An Unusual Treatment-Related Complication in a Patient with Growth Hormone-Secreting Pituitary Tumor

Mohammed Ahmed, Imaduddin Kanaan, Ayman Rifai, Asma Tulbah and Nadia Ghannam

Departments of Medicine (M.A., N.G.), Neurosciences (I.K.), Radiology (A.R.), and Pathology (A.T.), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Address all correspondence and requests for reprints to: Mohammed Ahmed, Department of Medicine (Mail Box Code-46), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.


    Case Report
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A 42-yr-old male patient presented with acromegalic features. He had experienced blurred vision and decreased libido for the past 4 months. On examination, he had acromegalic features, decreased vision bilaterally, and visual defect, which was worse on the left side. Formal visual field assessment using Goldmann perimetry showed a right relative temporal hemianopia with central scotoma and a left constricted visual field. His visual acuity was 20/300 (right eye) and 20/200 (left eye).

Laboratory data

Random GH was >200 (reference range, 0–7 µg/L). GH monitoring following 75 g of oral glucose loading showed: time (min), 0, 30, 60, 90, 120; GH (µg/L), 134, 74, 90, 39, 31.4; blood sugar (mmol/L), 5.9, 11, 15, 15.3, 12.3.

Other serum hormone levels were: PRL, 80 and 105 (reference range, 0–20 µg/L); testosterone, 4.16 (10.4–41.6 nmol/L); LH, <1 (5–20 IU/L); FSH, 15.2 (4–19 IU/L); total T4, 114.5 (68.2–160 nmol/L); T3 resin uptake, 0.27 (0.25–0.35); Free thyroxine index (FTI), 30.9 (17–56 nmol/L); TSH, 2.7 (1.1–7.2 mU/L); cortisol morning sample, 220.7 (193–689.7 nmol/L); and cortisol afternoon sample, 187.6 (55.2–193 nmol/L).

Imaging data

A skull x-ray showed massive enlargement of the sella turcica with destruction at the base of the skull. Computerized tomography (CT) scan of the head showed an invasive pituitary tumor with suprasellar extension involving the hypothalamus and optic chiasma, with parasellar extension into both cavernous sinuses and inferiorly into the sphenoid and ethmoid sinuses with diffuse bone destruction (Fig. 1Go).



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Figure 1. CT scan axial view without contrast showing a large mass in pituitary fossa destroying base of skull with invasion of ethmoid (a; arrowhead), axial view showing marked diffuse enhancement following contrast administration (b), and coronal view with contrast, showing tumor extending into cavernous sinuses bilaterally (c; arrowheads) and suprasellar region (arrow), with impingement into optic chiasmal area.

 
The patient was treated with bromocriptine (BC) 2.5 mg daily for 2 days, then 5 mg twice daily; by the fourth day the patient reported visual improvement, and on the fifth day, visual field testing using Goldmann perimetry showed normal findings and visual acuity improved to 20/50 (OD) and 20/40 (OS). BC was continued and depo-testosterone was added.

External radiotherapy (RT) by linear accelerator (8 MeV) was used to administer 5040 cGy over 42 days in 28 fractions to the right and left lateral pituitary fossa in a parallel pair. Post-RT, signs of acromegaly relented gradually, and clinical improvement was noticed. Multiple GH levels monitored over the next 67 months showed normal values ranging from <0.5–2.5 µg/L and serum insulin-like growth factor-I (IGF-I) levels ranging from 229–352 (100–558.6 µg/L).

A follow-up CT scan 9 months post-RT showed an impressive decrease in tumor size to half the original bulk, and at 17, 27, and 38 months (Fig. 2Go) post-RT there was continuing decrease in the suprasellar extension of the tumor; however, the inferior portion of the tumor remained unchanged, and invasion of the floor of the middle fossa with bone destruction continued, as well as invasion of the left parasellar and ethmoidal sinuses. A follow-up CT scan 22 months later showed no further change. BC was continued in a dose of 5 mg twice daily; replacement hydrocortisone and T4 were added to provide coverage for radiation treatment related hormonal deficiencies.



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Figure 2. CT scan, axial view without contrast, below level of diaphragm sella, 38 months after completion of radiotherapy, showing marked shrinkage of tumor with herniation of cerebrospinal fluid in pituitary fossa; continued destruction of ethmoid sinus (arrowhead) at tumor bed is evident.

 
The patient was readmitted 81 months following the initial presentation with symptoms for 3 weeks of recent severe headaches, deterioration in vision, and diplopia. There were no clinical signs of recurrence of acromegaly.

Ophthalmological evaluation revealed bilateral blindness secondary to pressure effect on the optic chiasma; he had bilateral optic atrophy. There was paralysis of the left lateral rectus and the right inferior rectus muscles.

Differential diagnosis and literature review

The differential diagnosis at this time included conditions that would cause an acute increase in the volume of the adenoma. About 10% of pituitary adenomas undergo acute or subacute changes in the form of hemorrhage, necrosis, or edematous swelling, with clinical signs and symptoms of a change in the pattern of headache, which often becomes severe in nature and frontal in location, a rapid deterioration in vision, and ophthalmoplegia (1). An appropriate diagnosis may be elusive and a high index of suspicion is necessary to arrive at the correct diagnosis. The clinical course of our patient at the last presentation was certainly compatible with an acute ischemic or hemorrhagic insult insofar as he harbored a large tumor, had a recent change in the pattern of headache, visual loss, and ophthalmoplegia; these findings are most consistent with pituitary apoplexy, necrosis, or infarction of the pituitary tumor. Pituitary apoplexy is a rare disorder; in our experience it has occurred in 13 out of 300 patients with pituitary tumor (2). Commonly misdiagnosed conditions include ruptured intracranial aneurysm, meningitis, or sphenoid mucocele. The CT/magnetic resonance imaging is especially helpful in arriving at the right diagnosis. The finding of acute or subacute bleeding within an enlarged sella is highly suggestive of pituitary apoplexy. We have detailed previously the CT scan findings in patients with apoplexy (2). These consist of fluid-fluid level, or hyperdensity, without contrast and hypodensity, or ring enhancement, with contrast administration. As seen in Fig. 3Go, such findings were not evident on the CT scan of this patient, which instead showed a significant increase in the size of an invasive pituitary tumor compared with the study done 19 months previously. These findings raise a real possibility of tumor recurrence, notwithstanding the fact that the patient had received radiation therapy previously, which does indeed appear to reduce the recurrence rate of pituitary adenoma (3). Tumor recurrence is by far the commonest cause of visual deterioration, as had occurred in this patient. Recurrence of visual failure can be accounted for by other conditions as well, such as arachnoid adhesions associated with progressive empty sella, however, a finding of empty sella was not evident on the CT scan of this patient. Another cause of recurrence of visual failure in this setting is delayed radionecrosis resulting in optic nerve and chiasmal damage. This can occur as a late complication of radiation treatment (4).



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Figure 3. CT scan, coronal view with contrast, at level of sella turcica, 79 months after radiotherapy shows mass in sellar-parasellar region (arrowhead) markedly increased in size, invading suprasellar cistern (a), coronal view with contrast, showing destruction of skull base (b; arrowhead), and coronal view with contrast, at maxillary sinus level demonstrating invasion of ethmoid and right maxillary sinuses (c; arrowhead).

 
Although tumor recurrence seemed most likely to account for the recurrence of the patient’s visual deterioration, visual field examination in general does not make this distinction. However, severe visual impairment resulting from bilateral optic atrophy, coupled with ophthalmoplegia and findings of tumor recurrence on CT scan made this diagnosis indisputable.

Follow-up course

At follow-up serum hormone levels were: GH 1.3, <0.25 µg/L, IGF-1, 352 µg/L; PRL, 120 µg/L; cortisol (1600 h), 110.4 nmol/L; free T4, 55.3 (10–36 pmol/L); T3, 55 (65–162 nmol/L); and TSH, 1.7 mU/L. A bilateral cerebral angiogram showed findings of a hypovascular pituitary tumor with an associated thrombus in the left internal carotid artery proximal to its bifurcation into the cavernous sinus. There was marked narrowing of the parasellar portion of the right carotid artery and the proximal anterior cerebral arteries bilaterally caused by encasement by the tumor.

The aforementioned results of the GH and IGF-I levels make it clear that the recurrent tumor was not a GH-secreting tumor. What was its precise nature?

Further clinical course

Three days following admission, the patient underwent transsphenoidal surgery and partial removal of the tumor was achieved. There was some destruction of the posterior part of the sphenoid sinus by the tumor, which was protruding and destroying the base of the sphenoid sinus. The tumor was necrosing and it had destroyed the skull base intra- and extrasellarly, as well as the posterior ethmoid sinuses. Tumor that had invaded laterally into the cavernous sinuses was not removed at operation.

Histological examination (Fig. 4Go) showed fragments of normal pituitary tissue, and those of a moderately cellular tumor composed of spindle cells arranged in intersecting fascicles. Remnants of normal pituitary glandular epithelium were also seen scattered diffusely among the tumor cells. These remnants stained strongly positive focally with immunohistochemical stains for FSH and PRL in a nonuniform manner and stained negative for human growth hormone. The spindle cells in the tumor showed moderate nuclear pleomorphism, and several mitoses were seen (Fig. 5Go). Immunohistochemically, the tumor cells were positive for vimentin only and were negative for ACTH, TSH, LH, FSH, HGH, and cytokeratin. Ultrastructural studies showed cells with enlarged, irregular nuclei. Dilated cisternae of rough endoplasmic reticulum and prominent Golgi complexes were seen within the cytoplasm. These features supported a diagnosis of spindle cell sarcoma most compatible with fibrosarcoma of intermediate grade.



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Figure 4. Spindle cell tumor. Spindle cells arranged in fascicles. Remnants of normal pituitary epithelium are seen in left upper corner. (Hematoxylin and eosin; original magnification x100).

 


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Figure 5. Spindle-shaped cells demonstrating moderate nuclear pleomorphism and mitoses. (Hematoxylin and eosin; original magnification x250).

 
Postoperatively, CT scan findings continued to show a large, residual, enhancing, parasellar tumor, and there was no improvement in the patient’s vision. He was subsequently discharged and was later reported to have died.


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Pituitary sarcoma is a rare complication arising after radiotherapy for pituitary tumor. It is a special instance of the effects of ionizing irradiation on the pituitary gland. As early as 1959, Terry et al. (5) documented for the first time the occurrence of fibrosarcoma of the pituitary in three patients with pituitary adenoma who were previously treated using radiation. Since then further cases have been reported (6, 7, 8, 9, 10, 11, 12, 13, 14) (Table 1Go). However, the experience with patients postradiation for pituitary fibrosarcoma remains limited: in only a few patients with GH-secreting tumors has irradiation been followed by the development of sarcoma (6, 7). An additional case of a GH-secreting pituitary tumor in which fibrosarcoma developed 79 months following irradiation is described here. This case illustrates the following special features of postirradiation pituitary fibrosarcoma: it behaved as an aggressive space-occupying lesion compressing surrounding brain structures, it showed no evidence of apparent metastases, and it histologically demonstrated the presence of bizarre fibroblastic proliferation. The long latent period following radiation falls within the reported range of 60–324 months, and the fractionated radiation dosage of 5040 cGy over 6 weeks conforms with the previously reported range of 2400–15,815 cGy (5, 6, 7, 8, 9, 10, 11, 12, 13, 14).


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Table 1. Review of patients with postirradiation pituitary sarcoma

 
This represents the only case of pituitary sarcoma following irradiation in our experience. The evidence that irradiation caused pituitary fibrosarcoma is circumstantial. Spontaneously occurring pituitary fibrosarcomas are extremely rare, and since 1975, none has been seen among more than 400 cases of pituitary tumor at our institution. Tissues other than the pituitary gland, which fall in the radiation path, have also been reported as having undergone neoplastic (mostly sarcomatous) degeneration (15, 16, 17, 18, 19). These include brain tumors, fibrosarcoma of the skin, soft tissues, clivus, pituitary fossa, or the frontal bone (15, 16, 17, 18, 19). No case of postirradiation pituitary sarcoma has been reported before about 1950, when the dose of pituitary radiation varied between 1500 and 2500 cGy (12). However, such a complication has been recognized with doses exceeding 3000 cGy (12). Currently, the accepted dose for irradiation of a pituitary adenoma is about 4500 cGy given over a period of about 4–6 weeks (17). A response should occur within 6–24 months. Additional irradiation for a recurrence would be valueless (17).

Goldberg et al. (6) suggested that multiple courses of radiation treatment could be a risk factor for developing sarcoma. However, most cases subsequently reported, including the present one, have had a single course of radiation (10, 11, 12, 13, 14). Although the majority of reported cases have undergone orthovoltage radiation, the more recent ones have had the higher energy radiation of cobalt-60, betatron, linear accelerator therapy, or the heavy particles of cyclotron radiotherapy (10, 11, 12). Notwithstanding the lack of information on the use of gamma-knife, it is obvious that all other current forms of radiation therapy used in the treatment of pituitary adenoma have the potential to induce fibrosarcoma in susceptible individuals.

The lesion typically begins as a pituitary adenoma, and serial biopsies have shown the presence of increasingly bizarre fibroblastic proliferation (13). There has been a unanimity in interpreting the spindle-cell sarcomatous element as diagnostic of fibrosarcoma (13). In the reported cases, it is stressed that none of these lesions metastasized, and atypical cytological changes in adenoma do not necessarily indicate metastatic potential (9, 13).

In summary, a fibrosarcoma developed in the pituitary gland of a patient who had been irradiated 79 months previously for treatment of a GH-secreting adenoma. The neoplasm was a large, aggressively growing, spindle cell tumor that eroded the surrounding structures. The lesion developed in the path of irradiation after a long latent period, with no apparent metastases, contained histologically identifiable benign appearing pituitary tissue interspersed within the spindle cell tumor, and resulted in the patient’s death.

Because irradiation is an effective treatment for pituitary adenoma and the occurrence of fibrosarcoma is only a rare complication, its use will continue. It is therefore important to be aware of such an occurrence. A rapidly growing, locally destructive pituitary lesion, associated with changes in vision and/or visual field, in a patient who had been previously irradiated for a pituitary adenoma, should alert one to the possibilities of not only apoplexy or a recurrence but, albeit more unusually, of a fibrosarcomatous degeneration. These conditions require prompt attention. Early diagnosis may render surgery feasible, as the only hope for palliation in a case of pituitary sarcoma.

The final diagnosis for this patient was pituitary sarcomatous degeneration of a previously irradiated GH-secreting tumor.

Received January 6, 1997.

Revised June 5, 1997.

Accepted June 11, 1997.


    References
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 Case Report
 Discussion
 References
 

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