Pediatric pituitary adenomas in Northeast Mexico. A follow-up study

Accurate information concerning the incidence and prevalence of PA in children and adolescents are deficient owing to its rarity. Although these tumors are very nearly always benign, because of their location (mass effects) and interference with normal pituitary function, morbidity may become significant. Due to this vulnerable and developing patient population, early diagnosis and subsequent sustained therapy are of primary importance.

The present study show some discrepancies compared to previous findings [3, 5]. The cohort had a mean age at diagnosis of 17.2 years (pubescent and postpubescent, range 14–19 years) and the population comprised adolescents but no prepubescent children. In addition, the distribution of pediatric PA, related to secretion, is atypical. The most common types usually encountered at prepubescent age are prolactinomas and ACTH-secreting adenomas. The last category was uncommon in this investigation (1 case). Most common were prolactinomas (63%) and NF (21%). This may be a bias and can be a potential limitation. The reason is that this study was realized in a regional specialist hospital of third level. As pediatric PA occur very infrequently within the pediatric age range, pediatric specialists in Mexico do not have experience in providing accurate diagnosis of PA. For example, ACTH cases may be inaccurately diagnosed as obesity. Mexico have high incidence of obesity problems in children. The pediatric specialist try to solve obesity with diet control while the individual suffer from PA resulting in a late PA diagnose. Mexican pediatric doctors need further education regarding general PA diagnosis, especially in ACTH cases, to improve accurate diagnoses resulting in early therapeutic intervention.

The microadenomas in this study were prolactinomas 9/27 and NF 2/9. Prolactinomas presented typical symptoms, e.g., amenorrhea, polymenorrhea, galactorrhea, hypothyroidism, visual disturbances, headache, and weight gain, similar as reported by Acharya et al. [21]. The symptoms associated with the macroadenomas (e.g., amenorrhea, headache, visual disturbances hypothyroidism) were in accordance as previously reported by Colao et al. [22]. Headache with visual field disturbance was recorded in one patient with suprasellar extension. No case with gynecomastia was recorded; however, in young patients gynecomastia should be carefully investigated since teenagers may not refer to it as a symptom.

Galactorrhea, spontaneous flow of milk from the breasts, occurred in 36% of the patients in the present study, similar as the findings of Cannavo et al. [23].

The most common childhood/adolescence PA is prolactinomas [3, 8, 13, 15] and also in the present study. Sixty three percent were prolactinomas and with female predominance which is also similar in the adult population [3, 4, 18‐20, 22, 24].

Regarding micro- or macroadenomas, males are more likely to have macroadenomas at presentation [14, 17, 18, 25, 26] and it was confirmed also in the present study all macroadenomas were in males, 8 out of 43 patients.

One overweight prepubertal patient with an ACTH releasing PA was found. These tumors are rare in the pediatric population and are found most often in prepubescent children [18]. No Nelson or Cushing syndrome patients were found in the current investigation. Cushing tumors are unusual in children [27].

Somatotropinomas GH-secreting adenomas account for 5–15% of pediatric pituitary tumors [9, 13, 17, 24, 28]. Somatotropinomas are commonly macroadenomas at presentation and frequently cause headaches and visual disturbances in addition to the endocrine and metabolic symptoms [13]. Pediatric somatotropinomas is uncommon but usually more aggressive than in adults being invasive in 30–60% of the cases. Acromegaly features are present in 37% of pediatric patients [28]. In the present investigation 12% (5/43) were somatotropinomas (macroadenomas) and 4 of them were invasive. Presenting symptoms were headache, visual disturbance, hypothyroidism, hypopituitarism, and acromegaly.

NF adenomas account for 33–50% of pituitary tumors in some adult’s series, but represent only 4–6% or less of cases in the pediatric patient population [8, 13]. Those tumors are very rare in childhood. Weeb et al. [5] reported 1/20 cases, and Mehrazin et al., 2/21 cases [29]. Haddad et al. [16] and Kane et al. [9] failed to report any non-secretory adenomas. Kunwar et al. [24] and Minerman et al. [18] reported 4/150 and 4/136, respectively. These tumors are frequently macroadenomas at diagnosis presenting growth and/or pubertal failure or with headaches and visual disturbance [13]. In the present study, 7/9 of cases of NF adenomas were macroadenomas. Common symptoms were headache, hypothyroidism, overweight, visual disturbance.

Weight gain and obesity occurring as a result of pituitary tumors or their treatment may lead to significant morbidity and mortality [6, 30]. In the present study, of the prolactinoma patients, 39% were overweight and 27% were obese.

Medical management of prolactinomas with BRC and CBG are typically first line treatment for the normalization of prolactin levels and restoring pituitary function and reducing tumor size [3, 31]. Some authors claim that CBG is more effective and often better tolerated than BRC [4, 22, 25, 32]. Dopamine agonists are effective in reducing tumor size and controlling prolactin levels in 80–90% of microadenomas and about 70% of macroadenomas [31]. In the current investigation, 17 out of 27 treated patients treated with CBG or CBG/BRC were had complete response. It was found that CBG therapy once per week was better tolerated than BRC treatment.

Surgery is especially important in invasive adenomas [29] and for prolactinomas surgery is reserved for patients with acute threat to vision, hydrocephalus, cerebral spinal fluid leak, or for rare tumors that grow despite exposure to increasing doses of dopamine agonists [3, 14, 25]. In the present study, surgery was used for patients with macroadenomas invasive to the optical chiasm and when there was no response after DA treatment within 4 weeks. Fronto-temporal surgery was used in supra or/and parasellar or in optical nerve invasion cases. After surgery, the patients continued low dose CBG as adjuvant treatment to prevent recurrence.

GH secreting tumors are often large and locally invasive and TSF surgery remains the first-line therapy for treating this PA variant [3, 15, 25] and resulting in biochemical normalization in approximately 70–85% of microadenoma patients and in 50% of macroadenomas [15, 25]. This mode of surgery is effective in pediatric patients who show gigantism [15, 28]. Invasive GH adenomas often require multiple treatment modalities additional to surgery to obtain cure [28]. Kunwar et al. [24] suggest that surgery of prolactinomas in pediatric population has good outcome with long-term surgical cure of 82% for all prolactinomas, with very low morbidity and no mortality. Guaraldi et al. [1] did a review of all the suggested as treatments of PA. The standard surgery technique for prolactinomas is TSF, except in small children in whom the sphenoid sinus is not pneumatised [14].

In general PA patients needs to be fully informed of the long time risk of recurrence, and therefore, 68% of the seemingly cured patients, had a prophylactic CBG dose (0.5 mg/week). Long time careful follow up is also recommended. MRI scans and control of hormone levels are essential parts of the long time follow-up procedures.

Concerning the use of radiation therapy for PA, historically radiation therapy used to be adjuvant treatment for recurrent or residual PA. However, its use as adjuvant in these days limited because of its slow rate of hormone normalization and increased incidence of early and late complications [15]. In the case of prolactinomas external radiotherapy is rarely used and only after unsuccessful surgery and/or failing drug therapy [33].

Rarely, pituitary tumors result in metastases, qualifying as pituitary carcinomas according to the latest WHO definition. In the same classification, a subset of tumors with relatively distinct histopathological features were identified and defined as atypical adenomas expected to follow a more aggressive clinical course. In general, aggressive pituitary tumors are typically difficult to manage because of their size, invasiveness, rapid growth, and high frequency of recurrence. These PAs need to be carefully defined clinically and radiologically, identifying histological and molecular markers to identify which patients do have increased risk of early recurrence and disease progression. Currently, no single marker or classification system of pituitary tumor aggressiveness exist. Histology markers as Ki67, p53, 06-methylguanine DNA methyltransferase (MGMT), MSH1, MSH2 can be used to identify “aggressive” pituitary tumors to guide diagnostic and therapeutic decision [11, 34]. Several novel biomarkers have been studied in order to assess their validity as predictive markers of pituitary tumor aggressive behavior. Genomic imbalance has been reported to occur frequently in pituitary tumors [11, 35]. In the present study, 40% of the pituitary tumors were diagnosed as invasive, possible dependent on late diagnoses by the pediatric specialist; however, no histopatological marker was used to study tumor aggressiveness and no genetic studies were done. The PA family history in all these patients was negative.

In summary, the results of this study are that pediatric PA most frequently were macroadenomas (70%) with prolactinomas (PRL) dominating (63%). In total, 40% were diagnosed as invasive (6/27 PRL, 6/9 NF, 4/5 GH and 1/1 ACTH).

The study also shows an unclear decision-making scheme, adapted for late-diagnosis, late-treatment and follow-up. Therefore outcome of medical therapy, surgery, or combined treatments (drug, surgery and radiation therapy or radiosurgery) are not distinguished.