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Adrenal cancer overview

Published: July 04, 2009. Updated: December 31, 2009

 

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Adrenal cancer specifically refers to malignant adrenal tumors, which include neuroblastoma, adrenocortical carcinoma, and a minority of adrenal pheochromocytomas.

Incidence

  • Adrenocortical carcinoma is a rare tumor that affects only up to 2 persons per one million population.
  • Adrenocortical carcinoma accounts for 0.2% of all cancer-related deaths.

Gender

  • The male-to-female ratio is approximately 1:3.
  • Female patients are more likely than male patients to have an associated endocrine syndrome.
  • Nonfunctional Adrenocortical carcinomas are distributed equally between the sexes.
  • Male patients tend to be older and have a worse overall prognosis than female patients.

Age

  • It occurs in 2 major peaks: in the first decade of life and again in the fourth to fifth decades.
  • The median age is 44 years at diagnosis but the tumor occurs at all ages. The median age at presentation for children is 4 years.

Race and ethnicity

Adrenocortical cancer has no racial or ethnic predilection.

Geography

Some reports suggest an inordinately high frequency of cases among children in southern Brazil, for unknown reasons.

Causes and risk factors

No established risk factors are available for adrenal cancer. This is due to the fact that they are very rare which has made epidemiological studies unfruitful and difficult.

Chromosomal abnormalities

At the genetic level adrenal neoplasms show the following abnormalities.

  • Mutation or loss of p53 tumor suppressor gene which is present on chromosome 17 (17p). Adrenocortical cancer is a frequent occurrence in Li-Fraumeni syndrome which harbors a germline mutation in TP53.
  • Frequent loss of heterozygocity on chromosomes 11p and 13q. Adrenocortical cancer is seen in Beckwith-Wiedemann syndrome which involves a mutation in 11p15.

Smoking

Risk for developing the disease is increased in men who smoked more than 25 cigarettes daily (odds ratio 2:0; 95% confidence interval [CI]1.0-4.4).

Contraceptive pills

Women who used oral contraceptives, especially before age 25 have an increased risk in developing adrenocortical cancer (odds ratio 1:8; 95% CI1.0 3.2).

Symptoms and signs

Functioning tumors

Approximately 60% of patients present with symptoms related to excessive hormone secretion (cortisol, aldosterone, androgens and estrogen). Functioning tumors may present with any of the following hormonal syndromes:

  • Hypercortisolism (Cushing's syndrome) is the most common presentation (30%). It is characterized by rapid onset of development of symptoms of Cushing's syndrome (3 months). Symptoms include: weight gain, muscle weakness, easy bruising, irritability, and insomnia. Other symptoms may include those related to the androgenic effects of cortisol.
  • Virilization (30%): hirsutism, acne, and irregular menses or amenorrhea in women. They may be more marked and include male-pattern baldness, deepening voice, breast atrophy, clitoral hypertrophy, decreased libido. In males manifestations of androgen excess are less noticeable. It can lead to precocious puberty in males.
  • Feminization (10%): Feminizing tumors in women cause breast tenderness and dysfunctional uterine bleeding. It can cause precocious puberty in females. These tumors in men are associated with gynecomastia, breast tenderness, testicular atrophy, and decreased libido.
  • Hyperaldosteronism (2.5%): Aldosterone-producing adrenal cortical carcinomas are extremely rare. Patients present with hypertension and hypokalemia, which are typical clinical manifestations of primary aldosteronism. Compared to patients with benign aldosteronesecreting adenomas, those with carcinoma have larger tumors, higher aldosterone levels, and more severe hypokalemia. Evaluation should include measurement of serum electrolytes, aldosterone, and plasma renin levels. Findings include severe hypokalemia with potassium levels below 2.5 mEq/L, hypernatremia, and metabolic alkalosis. Serum aldosterone levels are high, and plasma renin levels are suppressed.
  • Combined hormonal excess (35%).

Nonfunctioning tumors

40% of cases are nonfunctioning carcinomas and thus may be heralded by symptoms of local invasion by tumor or by metastases. Most present with large abdominal masses, abdominal pain or weight loss.

Metastasis

  • Lung 45%
  • Liver 42%
  • Lymph nodes 24%
  • Bone 15%
  • Pancreas 12%
  • Spleen 6%
  • Diaphragm 12%
  • Miscellaneous (brain, peritoneum, skin, palate) 12%

Diagnosis

CT scans

CT can reliably distinguish cortical hyperplasia from tumor.

Incidentally discovered adrenal masses found in 1 to 3% of patients undergoing abdominal scans by computed tomography (CT). Most of these masses are benign, and adrenal cortical adenomas are 60 times more common than primary carcinoma.

Criteria suspicious of malignancy

  • The typical malignant case is characterized by a large unilateral adrenal mass with irregular edges.
  • Masses less than 3 cm in diameter are usually benign; in contrast, the probability that the mass is malignant is generally increased when it measures more than 6 cm. There is uncertainty with masses measuring 3 to 6 cm and concern that adrenal cortical carcinomas could be missed in early stages of development.
  • The presence of contiguous adenopathy serves as corroborating evidence.

Rationale

  • Targeted CT scans of the adrenal using 3- to 5-mm sections offer the best resolution and are particularly useful in detecting tumors that are 1 cm or smaller.
  • CT has great sensitivity (more than 95%); however, it lacks specificity.
  • CT can be used to image the primary tumor plus local and distant metastases in cancer.

MRI

MRI is able to distinguish among adenoma, carcinoma, and pheochromocytoma. Signal loss on chemical shift MRI occurs in adrenal cortical cancer.

  • The sensitivity of MRI for distinguishing benign from malignant masses was 89%, specificity was 99%, and accuracy was 94%.

PET scans

Positron emission tomography (PET) studies have used fluorodeoxyglucose or methionine C 11. A better imaging tracer for adrenal tumors may be 11C-metomidate. Although this tracer does not distinguish benign from malignant tumors, the presence of uptake in extra-adrenal sites may indicate recurrence of disease or metastasis in patients who have undergone resection of an adrenocortical carcinoma.

  • The sensitivity was 100% and the specificity was 95%.

Ultrasonography

This test has less sensitivity in detecting adrenal tumors and is highly user-dependent in its interpretation and quality of results. It has particular utility, however, in the follow-up of previously detected incidentalomas.

Malignant lesions vary in echo texture and are heterogeneous in appearance, with focal or scattered echopenic or echogenic zones representing areas of tumor necrosis, hemorrhage, or calcification.

Angiography and adrenal venography

Selective angiography and adrenal venography have a very small role in the diagnostic workup of adrenal masses. They may be helpful in identifying smaller lesions and for distinguishing tumors of the adrenal gland from tumors of the upper pole of the kidney. Vena caval contrast studies and angiography may provide additional staging information and allow for a more complete preoperative assessment.

Scintigraphy

Most adrenal cortical carcinomas fail to image with 131I-6 beta-iodomethylnorcholesterol scintigraphy. Because cortisol production suppresses ACTH secretion and the function of the contralateral adrenal gland, patients with cortisol-producing adrenal cortical carcinomas fail to show an image either at the site of the tumor or the contralateral gland. CT and iodomethylnorcholesterol scintigraphy can be used together in the diagnosis of small (less than 4 cm) euadrenal masses. Concordant images (CT image and increased uptake on the same side) are benign in 100% of cases, whereas discordant images (a CT tumor image on one side and increased uptake on the contralateral side) are malignant in 73% of the cases.

Adrenal function tests

Other investigations may include appropriate endocrine studies. The steroid profile in serum or urine can help distinguish between benign and malignant adrenal cortical tumors because of the presence of intermediary precursors in the steroid biosynthesis pathway or their metabolites in patients with malignant neoplasms.

Fine-needle aspiration and core biopsy

Never perform fine-needle aspirations on any adrenal mass without first definitively excluding a pheochromocytoma; otherwise, the procedure may precipitate a potentially fatal crisis.

Because the histologic analysis of these masses may be unreliable, fine and/or core tissue needle aspiration biopsies (percutaneous route) generally are not recommended except for possible metastatic deposits.

The fine-needle and/or percutaneous core biopsies may be CT-guided or ultrasound-guided. Presently, the only setting where this is justified is in the evaluation of patients with a known malignancy, in order to exclude adrenal metastases.

Pathology

Histologic Findings: A specific histologic diagnosis may be difficult in a case that is lacking clinical evidence of metastasis. Some of the macroscopic features that suggest malignancy include a weight of more than 500 g, the presence of areas of calcification or necrosis, and a grossly lobulated appearance. Most adrenal cortical carcinomas are large, but size alone either has no effect on survival time or has minimal effect.

Adrenal adenomas are usually well encapsulated and homogeneous on cross-section and do not metastasize; in contrast, adrenal carcinomas are large, multilobulated tumors with areas of necrosis and evidence of capsular and vascular invasion.

Various systems of histologic diagnosis have been proposed for adrenal cortical carcinomas, but the most commonly used system is the one described by Medeiros andWeiss. Nine histologic findings have been described:

  • High nuclear grade
  • Mitotic grade greater than 5 mitoses/50 high-power fields (HPF)
  • Atypical mitotic figures
  • Eosinophilic tumor cell cytoplasm
  • Diffuse architecture
  • Necrosis
  • Venous invasion
  • Sinusoidal invasion
  • Capsular invasion

Malignant tumors meet four or more of these histologic criteria. The three most commonly found are a mitotic rate greater than 5 mitoses/50 HPF, atypical mitotic figures, and venous invasion. The mitotic rate is an important criterion not only for distinguishing malignant from benign tumors, but also for predicting the clinical virulence of adrenal cortical carcinomas.

Patients with carcinomas having a high mitotic rate (more than 20 mitoses/10 HPF) have a shorter disease free survival period than patients whose carcinomas have a low mitotic rate (less than 20 mitoses/10 HPF).

Depending on the degree of cell differentiation, adrenal cortical carcinomas have been classified as well-differentiated or anaplastic. Although well-differentiated carcinomas may have a less aggressive course than the anaplastic tumors, cell differentiation may not predict survival independently of the mitotic rate.

Microscopically, adrenocortical carcinoma is a malignant neoplasm of the adrenal cortical cells demonstrating partial or complete histological and functional differentiation.

  • Differentiated: Functioning tumors are usually differentiated. Approximately 60% of adrenocortical carcinomas produce hormones.
  • Anaplastic: Production of hormones by anaplastic tumors is rare.
  • Hormonal.

Staging and prognostic factors

Staging Techniques

CT or MRI can image the extent of disease and should include the chest to rule out pulmonary metastases.

If the inferior vena cava is involved, either a cavagram or ultrasonography is useful to assess extent of tumor.

Evaluation of local extent

For the evaluation of the local extent of the disease and regional lymph node involvement please refer to CT and MRI imaging in the diagnosis section.

Pulmonary metastasis (45%)

1. Chest x-ray

A chest radiograph in two planes is indicated on a regular basis to screen for metastatic disease in the follow-up of patients with primary tumors that preferentially spread to the lungs.

Benefits

  • Sensitivity and specificity for chest radiography were 50 and 90%, respectively for nodules >5mm.
  • It more accurately detects a 1-cm nodules 1cm or greater.

2. Chest CT

When metastatic nodules are identified, helical computed tomography (CT) of the chest should be performed to assess their number and characteristics.

Benefits

  • A high-resolution CT scan can identify nodules 3 mm in diameter.
  • CT has an overall sensitivity 62% in detecting pulmonary nodules (all sizes). However it underestimated the extent of the disease in 25%, and overestimated the extent of the disease in 14%.
  • Sensitivity is increased to 95% for intrapulmonary nodules = 6 mm and 100% for intrapulmonary nodules > 10 mm.

The limitations of CT scan in this study were mainly associated with pleural-based nodules and intrapulmonary nodules < 6 mm.

Liver metastasis (40%)

1. Ultrasonography of the liver

Ultrasonography is inexpensive and readily available, but its value compared to single-slice helical CT (SSCT), MSCT, and MRI is limited as a consequence of reduced sensitivity and specificity. In general, the US appearance of liver metastases is nonspecific.

Benefits

  • Sensitivity is operator dependent. It is valuable, inexpensive, quick, and portable, and it can depict lesions as small as 1 cm with a sensitivity approaching 80%.
  • The specificity of US in detecting liver metastases is poor, and its overall false-negative rate is 50%. However, the presence of multiple hepatic nodules of different sizes within the liver is nearly always due to metastases.

2. Abdominal CT

CT is the most sensitive technique for the detection of liver metastases.

Benefits

  • Contrast-enhanced scans offer a high degree of sensitivity, as high as 80-90%. The specificity is 99%.

Staging of adrenal cancer

  • Please refer to the TNM staging system for adrenocortical cancer

Prognostic factors (Risk factors for recurrence)

The two main prognostic factors for adrenal cancer are completeness of resection and stage of disease. Patients with evidence of invasion into local tissues or spread to lymph nodes have a worse prognosis.

Patients with carcinomas having a high mitotic rate (more than 20 mitoses/10 HPF) have a shorter disease free survival period than patients whose carcinomas have a low mitotic rate (less than 20 mitoses/10 HPF).

Prognostic factors currently under investigation

  • DNA ploidy

Treatment

For stages I to III, the mainstay of treatment is complete surgical resection, with or without regional lymph node dissection.

Stages I and II

Radical, complete resection of all cancer is critical for prolonged survival and potential cure. There is no consensus on effective adjuvant therapy.

Rationale

  • The median postoperative disease-free survival is only 12 months.
  • The overall 5-year survival rate is between 20% and 35%.
  • In one series, the 6-year survival after complete resection of all tumor was 60%.
  • Adrenal cancer resection can be performed with acceptable morbidity and an operative mortality of 3%.

Tumor size, hemorrhage, and mitotic count correlate with survival rates for patients undergoing curative resection. Tumor size less than 12 cm, mitotic rate less than six per high-power field, and absence of intratumoral hemorrhage are each associated with improved survival.

Irresectable localized lesions may undergo radiation therapy. Localized lesions may also undergo palliative excision especially if the lesion is functioning.

Stage III

The treatment of patients who have tumors with local invasion, but without clinically enlarged regional lymph nodes, is complete surgical removal. For those with enlarged regional lymph nodes, a lymph node dissection should be included in the procedure. These patients are at high risk for disease recurrence and should be considered for enrollment in a clinical trial.

If the carcinoma is intimately associated with the adjacent organs like the kidney, concomitant nephrectomy may be necessary. Even tumor thrombus within the inferior vena cava is not a contraindication to resection.

Irresectable localized lesions may undergo radiation therapy. Localized lesions may also undergo palliative excision especially if the lesion is functioning.

Stage IV

Chemotherapy

Unresectable or widely disseminated tumors may be palliated by antihormonal therapy with mitotane, systemic chemotherapy

1. Single agent chemotherapy: Op-DDD (mitotane) is the chemotherapy drug that is most often used for adrenal cancer. It is administered at a dosage of 2 to 6 g daily in two or three divided doses and increased until adverse reactions occur.

Adverse reactions include gastrointestinal toxicity, neuromuscular toxicity, and skin rash. Mitotane is associated with prolongation of the bleeding time and abnormal platelet aggregation. A decrease in urinary 17-hydroxysteroids and 17-ketosteroids occurs in most patients due to its effect on steroid metabolism.

Rationale

  • Partial responses occur in approximately 35% of patients and complete responses have been reported. There have been a few long-term survivors treated with mitotane.

2. Combination chemotherapy: Other chemotherapy has been combined with mitotane treatment. Patients with advanced adrenal cortical carcinoma have been treated with etoposide (VP-16) 100 mg/m2/d, cisplatin, 100 mg/m2 every 4 weeks, and mitotane.

Rationale

  • Mitotane, cisplatin and etoposide had a response rate of 33% with some complete responses.
  • Mitotane, etoposide, doxorubicin, and cisplatin has an overall response rate of 54% with some complete responses. It was proposed that this regimen may be able to reverse multidrug resistance.

See also: Chemotherapy regimens for adrenal cancer

Surgery

Prolonged remissions have been reported after resection of hepatic, pulmonary, and cerebral metastases from adrenal cortical carcinoma.

Radiotherapy

Palliation of bony metastases may be achieved by radiation therapy.

Recurrent cancer

Surgery

Recurrent or metastatic adrenal cortical cancer should also be resected, and reports suggest that radiofrequency ablation may be able to control recurrent tumor both inside and outside the liver.

  • Patients with recurrent adrenal cortical carcinoma that can be surgically resected have a 5-year survival rate of 50% versus 8% for nonoperable cases.

Radiation

Control of recurrent tumor can be achieved by radiofrequency ablation.

Abdominal radiation therapy may be useful in 65% of patients with local recurrences not amenable to resection, and the treatment has even relieved bowel obstruction.

Follow up

Patients should undergo monitoring of steroid hormone levels postoperatively. Measurement of urinary levels requires switching the glucocorticoid replacement therapy from hydrocortisone to dexamethasone. CT and MRI are also used to detect local recurrences and pulmonary metastases. If a localized recurrence is detected, it should be removed surgically.

Prognosis and survival

Overall 5-year survival for tumors resected for cure is approximately 40%. Median survival for patients with stage IV tumors is usually less than 9 months.


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