Aggressive Pituitary Tumors

Aggressive Pituitary Tumors

ABSTRACT: Although almost all pituitary tumors are benign adenomas, a surprisingly large number of these tumors invade tissues outside of the pituitary gland. Such invasion, by itself, is not diagnostic of pituitary carcinomas, which are exceedingly rare (0.13% of 2,342 pituitary tumors in one series). Several different criteria are available to determine whether a tumor is invasive. Intraoperative biopsies demonstrate an 85% incidence of microscopic invasion of the dura. Evidence of gross invasion at surgery and radiologic evidence of invasion on magnetic resonance imaging (MRI) and computed tomographic (CT) scans occur at a much lower incidence but may be more predictive of surgical cure. Invasive adenomas also have higher proliferation rates than do noninvasive adenomas, as shown by immunohistochemical detection of proliferating cell nuclear antigen (PCNA), Ki-67, and MIB-1. The expression of p53, increased epidermal growth factor receptors, and protein kinase C activity also correlate with invasion and aggressive behavior. Clinically significant invasion is more frequent with macroadenomas. Macroadenomas of all pituitary tumor subtypes except gonadotroph macroadenomas have a greater than 50% incidence of gross invasion. Currently, there is no accepted means of predicting an adenoma’s clinically significant invasiveness and long-term aggressiveness. [ONCOLOGY 12(9):1307-1315, 1998]


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
). 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]


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