MR Wick, DL Cherwitz, RC McGlennen and LP Dehner

The diagnosis of adrenocortical carcinoma (ACC) is often difficult, because this tumor may present with direct extension into adjacent renal parenchyma or with metastatic disease. Renal cell carcinoma and other histologically similar tumors are potentially confused with ACC by conventional light microscopy, and their separation from the latter is often impossible without the aid of additional studies. Furthermore, the distinction between adrenal cortical adenoma and ACC may also be problematic. Because of these factors, the authors studied 10 cases each of ACC, adrenocortical adenoma, and renal cell carcinoma (RCC) immunohistochemically, in an attempt to develop objective parameters which may aid in this differential diagnostic dilemma. Nontrypsinized, formalin-fixed, paraffin-embedded specimens were used in all cases, and tissue from the adrenocortical tumors was also studied for intermediate filament content after protease digestion. All 20 nontrypsinized adrenocortical neoplasms were positive for vimentin, but not for cytokeratin, epithelial membrane antigen, or blood group isoantigens. Conversely, each of 10 cases of RCC expressed epithelial membrane antigen, cytokeratin, and blood group isoantigens, but none was immunoreactive for vimentin. Two adrenocortical carcinomas and three adenomas manifested cytokeratin positivity after trypsin digestion. There were no significant differences between the immunostaining profiles of ACC and adrenocortical adenoma, which suggest that this distinction must still rely upon clinical and morphologic criteria.

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What is cancer of the adrenal cortex?

Cancer of the adrenal cortex, a rare cancer, is a disease in which cancer (malignant) cells are found in the adrenal cortex, which is the outside layer of the adrenal gland. Cancer of the adrenal cortex is also called adrenocortical carcinoma. There are two adrenal glands, one above each kidney in the back of the upper abdomen. The adrenal glands are also called the suprarenal glands. The inside layer of the adrenal gland is called the adrenal medulla. Cancer that starts in the adrenal medulla is called pheochromocytoma and is discussed in a separate PDQ patient information summary.

The cells in the adrenal cortex make important hormones that help the body work properly. When cells in the adrenal cortex become cancerous, they may make too much of one or more hormones, which can cause symptoms such as high blood pressure, weakening of the bones, or diabetes. If male or female hormones are affected, the body may go through changes such as a deepening of the voice, growing hair on the face, swelling of the sex organs, or swelling of the breasts. Cancers that make hormones are called functioning tumors. Many cancers of the adrenal cortex do not make extra hormones and are called nonfunctioning tumors.

A doctor should be seen if the following symptoms appear and won’t go away:

If there are symptoms, a doctor will order blood and urine tests to see whether the amounts of hormones in the body are normal. A doctor may also order a computed tomography scan of the abdomen, a special x-ray that uses a computer to make a picture of the inside of the abdomen. Other special x-rays may also be done to tell what kind of tumor is present.

The chance of recovery (prognosis) depends on how far the cancer has spread (stage) and on whether a doctor was able to surgically remove all of the cancer

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A 43-year-old female patient underwent abdominal ultrasonography and CT scan because of uncharacteristic abdominal pain. A 3-cm homogeneous adrenal tumor was diagnosed. The endocrine tests revealed an adrenal preclinical Cushing’s syndrome (PCS). Due to the latent hormone excess we decided to operate on the adrenal tumor. Since the tumor was small, laparoscopic adrenalectomy was performed. Histological evaluation showed an adrenocortical tumor of undetermined nature. Four months later the patient presented with a metastasizing cortisol- and androgen-producing adrenocortical carcinoma (ACC). After pretreatment with ketoconazole to suppress the biosynthesis of adrenal steroids under substitution with hydrocortisone, we reduced the tumor load by surgery. Postoperatively we continued ketoconazole and started o,p’-dichlorodiphenyldichloroethane as well as chemotherapy with doxorubicin and suramin. However, the patient died from ACC 7 months after adrenalectomy. It is known from several reports that PCS may persist clinically silently or may progress to full-blown Cushing’s syndrome. This is the first time a malignant course of PCS is described. Independent of the initial therapeutic strategy of PCS, i.e. surgery or regular follow-up visits, we must be aware that also relatively small adrenal tumors can harbor malignancy.

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(ACC) is a cancer affecting the cortex, or outer layer, of the adrenal gland. It typically has a poor prognosis, partly because of the cancer and partly because it usually causes Cushing’s syndrome. With aggressive treatment, the five-year survival without recurrence of the disease is about 30%. About three percent of all cortical tumors are the malignant form of adrenocortical carcinoma.

The adrenal glands are also called the suprarenal glands, and are located just behind each kidney (making it easy for the cancer to metastasize there). The cells in the cortex produce cortisol and certain sex hormones like androgen. Symptoms of adrenocortical carcinoma may include abdominal pain, weight loss, and extreme weakness. Other, rarer symptoms include weak bones, diabetes, hirsutism (excess hair, esp. on the face), swelling of sex organs and breasts, and deeper voice.

Treatment for adrenocortical carcinoma involves a complete surgical excision of the cancer and sometimes the entire gland, as well as chemotherapy. Radiation therapy has been experimented with, but the results are unclear. While the cancer is still active, cortisol is heavily overproduced and may require suppression while the patient is waiting for surgery and chemotherapy.

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We present a case of aldosterone-secreting adrenocortical carcinoma with concomitant myelolipoma. To the best of our knowledge, this is the first such reported case. The patient was a 43-year-old man with severe hypertension. Clinical workup revealed an increased serum aldosterone level, hypokalemia, and metabolic alkalosis, and a left adrenal mass was found on computed tomography. The patient underwent a unilateral adrenalectomy, which led to improvement in blood pressure, the serum potassium level, and aldosterone concentration. The tumor weighed 70 g and measured 5.0 cm. On microscopic examination, we found necrosis, focal cytologic atypia, diffuse eosinophilic cells comprising more than 75% of the tumor, 5 to 7 mitotic figures per 50 high-power fields, rare atypical mitosis, and venous invasion. At the periphery of the tumor but within the capsule, microscopic areas of myelolipoma were seen. Ki-67 staining was positive in 20% of the tumor cells. Although rare, aldosterone-secreting carcinoma associated with myelolipoma should be included in the differential diagnosis of adrenal gland masses.

Adrenocortical carcinoma is rare, with an annual incidence of about 1 case per million population,¹ but it has a mortality rate of more than 50%.² Aldosterone-secreting adrenocortical carcinomas are even rarer, accounting for only 2% to 7% of adrenocortical carcinomas in the largest series reported in the literature.³

Myelolipoma is a benign tumor that has been reported in association with adrenal hyperplasia, adrenocortical adenomas, ganglioneuroma,^4,5 pheochromocytoma,⁵ and corticomedullary mixed tumor.⁶ Only 4 cases of adrenocortical carcinoma with concomitant myelolipoma have been reported in the medical literature. To the best of our knowledge, myelolipoma associated with adrenocortical carcinoma and hyperaldosteronism has not been reported previously. Thus, we describe the first case of aldosterone-secreting adrenocortical carcinoma with a myelolipomatous component.

REPORT OF A CASE

Clinical History

A 43-year-old obese man (body weight, 107.8 kg; height, 1.73 m) with a family history of hypertension presented at our emergency room with vertigo in December 2003. Severe hypertension (206/110 mm Hg) was subsequently diagnosed with laboratory study results consistent with hyperaldosteronism (serum aldosterone, 26.6 ng/dL; normal, 1–21 ng/dL), hypokalemia (potassium, 3.1 mEq/L; normal, 3.6–4.8 mEq/L), and metabolic alkalosis (bicarbonate, 38 mEq/L; normal, 22–29 mEq/L). The levels of other cortical hormones and their metabolites were within normal limits. The results of pheochromocytoma workup were negative.

Abdominal magnetic resonance imaging revealed a 4.3-cm nodular mass in the left adrenal gland. Computed tomography of the abdomen revealed a 4.5 × 4.2-cm nodular mass of mixed heterogeneity . The patient underwent an uneventful unilateral adrenalectomy in February 2004 with substantial improvements in blood pressure (143/91 mm Hg) and serum potassium and aldosterone concentrations. He was discharged several days later with triamterene, potassium chloride, and clonidine. No recurrence or metastasis was noted at the most recent follow-up visit in late May 2004. He had negative computed tomography findings and blood pressure of 143/84 mm Hg.

PATHOLOGIC FINDINGS

Gross Features

The left adrenal gland weighed 70 g and measured 5.0 × 4.4 × 4.0 cm. The adrenal gland was almost totally replaced by a well-encapsulated bosselated tumor. A small portion of compressed nonneoplastic adrenal gland was seen on the surface. The cut surface of the tumor was multinodular, yellow, and soft with extensive areas of hemorrhage and necrosis .

Microscopic Features

On microscopic examination, the tumor was entirely encapsulated by a fibrous capsule of variable thickness. The cells were arranged in a sheetlike or trabecular pattern separated by relatively thick fibrous bands. The tumor was composed of mostly (>75%) round eosinophilic (compact) cells, with scattered foci of clear cells. There were extensive areas of hemorrhage, focal areas of necrosis, and areas of marked cytologic atypia with giant cells that had large, irregular, hyperchromatic nuclei. Five to 7 mitotic figures were seen in 50 high-power fields, with rare atypical mitosis. Focal vascular invasion was identified, but capsular invasion was not seen. At the periphery of the tumor but within the tumor capsule were few microscopic foci of myelolipoma composed of mature adipose tissue and normal-appearing trilineage hematopoietic cells. The transition between the tumor cells and the adipocytes was abrupt. The adjacent nonneoplastic adrenal gland was unremarkable.

Immunohistochemical Findings

Immunohistochemical staining for cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, vimentin, S100 protein, melanin A, chromogranin, synaptophysin, inhibin, and Ki-67 was performed on paraffin-embedded tissue. The tumor cells were strongly positive for vimentin and focally positive for synaptophysin and showed a moderately proliferative rate with Ki-67 (staining in 20% of tumor cells). The tumor cells were negative for the remaining markers. The adipocytes were positive for S100 protein. The normal adjacent cortical cells were positive for inhibin and melanin A. Cells in the normal medulla stained positive for chromogranin, synaptophysin, and S100 protein.

COMMENT

More than half of adrenocortical carcinomas secrete hormones, most commonly cortisol, followed by androgens, estrogen, and aldosterone.⁷ Pure aldosterone-secreting adrenocortical carcinomas are extremely rare, with fewer than 30 well-documented cases reported in the medical literature.³ To our knowledge, this is the first reported case of a pure aldosterone-secreting adrenocortical carcinoma associated with myelolipoma.

Only 4 cases of adrenocortical carcinoma with a concomitant myelolipomatous component could be found in the medical literature.^5,8,9 Two cases⁸ were reported with 49 other adrenal cortical carcinomas without specific description of the cases. The third case⁹ was found during the autopsy of a 57-year-old woman with multiple endocrine neoplasia syndrome type 1, which included hyperparathyroidism due to parathyroid hyperplasia, Zollinger-Ellison syndrome secondary to multiple islet cell adenomas, a 2.0-cm pituitary adenoma associated with a meningioma, a 23-g left adrenal adenoma, and a 325-g right adrenocarcinoma associated with myelolipoma. The fourth case⁵ was a 24-year-old man with Cushing syndrome; the size and weight of the lesion were not available. The myelolipoma component in these last 2 cases was similar to that in ours in that it was a lesion at the periphery of the adrenocortical carcinoma. In our case, the transition between the carcinoma and the myelolipoma was abrupt, and in some areas, the tumor nests within the myelolipoma simulated extracapsular extension.

Myelolipoma is a benign tumor that usually does not secrete hormones; however, its associations with Addison disease, Cushing syndrome, hermaphroditism, virilism, and extreme obesity have been reported.^9,10 One case of hyperaldosteronism due to an adrenal adenoma combined with a myelolipoma has been reported,¹¹ but no cases of hyperaldosteronism secondary to a carcinoma with a myelolipoma have been reported. We believe that the elevated level of aldosterone found in our case was due to the adrenocortical carcinoma, not the myelolipoma. The pathogenesis of adrenal myelolipoma is unknown, and it is unclear in this case whether the myelolipoma was an incidental finding or was somehow related to the presence of the carcinoma or the obesity of the patient.

The main conditions to be considered in the differential diagnosis of myelolipoma are lipomatous metaplasia (presence of adipose tissue only), which has been found in the adrenal glands and is associated with pseudocysts; hyperplasia; primary pigmented nodular adrenocortical disease; adenomas; and carcinomas.¹² In our case, the adipose tissue was associated with myeloid elements, which are features of myelolipoma.

Differentiating between adrenal adenoma and carcinoma in a small lesion can be challenging. Definitive diagnosis of malignancy in adrenocortical lesions is based on the presence of distant metastasis or local invasion. No single pathologic criterion of malignancy is reliable. Therefore, 3 multiparameter systems have been devised to help in delineating adrenocortical malignancies.¹³ Of the 3, the Weiss system,^2,14 which evaluates 9 histologic criteria commonly associated with metastasis or recurrence, is the most widely used because of its simplicity and reliability. The 9 criteria used are high nuclear grade (based on the Fuhrman nuclear grade on the highest-grade areas of the neoplasm), mitotic rate of more than 5 mitoses per 50 high-power fields, presence of atypical mitotic figures, more than 75% of tumor cells with eosinophilic cytoplasm, more than 33% of tumor cells forming sheets, confluent nests of tumor cell necrosis, venous invasion, sinusoidal invasion, and capsular invasion (invasion of nests or cords of tumor cells extending into or through the capsule with corresponding stromal reaction). Originally, the presence of 4 or more of these histologic findings was defined as indicative of malignancy²; later, the threshold was modified to 3 or more.¹⁴ In this same study, Weiss et al¹⁴ found that the mitotic rate was a strong predictor of behavior and divided adrenocortical carcinomas into low-grade and high-grade lesions on the basis of mitotic count. Any carcinoma with more than 20 mitoses per 50 high-power fields is considered high grade. In their report, patients with high-grade tumors had a median survival of 14 months, versus 58 months for those with low-grade tumors. The tumor in our case met 6 of the 9 Weiss criteria for malignancy: diffuse growth, more than 75% eosinophilic cells, more than 5 mitoses per 50 high-power fields, rare atypical mitotic figures, necrosis, and venous invasion. On the basis of the mitotic rate, this tumor was classified as a low-grade adrenocortical carcinoma.

Another feature that favored malignant diagnosis in our case was the proliferative rate as determined by Ki-67 immunostaining. Ki-67 is a monoclonal antibody that recognizes 2 nuclear proteins in proliferating cells during all non-G₀ phases of the cell cycle, and it has emerged as a promising, reliable indicator of cell proliferation.¹⁵ Although the exact Ki-67 threshold for malignancy in various studies has ranged from 4% to 10%,¹⁵ the cells in our case had 20% nuclear activity, a feature that supported the diagnosis of carcinoma.

In summary, we present the first case of aldosterone-secreting adrenocortical carcinoma with concomitant myelolipoma. The pathogenesis of the myelolipoma and its effect on the adrenocortical carcinoma are unknown. Aldosterone-secreting adrenocortical carcinoma associated with myelolipoma should be considered in the differential diagnosis of any adrenal mass.

References

1. Zografos GC, Driscoll DL, Karakousis CP, Huben RP. Adrenal adenocarcinoma: review of 53 cases. J Surg Oncol 1994;55:160–164. [PubMed Citation]

2. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163–169. [PubMed Citation]

3. Kendrick ML, Curlee K, Lloyd R. et al. Aldosterone-secreting adrenocortical carcinomas are associated with unique operative risks and outcomes. Surgery 2002;132:1008–1012. [PubMed Citation]

4. Merchant SH, Herman CM, Amin MB, Ro JY, Troncoso P. Myelolipoma associated with adrenal ganglioneuroma. Arch Pathol Lab Med 2002;126:736–737.

5. Goetz SP, Niemann TH, Robinson RA, Cohen MB. Hematopoietic elements associated with adrenal glands: a study of the spectrum of change in nine cases. Arch Pathol Lab Med 1994;118:895–896.

6. Chu AY, LiVolsi VA, Fraker DL, Zhang PJ. Corticomedullary mixed tumor of the adrenal gland with concurrent adrenal myelolipoma. Arch Pathol Lab Med 2003;127:329–332.

7. Schulick RD, Brennan MF. Adrenocortical carcinoma. World J Urol 1999;17:26–34. [PubMed Citation]

8. King DR, Lack EE. Adrenal cortical carcinoma: clinical and pathologic study of 49 cases. Cancer 1979;44:239–244.

9. Banik S, Hasleton PS, Lyon RL. An unusual variant of MEN syndrome: a case report. Histopathology 1984;8:135–144. [PubMed Citation]

10. Kenney PJ, Wagner BJ, Rao P, Heffess CS. Myelolipoma: CT and pathologic features. Radiology 1998;208:87–95. [PubMed Citation]

11. Whaley D, Becker S, Presbrey T, Shaff M. Adrenal myelolipoma associated with Conn syndrome: CT evaluation. J Comput Assist Tomogr 1985;9:959–960. [PubMed Citation]

12. Izumi M, Serizawa H, Iwaya K, Takeda K, Sasano H, Mukai K. A case of myxoid adrenocortical carcinoma with extensive lipomatous metaplasia. Arch Pathol Lab Med 2003;127:227–230.

13. Medeiros LJ, Weiss LM. New developments in the pathologic diagnosis of adrenal cortical neoplasms: a review. Am J Clin Pathol 1992;97:73–83. [PubMed Citation]

14. Weiss LM, Mederios LJ, Vickery AL. Pathological features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202–206. [PubMed Citation]

15. Terzolo M, Boccuzzi A, Bovio S. et al. Immunohistochemical assessment of Ki-67 in the differential diagnosis of adrenocortical tumors. Urology 2001;57:176–182. [PubMed Citation]

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Alexander Stojadinovic M.D.³, Murray F Brennan M.D.¹, Axel Hoos M.D., Ph.D.^1,2,

Atilla Omeroglu M.D.², Denis H Y Leung Ph.D.⁴, Maria E Dudas², Aviram Nissan M.D.¹,

Carlos Cordon-Cardo M.D.² and Ronald A Ghossein M.D.²

1.                    ¹Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

2.                    ²Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York

3.                    ³Department of Surgery, Walter Reed Army Medical Center, Washington, D.C.

4.                    ⁴School of Economics and Social Sciences, Singapore Management University, Singapore

Correspondence: Alexander Stojadinovic, M.D., Walter Reed Army Medical Center, General Surgery Service, 6900 Georgia Avenue, N.W., Washington, D.C. 20307; fax: 202-782-1234; e-mail: ta.stojadinovic@verizon.net.

Accepted 1 May 2003.

We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P < .001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P < .001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P < .001) and was significantly associated with mitotic rate and unfavorable morphologic index (P < .001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation–associated proteins.

Keywords:

Adenoma, Adrenal, Carcinoma, IHC, Tissue microarray

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What is cancer of the adrenal cortex?

Cancer of the adrenal cortex, a rare cancer, is a disease in which cancer (malignant) cells are found in the adrenal cortex, which is the outside layer of the adrenal gland. Cancer of the adrenal cortex is also called adrenocortical carcinoma. There are two adrenal glands, one above each kidney in the back of the upper abdomen. The adrenal glands are also called the suprarenal glands. The inside layer of the adrenal gland is called the adrenal medulla. Cancer that starts in the adrenal medulla is called phaeochromocytoma and is discussed in a separate patient information summary.

The cells in the adrenal cortex make important hormones that help the body work properly. When cells in the adrenal cortex become cancerous, they may make too much of one or more hormones, which can cause symptoms such as high blood pressure, weakening of the bones, or diabetes. If male or female hormones are affected, the body may go through changes such as a deepening of the voice, growing hair on the face, swelling of the sex organs, or swelling of the breasts. Cancers that make hormones are called functioning tumours. Many cancers of the adrenal cortex do not make extra hormones and are called nonfunctioning tumours.

A doctor should be seen if the following symptoms appear and won’t go away:

* pain in the abdomen,

* loss of weight without dieting, or

* weakness.

If there is a functioning tumour, there may be symptoms or signs caused by too many hormones.

If there are symptoms, a doctor will order blood and urine tests to see whether the amounts of hormones in the body are normal. A doctor may also order a computed tomography scan of the abdomen, a special x-ray that uses a computer to make a picture of the inside of the abdomen. Other special x-rays may also be done to tell what kind of tumour is present.

The chance of recovery (prognosis) depends on how far the cancer has spread (stage) and on whether a doctor was able to surgically remove all of the cancer.

 Stage Explanation

 Stages of cancer of the adrenal cortex

Once cancer of the adrenal cortex has been found, more tests will be done to see how far the cancer has spread. This is called staging. A doctor needs to know the stage of the cancer to plan treatment. The following stages are used for cancer of the adrenal cortex:

Stage I

The cancer is less than 5 centimeters (less than 2 inches) and has not spread into tissues around the adrenal gland.

Stage II

The cancer is more than 5 centimeters (greater than 2 inches) and has not spread into tissues around the adrenal gland.

Stage III

The cancer has spread into tissues around the adrenal gland or has spread to the lymph nodes around the adrenal gland. Lymph nodes are part of the lymph system and are small, bean shaped organs that make and store infection-fighting cells.

Stage IV

The cancer has spread to tissues or organs in the area and to lymph nodes around the adrenal cortex, or the cancer has spread to other parts of the body.

Recurrent

The cancer has come back (recurred) after it has been treated. It may come back in the adrenal cortex or in another part of the body.

Treatment Option Overview

How cancer of the adrenal cortex is treated

There are treatments for all patients with cancer of the adrenal cortex. Three kinds of treatment are used:

* Surgery (taking out the cancer).

* Chemotherapy (using drugs to kill cancer cells).

* Radiation therapy (using high-dose x-rays or other high-energy rays to kill cancer cells).

A doctor may take out the adrenal gland in an operation called an adrenalectomy. Tissues around the adrenal glands that contain cancer may be removed. Lymph nodes in the area may also be removed (lymph node dissection).

Chemotherapy uses drugs to kill cancer cells. Chemotherapy may be taken by pill, or it may be put into the body by a needle in a vein or muscle. Chemotherapy is called a systemic treatment because the drug enters the bloodstream, travels through the body, and kills cancer cells throughout the body.

Radiation therapy uses high-energy x-rays to kill cancer cells and shrink tumours. Radiation for cancer of the adrenal cortex usually comes from a machine outside the body (external radiation therapy).

Besides treatment for cancer (chemotherapy, radiation therapy, and/or surgery), a patient may also receive therapy to prevent or treat symptoms caused by the extra hormones that are made by the cancer.
Treatment by stage

Treatment depends on how far the cancer has spread, and a patient’s age and overall health.

Standard treatment may be considered because of its effectiveness in past studies, or participation in a clinical trial may be considered. Not all patients are cured with standard therapy, and some standard treatments may have more side effects than are desired. For these reasons, clinical trials are designed to find better ways to treat cancer patients and are based on the most up-to-date information. Clinical trials are ongoing in some parts of the country for patients with cancer of the adrenal cortex. For more information, call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237); TTY at 1-800-332-8615.

Stage I Adrenocortical Carcinoma

Treatment will probably be surgery to remove the cancer.

Stage II Adrenocortical Carcinoma

Treatment will probably be surgery to remove the cancer. Clinical trials are testing new treatments.

Stage III Adrenocortical Carcinoma

Treatment may be one of the following:

1. Surgery to remove the cancer. Lymph nodes in the area may also be removed (lymph node dissection).
2. A clinical trial of radiation therapy.
3. A clinical trial of chemotherapy if the size of the tumour can be measured with x-rays and/or if the tumour is making hormones.

Stage IV Adrenocortical Carcinoma

Treatment may be one of the following:

1. Chemotherapy. Clinical trials are testing new drugs.
2. Radiation therapy to bones where the cancer has spread.
3. Surgery to remove the cancer in places where it has spread.

Recurrent Adrenocortical Carcinoma

Treatment depends on many factors, including where the cancer came back and what treatment has already been received. In some cases, surgery can be effective in decreasing the symptoms of the disease by removing some of the tumour. Clinical trials are testing new treatments.

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General Information

Adrenocortical carcinoma is a rare tumor that affects only 1 to 2 persons per one million population. It usually occurs in adults, and the median age at diagnosis is 44 years. Although adrenal carcinoma is potentially curable at early stages, only 30% of these malignancies are confined to the adrenal gland at the time of diagnosis.[1] Radical surgical excision is the treatment of choice for patients with localized malignancies and remains the only method by which long-term disease-free survival may be achieved. Overall 5-year survival for tumors resected for cure is approximately 40%.

Retrospective studies have identified 2 important prognostic factors: completeness of resection and stage of disease. Patients without evidence of invasion into local tissues or spread to lymph nodes have an improved prognosis.[2] The role of DNA ploidy as a prognostic indicator is controversial, with some [3] studies showing correlation between aneuploidy and prognosis, and other studies [2,4] showing no correlation.

Approximately 60% of patients present with symptoms related to excessive hormone secretion, but hormone testing reveals that 60% to 80% of tumors are functioning.[5,6] Nonfunctioning carcinomas may be heralded by symptoms of local invasion by tumor or by metastases. Initial evaluation should include, in addition to appropriate endocrine studies, computed tomography and/or magnetic resonance imaging of the abdomen. Selective angiography and adrenal venography may be helpful in identifying smaller lesions and for distinguishing tumors of the adrenal gland from tumors of the upper pole of the kidney. Although the use of positron emission tomography may be effective in identifying unsuspected sites of metastases, its role as a staging tool is unclear.[7] The detection of metastatic lesions may allow effective palliation of both functioning and nonfunctioning lesions.

The most common sites of metastases are the peritoneum, lung, liver, and bone. Palliation of metastatic functioning tumors may be achieved by resection of both the primary tumor and metastatic lesions. Unresectable or widely disseminated tumors may be palliated by antihormonal therapy with mitotane, systemic chemotherapy, or (for localized lesions) radiation therapy. However, survival for patients with stage IV tumors is usually less than 9 months unless a complete remission is achieved.[6,8,9,10] To date, there is no convincing evidence that systemic therapy will improve the survival duration of patients with adrenal cancer.

References:

1.                    Norton JA: Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1528-39

2.                    Lee JE, Berger DH, el-Naggar AK, et al.: Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 118 (6): 1090-8, 1995.

3.                    Camuto P, Schinella R, Gilchrist K, et al.: Adrenal cortical carcinoma: flow cytometric study of 22 cases, an ECOG study. Urology 37 (4): 380-4, 1991.

4.                    Haak HR, Cornelisse CJ, Hermans J, et al.: Nuclear DNA content and morphological characteristics in the prognosis of adrenocortical carcinoma. Br J Cancer 68 (1): 151-5, 1993.

5.                    Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112 (6): 972-9; discussion 979-80, 1992.

6.                    Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322 (17): 1195-201, 1990.

7.                    Becherer A, Vierhapper H, Pötzi C, et al.: FDG-PET in adrenocortical carcinoma. Cancer Biother Radiopharm 16 (4): 289-95, 2001.

8.                    Brennan MF: Adrenocortical carcinoma. CA Cancer J Clin 37 (6): 348-65, 1987 Nov-Dec.

9.                    Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100 (6): 1170-7, 1986.

10.                 Wooten MD, King DK: Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72 (11): 3145-55, 1993.

Cellular Classification

Adrenocortical carcinoma can be classified as follows:

—      Differentiated: Functioning tumors are usually differentiated.

—      Anaplastic: Production of hormones by anaplastic tumors is rare.

—      Hormonal: Approximately 60% of adrenocortical carcinomas produce hormones. The associated clinical syndromes include the following:[1,2,3]

—      Hypercortisolism (Cushing’s syndrome).

—      Adrenogenital syndrome.

—      Virilization.

—      Feminization.

—      Precocious puberty.

—      Hyperaldosteronism.

—      Primary hyperaldosteronism (Conn’s syndrome).

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Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with incompletely understood pathogenesis and poor prognosis. Patients present with hormone excess (e.g. virilization, Cushing’s syndrome) or a local mass effect (median tumor size at diagnosis > 10 cm). This paper reviews current diagnostic and therapeutic strategies in ACC.

Evidence Acquisition: Original articles and reviews were identified using a PubMed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) covering the time period up until November 2005. The following search terms were used in varying combinations: adrenal, adrenocortical, cancer, carcinoma, tumor, diagnosis, imaging, treatment, radiotherapy, mitotane, cytotoxic, surgery.

Evidence synthesis: Tumors typically appear inhomogeneous in both computerized tomography and magnetic resonance imaging with necroses and irregular borders and differ from benign adenomas by their low fat content. Hormonal analysis reveals evidence of steroid hormone secretion by the tumor in the majority of cases, even in seemingly hormonally inactive lesions. Histopathology is crucial for the diagnosis of malignancy and may also provide important prognostic information. In stages I–III open surgery by an expert surgeon aiming at an R0 resection is the treatment of choice. Local recurrence is frequent, particularly after violation of the tumor capsule. Surgery also plays a role in local tumor recurrence and metastatic disease. In patients not amenable to surgery, mitotane (alone or in combination with cytotoxic drugs) remains the treatment of choice. Monitoring of drug levels (therapeutic range 14–20 mg/liter) is mandatory for optimum results. In advanced disease, the most promising therapeutic options (etoposide, doxorubicin, cisplatin plus mitotane, and streptozotocin plus mitotane) are currently being compared in an international phase III trial (www.firm-act.org). Adjuvant treatment options after complete tumor removal (e.g. mitotane, radiotherapy) are urgently needed because postoperative disease-free survival at 5 yr is only around 30%, but options have still not been convincingly established. National registries, international cooperations, and trials provide important new structures for patients but also for researchers aiming at systematic and continuous progress in ACC. However, future advances in the management of ACC will mainly depend on a better understanding of the molecular pathogenesis facilitating the use of modern cancer treatments (e.g. tyrosine kinase inhibitors).

ADRENOCORTICAL TUMORS ARE common tumors with a prevalence of at least 3% in a population over the age of 50 yr (1, 2). In contrast, adrenocortical carcinoma (ACC) is a rare malignancy (incidence 1–2 per 1 million population) with a heterogeneous presentation and a variable but generally poor prognosis (3, 4, 5). However, data on incidence are mainly based on the National Cancer Institute survey from the early 1970s and probably underestimate the true incidence. An exceptionally high annual incidence of ACC has been reported for children in southern Brazil (3.4–4.2 per 1 million children vs. an estimated worldwide incidence of 0.3 per 1 million children younger than 15 yr) and is related to a TP53 tumor suppressor gene mutation (6, 7, 8). Women are more often affected than men (ratio 1.5) (9, 10, 11, 12). The age distribution is reported as bimodal with a first peak in childhood and a second higher peak in the fourth and fifth decade (4, 12).

The molecular pathogenesis of ACC has been the topic of recent reviews (13, 14, 15, 16) but is still poorly understood. It is unclear whether ACCs evolve from adrenal adenomas after a second hit paradigm. Although such a sequence has been observed in occasional cases (17, 18), long-term follow-up data of incidentally discovered adrenal neoplasms suggest otherwise (19, 20, 21). Inactivating mutations at the 17p13 locus including the TP53 tumor suppressor gene and alterations of the 11p15 locus leading to IGF-II overexpression are frequently observed. In vitro experiments suggest that overexpressed IGF-II acting via the IGF-I receptor is relevant for adrenal cancer cell proliferation (22, 23, 24). Thus, the IGF-II IGF-I receptor pathway is a promising target for future therapies in ACC (25).

Patients present with evidence of adrenal steroid hormone excess in approximately 60% of cases. Rapidly progressing Cushing’s syndrome with or without virilization is the most frequent presentation. In patients from the German ACC Registry, autonomous cortisol secretion, either alone or in combination with other steroids, was detectable in 60% of the cases in which hormonal analysis had been performed prior to surgery (12). However, not in all of these cases was autonomous cortisol secretion clinically suspected. Androgen-secreting ACCs in women induce hirsutism and virilization with deepening of the voice, male pattern baldness, and oligoamenorrhea. Estrogen-secreting adrenal tumors in males lead to gynecomastia and testicular atrophy and are almost invariably malignant (26). High concentration of dehydroepiandrosterone sulfate (DHEA-S) is another clue suggesting ACC, whereas decreased serum DHEA-S concentrations are suggestive of a benign adenoma (26). Aldosterone-producing adrenocortical carcinomas present with hypertensionand pronounced hypokalemia (mean serum potassium 2.3 ± 0.08 mmol/liter) (27). However, severe hypokalemia is more likely caused by grossly elevated cortisol secretion, leading to insufficient renal cortisol inactivation by 11ß-hydroxysteroid dehydrogenase type 2 with consecutive activation of the mineralocorticoid receptor.

In many patients with a seemingly hormonally inactive ACC, high concentrations of steroid precursors like androstenedione or 17-hydroxyprogesterone can often be demonstrated, thereby establishing the adrenocortical origin of the tumor.

Hormonally inactive ACCs usually present with abdominal discomfort (nausea, vomiting, abdominal fullness) or back pain caused by a mass effect of the large tumor. In the Italian survey on adrenal incidentaloma, the occurrence of pain was significantly associated with ACC and was not fully explained by large tumor size per se (28). However, an increasing percentage of ACCs is discovered as incidentaloma during abdominal imaging (28, 29, 30, 31).

Only occasionally patients present with fever, weight loss, and anorexia, and it is a remarkable feature of non-cortisol-producing ACC that well-being is often little affected by even a large tumor burden.

Hormonal work-up

Careful endocrine assessment is mandatory prior to surgery in ACC (Table 1). The pattern of hormone secretion may point to the malignant potential of the lesion (e.g. estradiol in males, high concentration of serum DHEA-S, or secretion of steroid precursors) and may thus affect surgical strategy (open instead of minimal invasive surgery). In addition, autonomous cortisol secretion by the tumor is associated with the risk of postoperative adrenal insufficiency. Due to the variable hypercortisolemia and the rapid development of ACC, clinical features of Cushing’s syndrome are often incomplete or even missing (atypical or subclinical Cushing’s syndrome). To establish tumor markers for monitoring of tumor recurrence, a thorough hormonal work-up is essential. Finally, it is important to exclude a pheochromocytoma prior to surgery because imaging often cannot reliably differentiate between ACC and pheochromocytoma (26).

Imaging

Both size and appearance of an adrenal mass on computerized tomography (CT), magnetic resonance imaging (MRI), and more recently ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) have been used to distinguish between benign and malignant lesions. The size of the adrenal mass, as measured by CT or MRI remains one of the best indicators of malignancy. In the German Adrenal Cancer Registry (n = 215), the mean tumor size at diagnosis was 11.5 ± 4.7 cm (range 3–28 cm). However, ACCs smaller than 6 cm have been increasingly reported (5), and it is intuitively obvious that during early development ACCs are small, and surgical intervention would be most beneficial at this stage. According to the National Institutes of Health consensus conference, tumors larger than 6 cm are highly suspicious for malignancy and will be removed (1, 2). Therefore, tumors between 3 and 6 cm represent the main diagnostic challenge. To avoid misclassification of a small ACC as benign neoplasia, follow-up imaging is mandatory to detect early tumor growth and should be performed initially every 3–12 months (depending on tumor size and radiological appearance).

Thin-collimation CT. ACCs are inhomogeneous with irregular margins and irregular enhancement of solid components after iv contrast media. Sometimes calcifications are visible. Local invasion or tumor extension into the inferior vena cava as well as lymph node or other metastases (lung and liver) are often found in advanced ACC (Fig. 1). Measurement of Hounsfield units (HU) in unenhanced CT is of great value in differentiating malignant from benign adrenal lesions. Using a threshold value of 10 HU sensitivity and specificity for characterization an adrenal lesion as a benign adenoma in unenhanced CT was 71 and 98%, respectively, in a metaanalysis of 10 studies (32). However, in a recent series from Cleveland including 151 adrenal masses with histologically confirmed diagnosis, the median unenhanced HU was 19 (range: – 19 to 43) for adenomas and 36 (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43) for carcinomas, indicating overlap between both groups (33). For better discrimination of lipid-poor adenomas from ACC, a delayed contrast-enhanced CT can be used, analyzing washout of contrast medium. Adrenal lesions with an attenuation value of more than 10 HU in unenhanced CT or an enhancement washout of less than 50% and a delayed attenuation of more than 35 HU (on 10- to 15-min delayed enhanced CT) are suspicious for malignancy (34, 35, 36, 37, 38, 39, <