Volume increase in craniopharyngiomas under growth hormone and/or sex hormones substitution: Role of tumors receptors or mere coincidence?

Craniopharyngiomas are rare embryonic tumors with low grade of malignancy that arise in supra-or intra-sellar areas with severe ophthalmological, neurological, and endocrine damages. Among pituitary deficits, somatotroph and gonadotroph deficiencies are the most challenging because of potential increased risk of tumor growth and recurrence. While data exist to suggest that growth hormone (GH) treatment is safe, very little is known about sex hormones replacement on tumor growth. Our aim was to report 3 craniopharyngiomas with tumor increase under GH and/or estrogen (E2) therapy. The three patients, aged 21, 22, and 23, were studied for severe short stature related to calcified (n = 1) or apparently stable (for more than 2 years) craniopharyngiomas with somatotroph and gonadotroph deficiencies. After 4 months to 1 year GH (n = 2) and/or E2 replacement (n = 3), there was an increase in craniopharyngiomas' size with signs of intracranial hypertension in two cases. In our three craniopharyngiomas that were either totally calcified or stable before substitution, the tumor increase seemed to be the result of GH and/or E2 substitution. But, as spontaneous evolution of these tumors is unpredictable, we could not exclude a mere coincidence.

Introduction

Craniopharyngiomas are histologically benign epithelial tumors, but their ophthalmological, neurological, and endocrine consequences are very severe. The resulting pituitary insufficiency may be partial or total requiring replacement therapy. Hormone replacement can raise some issues because of possible volume increase and/or tumor recurrence risks under growth hormone (GH) or estrogens (E2) and/or progesterone substitution. If large tumors contraindicate growth hormone substitution, some authors have demonstrated that patients with small or totally calcified lesions can be treated safely with GH,[12] little is known about sex hormones substitution.

Our aim was to report three patients with craniopharyngiomas in whom the tumor size increased under GH therapy and/or E2 substitution. The three observations will be presented with illustration in volume modification. Then, a discussion on the possible role of GH and sex hormone receptors, whose presence has been demonstrated in some human craniopharyngiomas, will be done on the basis of literature review.

Case Reports

Case 1

A young woman, aged 22, was referred to our department for a large craniopharyngioma. She was diagnosed at 12 years of age (in 2001), when she was noted to have severe short stature (−4 SD compared to children of the same age). At that time cerebral CT scan showed a totally calcified intra- and suprasellar mass measuring 45 × 17 × 15 mm suggesting a craniopharyngioma or a pituitary stone with thyreotroph,somatotroph and gonadotroph deficiencies. The vision was normal. As the pituitary lesion was totally calcified no intervention was performed. She was treated with Levothyroxine and had regular radiological monitoring by Magnetic Resonance Imaging (MRI). At 15 years old, as the tumor was stable, biosynthetic GH was prescribed. One year later GH was stopped because brain MRI revealed a solid, cystic and calcified tumor with discrete increase in its size. After stopping GH, the tumor remained stable, but pubertal development was lacking. At 17 years old, estrogens were introduced because of an important psychological impact of her hypogonadism. But, 4 months later, there was a rapid increase of the craniopharyngioma [Figure 1] with intracranial hypertension that required a ventricular-peritoneal shunt.

Figure 1

2002: Pituitary process measuring 30 × 17 × 22 mm (height, transverse, and antero-posterior diameters). 2006: Tumor increase with hemorrhage under growth hormone therapy (40 × 28 × 22 mm). In 2008 (under estrogens), the tumor became larger (45 × 30 × 25 mm) with an important cyst

Case 2

A 23-year-old patient consulted for the first time at 18 for a lack of pubertal development with short stature. Her brain MRI showed an intra- and suprasellar mass measuring 28 × 20 × 20 mm suspect of craniopharyngioma. Her ophthalmological examination showed a very low visual acuity of the right eye. Pituitary assessment was normal except for somatotroph and gonadotroph deficits. She underwent partial transphenoidal resection of the tumor, and the pathological examination confirmed the craniopharyngioma.

The postoperative course was marked by an adrenal insufficiency (which was properly treated) with persistence of visual troubles. Radiological reassessment revealed a residual process of 10 × 11 × 10 mm, which remained stable for over 2 years. After that, the estrogens, then progesterone were introduced with a good result on breast development and genital bleeding. But, after 1 year, the MRI showed an increase in the craniopharyngioma size i.e., 19 × 17 × 18 mm [Figure 2].

Figure 2

2007: Before pituitary surgery: Intra- and suprasellar tumor measuring 28 × 20 × 20 mm. 2008 after surgery (hemorrhage lesion measuring 10 × 11 × 10 mm). In 2011, increase of the hemorrhage lesion after estrogens (19 × 17 × 18 mm)

Case 3

A young woman aged 21 was referred for complication of her craniopharyngioma, which was diagnosed at 11 years old when she consulted for severe short stature with excessive weight gain and headaches. An isolated growth hormone deficiency was diagnosed, and then she received hormone replacement without any radiological exploration!

After 1 year the headaches worsened. The MRI revealed a pituitary lesion measuring 30 mm in height with solid, cystic, and calcified components pleading for a craniopharyngioma reaching the chiasmatic area. At the age of 12, the neurosurgery was done, and then a panhypopituitarism was diagnosed. She was treated with glucocorticoids and thyroid hormones. Then, she was lost in sight before radiological exploration.

Two years later, visual acuity decreased and the MRI revealed a 27 × 18 mm tumor (residual or recurrence?) with tri-ventricular hydrocephalus needing surgery.

At the age of 18, as her residual tumor seemed stable, she received estrogens for her hypogonadism. After 8 months, intracranial hypertension with impaired consciousness appeared, and then she was operated on for the third time [Figure 3].

Figure 3

Important increase of the tumor size and hydrocephaly (in 2008) comparing to 2006

Discussion

Craniopharyngiomas are embryonic tumors, which are relatively uncommon as they account for only 9-11% of all intracranial tumors diagnosed in childhood,[34] and sometimes, in adulthood. These embryonic tumors, arising from the remnants of Rathke's pouch, can be developed in the hypothalamus, the pituitary stalk, or inside the sella turcica.

Their pathogenesis is still debated.[5] But, according to a recent genetic study, it seems that some human craniopharyngiomas, and especially the adamentinomatous ones, which are very aggressive comparing to the papillary forms, are apparently due to a mutation in the wingless β catenin signaling which is a critical regulator of stem cells progenitor.[6]

Although histologically benign, craniopharyngiomas are considered as locally very invasive tumors, because of their unfavorable prognosis. The dire prognosis is due to numerous and serious complications such as visual loss, memory troubles, epilepsy, and endocrine morbidities. Among pituitary deficits, the most common are growth hormone and gonadal deficiencies as a meta-analysis, performed on 121 cases, showed GH deficiency varies from 88% to 100% and gonadal deficit is observed in 74-94%.[7] Therefore, hormonal substitution is required to achieve normal growth, bone mineralization, sexual development, and to improve the quality of life. But, the result of GH replacement on craniopharyngiomas increase and/or recurrence is still debated, and little is known about sex hormones replacement.

For growth hormone, although GH receptors are well demonstrated in some craniopharyngiomas,[89] many authors continue to think GH is safe,[10111213] and craniopharyngiomas volume increase and recurrence are related to the quality of surgery excision and to the natural outcome where male gender, early onset, and cranial hypertension are the most important predictive factors of tumor progression and recurrence.[14] Others, less optimistic, think GH should be indicated only if the craniopharyngioma is stable for at least 1 year after surgery, and growth retardation is clinically evident as some children continue to grow despite a lack of GH response to different stimulation tests. Therefore, when GH therapy is indisputable, the treatment should be carefully weighed to avoid recurrence and/or increase in tumor volume.

For sex hormones, little is known about their action on human craniopharyngiomas. In 1994, Thapar[15] was apparently the first to describe oestrogen receptors in human craniopharyngiomas. In 1997, Honegger proved the same thing for progesterone receptors, and demonstrated their activity in vitro.[16] This result was confirmed by Izumoto[17] who analyzed 43 craniopharyngiomas. Among those, 30% were positive for female sex hormone receptors. A positive correlation between estrogen or progesterone receptors and tumor recurrence rate has been proved in vitro for the first time.[18] Then after, Hofmann and colleagues, who analyzed 50 cell culture mediums, obtained from 20 craniopharyngiomas, have confirmed estrogen receptors in some of them, and demonstrated a tumor growth after adding estrogens.[18] In addition, a positive correlation between craniopharyngiomas’ tumor size, cell proliferation, and expression of estrogen receptors was also proved.

Our clinical observations plead for a link between hormonal treatment (GH or E2 and/or progesterone) and tumor growth, but we were unable to exclude totally a spontaneous increase of these craniopharyngiomas. In our cases, tumor expansion was observed between 4 months and 1 year after the beginning of hormonal treatment. In two out of three cases, intracranial hypertension was rapid and severe. So we think that indication of estrogen and/or progesterone or GH therapy must be carefully weighed in patients harboring craniopharyngiomas.

Conclusion

In addition to surgical management of craniopharyngiomas, substitution of endocrine deficiencies is required. Limited literature exists about tumor growth under GH and argues for the safety of GH. However, to our knowledge there is not any clinical report describing an unfavorable change in the size of craniopharyngiomas under estrogens and/or progesterone. Our observations argue for a link between GH and/or sex hormones therapy and size increase in some craniopharyngiomas. In addition, in vitro studies have confirmed the existence of estrogen receptors and/or progesterone ones in some craniopharyngiomas too. These findings should encourage caution for GH and female sex hormones prescription in patients harboring craniopharyngiomas. On another hand estrogen and progesterone receptors assay maybe useful for additional radiotherapy in patients who had incomplete tumor resection.[17]