Endocrine cancers

Related conditions: Prolactinoma, acromegaly, gigantism, pituitary adenoma, thyroid cancer (papillary, medullary, follicular, C-cell, anaplastic), parathyroid adenoma, parathyroid carcinoma, pheochromocytoma, insulinoma, glucagonoma, somatostatinoma, multiple endocrine neoplasia (MEN) type 1 (Wermer syndrome), MEN type 2A (Sipple syndrome), MEN type 2B, carcinoid tumor, islet cell tumor, Cushing disease

Definition: Endocrine cancers are a group of benign and malignant growths that originate from the tissues of the endocrine glands. The endocrine glands are responsible for regulating a number of bodily functions, including cellular metabolism, growth, development of male and female primary and secondary sex characteristics, the menstrual cycle, water and sodium balance, calcium distribution, and blood pressure. A number of functions also relate to reactions to stressors, which include the fight-or-flight response and immune system modulation.

The endocrine system is related functionally to the nervous system in that it maintains the long-term equilibrium of vital organ systems. Complex feedback loops at the pituitary (secondary) or hypothalamic (tertiary) level as well as physiologic demands normally regulate hormone secretion. The hypothalamus-anterior pituitary axis regulates several glands, including the adrenal cortex, thyroid gland, and reproductive system. The hypothalamus-posterior pituitary axis directly regulates physiologic functions such as breast milk ejection and uterine contraction, and stimulates water retention in the kidneys. The autonomic axis regulates body functions in response to stress and injury and includes the adrenal medulla, the juxtoglomerular apparatus in the kidney, and the alpha and beta islet cells in the pancreas. The parathyroid gland does not belong to any axis. Endocrine cancers can alter this equilibrium, leading to potentially life-threatening conditions in extremis.

Risk factors: The risk factors for developing an endocrine cancer depend on the cellular origin of the cancer and the stimulus that promotes cancer cell proliferation, and they can generally be classified as environmental or hereditary. Environmental risk factors may include exposure to radiation as in the case of thyroid cancers. Although spontaneous cases do arise, such as in cases of parathyroid adenomas and insulinomas, other endocrine cancers arise as part of a distinct clinical syndrome with multiple endocrine gland involvement.

The most prominent risk factor for the development of hereditary endocrine tumors is a genetic predisposition. The MEN syndromes are autosomal dominant, with a 50 percent probability of offspring inheriting the disease.

Etiology and the disease process: The transformation of a normal endocrine cell into a cancerous cell is often caused by a single or a number of additive unrepaired gene alterations that prevent uncontrolled cellular division and programmed cell death. These cancer cell transformations do not differ much from the transformation of cells in other organs and have common etiologic agents such as the tumor-suppressor gene TP53. However, specific tumor-suppressor gene mutations are responsible for the genesis of certain endocrine cancers. MEN 1 originates from either a mutation within the embryonic crest cell or inactivation of the tumor-suppressor gene MEN1, located on the long arm of chromosome 11 (11q13). MEN 2A, 2B, and familial medullary thyroid carcinoma originate from a mutation in the RET proto-oncogene, located on the long arm of chromosome 10 (10q11.2). MEN1 tumor-suppressor gene mutations, along with changes in the RET proto-oncogene, have also been implicated in sporadic medullary thyroid carcinoma cases. Papillary thyroid cancer genesis has been attributed to mutations in the PTC and TRK-A genes, in conjunction with the RET proto-oncogene and RAS oncogene, respectively.

Endocrine cancers may be functional or nonfunctional. Functional endocrine cancers are so named because the hormone secretions from the cancer cells have the same effect on the same target organs as do hormones from normal endocrine cells. These cancer cell hormones may be structurally identical or slightly altered. Functional endocrine cancers do not respond in a normal fashion to the inhibitory feedback mechanisms in normal endocrine cells. Although some cancers lack receptors that decrease or halt hormone secretion, other cancers may be stimulated by their own secretions in a way that resembles the inhibitory mechanisms of some endocrine glands. Nonfunctional endocrine cancers do not secrete hormones or hormone-like molecules. They may be derived from hormone-secreting cells but are more often derived from stromal tissue (tissue surrounding supporting tissue). They may nonetheless interfere with normal gland function by compressing or infiltrating surrounding tissue.

Incidence: According to the American Cancer Society, about 65,630 new cases of endocrine cancer were reported in 2014, affecting women more than twice as often as men. By affected organ, thyroid cancers are the most common of all endocrine cancers, followed by pituitary gland cancers. Specific data regarding the rarer cancers are sparse. Some endocrine cancers, such as thyroid cancer, tend to appear in individuals older than fifty years.

Symptoms: Symptoms of endocrine cancer are generally related to both the indirect effects of malignancy, such as fever, malaise, loss of appetite, weight loss, or paraneoplastic syndrome, and the direct and gland-specific effects of the tumor. The specific symptoms of endocrine cancers are classically related to the endocrine gland axis from which they originate, wherein serum measurements of the hormones causing symptoms directly or indirectly follows. For example, a tumor in the thyroid gland causing symptoms of increased cellular metabolism (sweating, irritability, palpitations, irregular heartbeats, heat intolerance) may be confirmed by measurements of both thyroid-stimulating hormone (TSH) and thyroid hormone. Alternately, a TSH tumor would be suspected in a patient who exhibits hyperthyroid symptoms but has a normal thyroid gland, being mindful of the loss of the inhibitory feedback mechanism in these tumors. Other endocrine cancers may require a combination of laboratory tests relating to their functional status in addition to hormone levels. For example, a simple parathyroid gland tumor secreting parathyroid hormone-like substances may manifest in a patient with recurrent kidney stones and heart rhythm disturbances from a high serum calcium with a correspondingly low phosphorus level because of bone demineralization.

Symptom overlap is more often present because of the different possible locations of a tumor along the hypothalamic-pituitary-target organ axis, requiring an exhaustive diagnostic workup. For instance, an anterior pituitary tumor such as a prolactinoma may have the symptoms of milk production and cessation of menses in a nonpregnant woman. Similarly, a gonadotropic hormone-secreting tumor or gonadotropin-releasing hormone (GnRH) tumor in the hypothalamus may also halt the menstrual cycle.

Endocrine cancers can also manifest by compressing or infiltrating adjacent tissue and structures, altering their function. An example is anterior pituitary tumors, which may initially manifest as a partial blindness termed bilateral hemianopsia (involving the right and left visual fields of the right and left eyes, respectively) in which right and left optic nerve fibers are compressed as they cross below the anterior pituitary. The specific pituitary cells may be nonfunctional or secrete excess hormones that can affect the axis accordingly. Posterior pituitary tumors may also manifest in this fashion. Other cancers may remain undetected or grow to large sizes (as with ovarian cancers).

The hereditary multiple endocrine neoplasia (MEN) syndromes consist of two main variants, MEN 1 and MEN 2. MEN 1 has pituitary, parathyroid, and pancreas involvement. MEN 2A manifests as medullary thyroid cancer (MTC), pheochromocytoma, an adrenal medulla tumor, and parathyroid hyperplasia (overproliferation). MEN 2B is essentially type 2A without parathyroid involvement and with the addition of mucosal neuromas and gut ganglioneuromas (nerve cell tumors) with a Marfanoid body habitus (long limbs and fingers, flexible joints, lens dislodgement, and mitral valve prolapse). Isolated MTC may also be familial and is less aggressive compared with MEN-associated MTC.

Screening and diagnosis: As clinical symptoms and signs of endocrine cancers can vary widely from textbook-style presentations, diagnosis is generally oriented toward confirming clinical suspicions through routine laboratory tests and tests measuring hormone levels. Although interpretation of some tests such as thyroid function tests and a twenty-four-hour urine collection for catecholamine metabolites of epinephrine and norepinephrine (metanephrine, vanillylmandelic acid, or VMA) for a suspected pheochromocytoma may be straightforward, other tests approach diagnosis by process of elimination. Tests that require such multiple steps include the dexamethasone suppression test and the progesterone challenge test. The dexamethasone suppression test involves a screening of a twenty-four-hour urine collection for cortisol as well as evaluation of the anterior pituitary (Cushing syndrome) and adrenal cortex hormone levels in response to low and high doses of dexamethasone. The progesterone challenge is similar in that it assesses the onset of bleeding with administration of suppressing doses of estrogen and progesterone to assess the presence of an androgen-secreting tumor, among other, nontumor-related diseases. These tests may also be used to assess baseline glandular functioning. Tumor markers such as cancer antigen 125 (CA 125) for ovarian cancer are rarely used alone to confirm diagnoses, although they can be used to monitor for disease recurrence.

Visualization of a suspected cancer is carried out as much as possible. Imaging studies provide information for determining whether surgery is possible. If surgery is a plausible option, imaging studies provide surgeons with a means by which to plan their approach. Conventional imaging studies include computed tomography (CT) and magnetic resonance imaging (MRI). Organ-specific studies such as thyroid scans or OctreoScans for islet cell tumors rely on tumor uptake of radiolabeled substances to disclose their location. Thyroid scans also help determine the presence of hormone activity, which is absent in most thyroid cancers. Occasionally, local or distal spread of tumors may occur, in which case more comprehensive imaging studies of probable areas of spread, such as the chest, abdomen, pelvis, or head, are conducted.

A biopsy of tumors with high-yield procedures such as fine needle aspiration of thyroid nodules or masses can greatly aid in planning future treatment. Occasionally, this may be done during an operation through frozen section, in which a tumor specimen is frozen and thinly sliced for microscopic evaluation by a pathologist.

Formal, regular screening is not usually done because of the rareness of these cancers but may be conducted when patients have a family history of multiple endocrine gland involvement. Although tumors that are hereditary have a clear genetic etiology, routine genetic testing such as that for RET is reserved for patients with medullary thyroid cancer.

Treatment and therapy: Treatment of endocrine cancers generally consists of surgical removal of the lesions alongside chemotherapy or radiotherapy. Medical therapies are often limited but nonetheless essential in reducing complications. These include ensuring the control of other diseases and correcting blood pressure and fluid and electrolyte derangements, particularly in patients in whom the thyroid, parathyroid, pancreatic islet cells, and adrenal glands are involved. The surgical approach for endocrine cancers usually conforms to the relevant local anatomy while achieving optimal visualization even if the surgical field may be quite limited. For instance, a transsphenoidal approach to the pituitary gland involves making a surgical “window” through the posterior aspect of the mouth, as opposed to thyroid surgery at the base of the neck. Spread to neighboring structures may entail lymph node sampling conforming to the lymph drainage within the area of the tumors in addition to removal of secondary sites of spread wherever possible. Chemotherapy and radiotherapy are instituted for most endocrine cancers to eliminate remaining tumor cells not removed by surgery and thus decrease the chance for recurrence.

Prognosis, prevention, and outcomes: The 2014 ratio of deaths to incidence in the United States from endocrine cancers irrespective of cause was estimated at approximately 4 percent. Total deaths from endocrine cancers from the same year were estimated at 2,820. Most endocrine cancers have high five-year survival rates approaching 95 percent or more. Thyroid cancers in particular have high five-year survival rates, around 96 percent if detected early. As with all other cancers, this may drop to 5 percent in advanced disease involving more malignant variants (medullary, follicular, anaplastic). Cancers that are detected late, such as ovarian or adrenal cancers, have correspondingly lower survival rates of 50 percent and 40 percent, respectively.

Complications from surgery include bleeding, marked reduction or total loss of endocrine gland function, or interruption of hypothalamic-pituitary axis equilibrium. Hormone replacement therapy may eventually be lifelong, particularly in thyroid and pituitary gland cancers. Preventive measures include proper radiation shielding of neck and genital areas.

Bibliography

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Clark, Orlo H. Endocrine Tumors. Hamilton: BC Decker, 2003. Print.

Kelloff, Gary, Ernest T. Hawk, and Caroline C. Sigman. Cancer Chemoprevention. Totowa: Humana, 2005. Print.

McDermott, Michael T. Endocrine Secrets. 4th ed. Philadelphia: Elsevier, 2013. Print.

Raghavan, Derek, et al. Textbook of Uncommon Cancer. 4th ed. Chichester: Wiley, 2012. Print.

Stratakis, Constantine A. Endocrine Tumor Syndromes and Their Genetics. Basel: Karger, 2013. Print.