The adrenal gland is composed of cortex and medulla. The cortical gland accounts for about 80-90% of the gland, and can be divided from outside to inside into: the globular zone, which accounts for about 15% of the cortex, mainly secretes salt corticosteroids and is regulated by the renin-angiotensin system; the fasciculus, which is the thickest, accounts for about 75% of the cortex and mainly secretes glucocorticoids; the reticular zone, which is adjacent to the medulla, accounts for about 10% of the cortex and can produce androgens and estrogens. The fasciculus and reticular zone are one and the same and are regulated by adrenocorticotropic hormone (ACTH) secreted by the pituitary gland. The medulla is located in the center of the gland. The medullary cells, also known as chromophores, are divided into: norepinephrine-producing cells (80%) and epinephrine-producing cells (20%).
Adrenal tumors are divided into cortical and medullary tumors according to their origin and location. Cortical tumors mainly include Cushing’s adenoma and adenocarcinoma occurring in the fasciculus and reticular zone and aldosterone adenoma and adenocarcinoma occurring in the globus pallidus. Medullary tumors are mainly pheochromocytomas. In addition, there are non-functional adrenal tumors that do not have endocrine function, such as adrenal cyst, adrenal medullary lipoma, neuroblastoma, etc.
1. Etiology and pathogenesis: The cause of adrenal tumors is not clear. The relationship between ACTH stimulation and tumor; the relationship between P53 gene loss, mutation, recombination and inactivation and adrenal carcinoma; chromosome 17P allele deletion associated with adrenal cortical carcinoma, etc. have been reported.
2.Diagnosis and differential diagnosis
The diagnosis of adrenocortical tumor is divided into two steps: the first step is to determine whether there is cortisolism or aldosteronism; the second step is to determine which kind of tumor is causing it. Most of the outpatient visits are further examined by symptoms or physical examination finding occupancy. In Cushing’s syndrome, ACTH, 24hUFC, blood F-rhythm and blood pressure monitoring are performed, and thin-scan CT+3D reconstruction of the adrenal glands is performed for Cushing’s syndrome, such as round red face, centripetal obesity, wide purple lines, polycythemia, thin skin and thinning of the lower limbs. Thin-scan CT examinations; those with severe persistent or paroxysmal hypertension, palpitations, cold sweats and dizziness, without excluding pheochromocytoma/paraganglioma, need to measure 24h urinary catecholamines or blood MN and NMN, and functional localization is feasible with MIBG imaging or oxytocin imaging.
(1) Cushing’s adenoma: As above with typical clinical presentation. A low-dose dexamethasone suppression test is required to determine cortisolism. Standard two-day test: The day before dosing, collect a 24-hour urine specimen (usually from 8 a.m. to 8 a.m. the next day) to measure 17-OHCS, free cortisol and creatinine. After urine collection, dexamethasone was started at 0.5 mg/dose every 6 hours for 8 doses. Urine specimens were collected 6 hours after the last oral dose of dexamethasone, and blood was collected to measure cortisol and ACTH (or no blood was collected). Compare the 24-hour urine 17-OHCS or UFC levels the day before and the day after dosing. A normal response is a 17-OHCS of less than 6.9 umol/24-hour urine (2.5 mg/24-hour urine) or a UFC of <55 nmol/24-hour urine (20ug/24-hour urine) on the second day of dosing. According to the data of Peking Union Medical College Hospital, the compliance rate was 84.7% with 17-OHCS as the index and 89.7% with UFC as the index. Single day overnight method: i.e., dexamethasone 1.0 mg or 1.5 mg was taken between 23:30 and 24:00, and plasma cortisol was measured on the control day and at 8:00 a.m. on the day after taking the drug. If the blood cortisol was below 140 nmol/L (5ug/dl) at 8 am after dosing, it was suppressed. Patients with cortisolism were not suppressed. The overnight method has a 90% compliance rate. This test is of great value in cortisolism. Medical cortisolism caused by heavy application of glucocorticoids or ACTH, pseudo-Cushing's syndrome caused by long-term consumption of alcoholic beverages, and simple obesity need to be excluded in determining the diagnosis.
At present, as far as domestic conditions are concerned, the high-dose dexamethasone suppression test is still the most important means of etiologic differential diagnosis, with a reliability of about 80%. The method is the same as the two-day method of small-dose dexamethasone suppression test, except that the oral dose of dexamethasone can be increased from 0.5 mg to 2 mg each time. In normal subjects, 24-hour urinary 17-OHCS was suppressed to 6.9 umol/24-hour urine (2.5 mg/24-hour urine), urinary free cortisol was below 28 nmol/24-hour urine, and blood cortisol and ACTH concentrations were low or even undetectable. In patients with Cushing’s syndrome, urinary 17-OHCS and free cortisol were significantly suppressed, with most suppressed by 50% or more, and not suppressed in patients with primary adrenocortical tumors and ectopic ACTH syndrome. Blood ACTH and related peptide N-POMC assay is nearly 100% reliable for the identification of ACTH-dependent and non-dependent types. Normal values (exoneration method): plasma ACTH: 2.31-18 pmol/L (10.5-82 pg/ml) at 8 a.m.; 1.7-16.7 pmol/L (7.6-76 pg/ml) at 4 p.m.; 0-8.7 pmol/L (0-39.7 pg/ml) at midnight. Plasma N-POMC basal values ≤ 100 pg/ml plasma or ≤ 182.9 ± 78.2 pg/ml serum. Blood ACTH was suppressed below normal in patients with adrenal cortisol tumors or carcinomas. ACTH-dependent cortisolism was above normal or within the normal range, with patients with ectopic ACTH syndrome generally having plasma ACTH levels above 100 pg/ml, individually above 1000 pg/ml, and above 300 pg/ml in about 60% of patients.
CT scans of the adrenal glands have a positive detection rate of almost 100% for occupying adrenal lesions. In addition, radionuclide examinations, such as 131I-labeled cholesterol post-intravenous visualization of the adrenal area and PET, are specific and accurate, but are not yet commonly used. When CT and radionuclide cannot be used for correct diagnosis, especially for localization and even characterization of small adrenal tumors, highly selective adrenal arteriography and venography are often used.
The differentiation between adrenal adenoma and adenocarcinoma is generally not difficult, and the CT manifestations are different. CT presentation of adenoma: the adrenal gland on the diseased side is enlarged and morphologically deranged. The density of the tumor can be isointense or hypointense, generally uniform, and the size of Cushing’s adenoma is about 2-100px with moderate enhancement. Adenocarcinoma CT manifestation: inhomogeneous density, relatively large volume, uneven margins and calcification, easily invade adjacent tissues and organs, often with lymphatic and vascular invasion. If there is metastasis, it is definitely malignant. 24-hour urine 17-KS measurement is of special value to distinguish the two. Normal values: women 17-52umol/24hour urine (5-15mg/24hour urine); men 34-69umol/24hour urine (10-20mg/24hour urine). Benign tumors are normal or low, while malignant tumors can exceed the normal value several times.
(2) Aldosterone-producing adrenocortical adenoma and adenocarcinoma (also known as aldosteronoma and malignant aldosteronoma)
Protoaldosteronism should be considered in the following clinical situations: (1) children and adolescents with hypertension; (2) hypertension with no significant effect after antihypertensive treatment; (3) hypertension with spontaneous hypokalemia or easily promoted hypokalemia; (4) hypertension with periodic paralysis or muscle weakness and hypokalemia even after the onset of paralysis or hypokalemia on electrocardiogram.
When prodromalgia is suspected, further laboratory tests should be performed: (1) Blood potassium is low, with a mean value of 2.24 mmol/L and a minimum of 1.4 mmol/L. Some people have intermittent hypokalemia; (2) Blood sodium is often normal or slightly above normal. The mean value is 142.7 mmol/L; ③ blood CO2CP is generally normal high or above normal, and may not be high in those with advanced renal dysfunction; ④ urinary potassium 24-hour urinary potassium excretion generally exceeds 30 mmol/24 hours, and the literature reports an average of 54.9 mmol/24 hours of urinary potassium; ⑤ blood aldosterone If it is greater than 186.6 umol/L, it has diagnostic value; ⑥ plasma Renin activity in proaldosteronism does not exceed 2.46 mol/L.h (3.0 ng/ml.h); (vii) Aldosterone suppression test This test is the key to confirm the diagnosis of proaldosteronism. The common test method uses oral sodium chloride. All drugs that affect the renin-angiotensin-aldosterone system should be stopped before the test. Before the start of the test, 24-hour urine is taken to measure aldosterone, potassium, sodium, creatinine, and cortisol, and blood is drawn to measure potassium, aldosterone, cortisol, and renin activity. Total sodium chloride intake was 10-12 g per day for 4-5 days. Finally, blood was drawn early in the morning and urine was kept for 24 hours to retest the above indicators. The test is more reliable if urinary sodium excretion exceeds 200 mmol/24 hours. Potassium supplementation needs to be continued throughout the test. In normal subjects, urinary aldosterone excretion is suppressed to below 27.7-38.8 nmol/24 hours (10-14ug/24 hours). In patients with proaldosteronism, plasma aldosterone levels remain above 554 pmol/L (20 ng/dl) and urinary aldosterone values are above 38.8 nmol/24 hr (14ug/24 hr). In conclusion, proaldosteronism is diagnosed in hypertensive patients with increased aldosterone secretion, spontaneous hypokalemia combined with hyperkalemia, reduced plasma renin activity, high aldosterone secretion not suppressed by a high sodium diet, and normal glucocorticoid secretion.
Protoaldosteronism is 95% adenoma and idiopathic cortical hyperplasia. Therefore, the etiological differentiation is mainly between adenoma and idiopathic hyperplasia. (1) Postural test and plasma 18-hydroxycorticosterone assay: blood aldosterone levels in idiopathic cortical hyperplasia increased by at least 33% after the standing test, whereas there was no significant increase in adenoma. The accuracy of the standing test was 85%. Plasma 18-hydroxycorticosterone value at 8 am: adenoma exceeds 100 ng/dl, while idiopathic cortical hyperplasia is less than 100100 ng/dl, with an accuracy of 80%. The plasma aldosterone was measured by taking 8 mg of cycloheximide orally, and blood was collected every half hour before and after the dose, for a total of 4 times over 2 hours. Most of the patients with idiopathic cortical hyperplasia had a decrease in plasma aldosterone of more than 4ng/dl or more than 30% from the basal value, and most of the patients had the most obvious decrease 90 minutes after taking the drug, with an average decrease of about 50%. There is no change in plasma aldosterone in patients with aldosteronism. (iii) CT scan is the preferred method for detecting aldosteronism. Idiopathic cortical hyperplasia is characterized by normal or enlarged adrenal gland size bilaterally; adenoma is solitary, mostly on one side, about 1-50px in size, with low enhancement, and the detection rate of tumors above 25px is up to 90% on thin (8.75px) CT scan. Isotope iodinated cholesterol scan is a common diagnostic method being used in China, with an accuracy rate of 70-90%. Adenoma takes up more radioactive markers than normal adrenal glands, and the scanner shows a hot area of radioactive concentration that is not suppressed with dexamethasone, while cortical hyperplasia takes up normal amounts and can be suppressed by dexamethasone, and cortical carcinoma is not shown. ⑤ Adrenal vein cannulation for blood collection Adrenal vein blood collection for detection of aldosterone and cortisol is almost 100% correct, but it is an invasive test and catheter insertion requires a high degree of skill, so it is not routinely performed, but only when the above tests cannot identify hyperplasia or tumor. Adrenal malignant aldosterone tumors are extremely rare, accounting for about 1% of proaldosteronism. Less than 50 cases have been reported internationally, and 6 cases have been found in China. Due to the rarity of the disease and the lack of experience in diagnosis and treatment, cancer cells often secrete glucocorticoids in addition to a large amount of aldosterone, and thus the corresponding clinical symptoms can be seen to appear. Pathologically, it is often difficult to make a definite diagnosis based on cytological examination alone, and the diagnosis can only be confirmed if it is indeed proved that there is true cell infiltration in blood vessels and envelope or characteristic thick-walled blood vessels. The diagnosis can only be confirmed if there is true cell infiltration in blood vessels and envelope or characteristic thick-walled blood vessels.
2.Pheochromocytoma
(1) Qualitative diagnosis: The typical clinical manifestation of pheochromocytoma is hypertension, with irregular fluctuations in blood pressure, a wide range, or paroxysmal episodes, or persistent hypertension, or persistent hypertension with paroxysmal exacerbation, with a mean diastolic blood pressure ≥ 14 Kpa (150 mmHg), and ineffective general antihypertensive drugs or paradoxical response, the possibility of pheochromocytoma should be considered and further examination is needed.
Pharmacological tests: The main tests are the histamine excitation test and the phenazopyridine test. Due to the dangers of both tests, such as hypertensive microsign, blood pressure drop, cardiac arrest, etc., there has been a trend of gradually abandoning their application at home and abroad.
Measurement of myeloid hormones.
① 24-hour urinary catecholamine levels are 258-891 nmol/day for normal adults in men and 239-806 nmol/day in women. The 24-hour urinary levels in patients with this disorder can be 10-100 times higher than the normal values. Some hospitals measure 24-hour urinary levels of vanillylmandelic acid (VMA), which is also useful for diagnosis. In recent years, metanephrine levels have been measured with a false negative rate of only 4%.
The content of myeloid hormone in blood is very small and unstable, so it is difficult to determine, and has not been commonly used in clinical practice. The normal values determined by various institutions also vary. The generally accepted range is 8.87-32.5 nmol/L for norepinephrine and 0.98-5.16 nmol/L for epinephrine. norepinephrine values in this disease may be significantly increased.
(2) Localization and diagnosis
Ultrasound examination: This technique is more accurate in the localization of pheochromocytoma in the adrenal area, which can show round or ovoid tumor shadow, separated from surrounding tissues, with clear envelope. The accuracy rate of localization can reach 89-97%, which is a good and easy screening method.
CT and MRI scans: They are of high diagnostic value for patients suspected of having pheochromocytoma, with a round or ovoid shape, lobulated and clearly defined borders, and a substantial adrenal mass with a CT value of 30-60Hu. The CT diagnostic accuracy is over 95%. MRI shows similar morphology to CT, and it is believed that MRI is better than CT especially for extra-adrenal pheochromocytoma.
Isotope iodine benzylguanidine imaging (MIBG) is used for the circumferential investigation and diagnosis of pheochromocytoma, with a confirmation rate of 90%. When a whole-body scan is performed, it can show both extra-adrenal or extra-abdominal tumors and track metastatic cancer, which is superior to CT.
PET-CT is a new radionuclide technology, which has the ability to detect primary tumors that cannot be found by conventional diagnostic techniques, and is particularly relevant in the diagnosis of adrenal diseases, especially in the differentiation of benign and malignant.
(3) Differential diagnosis
Differentiation of benign and malignant pheochromocytomas Benign pheochromocytomas account for the majority of cases, about 90%. It is difficult to determine the benignity and malignancy of the tumor based only on the histological manifestation of pathological sections. Malignant pheochromocytoma can only be diagnosed by the presence of tumor growth in organs without embryonic residual ganglion cells, such as liver, lung, brain, bone and lymph, or by local recurrence of the primary tumor. The diagnosis can only be established when the infiltration extends to non-neurological tissues.
Various causes of hypertension Bendazoline test. Catecholamine and VMA assay can help to differentiate.
3.Treatment and prognosis
All adrenal tumors with surgical indications should be surgically removed. For those who have serious complications and cannot tolerate surgery, or whose malignant tumor has metastasized, drug therapy, chemotherapy, radiotherapy, etc. should be performed.
(1) Adenoma and adenocarcinoma of Cushing’s syndrome: Since the tumor secretes corticosteroid autonomously, ACTH is suppressed and the adrenal cortex outside the tumor and the contralateral adrenal cortex are atrophied, so glucocorticoid supplementation is needed on and after surgery. Surgical resection of adenoma is good and the prognosis is good. Adenocarcinoma has a short history and rapid development. Metastasis to the lung, liver and lymph nodes is common, and local infiltration is already present in 2/3 of diagnosed cases, and anti-cancer drugs are not effective. Even if radical surgery is performed, the 5-year survival rate is 25%. Treatment plan: ① If radical surgery cannot be performed, tumor tissue should be excised as widely as possible to reduce tumor volume and increase drug dose to prolong survival time. Even if metastasis occurs, if available, operate again; ② bis-chlorophenyl dichloroethane (O,P-DDD) mitotane is an adrenocorticotropic hormone catabolic drug, which can achieve the effect of pharmacological adrenalectomy; ③ local radiotherapy This method is still controversial; ④ adrenocorticotropic hormone synthase inhibitors such as aminoglutethimide, mepyrone, ketoconazole, etc., which are beneficial to improve the symptoms of Cushing’s syndrome. ⑤ anti-cancer drugs such as vincristine, fluorouracil and cyclophosphamide, which can be used alone or in combination; ⑥ immune agents such as interferon and interleukin can be applied, but the efficacy is uncertain.
(2) Protoaldosterone adenoma and adenocarcinoma Because the tumor secretes aldosterone autonomously, the patient has low blood potassium, high blood sodium and high blood pressure, so potassium supplementation, low sodium diet and aldosterone antagonist (spironolactone) should be applied before surgery to normalize the patient’s blood electrolytes and lower blood pressure. Bilateral adrenalectomy requires corticosteroid supplementation. Surgical excision of adenomas is effective. In Europe, the cure rate has been reported to be 80-90% in recent years. The number of adenocarcinoma cases is very small, and there is no definite statistical report on its cure and survival rate in 3-5 years.
(3) Pheochromocytoma: Adequate and effective preoperative preparation is the key to reduce or eliminate surgical death. The large amount of norepinephrine and epinephrine secreted by pheochromocytoma after uninterrupted input into the body causes the whole vascular bed to be in a tight pathological state for a long time, and the blood volume is sharply reduced. When the tumor is removed, the blood vessels suddenly relax and dilate, causing an extreme disproportion between vascular volume and blood volume, resulting in immediate, dangerous and persistent hypotension, which can lead to death. Based on this change in pathological mechanism, the current preoperative preparation for pheochromocytoma mainly uses alpha-blockers: phenazopyridine or doxazosin. Preoperatively, blood pressure should be controlled to strive for a normal range, heart rate should not exceed 90 beats/min, and erythrocyte pressure volume should be about 45%. Bilateral adrenalectomy is proposed, and postoperative glucocorticoid supplementation is still required. During the operation, the tumor should be removed as much as possible with the envelope and surrounding tissues intact to avoid residual tumor and recurrence. The tumor may be multiple, especially in children, those with family tendency or multiple endocrine neoplasms. The operation should be performed gently and meticulously, striving for early ligation of the tumor supply vessels and avoiding squeezing the tumor to reduce hypertension caused by the release of catecholamines into the blood. Postoperatively, blood pressure and heart rhythm disorders should be strictly controlled. If handled properly before and during surgery, it is generally not necessary to rely on norepinephrine to maintain blood pressure after surgery. For patients without surgical indications, in addition to MIBG treatment, drugs are applied to control blood pressure and heart rate, mainly α-adrenergic receptor blockers, β-adrenergic receptor blockers and angiotensin inhibitors. The effect of chemotherapy and radiotherapy is less satisfactory. The prognosis of pheochromocytoma is related to many factors such as age, benignity and malignancy of the tumor and family history. After resection of benign tumor, most patients’ blood pressure will drop to normal soon, but plasma and urinary catecholamines and their metabolites may still be high for several days or even a month. 20-30% of patients may not fully recover from cardiovascular, renal or brain complications caused by long-term hypertension, but they can be controlled by conventional antihypertensive drugs. 5-year survival rate is more than 96%, while that of malignant tumor is only 44%. Malignant tumors should be followed up for a long time and once they recur, they should be operated again as much as possible to improve the efficacy.