Resident Conference Presented by Rachel Dunagin, M.D. November 15, 2005 Case Presentation CC: Chronic Cough Mr.
Download ReportTranscript Resident Conference Presented by Rachel Dunagin, M.D. November 15, 2005 Case Presentation CC: Chronic Cough Mr.
Resident Conference
Presented by Rachel Dunagin, M.D.
November 15, 2005
Case Presentation
CC: Chronic Cough
Mr. DW, a 74yo WM, presented to PHD for direct admission by PCP: abnormal finding on imaging.
HPI: He complains of a cough
Productive of white mucus Duration: past several months
3 4 wks PTA developed “pneumonia” – treated with Levaquin by PCP; febrile to 102
CXR was done at the time the antibiotic was prescribed and read as normal
Case Presentation
2d PTA returned to PCP office for routine physical exam
Patient continued to complain of “nagging” cough
Especially pronounced after meals
Productive of white mucus
Denied fever/chills
PCP ordered CT chest
Patient History
PMHx:
Cough 3/05 thru present (6/05)
HTN
Arthritis Superficial “clot” of LE 2001 PSHx:
Left ear surgery
Appendectomy All:
NKDA Meds:
Lotensin/HCTZ 20/12.5
Benzepril 20
Aspirin 81 Tums Flaxseed Oil Vitamin E Claritin D.
SocHx:
Married with 4 kids
Retired from DISD
Denies tobacco or drugs Rare Etoh FamHx:
sister/brother/mom-HTN
dad-CVA ROS:
Weight loss (5 pounds in 3wks)
Decreased appetite Edema BLE Cough otherwise negative
Physical Exam
Vital Signs: stable, afebrile
HEENT: NC/AT, pupils equal and reactive, EOMI, nares patent, OP clear
Neck: supple, no JVD, no LAD, no thyromegaly
Heart: RRR, no m/g/r
Lungs: CTAB, no w/c/r
Abd: soft, NT/ND, NABS, no HSM
Ext: 1+ edema LLE, trace RLE, 2+ pulse, neg Homan’s sign
Labs (from PCP’s office)
Na 142 K 4.1 Cl 103 Bicarb 26 BUN 22 Cr 1.6
Glc 138 Ca 9.4 TP 7.1 Alb 4.1 Glob 3 AlkP 78 AST 22 ALT 14 TB 0.7
WBC 6.4 Hgb 14.2 Hct 41.8 MCV 96 Plt 239
TSH 2.35
TG 120 Chol 181 HDL 43 LDL 114
EKG NSR 74 + PVC, no Q waves or ST changes
UA: negative
Imaging report
CT Chest: done 1 day prior to admission
3 Pulmonary Emboli
Report of CT Chest:
-
clot in right superior pulmonary artery
-
& in second order branches of upper & lower lobes.
-No left sided pulmonary emboli are appreciated.
Upon Admission CT Angio done:
-
filling defects seen within the right upper and lower lobe pulmonary arteries with extension into the second order branches as seen previously. - & filling defect within a segmental branch supplying the left lower lobe.
30.6 HUs
A low density mass measuring approximately 3 cm in diameter is noted. The CT attenuation is approximately 28 Hounsfield units. Adrenal adenoma would be a possibility but cannot be confirmed.
Adrenal Incidentaloma: Introduction
What is an adrenal incidentaloma and why should we care?
Definition: “Clinically inapparent adrenal mass detected through imaging for non adrenal disease”
First described approx 20 years ago
Is it common?
Based on autopsy reports, adrenal masses are AMONG THE MOST common tumors in humans
Found in ~3% of 50 year olds
Found in up to 10% of elderly patients
Advances in imaging (including CT, MRI, US) may reveal even higher numbers
So…is it time to panic ?
So…is it time to panic ?
NO
…Most adrenal masses cause no serious health problems
Approx 1 of every 4000 is malignant
Trivia: W hich adrenal is affected more frequently?
US studies show right adrenal more often affected
Likely because of better ultrasound visualization of right adrenal gland
Autopsy and CT studies show both adrenal equally affected
Outline
Causes, Prevalence, Natural History
Diagnostic Evaluation
Treatment, Follow-up
Bottom Line for the PCP
Conclusion of Case Presentation
Prevalence
At autopsy, <1% in patients <30 years old ~3% in 50 year olds Up to 10% in elderly
Women > Men ? if this reflects sex differences in undergoing imaging procedures
Causes
Benign Adrenocortical Masses
Pheochromocytoma
Adrenocortical carcinoma
Metastases
Other
Benign Adrenocortical Masses (Adenoma)
Do not degenerate into malignant lesions
Incidence increases with age
Its small size makes it difficult to differentiate from focal hyperplasia and accessory cortical nodules
Benign Adrenocortical Masses (Adenoma)
Higher incidence in patients with congenital adrenal hyperplasia (82% in homozygous, 45% in heterozygous)
Size variable: 1.4 – 9cm with mean of 3.3 cm
Majority are non-hypersecretory, but 5 47% secrete cortisol and 1.6-3.3% secrete mineralcorticoids. Extremely rarely secrete androgens/estrogens
Pheochromocytoma
Catecholamine-producing tumor
Hypersecretion of norepinephrine, epinephrine and dopamine
Classic Triad: episodic headache, diaphoresis, and palpitations (tachycardia/anxiety)
Half have paroxysmal hypertension, most of the rest have what appears to be essential hypertension.
Pheochromocytoma
May see encephalopathy, retinopathy and proteinuria associated with malignant hypertension
When associated with MEN2 syndrome
1/2 have symptoms
1/3 have hypertension
Pheochromocytoma: Other Symptoms
Pallor
Orthostatic hypotension
Visual blurring
Papilledema
Weight loss
Polyuria
Polydipsia Increased erythrocyte sedimentation rate (ESR)
Psychiatric disorders
Dilated cardiomyopathy
Hyperglycemia
Insulin resistance
Impaired glucose tolerance
Type 2 diabetes mellitus
Pheochromocytoma
Account for 1.5 – 33% of incidentalomas
Mayo Clinic reviewed 40,078 autopsies between 1928 and 1977
Pheochromocytoma found in 0.13%
Only diagnosed in 24% while alive
Histology: large pleiomorphic chromaffin cells
10-13% are malignant
However no widely accepted pathological criteria to differentiate benign from malignant exists.
Thus, metastases are the only irrefutable proof of malignancy
Pheochromocytoma
90% located in adrenal glands
10% in paraaortic sympathetic chain, aortic bifurcation, and urinary bladder.
Bilateral in 10% of pts (esp in familial pheochromocytomas associated with MEN IIA and IIB)
Adrenocortical carcinoma
Rare Incidence is 0.6 – 2 cases per million per year Interestingly, Southern Brazil’s incidence is 10x higher (reasons unknown).
Represents 0.02 -0.2% of all cancer related deaths
Bimodal age distribution: 1 decades st and 5 th
Functional or nonfunctional Functional tumors: Females > Males Nonfunctional tumors: Males > Females
Functional Tumors
Androgen-secreting tumors resulting in virilization - commonly in kids (84%), less in adults (<10%)
Estrogen-secreting tumors resulting in feminization are rare (<10%)
Hypercortisolism resulting in Cushing’s syndrome (45% adults vs 6% kids) or mixed Cushing-virilizing syndrome (25% adults)
Isolated primary mineralcortisolism – rare (<10%)
Adrenocortical Carcinoma
Prognosis – poor; mean survival = 18 months
Based on extent of disease, not impacted by sex or functional status
Common Symptoms of Non-functional tumors: weight loss, weakness, anorexia, nausea, emesis, severe abdominal gas, and myalgia
Abdominal pain + palpable tumor = advanced disease
Fever = tumor necrosis, hemorrhage, or opportunistic infection
Metastases
75% of incidentalomas in cancer patients are metastatic lesions.
Virtually any primary can be origin
Large proportion from lymphoma, lung cancer (35%) and breast cancer (39%)
Melanoma, leukemia, kidney and ovarian cancer also common
Review of 1000 consecutive autopsies of patients with carcinoma, adrenal glands involved 27% of cases.
Other Etiologies
Adrenal Myelolipoma
Ganglioneuromas
Adrenal Hyperplasia
Hematomas
Angiomyelolipomas
Malignant Epithelial Carcinoma
Epithelioid Angiosarcoma
Neurinoma
FIG. 1. Top, Distribution of diagnosis by tumor size. Data from eight studies with 103 diagnoses determined by histology (35 40 41 47 53 55 72 73 ). Bottom, Distribution of 380 clinically inapparent adrenal masses by histological confirmed diagnosis. [Reproduced with permission from F. Mantero et al.: J Clin Endocrinol Metab 85:637 –644, 2000 (60 ). © The Endocrine Society.]
Natural History
Large clinically inapparent adrenal masses (> 6cm)
25% = adrenal cortical carcinoma, thus poor outcomes (less than 50% 5 year survival)
treated surgically
Nonfunctioning adrenal masses
5-25% increase in size by at least 1 cm.
Risk of malig = 1/1000
Up to 20% develop hormone overproduction
Masses > 3 cm more likely to develop hyperfunction
Transformation rate of small (<3cm) nonfunctioning masses is low.
Diagnostic Evaluation 2 Main Questions
1.
Hormonally active or nonfunctioning?
2.
Malignant or benign?
Detailed Endocrine Evaluation
Goal: determine if patient has pheochromocytoma, subtle glucocorticoid excess, primary aldosteronism, virilizing or feminizing tumors.
History of or episodic hypertension, tachycardia, profuse sweating
Hirstuism, striae, central obesity, gynecomastia
Specific Hormonal Evaluation
Subclinical Hypercortisolism (5-47% of adrenal incidentalomas):
Overnight 1mg dexamethasone suppression test
Normal individual, 0800 serum cortisol concentration is suppressed to <139.75nmol/L (<5 μg/dL).
>10 μg/dL are suggestive of Cushing’s syndrome
Levels inbetween are equivocal
Specific Hormonal Evaluation
Hyperaldosteronism (1.6-3.8% of adrenal incidentalomas):
If patient has HTN, check serum K and plasma aldosterone concentration:plasma renin activity ratio
Historically, spontaneous hypokalemia (<3.5mmol/L) was hallmark of primary aldosteronism in hypertensive pts.
But NORMOkalemic primary aldosteronism appears at frequency 7-38% higher than previously thought (Bravo 1994, Stowasser 2001 & 2003)
Specific Hormonal Evaluation
Of 90 normokalemic patients with adrenal
If Aldosterone( μg/dL):Renin(μg/mL/hr) > 30 & plasma aldosterone concentration is >0.5nmol/L – highly suggestive of autonomous aldosterone production
Specific Hormonal Evaluation
Note patients with kidney failure and those
Additional Tests: 25mg Captopril Test, Salt loading tests, or fludrocortisone suppression test confirm the diagnosis; Elevated level urinary excretion of methyloxygentaed cortisol metabolites (18 hydroxycortisol and 18-oxo-cortisol).
Specific Hormonal Evaluation
Pheochromocytoma:
Elevated 24hr urinary excretion of free catecholamines (norepinephrine and epinephrine) or catecholamine metabolites [vanillylmandelic acid (VMA) and total metanephrines]
Specific Hormonal Evaluation
Plasma free metanephrines (normetanephrine and metanephrine) have good specificity and sensitivity and are recommended screening tests; however plasma catecholamines are not recommended due to poor sensitivity and specificity leading to false positives
Caution: Acetaminophen use interferes with assays of plasma free metanephrines, results in false-positive tests
Other possible tests: pharmacologic testing with glucagon or clonidine
Pheochromocytoma
Sensitivity (%) Upper Reference Limit Plasma (nmol/d) Free metanephrines Catecholamines Urine (µmol/d) Fractionated metanephrines Female Male Catecholamines Total metanephrines VMA 0.3 (0.6) 0.5 (2.9) 1 2 0.7 (1.7) 1 1.2 (3.0) 1 0.1 (0.5) 6 40 2
1 Metanephrine (Normetanephrine)
99 92 97 91 88 Specificity (%) 82 72 45 75 89 77 86
2 Epinephrine (Norepinephrine)
Wait.. What was this about Clonidine and Glucagon?
Clondine Suppression Test
Clonidine, a central alpha-2 agonist, normally suppresses sympathetic nervous system activity, but does not decrease catecholamine secretion from pheochromocytoma
If plasma norepinephrine levels decrease >50% or to less than 2.96nmol/L after clonidine = normal response.
If remains consistently elevated before and after clonidine, indicates pheochromocytoma.
False-positives if on diuretics or tricyclic antidepressants
Serious complication: hypotension
Wait.. What was this about Clonidine and Glucagon?
Glucagon Stimulation Test
Used when high plasma levels of normetanephrine or metanephrine and normal to slightly elevated plasma catecholamine levels
Give 1-2mg IV glucagon, after 2 minutes > 3x increase in norepinephrine indicates pheochromocytoma with high specificity, simultaneous increase in blood pressure may occur.
Test is not sensitive, thus negative result does not exclude the diagnosis
Serious complication: hypertensive crisis, so only done with experience operator
Specific Hormone Evaluation
Sex Hormone-secreting Masses:
Benign adenomas rarely secrete sex hormones, so routine evaluation of testosterone and estradiol is not recommended in patients with adrenal masses
Exception = Clinically suspected virilizing or feminizing tumor or if adrenocortical carcinoma is suspected based on radiology or history
Imaging
CT
MRI
US
CT
Lesions <4cm usually benign Adrenal adenomas
small, homogeneous, well-defined lesions with clear margins, constant in size
contain large amount intracytoplasmic lipid
allows a quantitative evaluation by measurement of the attenuation value of the lesions (expressed as Hounsfield units)
usually have < 18 HUs on noncontrast CTs.
100% Specificity with 68-89% sensitivity at 20-21 HUs.
Conclusion of several studies, no further w/u necessary if < 10 HUs (suggests lipid-rich adrenal adenoma)
CT
The problem: Lipid-poor adenomas represent 10-40% of adenomas
They have a higher attenuation value than lipid-rich adenomas
Therefore, not all adenomas can be characterized using non-contrasted CT
Solution: 3-minute delayed contrast CT using thresholds between 64 and 70HUs to differentiate adenoma from nonadenoma Washout Method malignancy.
– calculate % enhancement washout after 10-15min delay. If relative washout is >40-50% = highly suggestive of benign mass (sensitivity 96%, specificity 100%), is lower relative washout value suggests
FIG. 4.
Radiological panel of an adrenal cortical adenoma. Findings in a 66-yr-old woman with a history of breast cancer. Panels A and B demonstrate the use of CT for calculation of the relative enhancement washout. A, The contrast-enhanced CT shows a left-sided 1.5-cm adrenal mass (
arrow
) with a mean attenuation of 32.9 HU. B, On the 12-min delayed image, the attenuation of the left adrenal (
arrow
) is 12.9 HU. The relative enhancement washout is calculated using the following equation: percentage of relative enhancement washout = (1 – delayed enhanced HU value/initial enhanced HU value) x 100. With a relative washout of (1 – 12.9 /32.9) x 100 = 61%, the delayed enhanced CT is indicative of an adrenal adenoma (196 215 )
CT (cont)
Lesions >6cm more likely to be malignant – consider surgery
Pheochromocytomas
Rounded or oval masses, density similar to liver on noncontrast CT
CT (cont)
Larger lesions show cystic component due to central necrosis or hemorrhage
10% have calcification
Are hypervascular, so have intense enhancement with contrast.
CT Sensitivity = 93-100%
However, nearly 1/3 show nonspecific appearance that may overlap with adrenocortical carcinoma
MRI
Useful in staging adrenal carcinomas
Especially extent of infiltration into IVC
Malignant masses
Denser than benign masses because of higher fluid content
Therefore appear brighter on T2-weighted images Pheochromocytomas
Low T1 and bright T2 signal intensities Central necrosis
Metastases
Hypointense compared to liver on T1-weighted images and hyperintense on T2-weighted images
Strong contrast enhancement with delayed washout after paramagnetic contrast injection
CT vs MRI
Trials comparing noncontrast MRI to combined non-contrast/contrast CT found superior, similar and inferior MRI test performance, depending on which technique was used (chemical-shift MRI, adrenal mass to reference organ ratio, etc) McNicholas 1995, vanErkel 1994, Krestin 1991, Schwartz 2000
CT vs MRI
Studies on qualitative comparison of test accuracy concluded that combined noncontrast/contrast MRI was superior to both combined noncontrast/contrast CT and noncontrast MRI alone. Krestin 1991
Ultrasound
Operator dependent
Compounding factors: obesity, overlying gas
Decreased sensitivity compared to CT/MRI
Ultrasound
1995 Suzuki reported series of 61 patients with adrenal masses
US correctly identified all adrenal tumors > 3cm
Identified 65% of masses < 3cm
CT/MRI identified 100%
Usefulness: follow-up benign lesions
On the horizon: EUS
Fine Needle Aspiration
Performed under CT or US guidance
Based on review of 8 studies investigating the test performance for FNA to diagnose adrenal masses:
Sensitivity 81-100%
Specificity 83-100% to diagnose malignancy
Higher sensitivity and accuracy if mass > 3 cm or needle > 19 gauge
Fine Needle Aspiration
No conclusions of risk of needle-track metastases from FNA biopsy of adrenal carcinoma can be drawn from present studies.
In total, 36 complications (4%) have been reported on 888 adrenal mass biopsies, including 26 complications that were potentially serious and 9 patients (1%) requiring in-hospital treatment.
Wide range of biopsy technique, incomplete/unclear reporting, and small study sizes make it difficult to evaluate the risk of biopsies.
Fine Needle Aspiration
May be useful in the diagnostic evaluation of patients with a history of malignancy (particularly lung, breast and kidney) and a suspicious adrenal mass on imaging (particularly if heterogeneous and >20HUs)
Pheochromocytoma hypertensive crisis MUST be ruled out before FNA attempted due to potential of life-threatening
Surgery or NonSurgical Management?
Functional Lesions
Glucocorticoids, Mineralcorticoids, Adrenal sex hormones, Catecholamines
Confirmed biochemically
Adrenalectomy – Treatment of Choice
Or medical therapy
Inhibitors of adrenal cortical steroid hormone biosynthesis (ie in patients with Cushing syndrome who are poor surgical candidates)
Aldosterone antagonists for aldosterone secreting tumors.
Surgery or NonSurgical Management?
Nonfunctional Lesion
Management is not straightforward
Silent Pheochromocytoma: high risk for hypertensive crisis thus should undergo adrenalectomy
Next question – Benign vs Malignant
Benign vs Malignant: A Question of Size
> 6cm: Excise the lesion
< 4 cm: low risk, unlikely to have malignant potential, not resected
Lesions between 4 and 6 cm, either close follow-up or adrenalectomy
Adrenalectomy strongly considered if rapid growth rate, decreased lipid content on imaging or other imaging findings suggestive of malignancy
Follow-up
Most adrenal lesions remain stable, but 5-25% enlarge and 3-4% decrease in size Imaging – if not excised, lesion should be re evaluated with CT in 6-12 months
If does not increase in size, no data to support further imaging.
Hormone excess may develop in up to 20% of patient during follow-up but is unlikely in patients smaller than 3cm.
Cortisol hypersecretion is the most common and is usually subclinical
Risk for tumor hyperfunction plateaus after 3-4 years
Bottom Line from NIH Conference
All patients with an incidentaloma should have a 1-mg dexamethasone suppression test and measurement of plasma free metanephrines.
Patients with hypertension should also undergo measurement of serum potassium and plasma aldosterone concentration-plasma renin activity ratio.
A homogeneous mass with a low attenuation value (<10 HUs) on computed tomography is probably a benign adenoma.
Bottom Line from NIH Conference
Surgery should be considered in all patients with functional adrenal cortical tumors that are clinically apparent
All patients with biochemical evidence of pheochromocytoma should undergo surgery
Data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenomas
Bottom Line from NIH Conference
Recommendations for surgery based on tumor size are derived from studies not standardized for inclusion criteria, length of follow-up, or methods of estimating the risk for carcinoma. Nevertheless, patients with tumors >6cm usually are treated surgically, while those with tumors <4cm are generally monitored. In patients with tumors between 4 and 6cm, criteria in addition to size should be considered in the decision to monitor or proceed to adrenalectomy
Bottom Line from NIH Conference
The literature on adrenal incidentaloma has proliferated in the last several years. Unfortunately, the lack of controlled studies makes formulating diagnostic and treatment strategies difficult. Because of the complexity of the problem, the management of patients with adrenal incidentalomas will be optimized by a multidisciplinary team approach involving physicians with expertise in endocrino logy, radiology, surgery and pathology. The paucity of evidence-based data highlights the need for well-designed prospective studies.
Bottom Line from NIH Conference
Open or laparoscopic adrenalectomy is an acceptable procedure for resection of an adrenal mass. The procedure choice will depend on the likelihood of an invasive adrenal cortical carcinoma, technical issues, and the experience of the surgical team.
In patients with tumors that remain stable on two imaging studies done over at least 6 months apart and do not exhibit hormonal hypersecretion over 4 years, further follow-up may not be warranted.
Grumbach, M. M. et. al. Ann Intern Med 2003;138:424-429
Mr. DW
Labs showed elevated urine catecholamines
Cortisol, free, urine
Epinephrine, urine
Dopamine, urine Norepinephrine, urine
Metanephrines, urine Normetanephrine, urine
34.0 ug/d
39 ug/d (H)
242 ug/d 55 ug/d
1,677 ug/d (H) 1,217 ug/d (H)
MRI was done. Diagnosed with Pheochromocytoma
Upon further questioning, denied any elevation of blood pressure, headaches, diaphoresis, palpitations, pallor
Placed on Alpha-blockers. Anti-coagulated for 3 PEs.
Eventually returned to hospital for scheduled Lap Adrenalectomy. No complications. Doing well.
References
Barzon, Luisa. Risk Factors and Long-Term Follow-Up of Adrenal Incidentalomas. Journal of Clinical Endocrinology and Metabolism 84(2):520-526.
Bravo, M. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochormocytoma. Endocrine Review 15:356-368.
Grumbach, Melvin. NIH Conference: Management of Clinically Inapparent Adrenal Mass (“Incidentaloma”) Annals of Internal Medicine 138(5): 424 430.
Mansmann, Georg. The Clincally Inapparent Adrenal Mass: Update in Diagnosis and Management Endocrine Reviews 25(2): 309-340.
Pacak, K. Recent Advances in genetics, localization, and treatment of pheochromocytoma. Annals of Internal Medicine 134:315-329 Slawik, Marc. Adrenal Incidentaloma. www.endotext.com
(ch.20) Sjoberg, RJ. The clonidine suppression test for pheochromocytoma. A review of its utility and pitfalls. Archives of Internal Medicine. 152:1193 1197.
www.vectorpoint.ws/illuspages/panic.html
Young, William. The Adrenal Incidentaloma. www.Uptodate.com
End of Show
Other: Adrenal Myelolipoma
Benign, composed of fat and hematopoietic tissue
Majority are functionally inactive Patients asymptomatic, but can become symptomatic if large (pain/ retroperitoneal hemorrhaging)
Slow growing, <5cm No therapy unless:
rare, large type (can be >5.5kg)
symptomatic
or rapid growing, then surgery is curative.