Aggressive Pituitary Tumors

Aggressive Pituitary Tumor Subtypes

Corticotroph Tumors

Corticotroph tumors arise from the adrenocorticotropic hormone (ACTH)-producing cells of the anterior pituitary gland. A majority (80%) of patients with endogenous Cushing’s syndrome harbor ACTH-secreting pituitary tumors. Three-quarters of these patients have microadenomas, one-fifth harbor macroadenomas, and the rest have corticotroph hyperplasia.[3]

Corticotroph Macroadenomas--Blevins et al found similar clinical and biochemical features in macroadenoma and microadenoma patients, but tumor-related mass effects were more common in patients with larger tumors.[3] About two-thirds of macroadenomas were invasive.

Cavernous sinus invasion and a tumor size ³ 2.0 cm predicted failure of initial transsphenoidal surgery. Only two-thirds of macroadenoma patients entered remission following initial surgery. Adjuvant surgical procedures proved useful in the management of tumor-related mass effects and hypercortisolism but not in producing remission. Recurrences plagued 36% of patients whose disease had remitted. Adjuvant conventional radiotherapy resulted in normalization of cortisol levels and clinical improvement in some patients, but eucortisolism was not sustained.

Silent Corticotroph Adenomas--Patients harboring these neoplasms typically present with tumor-related mass effects due to macroadenomas and, by definition, exhibit no clinical and biochemical features of hypercortisolism.[25,26] Pituitary apoplexy occurs in nearly one-third of patients. These tumors are invasive, relentlessly progressive, and have a tendency to recur following surgery.

Silent corticotroph adenomas are usually first recognized at the time of an immunohistochemical examination of resected tumor tissue from patients presumed to have "nonfunctional" tumors. These ACTH-immunopositive tumors account for 2% to 6% of all resected nonfunctional pituitary adenomas and for 43% of all corticotroph adenomas.[25] Rarely, they secrete biologically inactive ACTH precursors and proopiomelanicortin (POMC) fragments that can be detected by specific immunoradiometric assays.[26,27] In some cases, these tumors acquired the ability to secrete biologically active ACTH, and the patients developed Cushing’s syndrome.[23]

Nelson’s syndrome has been characterized by a constellation of features, including an expanding ACTH-secreting pituitary tumor, widespread hyperpigmentation, and markedly elevated ACTH levels in patients treated with bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome.[28] Nelson’s syndrome has been reported in as many as 50% of patients within 1.5 to 13 years following bilateral adrenalectomy.[28-30] Patients < 35 years old are at a greater risk for this disorder.[30]

Prophylactic sellar irradiation has been reported to reduce the incidence of Nelson’s syndrome from 50% to 25%.[29] This disorder is not as common as it once was because of advances in microsurgical techniques; transsphenoidal surgical resection is now the preferred treatment for ACTH-secreting pituitary tumors.

Large tumors are invasive in about two-thirds of patients.[8] Tumor progression can result in extensive destruction of parasellar tissues and complications, including CSF rhinorrhea and meningitis.[3] Death ensues because of uncontrolled tumor growth in some patients.[3] Surgical debulking and radiotherapy are the mainstays of therapy for these tumors.

Corticotroph Carcinomas--Most corticotroph carcinomas present as invasive ACTH-secreting adenomas refractory to standard therapy.[20-23] Distant visceral, nodal, and skeletal metastases follow a protracted course of multiple recurrences and progression of residual tumors. A majority of patients succumb to complications related to either hypercortisolism or direct intracranial invasion of vital structures, including the hypothalamus and brainstem.

Lactotroph Tumors

Lactotroph tumors arise from the prolactin-producing cells of the anterior pituitary gland. These tumors account for 40% of all pituitary adenomas. Women typically have microadenomas and men usually have macroadenomas. The biological basis of this sexual dimorphism has not been fully established.

Macroprolactinomas are invasive in more than one-half of patients.[8] Some of these tumors remain within the sella, while others extend beyond its confines and extensively invade the bones comprising the base of the skull (Figure 1).

Fortunately, most macroprolactinomas are sensitive to the inhibitory effects of dopamine(Drug information on dopamine) and dopamine agonists (eg, bromocriptine(Drug information on bromocriptine) [Parlodel], cabergoline(Drug information on cabergoline) [Dostinex], and pergolide(Drug information on pergolide) [Permax]).[31,32] In a multicenter study conducted by Molitch et al, prolactin levels normalized in 12 of 16 women and 6 of 11 men with macroprolactinomas during treatment with bromocriptine.[31] Prolactin levels decreased to < 11% of baseline in all but one patient. Tumor size decreased by 50% or more in 64% of patients.

Nearly one-fifth of prolactinomas have been resistant to treatment with dopamine agonists,[33,34] and, in some cases, paradoxical rapid growth has occurred in response to such treatment. Only about one-third of macroprolactinoma patients have achieved remission following surgery.[32] Recurrences have occurred in 20% to 40% of patients.[32] Normalization of prolactin levels following adjuvant radiotherapy has been unusual.

Giant Prolactinomas--These rather large (> 4 cm) tumors are five times more common in men than in women.[35-37] Giant prolactinomas are aggressive and have a propensity to invade destructively the cavernous sinuses, sphenoid bone, orbit, nasopharynx, and auditory canal. These tumors often extend suprasellarly, invade the subarachnoid space, and displace brain tissue as they grow. Marked hyperprolactinemia is the rule. In a review of 12 patients, Loh et al reported prolactin levels ranging from 1,173 to 29,180 ng/mL (mean, 6,937 ng/mL).[35]

Treatment with dopamine agonists reduces prolactin concentrations by ³ 90% in most patients, but levels rarely normalize.[35-37] Marked reductions in tumor size have been observed. Reported complications of dopamine agonist treatment in these patients include CSF rhinorrhea, meningitis, and pneumocephalus.[38]

Lactotroph carcinomas most often spread to other intracranial sites; however, distant metastases are also common. Resistance to treatment with dopamine agonists has been described in one affected patient.[39]

Somatotroph Tumors

Somatotroph tumors stem from the growth hormone (GH)-producing cells of the anterior pituitary gland. Acromegaly is the constellation of clinical features that occur as a result of GH and resultant insulin-like growth factor-1 (IGF-1) hypersecretion.[40] More than 95% of cases of acromegaly are due to a GH-secreting pituitary adenoma.

Nabarro described a series of 256 patients with acromegaly[41]; 18% of these patients had microadenomas, 47% had intrasellar macroadenomas, and 35% had invasive macroadenomas.

Invasive and Giant Somatotroph Adenomas--Between one-third and one-half of acromegalic patients have invasive macroadenomas, one-fifth have suprasellar extension, and one-tenth have giant adenomas that extend far beyond the confines of the sella.[4,40] Morbidity and mortality in these patients are more often due to complications of persistently elevated GH levels (eg, diabetes mellitus, hypertension, heart disease, and neoplasia) than to local tumor progression.

Fahlbusch et al reported their results using surgery to treat 53 acromegalic patients with invasive adenomas.[4] Only 25% to 40% of patients with invasive tumors and 17% of patients with giant adenomas entered remission following surgery.

In a review of the literature on the treatment of acromegaly with dopamine agonists, Jaffe and Barkan found that bromocriptine normalized IGF-1 levels in 10% of patients.[42] In one double-blind, randomized trial, octreotide(Drug information on octreotide) (Sandostatin) decreased GH and IGF-1 levels in nearly two-thirds of patients and resulted in some degree of tumor shrinkage in 50% of patients.[43] Clinical indicators of disease activity improved significantly in most patients.

Conventional radiotherapy is used widely in the management of patients with residual and recurrent disease. Levels of GH and IGF-1 decrease significantly in patients treated with radiotherapy, but normalization of the dynamics of GH secretion and cure, according to strict definitions, are uncommon.[44] Radiotherapy has been shown to prevent further tumor growth in patients with residual disease.[44]

Sparsely and Densely Granulated Somatotroph Adenomas--Growth hormone-secreting pituitary adenomas constitute a heterogeneous group of tumors. Each tumor type has well-defined histologic and electron microscopic characteristics.[45] The most common tumor subtypes are the sparsely and densely granulated variants, which can be distinguished by electron microscopy and, to some extent, by routine histology. The distinction is important clinically because sparsely granulated tumors have a worse overall prognosis, than the densely granulated variants.[45]

On routine hematoxylin and eosin (H&E) stains, the sparsely granulated tumors are chromophobic, whereas the densely granulated tumors are eosinophilic. Sparsely granulated tumors are usually histologically diffuse, rather than trabecular or sinusoidal like their densely granulated counterparts. Nuclear and cellular pleomorphism is not uncommon in the sparsely granulated tumors.

Silent Somatotroph Adenomas--Patients harboring these tumors usually present with signs and symptoms due to tumoral mass effects and, by definition, have no clinical features of acromegaly.[46-48] Most patients are young women who also have mild to moderate hyperprolactinemia, galactorrhea, and menstrual disturbances. Some patients have elevated GH levels and oral glucose suppression tests characteristic of pathologic GH secretion, but clinical stigmata of acromegaly are usually not present.[47] These rather large, often invasive, and rapidly growing tumors are GH-immunopositive.

Somatotroph carcinomas are uncommon among pituitary carcinomas. Treatment with bromocriptine decreased GH levels by 46% and improved symptoms related to metastases in one patient.[21] Resection of isolated distant metastases resulted in clinical and biochemical remission of acromegaly in two patients.[49,50]

Acidophil Stem-Cell Tumors

These undifferentiated tumors arise from the candidate progenitor of the GH-prolactin cell lines.[51-53] They are usually large, aggressive tumors that extensively erode parasellar bony structures. One-half of affected patients harbor tumors that invade the sphenoid sinus and/or extend into the nasopharynx.[51,53] The duration of clinical symptoms is usually rather short, suggesting that these tumors progress very rapidly. Varying degrees of hyperprolactinemia are present, and one-fifth of patients have acromegaly.[51]

Thyrotroph Tumors

Thyroid-stimulating hormone (TSH)-producing cells of the anterior pituitary give rise to thyrotroph tumors. A majority of these are aggressive, rather large macroadenomas.[5,54-58] Three-quarters of patients have invasive tumors. A greater number of patients with microadenomas are being diagnosed in recent years because treating physicians increasingly recognize the clinical importance of inappropriate TSH secretion in patients who are hyperthyroid.

Most affected patients present with goiter, thyrotoxicosis, and tumoral mass effects.[54,55] Many have been treated with thyroid ablation for presumed Grave’s disease or toxic multinodular goiter. In these patients, a decline in thyroid hormone levels and lack of tumor response to thyroid hormone may explain the aggressive behavior of the tumors.

Surgery results in cure in only one-third of patients. A combination of radiotherapy and surgery probably results in a higher cure rate than does surgery alone (42% vs 31%).[55,59] Normalization of TSH and T4 levels does not always imply that antitumor therapy has eradicated the tumor.[58] Treatment with octreotide normalizes T4 and T3 levels in nearly three-quarters of patients and results in partial tumor shrinkage in about 40%.[59]

Thyrotroph Carcinoma--Only one thyrotroph carcinoma has been described thus far.[60] The patient underwent transsphenoidal and transcranial surgery, as well as radiotherapy for a TSH-secreting macroadenoma. Her residual tumor was stable for 4 years and then rapidly increased in size. Additional radiotherapy and treatment with octreotide resulted in tumor shrinkage. Eight months later, she presented with a sacral mass and was subsequently diagnosed with widespread metastases to lung, liver, and bone.

Gonadotroph Tumors

About one-fifth of "nonfunctional" tumors are invasive.[8] Nearly one-half of null cell adenomas are invasive.[8] About two-fifths of patients have either residual or recurrent tumor after initial surgery.[61] One gonadotroph cell carcinoma has been described in the literature.[62]

Conclusions

Aggressive pituitary tumors are relatively common. They are more difficult to ameliorate and tend to recur following initially successful surgery. Patients with pituitary tumors should be suspected of having aggressive neoplasms until proven otherwise. After primary therapy, they should be followed closely for the remainder of their lives to permit treatment of recurrent disease and comorbidities as early as possible.