Pituitary Cancer

Etiology

The exact underlying etiology of pituitary gland tumors is not yet known but most likely occurs due to genetic abnormalities and alterations. There are ongoing studies focusing on the underlying molecular mechanisms of pituitary tumor behavior. Transcriptional and post-transcriptional regulation by way of methylation, histone regulation[6][7], and modification of the expression of long non-coding ribonucleic acids (RNAs) or specific microRNAs have been found to correlate with malignancy in a few studies.[8] Pituitary tumors associated with specific germline mutations (MEN1, AIP, GPR101) have been shown to be more frequently resistant or invasive.[9]

Some hereditary conditions are also related to an increased risk of pituitary tumors. For example, multiple endocrine neoplasias (MEN)-1 syndrome is often associated with pituitary adenomas. No environmental or lifestyle changes have been directly linked to the underlying etiology of pituitary tumors, and therefore there are no preventable recommendations at this time.[10][11]

Epidemiology

The prevalence of pituitary carcinoma is extremely low and estimated at 1/1,000,000, which is <.01% of all detected anterior pituitary gland tumors.[12] Pituitary carcinomas usually originate from functioning pituitary gland tumors and are mostly represented by lactotroph and corticotroph carcinomas, with each representing around one-third of cases.[13][14] 

The median age at diagnosis of pituitary carcinoma is 44 to 45.[13][15] The median latency period from the time of diagnosis to the occurrence of the first metastasis is approximately 5 to 7.5 years.[15][13] A switch from a non-functioning pituitary tumor to a functioning tumor has been documented in cases where pituitary adenomas have progressed to pituitary carcinomas.[16][17][15]

Pathophysiology

The pathophysiology of pituitary cancer is genetically related, but most mutations are unknown and actively being studied. There are ongoing efforts to determine the association with specific gene mutations. 

There are six hormones produced and secreted by the anterior pituitary, which include luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotrophic hormone (ACTH), prolactin, thyroid-stimulating hormone (TSH), and growth hormone (GH). The hormones stored in the posterior pituitary gland are oxytocin and anti-diuretic hormone (ADH).[1]

The release of LH and FSH is controlled by gonadotropin-releasing hormone (GnRH) from the hypothalamus, while ACTH hormone secretion is controlled by the release of corticotropin-releasing hormone (CRH) from the hypothalamus. TSH is released after being stimulated by the thyrotropin-releasing hormone (TRH) from the hypothalamus. The hypothalamic hormones that control the release of GH are regulated by two hormones, including growth hormone-releasing hormone (GHRH), which stimulates the release, and somatostatin, which inhibits the release of GH. The release of prolactin is inhibited by dopamine release from the hypothalamus.[18]

Pituitary gland tumors are rarely cancerous and mostly benign. Pituitary tumors may function with hormone production or non-functioning without producing hormones. Functioning tumors cause different types of signs and symptoms depending on the specific hormone they secrete.[19]

Histopathology

The most common subtypes of pituitary carcinoma are corticotroph and lactotroph carcinomas.[16] Some carcinomas may appear similar to benign tumors of the pituitary gland and lack features such as cellular atypia and cellular dedifferentiation. To date, there is no single pathologic marker for malignancy of the pituitary gland. The concept of 'high-risk adenomas' has been proposed, which includes rapid growth, a high Ki67 index, and radiologic invasion.[20] 

It has been proposed that tumors that are invasive, clinically aggressive, and highly proliferative (mitotic count >2, Ki67 index ≥10%, and p53 positive) should be considered pituitary tumors with malignant potential.[21] There are numerous prior and active studies focusing on the molecular mechanisms of pituitary tumor behavior. Corresponding markers have, unfortunately, been poorly validated to date. 

History and Physical

The clinical presentation of pituitary tumors is classically divided into functional (secreting) and non-functional (nonsecretory) tumors. In general, functional tumors present earlier as a result of symptoms related to the physiologic effects of the excess hormones they secrete.[22] Unless incidentally discovered on radiographic imaging for work-up of a different indication, non-functional pituitary tumors typically do not present until they are large enough to result in neurologic deficits due to mass effect on adjacent structures. Pituitary carcinoma is suspected if neck or back pain is present, suggesting possible spine metastases. 

Structures that are commonly compressed by pituitary tumors resulting in symptoms include the optic chiasm, the cavernous sinus, and the third ventricle. Mass effect on the optic chiasm due to tumor growth superiorly through the diaphragma sella commonly presents as bitemporal hemianopsia and may also cause a decrease in visual acuity. Cranial nerves within the cavernous sinus include the oculomotor nerve (III), trochlear (IV), first and second divisions of the trigeminal nerve (V1, V2), as well as abducens nerve (VI). If a pituitary tumor exerts a mass effect on the cranial nerves in the cavernous sinus, it may result in ptosis, diplopia, or facial pain. Occlusion of the cavernous sinus itself may result in chemosis and ptosis. If the third ventricle is involved, the mass effect may result in obstructive hydrocephalus. Larger pituitary tumors, such as macroadenomas, may produce non-specific symptoms, such as headaches, potentially due to increased intrasellar pressure. Invasive pituitary tumors may infrequently present with cerebrospinal fluid (CSF) rhinorrhea.[23]

Symptoms Related to Hormone Oversecretion

1. Prolactin: Oversecretion of prolactin may cause impotence in men. In females, over-secretion of prolactin can cause amenorrhea-galactorrhea syndrome. 
2. Growth hormone (GH): Produces gigantism in prepubertal children. In adults, it presents as acromegaly. 
3. Adrenocorticotropic hormone (ACTH): Overproduction of ACTH results in Cushing's disease, which presents with a constellation of findings that is not limited to but includes hypertension, cutaneous purple striae, reduced libido in men and women, atrophic skin with easy bruising, depression, generalized muscle wasting, and weight gain, which is characterized by centripetal fat distribution in addition to fat deposition in the upper thoracic spine, supraclavicular fat pad with a round face and slender extremities. 
4. Thyrotropin (TSH): Secondary hyperthyroidism, which may present with symptoms of hyperthyroidism such as sweating, intolerance to heat, diarrhea, and weight loss, among others. 
5. Follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH): Oversecretion of the gonadotropins typically does not produce a clinical syndrome. Oversecretion of FSH may produce ovarian hyperstimulation in women of reproductive age, causing ovarian cysts in addition to amenorrhea and galactorrhea.[24]

Symptoms related to the underproduction of pituitary hormones may be caused by compression of the normal pituitary gland by large pituitary tumors. The order of sensitivity of compression in which pituitary hormones become depressed is GH, gonadotropins (FSH & LH), TSH, ACTH, and prolactin. The order may be remembered by the mnemonic Go Look For The Adenoma Please.

Pituitary apoplexy can occur due to the rapid expansion of a pituitary tumor from necrosis or hemorrhage; any characteristically presents with headache, neurologic deficit, and/or endocrinologic deficit. In contrast to the typical situation with pituitary tumors, pituitary apoplexy more commonly presents with ophthalmoplegia rather than visual pathway deficit.[25]

Evaluation

Laboratory Tests

Laboratory testing involves both blood and urine testing. Specific hormonal level testing is usually dictated by correlating symptoms; however, more commonly, a panel of hormone testing is performed when incidental or nonfunctioning tumors are involved. An endocrinologic workup is performed primarily to rule out hypersecretory tumors. Routinely tested levels include prolactin and insulin-like growth factor (IGF-1). Early morning cortisol levels are reserved for patients with symptomatic manifestations of Cushing disease.[26]

Hyposecretory adenomas are tumors that cause the hyposecretion of hormones from the pituitary gland and can involve one or more hormones. Hyposecreting tumors require measuring levels of multiple hormones such as thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), free T4, total testosterone (in men), and cortisol. Hypogonadotropic hypogonadism requires magnetic resonance imaging (MRI) of the brain at the time of diagnosis to rule out a pituitary tumor as the underlying etiology. Confirmatory testing with stimulatory testing follows basic laboratory testing, and these tests are specific to the hormone of interest.[27][28][29]

Imaging

A sellar MRI is the recommended radiographic imaging technique for evaluating the pituitary gland. On imaging or gross pathology, they can be classified according to their size as macroadenomas when greater than 1 centimeter or microadenomas when less than 1 centimeter.[30] A computed tomography angiography (CTA) of the head may also be useful for pre-operative planning to evaluate the relationships of adjacent vascular structures, such as the internal carotid artery. In the absence of histopathologic features of malignancy, pituitary carcinoma is confirmed when systemic and/or craniospinal metastasis is identified radiographically, typically with spinal MRIs if suspected.[31]

Treatment / Management

Surgery

It is estimated that approximately 80.5% of pituitary carcinomas have been treated at least twice with surgery (including 27.9% of patients who underwent at least four surgeries).[16] Surgical debulking can be beneficial in patients with mass-effect on adjacent structures such as the optic pathway, third ventricle, or in advanced cases, the brainstem.  (B3)

Radiotherapy 

In one survey, it was estimated that approximately 42.9% of patients with pituitary carcinoma were treated with at least two courses of radiotherapy.[16] The optimal technique(s) should be discussed with specialists in radiotherapy and radiosurgery on a case-by-case basis. Conformal radiotherapy can be considered and aims to provide antitumoral and antisecretory objectives. Data on the utility of conformal radiotherapy is limited to aggressive, rapidly growing tumors and pituitary carcinoma. There are a few case reports of using two different radiation modalities to treat aggressive pituitary tumors with suboptimal efficacy.[32] Radiotherapy should be considered as a part of a multimodal treatment approach as its efficacy is often delayed.(B2)

Chemotherapy

Temozolomide is an oral alkylating agent which exerts its pharmacologic effect by deoxyribonucleic acid (DNA) methylation, resulting in irreversible DNA damage. Temozolomide is the recommended first-line chemotherapy. Temozolomide has been shown to improve progression-free and overall 5-year survival rates in responders.[33][34][35] Despite temozolomide being the first-line chemotherapeutic agent, only 6% of patients with pituitary carcinoma showed a complete radiologic response (mass absent radiographically), 31% showed partial response (tumor size decreased by >30%), stable disease was seen in 33% (tumor size increased by < 10% or decreased by < 30%), and progressive disease (tumor size >10% or new metastasis) was seen in 30%.[16] Improved response to temozolomide was observed in three specific situations: concomitant administration of radiotherapy, clinically functioning pituitary tumor, and low O6-Methylguanine-DNA Methyltransferase (MGMT) immunohistochemical expression.[16](B3)

For tumors that are progressing on or after the first course of temozolomide, there are, unfortunately, no other evidence-based treatments available at this time; therefore, maximizing and prolonging temozolomide efficacy is critical. Despite limited experience, options include long-term treatment with temozolomide as long as it is effective and clinically tolerated.[36][37] Additionally, using temozolomide earlier in the management of pituitary carcinoma as a part of the Stupp protocol instead of as “rescue therapy” is an option.[36][38][39]   

Antisecretory Medications

Controlling pituitary hormone hypersecretion is as mandatory in patients with pituitary cancer as in any patient with a functional pituitary tumor. For patients with lactotroph tumors, dopamine agonists, such as cabergoline, can be given at high doses.[40] In patients with hypercortisolism, steroidogenesis inhibitors, such as metyrapone or ketoconazole (11-beta-hydroxylase inhibitor, and antifungal agent, respectively), are crucial to avoid morbidity and mortality from excess cortisol.[41] Finally, for somatotrophic tumors, somatostatin analogs (octreotide), growth hormone receptor antagonists (pegvisomant), or dopamine agonists can be continued at maximally tolerated doses. (A1)

Future Therapies  

Potential future therapeutic options that are currently being studied include immunotherapy as well as molecularly targeted therapies such as bevacizumab (anti-VEGF antibody), everolimus (mTOR inhibitor), and several tyrosine kinase inhibitors (TKIs).[42]

Differential Diagnosis

Pituitary cancer arises from the pituitary gland. A helpful mnemonic for the radiographic differential diagnosis of lesions within the pituitary region is SATCHMO. Satchmo is best known as the nickname for the famous musician Louis Armstrong. 

• S: Sarcoidosis, sellar tumor (pituitary adenoma, pituitary carcinoma)
• A: Aneurysm (typically superior hypophyseal)
• T: Teratoma, tuberculosis (other granulomatous diseases)
• C: Craniopharyngioma, chordoma, cleft cyst (Rathke's)
• H: Hypothalamic glioma, hamartoma, histiocytosis 
• M: Meningioma, metastasis 
• O: Optic nerve glioma

Radiation Oncology

It has been estimated that approximately 42.9% of patients with pituitary carcinoma are treated with at least two courses of radiotherapy.[16] The optimal technique(s) should be discussed with specialists in radiotherapy and radiosurgery on a case-by-case basis. Conformal radiotherapy can be considered and is aimed at providing antitumoral and antisecretory objectives. Data on the utility of conformal radiotherapy is limited to aggressive, rapidly growing tumors and pituitary carcinoma. There are a few case reports of using two different radiation modalities to treat aggressive pituitary tumors with suboptimal efficacy.[32] Radiotherapy should be considered as part of a multimodal treatment approach as its efficacy is often delayed.

Medical Oncology

Temozolomide is an oral alkylating agent which exerts its pharmacologic effect by deoxyribonucleic acid (DNA) methylation, resulting in irreversible DNA damage. Temozolomide is the recommended first-line chemotherapy. Temozolomide has been shown to improve progression-free and overall 5-year survival rates in responders.[33][34][35] Despite temozolomide being the first-line chemotherapeutic agent, only 6% of patients with pituitary carcinoma showed a complete radiologic response (mass absent radiographically), 31% showed partial response (tumor size decreased by >30%), stable disease was seen in 33% (tumor size increased by <10% or decreased by <30%), and progressive disease (tumor size >10% or new metastasis) was seen in 30%.[16] Improved response to temozolomide was observed in three specific situations: concomitant administration of radiotherapy, clinically functioning pituitary tumor, and low O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemical expression.[16]

For tumors that are progressing on or after the first course of temozolomide, there are, unfortunately, no other evidence-based treatments available at this time; therefore, maximizing and prolonging temozolomide efficacy is critical. Despite limited experience, options include long-term treatment with temozolomide as long as it is effective and clinically tolerated.[36][37] Additionally, using temozolomide earlier in the management of pituitary carcinoma as a part of the Stupp protocol instead of as “rescue therapy” is an option.[36][38][39]   

Controlling pituitary hormone hypersecretion is as mandatory in patients with pituitary cancer as in any patient with a functional pituitary tumor. For patients with lactotroph tumors, dopamine agonists, such as cabergoline, can be given at high doses.[40] In patients with hypercortisolism, steroidogenesis inhibitors, such as metyrapone or ketoconazole (11-beta-hydroxylase inhibitor, and antifungal agent, respectively), are crucial to avoid morbidity and mortality from excess cortisol.[41] Finally, for somatotrophic tumors, somatostatin analogs (octreotide), growth hormone receptor antagonists (pegvisomant), or dopamine agonists can be continued at maximally tolerated doses. 

Potential future therapeutic options that are currently being studied include immunotherapy as well as molecularly targeted therapies such as bevacizumab (anti-VEGF antibody), everolimus (mTOR inhibitor), and several tyrosine kinase inhibitors (TKIs).[42]

Prognosis

The overall prognosis of benign pituitary tumors remains fair in terms of mortality compared to other neurohormonal tumors. The survival rate is approximately 82% five years after diagnosis.[43] The prognosis is much less favorable for pituitary carcinoma. The mean survival time for pituitary carcinoma is <4 years once metastases have been identified.[14]

Complications

One of the most notorious and severe complications of any pituitary tumor is blindness. The encroachment of the tumor on the chiasm or nerves can cause partial or complete blindness. Some tumors that do not present with visual defects can progress rapidly to cause vision loss.[44]

Diabetes insipidus can occur in macroadenomas, which causes vasopressin deficiency and can, in turn, cause increased thirst and polyuria.[45]

Pituitary apoplexy, or hemorrhage of the pituitary gland, requires emergent attention and can cause a severe headache, ophthalmoplegia, and visual disturbances immediately at onset.

Due in part because of need for repeat surgery, as well as the severity of the underlying disease, an increased number of surgical complications, including hydrocephalus requiring placement of a ventricular shunt, is observed.[46][47] To minimize the risk of major adverse events and complications, surgery should be performed by a neurosurgeon with a high volume of experience in treating pituitary masses.[4] Cases of sellar fibrosarcomas, osteosarcomas, and undifferentiated pleomorphic sarcomas have been reported in patients treated with radiotherapy for pituitary adenoma, developing after a mean of 10.5 years.[48] There is some controversy surrounding radiotherapy’s pathogenic role in transforming benign into malignant pituitary tumors. In a large patient series including 641 benign pituitary tumors, the rate of suspected malignant transformation when patients were followed over eight years was not statistically different from that of the general population.[49]

Additional peri-operative complications which may occur include infection (meningitis or pituitary abscess), CSF leak, entry into the cavernous sinus with possible injury to structures contained within the sinus, and rarely internal carotid artery rupture, which may occur intraoperatively or in a delayed fashion due to a pseudoaneurysm created during surgery.[50][51][52][51]