Pheochromocytoma screening: Difference between revisions

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==Overview==
==Overview==
'''''Familial pheochromocytoma'''''  associated with multiple endocrien neoplasia, VHL and neurofibromatosis1 should be screened by plasma fractionated metanephrines levels as the best initial test. 24-hour urinary fractionated metanephrines should be done. and imaging should be considered if initial test is positive.
Familial pheochromocytoma is associated with [[Multiple endocrine neoplasia|multiple endocrine neoplasias]], [[Von Hippel-Lindau tumor suppressor|VHL]] and [[Neurofibromatosis type I|neurofibromatosis1]] and should be [[Screening (medicine)|screened]] by [[plasma]] fractionated [[Metanephrine|metanephrines]] levels. The next step is to obtain 24-hour [[urinary]] fractionated [[metanephrine]] levels. Imaging should be considered if the initial tests are positive. [[Genetic]] testing also should be performed in high-risk patients.
==Screening==
===Biochemical screening===
* According to the Endocrine Society, [[biochemical]] [[Screening (medicine)|screening]] for pheochromocytoma in recommended among patients with:
** [[Von Hippel-Lindau tumor suppressor|VHL syndrome]]- started at 5 years of age with [[biochemical]] surveillance every year for the rest of life.
** Signs or symptoms suggesting catecholamine excess, especially if the symptoms are paroxysmal.
** Unexpected blood pressure changes to drugs, surgery, or anesthesia
** Unexplained blood pressure variability
** Incidentaloma, even if the patient is normotensive
** Blood pressure that is difficult to control
** History of previous treatment for pheochromocytoma or paraganglioma
** Hereditary risk of pheochromocytoma or paraganglioma in family members
** Syndromic features relating to a pheochromocytoma-related hereditary syndromes <ref name="pmid24893135">{{cite journal| author=Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH | display-authors=etal| title=Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2014 | volume= 99 | issue= 6 | pages= 1915-42 | pmid=24893135 | doi=10.1210/jc.2014-1498 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24893135  }} </ref>
*[[Plasma]] fractionated [[metanephrine]] level is the best test. If elevated, 24-hour [[urinary]] fractionated [[Metanephrine|metanephrines]] should be done.


Genetic testing also should be performed in high risk patients.      
===Imaging screening===
[[Anatomic]] imaging should be used when [[norepinephrine]] levels are elevated more than two times upper normal limits.<ref name="pmid26451910">{{cite journal| author=Aufforth RD, Ramakant P, Sadowski SM, Mehta A, Trebska-McGowan K, Nilubol N et al.| title=Pheochromocytoma Screening Initiation and Frequency in von Hippel-Lindau Syndrome. | journal=J Clin Endocrinol Metab | year= 2015 | volume= 100 | issue= 12 | pages= 4498-504 | pmid=26451910 | doi=10.1210/jc.2015-3045 | pmc=4667160 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26451910  }}</ref>
* For high-risk children, [[Screening (medicine)|screening]] for pheochromocytoma should begin by 11 years of age.
* For moderate risk patients, [[Screening (medicine)|screening]] should be started by 16 years of age.
* If positive, [[Adrenal gland|adrenal]] imaging ([[Computed tomography|CT]]) or ([[Magnetic resonance imaging|MRI]]) should be performed.


==Screening==
=== Genetic screening ===
* According to the Endocrine Society, screening for '''''familial pheochromocytoma''''' is associated with many syndromes. [[Multiple endocrine neoplasia type 2|Multiple endocrien neoplasia]] (MEN2) is one of them. Biochemical screening for family members of MEN2 patients is mandatory.
* Genetic testing should be performed in:<ref name="pmid24893135">{{cite journal| author=Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH et al.| title=Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2014 | volume= 99 | issue= 6 | pages= 1915-42 | pmid=24893135 | doi=10.1210/jc.2014-1498 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24893135  }}</ref>
* Biochemical screening for pheochromocytoma in pediatric patients with [[Von Hippel-Lindau tumor suppressor|VHL]] starting at 5 years of age with lifelong biochemical surveillance every year and the use of anatomic imaging when [[norepinephrine]] levels are elevated more than two times upper normal limits.<ref name="pmid26451910">{{cite journal| author=Aufforth RD, Ramakant P, Sadowski SM, Mehta A, Trebska-McGowan K, Nilubol N et al.| title=Pheochromocytoma Screening Initiation and Frequency in von Hippel-Lindau Syndrome. | journal=J Clin Endocrinol Metab | year= 2015 | volume= 100 | issue= 12 | pages= 4498-504 | pmid=26451910 | doi=10.1210/jc.2015-3045 | pmc=4667160 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26451910  }}</ref>
** Patients with a [[family history]] of pheochromocytoma
* Plasma fractionated metanephrines as the best test in this case. Normal values are enough to stop any further tests but if elevated results, 24-hour urinary fractionated metanephrines should be done.
**[[Tumors]] or [[malignant]] or extra-[[Adrenal gland|adrenal]] pheochromocytoma
* '''Genetic testing''' should be performed in:<ref name="pmid24893135">{{cite journal| author=Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH et al.| title=Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2014 | volume= 99 | issue= 6 | pages= 1915-42 | pmid=24893135 | doi=10.1210/jc.2014-1498 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24893135  }}</ref>
** Families whose infants or young children have [[Hirschsprung's disease|Hirschsprung disease]]
** Patients with a family history of pheochromocytoma,
**[[First degree relative|First-degree relatives]] of a patient with proven [[Germline mutation|germline]] ''[[RET proto-oncogene|RET]]'' [[mutation]]
** Bilateral or multifocal lesions.
** Patients with [[cutaneous]] lichen [[amyloidosis]]
** Tumors or malignant or extra-adrenal pheochromocytoma,
** Patients with known ''[[RET proto-oncogene|RET]]'' mutations.
** Young patients who are aged 50 years or under.
** Parents whose young children have [[Multiple endocrine neoplasia type 2|MEN 2A/2B]]
*Genetic screening — In general, the primary and most compelling purpose of genetic screening in human tumor predisposition syndromes is to prevent disease-related morbidity and mortality that would otherwise occur [2,26,56,57]. Genetic counseling and genetic testing for ''RET'' germline mutations should be offered to the following groups [1]:  ●First-degree relatives of a patient with proven germline ''RET'' mutation  ●Parents whose infants or young children have the clinical characteristics of MEN type 2B (MEN2B)  ●Patients with cutaneous lichen amyloidosis (CLA)  ●Families whose infants or young children have Hirschsprung disease (HD)  In an MEN2 family, a sample from one subject already known to be affected should be tested in order to determine the specific ''RET'' mutation for that family. All subjects of unknown status in that family should then be definitively genotyped. ''RET'' genotyping requires only a small blood sample and can therefore be performed at birth or soon thereafter. At the latest, genotyping should be done before the time at which prophylactic thyroidectomy would be performed in the event of a positive result.  ●Known ''RET'' mutation present – For those with ''RET'' mutations, prophylactic thyroidectomy in family members is timed based upon the specific DNA mutation in the ''RET'' proto-oncogene occurring in the family (table 6). The risk-benefit equation is strengthened by the ease of thyroid hormone replacement after thyroidectomy and the relatively low morbidity of the surgery, even in children, when performed by high-volume surgeons [58]. The timing of prophylactic thyroidectomy is reviewed separately. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Preventive surgery'.)  ●Known ''RET'' mutation absent – A family member who has not inherited the specific ''RET'' mutation that causes that family's MTC needs no further evaluation.  Thus far, family screening efforts appear to be suboptimal, as a high proportion of patients continue to receive less than optimal initial surgical treatment. According to the population-based Surveillance, Epidemiology, and End Results (SEER) registry, there has been no change in stage at diagnosis or significant improvement in survival noted over the last 30 years [59,60]. Although the SEER registry does not contain information regarding hereditary or biochemical results, an estimated 50 percent had a familial form of MTC (FMTC). This suggests that many MEN2/FMTC patients underwent surgery that was less than optimal for the stage of the disease. Summary information concerning MEN2 may be useful for counseling patients and affected families. Family alliances can provide such information: GeneTests or EndocrineWeb.  Sensitivity/specificity — One potential problem relates to the rare MEN2 families with no detectable ''RET''mutation. In addition, as with any genetic test, other potential sources of error exist such as sample mix-up, cross-contamination of the polymerase chain reactions used in the tests, and DNA polymorphisms that would prevent amplification of one ''RET'' allele, a situation that could result in a false-negative screening test. To date, however, neither false-negative nor false-positive ''RET'' tests have been described in MEN2 families in which a specific ''RET'' mutation was detected in an index case.  Availability of genetic diagnosis — Genetic diagnosis of MEN type 2A (MEN2A), FMTC, and MEN2B is readily available commercially. A list of testing laboratories is available at the MD Anderson Cancer Center website and through the genetic testing resource GeneTests. In Europe, a listing of commercial laboratories can be found at the European Directory of DNA Diagnostic Laboratories.  Clinicians should inquire as to the protocol and methodology of the offered ''RET'' DNA test. One important issue is whether all relevant exons (exons 10, 11, and 16, and, if those are negative, exons 8, 13, 14, and 15) will be sequenced if the ''RET'' mutation in that family is unknown.  Counseling — Before blood samples are taken for DNA analysis, detailed information about the consequences of DNA analysis must be provided to the family. Psychological support may well be needed before DNA test results are disclosed and during follow-up after diagnosis to minimize distress. Written consent must be obtained [61]. Given the rarity of this disease and the potential complications of a total thyroidectomy in young children, patients should be referred to academic centers with expertise in MEN2.  Reproductive options — Patients with MEN2 and a known familial ''RET'' mutation should be counseled that prenatal testing and preimplantation genetic testing are available options if they choose to pursue fertility [26]. Prenatal testing is performed in the first or second trimester via chorionic villus sampling or amniocentesis, respectively. Preimplantation genetic diagnosis (PGD) is done as part of in vitro fertilization (IVF); single embryonic cells are tested for the ''RET'' mutation. Only embryos without a ''RET'' mutation are then transferred to the uterus. The various reproductive options available to prospective parents require thoughtful discussion and genetic counseling.  Monitoring for MEN2-associated tumors — Affected family members require screening for multiple endocrine neoplasia type 2 (MEN2)-associated tumors.  When RET mutation is known — When the ''RET'' mutation is known, monitoring for MEN2-associated tumors is based upon the specific mutation and degree of risk it confers for MTC, pheochromocytoma, and primary hyperparathyroidism.  Medullary thyroid cancer — Children with certain ''RET'' mutations can develop clinically apparent MTC at an early age. The goal in patients with known ''RET'' mutations (but without clinically apparent disease) is to perform a prophylactic thyroidectomy before MTC develops or when it is still confined to the thyroid gland (table 6). (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Preventive surgery'.)  Children with the highest risk mutation (codon 918) should have thyroidectomy within the first year of life and, therefore, do not require monitoring.  For children with high-risk mutations (codons 634, 883), we begin monitoring at age three years, and for children with moderate risk mutations, we begin monitoring at age five years. We monitor with an annual physical examination, neck ultrasound, and measurement of serum calcitonin. The detection of a serum calcitonin level (basal or stimulated) above the upper limit of normal is an indication for surgery.  Pheochromocytoma — The risk of developing pheochromocytoma is variable depending upon genotype [62-64]. For children in the highest and high-risk categories, screening for pheochromocytoma should begin by age 11 years (table 5). For children in the moderate-risk category, we begin screening by age 16 years. Patients should be screened yearly by measuring plasma fractionated metanephrines or 24-hour urinary metanephrines and normetanephrines. If biochemical results are positive, adrenal imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is the next step. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Additional evaluation after biochemical diagnosis'.)  There is large variability in the penetrance of pheochromocytoma among different reported kindreds, depending upon the specific ''RET'' germline mutation. These findings help guide screening and therapy for MEN2 patients [65-69]. As an example, compared with families with mutations in codons 634 and 918, pheochromocytomas are rare in families with mutations in codons 533, 609, 611, 618, 620, 630, 633, 666, 768, 790, 791, 804, and 891, although they do still occur.  Due to screening programs, pheochromocytomas may be diagnosed at a young age and before symptoms are present.  Hyperparathyroidism — The hyperparathyroidism in MEN2A is often mild and asymptomatic. In one study, the mean age at diagnosis was 33 years, but children diagnosed as young as two years of age has been reported [1,27,70,71]. Biochemical screening for hyperparathyroidism should be performed yearly beginning at age 11 years in high-risk patients and 16 years in moderate-risk patients (patients in the highest risk category [MEN2B] are not at risk for developing hyperparathyroidism) (table 5) [1]. We measure serum calcium (corrected for albumin). If it is elevated, we measure intact parathyroid hormone (PTH). The diagnosis is established by finding high (or inappropriately normal) serum PTH concentrations in the presence of hypercalcemia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)  When RET mutation is unknown  Biochemical testing — For closely related MEN2 family members who refuse DNA analysis for themselves or their children, or for families who meet the clinical criteria for MEN2 but have negative sequencing of the entire ''RET'' coding region, biochemical testing can be performed to detect MEN2-related tumors. If biochemical testing is used, yearly testing starting at age five and continuing until at least age 35 years (or until a positive test occurs) is necessary [7]. For families with a clinical diagnosis of MTC prior to age five years, biochemical screening for MTC should begin at the youngest age of first diagnosis.  Either a pentagastrin or a calcium stimulation test can be used to screen for C-cell hyperplasia/MTC. Where available (not in the United States), pentagastrin is the preferred stimulation test. Testing should also include plasma fractionated metanephrines or 24-hour urinary metanephrines and normetanephrines (to screen for pheochromocytoma) and serum calcium (to screen for hyperparathyroidism).  Choice of biochemical test for MTC — Owing to the unavailability of pentagastrin in many countries, there is growing interest in the calcium stimulation test. However, there are few data using the calcium stimulation as a confirmatory test in patients with elevated basal calcitonin levels, and cut points for the discrimination of normal, C-cell hyperplasia, and medullary thyroid cancer (MTC) have not been standardized [72]. In one study, basal and stimulated calcitonin levels were measured in over 100 patients with thyroid disease (MTC in remission or persistence, ''RET'' gene mutation carriers, nodular goiter) and in 16 healthy volunteers [73]. In all groups, the levels of calcitonin stimulated by either pentagastrin or calcium were significantly correlated. In this study, calcium stimulated calcitonin levels above 32.6 pg/mL (females) and 192 pg/mL (males) had the best accuracy to differentiate normal subjects from patients with C-cell hyperplasia or MTC [73]. Criteria for abnormal calcitonin values may vary in local or commercial laboratories [74]. ●Pentagastrin stimulation test – The pentagastrin stimulation test uses a slow intravenous injection of pentagastrin (0.5 mcg/kg body weight) over three minutes. Blood samples for calcitonin are obtained at baseline and two and five minutes after pentagastrin infusion [75,76]. If stimulated calcitonin values are ≥200 pg/mL, MTC is likely and thyroidectomy and lymphadenectomy are required. If values are <100 pg/mL, the risk of MTC is low and periodic monitoring of basal and stimulated serum calcitonin levels is recommended. If the stimulated calcitonin values are between 100 and 200 pg/mL, the risk is uncertain. Such values could be indicative of C-cell hyperplasia or micro MTC. Some advise surgery [77,78], others observation (following calcitonin levels) [79].  Side effects of pentagastrin include abdominal cramping, extremity paresthesia, and feeling of warmth, lasting up to one to two minutes [76]. Pentagastrin is not available in many countries, including the United States.  ●Calcium stimulation test – The calcium stimulation test uses an infusion of calcium gluconate (2.5 mg elemental calcium/kg body weight over 30 seconds) administered in a fasting state (no food after midnight) [54,76]. Blood samples for calcitonin are obtained at baseline and two and five minutes after the stimulus. In one study, calcium-stimulated calcitonin levels above 32.6 pg/mL (females) and 192 pg/mL (males) had the best accuracy to differentiate normal subjects from patients with C-cell hyperplasia or MTC [73].  The most common side effects are temporary flushing and feeling of warmth (98 percent) [76]. Facial paresthesias are less common (20 percent).


==References==
==References==
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Overview

Familial pheochromocytoma is associated with multiple endocrine neoplasias, VHL and neurofibromatosis1 and should be screened by plasma fractionated metanephrines levels. The next step is to obtain 24-hour urinary fractionated metanephrine levels. Imaging should be considered if the initial tests are positive. Genetic testing also should be performed in high-risk patients.

Screening

Biochemical screening

  • According to the Endocrine Society, biochemical screening for pheochromocytoma in recommended among patients with:
    • VHL syndrome- started at 5 years of age with biochemical surveillance every year for the rest of life.
    • Signs or symptoms suggesting catecholamine excess, especially if the symptoms are paroxysmal.
    • Unexpected blood pressure changes to drugs, surgery, or anesthesia
    • Unexplained blood pressure variability
    • Incidentaloma, even if the patient is normotensive
    • Blood pressure that is difficult to control
    • History of previous treatment for pheochromocytoma or paraganglioma
    • Hereditary risk of pheochromocytoma or paraganglioma in family members
    • Syndromic features relating to a pheochromocytoma-related hereditary syndromes [1]
  • Plasma fractionated metanephrine level is the best test. If elevated, 24-hour urinary fractionated metanephrines should be done.

Imaging screening

Anatomic imaging should be used when norepinephrine levels are elevated more than two times upper normal limits.[2]

  • For high-risk children, screening for pheochromocytoma should begin by 11 years of age.
  • For moderate risk patients, screening should be started by 16 years of age.
  • If positive, adrenal imaging (CT) or (MRI) should be performed.

Genetic screening

References

  1. ↑ 1.0 1.1 Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH; et al. (2014). "Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline". J Clin Endocrinol Metab. 99 (6): 1915–42. doi:10.1210/jc.2014-1498. PMID 24893135.
  2. ↑ Aufforth RD, Ramakant P, Sadowski SM, Mehta A, Trebska-McGowan K, Nilubol N; et al. (2015). "Pheochromocytoma Screening Initiation and Frequency in von Hippel-Lindau Syndrome". J Clin Endocrinol Metab. 100 (12): 4498–504. doi:10.1210/jc.2015-3045. PMC 4667160. PMID 26451910.
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