Perioperative management - Left adrenalectomy, laparoscopic

There is consensus in the guidelines that most adrenal tumors (ATs) should be operated on minimally invasively if indicated. Tumor diameter > 6 cm and clear evidence of malignancy in preoperative imaging are considered limits of minimally invasive surgery. Regarding tumor size, a 6 cm rule is often assumed, larger tumors should be excised conventionally open. In contrast, numerous studies have shown that even large adrenal tumors > 6 cm can be safely approached minimally invasively with appropriate expertise. Due to lack of evidence, the 6 cm rule cannot therefore be regarded as an absolute limit. This decision requires special information and consent of the patients. If this is present, the adrenalectomy, if the tumor can be completely removed without capsule rupture, can be performed minimally invasively regardless of tumor size.

Nevertheless, conventional adrenalectomy is generally recommended for large tumors, especially in cases of imaging suspicion of malignancy.

Laparoscopic and retroperitoneoscopic procedures are equivalent. The choice of access route depends on the experience and preference of the surgeon. 

Note: Laparoscopic adrenalectomy (AE) has not changed technically significantly since its first description in 1992 and is the preferred method in many places due to the familiar access and orientation.

Partial adrenal resection (adrenal-sparing adrenalectomy) has a role in patients with Conn's syndrome, which is caused by small, usually eccentrically located tumors, and bilateral tumors, where the surgical intervention aims to preserve adrenocortical function. The aim is to preserve at least one third of an adrenal gland. The central adrenal vein does not need to be preserved. In unilateral surgery only, corticosteroid hormone production is usually completely taken over by the contralateral adrenal gland.

• Endocrine-active tumors of the adrenal cortex (Conn or Cushing adenomas, tumors with sex hormone secretion) up to 10 cm
  
  
  • Conn's syndrome (primary hyperaldosteronism, PHA):
    
    The most common cause of secondary hypertension is primary hyperaldosteronism.
    
    Screening for incidentaloma and concomitant hypertension and/or unclear hypokalemia. Morphologically, adrenal hyperplasia or one or more adenomas may be present.
    
    In unilateral aldosterone-producing adenoma or unilateral adrenal hyperplasia, unilateral adrenalectomy is indicated. In solitary aldosterone-producing adenoma, partial removal of the affected adrenal gland can also be performed.
    
    In patients with PHA and bilateral adrenal changes, surgery can be considered if adrenal venous sampling (AVS through selective adrenal vein blood sampling) shows functional localization.
     
  • Cushing's syndrome(hypercortisolism)
    
    A florid adrenal Cushing's syndrome with classic clinical stigmata represents an indication for surgery.
    
    In subclinical Cushing's syndrome, there is only a relative indication for surgery. Here, an affected person shows biochemical cortisol excess, but clinical manifestation is absent. Comparative data on mortality or cardiovascular events of surgery versus medical therapy of comorbidities are lacking. The decision for surgery depends mainly on the age and wishes of the patient.
    
    Before possible surgical removal of the AT, the ACTH independence of the cortisol excess must be confirmed so that the procedure is not performed erroneously, although the cause of the hormone excess is, for example, pituitary.
    Exclusion of ACTH-dependent hypercortisolism (adenoma of the anterior pituitary lobe) (central Cushing's syndrome) or paraneoplastic syndrome with ectopic ACTH secretion in tumor disease.
     
  • Sex hormone-producing adrenal cortex tumors
    
    An adrenocortical carcinoma is the most common cause of clinically relevant, pathological androgen/estrogen secretion from the adrenal gland, adenomas are very rare.
     
• Adrenal cortex carcinoma Adrenocortical carcinoma (ACC) up to ENSAT stage II 
  Link to ENSAT classification and size ≤ 6cm
  
  
  • At initial diagnosis almost always > 4cm and shows endocrine activity in 50-80%. Typically, there is cortisol production or mixed hormonal production (androgens/estrogens and cortisol).
  • For adrenal cortex carcinoma, open adrenalectomy is the gold standard. For tumors < 6 cm without evidence of local or lymph node infiltration (ENSAT std. I+II), minimally invasive adrenalectomy can be performed.
  • A radical tumor resection with removal of the adrenal gland and all fat/connective tissue in the affected compartment without capsule opening with lymphadenectomy, this in uncertain data situation, is recommended. A definition regarding the extent of the required lymphadenectomy does not yet exist.
  • Note: The rate of local and peritoneal recurrences is increased in the laparoscopic group according to current evidence. Conversion from laparoscopic to open adrenalectomy worsens overall survival.
     
• Pheochromocytoma (PC) Adrenal marrow tumor with catecholamine excess
  
  
  • About 1/3 of all pheochromocytoma patients are attributable to a hereditary tumor syndrome. Genetic screening is an indispensable part of pheochromocytoma diagnostics.
  • Familial syndromic forms include multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), and germline mutations of succinate dehydrogenase subunit B and D (SDHB and SDHD).
  • They differ from sporadic forms in age of onset, tumor location, and their risk of malignant degeneration.
  • Syndrome-associated hereditary pheochromocytomas have a lower malignancy rate than sporadic tumors but often occur multifocally/bilaterally. The goal here is to enable a life without steroid dependence. Therefore, in this situation, a minimally invasive organ-sparing adrenal resection should be discussed.
  • An important exception are SDHB-associated tumors with particularly high malignancy and recurrence risk.
  • Overall, 10% of PCs are malignant. Proof of a malignant pheochromocytoma is exclusively metastases. 
     
• Incidentalomas

An adrenal incidentaloma is an incidental, usually asymptomatic mass (lesion) of the adrenal gland that was not discovered due to clinical suspicion of an endocrine disease. Usually, a size of 1 cm in diameter or more is considered a relevant finding. Smaller lesions are often considered incidental findings without further need for action, unless they show abnormalities.

Note: Incidentalomas must be assessed using biochemical and radiological methods.

Only detectable infiltration of neighboring structures or detection of distant metastases are proof of malignancy. Determination of Hounsfield units (HU) can provide additional clues.

• Myelolipomas/adrenal cysts do not represent an indication for surgery. Tumor diameter is prognostically insignificant as these are benign tumors. Flank pain due to tumor size or hemorrhage in the retroperitoneum can rarely represent an indication for surgery.
   
• Adrenal metastases (from malignant tumors of other origins) should be removed if no other metastases are present and tumor-free status is achieved by removal.
  
  Metastasis adrenalectomy should be performed minimally invasively, provided the metastasis can be removed in toto and without tumor cell seeding. An open approach remains reserved for the few cases where there is evidence of local infiltration or if the metastasis exceeds 6 cm.

Lymph node dissection

In enlarged lymph nodes, locoregional lymphadenectomy should be performed. The data situation regarding periadrenal/renal hilar lymphadenectomy is unsatisfactory.

• No adrenalectomy without prior determination of hormone activity!
   
• Pronounced adhesions after previous operations
  Note: A retroperitoneoscopic approach may be useful here.
   
• Due to the very low risk of malignancy, surgery is generally not indicated for hormonally inactive tumors that are not suspected of being malignant and < 4 cm. If surgery is performed nonetheless, this must be justified.
   
• primary open approach for large malignant tumors with infiltration of surrounding structures or proven lymph node metastases
   
• For bilateral primary hyperaldosteronism (idiopathic adrenal hyperplasia) without side assignment: Initiation of therapy with aldosterone antagonists.
   
• No adrenalectomy but parenchyma-sparing adrenal resection (to preserve function, one third of an adrenal gland should be left).
  
  
  • In hereditary (bilateral) pheochromocytomas, since the probability of a metachronous contralateral PC is high and the risk of malignancy is considered low.
  • Cushing's syndrome based on bilateral macronodular hyperplasia.  Tightrope walk between cortisol control and residual hormone function. After a total adrenalectomy, there is a substitution obligation with the risk of a life-threatening Addisonian crisis (acute adrenal insufficiency).
     
• Myelolipomas and adrenal cysts should only be removed if there are clinical symptoms.
   
• The further contraindications depend on the underlying diseases (surgical risk) and the importance of adrenalectomy for the patient's quality of life or life expectancy.

Adrenal tumors include benign and malignant changes of the adrenal glands that affect morphology and/or function. The goal of diagnostics is to assign morphological and/or functional changes for the evaluation of therapeutic options.

Diagnostics include taking a medical history and physical examination, with determination of blood pressure and heart rate being mandatory components. In addition, endocrinological methods and imaging procedures are required.

Tumorous changes of the adrenal glands should always be investigated for possible hormonal activity: catecholamines, aldosterone, cortisol, sex hormones or their precursors.

Clinical Presentation

Typical leading symptoms in PC are severe hypertension, paroxysmal headaches and palpitations. Pathognomonic for hypercortisolism (Cushing's syndrome) are central obesity, buffalo hump, moon face, striae rubrae, hirsutism and plethora.

Screening for PHA in hypertension or hypokalemia

Laboratory Diagnostics/Hormonal Diagnostics:

Initial screening tool for suspected autonomous cortisol secretion (ACS) is the dexamethasone suppression test.

Based on the level of dexamethasone-suppressed serum cortisol, a distinction is made in clinically asymptomatic patients between a non-functional adrenal tumor and a "(possible) autonomous cortisol secretion".

Values above 5 ng/dl cortisol in serum confirm the diagnosis. Necessary for the diagnosis is a low to suppressed ACTH (< 10 pg/ml), to exclude pituitary cortisolism or ectopic ACTH production.

Diagnostics for PC include determination of metanephrines in plasma or 24-hour collected urine. A clonidine test can be considered if the findings remain borderline.

3-Methoxy-tyramine in plasma as a tumor marker for an SDHB mutation in a PC > 5cm serves as preoperative screening for the presence of metastases.

In primary hyperaldosteronism (PHA) (Conn's syndrome), there is autonomous, i.e., renin-independent aldosterone secretion. Screening parameter is the aldosterone-renin ratio (ARR), which can also detect patients with mild primary hyperaldosteronism. Aldosterone and renin are normally determined in the morning after 5 to 15 minutes of sitting.

If the ratio is elevated, a confirmation test must be performed in accordance with guidelines, e.g., a saline infusion test (2l NaCl 0.9% i.v. over 4 hours). In healthy individuals, this leads to suppression of aldosterone after 4 hours, while in patients it does not. The influence of antihypertensive medications on the RAAS (renin-angiotensin-aldosterone system) must be considered.

Sex hormones as well as steroid precursors in the clinical presentation of sex hormone excess (hirsutism, gynecomastia in men), tumor > 4 cm or imaging suspicion of ACC: steroid precursors (DHEA/DHEA-S, androstenedione, 17-α-hydroxyprogesterone), testosterone in women, 17β-estradiol in men and postmenopausal women.

Note: Approximately 60 – 80% of adrenocortical carcinomas secrete hormones (functionally active), the most commonly produced hormones are glucocorticoids (esp. cortisol) and androgens.

Human Genetic Testing

Current guidelines recommend genetic testing in all patients with pheochromocytoma regardless of age, tumor number or location.

Note: Pheochromocytoma (PC) represents an indicator lesion for hereditary syndromes. In unilateral involvement, a hereditary disease is present in 12%, in bilateral PC, young patients or conspicuous family history in 30%.

Imaging Procedures:

Computed Tomography

As a basic procedure for imaging adrenal tumors, CT with and without contrast medium is recommended. It enables determination of the size of the adrenal tumor and its fat content (Hounsfield units, HU), as well as assessment of possible surrounding infiltrations.

Native CT (Native CT with determination of density values of the adrenal lesion in Hounsfield units (HU))

Native CT is the first important step in the evaluation of an adrenal tumor, especially for determining tissue density (HU).

Lesions with < 10 HU can be classified as adenomas with a sensitivity of 70% and specificity of 95% and are primarily not suspicious for malignancy.

Contrast-enhanced CT is used additionally if the diagnosis in native CT is not clear.

Dynamic contrast-enhanced CT with determination of the so-called "washout behavior" of the contrast medium after 15 min: Adenomas store contrast medium for less time, malignant tumors retain contrast medium longer.

MRI with Chemical Shift Imaging (also "In-Phase/Out-of-Phase MRI")

• Is a special MRI technique based on the different behavior of fat and water protons in the magnetic field.
• In the opposed-phase sequence (Out-of-Phase image), lipid-rich adenomas lose signal intensity, while other tissues such as metastases, carcinomas, pheochromocytomas typically contain no or little fat and do not do this.

For the assessment of possible metastasis, diagnostics should include a CT or MRI of the abdomen as well as a CT of the thorax.

Functional Imaging Nuclear Medicine Diagnostics

MIBG Scintigraphy (123I- or 131I-Metaiodobenzylguanidine)

specific for classic pheochromocytomas, but limited in SDHB

In young patients, suspicion of metastasis, large tumors, multifocality, extra-adrenal manifestations, syndromic disease (multiple endocrine neoplasia 2a/b, von Hippel-Lindau syndrome, neurofibromatosis type 1, mutation of mitochondrial succinate dehydrogenase (SDHx)) examination of first choice. In metastatic disease, the possibility of palliative radiotherapy can be checked at the same time.

PET/CT
In functional imaging, the 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with simultaneous CT currently has the greatest importance. It is very sensitive for many malignant tumors, especially for aggressive and poorly differentiated tumors. An indication exists for an unclear incidentaloma >4 cm, suspicion of adrenal metastasis, suspicion of ACC, suspicion of SDHB mutation in PC.
In addition, PET-CT enables whole-body staging regarding metastases except for the brain. Additional skull/brain diagnostics, for example by means of MRI, should therefore always be performed, especially in NSCLC (non-small cell lung cancer).
In the diagnostics of pheochromocytomas and simultaneous suspicion of a familial disease to exclude bilateral disease or extra-adrenal location as well as metastases, an 18F-fluorodihydroxyphenylalanine (DOPA)-PET/CT should be performed due to its high specificity.

Adrenal Vein Sampling (AVS) (selective adrenal vein catheter)

For functional lateralization of primary hyperaldosteronism to avoid the risk of unnecessary or inappropriate adrenalectomy.
In the case of clear localization by CT or MRI and especially in younger patients, primary surgery without AVS is justified,

Puncture Biopsy

A biopsy of the adrenal mass is – with very few exceptions (suspicion of adrenal metastasis and malignancy history with unclear imaging) – generally discouraged. A major reason for this is the fact that reliable differentiation between adenoma and carcinoma is often not possible based on a biopsy and there is a risk of tumor cell dissemination.

In any case, a pheochromocytoma should be biochemically excluded beforehand.

Alpha blockade:

International and national guidelines recommend alpha blockade before resection of a pheochromocytoma to prevent cardiovascular complications.

Preoperatively, adequate alpha receptor blockade (gold standard phenoxybenzamine) should be performed for at least 10-14 days to avoid severe catecholamine-mediated blood pressure crises due to intraoperative manipulation of the tumor.

Phenoxybenzamine provides non-competitive, irreversible alpha-1 and alpha-2 blockade. A common side effect is reflex tachycardia (alpha-2 receptor blockade), which can be additionally treated with beta-receptor blockers.

This approach is increasingly discussed controversially and is more and more being replaced by an individualized approach. In selected cases without arterial hypertension, preoperative alpha blockade can be omitted.

Cortisol substitution:

In patients with florid Cushing's, there is a risk of postoperative adrenal insufficiency, so peri- and postoperative cortisol substitution is recommended. Additionally, preoperative antihypertensive therapy, electrolyte balancing, and diabetes management are usually required.

Potassium deficiency:

In PHA, hypokalemia should be corrected. In this case, an aldosterone antagonist is administered preoperatively for at least two weeks, with potassium initially substituted.

• For all other adrenal tumors, no specific medicinal pretreatment is required.
• For an adrenalectomy, antibiotic prophylaxis is not required except in cases of Cushing's syndrome.

Before surgery, all patient cases should be discussed in an interdisciplinary tumor board.

The risks of the procedure depend on the patient's age and overall condition, particularly on the symptoms of hormonal hyperfunction.

General information on surgical risks:

• Thrombosis
• Embolism
• Infections
• Vascular-nerve injury
• Bleeding/post-bleeding with transfusion of donor blood
• Injury to adjacent organs
• Conversion to conventional procedure
• Trocar hernia

Specific information:

• Spleen injury possibly splenectomy
• Injury to the left renal vein with bleeding
• Injury to the pancreatic tail with formation of a fistula or abscess
• Injury to the diaphragm
• Injury to the left colonic flexure
• Injury to the stomach
• Hormonal reaction; Addisonian crisis
• Persistence of arterial hypertension in Conn's syndrome
• High risk of thromboembolism and infection in Cushing's syndrome
• In bilateral adrenalectomy, lifelong intake of cortisone and mineralocorticoid, development of a Nelson tumor (ACTH-producing pituitary tumor) in 10 - 25% after approx. 10 years
• In pheochromocytoma, risk of local recurrence due to tumor capsule opening with cell seeding.