Carcinoma adrenocortical

Patients with Li-Fraumeni syndrome have increased susceptibility to a variety of cancers, including bone and soft-tissue sarcomas, breast tumors, brain cancers, leukemia, and adrenocortical carcinoma, all arising at an early age (often before 30 years). 

Osteosarcoma has recently been diagnosed in a 12-year-old girl. Family history indicates that her paternal aunt died of breast cancer at age 29 after having survived treatment for an adrenocortical carcinoma. An uncle died of a brain tumor at age 38 and the patient s father, age 35, has leukemia. 

Mitotane, or o,p -DDD, is an oral medication used in the treatment of adrenocortical carcinoma. Chemically it is an isomere of DDT. Following its metabolism in the adrenal cortex to a reactive acyl chloride intermediate, mitotane covalently binds to adrenal proteins, specitically inhibiting adrenal cortical hormone production. The drug accumulates in fat tissue. It is eliminated mainly by the kidneys with a half-life of 18-159 days. Common side effects include anorexia, nausea, lethargy, sleepiness and skin problems. 

For obvious reasons of structural analogy to heparinoids the focus of this review is on sulfated carbohydrate derivatives. While it is not in all cases clear that these compounds really mimic the physiological activity of heparinoids, it is even less so for non-carbohydrate sulfates or sulfonates. Examples of the latter class include suramin and the simple 1,3-propanediol disulfate. Suramin is a sulfonat-ed bis-naphthalene derivative used as a drug to treat African trypanosomiasis and onchocerciasis (a filarial infection) it was also tested in a number of other indications including adrenocortical carcinomas and AIDS. A wider use is, however, restricted by various toxic effects [66]. 1,3-Propanediol disulfate reduced inflammation-associated amyloid progression in vivo after oral administration which may be relevant to the treatment of Alzheimer s disease [67]. 

DOC, which also serves as a precursor of aldosterone (Figure 39-1), is normally secreted in amounts of about 200 mcg/d. Its half-life when injected into the human circulation is about 70 minutes. Preliminary estimates of its concentration in plasma are approximately 0.03 mcg/dL. The control of its secretion differs from that of aldosterone in that the secretion of DOC is primarily under the control of ACTH. Although the response to ACTH is enhanced by dietary sodium restriction, a low-salt diet does not increase DOC secretion. The secretion of DOC may be markedly increased in abnormal conditions such as adrenocortical carcinoma and congenital adrenal hyperplasia with reduced P450cll or P450cl7 activity. 

Mitotane (Lysodren] Suppresses adrenal gland used primarily to treat adrenocortical carcinoma Gl distress (nausea, vomiting, diarrhea, loss of appetite] CNS toxicity (lethargy, fatigue, mood changes] skin rashes... 

G. Martin, A. Pilon, C. Albert, M. Valle, D.W. Hum, J.C. Fruehart, J. Najib, V. Clavey and B. Staels, Comparison of expression and regulation of the high-density lipoprotein receptor SR-BI and the low-density lipoprotein receptor in human adrenocortical carcinoma NCI-H295 cells, Eur. J. Biochem. 261 (1999) 481-491. 

This drug (Figure 39-5) is a dichloro analog of the insecticide DDT that was first found to be adrenolytic in dogs. Subsequently, it was found to be useful in the treatment of an adrenocortical carcinoma, and it is labeled for this clinical indication. The drug produces tumor regression and reduces the excessive adrenal steroid secretion that often occurs with this malignancy. Toxicities are listed in Table 55-6. 

An in vitro and in vivo study of antimmor effects of gossypol on human SW-13 adrenocortical carcinoma. Cancer Res. 

Kasperlik-Zaluska AA. Clinical results of the use of mitotane for adrenocortical carcinoma. Braz J Med Biol Res 2000 33(10) 1191-6. 

Indications Inoperable adrenocortical carcinoma Category Antineoplastic Half-life 18-159 days... 

Rationale Patients with Cushing s syndrome caused by an ACTH-producing pituitary adenoma usually show suppression of cortisol with high-dose dexamethasone. Patients with Cushing s syndrome from other causes (adrenocortical adenoma, adrenocortical carcinoma, or ectopic production of ACTH) usually do not demonstrate any change in cortisol concentration. 

Feminizing adrenocortical carcinomas are also rare. They result in elevation of plasma DHEA-S, DHEA, androstenedione, estrone, and estradiol concentrations. Serum cortisol concentrations may be normal or elevated in those patients with Cushing s syndrome. Gynecomastia and sexual dysfunction occur in men and precocious pseudopuberty in women. Steroid hormone production fails to decrease normally after treatment with dexamethasone. 

Weingartner K, Gerharz EW, Bittinger A, Rosai J, Leppek R, Riedmfller H. Isolated clinical syndrome of primary aldosteronism in a patient with adrenocortical carcinoma Case report and review of the literature. Urol Int 1995 55 232-5. 

Gazdar AF, Oie HK, Shackleton CH, Chen TR, Triche TJ, Myers CE, Chrousos GP, Brennan MF, Stein CA, La Rocca RV (1990) Establishment and characterization of a human adrenocortical carcinoma cell line that expresses multiple pathways of steroid biosynthesis. Cancer Res 50(17) 5488-5496... 

Bird IM, Mason JI, Rainey WE (1994) Regulation of type 1 angiotensin II receptor messenger ribonucleic acid expression in human adrenocortical carcinoma H295 cells. Endocrinology 134(6) 2468-2474... 

Sanderson, J.T., W. Seinen, J.P. Giesy and M. van den Berg. 2-Chloro-s-triazine herbicides induce aromatase (CYP19) activity in H295R human adrenocortical carcinoma cells a novel mechanism for estrogenicity. Toxicol. Sci. 54 121 — 127, 2000. 

One true exception to the last statement is represented by the ability of MART-l/melan-A (but not HMB-45, NKI-beteb, or HMB-50) to label the tumor cells of a subset of adrenocortical carcinomas and sex-cord tumors of the gonads (Fig. 7.13). " 4° No evidence of true melanocytic differentiation has been seen in such neoplasms, and MART-1 antibodies are presumably recognizing an antigenic epitope in those steroidogenic proliferations, which is shared with the gplOO/PMel 17 molecules. 

FIGURE 7.13 Diffuse labeling for MART-1 /melan-A (with antibody clone A1 03) in adrenocortical carcinoma. 

Melan-A decorates adrenocortical carcinomas and sex-cord tumors of the ovary. 

Fetsch PA, Powers CN, Zakowski MF, Abati A. Anti-alpha-inhibin marker of choice for the consistent distinction between adrenocortical carcinoma and renal cell carcinoma in fine-needle aspiration. Cancer. 1999 87 168-172. 

Sasano H, Suzuki T, Moriya T. Recent advances in histopathol-ogy and immunohistochemistry of adrenocortical carcinoma. Endocr Pathol. 2006 17 345-354. 

Adrenocortical carcinomas have a proliferative index (assessed with MIB-1) in excess of 8% and are positive for p53 in approximately 45% of cases. 

Komminoth P, Roth J, Schroder S, et al. Overlapping expression of immunohistochemical markers and synaptophysin mRNA in pheochtomocytomas and adrenocortical carcinomas Implications fot the diffetential diagnosis of adrenal gland mmors. Lab Invest. 1995 72 424-431. 

Tartour E, Caillou B, Tenenbaum F, et al. Immunohistochemi-cal study of adrenocortical carcinoma Predictive value of the Dll monoclonal antibody. Cancer. 1993 72 3296-3303. 

Miettinen M. NE differentiation in adrenocortical carcinoma New immunohistochemical findings supported by electron microscopy. Lab Invest. 1992 66 169-174. 

Wick MR, Cherwitz DL, McGlennen RC, Dehner LP. Adrenocortical carcinoma An immunohistochemical comparison with renal cell carcinoma. Am Pathol. 1986 122 343-352. 

An additional 10 cases of adrenocortical carcinomas were studied for CD56 expression. Of 30 cases, 25 were CD56-positive. tAn additional 5 cases of malignant mesothelioma were studied for CD1 38 expression. Of 21 cases, 1 was CD138-positive. 

Pan CC, Chen PC, Tsay SH, Ho DM. Differential immuno-profiles of hepatocellular carcinoma, renal cell carcinoma, and adrenocortical carcinoma a systemic immunohistochemical survey using tissue array technique. Appl Immunohistochem MolMorphol. 2005 13 347-352. 

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