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Primary Adrenal Malignancy
Introduction
Adrenal masses are found in 2% to 9% of adults. In patients with a known history of malignancy, incidentally detected adrenal masses may be either benign or metastastic (the incidence of metastasis in this scenario varies from 25% to 72%, depending upon the type of primary tumor).
In patients with no history of malignancy, the vast majority of adrenal masses tend to be benign adenomas, followed by other benign lesions such as myelolipomas, hematomas, cysts, and granulomatous lesions. The primary adrenal neoplasms, adrenal cortical carcinoma (ACC) and malignant pheochromocytoma, are relatively rare cancers discussed separately in this chapter. Both are usually diagnosed at advanced stages of disease and are associated with relatively poor survival rates.
I
Adrenal Cortical Carcinoma
Epidemiology and Risk Factors
ACC has a population incidence of 0.5 to 2 per million, with an annual incidence of 0.78 per million. The age distribution is bimodal, with the first peak in children before the age of 5 years and a second peak in adults in the fifth to sixth decades. The mean age at diagnosis in adults is approximately 45 years. ACC is more common in female adults than in male adults, with a ratio of 1.5:1, and is slightly more common on the left side. Bilateral tumors are uncommon.
Most cases of ACC are sporadic, with no clear etiology. Smoking and oral contraceptives may be risk factors. ACC is associated with complex hereditary syndromes in some patients, including Li–Fraumeni syndrome, Carney complex, Beckwith–Weidmann syndrome, multiple endocrine neoplasia type I, and Gardner syndrome. Sporadic cases are associated with mutations of the tumor suppressor gene P53 .
Anatomy and Pathology
Anatomy
The adrenal glands are located in the retroperitoneum in the superior aspect of the perirenal space and are bounded by the perirenal fascia. The glands are composed of medial and lateral limbs that converge upon a central ridge. The right adrenal gland is usually the more superiorly located, lying just above the right kidney, posterior to the liver and inferior vena cava (IVC) and lateral to the right diaphragmatic crus. The left gland lies anteromedial to the superior pole of the left kidney, posterior to the pancreatic tail and splenic vessels, and lateral to the left diaphragmatic crus.
Arterial supply to the glands is provided by superior, middle, and inferior adrenal arteries. The superior adrenal arteries arise from inferior phrenic arteries, the middle adrenal arteries arise from the aorta, and the inferior adrenal arteries arise from the renal arteries. The right adrenal vein usually drains directly into the IVC, but in 8% to 21% of people it forms a common trunk with an accessory hepatic vein before draining into the IVC. The left adrenal vein drains into the left renal vein. Both glands have lymphatic drainage via the retrocrural, upper caval, and aortic lymph nodes.
The adrenals have an outer cortex that accounts for 90% of the volume of the adult adrenal gland. The cortex is derived from the mesoderm and is part of the endocrine system, secreting androgens and the corticosteroids cortisol and aldosterone ( Fig. 22.1 ). ACC arises from the cortex.
Key Points
Pathology
On gross pathology, ACC is usually a bulky, coarsely lobulated, yellow to tan tumor with an average weight range of 510 to 1210 g. Areas of necrosis and hemorrhage cause a variegated appearance.
ACC is most commonly diagnosed histopathologically using the Weiss criteria. The nine criteria are (1) nuclear grades 3 to 4, (2) mitotic rate greater than five per 50 high-power fields, (3) atypical mitoses, (4) tumors with 25% or fewer clear cells, (5) diffuse architecture, (6) microscopic necrosis, (7) venous invasion, (8) sinusoidal invasion, and (9) capsular invasion. An adrenal mass is considered malignant if it is positive for three or more of these criteria.
Pathologic features with prognostic significance for ACC include tumor size, the presence of intratumoral hemorrhage, and the number of mitotic figures. Primary tumors larger than 12 cm have a 5-year survival rate of 22% versus 53% for smaller tumors. Intratumoral hemorrhage is a negative prognostic factor compared with tumors without hemorrhage. Patients with a mitotic rate of greater than 20 per 50 high-power fields have a median survival time of 14 months compared with 58 months for mitotic rates lower than 20.
ACCs do not have pathognomonic immunohistochemical findings, although they frequently stain positive for vimentin and negative for cytokeratin. At a molecular level, over 85% of ACCs may demonstrate loss of heterozygosity in 17p13, whereas overexpression of insulin-like growth factor can be seen in 90% of ACCs.
Key Points
Pathology of Adrenal Cortical Carcinoma
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Arises from the adrenal cortex.
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Usually a large tumor with internal hemorrhage and necrosis.
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Weiss criteria used for histopathologic diagnosis.
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Large size, internal hemorrhage, and mitotic rate greater than 20 per 50 high-power fields are associated with poorer outcomes.
Clinical Presentation
The presenting symptoms of ACC depend on tumor size, the presence of metastases, and functional status. Functional tumors account for 50% to 79% of ACCs, and they can secrete cortisol, estrogens, androgens, or aldosterone. Cortisol hypersecretion is the most common and presents as Cushing syndrome with weight gain, proximal muscle weakness, hyperglycemia, hypertension, and hypokalemia. Aldosterone hypersecretion causes hypertension and hypokalemia, but these symptoms are more commonly seen with cortisol excess. Virilization can be seen in women with androgen-secreting tumors, whereas men with estrogen-secreting tumors may develop symptoms of feminization.
Nonfunctional tumors can produce symptoms related to mass effect, including abdominal or back pain, early satiety, nausea, vomiting, and/or a palpable mass. They can also present with fever and weight loss. Nonfunctional tumors tend to present in older patients, with a male predominance. Nonfunctional masses can be discovered incidentally in patients who are undergoing imaging for other reasons. Finally, patients can present with symptoms related to metastatic disease.
Staging Classification
The tumor-node-metastasis (TNM) staging system for adrenal tumors was established in 2004 by the Union for International Cancer Control and the World Health Organization.
The TNM classification system is based on the primary tumor size and local invasion (T), regional lymph node involvement (N), and the presence or absence of metastatic disease (M). Table 22.1 , Table 22.2 (on p. 366).
Table 22.1
Tumor-Node-Metastasis Staging of Adrenal Cortical Carcinoma
From Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017:911–918.
| T1 | Tumor ≤5 cm, no invasion |
| T2 | Tumor >5 cm, no invasion |
| T3 | Tumor extends outside of adrenal gland into the surrounding fat |
| T4 | Tumor invades adjacent organs |
| N0 | No involvement of regional lymph nodes |
| N1 | Positive regional lymph node(s) |
| M0 | No distant metastases |
| M1 | Distant metastases |
Table 22.2
Staging of Adrenal Cortical Carcinoma
From Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual . 8th ed. New York: Springer; 2017:911–918.
| Stage I | T1, N0, M0 |
| Stage II | T2, N0, M0 |
| Stage III | T1, N1, M0 |
| T2, N1, M0 | |
| T3, N0, M0 | |
| Stage IV | T3, N1, M0 |
| T4, N0–N1, M0 | |
| Any T, any N, M1 |
Stage I and stage II disease are localized to the adrenal gland. Stage III disease is locally invasive or has regional nodal metastasis. Stage IV disease is locally invasive with regional nodal involvement, invades adjacent organs, or is metastatic ( Fig. 22.2 ).
ACC has a grim survival rate, with a 5-year overall survival rate of only 32% to 48%. This is because approximately 70% of ACCs present at stages III and IV. Stage I and stage II disease have a 5-year survival rate of 62% compared with 7% for stage IV disease.
Patterns of Tumor Spread
ACCs can spread by direct extension, first into the surrounding fat and then into adjacent structures such as the liver and kidneys ( Fig. 22.3 ). Tumor thrombus can involve the adrenal and renal veins and IVC ( Fig. 22.4 ). Metastases from hematogenous dissemination most commonly involve the bones, liver, and lungs ( Fig. 22.5 ). ACC also spreads through the lymphatic system to involve the retrocrural, upper caval, and aortic nodes ( Fig. 22.6 ). Simultaneous hematogenous and lymphatic dissemination frequently occurs ( Fig. 22.7 ).
Key Points
Imaging
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