Aggressive Pituitary Tumors

Introduction

Autopsy studies have demonstrated clinically unsuspected adenomas in as many as 27% of pituitary glands examined.[1] Most of these adenomas are presumed to be insignificant because the mean annual incidence of clinically important pituitary tumors is only 8 per 100,000 adult women.[2] Pituitary adenomas do account for 10% of all intracranial neoplasms, however, and many tertiary-care centers evaluate and treat over 100 affected patients each year.

Most pituitary adenomas are benign, slow-growing neoplasms that arise from the epithelial cells comprising the anterior pituitary gland. Some exhibit rather aggressive growth patterns, however, and may invade and destroy parasellar structures, recur and exhibit relentlessly progressive growth despite intensive antitumor therapy, and metastasize to intracranial and other distant sites. This review will focus on the biology, clinical presentations, and responses to treatment of the aggressive pituitary tumor subtypes.

Invasive Pituitary Adenomas

One of the more important determinants of surgical success is whether the patient’s pituitary adenoma has escaped the confines of the sella turcica and invaded parasellar structures. Several studies have clearly illustrated that cure rates are lower and recurrence rates are higher in patients with invasive adenomas.[3-5] Accurate and reliable methods to identify patients with clinically significant invasion at the outset are needed.

Radiologic and Intraoperative Biopsy Findings

Magnetic resonance imaging (MRI) and computed tomography (CT) are widely employed in the evaluation of patients with pituitary adenomas. These imaging modalities provide excellent definition of intrasellar and parasellar tissue planes (MRI) and the bony limits of the sella (CT). Many expansive noninvasive adenomas remodel and erode the bony confines of the sella and simply compress parasellar structures. Thus, radiologic features, such as erosion of the sellar floor and lateral tumor growth "into" the cavernous sinuses, are not reliable indicators of invasion.

Reliable radiologic signs of invasion include: (1) a tumor that completely encircles or extends beyond the lateral limit of the intracavernous carotid artery, (2) complete erosion of the clivus, and (3) the presence of tumor within the sphenoid sinuses (Figure 1). In many cases, intraoperative inspection of the sellar walls and parasellar tissues is necessary in order to determine whether invasion has occurred.

Attempts to determine whether intraoperative biopsies of intrasellar and parasellar tissues may be worthwhile measures of invasion have revealed that, surprisingly, most adenomas are invasive.[6,7] Selman et al evaluated biopsies of the dura from 60 patients who underwent transsphenoidal surgery for pituitary adenomas.[6] They noted gross invasiveness in 40% of patients at the time of surgery but found dural microinvasion in 85% of patients. Microinvasion was seen with 69% of microadenomas and with 94% of macroadenomas that extended into the suprasellar region.

Pituitary adenomas are often cured by surgery, and recurrences are much less common than would be expected based on these rates of dural invasion. Most pituitary specialists, therefore, believe that radiologic and gross intraoperative findings of invasion correlate better with clinical outcomes. Scheithauer et al summarized their findings of gross invasion by 365 pituitary adenomas.[8] Invasion by macroadenomas was more common than invasion by microadenomas. The frequencies of invasion by some of the more aggressive pituitary adenoma subtypes are shown in Table 1.

Signs and Symptoms

Invasive adenomas infiltrate and often destroy parasellar tissues, including the dura, bone, cavernous venous sinuses, cranial nerves, paranasal sinuses, subarachnoid space, and leptomeninges. Symptoms and signs depend on the direction and extent of tumoral growth. Patients with indolent tumors may be entirely asymptomatic or have features attributable to anterior pituitary hormonal hypersecretion or pituitary hypofunction.

Anterior-inferior growth into the sphenoid may be accompanied by sinus headaches, cerebrospinal fluid (CSF) rhinorrhea, and epistaxis. Rare patients present with a nasopharyngeal mass. Posterior-inferior growth into the bones comprising the base of the skull may cause headaches, marked bone destruction, and structural abnormalities. Lateral extension into the cavernous sinuses may be accompanied by headache and ophthalmoplegia or facial pain due to compression or, rarely, invasion of the cranial nerves traversing the cavernous sinuses. Suprasellar extension may be rather impressive and can result in headaches, visual compromise, hypothalamic dysfunction, and other problems related to compression of the brain.

Immunohistochemical Studies

Routine histologic and cytologic features have not been shown to reliably correlate with the biological behavior of pituitary tumors.[9] A number of immunohistochemical tools that are more sophisticated than routine immunohistochemical tests used to detect anterior pituitary hormones have been applied to the study of pituitary adenomas.[10-18] Determinations of the proliferation rates of pituitary adenomas by immunohistochemical detection of proliferating cell nuclear antigen (PCNA), Ki-67, and MIB-1 have shown that invasive and recurrent adenomas have higher growth fractions than do noninvasive adenomas.[10-15]

Thapar et al employed MIB-1 immunochemistry to study the proliferation rates in 70 patients with pituitary adenomas, 33 of whom had invasive tumors, and in 7 patients with pituitary carcinomas.[14] They found higher mean proliferative indices in invasive adenomas and carcinomas than in noninvasive adenomas and normal pituitary glands (Table 2). These findings indicate that the growth fraction of pituitary tumors may be a reliable predictor of tumor behavior.[14]

Additional studies should be performed to determine whether the results of MIB-1 immunohistochemistry would be useful in designing a therapeutic plan for pituitary tumor patients. Preliminary studies have illustrated that decreased immunohistochemical staining of pituitary tumors for the purine-binding factor product of nm23, a metastasizing-suppressor gene, may be a sensitive marker of adenoma invasiveness.[16] Definitive p53 expression, overexpression of epidermal growth factor receptor, and increased protein kinase C activity in pituitary tumors have also been shown to correlate with aggressive behavior.[17-19]

Pituitary Carcinomas

Pituitary carcinomas accounted for 0.13% of 2,342 pituitary tumors treated surgically at Marienkrankenhaus in Hamburg, Germany, between 1970 and 1994.[20] As of 1996, at least 67 cases had been described.[20]

In most published series of pituitary carcinoma, men and women have been affected equally.[20-22] The majority of affected patients were middle-aged, but patients ranged in age from 7 to 75 years. In many cases, a diagnosis of carcinoma was not established until the postmortem demonstration of distant metastases in patients with preexisting tumors.[21] In other cases, signs and symptoms of metastatic disease prompted evaluations, which revealed that affected patients actually had carcinomas. Known pituitary disease had been present for more than 10 years prior to a diagnosis of carcinoma in some patients.[20]

Invasion by itself is not diagnostic of carcinoma. Accordingly, a diagnosis of pituitary carcinoma should not be made unless the following criteria are fulfilled:

• The patient must have a documented history of a pituitary tumor;

• A carcinomatous metastasis must be present;

• The primary tumor and metastatic deposits must be histologically and immunohistochemically similar; and

• Alternative primary and metastatic tumors must be excluded.[20]

Metastases to other intracranial sites, the leptomeninges, spinal cord, and cauda equina occur via subarachnoid spread of the primary tumor. Hematogenous metastases to viscera, including the liver, lungs, kidneys, and heart, as well as the lymph nodes and skeletal system, are common. About two-thirds of reported carcinomas have been hormone-producing tumors (Table 3).[20] The mean survival following the onset of signs and symptoms of pituitary disease is approximately 4 years.[21]

Pituitary carcinomas have been shown to have higher proliferative indices and are more commonly p53-immunopositive than are invasive and noninvasive adenomas (Table 2 and Table 4).[14,17] An increasing load of genetic abnormalities and loss of heterozygosity at several loci known to harbor tumor-suppressor genes (11q13, 13q12-14, 10q26, 1p31-35) have been demonstrated in both invasive adenomas and carcinomas.[23,24] A long-term, prospective study is reportedly underway to determine whether loss of heterozygosity provides useful information for therapeutic decision-making.[24]