• Incidentally detected giant oncocytoma arising in retroperitoneal heterotopic adrenal tissue.

• Loss of expression of the ubiquitous transcription factor cAMP response element-binding protein (CREB) and compensatory overexpression of the

• Adrenal tumor with caval extension--case report and review of the literature.

• Analysis of numerical chromosomal aberrations in adrenal cortical neoplasms by fluorescence in situ hybridization.

• Retroperitoneoscopic adrenalectomy in an infant with adrenocortical virilizing tumor.

• Usefulness of CT scan, MRI and radiocholesterol scintigraphy for adrenal imaging in Cushing's syndrome.

• Value of topoisomerase II alpha, MIB-1, p53, E-cadherin, retinoblastoma gene protein product, and HER-2/neu immunohistochemical expression for

• Calretinin and inhibin are useful in separating adrenocortical neoplasms from pheochromocytomas.

• Long-term (15 years) outcome in an infant with metastatic adrenocortical carcinoma.

1
UI - 12204066
AU - Corsi A; Riminucci M; Petrozza V; Collins MT; Natale ME; Cancrini A;
TI - Bianco P Incidentally detected giant oncocytoma arising in retroperitoneal heterotopic adrenal tissue.
SO - Arch Pathol Lab Med 2002 Sep;126(9):1118-22
AD - Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
A nonfunctional retroperitoneal oncocytoma incidentally discovered in a 40-year-old woman is described. The tumor, which was 17 cm in largest dimension, was completely separated from the kidneys and adrenal glands and consisted of nests of polygonal cells with large, granular, eosinophilic cytoplasm. Significant nuclear atypia, necrosis, and mitosis were absent. Ultrastructural analysis confirmed the oncocytic nature of the neoplastic cells. Since neoplastic cells were not immunoreactive for chromogranin and did not contain dense-core secretory granules, the diagnosis of oncocytic paraganglioma was excluded. Cells immunoreactive for 3beta-hydroxysteroid dehydrogenase, the enzyme catalyzing the conversions of pregnenolone to progesterone and dehydroepiandrosterone to androstenedione, were identified in the tumor, thus strongly indicating adrenocortical tissue origin. Multiple nests of 3beta-hydroxysteroid dehydrogenase-positive cells were detected in the loose retroperitoneal connective tissue. These findings strongly support the origin of the tumor from heterotopic retroperitoneal rests of the adrenal gland. To our knowledge, only 1 similar case has been described in the literature to date.

2
UI - 10634409
AU - Groussin L; Massias JF; Bertagna X; Bertherat J
TI - Loss of expression of the ubiquitous transcription factor cAMP response element-binding protein (CREB) and compensatory overexpression of the activator CREMtau in the human adrenocortical cancer cell line H295R.
SO - J Clin Endocrinol Metab 2000 Jan;85(1):345-54
AD - Groupe d'Etude en Physiopathologie Endocrinienne, Centre National de la Recherche Scientifique, UPR1524, Institut Cochin de Genetique Moleculaire, Universite Rene Descartes-Paris V, France.
The pituitary hormone ACTH, acting through the cAMP pathway, plays a key role in proliferation and differentiation of the adrenal cortex. CAMP response element (CRE)-binding protein (CREB) is an ubiquitous transcription factor that binds to the CRE present in the promoter of numerous genes and mediates transcription stimulation by cAMP. Characterization of CRE-binding proteins was performed in the H295R cell line, which is considered a model for human adrenocortical tumor studies. Western blot and RT-PCR studies demonstrated that CREB is not expressed in the human adrenocortical cancer cell line H295R, whereas it is expressed in normal adrenal. During transient transfection experiments, cAMP stimulation of two reporter genes containing canonical CRE was maintained. Cotransfection of the dominant negative inhibitor A-CREB, which prevents transcription factors containing a CREB-like leucine zipper domain to bind DNA, completely inhibited cAMP-induced stimulation of CRE activity. Western blot and RT-PCR studies showed that activating transcription factor-1 (ATF-1), CRE modulator-alpha/gamma (CREMalpha/gamma), and CREMtau2alpha are expressed in H295R cells. High amounts of CREM proteins were present in H295R, demonstrating an overexpression of this transcription factor in the absence of CREB. Furthermore, expression of the activator isoform CREMtau was very high in H295R compared to normal adrenal cortex. Transfection assays demonstrated that CREMtau2alpha is a potent stimulator of CRE activity in H295R. Finally, gel retardation assays showed that CREM and ATF-1 are the nuclear proteins that specifically bind the CRE in H295R cells, whereas CREM binding to CRE is not observed in a CREB-expressing cell line. H295R cells are the first established nontransgenic cell line that does not express the ubiquitous transcription factor CREB. H295R demonstrates that CREMtau up-regulation can compensate for CREB deficiency to maintain CRE regulation by cAMP and is a model of compensation mechanisms between the members of the CREB/ CREM/ATF-1 family of transcription factors. This loss of CREB expression and the overexpression of CREM could be linked to cellular transformation, as the normal adrenal cortex express high levels of CREB and no or low levels of CREMtau.

3
UI - 12002362
AU - Chesson JP; Theodorescu D
TI - Adrenal tumor with caval extension--case report and review of the literature.
SO - Scand J Urol Nephrol 2002 Feb;36(1):71-3
AD - Department of Urology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Extension of adrenal cortical carcinomas into the IVC is rare. We describe one such tumor that extended to the level of the right atrium. In an effort to aid recognition and guide work-up of an upper pole lesion, we review the literature comprised of 77 similar cases and analyze the data in terms of patient demographics, anatomic distribution, clinical and laboratory evidence of endocrine function. Our review suggests that over half of all adrenal lesions with IVC extension will be clinically nonfunctional, including up to 17% of pheochromocytomas.

4
UI - 12352395
AU - Shono T; Sakai H; Takehara K; Honda S; Kanetake H
TI - Analysis of numerical chromosomal aberrations in adrenal cortical neoplasms by fluorescence in situ hybridization.
SO - J Urol 2002 Oct;168(4 Pt 1):1370-3
AD - Department of Urology, Nagasaki University School of Medicine, Sakamoto, Japan.
PURPOSE: We identified numerical chromosomal aberrations in adrenal cortical neoplasms using interphase fluorescence in situ hybridization (FISH) and correlated these aberrations with DNA ploidy and endocrine dysfunction. MATERIALS AND METHODS: Our study included 25 adenomas and 2 carcinomas associated with primary aldosteronism or Cushing's syndrome. Eight normal adrenal tissue samples served as controls. Isolated nuclei from frozen samples were used for FISH and formalin fixed, paraffin embedded tissues from the same materials were analyzed by flow cytometry for DNA ploidy. For FISH we used centromere specific probes for chromosomes 3, 7, 8, 11 and 12. RESULTS: None of the normal adrenal tissues had any numerical chromosomal aberrations in any chromosome analyzed or any abnormal findings on DNA ploidy analysis. Tetrasomy of chromosomes 3, 7, 8, 11 and 12 was detected in 8, 13, 14, 11 and 12 of the 17 adenomas associated with primary aldosteronism, and in 2, 0, 0, 0 and 0 of the 8 associated with Cushing's syndrome, respectively. DNA flow cytometry revealed tetraploidy in 11 of the 17 cases of primary aldosteronism and in 1 of the 8 of Cushing's syndrome. Five diploid adenomas associated with primary aldosteronism also showed tetrasomy in 2 or more chromosomes. One of the 2 carcinomas showed aneuploidy and aneusomy of chromosomes 8, 11 and 12 but the other showed no abnormal peaks on DNA histography and no numerical chromosomal aberrations. CONCLUSIONS: All chromosomes analyzed in adenomas associated with primary aldosteronism frequently showed tetrasomy, whereas few chromosomal abnormalities were detected in adenomas associated with Cushing's syndrome. Our results indicate that DNA tetraploidy is common in adrenal cortical adenomas associated with primary aldosteronism. Interphase FISH strongly supported flow cytometry findings and could provide further information on individual chromosomes.

5
UI - 12163900
AU - Tobias-Machado M; Cartum J; Santos-Machado TM; Gaspar HA; Simoes AS;
TI - Cruz R; Rodrigues R; Juliano RV; Wroclawski ER Retroperitoneoscopic adrenalectomy in an infant with adrenocortical virilizing tumor.
SO - Sao Paulo Med J 2002 May 2;120(3):87-9
AD - Department of Urology, Pediatric Oncology and surgery, Faculty of Medicine of ABC, Sao Pablo, Brazil. telmamsm@icr.hcnet.usp.br
CONTEXT: Adrenocortical virilizing tumors are rare in the pediatric age group. Laparoscopic surgery is the gold standard method for treatment of adrenal functional tumors under 6 cm in size, in adults. There has been very little use of laparoscopy in children and there is no report of its application in the treatment of adrenal carcinoma in childhood. DESIGN: Case report. CASE REPORT: We performed the first laparoscopic resection using retroperitoneal access for the treatment of an adrenocortical virilizing tumor in a pediatric patient. We believe that retroperitoneoscopic access is a viable and promising option for the treatment of adrenal tumors in children.

6
UI - 11973488
AU - Lumachi F; Zucchetta P; Marzola MC; Bui F; Casarrubea G; Angelini F;
TI - Favia G Usefulness of CT scan, MRI and radiocholesterol scintigraphy for adrenal imaging in Cushing's syndrome.
SO - Nucl Med Commun 2002 May;23(5):469-73
AD - Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, 35128 Padova, Italy. flumachi@unipd.it
The aim of this study was to evaluate the sensitivity and accuracy of computed tomography (CT) scanning, 75Se-selenomethyl-norcholesterol scintigraphy (SNS) and magnetic resonance imaging (MRI) in patients with Cushing's syndrome (CS) undergoing adrenalectomy. A series of 67 patients with CS due to benign adrenal disease was reviewed. There were 11 (16.4%) men and 56 (83.6%) women, with an overall median age of 44 years (range 19-69 years). Prior to surgery all patients underwent both CT and SNS, and 58 (86.6%) underwent adrenal MRI. Thirty-five (52.2%) of the patients (group A) had histologically confirmed unilateral adrenal involvement (33 patients with a solitary adrenocortical adenoma, and two with unilateral nodular cortical hyperplasia), while 32 (47.8%) of the patients (group B) had CS caused by bilateral adrenal involvement, including two patients with multinodular adrenal hyperplasia. The sensitivity, specificity and accuracy of adrenal imaging in group A were 97.1%, 100% and 98.5% for SNS, 94.3%, 68.7% (P<0.05, chi2 test) and 82.1% for CT scan, and 92.3%, 60.0% (P<0.05) and 64.3% (P<0.05) for MRI, respectively. In group B the sensitivity, specificity and accuracy were 100%, 97.2% and 98.5% for SNS, 64.5% (P<0.05), 97.2% and 82.1% for CT scan, and 60.0% (P<0.05), 92.3% and 35.7% (P<0.05) for MRI, respectively. In conclusion, SNS represents the most sensitive and specific adrenal imaging study and should be used in all patients with confirmed biochemical diagnosis of CS undergoing adrenalectomy. The sensitivity and specificity of CT scan and MRI are similar, but the latter shows a lower accuracy, especially in patients with bilateral adrenal involvement.

7
UI - 11556748
AU - Gupta D; Shidham V; Holden J; Layfield L
TI - Value of topoisomerase II alpha, MIB-1, p53, E-cadherin, retinoblastoma gene protein product, and HER-2/neu immunohistochemical expression for the prediction of biologic behavior in adrenocortical neoplasms.
SO - Appl Immunohistochem Mol Morphol 2001 Sep;9(3):215-21
AD - Magee Women's Hospital and University of Pittsburgh, Pennsylvania, USA.
Prediction of biologic behavior in adrenocortical neoplasms is difficult because of the lack of availability of reliable clinical, biochemical, and pathologic prognostic markers. Reliable objective markers predictive of clinical outcome in adrenocortical neoplasms are needed to assign optimal treatment of potentially malignant tumors. In the current article, the authors evaluated a set of molecular markers (topoisomerase II alpha (Topo II alpha), MIB-1, p53, human epithelial cadherin (E-cadherin), retinoblastoma gene protein product, and HER-2/neu) and correlated their expression with histologic diagnosis and clinical outcome. Paraffin-embedded, formalin-fixed tissue blocks from 30 cases of adrenocortical neoplasms (15 benign and 15 malignant) were obtained from the surgical pathology archives at the University of Utah Health Sciences Center (Salt Lake City, UT) and the Medical College of Wisconsin (Milwaukee, WI). Age, gender, recurrence, tumor size and weight, hemorrhage, necrosis, pleomorphism, mitotic count, capsular and lymphovascular invasion, hyaline globules, intranuclear inclusions, and immunohistochemical expression of Topo II alpha, p53, MIB-1, E-cadherin, retinoblastoma gene protein product, and HER-2/neu were studied. Clinical data were obtained from the clinical charts, or communication with the treating physician, or both. Adrenocortical neoplasms with hemorrhage, necrosis, large size (>5 cm), weight more than 100 g, nuclear pleomorphism, lymphovascular invasion, and brisk mitotic rate (more than 5 per 30 high-power fields) were more likely to behave in a malignant fashion (P approximately 0.001-0.009). The difference in proliferation indices in benign and malignant neoplasms was statistically significant (P < 0.001). The difference in p53 staining in benign and malignant neoplasms also was statistically significant (P < 0.001). Higher p53 labeling index (>20%) was present in 73% (11/15) of malignant lesions but was found in only 1 of 15 (6.6%) benign lesions. The difference in retinoblastoma staining between benign and malignant neoplasms was statistically significant (P = 0.004). There was no significant difference in staining pattern of E-cadherin expression between benign and malignant lesions. HER-2/neu overexpression was not observed in any of the benign or malignant adrenocortical neoplasms.

8
UI - 11893039
AU - Jorda M; De MB; Nadji M
TI - Calretinin and inhibin are useful in separating adrenocortical neoplasms from pheochromocytomas.
SO - Appl Immunohistochem Mol Morphol 2002 Mar;10(1):67-70
AD - Department of Pathology, University of Miami/Jackson Memorial Medical Center, Florida 33136, USA. mjorda@med.miami.edu
Most adrenocortical neoplasms and pheochromocytomas can be diagnosed by a combination of clinical findings and morphologic features. Occasionally, however, this histologic differential diagnosis requires ancillary tests, such as immunohistochemistry. Both tumors are generally negative for epithelial markers but express synaptophysin. Inhibin and chromogranin are used for the diagnosis of adrenocortical neoplasms and pheochromocytomas, respectively. Both antigens, however, are expressed focally and may be completely negative, particularly in small biopsies. The authors investigated the potential value of adding calretinin to inhibin in the differential diagnosis of these tumors. Fifty-five primary adrenal neoplasms including 33 adrenocortical tumors (21 adenomas and 12 carcinomas), 22 pheochromocytomas, and 7 healthy adrenal glands were examined immunohistochemically for the expression of calretinin and inhibin. Inhibin was demonstrated in 24 (73%) adrenocortical neoplasms. When calretinin was added, the number of tumors staining positively for the two markers alone or in combination increased to 31 (94%). Both antigens showed a focal pattern of distribution in many cases. None of the pheochromocytomas reacted for any of these two markers. Healthy adrenal gland showed a distinct positive and negative pattern of immunoreactivity for both antigens in cortex and medulla, respectively. There were no differences between staining patterns of calretinin and inhibin in healthy adrenal cortex, adrenocortical adenomas, and adrenocortical carcinomas. The authors conclude that the addition of calretinin to inhibin increases the sensitivity of the diagnosis of adrenocortical neoplasms. When used together, they are highly specific and sensitive for the differential diagnosis of these tumors from pheochromocytomas. These markers, however, do not distinguish between benign and malignant adrenocortical neoplasms.

9
UI - 12364417
AU - De Leon DD; Lange BJ; Walterhouse D; Moshang T
TI - Long-term (15 years) outcome in an infant with metastatic adrenocortical carcinoma.
SO - J Clin Endocrinol Metab 2002 Oct;87(10):4452-6
AD - Division of Endocrinology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Adrenocortical carcinoma is a rare malignancy in children, with a high mortality. Little is known about long-term outcome, especially in infants treated with mitotane. We report the successful long-term outcome of a case of metastatic adrenocortical carcinoma presenting in infancy treated with surgical resection and mitotane. The patient presented at 2 months of age with Cushing's syndrome, a large adrenal mass, and elevated adrenal steroid levels. The tumor was removed surgically. Intraoperative findings included an adrenal tumor (confirmed malignant pathologically) invading the adrenal vein and vena cava. After surgery he was treated with mitotane at a dose of 2 g/d. Six months after surgery 11-deoxycortisol levels increased, and a computed tomography scan showed a pulmonary metastasis. Mitotane was increased to 2.5 g/d, and the metastasis was removed surgically. Plasma mitotane levels ranged 10-15 micro g/ml. Tumor markers remained normal, and mitotane was discontinued at 18 months. During therapy the patient's somatic growth was poor. His motor and speech development was delayed. After mitotane was discontinued he demonstrated catch-up growth. This case shows successful long-term outcome and recovery from the toxic effects of mitotane.

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