The Role of Immunohistochemistry in Histopathological Diagnostics of Clinically “Silent” Incidentally Detected Adrenal Masses

Abstract

Background: The detectability of adrenal incidentalomas (incidentally found adrenal tumours) in the whole population is estimated at 0.1%; 0.42% in non-endocrine patients and at 4.3% in oncologically diagnosed ones. Even up to 16% of incidentalomas of adrenal glands can be malignant lesions. The issue of crucial importance is the histopathological differentiation between benign lesions and malignant tumours of the adrenal cortex and medulla.

Objectives: To evaluate whether the immunohistochemical analysis of the expression of p53, p21, PCNA and Ki67 in the tumour's tissue can be useful in the histopathological diagnostics of adrenal incidentalomas and whether it is important for prognosis.

Material and methods: Our series consisted of 74 tumour samples from 164 patients operated for incidentalomas. There were 43 cortical adenomas, 11 cortical adrenocarcinomas and 20 PHEOs (including 5 malignant lesions). Using monoclonal antibodies, the expression of p53, p21, PCNA and Ki67 was evaluated.

Results: We found a statistically significant correlation between the expression of p53, p21, Ki67 and the differential diagnosis of adrenal cortical adenoma and adrenocortical carcinoma (for proteins: p53 p=0.010, for p21 p=0.010, for Ki67 p<0.001). The statistical significant correlation between PCNA protein and diagnosis of adrenal cortical adenoma and adrenocortical carcinoma was not found. The statistically significant correlation between p21, PCNA proteins and the diagnosis of benign and malignant PHEOs was not estimated. There was no expression of Ki67 or p53 protein above the assumed level in benign and malignant pheochromocytomas. The statistically significant correlation between p53, p21, PCNA or Ki67 and the occurrence of metastases in adrenocarcinoma and malignant PHEOs was not found.

Key words

adrenal incidentalomas - expression of p53 - p21 - PCNA - Ki67 - immunohistochemistry

References

• 1 Allison RT, Best T. P53, PCNA and Ki-67 expression in oral squamous cell carcinomas: the vagaries of fixation and microwave enhancement of immunocytochemistry.  J Oral Pathol Med. 1998;  27 ((9)) 434-440
• 2 Aron DC. Adrenal incidentalomas and glucocorticoid autonomy.  Clin Endocrinol (Oxf). 1998;  49 ((2)) 157-158
• 3 Bernini GP, Moretti A, Viacava P, Bonadio AG, Iacconi P, Miccoli P, Salvetti A. Apoptosis control and proliferation marker in human normal and neoplastic adrenocortical tissues.  Br J Cancer. 2002;  86 ((10)) 1561-1565
• 4 Bertherat J, Gimenez-Roqueplo AP. New insights in the genetics of adrenocortical tumors, pheochromocytomas and paragangliomas.  Horm Metab Res. 2005;  37 ((6)) 384-390
• 5 Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects.  Endocr Rev. 2003;  24 ((4)) 539-553
• 6 Dackiw AP, Lee JE, Gagel RF, Evans DB. Adrenal cortical carcinoma.  World J Surg. 2001;  25 ((7)) 914-926
• 7 Fu CG, Tominaga O, Nagawa H, Nita ME, Masaki T, Ishimaru G, Higuchi Y, Tsuruo T, Muto T. Role of p53 and p21/WAF1 detection in patient selection for preoperative radiotherapy in rectal cancer patients.  Dis Colon Rectum. 1998;  41 ((1)) 68-74
• 8 Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JK, Oertel YC, Posner MC, Schlechte JA, Wieand HS. Management of the clinically inapparent adrenal mass („incidentaloma”).  Ann Intern Med. 2003;  138 ((5)) 424-429
• 9 Hoss A, Urist MJ, Stojadinovic A, Mastorides S, Dudas ME, Leung DH, Kuo D, Brennan MF, Lewis JJ, Cordon-Cardo C. Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors.  Am J Pathol. 2001;  158 1245-1251
• 10 Ignaszczak-Szczepaniak M, Sawicka J, Sowinski J, Horst-Sikorska W. Genetics in development of adrenal cortex neoplasia.  Endokrynol Pol. 2003;  54 339-349
• 11 Ito Y, Obara T, Okamoto T, Kanbe M, Tanaka R, Ihara M, Okamoto J, Yamazaki K, Jibiki K. Efficacy of single - voided urine metanephrine and normetanephrine assay for diagnosis pheochromocytoma.  World J Surg. 1998;  22 ((7)) 684-688
• 12 Kasperlik-Zaluska AA, Migdalska BM, Makowska AM. Incidentally found adrenocortical carcinoma. A study of 21 patients.  Eur J Cancer. 1998;  34 ((11)) 1721-1724
• 13 Kubiak R, Kopczynski J, Pasz-Walczak G, Jesionek-Kupnicka D, Kordek R. Usefulness of immunohistochemistry in differential diagnosis of epithelial renal and adrenal gland tumors.  Wspolczesna Onkologia. 2004;  8 ((6)) 308-312
• 14 Lack EE. Tumours of the adrenal gland. In: Diagnostic Histopatology of Tumors, 2nd ed Ch. Fletcher. Curchill Livingstone 2000 19: 1057-1080
• 15 Linde NG, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment.  J Urol. 2003;  169 ((1)) 5-11
• 16 Linos DA. Management approaches to adrenal incidentalomas (adenomas): a view from Athens, Grecce, Italy.  Endocr Metab Clin North Am. 2000;  29 107-109
• 17 Martins AC, Cologna AJ, Tucci  Jr  S, Suaid HJ, Falconi RA. Clinical features and immunoexpression of p53, MIB-1 and proliferating cell nuclear antigen in adrenal neoplasms.  J Urol. 2005;  173 ((6)) 2138-2142
• 18 Orlando C, Gelmini S. Telomerase in endocrine and endocrine - dependent tumors.  J Steroid Biochem Mol Biol. 2001;  78 ((3)) 201-214
• 19 Song SY, Park S, Kim SR, Suh YL. Oncocytic adrenocortical carcinomas: a pathological and immunohistochemical study of four cases in comparison with conventional adrenocortical carcinoma.  Pathol Int. 2004;  54 ((8)) 603-610
• 20 Stojadinovic A, Brennan MF, Hoos A, Omeroglu A, Leung DH, Dudas ME, Nissan A, Cordo-Cardo C, Ghossein RA. Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis.  Mod Pathol. 2003;  16 ((8)) 742-751
• 21 Stojadinovic A, Ghossein RA, Hoos A, Nissan A, Marshall D, Dudas M, Cordon-Cardo C, Jaques DP, Brennan MF. Adrenocortical carcinoma: clinical, morphologic and molecular characterization.  J Clin Oncol. 2002;  20 ((4)) 941-950
• 22 Stratakis CA. Genetics of adrenocortical tumors: gatekeepers, landscapers and conductors in symphony.  Trends Endocrinol Metab. 2003;  14 ((9)) 404-410
• 23 Sworczak K, Babinska A, Stanek A, Lewczuk A, Siekierska-Hellmann M, Blaut K, Drobinska A, Basinski A, Lachinski AJ, Czaplinska-Kalas H, Gruca Z. Clinical and histopatological evaluation of adrenal incidentaloma.  Neoplasma. 2001;  48 ((3)) 221-226
• 24 Sworczak K, Bielawski KP, Falkiewicz B, Babinska A, Zaczek A, Lisowska U. Dysregulation of erbB family genes and ErbB (HER) receptors in pheochromocytoma.  Współczesna Onkologia. 2004;  8 ((4)) 213-218
• 25 Sworczak K, Zaczek A, Babinska A, Lisowska U, Bielawski KP, Falkiewicz B. Gene copy numbers of erbB oncogenes in human pheochromocytoma.  Oncology Rep. 2002;  9 1373-1378
• 26 Takehara K, Sakai H, Shono T, Irie J, Kanetake H. Proliferative activity and genetic changes in adrenal cortical tumors examined by flow cytometry, fluorescence In situ hybridization and immunohistochemistry.  Int J Urol. 2005;  12 ((2)) 121-127
• 27 Terzolo M, Boccuzzi A, Bovio S, Cappia S, Giuli P De, Ali A, Paccotti P, Porpiglia F, Fontana D, Angeli A. Immunohistochemical assessment of Ki-67 in the differential diagnosis of adrenocortical tumors.  Urology. 2001;  57 ((1)) 176-182
• 28 Torlontano M, Chiodini I, Pileri M, Guglielmi G, Cammisa M, Modoni S, Carnevale V, Trischitta V, Scillitani A. Altered bone mass and turnover in female patients with adrenal incidentaloma: the effect of subclinical hypercortisolism.  J Clin Endocrinol Metab. 1999;  84 ((7)) 2381-2385
• 29 Tupikowski W, Bednarek-Tupikowska G, Florczak A. Adrenocortical carcinoma and its treatment.  Postepy Hig Med Dosw. 2004;  58 27-36
• 30 Tutuncu NB, Gedik O. Adrenal incidentaloma: report of 33 cases.  J Surg Oncol. 1999;  70 ((4)) 247-250
• 31 Slooten H Van, Schaberg A, Smeenk D, Moolenaar AJ. Morphologic characteristics of benign and malignant adrenocortical tumors.  Cancer. 1985;  55 ((4)) 766-773
• 32 Vargas MP, Vargas HI, Kleiner DE, Merino MJ. Adrenocortical neoplasms: role of prognostic markers MIB-1, P53, and RB.  Am J Surg Pathol. 1997;  21 ((5)) 556-562
• 33 Weiss LM, Medeiros LJ, Vickery AL. Pathologic features of prognostic significance in adrenocortical carcinoma.  Am J Surg Pathol. 1989;  13 202-206

Correspondence