Are You Sure the Patient Has a Craniopharyngioma?
Craniopharyngiomas are benign tumors which develop in the sellar/suprasellar region adjacent to the pituitary gland. Patients may be diagnosed years after the onset of symptoms due to the nonspecific and insidious nature of symptoms. Adult patients will often complain of headache, visual deficits resulting from mass effect on the optic nerves or chiasm, or signs of pituitary insufficiency. Symptoms in children are similar; parents may describe their child bumping into objects, or appearing clumsy, as a result of visual field deficits. There may be signs of delayed growth and development, or headache and lethargy if the tumor has grown to the point of causing obstructive hydrocephalus. There are 0.5 – 2.0 cases per million persons per year and cases are bimodal in distribution; 30 – 50% of cases are diagnosed during childhood, while the remainder develop in adults between 50 and 75 years of age.
What Else Could the Patient Have?
The differential diagnosis of sellar/peri-sellar lesions is broad including the following:
Rathke’s cleft cyst
Glioma (hypothalamic or optic tract)
Tumors of the sellar region can be difficult to differentiate radiographically, however, imaging may narrow the differential diagnosis based on enhancement patterns and the lesion’s relationship to the surrounding structures. Solid tumors originating within the pituitary gland are most likely pituitary adenomas; cystic lesions within the sella are usually Rathke’s cleft cysts. Combined cystic and solid lesions which are distinct from the pituitary are often craniopharyngiomas, which constitute the leading diagnosis in a child with a calcified sellar/suprasellar abnormality.
Masses isolated to the pituitary stalk are likely germinomas in children and may be inflammatory lesions or, rarely, metastatic carcinoma in adults. Inflammatory lesions (infundibulo hypophysitis) can mimic tumors in this location. In the suprasellar region, gliomas can rarely arise from the optic chiasm, while germinomas, hamartomas and gliomas arise from the hypothalamus. Dural-based lesions are usually meningiomas. Given the proximity to the carotid arteries, lesions emanating from the cavernous sinus and carotid canal may be vascular in origin, usually with a prominent flow void. Finally, lesions which arise inferior to the pituitary gland, especially in the bone of the clivus are often metastases or chordomas.
Pituitary adenomas are the most frequently encountered lesion of the sella and account or 10 percent of all intracranial tumors. They are classified into functioning (secretory tumors) or non-functioning tumors and are further defined by their cell of origin. Patients may present with the secondary sequelae of hormonal insufficiency or excess.
Cysts may develop as an isolated lesion or as part of a solid tumor, e.g., a pituitary adenoma. The most common simple cyst is the Rathke’s cleft cyst, often seen as an incidental finding. Rathke’s cleft cysts arise from remnants of normal developmental tissue of the pars intermedia and tuberalis. These cysts are benign, but may become symptomatic if they enlarge and compress surrounding structures. They can be difficult to differentiate radiographically from craniopharyngiomas. Arachnoid cysts develop after cerebrospinal fluid (CSF) collects between arachnoid planes and is trapped by a one-way valve. Treatment is surgical fenestration and obliteration.
Meningiomas arise from the sella (diaphragm or tuberculum) ultimately creating mass effect anterior or posterior to the pituitary stalk. Meningiomas often have uniform contrast enhancement and are rarely associated with cysts in this region. Compression of surrounding structures may lead to visual compromise or pituitary insufficiency.
Inflammation of the hypophysis may be secondary to an autoimmune process or tissue invasion from other inflammatory conditions, resulting in pituitary dysfunction and homogeneous enhancement on radiographic imaging. Lymphocytic hypophysitis should be considered in pregnant or post-partum female patients with enlargement of the pituitary gland. Sarcoidosis may occur in isolation in the pituitary; however, often it is associated with leptomeningeal or systemic disease.
Germinomas are germ-cell tumors primarily affecting patients < 20 years old. These lesions are most often seen in the pineal region, however, they may also arise in the suprasellar region and are amenable to radiotherapy. Teratomas, another germ cell tumor, make up 33–50% of fetal brain tumors and are associated with increased serum levels of carcinoembryonic antigen (CEA) and alpha feto protein (AFP).
Chordomas are slow growing malignant tumors that invade and destroy bone and other adjacent structures, usually of the midline clivus. They arise from the primitive notochord and affect adults 30 – 65 years of age. Chordomas heterogeneously enhance on radiographic imaging, and are often bright on T2 weighted imaging. Gliomas rarely arise from the optic nerve, chiasm, or hypothalamus. There is an increased risk of optic gliomas in patients with family history of neurofibromatosis type 1 (NF1). Decreased vision, proptosis, pituitary dysfunction, and headache associated with increased intracranial pressure have been associated with these lesions.
Carcinomas of the breast, lung, and prostate may rarely give rise to pituitary metastases. These tumors can present with diabetes insipidus and cranial neuropathies
Although rare, intracranial aneurysms may arise from the infra- and supra-clinoidal segments of the internal carotid artery. These lesions may cause visual impairment or pituitary dysfunction. These lesions may resemble tumors on radiographic imaging; therefore it is imperative to identify these lesions preoperatively. Lesions which appear to originate from the cavernous sinus or any suspicious lesion should be studied with a Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI) Angiography preoperatively.
Key Laboratory and Imaging Tests
Patients often first present to their primary care physician/pediatrician with symptoms of pituitary insufficiency and visual loss, prompting neuroendocrine, neuro-ophthalmologic, and radiographic evaluations.
Magnetic Resonance Imaging (MRI) of the brain with gadolinium is the imaging procedure of choice. It will often reveal an enhancing lesion of the sellar/suprasellar region, with considerable variability in signal intensity due to the solid and cystic components. Solid portions of the tumor enhance with contrast, cystic membranes appear T1 iso-intense or may enhance, and intra-cystic component may be hypo-, iso- or hyper-intense depending on protein content. A CT of the brain without contrast is helpful to identify calcifications seen in over 90% of craniopharyngiomas.
Hypothalamic-pituitary dysfunction may occur due to mass effect and compression of the pituitary gland. Anterior pituitary gland dysfunction occurs more commonly than posterior gland dysfunction but both may be seen. Patients often have decreased growth hormone (75% cases), gonadotropins (40% cases), adrenocorticotropic hormones (25% cases), Thyroid Stimulating Hormone (TSH) and free thyroxin (25% cases) and diabetes insipidus. Children with craniopharyngiomas may have delayed growth and sexual development, while adults have low gonadotropin levels in combination with other deficiencies.
Other Tests That May Prove Helpful Diagnostically
If not completed as part of the initial diagnostic evaluation, a complete ophthalmologic exam is invaluable to document baseline visual abnormalities as monitoring for progression may prompt further treatment.
Both disease and treatment, especially in children, may impair cognitive development. It is important to assess both at presentation and after treatment so that early intervention, if necessary, can be undertaken.
Craniopharyngiomas are described islands of squamous epithelial cells often with calcification, keratin and cysts interwoven on H&E staining. The important pathological distinction, sometimes difficult, is between craniopharyngiomas and Rathke’s cleft cysts, as the distinction carries prognostic significance regarding recurrence risk and need for further treatment.
There are two subtypes of craniopharyngiomas, adamantinomatous and papillary. Adamantinomatous craniopharyngiomas are the most common pituitary-related tumor in childhood, with a peak incidence in children under 15 and a second peak of incidence in adults 50 to 74 years. Genetic analysis has shown that β-catenin gene mutations are a hallmark feature of nearly all adamantinomatous subtypes, distinguishing them from the papillary craniopharyngiomas which lack these mutations. Genotyping of the papillary subtype, which occurs predominantly in adults, has shown that these tumors harbor the BRAF V600E mutation.
Management and Treatment of the Disease
Primary treatment remains surgical excision, but the extent of attempted excision and its possible combination with postoperative radiotherapy have led to considerable debate in the literature over the years. With high survival rates and predominance of the pediatric subgroup, the sequelae of treatment can impact the quality of life profoundly.
Careful pre- and intraoperative evaluation of the tumor’s relationship to the optic chiasm, carotid arteries, pituitary gland and hypothalamus should guide the extent of resection. A gross total surgical resection, once considered curative, has been recently reported to have a 35% recurrence rate. Given the low malignancy of these tumors, current treatment strategies aim for gross total surgical resection when safe, with a low threshold for subtotal removal followed by post-operative radiotherapy. For example, tumors which infiltrate the hypothalamus should be limited to subtotal resection and decompression of the optic apparatus followed by radiotherapy in order to minimize morbidity.
Small craniopharyngiomas often have distinct boundaries from surrounding structures, which affords a surgical plane amenable to resection. In contrast, larger lesions are both more difficult to approach and more difficult to mobilize during surgery, given their location extending into the hypothalamus and third ventricle and likely adherence to these structures. This will decrease the likelihood of a gross total resection, and increase the risk of damaging surrounding structures. In these circumstances, a subtotal resection directed at decompression of the optic apparatus and debulking the tumor for subsequent radiotherapy should be the primary objective of the surgery. The tumor can be approached either transsphenoidally, if the tumor is primarily intrasellar or encapsulated suprasellar, or via a craniotomy if there is significant intracranial extension with a relatively normal sella.
While stereotactic radiotherapy is usually used as adjuvant therapy for subtotal resection or recurrence, it has also been used as primary therapy for small lesions. It is imperative to minimize dose to the surrounding hypothalamus, especially in younger patients. Where available, proton therapy provides more conformal therapy utilizing the Bragg peak to maximize targeted therapy while minimizing side effects. After subtotal resection, radiotherapy decreases the likelihood of progression. In a recent study, patients with subtotal resection had progression in 21% with subsequent radiotherapy as opposed to 71-90% with surgery alone. The management of recurrent craniopharyngioma cysts can be problematic. Repeat aspiration or transsphenoidal drainage may be necessary; while radiation may halt cyst recurrence, its effects are not immediate. Placement of indwelling cyst drainage catheters and the use of instilled P32 has been beneficial in some cases. Surveillance imaging (MRI) is imperative to monitor for tumor recurrence or growth after treatment at 6 – 12 month intervals. Whether subtotal or gross resection, craniopharyngiomas may recur, and the decision for additional surgical resection or radiotherapy depends on the age of the patient, location of the recurrent tumor, and any mass effect. Repeat surgery can be complicated by scar formation from previous surgery and response to radiation therapy, increasing the complexity of resection and decreasing the likelihood that the tumor may be separated from adjacent structures.
Beyond surgery and radiation, medical therapy has recently been used to target the BRAF V600E oncogenic driver of adult papillary craniopharyngiomas. A patient with rapidly recurrent papillary craniopharyngioma with this genomic profile was treated with oral RAF inhibitor, dabrafenib, as well as trametinib, a MEK inhibitor shown in melanoma studies to enhance the effects of BRAF inhibition. This patient had a dramatic response to this therapy, whereby enhancing tumor volume had been reduced by 85% and tumor-associated cyst had been reduced by 81%. This finding has opened the possibilty of treating patients with some papillary craniopharyngiomas with targeted medical therapy.
While there exists controversy over the best management of craniopharyngiomas, the decision as to the extent of attempted resection (complete or subtotal) with or without adjuvant therapies is complex, requiring a multi-disciplinary approach. The potential for short and long term significant side effects of surgery and radiotherapy must be carefully weighed. A retrospective study of children with craniopharyngioma identified a 9.8-point loss in full-scale intelligence quotient after complete resection compared with 1.25-point loss after limited resection followed by irradiation.
Further demonstrating the complexity of repeat surgery, there was a 13.1-point loss after repeat surgical intervention. Endocrinological dysfunction both pre- or post-operatively must be carefully assessed. Given the proximity to the pituitary and hypothalamus, patients are at risk for hormonal insufficiency, eating disorders, sleep dysfunction, obesity, and behavioral problems. Patients should be closely monitored for recurrence with interval MRIs.
What’s the Evidence?/References
Freda, PU, Post, KD. “Differential diagnosis of sellar masses”. Pituitary. vol. 28. 1999. pp. 81-117. (A good review of sellar masses.)
Bunin, GR, Surawicz, TS, Witman, PA, Preston-Martin, S, Davis, F, Bruner, JM. “The descriptive epidemiology of craniopharyngioma”. Neurosurg Focus. vol. 3. 1997. pp. e1(A good review of the background and epidemiology of craniopharyngioma.)
Muller, HL. “Childhood craniopharyngioma”. Pituitary. vol. 14. 2013. pp. 56-67. (A detailed review of the complexity in the treatment decisions in craniopharyngioma.)
Al-Brahim, NY, Asa, SL. “My approach to pathology of the pituitary gland”. J. Clin. Pathol. vol. 59. 2006. pp. 1245-53. (A comprehensive paper outlining the pathological diagnosis of tumors of the pituitary gland.)
Sekine, S, Shibata, T, Kokubu, A, Morishita, Y, Noguchi, M, Nakanishi, Y, Sakamoto, M, Hirohashi, S. “Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations”. Am J Pathol. vol. 161. 2002. pp. 1997-2001.
Brastianos, PK, Taylor-Weiner, A, Manley, PE, Jones, RT, Dias-Santagata, D, Thorner, AR, Lawrence, MS, Rodriguez, FJ, Bernardo, LA, Schubert, L, Sunkavalli, A, Shillingford, N, Calicchio, ML, Lidov, HG, Taha, H, Martinez-Lage, M, Santi, M, Storm, PB, Lee, JY, Palmer, JN, Adappa, ND, Scott, RM, Dunn, IF, Laws, ER, Stewart, C, Ligon, KL, Hoang, MP, Van Hummelen, P, Hahn, WC, Louis, DN, Resnick, AC, Kieran, MW, Getz, G, Santagata, S. “Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas”. Nature genetics. vol. 46. 2014. pp. 161-165. (Hallmark papers on the characteristic mutations of craniopharyngioma subtypes.)
Veeravagu, A1, Lee, M, Jiang, B, Chang, SD. “The role of radiosurgery in the treatment of craniopharyngiomas”. Neurosurg Focus. vol. 28. pp. E11
Kiehna, EN1, Merchant, TE. “Radiation therapy for pediatric craniopharyngioma”. Neurosurg Focus. vol. 28. pp. E10(Good reviews of the various radiation strategies for craniopharyngioma.)
Karavitaki, N. “Management of craniopharyngiomas”. J Endocrinol Invest. vol. 37. 2014. pp. 219-28. (A good review of the treatments strategies for craniopharyngioma.)
Muller, HL. “Craniopharyngioma”. Endocr Rev. vol. 35. 2014. pp. 513-43. (A comprehensive review of craniopharyngiomas, the treatment, and the literature.)
Mortini, P, Losa, M, Pozzobon, G, Barzachi, R, Riva, M, Acerno, S, Angus, D, Weber, G, Chumell, G, Giovanelli, M. “Neurosurgical treatment of craniopharyngioma in adults and children: early and long-tern results in a large case series”. J Neurosurg. vol. 114. 2011. pp. 1350-1359. (Early and long-term results of a large case series of patients with craniopharyngioma in both adults and children.)
Brastianos, PK, Shankar, GM, Gill, CM, Taylor-Weiner, A, Nayyar, N, Panka, DJ, Sullivan, RJ, Frederick, DT, Abedalthagafi, M, Jones, PS, Dunn, IF, Nahed, BV, Romero, JM, Louis, DN, Getz, G, Cahill, DP, Santagata, S, Curry, WT, Barker, FG. “Dramatic Response of BRAF V600E Mutant Papillary Craniopharyngioma to Targeted Therapy”. J Natl Cancer Inst. vol. 108. 2015.
Aylwin, SJ, Bodi, I, Beaney, R. “Pronounced response of papillary craniopharyngioma to treatment with vemurafenib, a BRAF inhibitor”. Pituitary. 2015. (Case reports of novel use of targeted medical therapy for papillary craniopharyngiomas.)
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