Pheochromocytoma and Paraganglioma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Pheochromocytoma and Paraganglioma

Pheochromocytomas and extra-adrenal paragangliomas are rare tumors arising from neural crest tissue that develops into sympathetic and parasympathetic paraganglia throughout the body.

In 2004, the World Health Organization classification utilized the term pheochromocytoma exclusively for tumors arising from the adrenal medulla, and the term extra-adrenal paraganglioma for similar tumors that arise from other locations.

Incidence and Mortality

The incidence of pheochromocytoma is 2 to 8 per million persons per year.[1,2] Pheochromocytoma is present in 0.1% to 1% of patients with hypertension,[3,4,5] and it is present in approximately 5% of patients with incidentally discovered adrenal masses.[6] The peak incidence occurs in the third to fifth decades of life; the average age at diagnosis is 24.9 years in hereditary cases and 43.9 years in sporadic cases.[7] The incidence is equal between men and women.[8]

Anatomy

Pheochromocytomas and extra-adrenal paragangliomas arise from neural crest tissue. Neural crest tissue develops into sympathetic and parasympathetic paraganglia.

Sympathetic paraganglia include the following:

• The adrenal medulla.
• The organ of Zuckerkandl near the aortic bifurcation.
• Other paraganglia along the distribution of the sympathetic nervous system.

Parasympathetic paraganglia include the following:

• The carotid body.
• Other paraganglia along the cervical and thoracic branches of the vagus and glossopharyngeal nerves.

Risk Factors

No known environmental, dietary, or lifestyle risk factors have been linked to the development of pheochromocytoma.

Hereditary Predisposition Syndromes

Of all pheochromocytomas and extra-adrenal paragangliomas, 35% occur in the setting of a hereditary syndrome.[7,8,9] Major genetic syndromes that confer an increased risk of pheochromocytoma are included in Table 1.

Pheochromocytomas and extra-adrenal paragangliomas can also occur in the following two other very rare syndromes:

• The Carney triad of extra-adrenal paraganglioma, gastrointestinal stromal tumor (GIST),[21] and pulmonary chondroma.
• The Carney-Stratakis dyad of paraganglioma and GIST.[22]

Genetic counseling and testing

It has been proposed that all patients diagnosed with a pheochromocytoma or paraganglioma should consider genetic testing because the incidence of a hereditary syndrome in apparently sporadic cases is as high as 25%.[7,8,23] Early identification of a hereditary syndrome allows for early screening for other associated tumors and identification of family members who are at risk. In addition, some patients with a hereditary syndrome are more likely to develop multifocal, malignant, or recurrent disease. Knowledge of the specific genetic mutation permits increased vigilance during preoperative localization or postoperative surveillance of such patients.

Certain subgroups of patients are at very low risk of having an inherited syndrome (e.g., <2% in patients diagnosed with apparently sporadic pheochromocytoma after age 50 years).[7] Therefore, genetic testing for all patients diagnosed with a pheochromocytoma or paraganglioma may not be practical or cost effective from a population standpoint. It is recommended that every patient diagnosed with a pheochromocytoma or extra-adrenal paraganglioma should first undergo risk evaluation for a hereditary syndrome by a certified genetic counselor.[24]

Genetic testing is often recommended in the following situations:

• Patients with a personal or family history of clinical features suggestive of a hereditary pheochromocytoma-paraganglioma syndrome.
• Patients with bilateral or multifocal tumors.
• Patients with sympathetic or malignant extra-adrenal paragangliomas.
• Patients diagnosed before age 40 years.

In patients with a unilateral pheochromocytoma and no personal or family history suggestive of hereditary disease, genetic testing can be considered if patients are between the ages of 40 years and 50 years, but genetic testing is generally not recommended if patients are older than 50 years. If a mutation is identified, predictive genetic testing should be offered to asymptomatic at-risk family members. For more information, see Genetics of Endocrine and Neuroendocrine Neoplasias.

Clinical Features

Patients with pheochromocytomas and sympathetic extra-adrenal paragangliomas may present with symptoms of excess catecholamine production, including the following:

• Hypertension.
• Headache.
• Perspiration.
• Forceful palpitations.
• Tremor.
• Facial pallor.

These symptoms are often paroxysmal, although sustained hypertension between paroxysmal episodes occurs in 50% to 60% of patients with pheochromocytoma.[25] Episodes of hypertension can be variable in frequency, severity, and duration and are often extremely difficult to manage medically. Hypertensive crisis can lead to cardiac arrhythmias, myocardial infarction, and even death.

Patients are often very symptomatic from excess catecholamine secretion. Symptoms of catecholamine excess can be spontaneous or induced by the following:

• Strenuous physical exertion.
• Trauma.
• Labor and delivery.
• Anesthesia induction.
• Surgery or other invasive procedures, including direct instrumentation of the tumor (e.g., fine-needle aspiration).
• Eating foods high in tyramine (e.g., red wine, chocolate, and cheese).
• Urination (e.g., bladder wall tumor, which is rare).

Phenoxybenzamine (an alpha-adrenergic receptor blocker) is an effective treatment for catecholamine excess and metyrosine (a catecholamine synthesis antagonist) can be added if needed.

Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines. These tumors usually present as a neck mass with symptoms related to compression or are incidentally discovered on an imaging study performed for an unrelated reason. In addition, approximately half of patients with pheochromocytoma are asymptomatic because their neoplasms are discovered in the presymptomatic state by either abdominal imaging for other reasons (e.g., adrenal incidentalomas) or genetic testing in at-risk family members.[20,26,27,28]

Diagnostics

The diagnosis of pheochromocytoma is usually suspected by the presence of an adrenal mass or is discovered incidentally. Biochemical testing is done to document excess catecholamine secretion. Once the biochemical diagnosis of a catecholamine-secreting tumor is confirmed, localization studies should be performed. Controversy exists as to the optimal single test to make the diagnosis.

Biochemical testing

24-hour urine collection

A 24-hour urine collection for catecholamines (e.g., epinephrine, norepinephrine, and dopamine) and fractionated metanephrines (e.g., metanephrine and normetanephrine) has a relatively low sensitivity (77%–90%) but a high specificity (98%). Pretest probability is also important. The specificity of plasma-free fractionated metanephrines is 82% in patients tested for sporadic pheochromocytoma versus 96% in patients tested for hereditary pheochromocytoma.[29,30]

Plasma-free fractionated metanephrines

Measurement of plasma-free fractionated metanephrines appears to be an ideal case-detection test for patients at higher baseline risk of pheochromocytoma. Examples of these patients might include the following:

• Patients with an incidentally discovered adrenal mass.
• Patients with a family history of pheochromocytoma.
• Patients with a known inherited predisposition to pheochromocytoma.

The test is associated with a relatively high false-positive rate in patients with a lower baseline risk of pheochromocytoma. Measurement of plasma-free metanephrines (e.g., metanephrine and normetanephrine) has a high sensitivity (97%–99%) but a relatively low specificity (85%).

In general, it is reasonable to use measurement of plasma-free fractionated metanephrines for initial case detection, which is followed by 24-hour measurement of urine-fractionated metanephrines and catecholamines for confirmation. Test results can be difficult to interpret because of the possibility of false-positive results. False-positive results can be caused by any of the following:[25,29]

• Common medications (e.g., tricyclic antidepressants).
• Physical or emotional stress.
• Inappropriately low reference ranges based on normal laboratory data rather than clinical data sets.[31]
• Common foods (e.g., caffeine and bananas) that interfere with specific assays and medications.

A mildly elevated catecholamine or metanephrine level is usually the result of assay interference caused by drugs or other factors. Patients with symptomatic pheochromocytoma almost always have increases in catecholamines or metanephrines two to three times higher than the upper limits of reference ranges.[25]

Provocative testing (e.g., using glucagon) can be dangerous, adds no value to other current testing methods, and is not recommended.[32]

Imaging studies

Computed tomography (CT) imaging or magnetic resonance imaging (MRI) of the abdomen and pelvis (at least through the level of the aortic bifurcation) are the most commonly used methods for localization.[33] Both have similar sensitivities (90%–100%) and specificities (70%–80%).[33] CT imaging provides superior anatomic detail compared with MRI.

Additional functional imaging may be necessary if CT imaging or MRI fails to localize the tumor. It might also be useful in patients who are at risk for multifocal, malignant, or recurrent disease. Iodine I 123 (123I)-metaiodobenzylguanidine (MIBG) scintigraphy coupled with CT imaging provides anatomic and functional information with good sensitivity (80%–90%) and specificity (95%–100%).[33] 131I-MIBG can be used in the same way, but the image quality is not as high as with 123I-MIBG.[34] Other functional imaging alternatives include gallium Ga 68 (68Ga)-DOTATATE and fluorine F 18-fludeoxyglucose positron emission tomography (PET), both of which can be coupled with CT imaging for improved anatomic detail.[35,36]

It is rare for localization of a catecholamine-secreting tumor to be unsuccessful if currently available imaging methods are used.

Prognosis and Survival

There are no clear data regarding the survival of patients with localized (apparently benign) disease or regional disease. Although patients with localized (apparently benign) disease should experience an overall survival approaching that of age-matched disease-free individuals, 6.5% to 16.5% of these patients will develop a recurrence, usually 5 to 15 years after initial surgery.[37,38,39]

Approximately 15% to 25% of patients with recurrent disease experience distant metastasis. The 5-year overall survival rates in those with metastatic disease range from 50% to 70%.[40,41,42,43] Carriers of SDHB pathogenic variants have an increased risk of developing metastatic disease of approximately 25% to 50%.[44] The most commonly associated gene with metastatic pheochromocytoma and paraganglioma is SDHB (over 40% of cases).[45,46]

Follow-up Evaluation

Long-term follow-up is essential for all patients with pheochromocytoma or extra-adrenal paraganglioma, even when initial pathology demonstrates no findings that are concerning for malignancy.[5]

• After resection of a solitary sporadic pheochromocytoma, patients should undergo baseline postoperative biochemical testing followed by annual lifelong biochemical testing.
• Patients who have undergone resection of a noncatecholamine-producing tumor should initially undergo annual imaging with computed tomography imaging or magnetic resonance imaging and periodic imaging with radiolabeled metaiodobenzylguanidine or 68Ga-DOTATATE PET/CT to monitor for recurrence or metastasis.
• Patients who have undergone resection of a pheochromocytoma or paraganglioma in the setting of a hereditary syndrome require lifelong annual biochemical screening in addition to routine screening for other component tumors of their specific syndrome.[5]

References:

1. Beard CM, Sheps SG, Kurland LT, et al.: Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 58 (12): 802-4, 1983.
2. Stenström G, Svärdsudd K: Pheochromocytoma in Sweden 1958-1981. An analysis of the National Cancer Registry Data. Acta Med Scand 220 (3): 225-32, 1986.
3. Sinclair AM, Isles CG, Brown I, et al.: Secondary hypertension in a blood pressure clinic. Arch Intern Med 147 (7): 1289-93, 1987.
4. Anderson GH, Blakeman N, Streeten DH: The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 12 (5): 609-15, 1994.
5. Omura M, Saito J, Yamaguchi K, et al.: Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res 27 (3): 193-202, 2004.
6. Young WF: Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 29 (1): 159-85, x, 2000.
7. Neumann HP, Bausch B, McWhinney SR, et al.: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346 (19): 1459-66, 2002.
8. Amar L, Bertherat J, Baudin E, et al.: Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23 (34): 8812-8, 2005.
9. Jiménez C, Cote G, Arnold A, et al.: Review: Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J Clin Endocrinol Metab 91 (8): 2851-8, 2006.
10. Baysal BE, Ferrell RE, Willett-Brozick JE, et al.: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287 (5454): 848-51, 2000.
11. Hao HX, Khalimonchuk O, Schraders M, et al.: SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325 (5944): 1139-42, 2009.
12. Niemann S, Müller U: Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26 (3): 268-70, 2000.
13. Astuti D, Latif F, Dallol A, et al.: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69 (1): 49-54, 2001.
14. Burnichon N, Brière JJ, Libé R, et al.: SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19 (15): 3011-20, 2010.
15. Letouzé E, Martinelli C, Loriot C, et al.: SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23 (6): 739-52, 2013.
16. Castro-Vega LJ, Buffet A, De Cubas AA, et al.: Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 23 (9): 2440-6, 2014.
17. Clark GR, Sciacovelli M, Gaude E, et al.: Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab 99 (10): E2046-50, 2014.
18. Eijkelenkamp K, Olderode-Berends MJW, van der Luijt RB, et al.: Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas. Clin Genet 93 (5): 1049-1056, 2018.
19. Abermil N, Guillaud-Bataille M, Burnichon N, et al.: TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. J Clin Endocrinol Metab 97 (5): E805-9, 2012.
20. Else T, Greenberg S, Fishbein L: Hereditary Paraganglioma-Pheochromocytoma Syndromes. In: Adam MP, Ardinger HH, Pagon RA, et al.: GeneReviews. Seattle, Wash: University of Washington, 1993-2018, pp. Available online. Last accessed August 25, 2022.
21. Carney JA: Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 74 (6): 543-52, 1999.
22. Carney JA, Stratakis CA: Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 108 (2): 132-9, 2002.
23. Neumann HP, Pawlu C, Peczkowska M, et al.: Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292 (8): 943-51, 2004.
24. Lenders JW, Duh QY, Eisenhofer G, et al.: Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99 (6): 1915-42, 2014.
25. Lenders JW, Eisenhofer G, Mannelli M, et al.: Phaeochromocytoma. Lancet 366 (9486): 665-75, 2005 Aug 20-26.
26. Kopetschke R, Slisko M, Kilisli A, et al.: Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma. Eur J Endocrinol 161 (2): 355-61, 2009.
27. Motta-Ramirez GA, Remer EM, Herts BR, et al.: Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. AJR Am J Roentgenol 185 (3): 684-8, 2005.
28. Young WF: Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 356 (6): 601-10, 2007.
29. Lenders JW, Pacak K, Walther MM, et al.: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287 (11): 1427-34, 2002.
30. Sawka AM, Jaeschke R, Singh RJ, et al.: A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 88 (2): 553-8, 2003.
31. Perry CG, Sawka AM, Singh R, et al.: The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma. Clin Endocrinol (Oxf) 66 (5): 703-8, 2007.
32. Young WF: Phaeochromocytoma: how to catch a moonbeam in your hand. Eur J Endocrinol 136 (1): 28-9, 1997.
33. Ilias I, Pacak K: Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 89 (2): 479-91, 2004.
34. Furuta N, Kiyota H, Yoshigoe F, et al.: Diagnosis of pheochromocytoma using [123I]-compared with [131I]-metaiodobenzylguanidine scintigraphy. Int J Urol 6 (3): 119-24, 1999.
35. Janssen I, Wolf KI, Chui CH, et al.: Relevant Discordance Between 68Ga-DOTATATE and 68Ga-DOTANOC in SDHB-Related Metastatic Paraganglioma: Is Affinity to Somatostatin Receptor 2 the Key? Clin Nucl Med 42 (3): 211-213, 2017.
36. Janssen I, Chen CC, Millo CM, et al.: PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 43 (10): 1784-91, 2016.
37. Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997.
38. van Heerden JA, Roland CF, Carney JA, et al.: Long-term evaluation following resection of apparently benign pheochromocytoma(s)/paraganglioma(s). World J Surg 14 (3): 325-9, 1990 May-Jun.
39. Amar L, Servais A, Gimenez-Roqueplo AP, et al.: Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 90 (4): 2110-6, 2005.
40. Ayala-Ramirez M, Feng L, Johnson MM, et al.: Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab 96 (3): 717-25, 2011.
41. Fishbein L, Ben-Maimon S, Keefe S, et al.: SDHB mutation carriers with malignant pheochromocytoma respond better to CVD. Endocr Relat Cancer 24 (8): L51-L55, 2017.
42. Hamidi O, Young WF, Gruber L, et al.: Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: A systematic review and meta-analysis. Clin Endocrinol (Oxf) 87 (5): 440-450, 2017.
43. Asai S, Katabami T, Tsuiki M, et al.: Controlling Tumor Progression with Cyclophosphamide, Vincristine, and Dacarbazine Treatment Improves Survival in Patients with Metastatic and Unresectable Malignant Pheochromocytomas/Paragangliomas. Horm Cancer 8 (2): 108-118, 2017.
44. Andrews KA, Ascher DB, Pires DEV, et al.: Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet 55 (6): 384-394, 2018.
45. Fishbein L, Merrill S, Fraker DL, et al.: Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol 20 (5): 1444-50, 2013.
46. Neumann HPH, Young WF, Eng C: Pheochromocytoma and Paraganglioma. N Engl J Med 381 (6): 552-565, 2019.

Cellular Classification of Pheochromocytoma and Paraganglioma

Pathologic Classification

Pheochromocytoma and paraganglioma characteristically form small nests of uniform polygonal chromaffin cells ("zellballen"). A diagnosis of malignancy can only be made by identifying tumor deposits in tissues that do not normally contain chromaffin cells (e.g., lymph nodes, liver, bone, lung, and other distant metastatic sites).

Regional or distant metastatic disease is documented on initial pathology in only 3% to 8% of patients; thus, an attempt has been made to identify tumor characteristics associated with future malignant behavior. Pathologic features associated with malignancy include the following:

• Large tumor size.
• Increased number of mitoses.
• DNA aneuploidy.
• Extensive tumor necrosis.
• Vascular or capsular invasion.

In the absence of clearly documented metastases, no combination of clinical, histopathologic, or biochemical features has been shown to reliably predict the biologic behavior of pheochromocytoma. If no definite malignancy is identified, pathology generally provides insufficient prognostic information regarding the likelihood of recurrence or metastasis. These tumors cannot be considered benign by default; patients require continued lifelong surveillance.[1,2,3,4,5,6,7]

References:

1. Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997.
2. Thompson LD: Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 26 (5): 551-66, 2002.
3. Nativ O, Grant CS, Sheps SG, et al.: The clinical significance of nuclear DNA ploidy pattern in 184 patients with pheochromocytoma. Cancer 69 (11): 2683-7, 1992.
4. Wu D, Tischler AS, Lloyd RV, et al.: Observer variation in the application of the Pheochromocytoma of the Adrenal Gland Scaled Score. Am J Surg Pathol 33 (4): 599-608, 2009.
5. Kimura N, Watanabe T, Noshiro T, et al.: Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol 16 (1): 23-32, 2005.
6. Linnoila RI, Keiser HR, Steinberg SM, et al.: Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologic features. Hum Pathol 21 (11): 1168-80, 1990.
7. Tischler AS: Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med 132 (8): 1272-84, 2008.

Stage Information for Pheochromocytoma and Paraganglioma

AJCC Stage Groupings and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define pheochromocytoma and paraganglioma.[1] Although the AJCC staging system does not account for the unique characteristics of these tumors, it could increase the understanding of prognostic indicators for survival.

References:

1. Adrenal – Neuroendocrine tumors. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 919–27.

Treatment Option Overview

Only limited data are available from phase II clinical trials to guide the management of patients diagnosed with pheochromocytoma or paraganglioma. There are no phase III trials. Everything is based on case series, and the impact on survival is not known.

Localized and Regional Pheochromocytoma

Definitive treatment for localized and regional pheochromocytoma, including localized disease recurrence, consists of alpha- and beta-adrenergic blockade followed by surgery.

Metastatic Pheochromocytoma

For patients with unresectable or metastatic pheochromocytoma, treatment may include a combination of the following:

• Catecholamine blockade.
• Surgery.
• Chemotherapy.
• Radiofrequency ablation.
• Cryoablation.
• Radiation therapy.

Treatment for patients with localized, regional, metastatic, or recurrent pheochromocytoma is summarized in Table 2.

Preoperative Medical Preparation

Surgery is the mainstay of treatment for most patients; however, preoperative medical preparation is critical. Alpha-adrenergic blockade should be initiated at the time of diagnosis and maximized preoperatively to prevent potentially life-threatening cardiovascular complications, which can occur as a result of excess catecholamine secretion during surgery. Complications may include the following:

• Hypertensive crisis.
• Arrhythmia.
• Myocardial infarction.
• Pulmonary edema.

Phenoxybenzamine (a nonselective alpha-antagonist) is the usual drug of choice; prazosin, terazosin, and doxazosin (selective alpha-1-antagonists) are alternative choices.[1,2] Prazosin, terazosin, and doxazosin are shorter acting than phenoxybenzamine, and therefore, the duration of postoperative hypotension is theoretically less than with phenoxybenzamine; however, there is less overall experience with selective alpha-1-antagonists than with phenoxybenzamine.

A preoperative treatment period of 1 to 3 weeks is usually sufficient; resolution of spells and a target low normal blood pressure for age indicate that alpha-adrenergic blockade is adequate. During alpha-adrenergic blockade, liberal salt and fluid intake should be encouraged because volume loading reduces excessive orthostatic hypotension both preoperatively and postoperatively. If tachycardia develops or if blood pressure control is not optimal with alpha-adrenergic blockade, a beta-adrenergic blocker (e.g., metoprolol or propranolol) can be added, but only after alpha-blockade. Beta-adrenergic blockade must never be initiated before alpha-adrenergic blockade; doing so blocks beta-adrenergic receptor-mediated vasodilation and results in unopposed alpha-adrenergic receptor-mediated vasoconstriction, which can lead to a life-threatening crisis.

References:

1. Cubeddu LX, Zarate NA, Rosales CB, et al.: Prazosin and propranolol in preoperative management of pheochromocytoma. Clin Pharmacol Ther 32 (2): 156-60, 1982.
2. Prys-Roberts C, Farndon JR: Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg 26 (8): 1037-42, 2002.

Treatment of Localized Pheochromocytoma

Treatment Options for Localized Pheochromocytoma

Treatment options for localized pheochromocytoma include the following:

• Surgery.

Surgery

Surgical resection (i.e., adrenalectomy) is the definitive treatment for patients with localized pheochromocytoma. A minimally invasive adrenalectomy is generally the preferred approach if the following conditions can be met:

• Preoperative imaging reveals an adrenal pheochromocytoma that is approximately 6 cm or smaller in diameter.
• No radiographic evidence of invasion into adjacent structures or evidence of regional or metastatic disease (i.e., presumably a benign tumor).
• Normal contralateral adrenal gland.

Both anterior transabdominal laparoscopic adrenalectomy and posterior retroperitoneoscopic adrenalectomy have been demonstrated to be safe for most patients with a modestly sized, radiographically benign pheochromocytoma.[1,2] If preoperative imaging suggests malignancy, or if the patient has an extra-adrenal paraganglioma or multifocal disease, an open approach is generally preferred.

Intraoperative hypertension can be controlled with intravenous infusion of phentolamine, sodium nitroprusside, or a short-acting calcium-channel blocker (e.g., nicardipine). Tumor removal may be followed by a sudden drop in blood pressure that may require rapid volume replacement and intravenous vasoconstrictors (e.g., norepinephrine or phenylephrine). Postoperatively, patients should remain in a monitored environment for 24 hours. Postoperative hypotension is managed primarily by volume expansion, and postoperative hypertension usually responds to diuretics.

Treatment Options for Inherited Pheochromocytoma

Treatment options for inherited pheochromocytoma include the following:

• Surgery.

Surgery

The surgical management of pheochromocytoma in patients with the hereditary syndromes multiple endocrine neoplasia type 2 (MEN2) or von Hippel-Lindau (VHL) disease has been controversial. In both of these syndromes, pheochromocytoma is bilateral in at least 50% of patients; however, malignancy is very uncommon. Bilateral total adrenalectomy commits all patients to lifelong steroid dependence, and up to 25% of patients will experience Addisonian crisis (acute adrenal insufficiency).[3,4]

Recommendations generally favor preservation of adrenal cortical tissue in patients with MEN2 or VHL when possible. Patients who initially present with unilateral pheochromocytoma should undergo unilateral adrenalectomy, and patients who present with bilateral pheochromocytomas or who develop pheochromocytoma in their remaining adrenal gland should undergo cortical-sparing adrenalectomy, when technically feasible.[3]

Evidence (surgery):

1. A single-institution study included 56 patients with adrenal pheochromocytomas.[5]
   • Of the 30 patients who underwent one or more cortical-sparing adrenalectomies, 17 (57%) avoided the need for routine steroid replacement.
   • The clinical recurrence rate was low (3 of 30 patients) and none of the patients developed metastatic disease.[5][Level of evidence: 3iiDii]

A similar approach may be reasonable in other hereditary pheochromocytoma-paraganglioma syndromes that are characterized by benign disease, but there are insufficient data upon which to base unequivocal recommendations. For more information, see Genetics of Endocrine and Neuroendocrine Neoplasias.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Walz MK, Alesina PF, Wenger FA, et al.: Posterior retroperitoneoscopic adrenalectomy--results of 560 procedures in 520 patients. Surgery 140 (6): 943-8; discussion 948-50, 2006.
2. Gagner M, Breton G, Pharand D, et al.: Is laparoscopic adrenalectomy indicated for pheochromocytomas? Surgery 120 (6): 1076-9; discussion 1079-80, 1996.
3. Lee JE, Curley SA, Gagel RF, et al.: Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery 120 (6): 1064-70; discussion 1070-1, 1996.
4. de Graaf JS, Dullaart RP, Zwierstra RP: Complications after bilateral adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2--a plea to conserve adrenal function. Eur J Surg 165 (9): 843-6, 1999.
5. Yip L, Lee JE, Shapiro SE, et al.: Surgical management of hereditary pheochromocytoma. J Am Coll Surg 198 (4): 525-34; discussion 534-5, 2004.

Treatment of Regional Pheochromocytoma

Treatment Options for Regional Pheochromocytoma

Treatment options for regional pheochromocytoma include the following:

• Surgery.

Surgery

Surgical resection is the definitive treatment for pheochromocytoma or extra-adrenal paraganglioma that is regionally advanced (e.g., from direct tumor extension into adjacent organs or because of regional lymph node involvement). Data to guide management are limited because regional disease is diagnosed in very few patients who present with pheochromocytoma.[1] However, aggressive surgical resection to remove all existing disease can render patients symptom free.[2] Surgical management of these patients may require en bloc resection of all or part of adjacent organs (e.g., kidney, liver, inferior vena cava) along with extended lymph node dissection. Patients who have undergone complete resection of regional pheochromocytoma require lifelong monitoring for disease recurrence.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Amar L, Servais A, Gimenez-Roqueplo AP, et al.: Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 90 (4): 2110-6, 2005.
2. Zarnegar R, Kebebew E, Duh QY, et al.: Malignant pheochromocytoma. Surg Oncol Clin N Am 15 (3): 555-71, 2006.

Treatment of Metastatic Pheochromocytoma

Treatment Options for Metastatic Pheochromocytoma

Treatment options for metastatic pheochromocytoma include the following:

1. Surgery.
2. Palliative therapy.

The most common sites of metastasis for pheochromocytoma or extra-adrenal paraganglioma are lymph nodes, bones, lungs, and liver. Patients with known or suspected malignancy should undergo staging with computed tomography or magnetic resonance imaging as well as functional imaging (e.g., with iodine I 123-metaiodobenzylguanidine [MIBG]) to determine the extent and location of disease. Patients are often very symptomatic from excess catecholamine secretion. Phenoxybenzamine is effective, and metyrosine, which is a drug that blocks catecholamine synthesis, can be added if needed.

Surgery

If all identifiable disease is resectable, including a limited number of distant metastases, surgery can provide occasional long-term remission. If disease is unresectable, surgical debulking will not improve survival; however, it is occasionally indicated for symptom palliation.

Palliative therapy

Chemotherapy

Chemotherapy has not been shown to improve survival in patients with metastatic pheochromocytoma; however, chemotherapy may be useful for symptom palliation.

The best-established chemotherapy regimen is a combination of cyclophosphamide, vincristine, and dacarbazine (the Averbuch protocol).[1]

Evidence (chemotherapy):

1. A nonrandomized, single-arm trial included 18 patients with metastatic malignant pheochromocytoma or paraganglioma. Patients were treated with a combination of cyclophosphamide, vincristine, and dacarbazine.[2]
   • After 22 years of follow-up, the complete response rate was 11%, the partial response rate was 44%, the biochemical response rate was 72%, and the median survival was 3.3 years.[2][Level of evidence: 3iiiDiv]
2. A retrospective study showed a therapeutic benefit of temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Fifteen consecutive patients with metastatic pheochromocytoma or paraganglioma were enrolled; 10 (67%) carried a mutation in SDHB. The mean dose intensity of temozolomide was 172 mg/m² daily for 5 days every 28 days.[3]
   • The median progression-free survival was 13.3 months after a median follow-up of 35 months. Of the 15 patients, 5 (33%) had a partial response, 7 (47%) had stable disease, and 3 (20%) had progressive disease.[3][Level of evidence: 3iiDiv]

Several other chemotherapy regimens have been used in small numbers of patients, but the overall results were disappointing.[4,5]

Targeted therapy

Novel targeted therapies are emerging as potential treatment strategies for metastatic pheochromocytoma. Disappointing initial results were reported with the mammalian target of rapamycin (mTOR) inhibitor everolimus,[6] but results from a very small number of patients treated with the tyrosine kinase inhibitors sunitinib, axitinib, and cabozantinib have been more promising.[7,8][Level of evidence: 3iiiDiv]

Radiation therapy

Iodine I 131 (131I)-MIBG radiation therapy has been used for the treatment of patients with MIBG-avid metastases.[9,10] Approximately 60% of metastatic pheochromocytoma or paraganglioma sites are MIBG-avid;[11] protocol-based treatment with other experimental radiolabeled agents, such as radiolabeled somatostatin, can be considered for metastases that do not take up MIBG.

Evidence (radiation therapy):

1. A phase II study of high-dose 131I-MIBG radiation therapy included 49 patients with metastatic pheochromocytoma or paraganglioma.[11]
   • Eight percent of patients had a complete response, 14% had a partial response, and the estimated 5-year survival rate was 64%.[11][Level of evidence: 3iiiDiv]

   Iobenguane I 131 is a high-specific-activity 131I-MIBG agent made of labeled MIBG molecules that allows lower mass doses of MIBG to be administered for adult and pediatric patients (age >12 years) with advanced unresectable disease. It has been shown to be safe and generally well tolerated and was approved by the U.S. Food and Drug Administration via fast track designation in July 2018.

2. A phase II, open-label, multicenter trial included 68 patients with pheochromocytoma or paraganglioma. The primary end point was a greater than 50% reduction of all antihypertensive medications lasting for at least 6 months.[12][Level of evidence: 3iiiDiv]
   • Twenty-five percent of evaluable patients experienced a 50% or greater reduction of all antihypertensive medication for at least 6 months.
   • Overall tumor response was achieved in 22% of patients and, of those patients, 53% experienced durable tumor responses lasting 6 months or longer.

Other therapy

Other palliative treatment modalities include external-beam radiation therapy (e.g., for palliation of bone metastases) and embolization, radiofrequency ablation, or cryoablation (e.g., for palliation of bulky hepatic metastases or isolated bony metastases).

Pheochromocytoma and paraganglioma often express the somatostatin receptor proteins SSTR2 and SSTR3 which may allow for targeted treatment with somatostatin receptor agonists.[13,14] A meta-analysis of studies involving advanced or metastatic pheochromocytoma and paraganglioma patients treated with peptide receptor radionuclide therapy showed that 89.8% of pooled patients had achieved disease stabilization or a partial response.[15][Level of evidence: 3iiiDiv]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Averbuch SD, Steakley CS, Young RC, et al.: Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 109 (4): 267-73, 1988.
2. Huang H, Abraham J, Hung E, et al.: Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 113 (8): 2020-8, 2008.
3. Hadoux J, Favier J, Scoazec JY, et al.: SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer 135 (11): 2711-20, 2014.
4. Nakane M, Takahashi S, Sekine I, et al.: Successful treatment of malignant pheochromocytoma with combination chemotherapy containing anthracycline. Ann Oncol 14 (9): 1449-51, 2003.
5. Kulke MH, Stuart K, Enzinger PC, et al.: Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24 (3): 401-6, 2006.
6. Druce MR, Kaltsas GA, Fraenkel M, et al.: Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). Horm Metab Res 41 (9): 697-702, 2009.
7. Jimenez C, Cabanillas ME, Santarpia L, et al.: Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J Clin Endocrinol Metab 94 (2): 386-91, 2009.
8. Joshua AM, Ezzat S, Asa SL, et al.: Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma. J Clin Endocrinol Metab 94 (1): 5-9, 2009.
9. Buscombe JR, Cwikla JB, Caplin ME, et al.: Long-term efficacy of low activity meta-[131I]iodobenzylguanidine therapy in patients with disseminated neuroendocrine tumours depends on initial response. Nucl Med Commun 26 (11): 969-76, 2005.
10. Scholz T, Eisenhofer G, Pacak K, et al.: Clinical review: Current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 92 (4): 1217-25, 2007.
11. Gonias S, Goldsby R, Matthay KK, et al.: Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 27 (25): 4162-8, 2009.
12. FDA Approves AZEDRA Specified Use in Pheochromocytomas/Paragangliomas. J Nucl Med 59 (10): 17N, 2018.
13. Reubi JC, Waser B, Schaer JC, et al.: Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 28 (7): 836-46, 2001.
14. Mundschenk J, Unger N, Schulz S, et al.: Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy. J Clin Endocrinol Metab 88 (11): 5150-7, 2003.
15. Taïeb D, Jha A, Treglia G, et al.: Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups. Endocr Relat Cancer 26 (11): R627-R652, 2019.

Treatment of Recurrent Pheochromocytoma

Treatment Options for Recurrent Pheochromocytoma

Treatment options for recurrent pheochromocytoma include the following:

1. Surgery.
2. Palliative therapy.

After resection of a localized pheochromocytoma presumed to represent a benign tumor and documented normal postoperative biochemical testing, disease recurrence occurs in 6.5% to 16.5% of patients, and 50% of patients with disease recurrence develop metastatic disease.[1,2,3] Insufficient data exist to determine recurrence rates after complete surgical resection of regional or metastatic disease.

Surgery

Treatment for recurrent disease involves appropriate medical management (i.e., alpha-adrenergic blockade) followed by complete surgical resection, when possible.

Palliative therapy

Palliation of symptoms, including those related to catecholamine excess and local mass effect, is the primary focus of treatment for disease that is not resectable.

The following are options for patients with local-regional or metastatic disease who are not considered candidates for surgical resection:

• Chemotherapy.
• Targeted therapies.
• High-dose iodine I 131-metaiodobenzylguanidine radiation therapy.
• Ablation therapies.
• Radiation therapy.

For more information, see the Treatment of Metastatic Pheochromocytoma section.

Treatment Options for Inherited Pheochromocytoma or Paraganglioma

Patients with inherited pheochromocytoma or paraganglioma are at risk of recurrent disease in the form of additional primary tumors. Follow-up evaluation and management of additional primary tumors in such patients is essential. For more information, see the Treatment of Localized Pheochromocytoma section.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997.
2. van Heerden JA, Roland CF, Carney JA, et al.: Long-term evaluation following resection of apparently benign pheochromocytoma(s)/paraganglioma(s). World J Surg 14 (3): 325-9, 1990 May-Jun.
3. Amar L, Servais A, Gimenez-Roqueplo AP, et al.: Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 90 (4): 2110-6, 2005.

Treatment of Pheochromocytoma During Pregnancy

Pheochromocytoma diagnosed during pregnancy is extremely rare (0.007% of all pregnancies).[1,2] However, women with hereditary conditions that increase the risk of developing pheochromocytoma are often also of childbearing age, and the outcome of undiagnosed pheochromocytoma during pregnancy can be catastrophic.

Diagnosis

Prenatal diagnosis clearly results in decreased mortality for both mother and fetus.[3] Prior to 1970, a prenatal diagnosis of pheochromocytoma was made in only approximately 25% of cases, and the mortality rate for both mother and fetus was around 50%.[4,5] The prenatal diagnosis rate rose to greater than 80% through the 1980s and 1990s, and decreased maternal and fetal mortality rates were 6% and 15%, respectively.[4,6]

The diagnosis of pheochromocytoma should be suspected in any pregnant woman who develops hypertension in the first trimester, paroxysmal hypertension, or hypertension that is unusually difficult to treat.[2,7] Normal pregnancy does not affect catecholamine levels.[8] Thus, the usual biochemical tests are valid. Magnetic resonance imaging is the localization method of choice because it does not expose the fetus to ionizing radiation.

Treatment Options for Pheochromocytoma During Pregnancy

Phenoxybenzamine use is safe in pregnancy, but beta-adrenergic blockers should be initiated only if needed because their use has been associated with intrauterine growth restriction.[9,10] Resection of the tumor can often be performed safely during the second trimester, or tumor resection can be combined with cesarean delivery for patients diagnosed later in pregnancy.[2] Case reports have documented successful outcomes in the rare circumstance when surgical resection was delayed until a short time after vaginal delivery.[11] The successful management of pheochromocytoma in pregnancy depends on careful monitoring and the availability of an experienced team of specialists.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Harrington JL, Farley DR, van Heerden JA, et al.: Adrenal tumors and pregnancy. World J Surg 23 (2): 182-6, 1999.
2. Sarathi V, Lila AR, Bandgar TR, et al.: Pheochromocytoma and pregnancy: a rare but dangerous combination. Endocr Pract 16 (2): 300-9, 2010 Mar-Apr.
3. Freier DT, Thompson NW: Pheochromocytoma and pregnancy: the epitome of high risk. Surgery 114 (6): 1148-52, 1993.
4. Mannelli M, Bemporad D: Diagnosis and management of pheochromocytoma during pregnancy. J Endocrinol Invest 25 (6): 567-71, 2002.
5. Schenker JG, Granat M: Phaeochromocytoma and pregnancy--an updated appraisal. Aust N Z J Obstet Gynaecol 22 (1): 1-10, 1982.
6. Ahlawat SK, Jain S, Kumari S, et al.: Pheochromocytoma associated with pregnancy: case report and review of the literature. Obstet Gynecol Surv 54 (11): 728-37, 1999.
7. Keely E: Endocrine causes of hypertension in pregnancy--when to start looking for zebras. Semin Perinatol 22 (6): 471-84, 1998.
8. Jaffe RB, Harrison TS, Cerny JC: Localization of metastatic pheochromocytoma in pregnancy by caval catheterization. Including urinary catecholamine values in uncomplicated pregnancies. Am J Obstet Gynecol 104 (7): 939-44, 1969.
9. Butters L, Kennedy S, Rubin PC: Atenolol in essential hypertension during pregnancy. BMJ 301 (6752): 587-9, 1990.
10. Montan S, Ingemarsson I, Marsál K, et al.: Randomised controlled trial of atenolol and pindolol in human pregnancy: effects on fetal haemodynamics. BMJ 304 (6832): 946-9, 1992.
11. Junglee N, Harries SE, Davies N, et al.: Pheochromocytoma in Pregnancy: When is Operative Intervention Indicated? J Womens Health (Larchmt) 16 (9): 1362-5, 2007.

Changes to This Summary (08 / 25 / 2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pheochromocytoma and paraganglioma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Pheochromocytoma and Paraganglioma Treatment are:

• Ann W. Gramza, MD (Georgetown Lombardi Comprehensive Cancer Center)
• Franco M. Muggia, MD (New York University Medical Center)
• Jaydira del Rivero, MD (National Cancer Institute)

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PDQ® Adult Treatment Editorial Board. PDQ Pheochromocytoma and Paraganglioma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389312]

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Last Revised: 2022-08-25