Pheochromocytoma

PHEOCHROMOCYTOMA

Pheochromocytoma is a part of Pheochromocytoma and Paraganglioma group of syndromes. They are rare chromaffin tumors that arise from neural crest cells. Pheochromocytoma is tumor arising in the adrenal gland medulla, and paraganglioma arising in sympathetic or parasympathetic paraganglia. In other words, there are an adrenal tumor (pheochromocytoma) and extra-adrenal tumor (paraganglioma) that have the same origin and may have the same symptoms. The group of the sympathetic pheochromocytomas and paragangliomas include both adrenal and extra-adrenal tumors that secrete catecholamines and present with specific for pheochromocytoma complex of symptoms, while parasympathetic paragangliomas occur mostly in the head and neck and do not secret hormones typical for pheochromocytoma.

What is a pheochromocytoma?

A pheochromocytoma is a functional, catecholamie-secreting, tumor of adrenal gland medulla. It produces excessive amount of catecholamines, which include epinephrine, norepinephrine hormones and their derivatives. These hormones are responsible for regulating heart rate and blood pressure, among other functions. Overproduction of catecholamines by pheochromocytoma leads to hypertension with serious life-threatening complications such as heart attack and stroke. Pheochromocytoma is mostly benign, but have approximately 10 % rate of being malignant. It occurs most frequently in young to middle-aged adults between the ages of 30 and 60. Approximately 10% of them could be bilateral (involving both adrenal glands).

What is a paraganglioma?

Paragangliomas (paraganglion tumors) arise from neuroendocrine tissues (paraganglia) symmetrically distributed along the paravertebral axis from their predominant location at the base of the skull and neck to the pelvis. Thus paragangliomas may arise anywhere along these tracts and common sites of occurrence include abdomen (aortic bifurcation), retroperitoneum, chest and mediastinum and various head and neck locations such as jugulotympanic membrane, orbit, nasopharynx, larynx, vagal body and carotid body.

What causes pheochromocytoma and paraganglioma?

In approximately in 35% – 40% of cases these tumors are result of genetic mutations. There are several genetic syndromes that associate with development of pheochromocytoma and paraganglioma, such as MEN 2A and MEN 2B syndromes, von Recklinghausen’s disease, von Hippel-Lindau syndrome, Sturge-Weber syndrome, Succinated Dehydrogenase Mutations (SDHA, SDHB, SDHC, SDHD, and SDHAF2), mutation of TMEM127 and MAX genes, tuberous sclerosis, Carney’s syndrome, and Neurofibromatosis type 1 syndrome.

How common is pheochromocytoma?

Pheochromocytoma is a rare disease with an estimated incidence rate of 2 to 8 per million. Pheochromocytoma is present in 4-5% of adrenal incidentalomas (incidentally discovered adrenal masses). It suspected when patient develops high blood pressure in younger age with unexplained underlying causes. When “endocrine hypertension” is suspected then work up, along with other endocrine causes, includes evaluation for possible pheochromocytoma, especially with presence of know or newly diagnosed adrenal tumor. Pheochromocytoma is responsible for 0.2 – 0.6 % of all causes of hypertension in adults and 1% of hypertension in children.

What are the symptoms and signs of pheochromocytoma?

The most common symptom of pheochromocytoma is high blood pressure, which is sometimes extreme. Other symptoms include spells (attacks) with sudden onset of high blood pressure, anxiety, emotional stress. Other symptoms may include: rapid pulse, palpitations, headache, nausea, vomiting, and clammy skin. Significant elevation of blood pressure may leads to myocardial infarction (heart attack) and stroke. The person may experiences pressure from the tumor. Each individual may experience symptoms differently. Especially important to look for paroxysmal presentation of symptoms (intermittent spells) rather than persistent progression of the disease; paradoxical blood pressure response to drugs, anesthesia or stress; findings of adrenal incidentaloma in patient with hypertension; hereditary and syndromic features that would pint out to probability of development of pheochromocytoma within the specific syndrome. Hypertensive paroxysms can occur spontaneously, or may be induced. Direct trauma, mechanical pressure to the tumor or any type of stress (anesthesia, surgery, exercise, defecation, sexual intercourse, pregnancy, parturition, alcohol consumption, smoking and administration of various medications) may precipitate hypertensive paroxysms. Attacks or symptoms may last for minutes or hours.

How is pheochromocytoma diagnosed?

In addition to a complete medical history, physical examination, and family history, diagnostic procedures for pheochromocytoma include:

  • blood and urine tests to measure hormone levels such as 24-hour urinary catecholamines and metanephrines; serum catecholamines, metanephrines, and chromogranin A levels.
  • CT scan of the abdomen (Figure 1).
  • MRI of the abdomen, especially looking at T2-weighted image (Figure 2).
  • MIBG (iodine meta-iodobenzylguanidine) scan (Figure 3). MIBG scan is a functional study utilizing radioactive substances (radioisotope) introduced into the body to create an image of the functioning adrenal gland or extra adrenal paraganglioma.

Figure 1. CT scan showing large left adrenal pheochromocytoma

Figure 2. MRI scan showing large cystic left adrenal pheochromocytoma (T2 image)

Figure 3. MIBG scan showing large left adrenal pheochromocytoma

How is pheochromocytoma treated?

Surgical removal of the adrenal gland(s) with tumor is the only effective treatment for pheochromocytoma. Before removing the tumor, however, your physician has to prescribe drugs to control a high blood pressure for several weeks prior to surgery. Rarely, pheochromocytoma can be malignant and may metastasize to other organs. This may happens in about 10% of the patients. Chemotherapy following resection of the primary tumor is the treatment of choice for malignant pheochromocytoma.

Is preoperative preparation required?

The likelihood of complication from the surgery directly correlates with the adequacy of the preoperative management. The goal of preoperative therapy is to block catheholamine secretion from the tumor in order to achieve blood pressure control. Alpha-adrenergic blockade with Phenoxybenzamine and fluid administration is initiated for approximately 3 weeks prior to surgery. The starting dose of Phenoxybenzamine is 10 mg a day and it is gradual incremented to achieve adequate control of hypertension. This medication can cause significant side effects, such as tachycardia, nasal congestion, and abdominal pain. Because of it, patient’s heart rate and blood pressure should be closely monitored by an expert physician, preferably an endocrinologist. If tachycardia develops on Phenoxybenzamine therapy, physician will initiate beta-blockers to control heart rate. There are other options beside phenoxybenzamine. For example shorter acting prazosin, or doxazosin and terazosin; calcium channel blockers have been used as well.

What kind of surgery could be performed for a pheochromocytoma?

The procedure of choice for pheochromocytoma is laparoscopic adrenalectomy – removal of entire adrenal gland with tumor. If bilateral adrenal pheochromocytomas are detected, then a partial adrenal gland resection could be done by removal the portion of adrenal gland with tumor and leaving a normal part of the adrenal gland behind. This is done in order to prevent postoperative adrenal insufficiency. If malignancy is suspected prior to surgery, then there is a possibility of invasion into nearby organs and an open adrenalectomy should be undertaken. There is also a tumor size limiting factor for laparoscopic approach.

There are two approaches for minimally invasive (so called laparoscopic approach): anterior or lateral transperitoneal laparoscopic adrenalectomy (through the abdomen) and posterior retroperitoneoscopic adrenalectomy (without entering into the abdominal cavity, but through the back). The advantage of transperitoneal laparoscopic adrenalectomy is the ability to handle a larger, up to 8-10 cm, tumor through the laparoscopic approach. If tumor is too large to be handled laparoscopically, or cancer is present with invasion into nearby organs, then procedure could be easily converted to an open approach. The advantage of posterior retroperitoneoscopic adrenalectomy is the ability to remove the entire tumor without entering into the abdominal cavity and avoiding manipulations of other organ, such as liver on the right side and spleen with the tail of the pancreas on the left. Because of that, the duration of surgery with the posterior retroperitoneoscopic adrenalectomy is much shorter then with an anterior laparoscopic approach. The patient is experiencing significantly less postoperative pain with posterior retroperitoneoscopic approach compare to anterior laparoscopic approach. With posterior retroperitoneoscopic approach, there is no violation of abdominal wall and there is no risk of abdominal wall hernia development after the surgery (Figure 4 and 5).

Figure 4. Tumor removed by laparoscopic approach

Figure 5. Scar in two weeks after posterior retroperitoneal laparoscopic adrenalectomy.

Figure 13.  Left adrenal pheochromocytoma
5.0 cm x 4.0 cm x 2.5 cm

Figure 14.  Scar in 2 weeks after the left posterior retroperitoneoscopic adrenalectomy for 5 cm (2 inches) pheochromocytoma (tumor is on prior picture) in 51 year-old male

Figure 15.  Scar in 2 weeks after the left posterior retroperitoneoscopic adrenalectomy for 5 cm (2 inches) pheochromocytoma (tumor is on prior picture) in 51 year-old male

Who should perform a surgery for Pheochromocytoma?

Research has proven that the chance of having a safe and successful surgery depends on the experience of the surgeon. In general, a surgeon should do more than 20 adrenal operations a year to be considered an expert. Usually, this surgeon is an Endocrine Surgeon (a member of American Association of Endocrine Surgeons [AAES] and could be found on AAES website, a well-trained laparoscopic surgeon, or an experienced in laparoscopic procedures urologist. Patients should not be shy or embarrassed to ask how many adrenalecomies a surgeon has done and what their personal complication rate is.

Pathological evaluation after the surgery

All tumors are evaluated by pathologist with different stains to confirm diagnosis of pheochromocytoma and determine if this tumor is malignant or benign (grade that indicates likelihood of malignancy).

Pheochromocytoma, chromogranin stain

Pheochromocytoma, S100 stain

Pheochromocytoma, H & E stain, low power view

Pheochromocytoma, H & E stain, medium power view

Pheochromocytoma, H & E stain, high power view

What is life after surgery?

The removal of only one adrenal gland will have no consequences on quality of life. The removal of both adrenal glands will results in loss of all life sustaining adrenal hormones, the patient should be placed on a strict daily hormonal therapy, and with any type of stress or surgery an extra dose of adrenal hormones should be given.

Why consult an Endocrinologist?

The determination of cure and detection of possible re-occurrence in the other adrenal gland or as a paraganglioma in 10% of patients is the main reason to have a good follow up with an Endocrinologist. Perioperative medical preparation (alpha-blockade with Phenoxybenzamine and other drugs) is also better to be done by an Endocrinologist. Since pheochromocytoma could be a part of multiorgan syndrome, Endocrinologist can perform a differential diagnosis and an earlier detection of other, sometimes fatal, tumors, that are part of the specific genetic syndrome (for example, a finding of medullary thyroid carcinoma or primary hyperparathyroidism in MEN 2 syndromes).

Is genetic analysis or counseling needed?

Literature indicates that 35-40% of pheochromocytomas and paragangliomas are due to germ-line mutations in some of the susceptibility genes, therefore, genetic analysis has become an important part of the diagnostic work up and management of this condition. Genetic counselor will evaluate patient’s family history and will determine which genetic test to perform.

Additional Resources for pheochromocytoma on National Adrenal Diseases Foundation (NADF) and www.shifrinmd.com

References

Welander J, Söderkvist P, Gimm O. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2011 Dec 1;18(6):R253-76.

Johnathan Hubbard, William B. Inabnet, Chung-Yau Lo. Endocrine Surgery: Principles and Practice (Springer Specialist Surgery Series), Springer; 1st Edition (July 28, 2009)

Dimitrios A. Linos, Jon A. van Heerden. Adrenal Glands: Diagnostic Aspects and Surgical Therapy. Springer; 2005 edition (June 8, 2005)

Fishbein L, Orlowski R, Cohen D. Pheochromocytoma/Paraganglioma: Review of perioperative management of blood pressure and update on genetic mutations associated with pheochromocytoma. J Clin Hypertens (Greenwich). 2013 Jun;15(6):428-34.

http://www.endocrinediseases.org/adrenal/surgeon.shtml

L. Fishbeina, K. Nathansonb. Pheochromocytoma and Paraganglioma: Understanding the Complexities of the Genetic Background. Cancer Genet. 2012 January ; 205(1-2): 1–11.

L. Fishbein, R. Orlowski, D. Cohen. Pheochromocytoma/Paraganglioma: Review of Perioperative Management of Blood Pressure and Update on Genetic Mutations Associated With Pheochromocytoma. J Clin Hypertens (Greenwich). 2013;15:428–434.

S. Galan, P. Kann. Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clinical Endocrinology (2013) 78, 165–175