1. Surgical anatomy of adrenal
gland(cortex and
medulla)pheochromocytoma
clinical features,
pathophysiology and
managment
Under the guidance of
Dr.Kishore babu sir(chief)
Dr.Srinivasa madam(asst)
Dr.Shivaram Prasad sir(asst)
Dr.kavya madam(asst)
By
N.Lakshmi Mounika
S5 unit
2. Surgical anatomy of adrenal gland
• Adrenal glands are paired mustard coloured structures that are
positioned superior and slightly medial to kidneys in the
retroperitoneal space
• Right adrenal gland is shaped like a top hat,left adrenal gland is
shaped like a cocked hat
• Each gland weighs 4gms each,30-50mm height,30mm in breadth,4 to
6mm thickness
• It is a highly perfused gland after kidney and thyroid, receiving
2000ml/kg/min
3. Relations of adrenal gland
Right adrenal gland
• MEDIALLY BY IVC
• LATERALLY BY LIVER
ANTERIOR
RELATION
• INFERIORLY BY KIDNEY
• SUPERIORLY BY DIAPHRAGM
POSTERIOR
RELATION
• NOT RELATED TO PERITONEUM
PERITONEAL
RELATIONS
Left adrenal gland
• SUPERIORLY BY STOMACH
• INFERIORLY BY PANCREAS
ANTERIOR
RELATION
• MEDIALLY BY DIAPHRAGM
• LATERALLY BY KIDNEY
POSTERIOR
RELATION
• SEPERATED FROM STOMACH BY
PERITONEUM
PERITONEAL
RELATION
6. Embryology of adrenal gland
• Cortex and Medulla of adrenal gland appear as two distinct organs because
of their disparate embryologic origin
• Cortex develops from mesoderm near the gonads on the adrenogenital
ridge around fifth week of gestation
• Therefore ,Ectopic adrenocortical tissue may be found in
ovary,testis,spermatic cord
• Cortex differentiates into thin definitive cortex and thick inner fetal cortex
• Fetal cortex is functional and produces fetal adrenal steroids by 8th week of
gestation
• Fetal cortex involutes after birth resulting in decrease of adrenal weight
• Definitive cortex persists after birth and forms adult cortex
7. • Adrenal medulla is derived from ectodermal neural crest cells
also called as PARAGANGLION CELLS
• Paraganglion cells consist of neuroendocrine cells associated
with autonomic nervous system containing neurosecretory
vesicles
• Paraganglion cells migrate to para-axial and paravertebral areas
towards developing cortex and form medulla
• Most extra-adrenal tissue may regress but may persist at several
sites
• Extraadrenal Paraganglia occur throughout sympathetic nervous
system and some branches of parasympathetic system like
glossopharyngeal and vagus nerves.
8. Paraganglion cells associated with sympathetic
and parasympathetic nervous system- sympathetic
tumors are mostly secretory and parasympathetic
are non secretory types
9. • Paraganglia is divided into CHROMAFFIN PARAGANGLIA and NON-
CHROMAFFIN PARAGANGLIA ,based on the staining with chromium
salts
• Normally neural crest cells stain with chromium salts in adrenal
medulla
• The extradrenal sites ,where cells stain with chromium salts are present
in lumbar paravertebral space ,organ of zuckerkandl(near aortic
bifurcation) ,paravertebral space in left thorax ,in front of great
vessels
• Non-chromaffin paraganglia occur in the branchial grooves of following
arches
1st arch-orbital ciliary body,2nd arch-glomus tympanicum(along
glossopharyngeal nerve),3rd arch-carotid body,glomus jugulare(on
jugular bulb),4th arch-glomus intravagale(in the inferior ganglion of
vagus nerve),6th arch-aortic and pulmonary glomus bodies
• All these extradrenal neural crest cells are located between base of
skull and urinary bladder
10. • Paraganglia can be secretory or non secretory
• Functionally active secretory tumor in adrenal medulla are called
pheochromocytomas. These secrete epinephrine and
norepinephrine
• Secretory tumors from extra-adrenal sites are called
paraganglioma. These secrete noradrenaline
• Non-secretory tumors from extra-adrenal sites are called
chemodectomata.the most commonest site is carotid body,aortic
body,pulmonary body ,these paraganglia normally act as
chemoreceptors,responding to alteration in blood pH and blood
gases
• Tumors that arise from parasympathetic ganglia are called glomus
tumors which include glomus caroticum ,glomus jugulare, glomus
vagale
13. Arterial supply of adrenal gland
• From inferior phrenic artery
Superior part of
adrenal gland
• From aorta
Middle part of
adrenal gland
• From renal artery
Inferior part of
adrenal gland
15. Venous Drainage of adrenal gland
• Left adrenal vein is long (2cm)it drains into left renal vein after joining
left inferior phrenic vein
• Right adrenal vein is short and wide(0.5cm),it drains into IVC
• 20% of right adrenal vein drains into
1. Renal vein and IVC trifurcation
2. Renal vein confluence
3. Hepatic and IVC trifurcation
4. Hepatic vein confluence
18. Nervous innervation-Adrenal gland has
sympathetic innervation of autonomic nervous
system
SYMPATHETIC
INNERVATION
Coeliac plexus
and
splanchnic
nerves
Preganglionic
fibers are in
medulla
Hormones
secreted by
medulla take
postganglionic
fibers
19. Lymphatic drainage
• Lymphatic plexus lie underneath capsule and in medulla
• From Right adrenal gland ,it drains into para-aotic nodes and nodes
near right crus of diaphragm
• From left adrenal gland,it drains into nodes at origin of renal artery
,inferior phrenic artery and para-aotic nodes
20. Histopathology
• Cortex is made of three layers
1. ZONA GLOMERULOSA
2. ZONA FASCICULATA
3. ZONA RETICULARIS
22. ZONA
GLOMERULOSA-
Cells with
eosinophilic lipid
poor cytoplasm
ZONA
FASCICULATA-Lipid
laden radial
column cells
ZONA
RETICULARIS-
Nests of
eosinophilic cells
ADRENAL
MEDULLA-
Polyhedral cells
packed with
basophilic
secretory granules
23. Biochemistry and Physiology
• Adrenal steroids include aldosterone,cortisol,sex steroids
• It begins by transport of cholesterol into mitochondria and
undergoing various oxidative reactions
• Capillaries reach adrenal medulla which is steroid enriched,containing
phenylethanolamine-methyl-transferase,necessary for conversion of
norepinephrine to epinephrine
• Cyp17 is present only in zona fasciculata and reticularis, accounting
for synthesis of glucocorticoids and sex steroids
• Metabolism of these hormones is by
hydroxylation,sulfonation,conjugation to glucuronic acid
25. Mineralocorticoids
• Secreted by zona glomerulosa
• Its release is regulated by RAAS mechanism
• Aldosterone causes sodium and water retension and excretion of
potassium and hydrogen ions
• RAAS mechanism is stimulated in hypovolemia,shock,renal artery
stenosis and hyponatremia
26. Renin is secreted
from JG cells of
kidney
Renin causes
conversion of
angiotensinogen
to angiotensin 1
in liver
Angiotensin1 is
converted to
angiotensin2 by
angiotensin
converting
enzyme in lung
Angiotensin 2
stimulates
release of
aldosterone from
adrenal cortex
27. Glucocorticoids
• Corticotropin releasing hormone from hypothalamus stimulates release of ACTH
from anterior pituitary ,which stimulates release of cortisol from adrenal cortex
• ACTH is released in a pulsatile manner, displaying circadian rhythm, so cortisol is
highest in waking hours and decreases by early evening
• It generates a catabolic state in response to stress over carbohydrate,lipid and
protein metabolism
• It increases gluconeogenesis,protein and fatty acid catabolism increasing glucose
levels
• It decreases uptake of glucose into tissues and a general state of insulin
resistance is induced,So in cushings syndrome obesity,diabetes milletus etc
occurs
• It increases catecholamine activity over heart and maintains peripheral vascular
tone ,So acute adrenal insufficiency leads to hypotension, bradycardia etc
28. Sex steroids
• These are secreted by zona reticularis
• These include androstenedione,DHEA,DHEA-S
• Physiologic effects are weak in comparison to gonadal sex steroids
mainly in males
• In females,peripherally they are converted to
testosterone,dihydrotestosterone, supports normal pubic and axillary
hair, libido and a sense of well being
29. Catecholamine biosynthesis and physiology
• Synthesis of catecholamines begins with hydroxylation of tyrosine
• Sympathetic stimulation of medulla,leads to catecholamine release into
circulation
• Target tissue responses is mediated by alpha and beta receptors
• In flight and fight response,there is increase in contractility of
heart,increased blood flow to CNS and skeletal muscle
• Normetanephrine,metanephrine,vaniyl mandelic acid are metabolites of
noradrenaline and adrenaline which are the stable metabolites in plasma
and urine for biochemical diagnosis of pheochromocytoma than high
degree of fluctuation in adrenaline and noradrenaline
31. • Increases
smooth muscle
relaxation in
uterus,bronchi
and skeletal
muscle
• Increases
contractility of
heart
• Inhibits
sympathetic
activity in
central nervous
system
• Causes
vasoconstrictio
n of vessels in
skin and GIT
Alpha 1
receptor
Alpha2
receptor
Beta2
receptor
Beta 1
receptor
32. PHEOCHROMOCYTOMA
• In 1886, a young woman who is suffering with symptoms of
headache,palpitations,vertigo,diaphoresis,anxiety where her death autopsy
revealed bilateral adrenal tumors ,stained with chromium salts also called
PHEOCHROMOCYTOMA(dusky coloured tumor)
• Men and woman are equally affected
• Sporadic cases occur between 40 and50yrs of age
• Familial cases occur little earlier
• Symptoms are non specific
• Only 0.5%cases with these symptoms are diagnosed to have the disease
• Differential diagnosis include hyperthyroidism,hypoglycemia,heart
failure,coronary artey disease
33. Other names-10%tumor and biologic time
bomb disease
• 10%tumor-
10% are bilateral
10% are familial
10% are malignant
10% are extra adrenal
• Biologic timebomb
Because of its potential lethal effects on cardiovascular system
34. Pheochromocytoma in pregnancy
• Diagnosis in antenatal period results in12% fetal mortality
• Diagnosis in labour or postpartum increases maternal and fetal
mortality by 29%
• If diagnosed in first 24 weeks,surgery is done in second trimester
• If diagnosed in third trimester,surgery is postponed to after delivery
35. Hereditory pheochromocytoma and
paraganglioma syndrome
• These are associated with germline mutations of succinate
dehydrogenase subunits(SDHB,SDHD),Myc associated protein
X(MAX),Transmembrane protein 127(TMEM127)
• Loss of function of SDH leads to accumulation of krebs cycle
precursors which act as oncometabolites
• Loss of function of MAX,TMEM127 leads to celldeath escape and
enhanced survival
• SDHB gene variants account for secreting paraganglioma
• SDHD gene variants account for non secreting paragangliomas
• Affected individuals are surveilled regularly
37. Von Hippel-Lindau disease
• It is autosomal dominant disease
• It is defined by its genotype as type1(deletion mutation),type
2(missense mutation)
• Type 1 does not cause PPGL whearas type2 causes PPGL
• It is characterized by central nervous system and retinal
haemangioma,renal cysts and carcinoma,endolymphatic sac
tumors,broadligament cyst adenoma
• Tumors overproduce only noradrenaline
39. Neurofibromatosis type1
• NF1 is a tumor suppressor gene,loss of function mutation leads to cell
proliferation and cancer development
• It is characterized by café au lait spots,axillary
freckling,neurofibromas,lisch nodules,osseus lesions,PPGL
41. Multiple endocrine neoplasia
• MEN type2A and MEN type2B are caused by mutation in RET proto-
oncogene
• MEN type 2A is charaterised by medullary thyroid carcinoma
,pheochromocytoma and primary hyperparathyroidism
• MEN type2B is characterized by medullary thyroid
carcinoma,pheochromocytoma,marfanoid features,mucosal
neuromas etc
44. Malignant pheochromocytoma
• 2.5%-40% of pheochromocytomas are malignant
• Differentiation between benign and malignant tumors are difficult,except
when metastasis is present to liver,lung,axial skeleton and kidney
• Metastasis must be differentiated from multifocal primary disease in which
neuroectodermal cells are present
• An increased pheochromocytoma scale score,high number of Ki67 positive
cells,vascular invasion or breached capsule all lean more towards malignant
than benign
• Treatment is surgery for palliative benefit like decreasing the mass anatomic
effect and systemic impact of catecholamines
• It is radio and chemoresistant
• In recent study MIBG I131 was shown to achieve partial or complete response
in 22% patients
45. Histopathology
• Grossly-pheochromocytomas are greyish pink on cut surface,areas of
haemorrhage and necrosis are present
• Microscopically-tumor cells are polygonal containing basophilic
secretory vesicles
47. Clinical presentation
• Functioning PPGLs present with symptoms and signs of
catecholamine excess
• 90%patients with symptoms of sweating,palpitations and headache in
presence of adrenal tumor have pheochromocytoma
• Head and Neck paragangliomas present with side effects arising from
local mass effect-neck mass,dysphonia,tinnitus
• Paroxysms may be precipitated by physical training,induction of
general anesthesia and numerous drugs like tricyclic
antidepresants,opiates,metoclopramide
51. Biochemical diagnosis
• Biochemical diagnosis of pheochromocytoma is based on detection of
elevated levels of catecholamines and their metabolites in body fluids
• Pheochromocytomas are diagnosed by testing 24hr urine samples for
catecholamines and their metabolites as well as determining plasma
metanephrine levels
• Urinary metanephrines are 98%sensitive and 98% specific whereas VMA
metabolite measurement is less specific and sensitive because of high false
positive results
• Fractionated urinary catecholamines like
epinephrine,norepinephrine,dopamine are less specific for
pheochromocytoma because extra-adrenal tumors secrete norepinephrine
• Many physiologic and pathologic states alter the level of plasma
catecholamines so they are less specific than urinarytests
53. Clonidine suppression test
• To test for equivocal test results,clonidine suppression test is done
• Clonidine is an agent which suppresses neurogenically synthesized
catecholamine excess but not the secretion from pheochromocytoma
• A normal clonidine suppression test is defined by decrease in
catecholamines to <500pg/ml within 2-3hrs after oral administration
of 0.3gm of clonidine
• If catecholamines are not suppressed,the test is said to be positive
54. Radiological diagnosis
• Radiological studies are useful once the diagnosis has been made with
biochemical tests
• CT scans are useful to localize and to assess the extent of disease ,they
have sensitivity of 85 to95% and specificity of 70 to 100%
• MRI scans are 95%sensitive and100% specific because of characteristic T2 –
weighted images,where they have swiss cheese appearance
• MIBG(Metaiodobenzyl guanidine)-it is taken up by vesicles in adrenal
medulla because its structure is similar to norepinephrine .Normal
medullar tissue do not take up MIBG, so useful for localizing
pheochromocytoma,it has sensitivity of 77 to89% and specificity of 88-
100%
• PET scan uses 18F –DOPA and 18f-DOPAMINE,these radionuclides are
highly sensitive and superior to MIBG
59. Treatment
• Adrenelectomy is the treatment of choice in pheochromocytoma
• Adverse perioperative haemodynamic changes are observed with
pheochromocytoma lika intra-operative hypertension and post-
operative hypotension
• Medical management of pheochromocytoma is aimed chiefly at
blood pressure control and volume repletion in perioperative period
• Perioperative management can be divided as
preoperative,intraoperative and postoperative managment
60. Pre operative managment
• Irreversible and long acting alpha blockers such as phenoxybenzamine are started 1 to
3wks before surgery at doses of 10mg twice daily which may be increased to 300 to
400mg/day with rehydration
• Side effects of phenoxybenzamine includes orthostatic hypotension and nasal
congestion
• Alpha1 selective adrenergic blockers like prazosin,terazosin are used only when long term
pharmacologic therapy is required as in patients with metastatic pheochromocytoma
• Beta blockers like proponolol 10-40mg is added preoperatively every 6-8hrs ,when
patients have persistent tachycardia and arrhythmias
• Calcium channel blockers like nicardipine is used which inhibits norepinephrine mediated
calcium transport into vascular smooth muscle
• Catecholamine synthesis inhibitor such as metyrosine is used when alpha and beta
blockade is ineffective or poorly tolerated
• Beta blockers should never be used before alpha blockers because inhibition of beta
receptor stimulation (where vasodilatation of vessels is lost) will lead to unopposed
alpha adrenergic stimulation leading to hypertensive crisis
61. Intraoperative managment
• Chief goal of surgery is to resect tumor completely with minimum tumor
manipulation or rupture of tumor capsule
• Surgery should be performed with both noninvasive and invasive monitors
like arterial and central lines
• Inhaled agents like isoflurane,enflurane are preferred because they have
less cardiac depressant effect
• Fentanyl,ketamine,morphine are avoided as they cause catecholamine
release
• Common medications used for intraoperative blood pressure control
include nitroprusside,phentolamine,nicardipine
• Intra-operative arrhythmias are managed with beta blockers like esmolol
62. Surgery
• Open adrenelectomy is done for bilateral tumors,exta-adrenal
lesions,metastatic lesions, if size of the tumor>6cm
• Laparoscopic adrenal resection is now routine in treatment of
pheochromocytoma if tumor size is <5cm
63. PORTS PLACED IN LAPAROSCOPIC LEFT
ADRENELECTOMY-veress needle is placed medial
to anterior axillary line
73. Post-operative managment
• Post-operatively ,these patients are prone for hypotension due to loss
of adrenergic stimulus and subsequent vasodilatation
• Patients should be resusticated more aggressively ,if they become
hypotensive or oliguric
• Sometimes vasopressors are needed after tumor removal
• Lifelong yearly biochemical tests are performed to identify recurrent
,metastatic, metachronous pheochromocytomas
74. REFERENCES
• MC GREGOR’S SYNOPSIS OF SURGICAL ANATOMY
• SABISTON TEXTBOOK OF SURGERY
• SCHWARTZ’S PRINCIPLES OF SURGERY
• BAILEY AND LOVE’S SHORT PRACTISE OF SURGERY
• FISCHER’S MASTERY OF SURGERY
