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Pituitary Cancer


Pituitary Cancer

Article Author:
Wajeeha Saeed Butt
Article Editor:
Vijay Srinivasan
Updated:
8/10/2020 9:31:44 PM
For CME on this topic:
Pituitary Cancer CME
PubMed Link:
Pituitary Cancer

Introduction

The pituitary gland is also known as the master gland of the body because it regulates hormonal balance. The location of the pituitary gland is in the sella turcica posterior to the sphenoid sinus. The pituitary gland is divided into anterior pituitary, which is made of glandular tissue and posterior pituitary, which is composed of neural tissue. The pituitary gland is connected to the hypothalamus through the pituitary stalk, which consists of portal circulation for the anterior pituitary and neuronal connection for the posterior pituitary. The anterior pituitary gland is regulated by the hormones secreted by the hypothalamus, while the posterior pituitary hormones are produced by the hypothalamus itself and are then stored in the posterior pituitary for release.[1]

There are six hormones produced and secreted by the anterior pituitary, which includes 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 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 thyrotropin-releasing hormone (TRH) from the hypothalamus, and 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.[2]

Pituitary gland tumors are rarely cancerous and mostly benign. The pituitary tumors may be functioning with hormone production or non-functioning without the production of hormones. The functioning tumors cause different types of symptoms depending on the hormone they secrete.[3]

There is a wide variety of treatment modalities, including medical, radiological, and surgical, depending on the etiology, presentation, and symptomology.

Etiology

The exact cause of the pituitary gland tumor is unknown but most likely occurs due to genetic abnormalities and alterations. 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 gland abnormalities, including pituitary adenomas. Other causes may include non-hereditary acquired gene mutations like AIP and GNAS1 gene mutations. No environmental or lifestyle changes have been linked as the cause of this rare tumor, so there are no preventable recommendations at this time.[4][5]

Epidemiology

The incidence of pituitary tumors is largely based on population studies that are conflicting in nature. A recent 15-year study found that the incidence of pituitary tumors was discrepant. Among 100,000 cases diagnosed between 1992-2007, all pituitary adenomas occurred at a rate of 4.0, lactotroph adenomas as 2.2, nonfunctioning adenomas at 1.0, somatotroph adenomas at 0.34, and corticotroph adenomas at 0.17. This is a direct controversy as previous prevalence studies were undermined by at least a four-fold difference in the prevalence of this disease.[6][7]

Age and sex seem to be statistically insignificant correlations to the incidence and prevalence of pituitary tumors.

Pathophysiology

The pathophysiology of pituitary cancer is genetically related, but most of the mutations are unknown and will need ongoing research and further studies.

There are ongoing efforts to determine association with specific gene mutations such as MEN1, Gs-alpha, and AIP. The studies are yet to determine causation rather than a correlation of these genetic mutations.[8]

History and Physical

Pituitary tumors are also known as pituitary adenomas are typically benign tumors. Presentations vary but are largely classified into three presentations. This includes neurological symptoms, an incidental finding on imaging, or hormonal imbalance. On imaging or gross pathology, they can be classified according to their size as macroadenomas when greater than 1 centimeter or microadenoma when less than 1 centimeter.[9]

Symptoms of pituitary tumors are variable depending on the size and location of the tumor. Furthermore, a functioning secretory tumor can have a varying amount of symptomology when compared with a nonfunctioning tumor. Smaller sized tumors, in comparison, will not cause as many as its larger counterparts if they are both secretory tumors.[9]

  • Common to all macroadenomas regardless of which hormones are secreted is a visual field defect. As the adenoma grows larger, it encroaches on the optic chiasm and causes a pathognomic visual field defect. The diminished vision may be unilateral or bilateral and most commonly presents as bitemporal vision field defects.[10]
  • Other common neurological manifestations also include headache, Parinaud's phenomenon, cerebrospinal fluid rhinorrhea, diplopia, or pituitary apoplexy. Neurological symptoms seldom arise independently. Carefully obtained history will augment and facilitate not only the diagnosis but the pathology as well.[10]
  • The most common hormone of these deficiencies is related to the deficiency of gonadotropin. Lack of GnRH leads to hypogonadism. Conversely, the most common hypersecreting pituitary tumor is a prolactinoma. Specific to symptoms prolactinoma are amenorrhea, galactorrhea in females, and erectile dysfunction in males.[11][12]
  • Acromegaly is a pathological condition related to growth hormone excess. Conditions related to acromegaly include gigantism, increased sweating, and frequent headaches.[13]
  • GH deficiency in children can lead to dwarfism and in adults can cause other symptoms of fatigue and muscular atrophy. Routine well-child visit exams are able to detect a lack of progressive growth on children at appropriate ages that often leads to an early diagnosis of this condition.[14]
  • Excess of ADH will lead to a syndrome of inappropriate ADH secretion (SIADH), causing symptoms of generalized weakness and dizziness in most patients and can be as severe as causing status epilepticus. While inadequate production of ADH can cause symptoms of central diabetes insipidus, which includes polyuria and dryness of the mouth.[15]
  • Cushing's syndrome is caused by an excess of ACTH, leading to several different manifestations. Easy bruising, muscle weakness, rapid weight gain, and acne are common early features of this condition.[16][17]
  • Thyroid related pathological manifestations are very rare but can include symptoms of hypothyroidism or hyperthyroidism. There is not enough researched data to known the prevalence of the disease or disease course specific to pituitary adenomas and its correlation.[18]
  • ACTH deficiency often manifests in symptoms of weakness, nausea, vomiting, and weight loss. ACTH, however, can impact many other neurohormonal regulatory systems in the body and can present in a varying form of a constellation of symptoms.[16]
  • GnRH deficiency can cause amenorrhea in women, and impotence and loss of libido in adult males. GnRH deficiencies often are missed in childhood due to the lack of forthcoming symptoms that can be relayed to practitioners. They become more apparent at puberty and the years following with a lack of proper development.[19][20]

Evaluation

After careful review of the history and physical exam, typically, the clinician can direct diagnosis and imaging modalities.

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. Hormonal testing is performed primarily to rule out hypersecretory tumors. Routinely tested levels are a must and include prolactin, insulin-like growth factor (IGF-1). Early morning cortisol levels are reserved for patients with symptomatic manifestations of Cushing syndrome.[21]

Hyposecretory adenomas are tumors that cause 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 an MRI at the time of diagnosis to rule out a pituitary tumor as the cause. Confirmatory testing with stimulatory testing follows the basic laboratory testing, and these tests are specific to the hormone involved.[18][22][23]

Imaging

Imaging is a necessary component of a complete workup of a pituitary tumor. It determines the classification of microadenoma versus macroadenoma that guides further treatment and management. Initial computerized tomography (CT) can be done to determine the mass-effect. However, this is inadequate for the workup of a suspected pituitary tumor. A magnetic resonance imaging (MRI) of the pituitary gland with and without contrast is of paramount importance.

Macroadenomas identified on MRI that do not require surgical intervention at the time of diagnosis, a repeat hormonal testing, and MRI is performed after six months of the initial testing period.[10]

Microadenomas that are nonfunctioning require MRI after a year of diagnosis followed by periodic MRIs every 1 to 2 years to monitor for an increase in size or abutment towards the optic chiasm and nerves. There are no guidelines on repeat hormonal testing without new symptomatology for microadenomas and is left to the discretion of the clinician.[10]

Regardless of the size classifications, both microadenomas and macroadenomas, require a minimum of 3 years of follow up. This includes further imaging with MRIs and/or laboratory testing if warranted in newly symptomatic patients.[10]

Treatment / Management

Pituitary tumors have varying options for treatment. These options vary with increasing degree of risk. Management with watchful waiting for surgical and radiological interventions is the spectrum of options to successfully manage pituitary tumors.

Most commonly, pituitary tumors usually do not require any treatment. Treatment considerations occur on the basis of size, the involvement of the optic chiasm, symptoms, and patient wishes. Medical management with systemic medications for hormone supplementation or hormone regulation is determined to be necessary on the basis of symptoms. Surgical options are generally curative, but the patients must meet certain requirements. Radiation therapy discussed separately also remains an augmented method of management.[24][25]

Pituitary tumors that present with visual field defects or compression of the optic nerves or chiasm will require a neurosurgery evaluation at the time of presentation as surgical intervention is the gold standard treatment. Tumors that are found without visual field pathologies are monitored regularly for their increase in size or growth towards the optic chiasm and nerves.[25]

Nonsurgical modalities of treatment are limited to medical management. Typically hypo and hyper secreting tumors are managed with hormonal supplementation or antagonist, respectively. 

Specific treatments for specific hormonal excess are as follows:

-Prolactin secreting adenomas are treated with dopamine agonists such as cabergoline. Cabergoline is preferred over bromocriptine for a better safety profile.[26]

-SIADH is treated by treating the cause of the tumor, fluid restriction, and vasopressin antagonists.[27]

GH secreting tumors, TRH secreting tumors, Cushing disease-causing tumors are all treated with transsphenoidal surgery (TSS) - specifically transsphenoidal resection of the glandular tumor. Specific to GH secreting tumors, if remission is not achieved with surgical treatment alone, these patients are further treated with somatostatin analogs or radiation therapy.[25]

Differential Diagnosis

Differential diagnoses for pituitary tumors are limited due to the nature of the presentation. Differentials include other tumors found near the sella turcica. These are usually benign tumors such as craniopharyngiomas, meningiomas, and pituicytomas. There are a few malignant neoplasms that can occupy the same anatomical space, such as germ cell tumors, chondromas, and primary lymphomas.[28][29]

Surgical Oncology

Transsphenoidal surgery (TSS) is usually the preferred modality in a surgical approach. Operator preference is given to using an endoscope or a microscope for performing the surgery with neither being superior to the other. There are serious side effects, including partial or complete vision loss, hemorrhage, and meningitis, although they occur less frequently. Experienced surgeons have greater success rates and lower incidences of complications. As such, the most skilled surgeon with the most experience in removing pituitary tumors should be involved in the care of these patients.[25]

Hormonal therapy is recommended prior to surgical treatments in secretory adenomas. Post-surgical hormone management might be necessary if all of the glandular tissue was not removed successfully. Specifically in lactotroph adenomas, regardless of size, requires therapy with a dopamine agonist prior to resection. Macroadenomas that affect vision undergo transsphenoidal resection without treatment with dopamine agonists.[30][31]

Somatotroph adenomas that are large in size and/or impair vision, the first-line treatment is surgical resection. Despite the inability to remove the entire tumor, surgical resection is preferred to increase medication response.[32][33]

Cortioctroph secreting tumors, regardless of size, once again, transsphenoidal resection is the first-line therapy. Early re-exploration for incomplete resection is recommended to be performed early in the clinical course post-resection. Remission can occur in up to 70% of patients who have complete resection with or without re-exploration.[34][35]

Gondatroph secreting tumors and other nonfunctioning tumors are followed with serial imaging. Tumors encroaching the optic chiasm, or expanding rapidly are also recommended to be resected surgically.[36]

Radiation Oncology

Radiation therapy is of paramount value in the management of pituitary adenomas. Radiation therapy can be done using x-rays from a linear accelerator or gamma radiation, or protons. Single large dose radiation is known as stereotactic radiosurgery (SRS). Multiple sittings to deliver radiation is known as fractionated radiation therapy. Radiation therapy reduces the volume in more than 90% of patients but has a variable effect on hormonal hypersecretion. Radiation therapy can cause hypopituitarism in 80% of patients after ten years but has a very low risk on the optic chiasm.[24]

Radiation therapy remains an adjunct to medical or surgical therapy and is neither a first-line nor a single therapy modality. SRS is recommended for adenomas that are at least 3mm away from the optic chiasm and are smaller than 3 cm in diameter. Inversely, fractionated radiation therapy is done for adenomas larger than 3 cm and which are more proximal to the optic chiasm.

Dosage of radiation administered depends on the type of adenoma, its functioning state, its distance to the optic chiasm, and modality of radiation.[24]

Patients that are on medications to reduce endogenous hormonal levels will need to discontinue medications up to 1 month in advance and at least 1 month after radiation therapy.

Medical Oncology

Systemic therapy includes hormone replacement therapy (HRT) and drug therapies. These modalities can be given alone but more often combined with surgical and/or radiological therapies.[37][18]

HRT is often needed for patients with hypopituitarism of a certain hormone, as discussed above. This hormone is exogenously produced and given as a replacement of the deficient hormone. Examples include exogenous thyroid hormone, exogenous growth hormone, and exogenous testosterone.[34]

Hypersecreting tumors have various other medications to control the amount of circulating hormone. Bromocriptine and cabergoline are used in patients with excessive prolactin. Octreotide and pegvisomant are used to treat patients with acromegaly. Octreotide can also be used in specific circumstances for TSH secreting tumors.[38][29]

Staging

Pituitary cancer is almost always benign and rarely malignant and therefore there are no widespread consensus guidelines on a staging method. Patients with rare forms of malignant pituitary tumors are referred to specialists for recommendations on staging and further management.[28]

Prognosis

The overall prognosis of pituitary tumors remains fair in terms of morality when compared to other neurohormonal tumors. The survival rate is approximately 82% in 5 years after diagnosis.[39]

Tumors that undergo treatment in accordance with their presentation are almost always curative treatments. Although morbidity from hormonal regulation remains to be an issue, it does not have an impact on survival or quality of life.[39]

Hypersecreting adenomas tend to have a prolonged course and require careful monitoring of symptoms and re-imaging throughout life. They benefit from retreatment from modalities discussed above.[40][41]

Among the hyposecretory tumors, 18% of adenomas and 25% of prolactinomas require further treatment due to incomplete response to initial therapy. HRT post-resection in adenomas can be for a lifetime.[28]

Complications

One of the most notorious and serious complications for any type of 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.[10]

Other complications are dictated by the hormones involved and are relevant to the hormones involved, as discussed above.[42]

Diabetes insipidus can occur in macroadenomas, which cause a deficiency of vasopressin and can, in turn, cause increased thirst and polyuria.[43]

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

Surgical and radiological interventions have their own associated iatrogenic complications, as discussed in the appropriate sections.[14]

Deterrence and Patient Education

The pituitary gland is located in the base of the brain and is involved in hormonal regulation. The symptoms manifested depend on the size of the tumor. The symptoms that should be monitored include irregular menstrual cycles, milky discharge from breasts in females, and can cause erection problems or low sex drive in men. If there is an excess of steroid hormones, patients will typically have symptoms that will include weight gain, weak bones, and high blood pressure. There are several other related conditions or symptoms caused by other types of hormones that may present with big hands and large heads if noticed by the patient or parent in childhood. Patients can also experience chronic headaches and vision changes.

There are varying modalities of diagnosis that typically involve a combination of laboratory testing and imaging. This will be determined by the physician on a case-by-case basis.

The prognosis of all tumors remains good and has a good survival ratio exceeding 80%. Timely care from specialists can benefit patients' mortality and morbidity.

Enhancing Healthcare Team Outcomes

Pituitary tumors are rare, occurring tumors that require acute attention and benefit from specialists that are knowledgeable in the area. Improving outcomes is a matter of diligent care and communication between interdisciplinary teams. Patients require a thorough workup, including multiple endocrinological testing, imaging, and surgical involvement with possibly early radiological intervention. 

Patients should have access to and have continued discussions with specialists to discuss the risks and benefits of different treatment options. Evidence-based medicine should be practiced, and patients should be given appropriate consultations to the most experienced providers.

Typically the interprofessional team will include a primary care physician, an endocrinologist, and a neurosurgeon with previous experience in pituitary tumors with a good success rate.

There are ongoing trials that are needed to understand the rare occurrences of malignancies of pituitary tumors.



(Click Image to Enlarge)
CT Head Pituitary Macroadenoma
CT Head Pituitary Macroadenoma
Contributed by Scott Dulebohn, MD

References

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