. Complications Confirming other major pediatric surgical series,31,32 MTSA was safe in our experience with no mortality and a low risk of major morbidity (2.4%). Particularly, no complications specific to pediatric patients emerged. Moreover, we have not found any intraoperative limitation due to the nasal, sphenoid, and sellar anatomy typical of pediatric patients. In younger patients, drilling of an incompletely pneumatized sphenoid sinus to reach the sella may be necessary2,3,43 but this anatomic characteristic cannot be considered a contraindication to TSS. Limitations Some inherent limitations of this retrospective single center study should be kept in mind. The long study interval may raise concerns because of the changing definitions of surgical remission and the different methodologies to measure hormone concentrations. To reduce the risk of misclassification, diagnostic cut-off values were adjusted and a single endocrinologist analyzed all hormonal results. On the whole, the strength of this study is its single center nature, which allowed for homogenous indications and surgical techniques, and the relatively long follow-up, which was essential to analyze the data on recurrences and final disease control. Another limitation is the lack of Ki67 analysis and histological diagnosis according to the last WHO classification, due to the very long inclusion period of the study. No case of atypical adenomas was recorded in our pediatric population. Even though our series is one of the largest in the literature, the number of patients in each subtype of pediatric PA is quite small. Therefore, our results must be interpreted with great caution. Interpretation Our results demonstrate similar outcomes and complications in patients aged 18 yr or less and adults with the only exception for recurrences in GH-secreting adenomas. The last result, even with the above-mentioned limitation, is to notice for further investigation. Our data seem to suggest that pediatric GH-secreting adenomas tend to be bigger than in adults but not more invasive, consequently the reason for higher recurrence rate in gigantism is not completely clear. It could just be the result of delayed discovery, when the tumor is larger, or due to a different adenoma growth in young patients, explaining both the size and the recurrence. Generalizability The paper focused on remission/removal and recurrence of PA after surgery in adult and pediatric population, all treated by microsurgical approach. Comparison with more recent techniques, like pure endoscopic procedures, is beside our scope and therefore the results here presented might be not extended to all pituitary surgeries. However, the considerations about the recurrence risk after surgery, in adults and children or adolescents, should be related to tumor biology, precisely because the applied technique was always the same, and so these may be of interest regardless the surgical approach. CONCLUSION MTSA achieves hormonal remission or complete tumor removal with preservation of pituitary function in the majority of pediatric patients, with very low morbidity and without any complications specific to this age. Regular and long follow-up is important, especially in GH-secreting adenomas, as well as early diagnosis. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Richmond IL , Wilson CB . Pituitary adenomas in childhood and adolescence . J Neurosurg . 1978 ; 49 ( 2 ): 163 - 168 . Google Scholar CrossRef Search ADS PubMed 2. Dyer EH , Civit T , Visot A , Delalande O , Derome P . Transsphenoidal surgery for pituitary adenomas in children . Neurosurgery . 1994 ; 34 ( 2 ): 207 - 212 ; discussion 212 . Google Scholar CrossRef Search ADS PubMed 3. Partington MD , Davis DH , Laws ER Jr , Scheithauer BW . Pituitary adenomas in childhood and adolescence . J Neurosurg . 1994 ; 80 ( 2 ): 209 - 216 . Google Scholar CrossRef Search ADS PubMed 4. Kane LA , Leinung MC , Scheithauer BW et al. Pituitary adenomas in childhood and adolescence . J Clin Endocrinol Metab . 1994 ; 79 ( 4 ): 1135 - 1140 . Google Scholar PubMed 5. Kunwar S , Wilson CB . Pediatric pituitary adenomas . 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Katavetin P , Cheunsuchon P , Swearingen B , Hedley-Whyte ET , Misra M , Levitsky LL . Pituitary Adenomas in Children and Adolescents . J Pediatr Endocrinol Metab . 2010 ; 23 ( 5 ): 427 - 431 . Google Scholar CrossRef Search ADS PubMed 25. Haddad SF , VanGilder JC , Menezes AH . Pediatric pituitary tumors . Neurosurgery . 1991 ; 29 ( 4 ): 509 - 514 . Google Scholar CrossRef Search ADS PubMed 26. Espay AJ , Azzarelli B , Williams LS , Bodensteiner JB . Recurrence in pituitary adenomas in childhood and adolescence . J Child Neurol . 2001 ; 16 ( 5 ): 364 - 367 . Google Scholar CrossRef Search ADS PubMed 27. Roelfsema F , Biermasz NR , Pereira AM . Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis . Pituitary . 2012 ; 15 ( 1 ): 71 - 83 . Google Scholar CrossRef Search ADS PubMed 28. Mortini P , Losa M , Barzaghi R , Boari N , Giovanelli M . Results of transsphenoidal surgery in a large series of patients with pituitary adenoma . Neurosurgery . 2005 ; 56 ( 6 ): 1222 - 1233 ; discussion 1233 . Google Scholar CrossRef Search ADS PubMed 29. Rabbiosi S , Peroni E , Tronconi GM , Chiumello G , Losa M , Weber G . Asymptomatic thyrotropin-secreting pituitary macroadenoma in a 13-year-old girl: successful first-line treatment with somatostatin analogs . Thyroid . 2012 ; 22 ( 10 ): 1076 - 1079 . Google Scholar CrossRef Search ADS PubMed 30. Magiakou MA , Mastorakos G , Oldfield EH et al. Cushing's syndrome in children and adolescents. Presentation, diagnosis, and therapy . N Engl J Med . 1994 ; 331 ( 10 ): 629 - 636 . Google Scholar CrossRef Search ADS PubMed 31. Lonser RR , Wind JJ , Nieman LK , Weil RJ , DeVroom HL , Oldfield EH . Outcome of surgical treatment of 200 children with Cushing's disease . J Clin Endocrinol Metab . 2013 ; 98 ( 3 ): 892 - 901 . Google Scholar CrossRef Search ADS PubMed 32. Storr HL , Savage MO . Management of endocrine disease: paediatric Cushing's disease . Eur J Endocrinol . 2015 ; 173 ( 1 ): R35 - R45 . Google Scholar CrossRef Search ADS PubMed 33. Oldfield EH . Surgical management of Cushing's disease: a personal perspective . Neurosurgery . 2011 ; 58 (Suppl 1) : 13 - 26 . Google Scholar CrossRef Search ADS 34. Oliveira RS , Castro M , Antonini SR , Martinelli CE Jr , Moreira AC , Machado HR . Surgical management of pediatric Cushing's disease: an analysis of 15 consecutive cases at a specialized neurosurgical center . Arq Bras Endocrinol Metab . 2010 ; 54 ( 1 ): 17 - 23 . Google Scholar CrossRef Search ADS 35. Storr HL , Drake WM , Evanson J et al. Endonasal endoscopic transsphenoidal pituitary surgery: early experience and outcome in paediatric Cushing's disease . Clin Endocrinol . 2014 ; 80 ( 2 ): 270 - 276 . Google Scholar CrossRef Search ADS 36. Fideleff HL. Are there any regional differences in the clinical presentation of adult growth hormone deficient patients? J Postgrad Med . 2008 ; 54 ( 2 ): 84 - 85 . Google Scholar CrossRef Search ADS PubMed 37. Lafferty AR , Chrousos GP . Pituitary tumors in children and adolescents . J Clin Endocrinol Metab . 1999 ; 84 ( 12 ): 4317 - 4323 . Google Scholar CrossRef Search ADS PubMed 38. Fideleff HL. Are there any regional differences in the clinical presentation of adult growth hormone deficient patients? J Postgrad Med . 2008 ; 54 ( 2 ): 84 - 85 . Google Scholar CrossRef Search ADS PubMed 39. Colao A , Loche S , Cappa M et al. Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up . J Clin Endocrinol Metab . 1998 ; 83 ( 8 ): 2777 - 2780 . Google Scholar CrossRef Search ADS PubMed 40. Eren E , Yapici S , Cakir ED , Ceylan LA , Saglam H , Tarim O . Clinical course of hyperprolactinemia in children and adolescents: a review of 21 cases . J Clin Res Pediatr Endocrinol . 2011 ; 3 ( 2 ): 65 - 69 . Google Scholar CrossRef Search ADS PubMed 41. Abe T , Ludecke DK . Transnasal surgery for prolactin-secreting pituitary adenomas in childhood and adolescence . Surg Neurol . 2002 ; 57 ( 6 ): 369 - 378 ; discussion 378-369 . Google Scholar CrossRef Search ADS PubMed 42. Creo AL , Lteif AN . Pituitary gigantism: a retrospective case series . J Pediatr Endocrinol Metab . 2016 ; 29 ( 5 ): 597 - 602 . Google Scholar CrossRef Search ADS PubMed 43. Abe T , Ludecke DK , Saeger W . Clinically nonsecreting pituitary adenomas in childhood and adolescence . Neurosurgery . 1998 ; 42 ( 4 ): 744 - 749 ; discussion 750-741 Google Scholar CrossRef Search ADS PubMed Acknowledgment We are grateful to Prof Massimo Giovanelli who, since 1990, created in our Department a multidisciplinary team to evaluate and manage any PA adopting a multimodality strategy. COMMENTS The authors present a series of pediatric patients with pituitary adenomas treated at a single institution and compare it to a contemporaneous cohort of adult patients. Immediate and long-term outcomes are described for secreting and non-secreting tumors. The authors highlight important differences between pediatric and adult PAs, including the higher frequency of secreting tumors in children, and outline the existing literature on the natural history of these tumors in the pediatric population. They report on 85 children compared to 2917 adults over a 26-year period treated by a microscopic sublabial technique with occasional endoscopic assistance for larger tumors. In their series, the authors re-demonstrate the higher frequency of secreting tumors in children (89.5% vs 61% in adults), as well as more frequently occurring secreting macroadenomas in children. They achieve similar hormonal remission rates between children and adults for Cushing's Disease, Acromegaly and Prolactinoma, and non-secreting tumors were completely removed at a similar rate in children as in adults. Complications were uncommon, 2.4%, and consisted of 1 case of meningitis and 1 epistaxis. These and endocrine morbidities occurred at similar rates to the adult comparison cohort. This report adds to the growing literature on the safety and efficacy of ventral approaches to pediatric sellar and parasellar pathology. Previously thought to be limited by small anatomy, it has been repeatedly demonstrated now that these tumors can be removed with minimally invasive approaches with success rates and risk profiles comparable to adult patients. One criticism of this study is that it fails to assess the state-of-the-art of these approaches, using conventional microscopic techniques as the primary surgical tools, rather than endoscopic endonasal exposure. Additionally, the follow-up periods may be too brief to accurately report recurrence rates. For example, in the Cushing's group, recurrence occurred in 2 patients at >70 months, but the average follow-up was 48 months. Perhaps longer follow-up would show that their recurrence rate is not as low as it seems. Nonetheless, the comprehensive nature of their follow-up and delineation of secreting and non-secreting tumors in both children and adults warrants reporting. Theodore H. Schwartz New York, New York This paper presents a case series of 85 pediatric pituitary cases, including meticulous endocrine outcomes. There is significant value for the literature in this series and it helps to establish a gold standard for microscopic transsphenoidal approach (MTSA) for such tumors. In addition, the paper provides valuable insight into presentation and long-term control. Finally, it includes a comparison with the same group's adult series helping to demonstrate the differences in these populations. The results presented in this paper are very impressive, with the exception of nonfunctioning adenomas and GH-secreting adenomas, both of which had complete resection in only 55.6%. The addition of radiation for 4/9 NFPAs is concerning for a pediatric series, but the use of radiosurgery later in the series has become standard for cavernous sinus residual. Consideration should be given in the future to options such as ‘expanded’ endoscopic endonasal approaches which have been shown to provide improved access and resection rates for tumors with cavernous invasion (yet to show significantly improved outcomes for functional tumors). The authors do add that endoscopes were used for inspection, but this was only presumably later in the series and not throughout the entire series. Indeed, there are several aspects of the surgical technique used that could explain some of the limitations. The addition of image guidance, endoscopy, and otolaryngology for greater exposure and more lateral access could potentially improve outcomes, especially for the tumors with which they had most difficulty; namely larger tumors, such as the NFPAs and GH-secreting tumors. Certainly, the lack of sinus pneumatization in children leads to a smaller natural corridor and the addition of the above adjuvant techniques does provide greater access. The use of a sublabial approach in this series may have offset some of these challenges which would be more evident with a transnasal approach. Paul A. Gardner Pittsburgh, Pennsylvania This is a careful study of a relatively large number of pediatric patients having surgery for pituitary adenomas at a single institution over a 36-year interval. The results reinforce in many respects the observations from previous retrospective analyses on this topic. Based on the existing literature, there remains an unresolved contention that pediatric pituitary adenomas may exhibit faster growth and more aggressive features compared to their adult counterparts. Although this manuscript does not definitively answer this question, for the great majority of adenoma subtypes in the current study there did not appear to be any significant prognostic difference between pediatric and adult tumors. Also importantly, surgical remission for hormonally-active tumors was achieved at rates comparable to generally accepted rates for adult tumors in the literature. In the current analysis, the observed differences in outcome between adults and children for somatotropic adenomas should be viewed with caution, as the pediatric cohort in this study was very small (n = 5). The limitations for this type of retrospective analysis are notable, including bias related to case selection, patient referral, follow-up, non-adjudicated assessments of outcome, and variations in diagnostic and treatment protocols over the 36-year study interval, especially regarding endocrinologic criteria for surgical remission. Nevertheless, this manuscript is an important addition to the body of evidence concerning the clinical behavior of pediatric pituitary adenomas. Ultimately the questions regarding the differences between pediatric and adult pituitary adenomas will likely require a thorough genotypic and phenotypic comparison of these tumors to resolve the issue of differences in biologic behavior. Marc R. Mayberg Seattle, Washington Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

NeurosurgeryOxford University Press

Published: May 22, 2018

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