David T. Hughes
Paul G. Gauger
Presentation
A 69-year-old female was found to have an incidental 6.2 × 4.0 × 3.8 cm left adrenal mass on noncontrast CT scan of the abdomen obtained for abdominal pain. The patient has a recent history of new-onset hypertension, 25-lb weight loss and complaints of fatigue, muscle weakness, poor appetite, emotional lability, and insomnia. She has no significant family history of endocrine disease and no prior history of malignancy.
Differential Diagnosis
Nearly 4% of abdominal CT scans obtained for another indication demonstrate an incidental adrenal mass. Adrenal tumors can also be detected clinically due to manifestations of tumor hormone production. Of all adrenal masses, 80% are nonfunctional adenomas, while 15% are functional with laboratory evidence of hormonal overproduction. Functional tumors include pheochromocytomas, aldosteronomas, and cortisol-producing adenomas. In patients with a previous or present history of malignancy, adrenal metastasis should be considered in the differential. Adrenal cortical cancer (ACC) is a rare disease that can also be functional but should be considered on the differential of any adrenal mass, especially tumors larger than 4 cm. Less common benign masses include myelolipoma/lipoma, ganglioneuroma, epithelial cyst, and pseudocyst.
Workup
Key questions are (1) Is the tumor hormonally active? (2) Does it have radiologic characteristics of malignant lesion? (3) Does the patient have a history of previous malignancy?
On physical examination, evaluate for signs of hormonal excess including virilization, cushingoid appearance, and hypertension, which suggest functional tumors. Large, advanced ACC can present with a palpable abdominal mass or an enlarged liver due to metastases.
Laboratory Tests for Adrenal Incidentaloma
1. Plasma fractionated metanephrines or 24-hour urine metanephrines—must rule out pheochromocytoma for any adrenal mass; pheochromocytomas generally demonstrate metanephrine levels >2 times the upper limit of normal; ACC does not produce catecholamines in high amounts.
2. Serum potassium and aldosterone and plasma renin activity—rare cases of ACC are aldosterone producing; aldosterone to renin ratio >20 for aldosterone-secreting tumors.
3. 24-hour urinary-free cortisol or dexamethasone suppression test (1 mg DM at 11 pm, serum cortisol at 8 am). Degree of hypercortisolism cannot distinguish benign from malignant tumor. Low ACTH level will confirm corticotropin-independent hypercortisolism.
Additional Laboratory Tests for Concern of Adrenal Cancer
4. DHEA-S—high levels can be associated with ACC; virilization is the clinical manifestation of androgen overproduction
Imaging Studies
1. CT—adrenal protocol CT with thin cuts through the adrenals; includes noncontrast phase, contrast-enhanced phase at 60 seconds postcontrast and delayed phase at 10 minutes or 15 minutes postcontrast (depending on specific protocol)
Adenoma (Typical characteristics)
· Low attenuation (<10 Hounsfield units on noncontrast phase)
· Rapid washout (>60% washout at 15 minutes postcontrast)
· Smooth borders
ACC (Typical characteristics, Figure 1)
· Size >4 cm
· High attenuation (>10 Hounsfield units on noncontrast phase)
· Enhancement on contrast-enhanced phase
· Delayed contrast washout (<50% washout at 10 minutes postcontrast)
· Calcifications
· Irregular shape
· Central necrosis
FIGURE 1 • CT with oral and IV contrast and FDG-PET demonstrating left adrenocortical cancer with central necrosis.
2. MRI—useful in distinguishing between adenoma (lipid rich—signal intensity loss on out-of-phase sequences), pheochromocytoma (high intensity on T2 images) and ACC (central necrosis, hemorrhage, calcification, local invasion, IVC tumor thrombus)
3. FDG-PET—pheochromocytoma and ACC are FDG-avid (adrenal to liver max SUV ratio >1.45) (Figure 2); also helpful in evaluating for metastatic disease
FIGURE 2 • Right adrenalectomy. (Illustration courtesy Lippincott Williams & Wilkins, from Surgical Endocrinology by Gerard M. Doherty and Britt Skogseid.)
This patient’s laboratory studies showed elevated 24-hour urine cortisol (240 µg/24 h [normal 20 to 90 µg/24 h]) and nonsuppressible cortisol level with low-dose Dexamethasone (12 µg/dL [normal suppression <2 µg/dL]). Adrenal protocol CT demonstrated a left adrenal mass 6.2 × 4.0 × 3.8 cm that was heterogeneous with irregular borders and central necrosis as well as two 1-cm low attenuation liver lesions. FDG-PET was obtained to further characterize the hepatic lesions, which demonstrated an intensely FDG-avid left adrenal mass with no FDG avidity in the liver lesions and no distant metastases.
Diagnosis and Treatment
Adrenal tumors with evidence of hormone production or suspicion of ACC should be considered for adrenalectomy. Large adrenal masses, those with evidence of liver or pulmonary metastasis, viruilizing tumors or those with imaging characteristics outlined above should be considered high risk for ACC. Percutaneous biopsy is contraindicated given risk of tumor seeding and lack of additional information provided, except when there is a question of metastatic adrenal mass in a patient with a history of extra-adrenal malignancy. Prognosis for ACC is dependent on treatment at an early stage and complete surgical excision with negative margins. In patients with hormone-producing tumors with metastatic disease, surgical debulking can provide palliation from hormone-related symptoms. This not typically considered if >90% of the tumor burden cannot be removed with the palliative operation. In nonfunctioning tumors with metastatic disease or those where >90% resection is not possible, primary treatment with systemic chemotherapy and external-beam radiation is indicated.
This patient had no evidence of local invasion or distant metastasis on preoperative imaging studies. There was high suspicion for cortisol-producing ACC given imaging and biochemical characteristics. Open left adrenalectomy was discussed with the patient and was scheduled after a thorough preoperative evaluation.
Surgical Approach to Adrenalectomy
Adrenal masses that are at all suspicious for ACC based on clinical presentation or imaging characteristics should not be approached laparoscopically given higher rates of early local recurrence due to inadequate margins and tumor implants. The goals of surgical management include complete tumor resection with negative margins and control of tumor hormone production. Patients should be prepared for an en bloc resection of large tumors with consideration of bowel preparation and evaluation of renal function. Preoperative administration of splenectomy vaccinations should be considered for left-sided tumors. Potential for IVC resection, tumor thrombectomy, or hepatic resection should be considered. Cortisol-producing tumors should be treated with perioperative glucocorticoid supplementation due to suppression of HPA Axis. Hypokalemia and hypertension with aldosterone-secreting tumors should be treated with spironolactone preoperatively (Table 1).
TABLE 1. Key Technical Steps and Potential Pitfalls to Open Adrenalectomy for ACC
FIGURE 3 • Left adrenalectomy. (Illustration courtesy Lippincott Williams & Wilkins, from: Surgical Endocrinology by Gerard M. Doherty and Britt Skogseid.)
Special Intraoperative Considerations
Discovery of invasive characteristics or suspicion of ACC during laparoscopic adrenalectomy for a suspected adrenal adenoma or benign tumor should prompt conversion to open technique to obtain adequate resection margins. Right-sided ACC can invade into the IVC and require IVC resection or tumor thrombectomy. Conversion to thoracoabdominal incision to obtain supradiaphragmatic control of the IVC or cardiopulmonary bypass maybe required for extensive IVC involvement.
The patient underwent uneventful open left adrenalectomy via a subcostal incision after preparation with splenectomy vaccines and perioperative “stress-dose” hydrocortisone. The tumor was well localized without surrounding organ invasion. Final pathology demonstrated a 6-cm ACC with capsular invasion, focal extra-adrenal extension, negative margins and was classified as low grade (8/50 mitoses per high powered field). By AJCC staging, the patient was classified as having Stage III (pT2N0M0) because of extra-adrenal extension (Table 2).
TABLE 2. Adrenal Cortical Cancer AJCC Staging System
Postoperative Management
Routine postoperative management should include monitoring for hypoadrenalism manifesting as nausea, vomiting, abdominal pain, hypotension not responsive to fluid resuscitation, hypoglycemia, or hyperkalemia. Following complete resection, cortisol-producing ACC patients should undergo slow wean of glucocorticoid supplementation over a prolonged period of 12 to 18 months. However, in patients with incomplete resection and residual cortisol-producing ACC after operation, exogenous steroids may not be necessary.
Adjuvant treatment includes external-beam radiation for patients with positive or close margins or extra-adrenal extension to decrease local recurrence. A multistudy analysis of the use of mitotane for ACC patients has demonstrated an 11% complete response and a 52% partial response rate; however, no significant improvements in survival have been shown. Treatment with high-dose corticosteroids (>50 mg hydrocortisone daily) is required during mitotane treatment to avoid hypoadrenalism and Addison’s crisis due to its nonspecific adrenal suppressive effects. Cytotoxic chemotherapy regimens including doxorubicin, 5-fluorouracil, Adriamycin, and methotrexate are used for treatment of metastatic disease.
Recurrence occurs in two-thirds of patients typically in the first 1 to 2 years following surgical resection. Prognosis is based on stage of disease with Stage I and II patients having a 50% 5-year survival, while Stage III and IV patients or those with positive margins have a mean survival of 8 to 10 months. Postoperative surveillance initially includes chest/abdomen/pelvis CT every 3 months. FDG-PET is useful for restaging purposes and to delineate metastases, which typically have high standardized uptake values (SUV).
The patient in this scenario was recommended external-beam radiation and adjuvant mitotane therapy given the presence of extra-adrenal extension and Stage III disease but refused given concern for side effects. She elected to undergo routine CT imaging surveillance every 3 months.
TAKE HOME POINTS
· Virilizing features, mixed cortisol and aldosterone hypersecretion, and heterogeneous or large adrenal tumors (>4 cm) should raise suspicion of ACC.
· Percutaneous biopsy of adrenal tumors is not recommended except for suspicion of metastatic adrenal tumors in patients with a history of previous malignancy after biochemically ruling out pheochromocytoma.
· Laparoscopic adrenalectomy is NOT recommended for ACC given higher local recurrence rates due to positive or close margins.
· Complete resection often requires en bloc resection of kidney, spleen, pancreas, liver, or IVC for negative margins.
· Overall prognosis remains poor with overall 5-year survival of 25%.
SUGGESTED READINGS
Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab. 2006;91(6):2027–2037.
Broome JT, Gauger PG. Surgical techniques for adrenal tumors. Minerva Endocrinol. 2009;34(2):185–193.
Clark OH, Benson AB, Berlin JD, et al. NCCN clinical practice guidelines in oncology: neuroendocrine tumors. J Natl Compr Canc Netw. 2009;7(7):712–747.
Dackiw AP, Lee JE, Gagel RF, et al. Adrenal cortical carcinoma. World J Surg. 2001;25:914–926.
Rodgers SE, Evans DB, Lee JE, et al. Adrenocortical carcinoma. Surg Oncol Clin N Am. 2006;15(3):535–553.