SURGICAL MANAGEMENT OF ADRENAL TUMORS

SURGICAL MANAGEMENT OF ADRENAL TUMORSGuided by :Dr Prof P M Luka [MS] Dr Shipra Sharma[MS]Presented By: Dr Harsh Jain

Introduction

The adrenal glands are paired retroperitoneal organs composed of cortex and medulla and located above the kidney.Eustachius was the first to describe the organs in the mid-16th century.Gross examination revealsCortex- spiculated,mustard yellow colouredMedulla- central , brown colourWeight ~ 4-5 gramSize Length 4-6 cmWidth 2-3 cmRight adrenal is triangular in shape and left adrenal crescent in shape.

Relations

The right and left adrenal glands are located within Gerota fascia at the levels of the 11th and 12th ribs.

Medial aspect of the right adrenal gland is often retrocaval.

Right AdrenalLeft AdrenalAnteriorlyLiverStomach,Pancreas[body],splenic vesselsPosteriorlyDiaphragmDiaphragmSuperiorlyDiaphragmSpleenInferolaterallyRt KidneyLt KidneyMediallyIVCAorta

Left AdrenalRight Adrenal

Arterial Supply3 arterial sources of flow: Branches from Inferior Phrenic Artery Superior Adrenal A. Direct visceral branches from Aorta Middle Adrenal A. Branches from I/L Renal Artery Inferior Adrenal A.The main adrenal arteries branch to form a subcapsular plexusFrom subcapsular plexusSome branches continue directly to medullaOthers form sinusoids to cortexVenous Drainage:Medullary veins coalesce to form adrenal veinRight adrenal veinShortDrains directly into post IVCLeft adrenal veinLong as compared to right adrenal veinJoined by Inferior Phrenic vein prior to draining into Left Renal VeinThe overlapping of both arterial and venous anatomy makes partial adrenalectomy possible with little risk of subsequent adrenal infarction

Embryology

The adrenal gland consists ofSuperficial CortexDeeper MedullaAdrenal cortex and medulla are two embryologically and functionally distinct units.The cells of the cortex arise from coelomic epithelium (mesoderm).Cortex- intermediate mesoderm of urogenital ridgeThe cells of the medulla are derived from the neural crest (ectoderm).Medulla- Derived from Neural Crest Cells (from somites 18-24), located in adjacent sympathetic ganglia.

Physiology

Tumors of Adrenal CortexClassified according to Functional or non functional statusBenign or malignant features

Adreno-cortical tumors include-

Aldosteronoma[Conn Syndrome]Cortisol producing adenoma[Cushing syndrome]Virilizing/feminizing adrenal tumorsAdrenocortical carcinomaAdrenal MetastasesNonfunctioning adrenal tumors[Incidentaloma]

Primary AldosteronismDr. Jerome Conn first described primary aldosteronism in 1955 in a 34-year-old femalePrevalence: 5 - 13% of hypertensive patientsIn primary aldosteronism,aldosterone secretion is independent of RAAS,and plasma renin levels will be suppressed.

Increased fluid volumeAldosteroneReninAngiotensin IAngiotensin IIACTH

Subtype

Clinical CharacteristicsThird to sixth decades of lifeHypertension is the presenting feature in most patients.In minority of patients, hypokalemia is a/w headache, polydipsia, palpitations, polyuria, nocturia, and muscle weakness.The incidence and severity of target organ damage is greater in PAL as compared to other forms of HTNCardiac abnormalitiesLeft ventricular filling and diastolic dysfunctionIncreased left ventricular mass measurementProlonged QP intervalThe increased risk of CVS disease may be a/w the increased prevalence of metabolic syndrome in these patients

Diagnosis

Involves screening, confirmatory testing, and subtype differentiation.

Indications for Primary Aldosteronism Screening

Severe hypertension (160/110)Hypertension with hypokalemiaAdrenal Incidentaloma with hypertensionResistant hypertension (three or more oral agents with poor control)Early-onset hypertension ( 20 ng/dL for PAC

All positive tests must be confirmed with further testing

Confirmatory Test

Of the patients with positive screening tests, only 50% to 70% will be diagnosed with PAL on confirmatory testing

Of the confirmatory tests available

Following evaluate suppression of aldosterone following sodium loadingFludrocortisone suppression testOral sodium loading testIntravenous saline infusion test

Following evaluate suppression of ARR following administration of an ACE inhibitor.Captopril suppression test

Subtype DifferentiationSubtype differentiation of PAL is essential in selecting appropriate therapy, because surgical therapy is only successful for select subtypes

Adrenal CT scanRadiographic characteristics of aldosterone-producing adenomasunilateral low-density non-enhancing lesion of less than 10 Hounsfield units (HU)Average size of 1.6 to 1.8 cmNormal appearing contralateral adrenal gland.~ 20% of aldosterone-producing adenomas = < 1 cm in size. Therefore lateralization is not based on CT findings aloneAdrenal MRIMRI does not offer an advantage in delineating primary aldosteronism subtypes, and is a/w increased costRoutine use is not currently recommended

Lateralisation Studies

To establish lateralization of aldosterone secretion in surgical candidates, adrenal vein sampling should be performed.

Percutaneous access to the femoral vein is obtained, and catheter tips are positioned to collect samples from three sites: the right adrenal vein, left adrenal vein, and inferior vena cava (IVC).

Samples are evaluated for aldosterone and cortisol concentrations.

Lateralization of aldosterone secretion is determined by comparing the aldosterone to cortisol ratios of the dominant to nondominant sides.

Aldosterone is considered to be lateralized if ratio is greater than 2-4 : 1, depending on the use of ACTH stimulation

Alternative studies when AVS is inconclusive due to sampling error

Nuclear ScintigraphyPostural stimulation testing Measurement of cortisol metabolites

Treatment

Treatment strategies aim toRemove the source of Mineralocorticoid excess orBlock the effect of aldosterone on target organs

Indications of Surgery

Aldosterone-producing adenomaPrimary u/l adrenal hyperplasiaOvarian aldosterone-secreting tumourAldosterone-producing carcinoma

For adenoma mostly laparoscopic adrenalectomy is done and for adrenocortical tumor open adrenalectomy is preferred.

In the immediate postoperative period PAC and ARR should be evaluated to ensure biochemical cure.

Additionally, patients should maintain a high-sodium diet and be monitored for hyperkalemia for several weeks following surgery

Cushing SyndromeDefinitionHypercortisolism secondary to excessive production of glucocorticoids by the adrenal cortex is defined as Cushing syndromeIncidence: 2 - 5 cases/million people/yr

Pathophysiology :

Subtypes

ACTH-Independent Cushing SyndromeBenign Adrenal Adenoma ~ 10% of Cushing syndromeAdrenocortical carcinomas (~ 8% cases of Cushing Syndrome)ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH)< 1% of Cushing syndrome (very rare)Glands are enlarged (each gland > 60 g) and have multiple large nodules (upto 4 cm), which may be pigmented or non-pigmented.Usually affects both glandsPrimary Pigmented Nodular Adrenocortical Disease (PPNAD)Exceedingly rare, accounting for less than 1% of cases of Cushing syndrome.Unlike AIMAH, however, the adrenal glands in this condition remain normal in size and exhibit black or brown cortical nodules

Signs and Symptoms90 100 %Central obesityRounded face (moon face)Facial plethoraDecreased libido70 - 90 %Purple striaeMenstrual disturbancesHirsutismErectile dysfunctionHypertension50 - 70 %Muscle weaknessPosterior neck fat deposit (buffalo hump)Body bruisingGlucose intolerance/diabetesOsteopenia/osteoporosisEmotional lability/depression20 - 50 %HeadacheBackacheLimb edemaRecurrent infectionsHypokalemic alkalosisNephrolithiasis0 - 20 %AcneAlopecia

DiagnosisScreening Test:24-hour Urinary free cortisolThis test is considered the gold standard diagnostic test.Direct measure of free bioavailable cortisolNormal cutoff value of 50 mcg/ 24 hr urine volume is used.Low dose dexamethasone suppression testPatients take 1 mg of dexamethasone, a synthetic steroid, at 11 pm and cortisol level is measured at 8 am the next day.In normal patients cortisol should be below 5 mcg/dl.Late-night salivary cortisolThis is the latest diagnostic test for Cushings.Elevated cortisol levels b/w 11 PM & midnight = earliest indication of disease.Cortisol level should not exceed 145 ng/dl.

In adrenal tumors ACTH level is low and CT/MRI of the adrenal almost always identifies the tumor.

TreatmentApproach is multidisciplinaryTreatment goals:Correction of hypercortisolemiaRestoration of HPA axisManagement of Cushing syndrome sequelae

ACTH-Independent (Adrenal Cause)U/l adrenal mass ipsilateral adrenalectomyPartial adrenalectomy when preserving adrenals is essentialAIMAH and PPNADB/l adrenalectomy with lifelong replacement.Success with U/l resection of largest gland in AIMAH patients also reportedSmall adenomas can be removed with laparoscopic surgery techniques.Larger tumors are removed using open surgical techniques.In cases of bilateral adrenal hyperplasia, both glands may need to be removed. In this case, the patient will need hormone replacement for the rest of their life.

Adreno cortical CarcinomaIt is a rare malignancy with incidence of 0.5 to 2 per million.Bimodal age distribution,peaks in 1st and 4th -5th decade.Majority of cases are sporadic and unilateral.

Functional breakdown of ACC

Functional50%-80%Cushing Syndrome33%-53%Cushing Syndrome + Virilization20%-24%Virilization alone10%-20%Feminization6%-10%Hyperaldosteronism2.5%-5%Non functional20%-50%

DiagnosisFunctional Evaluation of ACC:TYPE OF ADRENALHYPERSECRETIONFUNCTIONAL EVALUATIONGlucocorticoid excessLow-dose dexamethasone suppression testorLate night salivaryor24-hour urine cortisolSexual steroids andsteroid precursorsDHEA-S17-OH-progesteroneAndrostenedioneTestosterone17-estradiol (only in men andpostmenopausal women)Catecholamine excessSerum or urinary metanephrinesMineralocorticoidexcessAldosterone to renin ratio (only in patientswith hypertension or hypokalemia)

ImagingCT Scan : radiographic characteristics of ACC on CT imaging include

irregular borders, irregular enhancement, calcifications,necrotic areas with cystic degeneration.Mean attenuation on noncontrast CT scan in ACC is significantly higher (39 HU) compared with adenomas(8 HU).No contrast washoutFor metastatic evaluationLymphadenopathyExtension to IVC and other adjacent organs.Distant metastases to lung and liver.

MRI:ACCs appear isointense relative to the liver or spleen on T1-weighted images and demonstrate intermediate to increased intensity on T2-weighted images.

essential tool in detecting the presence of a tumor clot and delineating its extent.

Percutaneous needle biopsy

Primary indication for needle biopsy is in cases of unresectable, locally advanced, or metastatic disease, to confirm the diagnosis prior to systemic medical therapy.

In cases of surgically resectable disease, the information obtained from biochemical and radiographic evaluation should be enough to justify extirpation.

TreatmentSurgeryApproach: Open transabdominal or retroperitoneal approach is preferredComplete surgical excision is essential in the management of adrenal cortical carcinomas and offers the best chance of cure.For locally advanced disease : enbloc resection should be performed, whenever possible.Cases of venous tumor thrombus involving the IVC may require vascular bypass techniques, IVC replacement, and/or IVC interruption.In cases of metastatic adrenal carcinoma, cytoreductive removal of the primary tumor and debulking metastatectomy should be considered if greater than 90% of the disease burden can be removed.In patients who are not candidates for complete tumor debulking, surgery should not be performed because it will delay systemic therapy.Rate of recurrence 60-80 % despite aggressive surgical resection.

Radiation

Adjuvant radiation has been noted to decrease local recurrence rates following complete tumor resection.Radiation therapy remains the treatment of choice in the management of bone and CNS metastasis.

Chemotherapy

Currently, mitotane remains the primary systemic therapy, either as a single agent or in combination with other cytotoxic drugs for adrenal cortical carcinomas.Efficacy of mitotane as adjuvant therapy is still debated.

Prognosis5-year survival in ACC is poor, ranging from 20% to 47%

Adrenal Incidentaloma

Adrenal incidentalomas are unsuspected adrenal masses greater than 1 cm in diameter identified on cross sectional imaging performed for seemingly unrelated causes.

It is important to emphasize that incidental does not mean insignificant.

Incidence : 1-4% patients undergoing abdominal imaging studies.

Adrenal Incidentaloma

Adenoma

Adrenal adenomas are by definition benign and the vast majority are metabolically silent.According to an NIH 2002 consensus panel, an adrenal mass with an attenuation of less than 10 Hounsfield units (HU) on unenhanced CT is strongly suggestive of a benign adrenal adenoma.Adenomas that are metabolically active should undergo resection in acceptable surgical candidates.

OncocytomaAdrenal oncocytic tumors are extremely rare neoplasms.Unlike renal oncocytomas, a large proportion of adrenal lesions are malignant.

MyelolipomaMyelolipoma is a rare lesion of the adrenal gland that contains hematopoietic elements and mature adipose tissues.Classically, myelolipomas are metabolically non-functional lesions.The presence of macroscopic fat in an adrenal mass is virtually diagnostic of a myelolipoma. Asymptomatic myelolipomas are treated conservatively.

Adrenal CystsFour histologic types of adrenal cysts have been described, including pseudocysts, endothelial,epithelial, and parasitic cysts.7% of the lesions were associated with malignancySymptomatic adrenal cysts should be surgically removed, while small nonfunctional asymptomatic lesions with benign radiographic appearance may be treated conservatively with regular follow-up.

Diagnostic Algorithm

PheochromocytomaTumour of catecholamine-producing cells of adrenal medullaIncidence: ~ 1 2/1,00,000 individualsClassically, pheochromocytoma has been called the 10% tumour: 10% extra-adrenal, 10% familial, 10% bilateral, 10% paediatric, and 10% malignantHowever up to 25% of pheochromocytomas can be extraadrenal and upto 30% cases familial.Tumors arising from the right adrenal are more common, tend to be larger, and recur more frequently than those that arise in the left glandPediatric pheochromocytoma is the most frequently encountered endocrine neoplasm in children.

Clinical Features

Paroxysmal hypertension,headache, episodic sudden perspiration, and tachycardia are classic hallmark of pheochromocytoma

Clinical ManifestationsFREQUENCYHeadache 60%-90%Palpitations50%-70%Sweating55%-75%Pallor40%-45%Nausea20%-40%Flushing10%-20%Weight loss20%-40%Tiredness25%-40%Psychologic symptoms (anxiety, panic)20%-40%Sustained hypertension50%-60%Paroxysmal hypertension30%Orthostatic hypotension10%-50%Hyperglycemia40%

DiagnosisBiochemical Evaluation

ImagingCROSS-SECTIONAL IMAGING (CT Scan)Pheochromocytomas appear as well-circumscribed lesionsGiven their rich vascularity and low lipid content, Pheochromocytomas typically measure an attenuation > 10 HU on NCCT (mean 35 HU)Although nonspecific, Pheochromocytomas, unlike adenomas, do not exhibit rapid contrast washout on delayed imaging

MRISimilar to CT, magnetic resonance imaging is an excellent imaging modality for characterizing adrenal lesionsClassically light bulb sign is seen which was earlier believed to be diagnostic of pheochromocytoma

Functional ImagingMETAIODOBENZYLGUANIDINE (MIBG) SCINTIGRAPHYMIBG is a small-molecule analogue of norepinephrineWhen tagged with 131I or 123I, MIBG Scintigraphy has been used to evaluate PCCSelective uptake of MIBG by pheochromocytoma cells occurs123I-MIBG for identification of pheochromocytomaSensitivity = 83% to 100%Specificity = 95% to 100%Uses:Extra-adrenal, metastatic, or recurrent PCCTo localize diseases in patients with biochemical evidence but negative imagingfor large (>5 cm) tumours is important to assess for presence of metastatic disease prior to surgeryFDG-PET was recently shown as a useful clinical tool for patientsSensitivity and specificity as high as 100%

MIBG Scan showing right side pheochromocytoma

TreatmentPheochromocytoma is a surgical diseaseComplete resection of tumour is advised whenever possibleLaparoscopic adrenalectomy is standard of care for most tumoursOpen approach - for large and/or surgically difficult tumours

Pre-Operative Management

All patients with pheochromocytoma and an abnormal metabolic evaluation should undergo preoperative catecholamine blockade, including patients who do not exhibit evidence of blood pressure elevation and lack classic symptomatology

Preoperative Echocardiography is mandatory

ALPHA BLOCKADEIrreversible (Catecholamine) Blockade:Phenoxybenzamine is most commonly usedStarted 7 to 14 days prior to surgeryStart: 10 mg BD, POFinal dosing of 1 mg/ kg is usually sufficient to achieve adequate blockadeBETA BLOCKADEUsed in reflex tachycardia and arrhythmias that can result upon initiation of blockade blocker should never be started prior to appropriate blockadeSelective 1 blockers, such as atenolol and metoprolol, are generally preferred

CATECHOLAMINE SYNTHESIS BLOCKADE.Metyrosine-Blocks the rate-limiting step in biosynthesis of catecholaminesNot routinely used. Reserved for refractory or metastatic patientsCALCIUM CHANNEL BLOCKADEAmlodipin or nifedipine can also be used to maintain blood pressure.

INTRAVASCULAR VOLUME MANAGEMENT

Restoration of intravascular volume is the most important component of preoperative managementIntake of salt and fluid is encouraged once catecholamine blockade has been initiatedThe last dose of Phenoxybenzamine is usually given on the night prior to surgery, and the next mornings dose is held. (minimizes potentially prolonged hypotension following resection)Post operative Management

Hypotension and hypoglycaemia are common in the immediate post op period and patient should be actively monitored.

Follow upRepeat metabolic testing ~ 2 weeks after adrenalectomyIn patients in whom Metanephrine levels remain elevated MIBG imaging

Lifelong screening for recurrence is recommended 10-year recurrence rates are as high as 16%Annual biochemical follow-up is mandatoryPost-operative cross-sectional imagingTo document tumour resection and appropriate healing of the resection bedNeed for subsequent imaging should be guided by results of biochemical testing

Treatment of Malignant PCCLargely palliativeSurgical metastatectomy of resectable disease is the standard of careMedical treatment: with / blockade and -methyl-ParatyrosineLocal palliative tumour control by using ablation techniques and EmbolisationRadiotherapy: Systemic treatment of mets with radioactive 131I-MIBG may be instituted.Chemotherapy : Combination of Cyclophosphamide, Vincristine, and Dacarbazine (CVD)

Prognosis5-year survival ~ 50%

Surgical mortality rates < 3%

More likely to recur:

Extra-adrenal disease Hereditary Pheochromocytomas Right adrenal tumours Bilateral tumours Larger tumours

Functional adrenal massCortisol hypersecretionPheochromocytomaAldosterone hypersecretionMass > 4 cm with exception of myelolipomaMass with imaging findings that are suggestive of malignancy (lipid-poor, heterogeneous, irregular borders, infiltrates surrounding structures, etc.)Adrenal incidentaloma that grow greater than 1 cm on follow-up imagingExtremely large and/or symptomatic myelolipoma Isolated adrenal metastasis (multidisciplinary decision making required)During radical nephrectomy for renal cell carcinoma if:Adrenal abnormal or not visualized due to large renal tumor size on imagingLarge (7 cm) upper pole massVein thrombus to level of adrenal veinFailed neurosurgical treatment of Cushing disease, requiring bilateral adrenalectomySelect patients with ectopic adrenocorticotropic hormone (ACTH) syndrome, requiring bilateral adrenalectomy

SURGICAL INDICATIONS OF ADRENALECTOMY

Surgical Approaches for AdrenalectomyOpen adrenalectomy:Transabdominal approach:Subcostal or Midline approach. Thoracoabdominal approach.Retroperitoneal approach.Lumbodorsal posterior approach.Flank approach.Laparoscopic adrenalectomy:Transperitoneal Approach.Retroperitoneal Approach.Hand-assisted laparoscopic surgery.3. Robotic surgery.

Open AdrenalectomyTransperitoneal approachAdvantages are better exposure for larger tumors and excellent access to the great vessels and retroperitoneum. Disadvantages are prolonged ileus and difficult exposure in morbidly obese patients.

Retroperitoneal approach Advantage less ileus and may result in shorter hospital stays.Disadvantage - There is a smaller operative field, and access to larger tumors and surrounding involved organs may be difficult.

The transperitoneal approach may be attempted through a midline incision or subcostal incision. The subcostal incision can be extended into a full chevron for bilateral adrenalectomy or if a large unilateral tumor is encountered.

Thoracoabdominal ApproachThis approach is a maximally invasive way to ensure superb surgical exposure of the retroperitoneum, adrenal gland, and great vessels. Disadvantages are increased incisional pain, prolonged ileus, pulmonary morbidity, and a chest tube. The thoracoabdominal approach is reserved for large or invasive adrenal carcinomas.

Flank Retroperitoneal ApproachThe retroperitoneal approach results in less ileus and may result in shorter hospital stays. There is a smaller operative field, and access to larger tumors and surrounding involved organs may be difficult.

Lumbodorsal Posterior ApproachThe main advantage of this approach is the ability to easily access both adrenal glands for bilateral surgery. The disadvantages include a limited operative field and respiratory limitation. If bleeding is extensive, it can be difficult to control from this position.

Laparosocpic Transperitoneal ApproachTransperitoneal laparoscopic adrenalectomy can be performed through either an anterior supine approach or a lateral approach (more common). In general, the anterior supine approach allows bilateral adrenalectomy without having to reposition the patient. The lateral position is advantageous because greater workspace is available secondary to gravity-assisted retraction of the bowel.

Patient position & port position

Left laparoscopic AdrenalectomyIncision of the line of Toldt and medial dissection of the left colon with cautery endoscopic scissors.

Exposure and dissection of the renal vein and left adrenal vein.

Ligation and division of left adrenal vein

Division of adrenal arterial supply and superomedial dissection with downward traction on the kidney

The adrenal gland is mobilized off the medial aspect of the kidney

Placement of specimen in endoscopic extraction bag

Retroperitoneal laparoscopic ApproachAlthough less popular, retroperitoneoscopic adrenalectomy may be ideal for nonobese patients who have had previous abdominal surgery and for patients undergoing bilateral adrenalectomy.

Anatomic view of right adrenal gland from retroperitoneal approach

Robotic SurgeryThe advantages of robotics should be the superior three-dimension visualization and hand-like dexterity of the robotic arms to perform the microdissection of the plane between the adrenal and the great vessels. Currently, the da Vinci Surgical Robotic System is the only commercially available product to perform these procedures.

Complications of AdrenalectomyA- Hemorrhage from:B- Vascular injury:C- Adjacent organ injury:Inferior vena cavaAdrenal veinLumbar veinHepatic veinLigation of renal artery branchLigation of mesenteric arteryInferior vena cava involvementPneumothoraxPancreasLiverSpleenStomachColonKidney

Operative Complications

Postoperative Complications of Adrenal Surgery

Primary AldosteronismHypokalemia: secondary to continued potassium loss immediately postoperativeHyperkalemia: secondary to failure of contralateral adrenal to secrete aldosterone

Cushing SyndromeInadequate steroid replacement leading to hypocorticoidismFracture secondary to osteoporosisHyperglycemiaPoor wound healingIncreased risk of infections

PheochromocytomaHypotension secondary to -adrenergic blockade after tumor removal

OthersHemorrhagePneumothoraxPancreatitisPneumonia

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