1. Craniopharyngiomas Niki Karavitaki, Simon Cudlip, Christopher B. T. Adams and John A. H. Wass Department of Endocrinology (N.K., J.A.H.W.), Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; and Department of Neurosurgery (S.C., C.B.T.A.), Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom Endocrine Review, June 2006, 27(4): 371-397

2. Craniopharyngiomas are rare tumors with an overall incidence of 0.13 cases per 100,000 person-years. They account for 2–5% of all the primary intracranial neoplasms and 5.6–15% of the intracranial tumors in children. Although they are the commonest lesions to involve the hypothalamopituitary region in childhood populations, almost half of the total cases are diagnosed in adults. They may be detected at any age, even in the prenatal and neonatal periods, and a bimodal age distribution has been shown, with peak incidence rates in children of ages 5–14 yr and adults of ages 50–74 yr. In population-based studies from the United States and Finland, no gender differences have been found. Craniopharyngioma cases have been reported within two families, but it is not as yet clear whether there is any underlying genetic susceptibility. This seems unlikely with the numbers involved. Epidemiology

3. FIG. 1. Adamantinomatous craniopharyngioma. A, The epithelium consists of palisaded basal layer of cells (arrowhead), the intermediate stellate reticulum, and a layer of flattened, keratinized squamous cells. Nodules of "wet" keratin (arrow) are a distinctive feature (HE. x 10). B, Gliotic reaction rich in Rosenthal fibers (arrow) in the surrounding parenchyma (HE. x 40). [Courtesy of Dr O. Ansorge, Neuropathology Department, Radcliffe Infirmary, Oxford, UK.].

4. FIG. 2. Papillary craniopharyngioma. The characteristic epithelium in this histological type consists of mature squamous epithelium forming pseudopapillae downward into the underlying tissues. The absence of adamantinomatous epithelium and keratinizing nodules is characteristic (A, HE. x 5; B, HE. x 20). [Courtesy of Dr. O. Ansorge, Neuropathology Department, Radcliffe Infirmary, Oxford, UK.].

5. Feature Gross pattern of epithelium Keratin Keratohyaline granules Mucinous cells Ciliated cells Hyalinized stroma Calcification Necrosis Cholesterol Adamantinomatous craniopharyngioma Complex adamantinomatous Billowy 'wet' keratin forming discrete nodules Absent Rare Absent Frequent Papillary craniopharyngioma Papillary squamous Individual cells, nodules of keratinized cells Absent Frequent Rare Frequent Rare Absent Rare Rathke’s cleft cyst Simple columnar or cuboidal; focally squamous 1 Absent Frequent Absent Epidermoid cyst Stratified squamous Flaky, laminated Frequent Absent TABLE 1. Comparative pathological features of craniopharyngiomas and related lesions

6. No. of patients 57 67 241 74 61 56 121 122 75 119 Age (yr) All < 16 38 < 18 All < 21 26 < 19 32 ≦ 16 29 < 16 All <16.4 41 < 16 Ref. 12 96 40 86 145 44 89 90 15 74 Range Headache (%) 81 66 78 50 77 7 adults, 15 children 74 53 65 56 adults, 78 children 7–81 Nausea/vomitin g (%) 68 37 34 43 21 49 26 adults, 54 children 21–68 Papillo- edema (%) 53 31 25 29 10 16 32 6 adults, 29 children 6–53 Cranial nerves palsy (%) 6 20 8 children 2 3 15 9 adults, 27 children 2–27 Ataxia/un steadiness (%) 18 17 3 adults, 7 children 3–18 Cognitive dysfunction (%) 1 3232 36 20 adults, 8 children 10 13 17 adults, 10 children 3–36 Decreased consciousness/co ma (%) 7 3 29 8 16 4 adults, 10 children 3–29 Optic atrophy (%) 20 15 40 14 adults, 5 children 5–40 Visual field defects (%) 58 35 71 3 72 59 4 60 adults, 54 children 62 79 44 60 adults, 46 children 35–79 1 Memory loss, confusion, disorientation. TABLE 2A. Most common presenting clinical manifestations of craniopharyngiomas in children and adults

7. No. of patients 57 67 241 74 61 56 121 122 75 119 Age (yr) All < 16 38 < 18 All < 21 26 < 19 32 16 29 < 16 All < 16.4 41 < 16 Ref. 12 96 40 86 145 44 89 90 15 74 Range Decreased visual acuity or visual deterioration (%) 58 47 adults, 50 children 62 80 47 40 adults, 39 children 39–80 Growth failure 1 (%) 39 7 (42% with retarded bone age) 93 25 8 17 45 33 32 7–93 Failure of sexual development 1 (%) 20 (of pubertal children) 4 14 5 24 4–24 Hypo- gonadism (adults) (%) 85 10 40 28 10–85 Poor energy (%) 23 32 adults, 22 children 22–32 Somnolence (%) 9 20 10 adults, 5 children 5–20 Anorexia/poor weight gain or weight loss (%) 31 8 adults, 20 children 8–31 Obesity or weight gain (%) 4 children 8 15 13 adults, 5 children 4–15 Polyuria/p olydipsia (%) 9 12 6 23 13 3 adults 12 18 28 15 adults, 15 children 3–28 TABLE 2B.

8. No. of patients 42 74 61 35 75 143 18 121 Age (yr) All ≦ 17.2 38 < 18 All < 21 13 < 19 All < 16.3 30 < 16 No age range reported 42 < 16 Ref. 205 86 145 87 204 88 190 74 Range GH deficiency 13/18 (72) 12/34 (35) 27/35 (77) 13/15 (87) 59/82 (72), 17/23 in children (74) 7/18 (39) 21/22 (95), 15/15 in children (100) 35–100 FSH/LH deficiency 1 3/8 (38) 27/33 (82) 3/6 (50) 96/143 (77), 10/11 in children (91) 10/18 (56) 40/54 (74) 2 38–91 ACTH deficiency 4/17 (24) 18/74 (24) 7/34 (21) 12/35 (34) 16/50 (32) 45/143 (32), 8/30 in children (27) 9/18 (50) 40/65 (62), 15/22 in children (68) 21–68 TSH deficiency 7/29 (24) 31/74 (42) 7/34 (21) 13/35 (37) 20/62 (32) 35/143 (25), 6/30 in children (20) 7/18 (39) 29/81 (36), 7/28 in children (25) 20–42 Hyper-prolactinemia 7/29 (24) 12/37 (32) 59/143 (41), 5/30 in children (17) 6/18 (33) 24/44 (55) 2 17–55 DI 4/24 (17) 8/74 (12) 8/34 (23) 13/35 (38) 22/75 (29) 23/143 (16), 3/30 in children (10) 1/18 (6) 19/104 (18), 7/32 in children (22) 6–38 TABLE 3. Pituitary hormone deficits and hyperprolactinemia at presentation in children and adults with craniopharyngioma

9. FIG. 3. Skull x-ray film: craniopharyngioma causing enlarged sella with sellar destruction and suprasellar flocculonodular calcification. [Reprinted from A. S. Kashyap: Postgrad Med J 76:513–514, 2000 with permission from the BMJ Publishing Group.].

10. FIG. 4. Axial unenhanced (A) and contrast-enhanced (B) CT demonstrating an inhomogeneously enhancing soft-tissue mass (straight arrows) in the suprasellar cistern extending into the third ventricle. Specks of calcium (curved arrows) and small cysts are also shown. [Reprinted with permission from O. P. Eldevik et al.: Am J Neuroradiol 17:1427–1439, 1996. © American Society of Neuroradiology.]

11. FIG. 5. Axial CT brain demonstrating a suprasellar lesion with coarse calcification and dilatation of the temporal horns of the lateral ventricles. [Reprinted from D. R. Warakaulle and P. Anslow: Clin Radiol 58:922–933, 2003, with permission from the Royal College of Radiologists.]

12. FIG. 6. Sagittal T 1 -weighted MRI noncontrast (A) and contrast-enhanced (B) showing an intra-/suprasellar craniopharyngioma with a hyperintense cystic peripherally enhancing mass and a small solid inhomogeneously enhancing portion. [Reprinted with permission from S. Sartoretti-Schefer et al.: Am J Neuroradiol 18:77–87, 1997. © American Society of Neuroradiology.]

13. FIG. 7. Sagittal noncontrast (A) and contrast-enhanced (B) T 1 -weighted MRIs demonstrating a hypointense suprasellar tumor with peripherally enhancing cystic areas and an inhomogeneously enhancing solid tumor part. [Reprinted with permission from S. Sartoretti-Schefer et al.: Am J Neuroradiol 18:77–87, 1997. © American Society of Neuroradiology.]

14. FIG. 8. Unenhanced (A) and contrast-enhanced (B) sagittal T 1 -weighted MRIs showing an intra-/suprasellar multilobular cystic craniopharyngioma (straight arrows) with areas of calcification (curved arrows). [Reprinted with permission from O. P. Eldevik et al.: Am J Neuroradiol 17:1427–1439, 1996. © American Society of Neuroradiology.]

15. FIG. 9. Nonenhanced (A) and contrast-enhanced (B) coronal T 1 -weighted MRIs demonstrating an intra-/suprasellar craniopharyngioma extending into the third ventricle (two-toned arrows) with multiple calcifications (curved arrows) and small cysts (white arrows). [Reprinted with permission from O. P. Eldevik et al.: Am J Neuroradiol 17:1427–1439, 1996. © American Society of Neuroradiology.]

16. DiagnosisCharacteristics on CT and/or MRI Rathke’s cleft cystSmall, round, purely cystic lesion lacking calcification (58 ). On CT, typically a homogeneous, hypodense mass, which usually does not enhance. The MRI signal returned by the cyst is variable depending on its content [that of CSF or of a protein- rich fluid or of altered hemorrhage (113 115 )]. Some contain a nonenhancing intracystic proteinaceous nodule thought to be indicative of the diagnosis (249 ). Dermoid cystOn CT, round or lobulated, often with negative density values and foci of calcification; no contrast enhancement or surrounding edema. On T 1 -weighted MRI, high signal, due to the lipid content (250 ). Epidermoid cystOn CT, a lobulated mass with attenuation values similar to CSF. Calcification may be present. The MRI signal characteristics are usually similar to CSF. It does not enhance (250 ). Pituitary adenomaOn CT, macroadenomas are isodense or hypodense relative to brain tissue with variable patterns of enhancement after contrast administration. Calcification may be seen occasionally. On MRI, they have homogeneous low intensity on T 1 -weighted images and homogeneous enhancement after contrast administration that is less intense than the enhancement in the adjacent pituitary. Cysts or areas of necrosis cause foci of moderate hypointensity on T 1 - and hyperintensity on T 2 -weighted sequences, and heterogeneous enhancement with gadolinium. Hemorrhage in the subacute or chronic phase shows high signal on T 1 -weighted images. On CT, microadenomas show little inherent contrast to the normal pituitary tissue, and iv contrast demonstrates nonenhancement against a background of normal gland enhancement. On MRI, they are hypointense on T 1 -weighted sequences, and this contrast may or may not be amplified after gadolinium (113 249 ). TABLE 4. Differential diagnosis of craniopharyngioma in CT or MRI

17. GerminomaOn CT, well-delineated masses, usually hyperdense on noncontrast scans. Calcification is common. Most cases show strong homogeneous enhancement. On MRI, isointense on T 1 -weighted images and iso-to-hyperintense on T 2 -weighted images. Enhancement is intense and often heterogeneous (251 ). HamartomaTypically, a pedunculated mass, isodense on CT and isointense on MRI, relative to gray matter. It does not calcify or enhance after administration of contrast media (113 ). Suprasellar aneurysmOn unenhanced CT, slightly denser than the cerebral tissue, or if a large clot is present, substantially denser; it shows enhancement after contrast administration. On MRI, flowing blood within the aneurysm usually has a characteristic 'signal void,' often associated with regions of high signal intensity on T 1 -weighted images, suggesting blood. The presence of a clot or turbulent flow within the aneurysm may create a variety of different patterns. Angiography will confirm the diagnosis (249 252 ). Arachnoid cystCystic lesion with a clearly defined border. The density on CT and the signal intensity on MRI are similar to that of the CSF. It does not show calcification and does not enhance after contrast administration (113 ). Suprasellar abscessOn CT, a central area of hypodensity surrounded by a ring of increased density, which shows marked enhancement after iv contrast material. On MRI, the T 1 - weighted images show a marked hyperintense lesion with significant enhancement of the abscess wall after contrast administration. The T 2 -weighted scans show hyperintensity of the abscess contents surrounded by an area of increased signal intensity indicating edema (253 ).

18. Langerhans cell histocytosisHypothalamus and pituitary are frequent sites of involvement, showing enhancing mass lesions on CT or bright, gadolinium- enhancing areas on MRI. An enhancing, thickened infundibulum may also be seen (252 254 ). SarcoidosisOn CT, isodense lesion with contrast enhancement and generally without surrounding edema or calcification. On MRI, more variable appearance, but usually hyperintense on T 2 -weighted images (113 254 ). TuberculosisOn contrast-enhanced CT, an enhancing mass with hypodense central necrosis and hypodense surrounding edema. A T 1 gadolinium- enhanced MRI scan shows a strong rim enhancement, whereas a T 2 gadolinium-enhanced scan shows hyperintense vasogenic edema, hypointense granuloma ring, and a hyperintense central necrosis (253 ). Hypothalamic or optic pathway glioma On MRI, sharply marginated homogeneous suprasellar mass, clearly separate from the pituitary gland. Usually hypointense or isointense with gray matter and may or may not enhance. It is rarely calcified and usually lacks a cystic component (249 255 ). MeningiomaOn CT, isodense to slightly hyperdense dural-based lesion, with homogeneous enhancement after contrast administration. Minimal to extensive peritumoral edema and calcification may be present (256 ). On MRI, usually an isointense with gray matter lesion in both T 1 - and T 2 -weighted images. It shows dense uniform enhancement after contrast administration. Typical are the presence of a thickened dura in the region of the meningioma ('dural tail sign'), bony hyperostosis adjacent to the lesion, and normal sellar dimensions (249 ).

19. Recurrence rates at 10-yr follow-up (%) RTRT 2323 0 Surgery + RT Adults 51, children 22 (SR, PR, biopsy + aspiration) 23 (biopsy or aspiration), 12 (PR or SR), 0 (GTR) 14 (biopsy-aspiration-VP shunt-combination of the above-SR-GTR) 63 (SR) Details of RT Mean dose adults: 5700 rads (4000–6900) in 4–8 wk; children: 5500 rads (5000–6000) in 5–7 wk Median dose: 56 Gy (6–70) in 24–34 daily fractions (32% of patients) in 5–7 wk; 50 Gy (50–56) in 30–33 daily fractions (68% of patients) in 6–7 wk Median dose: 5464 cGy (5040–6598) in 180–200 cGy/d fractions over a median of 43 d (31–55) 5000–5500 cGy, no further details reported Median dose: 50 Gy (40–60) Ref. 107 1 132 2 145 3 44 4 123 5 118 6 111 7 No. of patients 109 173 61 56 57 73 115 Age (yr) 43 < 16 77 < 16 All 21 26 < 21 7 < 18 All < 16.4 29 Children GTR Adults 84, children 53 17 0 22 19 Limited surgery (PR/SR) Adults 90, children 93 (SR) 69 (SR + GTR) 50 (SR) 33 (SR), 25 (PR) 72 51 (SR), 84 (PR) Follow-up period, follow- up duration (range) 1950–1977, no data on follow-up duration 1950–1986, median 12 yr (0.08–35) 1970–1990, median 10 yr (2–20.5) 1981–1991, mean 49 months (7–187) No data on follow-up period, mean 6.5 yr (2.5– 15.5) 1973–1994, mean 6.5 yr 1983–1997, median 55.5 months (0.07–175) TABLE 5. Recurrence rates in patients with craniopharyngioma treated by various modalities

20. 19 62 26 34 53 0 59 (SR) 49 (SR), 77 (PR) 100 78 at 2.5 yr (SR) 62 (PR) 89 8 133 90 9 143 144 10 74 11 Ref. 121 36 122 25 71 103 No. of patients 31 ≦ 16 All < 16 29 < 16 All < 16 All 1.5–24.8 37 < 16 Age (yr) Recurrence rates at 10-yr follow-up (%) Mean dose: 5381 rads (4400– 6480) No details of RT reported Median dose: 54 Gy (44–55.8) Median dose: 5000 cGy (4000– 5400, apart 1 patient with 3500), 25–30 fractions (apart 2 patients with 13 fractions) Details of RT 1974–1991, no data on follow-up duration 1986–1998, 52 months (1–149) 1975–2000, 7 yr (0.4 month–21 yr) 1983–1996, median 10 yr (3–16) 1974–2001, median 7.6 yr 1964–2003, mean 94 months (0.3– 468) Follow-up period, follow-up duration (range) GTR 10 (SR) 16 (SR) 0 (GTR), 23 (PR) Limited surgery (PR/SR) Surgery + RTRT TABLE 5. Recurrence rates in patients with craniopharyngioma treated by various modalities

21. FIG. 10. Treatment algorithm for craniopharyngiomas