Pituitary Chondrosarcoma: An Unusual Cause of a ...

0021-972X/01/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 2001 by The Endocrine Society

Vol. 86, No. 1 Printed in U.S.A.

CLINICAL CASE SEMINAR Pituitary Chondrosarcoma: An Unusual Cause of a Sellar Mass Presenting as a Pituitary Adenoma C. A. ALLAN, G. KALTSAS, J. EVANSON, J. GEDDES, D. G. LOWE, P. N. PLOWMAN, AND A. B. GROSSMAN Departments of Endocrinology (C.A.A., G.K., A.B.G.), Neuroradiology (J.E.), Histopathology (J.G., D.G.L.), and Radiotherapy (P.N.P.), St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom ABSTRACT A 37-yr-old woman with clinical, endocrinological, and radiological features suggestive of a nonfunctioning pituitary tumor was found to have a chondrosarcoma of the pituitary sella. The bony structures around the sella were relatively uninvolved, other than showing minor erosion of the left side of the dorsum and the posterior wall of the sphenoid sinus. After partial resection of the tumor by the transsphenoidal route the patient received postop-

erative radiosurgery by a linear accelerator, stereotactic multiarc radiotherapy. Subsequent follow-up revealed reduction of the residual tumor. This case demonstrates that a chondrosarcoma may apparently arise directly from the pituitary fossa and suggests the efficacy of stereotactic radiosurgery, at least in the medium term. The origin, areas of involvement, management, and long-term prognosis of these rare tumors are reviewed. (J Clin Endocrinol Metab 86: 386 –391, 2001)

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Case Report

UMORS ARISING FROM the pituitary gland account for most of sellar and parasellar masses. About 10% of such lesions are of nonpituitary origin: benign or malignant neoplastic lesions, primary or secondary vascular abnormalities, and infectious or inflammatory processes can also occur (1). About 10% of such nonpituitary sellar masses are cartilaginous tumors originating from the skull base; chordomas are identified more frequently than chondrosarcomas (1, 2). Most patients with these rare slowgrowing tumors present with visual complaints, mainly diplopia, whereas around one third present with headache (3). Significant endocrinopathy is unusual although anterior pituitary hormonal deficiencies and mildly elevated serum PRL levels have been reported, particularly with chordomas (1). Sellar and parasellar cartilaginous tumors are, however, more likely to lead to cranial neuropathies and neurological sequelae secondary to bony destruction (2). Both sellar and parasellar chordomas and chondrosarcomas are usually associated with significant bony defects on pituitary radiology (4). We observed a case of a chondrosarcoma arising from the pituitary fossa associated with relatively minor bone changes, and which has so far responded to the combination of transsphenoidal surgery (TSS) and radiosurgery. We review the location, clinical manifestations, management, and long-term prognosis of these rare tumors.

A 37-yr-old female was referred to our department for further evaluation and management of a mass lesion occupying the pituitary fossa and extending into the left cavernous sinus. The patient gave a 3-yr history of generalized headaches and of sharp right-sided intermittent retro-orbital pain. Over the last 2 yr she had also developed blurring of vision in the left eye, recurrent episodes of conjunctivitis of the right eye, and episodes of intermittent diplopia; her menstrual pattern was regular throughout that period on the oral contraceptive pill. Physical examination revealed bilateral temporal hemianopia (more prominent on the left side), bilateral reduction in visual acuity (6/9 on the right eye and 6/24 on the left eye), and early optic atrophy. There was no diplopia or any evidence of other cranial nerve palsies on neuro-ophthalmologic examination; she was normally feminized and did not have galactorrhea. Basal endocrine investigations on the estrogen-containing oral contraceptive showed normal thyroid function [total serum T4, 163 nmol/L (normal range, 58 –140 nmol/L); serum TSH, 2.3 mU/L (normal range, 0.3– 4 mU/L)], normal serum cortisol (272 nmol/L; normal range at 0900 h, 200 – 600 nmol/L), mild hyperprolactinemia (serum PRL, 459 and 546 mU/L; normal, ⬍360 mU/L), and no clinical or biochemical evidence of significant diabetes insipidus (serum osmolality, 290 mOsmol/L; normal range, 275–295 mOsmol/L; urine osmolality, 560 mOsmol/L). Magnetic resonance imaging (MRI) showed a large mass apparently arising from within the sella with a significant suprasellar component compressing both optic nerves and the chiasm, indenting the floor of the third ventricle and involving the left cavernous sinus. There was some depression of the floor of the pituitary fossa on the left (Fig. 1, A–C). The mass was of low signal intensity on T1- and

Received June 14, 2000. Revision received August 29, 2000. Accepted September 12, 2000. Address correspondence and requests for reprints to: Prof. A. B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, London ECIA 7BE, United Kingdom. E-mail: a.b.grossman@mds. qmw.ac.uk.

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CLINICAL CASE SEMINAR

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FIG. 1. Coronal (A and B) and sagittal (C) T1-weighted scans of the pituitary mass lesion. The postgadolinium images (B and C) demonstrate moderate tumor enhancement. There is depression of the sellar floor on the left side and involvement of the dorsum sellae. Normal pituitary is marked by an arrow in B.

of high signal intensity on T2-weighted images. There was a heterogeneous enhancement following the administration of iv gadolinium (Fig. 1, B and C), whereas some apparently normal pituitary tissue was seen in the right side of the fossa (Fig. 1B). Review of the clinical, endocrinological, and radiological data suggested a probable nonfunctioning pituitary adenoma, and the patient underwent transsphenoidal removal of the mass. At operation, the sella was ballooned into the sphenoid sinus, the floor was paper-thin and in parts deficient, and the capsule was attenuated. Within the sella there was white partly calcified material that could not be sucked out and was removed piecemeal, apparently completely according to the surgical report. Intraoperatively there was a

cerebrospinal fluid breech that resolved after the insertion of a lumbar drain. Postoperatively, the patient developed transient episodes of self-limited diplopia; her visual fields essentially normalized on confrontation and on formal Goldmann perimetry. Repeated basal and dynamic pituitary testing revealed normal thyroid function (serum T4, 90 nmol/L; serum TSH, 2.1 mU/L), a normal peak cortisol response to insulin-induced hypoglycemia (718 nmol/L; normal, ⬎550 nmol/L) but with a subnormal GH response (peak serum GH, 8 mU/L; normal, ⬎20 mU/L), normoprolactinemia (serum PRL, 353 mU/L), and mild cranial diabetes insipidus (serum osmolality, 295 mOsmol/L; urine osmolality, 116 mOsmol/L). On stopping the oral contraceptive she remained amenorrheic and was, thus, presum-


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ably gonadotropin deficient. The patient was, therefore, initiated on oral desmopressin (200 ␮g once a day), and she spontaneously restarted the oral contraceptive. Histology revealed a well-differentiated cartilaginous tumor. Immunohistochemistry revealed negative staining for cytokeratin (CAM 5.2) and positive staining for S-100. These findings were consistent with a well-differentiated (low grade) chondrosarcoma (Fig. 2). A repeat MRI scan (data not shown) 3 weeks following the TSS showed a considerable amount of tissue still present in the suprasellar and left parasellar regions, but considerable reduction in the displacement and compression of the optic chiasm. In view of the nature of the tumor and the postoperative radiographic evidence of residual tumor, stereotactic “radiosurgery” via multiarc radiotherapy from a linear accelerator was administered as a single dose 3 months following the original TSS (5). A dose of 1800 cGy was delivered to the margin of the stereotactically mapped tumor but, due to the rostral extent of the tumor abutting the chiasm, was slightly underdosed such that the chiasmal dose did not exceed 800 cGy. Immediately after the radiosurgery the patient developed severe bilateral headache; this was assumed to be secondary to radiation-induced tumor swelling and responded to a short course of high-dose oral dexamethasone. Because such cartilaginous tumors are commonly associated with bone destruction, the patient underwent computed tomography (CT) scanning of the bony structures surrounding the pituitary fossa 10 days after surgery, but only minor erosion of the left side of the dorsum sellae and the posterior wall of the sphenoid sinus was seen, with no gross evidence of bone destruction (Fig. 3). Twelve months after the initial surgery the patient reported no further headaches and had no visual complaints. Clinical examination revealed a minor persistent left tem-

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FIG. 3. CT scan through the inferior aspect of the pituitary fossa at 10 days after TSS. There is minor erosion of the left side of the dorsum and posterior wall of the sphenoid sinus, but no abnormal calcification.

FIG. 2. The tumor is composed of crowded chondrocytes in a focally mineralized connective tissue matrix. The edges of the tumor were well defined and pushing. Ossification had occurred in places.


CLINICAL CASE SEMINAR

poral field defect that was confirmed on formal Goldmann perimetry. Full assessment of pituitary function showed persisting mild diabetes insipidus, GH deficiency (peak response to insulin-induced hypoglycemia, 1 mU/L; serum insulin-like growth factor I, 93 ng/mL; normal age-related range, 120 –330 ng/mL) and partial ACTH deficiency (peak serum cortisol response, 471 nmol/L). Her thyroid function tests remain normal (serum T4, 126 nmol/L; serum TSH, 1.8 mU/L), and she is normoprolactinemic (serum PRL, 300 mU/L). She remains on the oral contraceptive pill. MRI of the pituitary showed some residual tumor extending into the left cavernous sinus and suprasellar region indenting the optic chiasm (Fig. 4A). However, MRI scanning of the pituitary 18 months after the original surgery (and 15 months after stereotactic radiotherapy) revealed further evidence of tumor shrinkage (Fig. 4B). The patient currently remains well on the oral contraceptive pill and desmopressin replacement therapy, with regular clinical assessment every 6 months and re-imaging every 12 months. Discussion

Whereas most sellar lesions will be shown to be either functioning or nonfunctioning pituitary adenomas, our case

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demonstrates that nonadenomatous lesions may cause surprises. In a previous series of 911 sellar masses, only 83 were of nonpituitary origin, and of these 11% were cartilaginous in nature, mainly chordomas (2). Intracranial chondrosarcoma tends to be even rarer, with only 177 reported in the world literature in a recent review (3). Chondrosarcomas are malignant tumors of cartilage-forming cells that occur mainly in the axial part of the skeleton, representing less than 5% of skull base tumors with ⬃75% arising in the parasellar region (6). The most common areas of involvement in the skull are the petrosal bone, the occipital bone and clivus, the sphenoid bone, and, to a lesser extent, the ethmoidal bone; in only 6% was the primary location in the dural space (3). Two patients were originally described with chondrosarcomas originating from the pituitary in the classic neuropathology text by Russell and Rubinstein (7), but none has been published since then. Histologically, there has been some uncertainty about certain intermediate grades, especially the so-called chondroid chordoma (8). However, the latter is now generally thought to be a variant of the chondrosarcoma, and immunohistochemical criteria, particularly negative cytokeratin staining, has facilitated the diagnosis of chondrosarcomas as distinct from chordomas. With adequate tissue for analysis, there should be no difficulty in

FIG. 4. MRI scans (top, sagittal; bottom, coronal) of the pituitary region at 3 (left) and 18 (right) months following TSS. Immediately after the 3 months scan the patient received radiosurgery as a single fraction.


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making the distinction (8) Chondrosarcomas usually present with diplopia and oculomotor disorders (51% of cases); headache is less common (31%), whereas decreased visual acuity was noted in only 14% (3). Even less common presentations include hearing loss, dizziness, tinnitus, facial sensory disturbance, ataxia, and hemiparesis (9); no case presenting mainly with visual field defects has been described. Radiological examination almost always shows bone destruction and variable calcification on CT imaging, involvement of neural and vascular structures on MRI, and mostly hypovascularity on angiography (3). Information on the endocrine function of patients presenting with such tumors is even sparser. Because clearly established histopathological criteria distinguishing between chordomas and chondrosarcomas have been established, recent studies have shown that the 5-yr survival of chondrosarcoma is more favorable than chordomas, with even better results on longer follow-up (10 –12). It is, therefore, important in cases of cartilaginous tumors to achieve a definite histopathological distinction between chordomas and chondrosarcomas to plan further treatment. Chondrosarcoma and chordoma cells are positive for S-100 protein; chondrosarcoma cells, however, are negative for cytokeratin markers (CAM 5–2) and epithelial membrane antigens, unlike chordoma cells, which are positive for both (13–15). It has recently been shown that the most important predictor of long-term outcome is the extent of resection of the initial tumor (16). Local recurrence rates of 53% have been reported with a mean interval until regrowth of 32 months; in 80% of recurrent cases the initial resection was subtotal. However, the anatomical location of the tumors renders complete resection in intracranial sites extremely difficult and hazardous to achieve (3). Chondrosarcomas of the skull base are usually slowly growing low-grade malignancies that rarely metastasize outside the skull but expand locally to compress adjacent structures (11). Given the importance of residual tumor volume as a prognostic indicator, it is frequently necessary to proceed to adjuvant therapy, particularly because with such tumors it is often difficult to achieve extensive or near-total surgical clearance (3). Standard external beam radiotherapy has been disappointing with regard to local control, although most of the reported series refer to chordomas (17, 18). More promising results have been obtained with the use of proton beam irradiation following surgical resection; however, treatmentrelated visual impairment or pituitary insufficiency developed in 12 of 68 patients in one series (19). Using this as adjuvant treatment, 5- and 10-yr local control rates of 99% and 98%, disease-specific survival rates of 99%, and 3-year local control rates of 94%, have been achieved (11, 20). Stereotactic radiosurgery refers to the use of single high doses of concentrated radiation delivered with great precision due to stereotactic mapping and sophisticated radiation therapy technology. Such technology ensures that at the perimeter of the stereotactically mapped target the dose falls rapidly, thereby sparing adjacent normal structures from such high doses. Stereotactic radiosurgery has been used to treat skull base chondrosarcoma and seems to be of particular benefit when the irradiated tumor volume is small (21, 22). The

optimum dose-response range remains to be determined, but 20 Gy to the tumor margin in chondrosarcomas with a maximum diameter of 30 mm resulted in lack of tumor progression in six patients with chondrosarcoma or chordoma, with no reported adverse effects (23). In our patient the proximity of the optic chiasm limited the dose. Chemotherapy is not held to be an effective form of adjuvant treatment for chondrosarcomas, whether residual or recurrent. There has been one recent case report of a sustained response of recurrent chondrosarcoma to a combination of ifosfamide and doxorubicin at 52 months (24), but generally the literature regarding this treatment modality is unfavorable and this was not considered as a therapeutic option in our patient. In summary, this case illustrates that chondrosarcoma, a very unusual tumor to arise in the sella, can exhibit clinical, endocrinological, and radiological features similar to those of the more commonly encountered lesions in this region. The unusual consistency of the tumor should alert the neurosurgeon to perform as near-complete a resection as possible, because this is the most important predictor of outcome. Postoperative therapy with proton beam irradiation or radiosurgery through a linear accelerator are currently the adjuvant treatments of choice. Our case illustrates the effectiveness of stereotactic “radiosurgery” via multiarc radiotherapy, at least in the medium term. However, regular and prolonged follow-up is necessary to monitor further tumor recurrence. References 1. Freda PU, Post KD. 1999 Differential diagnosis of sellar masses. Endocrinol Metab Clin North Am. 28:81–117. 2. Freda PU, Wardlaw SL, Post KD. 1996 Unusual causes of sellar/parasellar masses in a large transsphenoidal surgical series. J Clin Endocrinol Metab. 81:3455–3459. 3. Korten AG, Ter Berg HJ, Spincemaille GH, van der Laan RT, Van de Wel AM. 1998 Intracranial chondrosarcoma: review of the literature and report of 15 cases. J Neurol Neurosurg Psychiatry. 65:88 –92. 4. Meyers SP, Hirsch WL, Curtin HD, Barnes L, Sekhar LN, Sen C. 1992 Chondrosarcomas of the skull base: MR imaging features. Radiology. 184:103–108. 5. Thomson ES, Gill SS, Doughty D. 1990 Stereotactic multiarc radiotherapy. Br J Radiol. 63:745–751. 6. Kunanandam V, Gooding MR. 1995 Parasellar chondrosarcoma: total excision improves prognosis. Br J Neurosurg. 9:87–91. 7. Russell DS, Rubinstein LJ. 1989 Secondary tumors of the nervous system. Pathology of tumours of the nervous system, ed 5. London: Edward Arnold; 819. 8. Bruner JM, Tien RD. 1998 Secondary tumors. In: Bigner DD, McLendon RE, Bruner JM, eds. Russell and Rubinstein’s pathology of tumors of the nervous system, ed 6, vol 2. London: Arnold; 421– 423. 9. Al-Mefty O, Borba LA. 1997 Skull base chordomas: a management challenge. J Neurosurg. 86:182–189. 10. Gay E, Sekhar LN, Rubinstein E, et al. 1995 Chordomas and chondrosarcomas of the cranial base: results and follow-up of 60 patients. Neurosurgery. 36:887– 896. 11. Rosenberg AE, Nielsen GP, Keel SB, et al. 1999 Chondrosarcoma of the base of the skull: a clinicopathologic study of 200 cases with emphasis on its distinction from chordoma. Am J Surg Pathol. 23:1370 –1378. 12. Watkins L, Khudados ES, Kaleoglu M, Revesz T, Sacares P, Crockard HA. 1993 Skull base chordomas: a review of 38 patients, 1958 – 88. Br J Neurosurg. 7:241–248. 13. Ishida T, Dorfman H. 1994 Chondroid chordoma versus low-grade chondrosarcoma of the base of the skull: can immunohistochemistry resolve the controversy? J Neuro-oncol. 18:199 –206. 14. Salisbury JR, Isaacson PG. 1986 Distinguishing chordoma from chondrosarcoma by immunohistochemical techniques. J Pathol. 148:251–252. 15. Rosenberg AE, Brown GA, Bhan AK, Lee JM. 1994 Chondroid chordoma—a variant of chordoma. Am J Clin Pathol. 101:36 – 41.


CLINICAL CASE SEMINAR 16. Kveton JF, Brackman DE, Glasscock ME, House WF, Hitselberger WE. 1986 Chondrosarcoma of the skull base. Otolaryngol Head Neck Surg. 94:23–32. 17. Stapleton SR, Wilkins PR, Archer DJ, Uttley D. 1993 Chondrosarcoma of the skull base: a series of eight cases. Neurosurgery. 32:348 –356. 18. Cummings BJ, Hodson DI, Bush RS. 1983 Chordoma: the results of magavoltage radiation therapy. Int J Radiat Oncol Biol Phys. 9:633– 642. 19. Austin-Seymour M, Munzenrider J, Goitein M, et al. 1989 Fractionated proton radiation therpay of chordoma and low-grade chondrosarcoma of the base of the skull. J Neurosurg. 70:13–17. 20. Hug EB, Loredo LN, Slater JD, et al. 1999 Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg. 91:432– 439. 21. Muthukumar N, Kondziolka D, Lunsford LD. 1998 Stereotactic radiosurgery

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for chordoma and chondrosarcoma: further experiences. Int J Radiat Oncol Biol Phys. 41:387–392. 22. Austin-Seymoor M, Munzenrider J, Gotein M, et al. 1989 Fractinated proton radiation therapy of chordoma and low grade chondrosarcoma of the skull base. J Neurosurg. 70:13–17. 23. Kondziolka D, Lunsford LD, Flickinger JC. 1991 The role of radiosurgery in the management of chordoma and chondrosarcoma of the cranial base. Neurosurgery. 29:38 – 45. 24. La Rocca RV, Morgan KW, Paris K, Baeker TR. 1999 Recurrent chondrosarcoma of the cranial base: a durable response to ifosfamide-doxorubicin chemotherapy. J Neuro-oncol. 41:281–283.
