Pediatric Pituitary Adenomas

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TABLE OF CONTENTS

[MATERIALS=20 AND...] [RESULTS= ]=20 [COMMENT= ]=20 [CONCLUSIONS= ]=20 [REFERENCES= ]=20 [TABLES<= /A>] [FIGURE= S]

=A9=20 Copyright by College of American Pathologists 2008=20

Archives of Pathology and Laboratory = Medicine:=20 Vol. 132, No. 1, pp. 77=9680.

Pediatric Pituitary Adenomas

Christopher Webb, MD; Richard A. Prayson, MD

From the Department of Anatomic Pathology, Cleveland Clinic=20 Foundation, Cleveland, = Ohio

Accepted August 8, 2007

Context.=97Pituitary adenomas are = relatively rare=20 occurrences in the pediatric population, and there are few studies=20 documenting the profile of these tumors in this age group.
Objective.=97To study the clinical and = pathologic=20 features of pediatric pituitary adenomas in conjunction with a = review of the=20 available literature.

Design.=97A retrospective = clinicopathologic review of=20 20 pediatric patients (younger than 20 years of age) with pituitary = adenomas=20 resected during a 24.5-year period (1981=962005).

Results.=97A total of 20 patients, = including 12=20 females and 8 males, comprise the study group. Mean age at onset of = symptoms=20 was 14.0 years (range, 5=9618 years). Four patients had onset of = symptoms=20 before the age of 12 years. The majority of patients presented with=20 headaches (n =3D 12), visual disturbances (n =3D 12) or, in females, = menstrual=20 dysfunction (n =3D 9/12). Tumor size based on radiographic data was = known for=20 19 tumors; 12 adenomas were greater than 1 cm in greatest dimension, = and 7=20 were less than 1 cm. On follow-up, 2 patients with total gross tumor = resections had recurrent adenomas; time to recurrence was 5 months = and 17=20 months, respectively. Nine adenomas stained solely for prolactin, 5 = for=20 adrenocorticotropic hormone, and 3 for growth hormone. Two stained = for=20 growth hormone and prolactin. One did not stain with hormone = antibodies.

Conclusions.=97Most pediatric pituitary = adenomas=20 present after the onset of puberty and present with frequent = headaches,=20 changes in visual acuity and, in females, menstrual dysfunction. = Most=20 (19/20) were secretory, with prolactinomas being the most common=20 type.

3D"" Pituitary adenomas in children are relatively = infrequent=20 occurrences.¹⁼⁹⁶⁸=20 Most studies report the incidence of these tumors to be between 1% and = 10% of=20 all childhood brain tumors⁹⁼⁹⁶¹²=20 and between 3% and 6% of all surgically treated adenomas.^9,^11,¹³=20 Variation in reported incidence is, to a certain degree, a matter of a = lack of=20 consensus on an age range for defining a pituitary adenoma as pediatric. = Cutoff=20 ages vary between 16 and 20 years of age, depending on the study. = Despite the=20 rarity of these tumors, they can have a significant effect on the = quality of=20 life of the patient, especially during childhood, when growth rates and=20 development are at a peak. Few characteristics of these tumors have been = consistently demonstrated in different studies. Variation among studies = has been=20 reported regarding age and sex predilection, tumor size, hormonal = production,=20 and recurrence rates. We report one institution's experience with = pediatric=20 pituitary adenomas. The clinical features of these patients and the = pathology of=20 their tumors are described and the literature reviewed.

MATERIALS AND METHODS Return=20 to TOC

3D"" Following institutional review board approval, a = computer=20 search of the surgical pathology files was performed for pituitary = adenomas=20 diagnosed between 1981 and 2005. Only patients who had symptoms and were = initially examined prior to the age of 20 years were considered for this = study=20 (slightly less than 2% of all adenomas). All available microscopic = slides,=20 including immunostains for follicle-stimulating hormone, luteinizing = hormone,=20 thyroid-stimulating hormone, prolactin (PRL), adrenocorticotropic = hormone=20 (ACTH), and growth hormone (GH) were reviewed to confirm the prior = diagnosis and=20 document information on tumor histology and hormonal immunoexpression. = If=20 neither slides nor immunostains were available, tissue blocks were used = to=20 create new slides with a full set of immunostains. If no prior slides or = blocks=20 were available, the patient was excluded from this retrospective = analysis.=20 Patients were also excluded from the study if histologic evidence of an = adenoma=20 was not identified, despite clinical data to suggest the presence of a = pituitary=20 adenoma. A total of 20 patients were identified that met our inclusion = criteria=20 and formed the study group.

3D"" Patient records were examined for clinical = information. Tumor=20 size was based on radiologic information. A microadenoma was defined as = a tumor=20 that measured less than 1 cm in greatest dimension. Tumor recurrence was = defined=20 as recurrent disease after a complete gross resection of the original = tumor and=20 was based on the clinical judgment of the treating physician as = documented in=20 the patient's record. Increasing size of residual disease after an = incomplete=20 resection was not classified as recurrent disease. Information for = comparative=20 purposes concerning patient age at diagnosis, sex, symptoms and physical = findings were based on documentation provided in the medical record at = the=20 patient's initial visit with the treating physician. All other pertinent = information concerning the patient's surgery and follow-up were gathered = from=20 the patient's medical record.

RESULTS Return=20 to TOC

3D"" The 20 study patients included 12 females and 8 = males who=20 ranged in age at the time of initial surgery from 8 to 19 years (mean, = 15.6=20 years). The clinicopathologic features of the patients and their = adenomas are=20 summarized in the Table=20 3D"" . The clinical presentation was quite variable, but = certain=20 symptoms occurred with greater frequency. The most common initial = complaints=20 were headache (n =3D 12) and visual disturbances (n =3D 12), including = decreasing=20 visual acuity and field defects. Menstrual irregularities were noted in = 9 of 12=20 females; 5 females complained of galactorrhea. Five patients presented = with=20 various symptoms of Cushing syndrome, including weight gain (n =3D 5), = round=20 facies (n =3D 4), striae (n =3D 4), hirsutism (n =3D 3), fatigue (n =3D = 2), mood=20 lability (n =3D 2), acne (n =3D 2), and excessive bruising (n =3D 1). = Other presenting=20 complaints included increased stature (n =3D 4), syncope (n =3D 2), hot = flashes (n =3D=20 2), weight loss (n =3D 1), polydipsia (n =3D 1), epistaxis (n =3D 1), = short stature (n=20 =3D 1), and nausea/vomiting (n =3D 1).

3D"" Tumor size ranged between 0.2 and 5.0 cm (mean, = 2.0 cm), with=20 12 macroadenomas and 8 microadenomas. Surgical intervention was = attempted in all=20 20 cases, with 12 reported gross total resections and 8 subtotal = resections.=20 Four patients who underwent subtotal resection required additional = surgical=20 intervention between 24 and 72 months after the initial surgery. Of = these 4, 1=20 remained symptomatic after surgery until lost to follow-up 10 years = after the=20 second surgery, 1 received gamma knife therapy after a second surgery = with=20 successful results, and 2 were lost to further follow-up after an = additional=20 operation. An additional patient who underwent subtotal resection = received=20 adjuvant radiation therapy 10 months after the initial resection with = only=20 limited results before being lost to follow-up 57 months after the = initial=20 resection.

3D"" Two patients who underwent gross total resections = had=20 additional surgical intervention. One patient with an ACTH-secreting = adenoma=20 maintained elevated cortisol levels after surgery, despite no = radiographic=20 evidence of residual disease. A second operation 5 months after the = first=20 surgery revealed a miniscule amount of additional tumor. The second = patient had=20 recurrence of disease symptoms at 7 months after the initial resection = and had=20 recurrent disease identified by magnetic resonance imaging 16 months = after the=20 initial resection. The patient transferred care to a different = institution=20 before additional therapy was initiated. A total of 13 patients had no=20 documented residual or recurrent tumor with an average follow-up of 50 = months=20 (range, 1=96130 months). Of these 13, however, 3 patients did have = symptoms=20 suggestive of, but never conclusively linked to, disease recurrence. Of = the 7=20 patients with documented residual or recurrent disease, 3 had = microadenomas, 3=20 had macroadenomas, and 1 had no information available on tumor size.

3D"" Microscopic review of the adenomas revealed 14 = acidophilic=20 tumors (Figure=20 1 3D"" ), 5 chromophobic tumors, and 1 basophilic tumor. Mitotic = activity=20 was 0 to 1 mitotic figures per 10 high-powered fields in 16 of the = adenomas (Figure=20 2 3D"" ). Four adenomas had increased mitotic activity (4 to 5 = mitoses per=20 10 high-powered fields). One tumor contained focal necrosis. = Calcifications were=20 focally noted in 3 adenomas (Figure=20 3 3D"" ), and 1 adenoma demonstrated microcystic degeneration.=20 Immunohistochemical staining revealed 19 secretory adenomas and 1 = nonsecretory=20 adenoma. Of the secretory adenomas, 9 stained positively for PRL (Figure=20 4 3D"" ), 5 stained for ACTH (Figure=20 5 3D"" ), 3 stained for GH alone (Figure=20 6 3D"" ), and 2 stained for both PRL and GH. None of the = adenomas stained=20 positively with antibodies to follicle-stimulating hormone, luteinizing = hormone,=20 or thyroid-stimulating hormone.

COMMENT Return=20 to TOC

3D"" The vast majority of pituitary adenomas arise in = adults. In=20 most studies, pediatric pituitary adenomas represent only 3% to 5% of = all=20 adenomas. Differences in incidence among studies in part are related to = how=20 =93pediatric=94 is defined (ie, age at the time of initial surgery or = age at actual=20 presentation).

3D"" In the current series, patient age at onset of = symptoms seemed=20 to vary slightly according to tumor type. Those patients with = ACTH-secreting=20 tumors presented earlier, with a median age of 14 years (range, 10=9617 = years),=20 whereas patients with GH-secreting tumors and prolactinomas presented = slightly=20 later, with a median age of 15 years (ranges, 11=9618 years for GH = adenomas and=20 11=9617 years for prolactinomas). While our results do not show striking = differences in age of onset, they do fit with the overall trend of other = studies, which show a tendency for ACTH-secreting tumors to present at = an=20 earlier age than other tumor types.^12,^14,¹⁵

3D"" Within our study, females represented 60% of all = cases,=20 outnumbering males 12 to 8. This is consistent with the female = predominance=20 found in multiple large studies.^10,^11,¹³=20 Only a few published studies have had male-female ratios skewed toward = male=20 predominance, but these studies have contained smaller sample sizes.^16,¹⁷=20 In compiling male-female ratios from 6 different studies^5,^10=9612,^14,¹⁶=20 in addition to the current study within the context of hormone = secretion,=20 females clearly represent the vast majority of prolactinomas (162 = females to 34=20 males) and a slight majority of ACTH-secreting tumors (60 females to 49 = males).=20 Pure GH-secreting tumors are slightly more likely to arise in males (25 = males to=20 19 females).

3D"" In our series of patients, the number of = macroadenomas (n =3D=20 12; 60%) was higher than that of microadenomas (n =3D 7; 35%). Tumor = size was not=20 known for 1 patient. This ratio is comparable to that of Kane et al,¹³=20 who reported that macroadenomas accounted for 59% of total tumors. Other = large=20 studies, however, show more equal numbers of macroadenomas and = microadenomas.^11,¹⁴

3D"" Tumor size appears to be related to hormone = secretion.=20 GH-secreting tumors tend to present as macroadenomas. Of the 12 = GH-secreting=20 tumors reported by Mindermann and Wilson,¹¹=20 11 were macroadenomas. In our series, all 3 GH-secreting tumors and both = GH/PRL-secreting tumors were macroadenomas. The ACTH-secreting tumors = tend to=20 present as microadenomas.^11,¹⁴=20 In our series, 3 were microadenomas, and only 1 was a macroadenoma = (information=20 was not available for 1 additional ACTH-secreting tumor).

3D"" The most common presenting complaints in the = current series=20 were headaches and visual disturbances. Headaches were reported by 12 = (60%) of=20 the 20 patients. Of these 12, all but 2 had macroadenomas. The = literature is=20 divided on the occurrence of headaches. In the study of = non=96ACTH-secreting=20 tumors by Kane et al,¹³=20 34 (60%) of 56 patients reported headaches. Partington et al,¹²=20 however, reported the occurrence of headaches in only 10 (28%) of 36. In = the=20 current study, visual disturbances were also reported by 12 patients = (60%), 9 of=20 whom also reported headaches. The occurrence of visual field defects in = many=20 studies is much less (10%=9620%).^10,^12,¹³=20 Of the 12 patients with macroadenomas, all of them had at least one = symptom=20 attributable to mass effect. Nine females presented with menstrual = dysfunction,=20 including all 7 females with prolactinomas and 2 of the 4 females with=20 ACTH-secreting tumors. Five females presented with galactorrhea, all of = whom had=20 prolactinomas.

3D"" Presenting complaints among patients did correlate = well with=20 tumor type. All 5 patients with ACTH-secreting tumors presented with = Cushingoid=20 features including but not limited to central obesity, moon facies, ease = of=20 bruisability, hyperpigmentation, hirsutism, fatigue, skin striae, = depression,=20 and mood instability. Mindermann and Wilson¹¹=20 similarly reported Cushingoid features in 38 of 42 patients with = ACTH-secreting=20 tumors. Of the 5 patients with GH-secreting tumors or GH/PRL-secreting = tumors, 4=20 presented with increased stature for age. All 5 presented with symptoms = of mass=20 effect (headaches or visual disturbances). Increased stature among = patients with=20 GH-secreting tumors was also reported with high frequency by Partington = et al¹²=20 (3/3) and Mindermann and Wilson¹¹=20 (7/ 12). Of the 9 patients with prolactinomas, all but 1 presented with = symptoms=20 of mass effect. As mentioned previously, menstrual irregularities and=20 galactorrhea occurred with increased frequency, as expected.

3D"" The largest group was the prolactinomas, = accounting for 45% of=20 tumors in the current study. This predominance of prolactinomas roughly=20 corresponds to the findings of Kane et al¹³=20 (52%) and Mindermann and Wilson¹¹=20 (52.9%). ACTH-secreting tumors comprised 25% of adenomas, GH-secreting = tumors=20 15%, and GH/PRL-secreting tumors 10%. There were no tumors in the = current series=20 that secreted luteinizing hormone, follicle-stimulating hormone, or=20 thyroid-stimulating hormone. Of the 20 adenomas in the current series, = only 1=20 was nonsecretory. These additional results are also similar to findings = of other=20 studies. Haddad et al¹⁴=20 and Kane et al¹³=20 failed to report any nonsecretory adenomas. Kunwar and Wilson¹⁵=20 and Mindermann and Wilson¹¹=20 reported 4 nonsecretory adenomas of 150 and 136 adenomas, = respectively.

3D"" Tumor behavior depended largely on whether the = patient=20 underwent total or subtotal resection. Of the 8 patients in this series = who=20 underwent subtotal resection, 5 required additional surgical/medical=20 intervention for symptomatic disease. Only 2 (17%) of the 12 patients = who=20 underwent total resection had documented recurrent disease. This = compares with=20 10% tumor recurrence documented by Mindermann and Wilson¹¹=20 and 25% tumor recurrence after initial remission reported by Partington = et al.¹²=20 Kane et al¹³=20 reported tumor recurrence in 8 (14%) of 56 patients.

CONCLUSIONS Return=20 to TOC

3D"" Pediatric pituitary adenomas are relatively = infrequent and are=20 quite variable in their presentation. Among pediatric patients, those = most at=20 risk for the development of pituitary adenomas tend to be postpubertal = and more=20 commonly females. Most pediatric pituitary adenomas appear to be = secretory, with=20 prolactinomas being the most common type. Tumor behavior tends to be = linked=20 closely with the results of the primary resection. Patients undergoing = subtotal=20 resection have a higher likelihood of residual disease effects from the=20 remaining tumor.

References Return=20 to TOC

1. Pandey P, Ojha BK, = Mahapatra=20 AK. Pediatric pituitary adenoma: a series of 42 patients. J Clin = Neurosci=20 2005;12:124=96127. [PubMed=20 Citation]

2. De = Menis E,=20 Visentin A, Billeci D. et al. Pituitary adenomas in childhood and = adolescence:=20 clinical analysis of 10 cases. J Endocrinol Invest = 2001;24:92=9697. [PubMed=20 Citation]

3. Abe = T, Tara LA,=20 Ludecke DK. Growth hormone-secreting pituitary adenomas in childhood and = adolescence: features and results of transnasal surgery. = Neurosurgery=20 1999;45:1=9610. [PubMed=20 Citation]

4. Kanter SL,=20 Mickle JP, Hunter SB. et al. Pituitary adenomas in pediatric patients: = are they=20 more invasive?. Ped Neurosci 1985=961986;12:202=96204. [PubMed=20 Citation]

5. Fraioli B,=20 Ferrante L, Celli P. Pituitary adenomas with onset during puberty. J=20 Neurosurg 1983;59:590=96595. [PubMed=20 Citation]

6. Shalet SM.=20 Pituitary adenomas in childhood. Acta Endocrinol (Copenh)=20 1986;279:434=96439.

7. Richmond=20 IL, Wilson CB. Pituitary adenomas in childhood and adolescence. J=20 Neurosurg 1978;49:163=96168. [PubMed=20 Citation]

8. Gold = EB.=20 Epidemiology of pituitary adenomas. Epidemiol Rev = 1981;3:163=96183. [PubMed=20 Citation]

9. Espay = AJ,=20 Azzarelli B, Williams LS, Bodensteiner JB. Recurrence in pituitary = adenomas in=20 childhood and adolescence. J Child Neurol 2001;16:364=96367. [PubMed=20 Citation]

10. Maira G,=20 Anile C. Pituitary adenomas in childhood and adolescence. Can J = Neurol=20 Sci 1990;17:83=9687. [PubMed=20 Citation]

11. Mindermann T,=20 Wilson CB. Pediatric pituitary adenomas. Neurosurgery = 1995;36:259=96269.=20 [PubMed=20 Citation]

12. Partington=20 MD, Davis DH, Laws ER Jr, Scheithauer BW. Pituitary adenomas in = childhood and=20 adolescence. J Neurosurg 1994;80:209=96216. [PubMed=20 Citation]

13. Kane LA,=20 Leinung MC, Scheithauer BW. et al. Pituitary adenomas in childhood and=20 adolescence. J Clin Endocrino Metab 1994;79:1135=961140. [PubMed=20 Citation]

14. Haddad SF,=20 VanGilder JC, Menezes AH. Pediatric pituitary tumors. = Neurosurgery=20 1991;29:509=96514. [PubMed=20 Citation]

15. Kunwar S,=20 Wilson CB. Pediatric pituitary adenomas. J Clin Endocrinol Metab=20 1999;84:4385=964389. [PubMed=20 Citation]

16. Dyer EH,=20 Civit T, Visot A, Delalande O, Derome P. Transsphenoidal surgery for = pituitary=20 adenomas in children. Neurosurgery 1994;34:207=96212. [PubMed=20 Citation]

17. Di = Rocco C,=20 Maira G, Borrelli P. Pituitary microadenomas in children. Child's = Brain=20 1982;9:165=96178. [PubMed=20 Citation]

Tables Return=20 to TOC

3D""=20 Summary of Clinicopathologic = Features of=20 Pediatric Pituitary Adenoma Patients*

Figures Return=20 to TOC

Click on thumbnail for full-sized = image.

3D""=20

3D"" Figure 1. 3D""=20 Acidophilic pituitary adenoma in patient 1 marked by a = proliferation of=20 cells with abundant eosinophilic cytoplasm (hematoxylin-eosin, original=20 magnification =D7200)

3D"" Figure 2. 3D""=20 Adenoma in patient 17 demonstrating mitotic activity=20 (hematoxylin-eosin, original magnification =D7400)

3D"" Figure 3. 3D""=20 Chromophobic adenoma in patient 19 displaying prominent = calcifications=20 (hematoxylin-eosin, original magnification =D7400)

3D"" Figure 4. 3D""=20 Adenoma from patient 9 with positive immunostaining for = prolactin=20 (original magnification =D7400)

3D"" Figure 5. 3D""=20 Adenoma in patient 14 with positive immunostaining for=20 adrenocorticotropic hormone (original magnification =D7400)

3D"" Figure 6. 3D""=20 Adenoma from patient 18 with positive immunostaining for = growth hormone=20 (original magnification =D7400)

The authors have no relevant financial interest in the = products or=20 companies described in this article.

Corresponding author: Richard = A. Prayson, MD,=20 Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, = 9500 Euclid=20 Ave, Cleveland, OH 44195 (E-mail: praysor@ccf.org)

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