www.elsevier.com/locate/jocn

Journal of Clinical Neuroscience 13 (2006) 438–442

Clinical study

Recurrence in craniopharyngiomas: Analysis of clinicaland histological features

Deepak Kumar Gupta a, B.K. Ojha a, Chitra Sarkar b, A.K. Mahapatra a,*, V.S. Mehta a

a Department of Neurosurgery, All India Institute of Medical Sciences, C.N. Centre, Ansari Nagar, New Delhi 110029, Indiab Department of Neuropathology, All India Institute of Medical Sciences, C.N. Centre, Ansari Nagar, New Delhi, India

Received 16 December 2004; accepted 5 May 2005

Abstract

The aim of this study was to investigate the recurrence patterns and significance of various clinical and histological features as pre-dictors of recurrence in craniopharyngiomas. A series of 234 craniopharyngiomas (156 males, 78 females; age range 1.6–65 years) wasreviewed. The mean follow-up period was 18.53 months (range 1–120 months). Peri-operative mortality was 7.4% and tumor recurrencewas observed in 26 patients (20.3%). Of the patients with recurrence, one had total tumor excision (recurrence-free survival (RFS) 14months), four had near-total excision (mean RFS 18.2 months) and 21 had subtotal tumor excision (RFS for symptomatic recurrence7.1 months). Histologically, an adamantinous pattern was seen in 81.4% of cases and a papillary pattern was seen in 18.6%. Brain tissuewas included in 67 cases and brain invasion was noted in 44 (all were of adamantinous histology). No correlation was noted betweenhistopathological subtyping or brain invasion and recurrence. The significant clinical factors predictive of recurrence included the extentof resection, tumor size greater than 4 cm and cystic tumors.� 2006 Elsevier Ltd. All rights reserved.

Keywords: Brain invasion; Craniopharyngioma; Histopathology; Radiotherapy; Recurrence; Recurrence-free survival

1. Introduction

Tumor recurrence is the most common problem of allforms of therapy for craniopharyngiomas. Despite radicalexcision, recurrence rates of 5–57% have been reported inmost large series of craniopharyngiomas.1–4 In contrastto some other central nervous system (CNS) tumors, con-troversy exists regarding the importance of histopatholo-gical factors (subtype, brain invasion) as predictors ofrecurrence and clinical outcome in patients with cranio-pharyngiomas.1,2,5–7 Histopathological examination of re-sected craniopharyngioma specimens frequently revealsisolated nests of tumor cells extending into, and apparentlyinvading, the surrounding gliotic brain tissue.5,8,9 The prog-nostic significance of microscopic brain invasion by these is-

0967-5868/$ - see front matter � 2006 Elsevier Ltd. All rights reserved.

doi:10.1016/j.jocn.2005.05.013

* Corresponding author. Tel.: +91 11 2659 4915/6594577; fax: +91 112658 9450/6862663.

E-mail address: akmahapatra_22000@yahoo.com (A.K. Mahapatra).

lands of tumor cells has not been analysed, although somehave suggested that this feature accounts for recurrence intumors otherwise thought to be totally resected.1,3,5,9 Thepresent study was undertaken to determine the significanceof various histopathological factors, in addition to severalclinical variables, as independent predictors of recurrencein patients with craniopharyngioma.

2. Methods

A total of 234 patients with craniopharyngioma (118adults and 116 children; age range 1.6–65 years) were oper-ated on over a period of 10 years. These patients were sub-sequently reviewed.

3. Results

The duration of symptoms ranged from 10 days to 7years (mean 11.3 months). Of 128 patients (67 children

Table 2Craniopharyngioma: radiological features

Radiology No.patientsa

Recurrence(n = 26)

Recurrence-free(n = 102)

p-value

Calcification 52/128 13/26 (50%) 39/102 (38.2%) 0.40Hydrocephalus 41/128 9/26 (34.6%) 34/102 (33%) 0.07Cystic tumor 36/128 14/26 (54%) 22/102 (21.6%) <0.001Tumor size (>4 cm) 44/128 15/26 (58%) 39/102 (38%) 0.01

a Patients with >6 months follow-up.

D.K. Gupta et al. / Journal of Clinical Neuroscience 13 (2006) 438–442 439

and 61 adults) who were followed up for more than 6months (mean follow-up, 46.5 months; range, 6–120months), 26 patients (20.3%), comprising 15 children and11 adults, had tumor recurrence at a mean of 96 months(range, 6.5 months–8 years). In the recurrence group, onepatient had complete tumor excision (recurrence-free sur-vival (RFS) 14 months), four patients had near-total exci-sion (of which, one patient received radiotherapy in viewfor small residual lesions seen on a postoperative computedtomography (CT) scan; mean RFS 18.2 months) and 21 pa-tients had subtotal tumor excision (of which, 12 patients re-ceived radiotherapy; mean RFS 9.0 months). All 21patients in the subtotal excision group had evidence of tu-mor progression on postoperative radiology and exhibitedsymptom recurrence after an average postoperative periodof 7.1 months. Recurrence was noted in 19 patients within1–5 years; three cases had tumor recurrence after 5 yearsand recurrence was reported in four cases 6–12 monthsafter surgery. Only one of 19 patients (5.3%) with total tu-mor excision developed recurrence 14 months after surgery.Recurrence-free survival was found to be better in patientswho had near-total tumor excision (18.2 months) com-pared with patients who had subtotal tumor excision andshowed symptomatic recurrence (7.1 months). Recurrencewas less often seen after radiotherapy in both the near-totalexcision and subtotal excision groups (16.6% and 16.9% ofcases, respectively; Table 1).

3.1. Radiological evaluation

Sixty-one per cent (142/234) of tumors were solid-cysticand 30% (70/234) were predominantly cystic. There wereno statistically significant differences between the recur-rence and recurrence-free groups in terms of the locationof the tumor, the presence/absence of hydrocephalus andcalcification (tumor calcification was noted in 50% of pa-tients (13/26) in the recurrence group and in 38.2% of pa-tients (39/102) in whom recurrence was not observed;Table 2). Recurrence was found to be significantly associ-ated with cystic tumors (54% (14/26) vs. 22% (22/102) inthe recurrence and recurrence-free groups, respectively;p < 0.001) and tumor size greater than 4 cm (58% (15/26)

Table 1Role of extent of resection and radiotherapy in recurrence of craniopharyngio

Treatment given Total patientsa (n = 128) Rec

Total resection 19/128 (14.8%) 1/19Post-op RT given 0 0Post-op RT not given 19 1/19

Near total resection 14/128 (10.9%) 4/14Post-op RT given 6 (42.9%) 1/6Post-op RT not given 8 (57.2%) 3/8

Subtotal resection 95/128 (74.2%) 21/9Post-op RT given 71 (74.7%) 12/7Post-op RT not given 24 (24.3%) 9/24

Post-op RT = postoperative radiotherapy.a Patients with >6 months follow-up.

vs. 38% (39/102) in the recurrence and recurrence-freegroups, respectively; p = 0.01; Table 2).

3.2. Histopathological evaluation

Of the 234 cases, histopathological slides were availablefor review in 214 cases. Of these, 176 (82.2%) were adaman-tinous tumors (Fig. 1a) and 40 (18.7%) were papillary tu-mors (Fig. 1b). Brain invasion was defined as the presenceof an isolated nest of tumor cells surrounded on all sidesby normal gliotic brain tissue and separate from the remain-der of the tumor (Fig. 1c, d). Tumor removal was consid-ered complete if the surgeon was convinced that there hadbeen complete tumor removal and if postoperative imagingshowed no evidence of residual tumor (Fig. 2). Tumorrecurrence was defined as deterioration of neurological sta-tus during follow up, with occurrence of a radiologicallydetectable tumor or growth of the tumor on follow up CTor magnetic resonance imaging (MRI) scans even withoutneurological deterioration. Brain tissue was included inthe surgical specimen in 67 cases, more so in patients withtotal and near-total tumor resection than in patients whohad subtotal or partial tumor excision (51.3% (20/39) vs.35.0% (57/163), respectively). Brain invasion was noted in44 cases in which brain tissue was included and all wereof adamantinous histology. Brain invasion was noted inmore patients in the recurrence group than in the recur-rence-free group (35% (9/26) vs. 11.8% (12/102), respec-tively). Although the inclusion of brain tissue wascommon in the group with recurrence, following statisticalanalysis, the presence or absence of brain tissue or braininvasion was not found to influence recurrence (p = 0.21;

ma

urrence (n = 26) Recurrence-free (n = 102) p-value

(5.3%) 18/19 (94.7%) <0.010

(5.2%) 18/19 (94.8%)

(28.6%) 10/14 (71.4%) 0.04(16.7%) 5/6 (83.3%)(37.5%) 5/8 (62.5%)

5 (22.1%) 74/95 (77.9%) 0.031 (16.9%) 59/71 (83.1%)(37.5%) 15/24 (62.5%)

Fig. 2. (a, b) Pre-operative magnetic resonance image (MRI) of a patient with adamntinous craniopharyngioma with brain invasion on histopathologicalexamination. Sagittal (a) and coronal (b) T1-weighted MRI with contrast (c, d) Postoperative MRI showing no recurrence after 18 months after completetumor excision. Sagittal (c) and coronal (d) T1-weighted MRI with contrast.

Fig. 1. (a) Photomicrograph of an adamantinous craniopharyngioma showing ghost cells (single arrow) and calcification (double arrow). Haematoxylinand eosin (H&E) stain; original magnification · 400. (b) Craniopharyngioma showing a papillary pattern of growth (arrow); H&E, original magnification· 200. (c) Brain invasion by craniopharyngioma (arrow); H&E, original magnification · 200. (d) Brain invasion by craniopharynigoma showing rosenthalfibers (arrow) around areas of invasion; H&E, original magnification · 400.

Table 3Role of histopathology in recurrence of craniopharyngioma

Histopathology Recurrence(n = 26)

Recurrence-free(n = 102)

p-value

HistopathologyAdamantinous 19 (73%) 87 (85%) 0.07Papillary 7 (27%) 15 (14.5%) 0.04

Brain tissue seen 17/26 (65%) 26/102 (25%) 0.08Brain invasion seen 9/26 (35%) 12/102 (11.8%) 0.21

440 D.K. Gupta et al. / Journal of Clinical Neuroscience 13 (2006) 438–442

Table 3). Inclusion of brain tissue in biopsy specimens ofpatients with papillary craniopharyngioma was very low(8 of 40 papillary tumors; 20%). Surprisingly, none of thecases of papillary craniopharyngioma showed evidence ofbrain invasion.

4. Discussion

Fahlbusch et al.,3 in their series of 148 craniopharyngio-mas, reported predominantly solid and cystic tumors in39.2% and 49.3% of cases, respectively. The majority of tu-mors in the present study (64%) were mixed (solid and cys-tic), whereas 30% were predominantly cystic in nature. Inthe recurrence group, 54% of tumors were cystic, whereasonly 38% of tumors in the recurrence-free group were cys-tic. Fahlbusch et al.,3 reported large tumors (greater than 4cm) in 12.8% of patients in their series. The majority of tu-

mors (87%) were greater than 1 cm in size and, of these,60% were 1–2 cm in diameter.3 In the present series, largetumors (greater than 4 cm) were noted in 43% and 40%had tumors 2–4 cm in diameter. Large tumors were notedin 58% of patients who had recurrence and in only 38%of patients in the recurrence-free group; this differencewas statistically significant (p = 0.01). These results arecomparable with those of Weiner et al.,4 who reported thatrecurrence was seen in 44% of patients with large tumors,whereas recurrence was not seen for any tumors lesser than2 cm in size.

Overall 10-year post-treatment survival rates for cranio-pharyngiomas have been reported to be 92.5% and 85.6%after total and subtotal removal respectively.10,11 The re-ported incidence of symptomatic recurrence in subtotallyresected tumors is up to 57%, whereas in totally resected tu-mors it is approximately 19%.11,12 Yasargil et al.,13 in theirseries of 144 patients, achieved total tumor resection in90%, with 16.5% morbidity and 16.7% mortality. Hoffmanet al.,10 in their series of 50 children, reported total tumorexcision in 45, with 2% mortality and 12% morbidity.Recurrence rates increase and RFS worsens in incom-pletely resected craniopharyngiomas, as was seen in thepresent series (recurrence was seen in 5.2%, 28.5% and22.1% of patients in the total excision, near-total excisionand subtotal excision groups, respectively). In the presentseries, RFS was noted to be greater in patients who had

D.K. Gupta et al. / Journal of Clinical Neuroscience 13 (2006) 438–442 441

near-total tumor excision (18.2 months) compared withthose who had subtotal/partial tumor excision and exhib-ited symptomatic recurrence (7.1 months). Symptomaticrecurrence after subtotal tumor resection was observed in21 patients, whereas recurrence was observed in only fourwho underwent near-total tumor excision. Subtotal resec-tion predisposed to tumor recurrence, regardless of patho-logical subtype.

Another area of controversy regarding these tumors isthe role of postoperative radiotherapy, with its unpredict-able effects on the hypothalamus, particularly in youngchildren.13–17 When radiotherapy was used in combinationwith surgery, the recurrence rate has been reported to fallto 27% in subtotally resected tumors.11 In the present ser-ies, 74.7% of patients in the subtotal excision group (71of 95 patients) and 42.9% of patients in the near-total exci-sion group (6 of 14 patients) were given postoperativeradiotherapy. The recurrence rate after radiotherapy inthe near-total excision group was 16.6%, whereas that inthe subtotal excision group was 16.9%. Recurrence rateswere higher in both the near-total and subtotal resectiongroups (37.5%) when radiotherapy was not given, indicat-ing that radiotherapy lessens the incidence of recurrencein patients after subtotal or near-total tumor excision.

Kahn et al.,18 concluded that long-term prognosis wasbetter in patients with papillary tumors and suggested thatthis may be due to the different growth propensity of thesetumors compared with adamantinous variants. Szeifertet al.,19 reported recurrence in 59% of adamantinous tumorsand no recurrence in papillary tumors. The results observedin the present series differ from those reported by Szeifertet al.,19 in that recurrence was observed in 10.8% (19/176)of adamantinous tumors and in 17.5% (7/40) of papillarytumors. The difference in the incidence of adamantinous tu-mors in the recurrence and recurrence-free groups (73% vs.85%, respectively) was not statistically significant. Similarly,in the present series, papillary tumors were seen in 27% ofpatients in the recurrence group and in 15% of patients inthe recurrence-free group, which was not significantly differ-ent. Adamson et al.,5 emphasised a better outcome in chil-dren with squamous papillary tumors compared withchildren with adamantinous tumors (84% vs. 74%, respec-tively). Neither Adamson et al.,5 not Kahn et al.,18 foundrecurrence in any patient with papillary craniopharyngiomaand stated that the recurrence of these tumors has neverbeen reported. In contrast with the results reported byAdamson et al.,5 and Kahn et al.,18 the data in the presentseries support the conclusion that recurrence of both papil-lary and adamantinous tumors is dependent more on theextent of surgical resection than histopathological charac-teristics. The present series does not support the notion thatcategorization of craniopharyngiomas according to micro-scopic appearance has any prognostic significance.

Based on the limited number of patients with recurrencein the present study, it can be surmised that papillary cra-niopharyngiomas, like adamantinous tumors, can recur,especially when resection is subtotal. It was found that

recurrence was more a function of the extent of surgicalresection than the histopathological characteristics of thetumors. Buerger et al.,20 reported a higher incidence ofrecurrence when microscopic evaluation revealed infiltra-tion of the brain by tumor cells, although these authorshad no data to support this speculation. In the present ser-ies, brain invasion was observed in 90% of cases (18/20) inthe total/near-total excision group compared with 50% ofcases (26/52) in the subtotal excision group. It was alsonoted that, when brain tissue was included, invasion wasmore commonly seen in adamantinous than papillary typetumors; in fact, not a single case of papillary tumor withbrain invasion was encountered in the present series. Of44 cases that had brain invasion, only nine patients (20%)developed tumor recurrence during the follow-up period.The presence of brain invasion did not influence recurrencein the present series.

5. Conclusions

The present study is one of the largest series investigatingthe role of clinicopathological factors in the recurrence ofcraniopharyngiomas. In contrast with previous reports, inthe present series papillary craniopharyngiomas showed arecurrence pattern similar to that observed for adamantin-ous tumors, especially when tumor resection was subtotal.For both tumor variants, the significant factors associatedwith recurrence were the extent of surgical resection, tumorsize (greater than 4 cm) and cystic tumors rather than histo-pathological subtype. Brain tissue was more commonly in-cluded when total/near-total resection was performed.Furthermore, brain invasion was noted more frequently inpatients who had total tumor resection. Brain invasionwas recorded only among adamantinous-type craniophar-yngiomas. None of the cases of papillary tumor showedbrain invasion. Recurrence was less often seen after radio-therapy in both the near-total and subtotal resection groups.Total excision with or without radiotherapy minimized therisk of recurrence and prolonged symptom-free survival.

References

1. Carmel PW, Antunes JL, Chang CH. Craniopharyngiomas inchildren. Neurosurgery 1982;11:382–9.

2. Dietze DD, Mickle JP. Recurrent craniopharyngioma. Contemp

Neurosurg 1991;13:1–8.3. Fahlbusch R, Honegger J, Paulus W, et al. Surgical treatment of

craniopharyngiomas. Experience with 168 patients. J Neurosurg

1999;90:237–50.4. Weiner HL, Wisoff JH, Rosenberg ME. Craniopharyngiomas: A

clinicopathological analysis of factors predictive of recurrence andfunctional outcome. Neurosurgery 1994;36:1001–11.

5. Adamson TE, Wiestler OD, Kleihues P, Yasargil MG. Correlation ofclinical and pathological features in surgically treated craniopharyn-giomas. J Neurosurg 1990;73:12–7.

6. Eldevik OP, Blaivas M, Gabrielson TO, Hald JK, Chandler WF.Craniopharyngioma: Radiologic and histologic findings and recur-rence. Am J Neuroradiol 1996;17:1427–39.

7. Miller DC. Pathology of craniopharyngiomas: Clinical importance ofpathological findings. Pediatr Neurosurg 1994;21(Suppl.1):11–7.

442 D.K. Gupta et al. / Journal of Clinical Neuroscience 13 (2006) 438–442

8. Kobayashi T, Kageyama N, Yoshida J, Shibuya N, Yonezawa T.Pathological and clinical basis of the indications for treatment ofcraniopharyngiomas. Neurol Med Chir (Tokyo) 1981;21:39–47.

9. Richmond IL, Wara WM, Wilson CB. Role of radiation therapy inthe management of craniopharyngiomas in children. Neurosurgery

1980;6:513–7.10. Hoffman HJ, De Silva M, Humphreys RP, Drake HM, Smith ML,

Blaser SI. Aggressive surgical management of craniopharyngiomas inchildren. J Neurosurg 1992;76:47–52.

11. Samii M, Samii A. Surgical management of craniopharyngiomas. In:Schmideck HH, Sweet HH, editors. Operative Neurosurgical Tech-

niques. Philadelphia: WB Saunders; 2000. p. 489–501.12. Duff JM, Meyer FB, Ilstrup DM, Laws ER. Long-term outcomes for

surgically resected craniopharyngiomas. Neurosurgery 2000;46:291–305.

13. Yasargil MG, Curcic M, Kis M, Siegenthaler G, Teddy PJ, Roth P.Total removal of craniopharyngiomas: Approaches and long-termresults in 144 patients. J Neurosurg 1990;73:3–11.

14. Effenterre RV, Boch AL. Craniopharyngioma in adults and children.A study of 122 surgical cases. J Neurosurg 2002;97:3–11.

15. Villani RM, Tomei G, Bello L, Sganzerla E, Ambrosi B. Long-termresults of treatment for craniopharyngioma in children. Childs Nerv

Syst 1997;13:397–405.16. Svolvos DG. Craniopharyngiomas: A study based on 108 verified

cases. Acta Chir Scand Suppl 1969;403:1–44.17. Vaishya S, Mahapatra AK. Craniopharyngiomas: Presentation

and management. A study of 152 cases. Neurosci Today 1999;3:203–206.

18. Kahn EA, Gosch HH, Seeger JF, Hicks JE. Forty-five yearsexperience with the craniopharyngioma. Surg Neurol 1973;1:5–12.

19. Szeifert GT, Spos L, Horvath M, et al. Pathological characteristics ofsurgically removed craniopharyngiomas: Analysis of 31 cases. Acta

Neurochir (Wien) 1993;124:139–43.20. Burger PC, Scheithauer BW, Vogel FS. Surgical Pathology of the

Nervous System and its Coverings. 3rd ed. New York: ChurchillLivingstone; 1991.