Home

HPV na Prática Clínica

Conheça a clínica
Corpo clínico
Fale Conosco

Doenças e Disfunções
.Infertilidade
.Disfunção erétil
.Infecção urinária
.DST
.Próstata
.Rim
.Bexiga
.Testículos
.Pênis
.Cálculos urinários
.Vasectomia
.Reversão de Vasectomia

Compre o livro
HPV na Prática Clínica

Mapa de acesso ao consultório

Evaluation of Incidental Renal and Adrenal Masses

JAMES C. HIGGINS, CDR, MC, USN, and JAMES M. FITZGERALD, MAJ, USAF, MC Naval Hospital, Jacksonville, Florida

Incidental renal or adrenal masses are sometimes found during imaging for problems unrelated to the kidneys and adrenal glands. Knowledgeable family physicians can reliably diagnose these masses, thereby avoiding unnecessary worry and procedures for their patients. A practical and cost-efficient means of evaluating renal lesions combines ultrasonography and computed tomographic scanning, with close communication between the family physician and the radiologist. Asymptomatic patients with simple renal cysts require no further evaluation. Patients with minimally complicated renal cysts can be followed radiographically. Magnetic resonance imaging is indicated in patients with indeterminate renal masses, and referral is required in patients with symptoms or solid masses. The need for referral of patients with adrenal masses is determined by careful assessment of clinical signs and symptoms, as well as the results of screening laboratory studies and appropriate radiologic studies. Referral is indicated for patients with incidental adrenal masses more than 6 cm in greatest diameter. Appropriate laboratory screening tests include the following: a 24-hour urinary free cortisol measurement for patients with evidence of Cushing's syndrome; a 24-hour urinary metanephrine, vanillylmandelic acid or catecholamine measurement for patients with evidence of pheochromocytoma; and a serum potassium level for patients with evidence of hyperaldosteronism. (Am Fam Physician 2001;63:288-94,299.)
The widespread use of abdominal computed tomographic scanning (CT) and ultrasonography has increased the detection of incidental renal and adrenal masses that are found on imaging for problems unrelated to the kidneys or adrenal glands. Based on careful clinical assessment, imaging studies and selected screening laboratory tests, family physicians can diagnose most of these masses and determine the need for referral.

Incidental Renal Masses
Autopsy results have shown that approximately 50 percent of persons older than 50 years have one or more renal cysts.1 Other studies indicate that almost one third of persons in this age group have at least one renal cyst that is identifiable on a CT scan.2 Most of these lesions are benign simple cysts that require no further evaluation, intervention or urologic consultation.
Approximately one third to one half of persons older than 50 years have one or more renal cysts. The primary reason to investigate a renal mass is to exclude a malignant neoplasm. One screening study using ultrasound examinations found clinically or pathologically malignant renal tumors in 12 (0.2 percent) of 5,898 consecutive patients 50 to 79 years of age.3 The lifetime risk of renal cell carcinoma in a 40-year-old man is 1.34 percent, and the risk of death is slightly greater than 0.5 percent.4
Renal masses can be broadly categorized into cysts, tumors and inflammatory lesions (Table 1). Although simple cysts are usually asymptomatic, they occasionally cause flank or abdominal pain, a palpable abdominal mass or hematuria. Malignant masses may produce the same symptoms, or they may be associated with paraneoplastic syndromes. Inflammatory lesions are not usually incidental because there is almost always an associated clinical history when symptoms are present. A history of fever, chills or urinary tract infection suggests an infected cyst or an abscess.
With the proper history and interpretation of the renal ultrasonogram and/or CT scan, family physicians can correctly identify the majority of renal masses, which are simple cysts. They can also identify complex cysts and solid masses, which require further evaluation. Probable benign cysts may undergo surveillance, whereas indeterminate or complex cysts should be referred for surgical evaluation.
When the ultrasound criteria for a simple cyst are met, the likelihood of malignancy is extremely small.

Ultrasound Examination
Many incidental renal masses are discovered on abdominal ultrasound examinations. Ultrasound criteria for the diagnosis of a simple renal cyst include the following: (1) spherical or ovoid shape; (2) absence of internal echoes; (3) presence of a thin, smooth wall that is separate from the surrounding parenchyma; and (4) enhancement of the posterior wall, indicating ultrasound transmission through the water-filled cyst.5
When the ultrasound criteria for a simple cyst are met, the likelihood of malignancy is extremely small. Asymptomatic patients with incidental renal cysts that meet these criteria require no additional evaluation.One study showed that ultrasound examination had a sensitivity of 79 percent for the detection of renal parenchymal masses.5 However, this imaging modality did not identify masses less than 5 mm in diameter.
When visualization is inadequate on ultrasound scanning or when the ultrasound examination shows evidence of calcifications, septa or multiple cysts that may obscure a potential malignancy, renal CT scanning with contrast medium should be performed. Symptomatic patients should also be evaluated with renal contrast CT scanning.

Hounsfield units = units of x-ray attenuation used in computed tomographic scanning. Each pixel is assigned a value on a scale from -1,000 to +1,000.

 

CT and MRI
Incidental renal masses may also be detected on the standard abdominal CT scan. The current "gold standard" for evaluating renal masses requires capturing CT images (5 mm or less in thickness) before and after (no less than 100 seconds) contrast medium is administered. The density of a renal mass is reported in Hounsfield units (H).6,7 The Hounsfield measurements of the relative densities of various substances, including tissues, are presented in Table 2
The two most important factors in the diagnostic work-up of an incidental adrenal mass are its size and "functioning."
In one study, CT scanning had a sensitivity of 94 percent for the detection of renal parenchymal masses, but magnetic resonance imaging (MRI) was statistically superior to CT scanning (P <0.001) in the correct characterization of benign lesions.5 Thus, MRI may be helpful for further evaluation of an equivocal lesion before an invasive procedure is performed. T2-weighted turbo-spin echo images are especially helpful in providing additional characterization of a lesion.

Differentiating Benign from Malignant Lesions
In 1986, Bosniak8 created a four-part classification of cystic renal masses found on CT scans. The system uses Hounsfield units to categorize these lesions in order of increasing probability of malignancy (Table 3).9

Class I lesions are simple benign cysts that require no further evaluation unless signs or symptoms develop. Class II lesions are also benign. These cysts, which are minimally complicated by previous infection or hemorrhage, can be followed radiographically. Class III lesions are "indeterminate" and have a malignancy rate of 50 percent9; hence, surgical exploration of these lesions is warranted in otherwise healthy patients. Class IV cystic lesions and solid renal masses that enhance with contrast medium are presumed to be malignant.
The Bosniak system provides a standard framework for the noninvasive classification of cystic renal masses. At least four evaluations of the Bosniak classification have been published.9 Despite its shortcomings, this categorization appears to be the best system currently available.9,10
The CT criteria for a renal mass to be called a Bosniak class I cyst include the following: uniform density of no greater than 20 H (assigned density of water is 0 H, with a range of -20 to +20 H5), no enhancement of the mass on radiographs obtained after the administration of contrast medium (i.e., no increase in the Hounsfield units) and round or oval shape with no perceptible wall. Bosniak class I cysts constitute the majority of incidental renal masses and require no additional evaluation or treatment. Rarely, some patients with large simple cysts may become symptomatic. Patients with symptoms should be referred to a urologist for discussion of the risks, benefits and nature of possible interventions (Figure 1)

Incidental Renal Mass *--Dosage should start low and be increased weekly until effective or not tolerated FIGURE 1. Management of incidental renal mass. (CT = computed tomographic scanning; MRI = magnetic resonance imaging)

Class II cysts have three distinct features: one or two nonenhancing septa, calcifications in the wall or septum, and hyperdense contents (50 to 90 H) resulting from the presence of blood, protein or colloid. These lesions should not enhance with contrast medium. In addition, they should be smaller than 3 cm in greatest diameter and should otherwise have the appearance of benign simple cysts. Bosniak8 did not recommend follow-up for lesions that fulfill these criteria. However, care should be taken in evaluating probable benign simple cysts, and surveillance seems prudent because there is a small chance that these cysts will develop into renal cell carcinomas.
Class III lesions are cystic masses with any or all of the following features: thick, irregular borders, irregular calcifications, thickened or enhancing septa and multilocular form. These lesions are difficult to distinguish from a renal cell carcinoma, which may have a cystic appearance. In four reviews, 12 of 29 class III lesions proved to be malignant.9 MRI may help to better characterize these lesions before urologic referral for potential surgical exploration and close follow-up.
Class IV lesions are malignant-appearing heterogeneous cysts with shaggy, thickened walls or enhancing nodules. Their unequivocal malignant appearance results from solid tumor necrosis and liquefaction. The diagnosis of these lesions is usually straightforward, and surgical excision is indicated.

Incidental Adrenal Masses

Incidental adrenal masses are also being discovered more frequently on CT scanning and ultrasound examinations. Most adrenal masses are detected first on abdominal CT scans, with an incidence of 0.6 to 1.3 percent on such scans.11 The vast majority of asymptomatic adrenal masses are benign, and patients with these lesions do not require subspecialist referral or treatment.12 The differential diagnosis of incidental adrenal masses, summarized from studies in the literature, is provided in Table 4.13

The two most important factors in the diagnostic work-up are the lesion's size and "functioning." The size of an adrenal mass is important: lesions larger than 6 cm in greatest diameter are more likely to be malignant.14 Even at a threshold size of 6 cm, it has been estimated that more than 60 adrenalectomies would have to be performed to remove one adrenal carcinoma.15
To determine whether an adrenal mass is functioning, the patient should be assessed for signs and symptoms of Cushing's syndrome, pheochromocytoma or hyperaldosteronism. Cushing's syndrome is characterized by hypertension, moon-shaped face, proximal muscle weakness, truncal obesity, buffalo hump, thin skin, abdominal striae and easy bruising. Classic features of pheochromocytoma include paroxysmal hypertension, headache, sweating and palpitations. Hypertension, hypokalemia and hypernatremia characterize hyperaldosteronism.
In 1990, a team of investigators16 proposed a screening endocrine laboratory evaluation of adrenal masses that is sensitive and cost-effective (Figure 2 and Table 5). The serum potassium level is used to screen for hyperaldosteronism in patients with hypertension. Measurement of 24-hour urinary metanephrine, vanillylmandelic acid or catecholamines is used to screen for pheochromocytoma. Because urinary catecholamine measurements have a higher false-negative rate for pheochromocytoma, some investigators have proposed the addition of plasma catecholamine measurements. It seems reasonable to add plasma catecholamine measurements to the screening endocrine evaluation because even though pheochromocytoma is rare, it can be a potentially life-threatening problem.

The best initial screening test for Cushing's syndrome is the 24-hour urinary free cortisol measurement.17 Although some authors16 do not support screening for Cushing's syndrome in the absence of clinical signs or symptoms, other investigators recommend routine measurement of 24-hour urinary free cortisol levels in all patients with incidental adrenal masses. Additional evaluation with a dexamethasone suppression test is warranted if Cushing's syndrome is suspected, a patient has signs or symptoms of the syndrome or the results of the 24-hour urinary free cortisol measurement are equivocal.

Laboratory screening for adrenal carcinoma using urinary 17-ketosteroid measurements is not advised because the test lacks sensitivity and specificity. Furthermore, adrenal cancer is rare.
Patients with a mass larger than 3 cm in greatest diameter, normal screening laboratory tests and no clinical signs or symptoms of adrenal disease can be followed by their family physician. Reasonable surveillance includes a CT scan or ultrasound examination in three months, and then every six months for two years.18

Referral of Patients With an Incidental Adrenal Mass
Referral is required for patients with an incidental adrenal mass larger than 3 cm if a change in the size of the lesion is noted on serial radiographic studies. Referral for surgical removal is required for all patients with adrenal masses larger than 6 cm because of the possibility of malignancy. Patients with masses between 3 and 6 cm in greatest diameter should undergo an MRI study and additional endocrine evaluation; referral may be advised.
Patients with abnormal screening laboratory results should be referred, regardless of the size of the mass, because hormone-producing tumors need to be surgically excised. Lastly, all patients with a history of a malignancy who are found to have an adrenal mass probably should undergo needle biopsy of the lesion because metastatic disease is the most likely pathology in this situation.19

Renal Cystic Masses:
1. Simple Renal Cyst
Thin-walled epithelium lined cavity which contains straw- colored or clear-colored liquid
Once thought to be rare - now reported 50% people over 50
2%-4% children

Ultrasound Criteria:
Anechoic
Sharply defined far wall
Enhancement
Nearly imperceptible cyst-wall thickness
Round or ovoid shape

Usually asymptomatic - if large may be punctured to relieve symptoms, if centrally located can cause obstruction

Multiple simple cysts can occur but are fewer in number, more regular in size than polycystic disease

Differentials:
Calyceal diverticuli
Renal Pseudoaneurysm
Locally dilated calyces

2. Atypical Renal Cysts:
Septated cyst
Wall calcification
Internal Echoes
Lobulated Shape
Thickened Wall

3. Multilocular Renal Cyst:
Also known as Multilocular Cystic Nephroma, Benign Cystic Nephroma, Fetal Renal Cystic Hamartoma, Pearlmann tumor
Rare, non-hereditary
Multiple, non-communicating cysts in one area
Remainder of kidney is normal
Half occur in young children - may contain elements of Wilm's tumor, other half occur in adults (women)

4. Autosomal Dominant (Adult) Polycystic Kidney Disease (ADPKD)
Bilateral
Numerous cysts of varying sizes
Increased echogenicity in visible cortex
Incidence 1/1000 - 1/1500 worldwide
Enlarged kidneys, hypertension presenting symptoms
At least one parent affected (50% chance in offspring)
Third most common cause of renal failure

5. Autosomal Recessive Polycystic Kidney Disease
Both parents must be carriers (25% chance occurrence in offspring)
Variable amounts (10% to 90%) of parenchyma involved in non-communicating cysts - age at onset of symptoms (prenatally to age 5) inversely related to amount of parenchymal involvement.
Prenatal - enlarged kidneys, oligohydramnios, lung hypoplasia, distended abdomen
still-birth or neonatal death

Neonatal
distended abdomen, renal failure
cystic and fibrotic changes in liver
death d/t renal failure within first year

Infantile - Juvenile Diagnosis
Hepato- and Spleno- megaly
Portal HTN
Esophageal Varices
Cystic and Fibrotic change in liver
Death due to hepatic fibrosis age 1-5

6. Multicystic Dysplastic Kidney (MCDK)
30% will show abnormality of contralateral kidney
results from embryonal malformation of kidney

7. Acquired Cystic Kidney Disease
Up to 90% of patients on long-term renal dialysis develop cystic changes in native kidney
Cysts seen throughout the kidney
Increased incidence of renal cell carcinoma with ACKD

8. Medullary Cystic Disease of Medullary Sponge Kidney:
Very small cysts within pyramids
Discrete cysts (<2cm) may be seen near corticomedullary junction
most cysts are very small causing increased echogenicity of pyramids
Occurs in young adults (autosomal dominant form) and in children (autosomal recessive)
Autosomal recessive form leads to renal failure

Solid Renal Masses:
1. Renal Cell Carcinoma (also known as hypernephroma or renal adenocarcinoma)
Most common renal solid mass in adulthood
All solid masses are worked up as malignant until proven otherwise

Staging:
1. Mass confined to the kidney with intact renal capsule
2. Involves perirenal fat but is contained within Gerota's fascia (may involve adrenal)
3. Involvement with renal vein or IVC and/or adjacent lymph nodes
4. Involvement of adjacent organs and/or distant mets

Increased incidence in patients with PCKD, TS, ACKD
Usually hypoechoic or isoechoic to nl. renal parenchyma
Hemorrhage or necrosis leads to complexity in 40%
1% - 2% cystic or arise contiguous to cyst
4% hyperechoic relative to nl renal parenchyma
Punctuate calcifications may occur

2. Angiomyolipoma:
Multiple occur in 80% of patients with tuberous sclerosis (TS)
50% of these tumors arise in other patients, usually solitary
Mesenchymal tumor - elements of fat, fiber, muscle
Usually of echogenicity similar to renal sinus
May show mixed echogenicity or complexity d/t hemorrhage

3. Renal adenomas:
Similar in appearance to RCC - seldom benign if > 3 cm. size

4. Oncocytoma:
Hypervascular mass with central stellate scar in center
Spoke wheel configuration of vessels

5. Transitional Cell Carcinoma:
Hypoechoic to isoechoic mass arising from epithelium lining
renal pelvis or ureters or bladder

6. Papillomas:
Benign counterpart to Transitional Cell Carcinoma

7. Squamous Cell Carcinoma:
Rare neoplasm with features similar to TCC but more invasive
SCC often follows chronic irritation d/t infections, stones, drug use

8. Renal Metastases:
Renal mets occur late in the disease process from primary lung, colon, melanoma, head, neck, breast, uterine CA
Usually small, multifocal, about 1/3 bilateral
Renal lymphoma - usually invasion from perinephric nodes
Enlarged kidneys with multiple, bilateral, hypoechoic renal masses

9. Leukemia
Diffuse enlargement of the kidney
Leukemic infiltrates may present as focal, poorly marginated, nodular masses that are hypoechoic to anechoic

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Naval or Air Force medical departments or the Naval or Air Force services at large.

The authors thank Michael R. Spieker, CAPT, MC, USN, and Gary L. Leffelman, CDR, NC, USN, Naval Hospital, Jacksonville, Fla., for their assistance in the preparation of the manuscript.

The Authors

JAMES C. HIGGINS, CDR, MC, USN,
is a staff physician in the family practice residency program at the Naval Hospital, Jacksonville, Fla., and assistant clinical professor of family medicine at the Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine, Bethesda, Md. A graduate of the Philadelphia College of Osteopathic Medicine, he is a board-certified family physician who completed a family medicine residency at the Naval Hospital, Jacksonville, and a faculty development fellowship in family medicine at the University of North Carolina at Chapel Hill School of Medicine.

JAMES M. FITZGERALD, MAJ, USAF, MC,
currently has a private urology practice in Lowell, Mass. Previously, he was a staff urologist at the Naval Hospital, Jacksonville. After graduating from Georgetown University School of Medicine, Washington, D.C., he completed a residency in pre-urology general surgery at Massachusetts General Hospital, Boston, and a residency in urology at Lahey Clinic Medical Center, Burlington, Mass.

Role of Percutaneous Biopsy and Aspiration in Patients with Cystic Renal Masses

Claudia Berman, MD
Radiology Service, H. Lee Moffitt Cancer Center & Research Institute

Neoplasm
The differential diagnosis for neoplastic disease in this age group(40-50 years old) includes renal cell carcinoma and multilocular cystic nephroma. Approximately 5% of renal cell carcinomas present as multiloculated, fluid-filled masses. Typical findings include extensive calcification, blood, or hemorrhage within the cysts; thick, irregular enhancing walls and septa ; and evidence of extension into the renal vein or of metastatic spread to regional lymph nodes or liver. The clinical features are nonspecific and are similar to those found in solid renal carcinomas. Half of the cases of von Hippel-Lindau disease have one or more renal cancers that are often multiloculated cystic masses.
Multiloculated cystic nephroma is a rare, nonhereditary cystic neoplasm with a capsule and septa that separate multiple epithelium-lined noncommunicating cysts. Its bimodal distribution peaks in children who are younger than four years of age and in adults (predominantly women) who are 30 to 70 years of age. Herniation of the tumor into the renal pelvis is suggestive of this entity, and hemorrhage is atypical.
The appearance of the CT scan and US examination for this patient may indicate Wilms' tumor, mesoblastic nephroma, and clear-cell sarcoma of the kidney. However, these are diseases of infancy or early childhood.

Benign Cystic Disease
Localized cystic disease of the kidney presents as multiple cysts involving only one portion of the kidney. It is neither genetically transmitted nor progressive, and it is not associated with neoplasia. The most suggestive finding on CT scan for localized cystic disease is the presence of a multiloculated mass that is not clearly demarcated from normal tissue. This appearance is due to the absence of a capsule. Smaller cysts may be present in the adjacent parenchyma that are slightly removed from the main mass.
Septated cysts are produced by two or more adjacent cysts or by a cyst with internal septations. Septations can be the result of hemorrhage or infection in a simple cyst, and they are often partial. The septations are either connective tissue or, in the case of adjacent cysts, compressed parenchymal tissue. Cystic spaces are characteristically large, and the septa are delicate.
Segmental multicystic kidney is often associated with other congenital renal anomalies. Although its appearance can be similar to that seen in this patient, it is usually diagnosed as a palpable mass in newborns.

Radiologic Criteria for Biopsy
Bosniak[2] has categorized cystic masses into four groups that reflect an increasing likelihood of malignancy. Category I is comprised of simple benign cysts that are well marginated with thin, smooth walls on CT scan. These do not enhance with contrast administration, and they measure less than 20 Hounsfield units (HU). On sonography, they are similarly well marginated, are anechoic, and have increased through transmission. Category II includes mildly complicated cysts, predominantly those with thin septa or small foci of wall or septal calcification. This category also includes simple cysts with attenuation measurements between 50 and 90 HU on CT scans, thought to be due to blood breakdown products within the cyst fluid. As with Category I cysts, contrast enhancement is absent. Category III includes indeterminate lesions that may have irregular margins, thickened or enhancing septa, and thick or irregular calcification. Category IV identifies probable malignancies that are likely to have thickened irregular or enhancing areas and calcification.
Category I lesions require no further follow-up. Category II lesions should be followed every three months for at least one year to ensure that no growth is occurring. Category III lesions require some type of histologic diagnosis, and Category IV lesions require surgical diagnosis.[3,4]
This case was identified as Category III due to uncertainty of margination and possible septal thickening. However, since a follow-up period of seven months showed no perceptible progression, the patient was classified as low risk in Category III, and a biopsy was performed percutaneously. Pathology established this mass to be benign.

References
1. Hartman DS, Davis CJ, Sanders RC, et al. The multiloculated renal mass: considerations and differential features. Radiographics. 1987;7:29-52.
2. Bosniak MA. The small (<=3.0 cm) renal parenchymal tumor: detection, diagnosis, and controversies. Radiology. 1991;179:307-317.
3. Miller WT, Coleman BG. Case #4: renal cell carcinoma. In: Siegel BA, Stephens DA, eds. ACR Syllabus: Diagnostic Ultrasonography II. Reston, Va: American College of Radiology; 1994:89-119.
4. Berman CG, Brodsky NJ. Genitourinary Malignancies in Oncologic Imaging: A Clinical Perspective. New York, NY: McGraw Hill; 1997. In press.

Pheochromocytoma

H. Christoph Klingler a, Paul J. Klingler bA, J. Kirk Martin Jr c, Robert C. Smallridge d, Stephen L. Smith c and Ronald A. Hinder c
[a] Department of Urology, University of Vienna, Vienna, Austria[b] Department of Surgery, University Hospital of Innsbruck, Innsbruck, Austria[c] Department of Surgery, Mayo Clinic Jacksonville, Jacksonville, Florida, USA[d] Department of Endocrinology, Mayo Clinic Jacksonville, Jacksonville, Florida, USA
A Reprint requests: Paul J. Klingler, M.D., Department of Surgery, University Hospital of Innsbruck, Anichstrasse 35, A-6215 Innsbruck, Austria
Manuscript received 12 June 2000 Revised 22 January 2001 Accepted 22 January 2001;

Article Outline

The adrenal gland is a complex structure composed of two physiologically and embryologically distinct parts, the cortex and medulla, which produce a wide variety of hormones. Dramatic physical changes and characteristic syndromes may result from imbalances of their synthesis, secretion, and regulation, dependent on the zone of origin. 1 The main cortical syndromes according to zone are Cushing syndrome (zona fasciculata), primary aldosteronism (zona glomerulosa), and virilism (zona reticularis). The adrenal medulla functions as a presynaptic sympathetic nerve synthesizing epinephrine and norepinephrine. Tumors from these chromaffin cells are known as pheochromocytomas and have a characteristic spectrum of metabolic and cardiovascular effects. 2

Pheochromocytoma is the most important disease of the adrenal medulla and produces catecholamines derived most commonly from the adrenomedullary chromaffin cells. Those tumors arising from extra-adrenal chromaffin cells are called paragangliomas. Pheochromocytomas occur in all races but less frequently in blacks. They are most frequent in individuals between 30 and 50 years of age and uncommon in those older than 60 years. They occur slightly more often in females than in males. 1,2 1,2 Pheochromocytomas are rare, except in certain familial settings, in which they are inherited as an autosomal dominant trait and may be the first clue of the presence of multiple endocrine neoplasia II or neuroectodermal syndromes such as neurofibromatosis von Recklinghausen, cerebelloretinal hemangioblastomatosis (von Hipple-Lindau disease and Sturge-Weber syndrome), and tuberous sclerosis (Bourneville disease). 1 The incidence of pheochromocytomas associated with these syndromes is reported to be as high as 23%. 1 Most pheochromocytomas are sporadic; 10% are bilateral. In familial cases, bilateral tumors may be present in up to 50% of patients. 2 Approximately 1 new case per 2 million persons is detected annually, and less than 0.1% of hypertensive patients harbor a chromaffin tumor as the primary cause of their increased blood pressure.

Despite the rarity of these tumors, they are clinically important, since, correctly diagnosed and properly treated, pheochromocytomas are curable. Undetected or untreated, they may be fatal. Pheochromocytomas may be clinically silent in up to 17% of patients, making diagnosis difficult. 3,4 3,4 In 76% of patients in whom pheochromocytomas had not been suspected clinically and were detected during autopsy, nonspecific symptoms and signs were present, of which hypertension was the most common finding. 2,3 2,3 Thus, potentially curable cases may be undiagnosed while patients are alive, and the symptoms may antedate definitive diagnosis by many years. More than 90% of pheochromocytomas are benign; however, it may be difficult to distinguish pathologically benign from malignant pheochromocytomas unless metastases to bone, liver, or lung are detected. [3] [4] [5] [6]

Clinical manifestations

A clinical hallmark of a pheochromocytoma is hypertension. It may occur with equal frequency as paroxysmal or sustained, but usually the hypertension is labile. A typical paroxysmal hypertensive crisis is characterized by an acute elevation in blood pressure that may last for 1 hour. 1 A severe headache, profuse sweating, and palpitations with tachycardia accompanied by anxiety symptoms are characteristic features of such a paroxysmal episode. A study of 2585 hypertensive patients, including 11 with pheochromocytoma, noted headache, sweating, and palpitations in 75% of these patients. 3 Together with hypertension, these three clinical symptoms indicated the diagnosis of pheochromocytoma with a specificity of 93.8% and a sensitivity of 90.9%. When hypertension was absent from this triad of symptoms, the diagnosis of pheochromocytoma could be excluded with a certainty of 99.9%. Hypertensive episodes may occur spontaneously or together with acute physical exercise, defecation, or palpation. 2,5 2,5 They are not provoked by psychological stress or anxiety but by drugs that lower the blood pressure acutely: opiates, cocaine, adrenocortical hormone, dopamine antagonists, radiographic contrast media, tricyclic antidepressants, tyramine, and amphetamines. 1,3,4,6 1,3,4,6 1,3,4,6 1,3,4,6

Diagnosis of a pheochromocytoma is usually straightforward; however, in its early course, a pheochromocytoma may be asymptomatic or present with only mild symptoms for years. 2,6 2,6 The extensive differential diagnosis for pheochromocytomas includes panic attacks and anxiety syndromes, angina pectoris, myocardial infarction, thyrotoxicosis, brain tumor, subarachnoidal hemorrhage, menopausal syndrome, hypoglycemia, shock, and others. 3,6 3,6 For these reasons, it is necessary to obtain a detailed medical history. It has been shown that pheochromocytomas produce various other hormones, including calcitonin, opioid peptides, somatostatin, adrenocortical hormone, and vasoactive intestinal peptide. 1,6 1,6 This constitutes a major diagnostic and therapeutic challenge and calls for a close interdisciplinary evaluation.

Diagnosis

The diagnosis of a pheochromocytoma is made from biochemical determinations, with demonstration of elevated levels of catecholamines or their metabolites in blood or urine. 3 The sensitivity and specificity of these tests have improved in recent years with the introduction of high-performance liquid chromatography with electrochemical detection. 3 In symptomatic patients, the sensitivity and specificity now approaches 100%. 1,3,6 1,3,6 1,3,6 Only a few drugs such as labetalol interfere with the measurement of catecholamines by high-performance liquid chromatography.

Urine tests
The most reliable urine test measures epinephrine and norepinephrine, with a sensitivity of approximately 97% and a specificity of up to 100%. 5,6 5,6 The measurement of vanillylmandelic acid in a 24-hour collection of urine is less reliable and may miss a pheochromocytoma in up to 35%. 6 The urine must be collected in strong acid (20 mL 6N HCl) in a leakproof container and refrigerated. Patients ideally should not be taking any medications, since various drugs interfere with catecholamines, including monoamine oxidase inhibitors, clonidine, amphetamines, levodopa, chlorpromazine, and quinidine. Theophylline and tetracycline increase the values of catecholamines and metanephrines, and reserpine, guanethidine, metyrosine, clofibrate, and disulfiram decrease the total catecholamine, metanephrine, and vanillylmandelic acid values. [1] [2] [3] [4] If antihypertensive therapy must be continued, calcium channel blockers, diuretics, vasodilators such as minoxidil or hydralazine, and angiotensin-converting enzyme inhibitors may be used, because they have only minimal biochemical interference with catecholamines. In patients with infrequent episodes of hypertension, a urine sample is best collected when the patient is hypertensive and a second sample 2 to 3 hours later.

Blood tests
When drawing blood to test for catecholamines, the patient should be fasting and supine, with the needle in place for at least 20 minutes before the sample is obtained. The sample should be frozen within 1 hour. The normal values for norepinephrine and for epinephrine are less than 500 pg/mL and less than 100 pg/mL, respectively; values greater than 2000 pg/mL and 400 pg/mL, respectively, are diagnostic of pheochromocytoma. 1,3,6,9,10 1,3,6,9,10 1,3,6,9,10 1,3,6,9,10 1,3,6,9,10 It is best to study patients in the morning after an overnight fast, since caffeine and similar beverages may yield false-positive results. 1,9,10 1,9,10 1,9,10 In rare circumstances, such as obtaining intermediate values, a suppression test with phentolamine (Regitine), a short acting alpha-adrenergic antagonist, may help to differentiate between the presence of a tumor and an exaggerated physiologic response. A reduction in blood pressure greater than 35 mm Hg systolic and 25 mm Hg diastolic during 1 to 10 minutes after administration of 1 to 5 mg phentolamine as an intravenous bolus is considered diagnostic. 3 As patients with pheochromocytomas may become hypotensive, it is prudent to start with a dose of 1 mg phentolamine and inject the other 4 mg after no response within 2 minutes. The same test may be performed with clonidine (Catapres). 6 The sensitivity is 97%, but the specificity is low at about 67%. 3,6 3,6 This was improved by combining the clonidine test with the glucagon test, yielding a specificity of 100%. 1,6 1,6

Provocative tests for pheochromocytoma (exercise, abdominal palpation, or by histamine, tyramine, or metoclopramide administration) should not be used, because several deaths have been reported. 1,3,6 1,3,6 1,3,6

Localization studies

Numerous imaging techniques exist that may demonstrate adrenal tumors. All radiologic imaging techniques have been reported to be helpful in making the differential diagnosis. Even a urogram or barium enema may give the first hint of an adrenal mass. Arteriograms and selected venous catheterization for the measurement of catecholamines are rarely used, except when an extra-adrenal tumor must be located and in some occasions of diagnostic uncertainty. 6,11,12 6,11,12 6,11,12 These are invasive techniques and impose the risk of a hypertensive crisis. 1,2 1,2 Only in unusual cases is a large cyst detected during physical examination. 13,14 13,14 Plain abdominal films may demonstrate mural calcifications. This has been described as a common feature of adrenal cysts and is reported in up to 15% of cases. [15] [16] [17] In a recent study, 69% of adrenal cysts had wall calcifications on computed tomography (CT) scan. 16

Most commonly, the diagnostic tools for adrenal lesions are retroperitoneal and/or abdominal ultrasound, followed by CT scanning or magnetic resonance imaging, and scintigraphy. [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]

The importance of ultrasonography is that it is a noninvasive screening tool and is capable of detecting suprarenal tumors and distinguishing between solid and cystic tumors. 13,14 13,14 It may help in the differential diagnosis by excluding other cystic structures such as septated fundus of the gallbladder or cysts of the liver, pancreas, spleen, or mesentery, as well as aneurysms of the aorta and its branches. However, a broad spectrum of sonographic presentations in adrenal pheochromocytomas has been reported and makes the differential diagnosis difficult. 21

The most useful imaging method for locating a pheochromocytoma is CT, which can visualize the normal adrenal gland in up to 95% of patients. 1,3,14,16,17 1,3,14,16,17 1,3,14,16,17 1,3,14,16,17 1,3,14,16,17 The major advantages include that CT is almost always available and is a noninvasive, safe, and quick procedure that detects tumors larger than 1.0 cm. With administration of contrast medium, a noticeable enhancement of a normal adrenal cortex may be found that defines a tumor of the adrenal medulla. The sensitivity is reported at more than 98% and the specificity at 98%. 16,17 16,17 Magnetic resonance imaging provides T1 and T2-weighted images with tissue specificities such that it may distinguish between pheochromocytoma and other adrenal masses. 18,19 18,19 The sensitivity is reported to be up to 100%, with a positive and negative predictive value of 83% and 100%, respectively. 19 The iodine-131 (131I)-labeled metaiodobenzylguanidine (MIBG) scan may also be used as a diagnostic tool. 20,22,23 20,22,23 20,22,23 The sensitivity varies between 90% and 100%, and the positive and negative predictive value is reported at 100% and 87%, respectively. Somatostatin receptor imaging (Octreotide scan) is another scintigraphic tool that was shown to be useful in the diagnosis of pheochromocytoma. 24 This is a dynamic scintigraphic study that is performed after intravenous administration of indium-111-pentetreotide followed by a whole body scan; however, only limited experience has been reported to date. 23,24 23,24 Both methods have the advantage of visualizing extra-adrenal locations such as neuroblastomas, metastases, and other amine precursor uptake and decarboxylation (APUD) tumors. 20 Thus, it is most practical in detecting multiple tumors, tumors in unusual locations (cardiac pheochromocytoma), and recurrent disease. 3,6,20,23,24 3,6,20,23,24 3,6,20,23,24 3,6,20,23,24 3,6,20,23,24

Detected pheochromocytomas are typically larger than 3 cm and cystic. Ito et al. 12 demonstrated that with an increasing diameter, cystic formation is more frequently found, and these patients are more likely to be clinically symptomatic. This is controversial, as Bravo et al. 23 state that small tumors frequently have rapid turnover of catecholamines and liberate large amounts of norepinephrine and epinephrine into the circulation. In large tumors, turnover is often slow, with large amounts of catecholamines metabolized within the tumor. A possible answer to this controversy might be that in symptomatic tumors, hemorrhagic necrosis is frequently found, which may explain the higher possibility of hormones being released into the circulation and provoking symptoms. 3,6,12,23 3,6,12,23 3,6,12,23 3,6,12,23

Therapeutic management

Surgical removal of a pheochromocytoma is the treatment of choice, as unresected tumors may produce a fatal hypertensive crisis. 1,6,24,25 1,6,24,25 1,6,24,25 1,6,24,25 This requires an integrated cooperative team effort by an internist or endocrinologist, an anesthesiologist, and a surgeon. The preoperative pharmacologic preparation with specific alpha-adrenergic (and possibly beta-adrenergic) blocking agents or a calcium channel blocker is universally accepted and mandatory. [26] [27] [28] [29] Even asymptomatic patients should undergo pharmacologic preparation preoperatively. This has greatly improved the safety of the operation. 25 The drug of choice for alpha-blockade is phenoxybenzamine (Dibenzyline). 29 Treatment is usually continued for 7 to 14 days before surgery. Administered orally, the initial dosage is 10 mg twice daily. This is increased up to 40 mg three times daily, but may be restricted by side effects such as hypotension. 25,26 25,26 Prazosin (Minipress), a pure alpha1-antagonist, and labetalol (Normodyne), an alpha and beta-antagonist, are also used in the treatment of pheochromocytomas. 6,26,27 6,26,27 6,26,27 Good response rates have been reported with the use of calcium channel blockers. 6,23,28,29 6,23,28,29 6,23,28,29 6,23,28,29 They are potent vasodilators and have the advantage of being quickly adsorbed. This enables them to control acute increases in blood pressure. Furthermore, they also block the release of catecholamines from the tumor cells. 27,28 27,28

During surgery, nitroprusside should be administered to control the hypertensive episodes. Acute increases in blood pressure may occur with tumor manipulation. 25,28 25,28 If tachycardia or arrhythmias occur during surgery, small amounts of a beta-blocker may be given intravenously. 6,23 6,23 Since patients with pheochromocytomas are usually volume-contracted preoperatively, the volume that is usually required within the first 48 hours is frequently large. 3,9,29,30 3,9,29,30 3,9,29,30 3,9,29,30 Postoperative hypertension may be attributed to pain after surgery, volume overload, autonomic instability, incomplete resection, or fixed essential hypertension. 6 In about 25% of patients, the hypertension is the essential form but may require less medical therapy after the removal of the pheochromocytoma. 1,29,30 1,29,30 1,29,30

Surgical procedure
A narcotic analgesic with a powerful tranquilizer is administered for preanesthetic medication. During the procedure, extended monitoring is necessary to control any immediate severe hypertension, hypotension, or arrhythmias. Even after optimal preparation, significant changes in blood pressure and tachyarrhythmias are common. 25,26,29,30 25,26,29,30 25,26,29,30 25,26,29,30 In the past, surgical therapy was very risky, with mortality rates as high as 50%. Currently, the operative mortality rate is far less than 5%, using careful medical preparation, knowledgeable anesthesiologist guidance, and an experienced surgical team. [30] [31] [32] [33] [34] [35] [36] [37]

The surgical removal of the adrenal gland may be performed as an open or laparoscopic procedure. 31 The results from the localization studies determine how to position the patient during surgery, because multiple tumors may be present. 30,31,35 30,31,35 30,31,35 Some argue that the transabdominal approach achieves an excellent exposure and avoids excessive tumor manipulation. 15,25,26 15,25,26 15,25,26 On the other hand, careful dissection and preparation from a posterior retroperitoneal access approaches the same surgical principles. [30] [31] [32] [33] [34] [35] [36] It is still debated whether a laparoscopic procedure, because of its minimal invasiveness, should be used for this particular entity. The reasons for its use include fewer stress components during surgery and meticulous preparation with small instruments. The reasons against its use include that manipulation and harvesting of large tumors is more difficult with the minimally invasive techniques. 31,32,34 31,32,34 31,32,34 However, in recent studies with experiences of up to 100 cases, it was shown that both lateral transabdominal and posterior retroperitoneal laparoscopic adrenalectomies can be performed safely and effectively. [30] [31] [32] [33] [34] [35] Some investigators tend to prefer the posterior approach because intraperitoneal adhesions and the risk of subsequent bowel obstruction are avoided, since the peritoneal cavity is not opened. Additionally, this access is thought to be particularly useful for pheochromocytomas with a retrocaval location. [3] [4] [5] [6] [7] [8] [9] However, abdominal exploration is not possible when resecting the adrenal glands from the posterior approach.

In the open technique, the patient is placed in a standard anterior reverse Trendelenburg position. An upper midline or transverse abdominal incision is made. In the case of a right adrenal tumor, the liver is first mobilized from the right and a Kocher mobilization performed to expose the suprarenal region. In the case of a left adrenal tumor, the spleen, left colonic flexure, and pancreatic tail must be mobilized to get access to the suprarenal region. The adrenal gland may be visualized either by its intense dark brown color or by the presence of the previous localized tumor. The pheochromocytoma should be manipulated as little as possible and the adrenal veins clipped or ligated immediately.

Using the open posterior approach, the patient is placed in a prone jackknife position, and the incision is placed to the right and/or left of the infracostal paravertebral region. Dissection moves down to the suprarenal region directly to the adrenal gland. The principles of freeing the tumor are the same as with the anterior approach.

The lateral transabdominal laparoscopic adrenalectomy is performed with the patient in a 60° semilateral reverse Trendelenburg position, tumor site up (Fig. 1). The surgeon is facing the patient's front. Most commonly, four ports are placed. Three are placed two finger breadths below the costal margin at the midclavicular, anterior axillary, and midaxillary or postaxillary lines and one at the navel. The latter is used for a 30° laparoscope, and through a midaxillary cannula, a fan retractor is inserted that helps to give a free view of the operation site. Atraumatic graspers and the electro-hook facilitate the dissection. Small vessels are immediately coagulated or clipped and larger vessels clipped or ligated. With the small instruments, a meticulous, almost bloodless, dissection is possible, and manipulation of the tumor is minimal. After freeing the tumor, it is put into an Endobag and removed. Recently, a laparoscopic direct supragastric left adrenalectomy technique was described that offers a complete visualization of the left adrenal gland with easy control of the left adrenal vein, avoiding mobilization of the spleen, pancreatic tail, and left colonic flexure. 36

With the laparoscopic posterior approach, patient placement is similar to the open technique in a prone jackknife position. The surgeon stands on the side of the adrenal tumor. Three 10-mm ports are placed posteriorly along the costal margin (12th rib) or iliac crest, lateral to the erectus spinous muscles (Fig. 2). A balloon dissector (Origin, Menlo Park, Calif) is helpful to expose the retroperitoneal space. The retroperitoneal anatomy is more difficult to explore because of the small working space and lack of intra-abdominal landmarks. The kidney is the anatomic guideline that helps to identify the adrenal gland superiorly. The dissection and freeing of the adrenal tumor is similar to that of the laparoscopic transabdominal approach, starting with clipping and dividing the adrenal vessels, together with cautious and meticulous separation of the tumor. The tumor is removed through an enlarged port incision.

After removal of the tumor, the extent of the preoperative localization studies determines whether the procedure is finished or additional surgical exploration is necessary. 1,3,6,30 1,3,6,30 1,3,6,30 1,3,6,30 If no preoperative localization was done, complete exploration of both suprarenal regions, the sympathetic chain around the abdominal aorta, and the pelvis should be undertaken. This can also be done laparoscopically by a transabdominal approach. Exploration can be limited when preoperative localization studies have been performed and were negative.

Pheochromocytomas in pregnancy
Pregnancy complicated by a pheochromocytoma is a dangerous and potentially fatal condition. Maternal and fetal mortality rates as high as 58% and 50% in unsuspected cases have been reported; even with the diagnosis established, a maternal and fetal mortality rate of 17% and 40%, respectively, is presented in published reports. 4,6,37 4,6,37 4,6,37 The management has to be individualized, but in the first two trimesters, maternal safety is the first priority. Prompt surgical removal of the tumor with appropriate preoperative preparation should be undertaken. In the third trimester, under adrenergic blockade, a cesarean section with synchronous removal of the tumor is recommended. 3,27,37 3,27,37 3,27,37

Postoperative management
A continuous control of blood pressure and cardiac monitoring is required immediately after surgery. Transient episodes of hypertension and hypotension are common postoperatively, reflecting fluid shifts and autonomic instability. 6,23 6,23 In some patients, vigorous fluid administration is necessary to support the blood pressure. In cases of hypertension in the early postoperative period, diuretics, calcium channel blockers, or beta-blockers may be helpful. If hypertension remains difficult to control and paroxysms occur, phentolamine should be administered to control the blood pressure. A response to phentolamine may suggest that not all of the pheochromocytoma has been removed and reintervention is required. Before that, catecholamines and their metabolites should be tested for confirmation of total removal of all functioning pheochromocytoma. These assays should be repeated if suggestive symptoms reappear and for several years thereafter to exclude diffuse malignant disease. [3] [4] [5] [6] [7] [8]

Malignant pheochromocytomas

It is difficult, if not impossible, for the pathologist to determine whether a pheochromocytoma is malignant with microscopic examination. 1,6,30,39 1,6,30,39 1,6,30,39 1,6,30,39 However, malignancy is confirmed by the presence of metastatic deposits and/or microvascular invasion. During surgery, each pheochromocytoma should be regarded as potentially malignant. [6] [7] [8] [9] [10] [11] [12] [13] [14] Therefore, the entire gland, together with the surrounding connective tissue and fat, should be removed, thus preventing local recurrent disease. 3,6,26,37,38,48 3,6,26,37,38,48 3,6,26,37,38,48 3,6,26,37,38,48 3,6,26,37,38,48 3,6,26,37,38,48 About 10% of pheochromocytomas are estimated to be malignant and, consequently, follow-up should be maintained for at least 5 years. [3] [4] [5] [6] [7]

Recurrent disease usually appears in the retroperitoneum or as metastatic disease in the lung, liver, and bones. 6,15,23,50 6,15,23,50 6,15,23,50 6,15,23,50 Bone metastases provoke symptoms earlier than metastases in other sites. The therapeutic options include aggressive surgical removal, combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine, radiation therapy, or 131I-labeled MIBG. [1] [2] [3] [4] [5] [6] [7] [8] [9] However, reports indicate response rates between 25% and 50% treated with chemotherapy and/or radiation therapy, and the median survival is about 5 years. The value of 131I-labeled MIBG and chemotherapy is an improvement in performance status and the control of hypertension; radiation therapy seems to give the best relief from pain in patients with bone metastases. 1,3,6,23,30,45,46,48 1,3,6,23,30,45,46,48 1,3,6,23,30,45,46,48 1,3,6,23,30,45,46,48 1,3,6,23,30,45,46,48 1,3,6,23,30,45,46,48 1,3,6,23,30,45,46,48 1,3,6,23,30,45,46,48

Prognosis

Nonmalignant, surgically treated pheochromocytomas have a 5-year survival rate higher than 95%, and the recurrence rate is less than 10%. 1,3,25,30,45 1,3,25,30,45 1,3,25,30,45 1,3,25,30,45 1,3,25,30,45 Resection cures hypertension in about 75% of patients, and in the remaining 25%, hypertension may recur but is usually well-controlled with standard antihypertensive treatment. 1,2,6,48 1,2,6,48 1,2,6,48 1,2,6,48 Underlying essential hypertension and/or irreversible vascular and renal damage are the major reasons for persistently elevated blood pressure. 1,3,6 1,3,6 1,3,6 In experienced hands, the surgical mortality rate is 0% to 3%. [5] [6] [7] [8] [9] [10] [11] [12] [13] In malignant disease, the 5-year survival rate is less than 50%. 1,15,25,30,46,50 1,15,25,30,46,50 1,15,25,30,46,50 1,15,25,30,46,50 1,15,25,30,46,50 1,15,25,30,46,50

Conclusions

Pheochromocytoma is a rare but life-threatening disease. Pheochromocytomas may mimic a variety of other diseases, but the tetrad of hypertension, headaches, excessive sweating, and palpitation should lead to the diagnosis, together with catecholamine assays. Localization studies are important to guide the intraoperative management, of which contrast-enhanced CT scans or magnetic resonance imaging studies and MIBG scintigraphy are the most important diagnostic tools. Surgical removal is the treatment of choice and should be performed promptly after diagnosis with appropriate preoperative medical preparation. Pheochromocytomas have a high cure rate, but the malignant counterpart has a poor prognosis.