Craniopharyngioma: long-term consequences of a chronic disease

Abstract

Childhood-onset craniopharyngiomas (CP) are rare embryonal malformations of low-grade histological malignancy. Hypothalamic involvement and/or treatment-related lesions result in impaired physical and social functionality and severe neuroendocrine sequelae. Quality of life in CP with hypothalamic involvement is impaired by severe obesity, physical fatigue, reduced motivation, dyspnea, diarrhea, and non-optimal psychosocial development. 567 CI patients have been recruited between 1998 and 2010 in the German Craniopharyngioma Registry. Only 5 of 567 patients (<1%) presented without confirmed signs of relapse/progression, visual impairment, and endocrine deficiencies during longitudinal follow-up of more than 5 years. Hypothalamic obesity in CP is associated with a severe increase in BMI during the early post-operative period. Patients with CP involving hypothalamic structures show reduced 10-years overall survival, whereas overall and progression-free survival rates are not related to the degree of surgical resection. Accordingly, gross-total resection should be avoided in cases of hypothalamic involvement to prevent further hypothalamic damage. As surgical expertise has been shown to have impact on postoperative morbidity, medical societies should establish criteria of adequate professional expertise for the treatment of CP. Based on these criteria, health authorities should organize the certification of centers of excellence authorized for treatment and care of patients with this chronic disease.

Keywords:

• chronic disease
• craniopharyngioma
• obesity
• quality of life
• survival

Chronic diseases are long-lasting conditions that can be controlled but not cured. Childhood-onset craniopharyngiomas (CPs) are rare intracranial embryonal malformations of the sellar region arising from remnants of Rathke’s pouch. In childhood and adolescence, its histological type is usually adamantinomatous with cyst formation. More than 70% of the predominantly childhood CP adamantinomatous type bear a mutation of the β-catenin gene, which is not detectable in the adult papillary type of CP.[1] These tumors show low-grade histological malignancy (WHO I) and frequently affect hypothalamic and pituitary regions and the optic chiasm. Hypothalamic involvement and/or treatment-related lesions to the above structures result in impaired physical and social functionality [2,3] that includes severe neuroendocrine sequelae, mainly hypothalamic obesity, with major negative impact on quality of life in surviving patients. [1–7] In total, 567 patients with childhood-onset CP have been recruited between 1998 and 2010 in the German Craniopharyngioma Registry. Only 5 of 567 recruited patients (<1%) presented without confirmed signs of relapse/progression, visual impairment and (neuro)endocrine deficiencies during longitudinal follow-up of more than 5 years. The CPs in this small subgroup of patients without obvious symptoms indicating a chronic state of disease were characterized by a small nonrecurrent tumor confined to the sellar area and without hypothalamic involvement, which could therefore be resected completely while preserving the integrity of the pituitary gland/stalk and visual and hypothalamic structures.

Current treatment options and strategies

For favorably localized tumors, the preferred treatment of choice especially at primary CP diagnosis is an attempt at complete resection with preservation of visual, hypothalamic and pituitary function. For unfavorably localized tumors too close to or too entangled with the optic nerve and/or the hypothalamus, a planned limited resection should be performed in order to preserve integrity and/or to avoid further damage to hypothalamic and optic structures.[8] The implantation of an intracystic catheter with a subcutaneous reservoir enables the possibility of repeated decompression of cysts and instillation of sclerosing agents (IFN-α).[9]

Irradiation is effective in preventing progression of residual tumor and a recommended treatment option in case of limited surgical perspectives with regard to hypothalamus-sparing aspects.[10] Preliminary experiences with proton beam therapy applied to CP are very promising, offering a more protective radio-oncological option than conventional external irradiation, especially for tumors localized in the vicinity of the optic nerve or chiasm, pituitary gland or hypothalamus.[11]

How treatment approaches evolved to their current status

The accelerated volume of research in the last decade and a half on childhood-onset CP highlights the ongoing challenges of treating and managing this chronic disease. For decades previously, gross total resection was the preferred treatment option, the conventional thought was that radical strategies at the time of initial diagnosis and treatment would result in the cure of CP. The rates of recurrence and hypothalamic sequelae were considered to be low or at least tolerable, but these rates were extrapolated from early reports frequently based on single-center studies and cohorts recruited over long time periods. In 2001, the results of cross-sectional studies reported for the first time that quality of survival in CP was severely impaired due to hypothalamic obesity.[12] A study on weight and height development before diagnosis of CP confirmed the hypothesis that hypothalamic involvement of the tumor had a pathogenic impact on growth and weight development in the history of patients before diagnosis of childhood-onset CP,[13] regardless of chosen therapeutic strategies.[10,14]

Gross total resection versus limited surgery with postoperative irradiation

The fact that CP is a disease that can be treated and controlled but not cured has been confirmed by recent studies showing that radical gross total resection in CP with hypothalamic involvement is associated with recurrence rates similar to progression rates after limited surgery, resulting in residual tumor.[2,3,10] The question of the appropriate time point of irradiation in patients with residual tumor is, therefore, under investigation,[15] as irradiation has been shown to be effective in prevention of relapses and progressions. Two studies comparing patient cohorts treated mainly by gross total resection with those receiving irradiation after limited surgery both showed that the rate of hypothalamic surgical lesions and the development of severe obesity decreased in cohorts surgically treated with hypothalamus-sparing strategies augmented in most cases by postsurgical irradiation.[10,15]

Surgical expertise

New research has also demonstrated that surgical expertise in the execution of tumor excision is associated with prognosis.[16] Müller et al. observed higher rates of surgical hypothalamic lesions resulting in more severe obesity in relation to CP patients’ load of treating surgical centers: the greater the patient load and therefore surgical experience, the lower the rate of surgical lesions.[14,17]

Patient rehabilitation and quality of life management

Rehabilitation of CP patients is frequently impaired by visual, endocrine, metabolic and neuropsychological disease and/or treatment-related morbidities.

Visual impairment

Due to frequent suprasellar tumor localization, visual deficits are relatively common in patients with CP. In fact, visual impairment as an initial clinical manifestation of CP is found in more than half of the affected patients, with some postsurgical improvement of vision in 41–48% of patients.[4]

Pituitary deficiencies

Pituitary deficiencies frequently occur before (40–87%) or after (85–95%) surgery due to the close proximity of the tumor to the pituitary gland and the necessity to sacrifice the pituitary when resecting the tumor. Managing pituitary deficiencies associated with growth failure and delayed sexual maturation is widely considered as a less challenging task than those posed by the lack of treatment options for hypothalamic neuroendocrine deficits.[4] Sterkenburg et al. [2] analyzed long-term prognosis in 261 patients with childhood-onset CP and found that 10-year overall survival was reduced in patients with hypothalamic involvement. However, a disturbing finding was that causes of death in this cohort were mainly related to pituitary deficits such as acute adrenal insufficiency. Whereas following surgical treatment 94% patients were on endocrine substitution for pituitary deficiencies, 34% of long-term survivors were not in follow-up care of an endocrinologist and 9% of patients stated that they were no longer treated by any physician. To avoid such potentially avoidable deaths, the more recent childhood CP studies emphasize that childhood-onset CP needs to be recognized as a chronic disease so that consequences of the disease and its treatment are constantly monitored.[1,2,4,6,14]

Neuropsychological morbidity and psychosocial status

A recent study on the psychosocial health in long-term survivors cited neuropsychological morbidity as a serious, treatment-resistant category of effects.[18] Factors include younger age at diagnosis, preoperative functional impairment, larger tumor volume and hypothalamic and third ventricle involvement at presentation. Despite over a quarter of century of literature documenting the neurocognitive challenges encountered by individuals treated for childhood-onset CP, intervention options remain dissatisfactory.

A retrospective analysis of a large cohort of survivors [2] revealed severe impairments of long-term psychosocial status after childhood-onset CP in terms of marriage, offspring, independence and vocational outcome.

Tumor and excision-exacerbated hypothalamic obesity

Medical treatment options for hypothalamic obesity – central stimulating agents such as methylphenidate, modafinil, dextroamphetamine, GLP-1 receptor agonists, metformin, somatostatin analogs and other substances – have been tested, mostly in small heterogeneous cohorts with mixed results.[1,19] Even though bariatric surgery, mainly gastric bypass, has been shown to be effective, [20] irreversible bariatric procedures such as Roux-en-Y gastric bypass are not recommended in children due to ethical and legal considerations based on their permanency. The pervasiveness of hypothalamic obesity in survivors of childhood-onset CP and its chronic, deteriorating effect on their quality of life and psychosocial status were confirmed in a recent retrospective analysis of long-term survivors of childhood-onset CP.[2] However, further investigation on psychosocial outcome and specific adult outcome such as marriage, occupation, length of schooling and ability to live independently is warranted.

Current status and long-term outlook

Based on the above-mentioned impact of initial involvement and treatment-related lesions of the hypothalamic–pituitary axis and optic structures on long-term morbidity and quality of survival, childhood-onset CP is indeed a chronic, noncurable disease. Whereas 20-year overall survival rate is high (0.88 ± 0.03), low progression-free survival (0.58 ± 0.05) [2] and low disease-free rate (<1%) in childhood-onset CP support the concept of CP as a chronic disease.

Key issues regarding the care of childhood-onset CP patients

At the time point of initial diagnosis, the decision about treatment strategy should be made by a multidisciplinary team within the context of recognized potential risk factors and a treatment plan for postoperative follow-up and rehabilitation. The multidisciplinary team should consist of state-of-the-art expertise on neurosurgery, neuroradiology, radiation oncology, endocrinology, neuropathology, neurology, ophthalmology and pediatric oncology.

Initial assessment and grading of hypothalamic tumor involvement and treatment algorithms aiming at hypothalamus-sparing surgical strategies [7,10,14–18] should be implemented by medical specialists using state-of-the-art methods and equipment.

In the case of hypothalamic involvement, gross total resection of CP should not be attempted.

As surgical expertise has been shown to have major impact on postoperative morbidity, medical societies should establish criteria of adequate professional expertise for the treatment and care of CP patients. Based on these criteria, health authorities should organize the certification of centers of excellence authorized for said treatment and care of patients with this disease.

Further research on molecular genetics in CP and neuroendocrine hypothalamic regulation of body composition and neuropsychological balance is imperative to foster novel treatment options for hypothalamic syndrome.

Due to the rareness of the disease, treatment of patients with CP should be performed in the context of multicenter national and international trials.

As nearly all patients experience chronic effects of the disease into adulthood, the transition from pediatric to internal medical care should follow common transition strategies of any chronic malady, with clinical and scientific collaboration between all physicians caring for these patients from childhood into adulthood.

In conclusion, it is my observation that patients suffering from this rare, chronic disease have a lifelong experience that brings with it valuable expertise regarding their situation. We as physicians should realize that we are not only obliged to provide knowledge and care but we are also privileged to share the individual experience of our patients living with this chronic disease.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgements

The author would like to thank all patients who have helped him and his team to better understand their medical, psychological and social needs. The author is grateful for the help of Mrs. Margarita Neff-Heinrich (Göttingen, Germany) in proofreading and editing the manuscript.

Additional information

Notes on contributors

Hermann L. Müller