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Tumors Metastatic to the Pituitary Gland: Case Report and Literature Review

Departments of Endocrinology, Diabetes and Metabolism (J.K., V.V., N.C.T.) and Pathology (D.P.), Evangelismos General Hospital, 10676 Athens; Department of Neurosurgery, University of Athens (S.K., D.S.), Evangelismos General Hospital, 10676 Athens; and Department of Pathology (G.K.), G. Gennimatas Athens General Hospital, 11527 Athens, Greece

Address all correspondence and requests for reprints to: Dr. John Komninos, Department of Endocrinology, Diabetes and Metabolism, Evangelismos General Hospital, 45-47 Ipsilantou Street, 10676 Athens, Greece. E-mail: jokomni{at}otenet.gr.

	Abstract

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Tumors metastatic to the pituitary gland are an unusual complication of systemic cancer typically seen in elderly patients with diffuse malignant disease. Breast and lung are the commonest sites of the primary tumor, whereas diabetes insipidus is the most frequent symptom at presentation. Their rarity and usually indolent course, as well as the lack of specific clinical and radiological features, impede their differentiation from other more common sellar area lesions, particularly when history of malignancy is absent. Management of these patients may also be very difficult because the prognosis depends on the course of the primary neoplasm. A 68-yr-old man, with no history of malignancy, presented with recent onset of hypopituitarism, mild diabetes insipidus, headaches, left oculomotor nerve palsy, and progressive bilateral deterioration of visual acuity and visual fields. Magnetic resonance imaging revealed a large sellar mass compressing the optic chiasm and invading the left cavernous sinus, whereas a prolactin elevation at 438.6 ng/ml (19.73 nmol/liter) was noted. Decompression of the sellar region was attempted, and pathology disclosed a metastatic hepatocellular carcinoma. On postoperative investigation, primary liver tumor was identified and confirmed by biopsy. The patient improved transiently but died 3 months after diagnosis because of deterioration of the liver disease. The relevant literature is reviewed in light of this unusual case, illustrating the problems in the diagnosis and management of patients with metastasis to the pituitary.

	Introduction

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IN 1857, L. BENJAMIN first described a case of metastasis to the pituitary (MP) gland in an autopsy of a patient with disseminated melanoma (1). Since then, a number of surgical and autopsy series and sporadic case reports have described metastatic tumors to the pituitary. MP is an infrequent clinical problem reported in 0.14–28.1% of all brain metastases in autopsy series (1, 2, 3). However, during the last few decades, MPs have been noted with increasing frequency, reflecting the improvement in survival rates of patients with cancer and the use of more sensitive imaging techniques (4, 5).

Breast and lung cancer are the most common primary neoplasms metastasizing to the pituitary. Most often they are part of a generalized metastatic spread, usually associated with five or more additional metastatic sites, especially osseous (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). Typically, they affect elderly patients in the sixth or seventh decade of life (6, 11), with no clear sex predominance. Nevertheless, MP may be the first manifestation of an occult primary tumor or the only site of metastasis (2, 4, 5, 12, 13) and may very occasionally occur in early adulthood (2, 14).

Since early studies, most authors underscore the prevalence of diabetes insipidus in MPs (2, 10, 15, 16, 17), reported at 100% in some series (2, 10), whereas symptomatic anterior pituitary failure and cranial nerve deficits have been less frequently described at presentation (15, 16, 17). This has been attributed to a trend of metastasis to the posterior lobe and infundibulum. Prolactin (PRL) elevation at levels less than 200 ng/ml (9.0 nmol/liter), consistent with stalk compression, is not uncommon in MPs (13) and usually rules out the presence of a PRL-secreting tumor.

Antemortem diagnosis is difficult because the majority of MPs are clinically silent and too small to cause radiological changes (7, 18). But even when symptomatic, metastatic tumors cannot be reliably distinguished from primary sellar tumors on the basis of clinical and radiographic presentation (6, 7, 12, 15). In fact, they may mimic a pituitary adenoma (1, 4, 7, 15, 16) or a variety of sellar area lesions, benign or malignant (tumor, granuloma, abscess, cyst, aneurysm, trauma, apoplexy), confusing the diagnosis, especially when clinical evidence of malignancy is absent (4, 8, 13, 19, 20, 21, 22). In cancer patients, the differentiation between metastasis and benign lesion is essential for the therapeutic plan, to avoid unnecessary operations in severely compromised patients (4, 9). Local therapy aiming at symptom relief may be beneficial; however, prognosis is determined by the primary tumor.

Here, we present a case of MP in which the absence of known malignant background and high PRL levels confused the diagnosis. Incidence, pathogenesis, diagnosis, and management of patients with MP are described.

	Case Report

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A 68-yr-old male presented with a 2-month history of headaches, weakness, fatigue, anorexia, and somnolence. When questioned, he also stated a decrease in shaving frequency and a mild polyuria. One month before admission, he developed gradual left palpebral ptosis, diplopia, and progressive deterioration of vision. A cranial computer tomography (CT) scan showed an isodense tumor around the optic chiasm, with inhomogeneous enhancement in contrast images. Subsequent magnetic resonance imaging (MRI) demonstrated a 2.9 x 1.8-cm sellar mass, which infiltrated the clivus, depressed the floor of the sella turcica, and extended into the left part of the sphenoid sinus. The tumor invaded the left cavernous sinus, encasing the internal carotid artery, which was laterally displaced. It also extended into the suprasellar cistern, compressing the optic chiasm and the floor of the third ventricle. Precontrast T1-weighted images (T1WI) showed an inhomogeneous high signal intensity tumor, isointense on T2-weighted images (T2WI) (Fig. 1). After gadolinium infusion, contrast and dynamic MRIs revealed rapid inhomogeneous enhancement and signal of flow void within the tumor, suggesting hypervascularity. Findings in the rest of the brain were unremarkable. Cerebral angiography depicted a suprasellar tumor blush with moderate vascularization not compatible with aneurysm, whereas the carotid arteries appeared dilated.

View larger version (185K): [in this window] [in a new window]   FIG. 1. A, Precontrast coronal MRI T1WI. B, Enhanced coronal T1WI. C, Axial T2WI. D, Sagittal T2WI showing pituitary mass with suprasellar extension and invasion of the left cavernous and sphenoid sinuses.

Routine laboratory tests showed a mild elevation of serum aspartate aminotransferase to 73 IU/liter (normal level, <37) and alanine aminotransferase to 46 IU/liter (normal level, <40). Basal endocrinological work-up showed corticotroph, gonadotroph, and somatotroph cell insufficiency, with normal levels of thyroid hormones (Table 1). Serum PRL was elevated at 438.6 ng/ml (19.73 nmol/liter) [normal level, <12.3 ng/ml (< 0.55 nmol/liter)], consistent with prolactinoma. Nevertheless, before the results of the endocrinological tests were available, the patient was subjected to an immediate decompressive transsphenoidal surgery (TSS), mainly in view of his increasing neurological deficits. On macroscopic exploration, the tumor was solid and fibrous, hemorrhagic, with rich vascularization, and infiltrated the sella turcica. Osseous infiltrations and intense hemorrhage inhibited the complete resection of the tumor.

View larger version (120K): [in this window] [in a new window]   FIG. 2. Carcinoma cells from pituitary tumor in sinusoidal pattern (A). Presence of round hyaline globules (B, arrows) and large vacuoles (C, arrows). Note glycogen granules (D, arrows). Immunoreactivity for hepatocyte antibody (E), -fetoprotein (F), and cytokeratins 8 and 18 (G). Magnification: A, x40 (hematoxylin-eosin stain); B and C, x100 (hematoxylin-eosin stain); D, x100 (periodic acid-Schiff stain); E, x40 (avidin-biotin complex); F and G, x100 (avidin-biotin complex); H, x80 (Ki-67 nuclear stain).

The postoperative routine laboratory tests showed a progressive deterioration of liver enzymes. Aspartate aminotransferase increased to 125 IU/liter, alanine aminotransferase to 140 IU/liter, and alkaline phospatase to 153 IU/liter (normal range, 39–117). -Fetoprotein also gradually increased to 3485.9 ng/ml (3485.9 µg/liter) [normal level, <15 ng/ml (<15 µg/liter)]. Liver ultrasonography disclosed two masses, 3 cm each, and parenchymal inhomogeneity, compatible with diffuse liver disease. The abdominal CT scan additionally depicted an enlargement of the head of the pancreas and the right adrenal, as well as infiltration of regional abdomen lymph nodes. Exploration with thoracic CT scan and bone scintiscan was negative. The diagnosis of HCC was eventually confirmed by a fine-needle aspiration biopsy taken from one of the liver masses.

A sequential pituitary MRI, undertaken 1 month after surgery, was largely unchanged. Adjuvant radiation therapy to the sellar region was recommended. The patient was discharged to start radiotherapy as an outpatient, but he was lost to follow-up. He died 3 months later because of deterioration of the liver disease. An autopsy was not performed.

	Discussion

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The pituitary gland is an uncommon site for metastasis. In surgical series, it is detected in less than 1% of patients subjected to TSS for sellar or parasellar tumors (Table 2). In autopsy series, latent MPs are revealed in approximately 5% of patients with known malignancy (Table 2), but in about two thirds of those, the pituitary is macroscopically normal (18). In breast cancer patients, the incidence is significantly higher. The latter may be explained by the hypothesis that the PRL-rich environment of the pituitary enhances the proliferation of breast tumor cells (5).

Metastatic deposits can reach the sella via several routes (5, 8, 9): 1) direct hematogenous spread to the pituitary parenchyma or diaphragma sellae; 2) spread from a hypothalamohypophyseal or infundibulum metastasis through the portal vessels; 3) extension from juxtasellar and skull base metastasis; and 4) meningeal spread through the suprasellar cistern. McCormick et al. (3), reviewing location of MP in 201 cases, found an involvement of the posterior lobe either alone or in combination with the anterior lobe in 84.6%, whereas only the anterior lobe was affected in 15.4%. The predilection for metastasis to the posterior lobe is mainly attributed to the lack of direct arterial blood supply of the anterior lobe (1, 2, 3, 5, 8, 10, 12, 15, 16, 18, 25, 26). The posterior lobe is supplied by the hypophyseal arteries, whereas the anterior is nourished by the portal vessels system and secondarily by the lower infundibular stem, which partly arises from the posterior lobe. Another contributing factor is that the posterior lobe has a larger area of contact with the adjacent dura (1, 18). Metastatic deposits in the anterior lobe are usually the result of contiguous spread from the posterior lobe (25). The anterior lobe seems to be susceptible to ischemic infarcts and is associated with a larger metastatic lesion of the posterior lobe (18, 25). However, extensive destruction of the anterior lobe leading to clinically evident anterior pituitary insufficiency is not common (16, 18).

The most common symptom seems to be diabetes insipidus (2, 10, 15, 16, 17), reflecting a predominance of metastasis to the posterior lobe. McCormick et al. (3), in their review of 40 symptomatic cases, noted diabetes insipidus in 70%, whereas only 15% had one or more anterior pituitary deficiencies. However, recent studies using more sensitive imaging techniques and endocrinological tests, allowing earlier and more accurate diagnosis, have increased the incidence of anterior lobe involvement (5, 15, 27), as shown in Table 4. During the course of the disease, most patients will develop diabetes insipidus (2), after invasion of the infundibulum or hypothalamus. Occasionally, diabetes insipidus is transient, because regeneration of neurohypophyseal fibers may occur, or intermittent (11). Corticotroph cell insufficiency may obliterate the presence of diabetes insipidus until corticosteroid treatment is instituted. In the series by Morita et al. (5), hypothyroidism and hypoadrenalism were the most frequent types of symptomatic hypopituitarism, with hypogonadism following next. Nevertheless, in exceptional cases, MPs may present with a hyperfunctional syndrome. Cushing’s syndrome and acromegaly have been reported in cases of metastasis to a preexisting corticotroph or somatotroph cell adenoma (20, 28), as well as in exceptional cases of metastasis originating from primary tumors with ectopic ACTH or GH secretion (26, 29). Syndrome of inappropriate antidiuretic hormone secretion has also been described. Ectopic antidiuretic hormone secretion by the primary tumor was confirmed in one case (30), whereas the mechanism remains obscure in other cases (13). Bilateral hemianopsia is the most common type of visual field impairment (1, 2). Infiltration of the adjacent cavernous sinus usually induces cranial nerve III palsy, or less frequently, nerve IV palsy. Compression of nerve VI is relatively uncommon because it is well sheltered within the cavernous sinus (6, 8). Facial numbness due to cranial nerve V dysfunction is also rare. Tumor extension to the septum pellucidum or the frontal lobes may result in cognitive deficit or psychiatric symptoms and in anosmia if cranial nerve I is affected. Stretching of the diaphragma sellae or ventricular distention can give rise to headaches or intracranial hypertension.

In clinical terms, preoperative diagnosis of MPs is difficult. Lumbar puncture is important (16) because it may be the only preoperative examination conclusive of malignancy in cases in which meningeal spread is present. Although history or coexistence of malignancy usually leads to the diagnosis, it is of limited diagnostic value because 1.8–16% of patients with known malignancy and a sellar tumor turn out to harbor a pituitary adenoma (5, 9). Yet, absence of known neoplastic disease does not exclude the diagnosis of MP. The examination of 190 symptomatic MPs (Table 4) showed primary tumor to be latent at presentation in 83 (43.7%). Besides, in 7–57.1% of cases, pituitary is reported to be the only site of metastasis (2, 5, 15, 17, 27). However, these percentages may be considered artificially high because this type of presentation is unusual and more likely to be reported (16).

Although symptoms of MPs at presentation may resemble those of pituitary adenomas, diabetes insipidus is reported in only 1% of adenomas (5, 15), being typically a late finding (2, 25). Thus, Schubiger and Haller (17) suggested that diabetes insipidus is the most important criterion for differentiation of MP from adenomas. Presentation with hypopituitarism, headaches, or visual disturbances, is less helpful in the differential diagnosis, being described in both MPs and adenomas. Ophthalmoplegia may help more, without being pathognomonic for metastasis either (5, 15, 17). In contrast, presentation with abducens nerve palsy should always raise the suspicion for malignancy (8). The rapidity of symptom development may also contribute to the diagnosis. Consequently, a rapidly growing sellar tumor (11), especially in patients treated with dopamine agonist (7, 15), or a sudden onset of diabetes insipidus, ophthalmoplegia, and headaches in a patient over 50 yr old, as reported here, strongly suggests MP, irrespectively of history of malignancy (2, 3, 5, 6, 15).

Radiological evaluation generally has not been fruitful in distinguishing MP from adenomas (1, 3, 4, 5), unless other metastatic brain lesions coexist, a relatively uncommon occurrence, as shown in Table 5. Plain skull radiographs, conventional tomographies, and cerebral angiography provide nonspecific findings, whereas in approximately one third no sellar abnormality is displayed (Table 5). High-resolution CT and MRI are more sensitive. The CT usually shows a hyperdense or isodense mass, homogeneously or inhomogeneously enhancing (if cystic degeneration, hemorrhage, or necrosis exists) in contrast images. The MRI may demonstrate an isointense or hypointense mass on T1WI, with a usually high-intensity sign on T2WI, homogeneously enhancing postgadolinium, as well as absence of high-signal intensity of the posterior lobe on T1WI. However, neither of these findings is highly specific for MP (5, 7, 8, 9, 11, 12, 13, 15, 17, 27). Rapid increase of a sellar tumor with aggressive infiltration of adjacent tissues should raise suspicion of MP (3, 5, 6, 17, 27). Moreover, MPs usually have a rapid growth and respect the diaphragm early in their course. Therefore, a dumbbell-shaped intrasellar and suprasellar tumor, with a clear indentation at the level of the diaphragma sellae, best seen on sagittal images, is suggestive of MP (2, 11, 17, 36), although this type of presentation has also sometimes been described in benign lesions. Schubiger and Haller (17) reported that invasion of the infundibular recess by a suprasellar mass is in favor of MP, because suprasellar adenomas usually push it posteriorly. They also found in five of their seven patients a linear enhancement of the infundibulum proximal to the tumor, an unusual finding in pituitary adenomas. In our case, MP was not dumbbell shaped and showed low-signal intensity on T2WI and inhomogeneous enhancement on precontrast T1WI, probably induced by tumor hemorrhage or by protein-rich content. This is a relatively uncommon radiological presentation for MP, as it is inferred from Table 5.

Treatment, being basically palliative, depends on the symptoms and the extent of the systemic disease (3, 4, 5, 6). In known cancer patients, a full investigation for additional metastases is mandatory. Reports of surgery of MPs indicate that the lesions tend to be firm, diffuse, invasive, vascular, and hemorrhagic; therefore, their total resection is unlikely (2, 4, 6, 10). In this setting, local radiation and/or chemotherapy are recommended as the initial course of treatment, especially in patients with widespread metastases, in combination with pituitary hormone substitution therapy (1, 2, 3, 4, 6, 10, 16). Surgical exploration and decompression, alone or combined with radiation, is essential if clarification of diagnosis is likely to affect therapy or if suprasellar extension causes progressive deterioration in vision or pain (2, 3, 4, 5, 6, 13, 15, 37). Surgery and radiation are well tolerated in noncompromised patients, being associated with low morbidity and minimal complications (5, 15). As noted in our case, tumor debulging is beneficial in alleviating the local symptoms, especially headaches and visual field defect, whereas symptoms such as diplopia and those related to anterior pituitary failure remain unaffected (1, 5, 6, 15, 37). The transsphenoidal approach, completeness of resection, and aggressive treatment (surgery plus local radiation) are associated with better symptom relief but do not affect survival rates (5, 37).

Prognosis of patients with MPs is poor, not because of the location per se but because of the aggressiveness of the primary neoplasia (16). As in the present case, most patients die a few months after diagnosis. Mean survival length in clinical series is 6–7 months (2, 5, 10). Ntyonga-Pono et al. (13), reviewing 72 patients from the literature, found that only 10% of patients survived more than 1 yr after diagnosis, the longest survival being 3 yr. Patients with a single MP may have a better outcome (2, 5). Age over 65 yr at presentation, metastasis from small-cell lung carcinoma, and short duration (<1 yr) between initial diagnosis of cancer and pituitary invasion have been related to a poorer outcome (5).

In conclusion, we present a patient with a sellar mass, ophthalmoplegia, headaches, hypopituitarism, mild diabetes insipidus, and marked hyperprolactinemia, thought initially to represent a prolactinoma, but which on histology of the partially resected tumor proved to be a metastasis of an undiagnosed HCC. Sudden onset of diabetes insipidus, ophthalmoplegia, and headaches in a patient over 50 yr old should always raise the suspicion for MP, regardless of a history of malignancy. Although radiation or chemotherapy is the treatment of choice, a surgical approach, for obtaining histological diagnosis and alleviating symptoms, may also be considered in patients with limited metastatic disease. The conventional limit of a PRL level of 200 ng/ml (9.0 nmol/liter), above which hyperprolactinemia is generally attributed to a prolactinoma, should always be used with caution.

	Footnotes

 
Abbreviations: CT, Computer tomography; HCC, hepatocellular carcinoma; MP, metastasis to the pituitary; MRI, magnetic resonance imaging; PRL, prolactin; T1WI, T1-weighted image(s); T2WI, T2-weighted image(s); TSS, transsphenoidal surgery.

Received March 6, 2003.

Accepted October 27, 2003.

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