Three12 106B Pathophysiology, Evaluation and Medical Management of Adrenal Disorders

  1. Causes of adrenal insufficiency?
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    If the condition is not anticipated and appropriate proactive therapies are not instituted, addisonian crises following simultaneous or staged  bilateral adrenalectomy can result in death.
  2. Clinical features of Addison's disease?
    • Profound fatigue and anorexia for many months before definitive diagnosis.
    • Hyperpigmentation, a hallmark of primary adrenal insufficiency, results from high serum concentrations of ACTH in response to increased hypothalamic release of POMC-derived peptides that stimulate the melanocortin (MC1) receptor of the skin 

    Acute anrenal insufficiency or adrenal crisis, is a life- threatening condition often preceded by hypotension  unresponsive to fluid resuscitation. Patients are easily  and often misdiagnosed with an acute abdomen,  whereas abdominal pain, nausea, vomiting, and fever  frequently accompany hypovolemia in these individuals. Pediatric patients can exhibit hypoglycemic seizures.
  3. Treatment of Addison's disease?
    Cortisol with fludricortisone 

    There should be a low threshold to consult advanced endocrinologist expertise, given the complexity and the potentially grave consequences of the condition.
  4. Pathophysiology of ACC?
    Two hereditary disorders

    • - Li- Fraumeni syndrome - Loss of TP53 function - 17p13 locus, Also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.
    • - Beckwith-Wiedemann syndrome – Increased insulin-like growth factor (IGF)

    • Other etiological risk factors
    • - Presence of contraceptive use in women younger than 25 years (due to increased exposure to estrogen), Relative increase in ACC has been noted during pregnancy and may be due to increased estrogen exposure,
    • - Men who smoke tobacco
  5. Clinical Characteristics of ACC?
    •  Incidental detection increased with the routine use of cross-sectional imaging
    •  Majority of patients still have advanced disease and tumour-related symptoms on presentation.
    •  Symptoms can be due to
    • a) Local or systemic disease burden - abdominal fullness, back pain, nausea, vomiting, or other constitutional symptoms.
    • b) Hypersecretion of adrenal hormones - 50% to 79% of adult ACCs, 90% of pediatric ACCs

    • Non-functional - 21-50%
    • Functional - 50-79%
    • Cushing syndrome - 33-53%
    • Cushing syndrome with virilization - 20-24%
    • Virilization alone - 10-20%
    • Feminization - 6-10%
  6. Functional breakdown for ACC?
    • Cortisol
    •  most common hormone secreted by ACC functional tumors
    •  Results in clinical manifestation of Cushing syndrome
    •  ACTH independent,
    •  Cushing-associated virilization has been noted to be more pronounced compared with that resulting from functional adenomas
    •  Symptomatic hypercortisolemia is an independent prognosticator of survival in patients with resected localized ACC

    • Androgens
    •  second most common
    •  virilization - result of 17-ketosteroids and DHEA
    •  In women - virilization, characterized by male-pattern baldness, hirsutism, and oligomenorrhea
    •  In Men -  peripheral conversion of androstenedione to estrogen,  Estrogen production can lead to feminization, noted in 1% to 3% of patients, characterized by testicular atrophy and gynecomastia 

    • Aldosterone
    •  Aldosterone hypersecretion is rarely associated with ACC
    •  associated with profound hypertension and hypokalemia.
    •  the symptoms of hypertension and hypokalemia are more likely secondary to other adrenal steroids produced by ACC, rather than the hypersecretion of aldosterone
  7. Diagnostic Tests for ACC?
    •  Suspicion for ACCs is based on clinical symptoms or radiographic findings
    •  Diagnosis should begin with a thorough history and physical examination focusing evaluation on signs and symptoms of adrenal hormone excess.
    • Functional evaluation
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    • CT - 90% of ACCs are larger than 5 cm - average size of 10 to 12 cm on presentation. 
    • Risk of malignancy based on size
    • - >6m - 25%
    • - 4-6 cm - 6%
    • - <4cm - 2%
  8. Radiographic characteristics of adrenal carcinomas
    •  presence of irregular borders
    •  irregular enhancement
    •  calcifications, and necrotic areas with cystic degeneration.
    •  Mean attenuation on noncontrast CT scan is significantly higher (39 HU) compared with adenomas (8 HU)
    •  ACC does not exhibit the brisk iodinated contrast washout characteristic of adenomas
    •  Presence of lymphadenopathy and local tumor extension into the IVC and other adjacent organs – requires metastatic evaluation - cross-sectional imaging of the chest, abdomen, and pelvis.
    •  Lung and liver – most common site of mets
    •  Evaluation for bone and central nervous system metastases - with site-specific symptoms.

    • MRI
    •  ACCs appear isointense relative to the liver or spleen on T1-weighted images and demonstrate intermediate to increased intensity on T2-weighted images.
    •  On gadolinium-enhanced images, adrenal carcinomas demonstrate marked contrast uptake
    •  Indication of MRI - suspicion for venous tumor thrombus (detecting the presence of a tumor clot and delineating its extent)

    • 18F-FDG PET
    •  ACC tends to be 18F-FDG PET avid
    •  The sensitivity and specificity of 18F-FDG PET in diagnosing benign from malignant tumors - 97% and 91%
    •  However, 18F-FDG PET cannot distinguish ACC from other malignancies and metastases.
  9. Role of Needle biopsy in ACC?
    •  Percutaneous needle biopsy is usually not performed before surgical excision because there is a clinically unacceptable risk for needle-tract seeding.
    •  Information obtained from biochemical and radiographic evaluation should be enough to justify complete excision
    •  Indication for needle biopsy - locally advanced or metastatic disease to confirm the diagnosis before systemic medical therapy
  10. The Weiss criteria - 1984?
    •  To distinguish benign from malignant adrenal tumors
    •  Nine pathologic features based on - tumour structure,  cytology, and invasion.
    •  The presence of three or more of the Weiss criteria is associated with malignancy, with a sensitivity of 100% and a specificity of 96%

    • Weiss Criteria - 
    •  High nuclear grade (grade 3 or 4 according to criteria of Fuhrman)
    •  Mitotic rate greater than 5 per 50 high-power fields
    •  Atypical mitoses
    •  Clear cells comprising 25% or less of the tumor
    •  Diffuse architecture (greater than one third of the tumor)
    •  Necrosis
    •  Invasion of venous structures
    •  Invasion of sinusoidal structures
    •  Invasion of capsule of tumor

    [@ wEISs - wCISs, Cytology, Invasion , Structure] - 3/9 is suggestive of malignancy
  11. The modified Weiss system?
    •  Recognition and interpretation of some of the histologic criteria of the Weiss system to be difficult and subject to interobserver variability.
    •  In 2002, Aubert et al proposed simplifying the Weiss system by eliminating criteria that were considered to be more subjective or difficult to interpret – used 5 histoloical criteria
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  12. Why not to use Weiss Pathologic criteria in pediatrics and Oncocytic features?
    Pediatric - Pediatric adrenocortical neoplasms that exhibit worrisome histologic findings associated with malignancy in adults, such as necrosis, nuclear pleomorphism, capsular invasion, vascular invasion, increased mitotic rate, and even atypical mitotic figures, ultimately prove to behave in a clinically benign manner.

    Similar to oncocytic neoplasms involving other organs, those occurring in the adrenal gland are composed exclusively of cells with copious, densely granular, eosinophilic cytoplasm resulting from the accumulation of mitochondria. every adrenal oncocytic tumor is composed of cells with eosinophilic cytoplasm (ie, clear cells comprising ≤25% of the tumor), and most will exhibit a diffuse architecture as well as high-grade nuclear atypia in at least a subset of the neoplastic cells. These parameters appear to be inherent features of adrenocortical oncocytic tumors, and the presence of these histologic findings alone has not been associated with neoplasms that have recurred or metastasized.
  13. Staging of ACC?
    • T1 - <5cm 
    • T2 - >5cm 
    • T3 - tumour infiltrates into surrounding tissue 
    • T4 - tumour invasion into adjacent organs 

    •  The American Joint Committee on Cancer (AJCC) staging of ACC is based on size of the primary tumor, degree of local invasion, and spread to regional lymph nodes or distant sites
    •  The European Network for the Study of Adrenal Tumors (ENSAT) staging system of ACC is similar to the AJCC staging system; however, it differs in the grouping of patients with advanced disease.
    •  ENSAT staging of ACC led to better predictive value in the prognosis of ACC patients.

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    ENSAT (2008) staging of ACC led to better predictive value in the prognosis of ACC patients.UICC - 2004

    ENSAT -  it still presented with some pitfalls such as not accounting for severe invasion into the inferior vena cava or N statu
  14. Management of ACC?
     Majority of patients with ACCs have advanced disease on presentation.

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    •  Those who have localized disease are at a high risk for local recurrence and metastatic progression.
    •  Despite aggressive surgical resection, adrenal carcinoma is associated with a high rate (60% to 80%) of recurrent disease.
    •  Thus, local and systemic adjuvant therapy is often administered, in spite of the lack of clear evidence demonstrating improved survival.

    • Surgery
    •  Complete surgical excision is essential in the management of ACC
    •  Approach – Open Vs Laparoscopic

    •  En Bloc resection of surrounding organs involved with locally advanced disease should be performed whenever possible to achieve negative surgical margins.
    •  Routine locoregional lymphadenectomy in all cases - should include (as a minimum) the periadrenal and renal hilum nodes. All suspicious or enlarged lymph nodes identified on preoperative imaging or intraoperatively should be removed.
    •  Cases of venous tumor thrombus involving the IVC may require vascular bypass techniques, IVC replacement, and/or IVC interruption.
    •  Perioperative hydrocortisone replacement in all patients with hypercortisolism that undergo surgery for ACC
    •  Metastatic adrenal carcinoma - cytoreductive removal of the primary tumor and debulking metastasectomy if more than 90% of the disease burden can be removed.
    •  Debulking surgery may not improve survival, it may alleviate tumor-related side effects and facilitate additional therapies.
    •  Local or distant disease recurrences after initial resection should be considered for surgical excision
    •  Low-grade tumors with prolonged disease-free intervals may be the best candidates for surgical management of recurrent disease compared with high grade tumors.
    • Locally recurrent disease and select metastatic lesions may be treated with ablative therapy using radiofrequency ablation or angioembolization if surgical excision cannot be performed

    • Systemic therapy
    • - M-EDP regimen - mitotane in combination with streptozotocin or etoposide, doxorubicin, and cisplatin [@ ManDEEP] 
    • - first-line regimen of choice in patients requiring systemic therapy

    • Radiation.
    •  Limited role for radiation therapy in the treatment of primary ACCs
    •  Treatment of choice in the management of bone and CNS metastasis
  15. Mitotane
    •  oral synthetic derivative of the insecticide dichlorodiphenyltrichloroethane (DDT)
    •  most commonly used chemotherapeutic agent in the treatment of ACC
    •  Duration - 2 years, but not longer than 5 years

    • MOA –
    •  direct cytotoxicity of cells in the adrenal cortex
    •  oxidative damage through the production of free radicals
    •  inhibition of enzymes involved with steroid synthesis – steroid replacement required during treatment

    • Side effects
    •  adrenal insufficiency
    •  gastrointestinal upset
    •  lethargy, depression
    •  feminization in males
    •  Rash
    •  elevation of hepatic enzymes
    •  elevation of hormone-binding globulins
    •  hypothyroidism, dyslipidemia
    •  thrombocytopenia.

    Mitotane plasma monitoring with the objective of reaching 14 to 20 mg/dL is recommended for ACC management

    [@ Mitotane 14-20, Tacrolimus, 12-14 in first week]
  16. Adjuvant Therapy
    •  Control of symptoms secondary to the hypersecretion of hormones
    •  ketoconazole, metyrapone, aminoglutethimide, and etomidate, and mifepristone, a direct glucocorticoid antagonist, have been used to decrease symptoms related to glucocorticoid excess

    Streptozotocin or streptozocin are same.
  17. Prognosis of ACC?
    •  Overall 5-year survival in ACCs is poor, ranging from 20% to 47%.
    •  Tumor size greater than 12 cm, age, positive surgical margins, high mitotic rate, cortisol production, tumor necrosis, atypical mitotic figures, and high Ki-67 staining – associated with poor survival

    After complete resection - radiological imaging every 3 months for 2 years, then every 3-6 months for a further 3 years, Continuation of follow-up imaging beyond 5 years
  18. Pediatric Adrenocortical Carcinoma
    •  The presentation, staging, and prognosis of pediatric ACC differ from those in adults.
    •  More than 90% of ACCs in children are functional at the time of presentation  - Virilization being the most common clinical manifestation
    •  Genetic syndromes should be considered in pediatric cases - particularly Li-Fraumeni syndrome, because a high rate of TP53 mutations has been noted in prior series.

    • Staging system in pediatric patients
    •  Stage I - completely excised with negative margins, <200g
    •  Stage II - completely excised with negative margins, >200g
    •  Stage III - presence of microscopic or macroscopic residual disease after surgical resection or inoperable tumors
    •  Stage IV disease is defined by the presence of hematogenous metastasis
  19. What is adrenal adenoma?
    • Adrenal adenomas are by definition benign, and the vast majority is metabolically silent. 
    • High intracytoplasmic lipid content is unique to adenomas, and this attribute affords accurate differentiation of adenomas from other adrenal lesions on cross-sectional imaging.
    • According to an NIH 2002 consensus panel, an adrenal mass with an attenuation of less than 10 HU on unenhanced CT is “strongly suggestive of a benign adrenal adenoma.
    • About 30% of adrenal adenoma have HU of >10HU 

    Treatment - Adenomas that are metabolically active should undergo resection in acceptable surgical candidates.
  20. Features of myelolipoma?
    A mixture of mature adipose tissue and relatively normal trilineage hematopoietic elements

    • Myelolipomas are a result of an adrenal stress response. 
    • Tumors vary greatly in size - may excess 10 cm 
    • Metabolically non functional lesions 

    • CT reveals a well-circumscribed adrenal lesion with varying amounts of mature adipose tissue (30 HU) interdigitated with higher-density myeloid components, which enhance on contrast administration. The presence of macroscopic fat in an adrenal mass is virtually diagnostic of a myelolipoma.
    • In contrast to the benign appearance of a myelolipoma, liposarcomas tend to be aggressive lesions that lack  regular borders and have a propensity for infiltrating surrounding tissues. When the diagnosis is in doubt, some experts believe that percutaneous biopsy may be helpful.

    NIH - myelolipoma can be regarded as an exception to the mandatory metabolic workup of a newly discovered adrenal mass

    Surgery is reserved for symptomatic cases
  21. Adrenal cyst important features?
    Four histologic types of adrenal cysts have been described: pseudocysts, endothelial cysts, epithelial cysts, and parasitic cysts [@ PEEP] 

    Compared with benign cysts, cystic adrenal neoplasms tend to be larger (>7 cm) and have thicker walls.

    • Diagnostic tests 
    • - routine endocrine evaluation 
    • - CT - >30 HU cysts are hemorrhagic
    • - aspiration of cysts should be done only after ruling out pheochromocytoma 

    • Treatment - depends on functional status, symptoms or malignancy potential 
    • - heterogenous, >5cm or sympaotmatic - further evaluation and excision 
    • - because of risk of malignancy, simple decortication is not advised, resection is treatment of choice in normal contralateral adrenal
  22. Discuss how to assess adrenal mass. (TU 71-5)
    Describe the assessment of morphology and functional characters of adrenal gland using image modalities. (TU 76-10)

    What are adrenal incidentaloma?
    • Adrenal masses > 1 cm in diameter identified on cross-sectional imaging performed for indications other than primary adrenal disease. 
    • It is important to emphasize that “incidental” does not mean “insignificant
    • 20% of adrenal incidentalomas are found to be potential surgical lesions - 11.2% are metabolically active, 7.2% are malignant
  23. Adrenal protocol CT?
    • Unenhanced CT - 
    • - first and single best test 
    • - <10HU - diagnostic of adrenal adenoma 
    • - 98% of lesions that exhibit an attenuation of 10 HU or less on noncontrast CT are adrenal adenomas, whereas less than 30% of adrenal adenomas are lipid poor (also known as atypical adenomas) and exhibit an attenuation of greater than 10 HU. 
    • - few low density (<10HU) pheochromocytoma has been reported 

    • Enhanced CT 
    • - single-phase studies (approximately 1 minute after the contrast bolus) is limited 
    • - morphologic features such as irregular margins and an enhancing rim can be quite specific for malignancy

    • CT washout study - goldstandard for adrenal imaging
    • - 30% of adrenal adenomas - >10 HU on unenhanced CT owing to their lower lipid content (atypical adenoma).
    • - Lipid-poor adenomas possess identical properties to lipid-rich adenomas regarding their rapid loss (washout) of enhancement after CT contrast load 
    • - limitation of washout study - cannot differentiate lipid-poor adenomas from RCC and hepatocellular carcinoma metastases
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    • - APW and RPW  [@ EDEUcation, three dots (RelatiVe) 40, 4 dots (AbsolUte) 60, less for less, more for more]] 
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    • CT washout studies are considered the gold standard and appear to surpass opposed phase chemical shift MRI in their sensitivity for identifying adenomas. 
    • Gadolinium-enhanced MRI washout studies do not  exhibit the diagnostic strength of iodine-based CT  washout studies and are not currently used in clinical practice. This shortcoming of MRI may be explained by the fact that gadolinium-induced signal intensity is less dose-dependent than enhancement from iodinated  contrast on CT imaging
  24. Gufler criteria in radiological evaluation of adrenal mass?
    • Differentiation of Adrenal Adenomas From Metastases With Unenhanced CT. 
    • The differentiation between adrenal adenomas and
    • metastases is improved by applying our scoring system compared with any single parameter alone. The total score is obtained by adding 10% of the density values to the size in centimeters, plus 2 if the contour of the lesion is blurred and plus 1 if the structure is inhomogeneous.
    • By setting the threshold at 7 points, all but 1 lesion were classified correctly.
  25. Risk of adrenal malignancy based on size?
    • >6m - 25% malignant 
    • 4-6 cm - 6% 
    • <4cm - 2% malignant

    Incidence of benign adrenal adenomas increases with age; therefore adrenal lesions in younger patients, even those smaller than 4 cm, must be managed with greater caution than similar lesions in an older patient. Likewise, lesions larger than 4 cm in older patients with significant comorbidities may be better served with observation than resection.

    Resect mass that grow >1cm in follow up (is it in one yr? )
  26. Indication of biopsy of adrenal mass?
    • All criteria should be fullfilled 
    • - Hormonally inactive (pheochromocytoma should be excluded) 
    • - Lesion is not characterized as benign on CT imaging 
    • - Management would be altered by knowledge of the histology
  27. Immunohistochemistry in adrenal mass?
    • Cortical tumors are positive for Inhibin α and Melan A 
    • Chromogranin is negative for cortical tumors, and almost alway positive for Pheochromocytom
    • Synaptophysin - positive in both cortical and pheochromocytoma 
    • Cytokeratin - strongly expressed by cortical tumors, negative in Pheo

    [@ CIMS - Cytokeratin, Inhibin, Melan A, Synaptophysin]
  28. SF1 Expression?
    The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling activity of genes related to the reproductive glands or gonads and adrenal glands

    SF1 positive means adrenocortical origin of tumor
  29. Assessment of functional status of adrenal mass?
    • NIH consensus  statement recommends metabolic testing for all adrenal incidentalomas. 
    • More than 10% of adrenal incidentalomas are metabolically active. 
    • Current practice is to test all new adrenal masses for cortisol and catecholamine hypersecretion.
    • Patients with history of hypertension -  aldosterone hypersecretion should also assessed
  30. Testing for cortisol hypersecretion?
    Three test are available 

    (1) LD-DST -  1mg dexamethasone at 11-12 PM, serum cortisol at 8-9AM, drug inducers decrease serum cortisol level 

    (2) a late-night salivary cortisol test - Because late-night serum cortisol measurements are impractical, salivary testing has gained acceptance, because salivary cortisol levels reflect near real-time serum cortisol levels, false positive in depression

    (3) a 24-hour UFC - not sufficiently sensitive to detect subclinical Cushing syndrome, test of choice for pregnant patients  

    • Endocrine Society recommend the use of either the LD-DST or the late-night salivary cortisol test to screen patients with adrenal  incidentalomas as part of a complete endocrinologist evaluation
    • Verify that exogenous steroids, including creams and nasal sprays, are not in use by the patient before testing.
  31. Testing for aldosterone secretion?
    Ratio of morning plasma aldosterone (ng/dL) to renin (ng/mL/hr) - ARR 

    Plasma aldosterone concentration (PAC) and PRA - (between 8 and 10 AM) 

    National Institutes of Health (NIH) 2002 - cutoffs of > 30 for the ARR and > 20 ng/dL for the PAC

    However, other institutions have recommended lowering the cutoffs to greater than 20 and greater than 15  ng/dL, respectively

    Lowest PRA value be set at 0.2 ng/mL/hr to avoid falsely elevated ratios. The concurrent elevated aldosterone level appears important for cases in which the ARR is elevated simply because of a low renin level
  32. Indication of evaluation of sex hormone level in adrenal lesion?
    Sex hormone levels are evaluated only in bilateral cases of adrenal mass, or ACC is suspected
  33. Testing for catecholamine hypersecretion?
    Free fractionated plasma metanephrines and the 24-hour urinary fractionated metanephrine test constitute the mainstay for pheochromocytoma testing

    2005 International Symposium on Pheochromocytoma concluded that one of these two tests should be used for initial diagnosis and screening for pheochromocytoma

    • Urinary fractionated metanephrines 
    • - 24 hour urine collection can be difficult, especially in children, urine collection may be inappropriate in patients in renal failure 

    • Plasma free metanephrines
    • - relatively new test with limited availability, applicable in patients with renal failure 

    • *Term “fractionated” is used if concentration values are reported for individual catecholamine or metanephrine compounds
    • Plasma metanephrine are in two forms - free or sulfate conjugated. Both of these metanephrines form the total metanephrine.
  34. Indication of surgery in adrenal incidentaloma?
    • • Functional adrenal mass - Cortisol, Pheo, Aldosterone
    • • Mass > 4 cm with exception of myelolipoma
    • • Imaging suggestive of malignancy (e.g., lipid poor, heterogeneous, irregular borders, infiltrates surrounding structures)
    • • That grows more than 1 cm in a year on follow up imaging
    • • Extremely large and/or symptomatic myelolipoma
    • • Isolated adrenal metastasis 
    • • During renal surgery for renal cell carcinoma 
    • • Failed neurosurgical treatment of Cushing disease, necessitating bilateral adrenalectomy
    • • Select patients with ectopic adrenocorticotropic hormone (ACTH) syndrome, requiring bilateral adrenalectomy 
    • • ACTH-independent macronodular adrenal hyperplasia (AIMAH)
    • • Primary pigmented nodular adrenocortical disease (PPNAD)
  35. Assessment and management of autonomous cortisol section in incidentaloma?
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Card Set
Three12 106B Pathophysiology, Evaluation and Medical Management of Adrenal Disorders
incidenteloma, ACC, adrenal insufficiency