**OR**

*Basic Principles and Practice in Surgery*

of local extension [3, 4].

**5. Hormone assessment**

3.Androgen (extremely rare)

**5.1 Cortisol-producing tumors**

long-evolving cases.

Adrenal carcinomas are usually larger than 4 cm and occasionally weigh more than 1 kg. Microscopically, the picture is varied: in some cases, the tumor is very similar to the adenoma, but in some cases, the tumor appears anaplastically, being composed of cells with large pleomorphism, bizarre nuclei, and atypical mitoses. Vascular or capsular invasion is a predictive sign of malignant behavior, being a sign

Differentiation with adenomas can be difficult and is based on macroscopic (tumor weight, hemorrhage, and capsule integrity) and microscopic aspects using the modified Weiss scoring system. The five criteria used in the updated Weiss system include >6 mitoses/50 high potency fields, ≤25% clear tumor cells in the cytoplasm, abnormal mitoses, necrosis, and capsular invasion. Each criterion is scored 0 when absent or 2 for the first two criteria and 1 for the last three when present. The

adrenal carcinoma can be diagnosed by the presence of a total score ≥ 3 [5]. Tumors are functioning in approximately 60% of all cases, but the presence of symptoms of hormonal hypersecretion is present in only 40%, possibly by the

In general, adrenal carcinomas rarely produce and secrete a single steroid hormone and are usually associated with overproduction and hypersecretion of multiple hormones and precursors. Most cases produce different types of steroid hormones [7–9]. Thus, hypersecretion of a single adrenocortical steroid usually indicates the benign nature of adrenocortical neoplasia. The most frequently seen

There are basically three types of production by adrenocortical tumors:

Such tumors generally produce minute quantities of cortisol, which, most of times, do not suffice to increase the excretion of free cortisol in urine. They are, nonetheless, able to cause suppression of the hypothalamic-pituitary axis. Ordinarily, there are no Cushing-related manifestations in those patients. For that reason, this condition has been known as subclinical Cushing's syndrome or subclinical hypercortisolism [11]. There might be the classic Cushing's syndrome in

A suppression test with 1 mg of dexamethasone should be carried out at night for tracking Cushing's syndrome. The patient orally takes 1 mg of dexamethasone at 11:00 pm the night prior to sample collection of plasmatic cortisol, which is to be carried out at 8:00 am the following morning. Values that determine abnormal response of cortisol in this test varied in several studies from 1.8 to 5.0 mcg/dL, yet

Levels of plasmatic cortisol <1.8 mcg/dL virtually exclude autonomous produc-

tion of cortisol, with sensitivity >95% and specificity from 70 to 80%. Cortisol levels between 1.8 and 5 mcg/dL have been considered to be

secretion of large quantities of biologically inactive hormones [5, 6].

combination is hypersecretion of cortisol and androgens [10].

1.Cortisol (corresponding to between 5 and 20% of cases)

2.Aldosterone (corresponding to 1% of cases)

most guidelines lead to the following interpretation:

**46**

undetermined.

At least two from the following results:

Levels of plasmatic ACTH < 10 pg/ml with an increased 24-hour free urinary cortisol and values > 3 mcg/dL of plasmatic cortisol at the 1 mg dexamethasone test [1]. **Figure 2** shows an algorithm of investigation of Cushing's syndrome.

Dehydroepiandrosterone sulfate is an adrenal androgen that is produced under stimulus of ACTH. Thus, an undetectable concentration of dehydroepiandrosterone sulfate in serum suggests a chronical suppression of ACTH levels [12].

Percentage of patients suffering from subclinical Cushing's syndrome that would evolve to the classic Cushing's syndrome is uncertain. It is estimated to be <1%, though [1].

Even though patients suffering from subclinical Cushing's syndrome do not present the classic stigmata related to hypercortisolism, they present, as suggested in some studies, in comparison with the population in general, higher occurrences of:


An increase in the carotid intima-media thickness has been recently reported, as well as alteration of coagulation parameters, decrease in the quality of life, and occurrences of mortality due to cardiovascular disease [1].

For those reasons, there is still no consensus about the approach to subclinical Cushing's syndrome. It may be treated clinically or through surgery [2].

Generally, in cases with many occurrences of comorbidity that might be attributed to hypercortisolism, such as systemic arterial hypertension, diabetes mellitus, dyslipidemia, osteoporosis, and central obesity, especially the ones that are difficult to control, a ponderation of the risk/benefit of surgical treatment by adrenalectomy of the affected adrenal should be carried out, as proposed for the treatment of classic Cushing's syndrome [2].

It is important to mention that up to 75% of patients might develop acute adrenal insufficiency (sometimes deadly) at the post-surgery phase of adrenalectomy in case they are not treated with glucocorticoid due to atrophy of the contralateral gland. This should be an additional functional endocrine characterization for the propaedeutic planning [1]. In case the adrenalectomy is carried out, there should be

### **Figure 2.**

*An algorithm for investigation of Cushing's syndrome in adrenal incidentalomas. Dexa, dexamethasone; SC, serum cortisol; UFC, urine-free cortisol; ACTH, adrenocorticotropic hormone. \*At least two measurements.*

a perioperative coverage of glucocorticoid due to the risk of adrenal insufficiency, hemodynamic crisis, and death [12].

Weight loss, improvement of hypertension, glycemic control, and normalization of bone renewal markers are frequently found in the post unilateral adrenalectomy scenario of patients with subclinical or classic Cushing's syndrome [12].

## **5.2 Aldosterone-producing tumors**

Also known as aldosteronomas, they are rare (less than 1% of cases), and their characteristic manifestation is systemic arterial hypertension associated with hypokalemia. Yet primary normocalcemic hyperaldosteronism is common (20–50% of cases) [1, 12]. For that reason, as most patients suffering from primary aldosteronism do not suffer from hypocalcemia, all patients suffering from hypertension and adrenal incidentaloma should be assessed through measurements of their aldosterone plasmatic concentration and plasma renin activity [12].

Initial endocrine investigation in such cases consists of dosing the levels of plasma aldosterone and plasma renin activity. In case the ratio between them is <27, the existence of hyperaldosteronism is virtually excluded. Other authors use further landmarks (between 20 and 30) to establish diagnosis as abnormal. Values >40–50 are almost hyperaldosteronism pathognomonic [1].

It is important to mention that if the laboratory can only assess the renin direct dosage (other than the plasma renin activity), the renin value must be divided by 12, so that the actual value of plasma renin activity is established, which will eventually be the one used for the ratio calculation. If the ratio is lower than 20, it can refute diagnosis. In case it is between 20 and 30, it indicates a likely diagnosis. Then, if it exceeds 30, with aldosterone dosage higher than 15 ng/dl, positive tracing should be considered and investigation should continue through tests for confirmation [2]. In patients with spontaneous hypokalemia, plasma renin below detection

**49**

**Figure 3.**

*is no need for further confirmatory testing.*

*Preoperative Assessment of Functioning Benign Adrenocortical Tumors: A Clinical Surgical…*

levels plus plasma aldosterone >20 ng/dL, it is suggested that there is no need for

The aldosterone and plasma renin activity relationship should never be used for patients under spironolactone, and in case doubtful results appear, other medications (a beta blocker, central alpha-adrenergic agonist, anti-inflammatory) that might cause a false increase of that relationship should ideally be suspended, as well as those drugs that cause a false reduction of the inhibitors of angiotensin-converting enzyme, aldosterone receptor blocker, thiazide, and dihydropyridine inhibitors of

Patients older than 40 years of age suffering from confirmed hyperaldosteronism, even with evidence of adrenal images compactible with such diagnosis, should be submitted to adrenal catheterization for assessment of whether that increased aldosterone production is really due to incidentaloma or to adrenal hyperplasia, whereas the occurrence of nonfunctioning incidentalomas in the population older

In such cases, adrenalectomy would not solve hormonal hyperproduction, which should be kept under control with the use of medication, aldosterone antagonists,

In cases of congenital adrenal hyperplasia due to a 21-hydroxylase deficiency, it is rather common to find adrenal masses, either uni- or bilateral ones, presumably

Sex-hormone-producing adrenal adenomas are very rare. Androgen-producing carcinomas are also uncommon. Nevertheless, patients generally manifest some virilization, which makes it unlikely for such tumors to be related to adrenal incidentalomas. Thus, the routine testosterone and estradiol dosage are not recommended for patients with adrenocortical incidentalomas who present trace of

*Algorithm for investigation of hyperaldosteronism in adrenal incidentalomas. \*Most commonly used* 

*hypokalemia, plasma renin below detection levels plus plasma aldosterone > 20 ng/dl, it is suggested that there* 

*In patients with spontaneous* 

*confirmatory tests: oral sodium loading test and intravenous saline infusion test. #*

*DOI: http://dx.doi.org/10.5772/intechopen.83514*

further confirmatory testing (**Figure 3**) [4].

than 40 is no longer negligible (around 4%).

**5.3 Androgen- and estrogen-producing tumors**

due to excessive chronic stimulation of adrenals by ACTH [1].

the calcium channel [2].

such as spironolactone [2].

*Preoperative Assessment of Functioning Benign Adrenocortical Tumors: A Clinical Surgical… DOI: http://dx.doi.org/10.5772/intechopen.83514*

levels plus plasma aldosterone >20 ng/dL, it is suggested that there is no need for further confirmatory testing (**Figure 3**) [4].

The aldosterone and plasma renin activity relationship should never be used for patients under spironolactone, and in case doubtful results appear, other medications (a beta blocker, central alpha-adrenergic agonist, anti-inflammatory) that might cause a false increase of that relationship should ideally be suspended, as well as those drugs that cause a false reduction of the inhibitors of angiotensin-converting enzyme, aldosterone receptor blocker, thiazide, and dihydropyridine inhibitors of the calcium channel [2].

Patients older than 40 years of age suffering from confirmed hyperaldosteronism, even with evidence of adrenal images compactible with such diagnosis, should be submitted to adrenal catheterization for assessment of whether that increased aldosterone production is really due to incidentaloma or to adrenal hyperplasia, whereas the occurrence of nonfunctioning incidentalomas in the population older than 40 is no longer negligible (around 4%).

In such cases, adrenalectomy would not solve hormonal hyperproduction, which should be kept under control with the use of medication, aldosterone antagonists, such as spironolactone [2].
