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Annals of Diagnostic Pathology
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Annals of DIAGNOSTIC PATHOLOGY
Immunohistochemical expression of glypican-3 in adrenocortical carcinoma: A potential cause of diagnostic pitfalls
ARTICLE INFO
Keywords: Adrenocortical carcinoma Hepatocellular carcinoma HSP-70 Glypican-3 Immunohistochemistry Pitfall
Sir,
We read with great interest the paper entitled “Three cases of adre- nocortical tumors mistaken for hepatocellular carcinomas/diagnostic pit- falls and differential diagnosis” by Park et al. [1], which was recently published in Annals of Diagnostic Pathology. The authors reported on three interesting cases of adrenocortical tumors arisen from ectopic adrenocortical tissue and mistaken for hepatocellular carcinomas (HCCs) [1]. Of note, while two cases had been diagnosed as HCC at imaging, the third one was an adrenocortical adenoma misdiagnosed as HCC on needle biopsy [1]. Misdiagnosis was due to similar histopathological aspect and to glypican-3 (GPC-3) positivity in the neoplastic cells [1]. Compared to HepPar-1, GPC-3 has higher sensitivity as a diagnostic marker for HCC, as its expression is maintained in poorly differentiated HCC [2,3]. Im- munohistochemistry against GPC-3 is mainly used to differentiate pre- neoplastic and neoplastic hepatocellular disorders [2]. However, use of GPC-3 as a diagnostic marker of HCC versus metastatic tumors is con- troversial; indeed, GPC-3 expression was observed in other tumors, such as renal cell carcinomas [3]. Herein we report a case of adrenocortical car- cinoma (ACC) mistaken for HCC due to histological aspect and GPC-3 positivity. In brief, a 52 year-old man presented with hypercortisolism, systemic hypertension, hypokalaemia and hyperglycemia. Computed To- mography (CT) scan showed a solid, multilobular mass with in- homogeneous enhancement, involving the right adrenal gland and right hepatic lobe. The patient underwent adrenalectomy and hepatic segmen- tectomy and the surgical specimen was sent for histological examination. The histopathology request form did not provide any clinical information. Gross examination revealed a tumor of 15 cm, partially encapsulated and infiltrating both hepatic and adrenal parenchyma. At histological ex- amination, the tumor was composed of nests and trabeculae of polygonal cells, with eosinophilic or clear cytoplasm, separated by a fibro-vascular network (Fig. 1a and b). Wide hemorrhagic and necrotic areas and nu- merous atypical mitotic figures were seen. Immunohistochemistry re- vealed that neoplastic cells were negative for cytokeratin 7, glutamine synthetase, HepPar-1 and alpha-fetoprotein, and positive for GPC-3 (Fig. 1c) and HSP-70 (Fig. 1d). Therefore, HCC was diagnosed. When the
endocrinologists received the histopathological report, they relayed their suspicion of a functioning adrenal tumor. Thus, further im- munohistochemistry was performed, showing extensive positivity for sy- naptophysin (Fig. 1e), calretinin and alpha inhibin (Fig. 1f), focal posi- tivity for melan-A and negativity for EMA, broad spectrum cytokeratin and chromogranin. In view of those findings and of clinical information re- ceived, the tumor was finally diagnosed as ACC.
Apart from the case described by Park et al. [1], GPC-3 expression was previously reported in a percentage of adrenocortical adenomas [4], but never in ACCs. Thus, this is the first report describing GPC-3 positivity in ACC. ACC may arise from adrenocortical ectopic tissue in the liver [1], but it may also directly extend from the right adrenal gland into the liver or even metastatize to the liver. In all those in- stances, ACC needs to be differentiated from HCC. Differential diagnosis may be challenging based only on histopathological findings. Indeed, both tumors may show tumor cells with nuclear atypia and eosino- philic/clear cytoplasm, arranged in trabeculae. In the present case, immunohistochemistry targeting HCC alone and the positivity for GPC- 3 were further misleading and led to a first diagnosis of HCC. Stains for synaptophysin, melan-A, inhibin-alpha -which are positive in adreno- cortical tumors [5,6] - finally allowed to achieve the correct diagnosis.
We found GPC-3 expression in 6/10 adrenocortical adenomas and in 0/7 -apart from the present case- ACCs taken from our archive (un- published data). Those data indicate that GPC-3 positivity is a rare event in ACC. However, albeit infrequent, the possibility that ACC can express GPC-3 should be kept in mind to avoid incorrect diagnosis re- lied on such immunohistochemical positivity. Indeed, misdiagnosis of ACC as HCC has relevant clinical consequences, since the post-surgical treatment of the two entities is completely different.
This case also emphasizes the importance of gathering clinical in- formation. Although half of the patients with ACC have non-specific symptoms or are incidentally diagnosed by imaging, the other half have symptoms related to adrenocortical hormone excess, as in the present case. Clinical information can be essential to solve the differential di- agnosis between tumors with overlapping histological and im- munohistochemical features, such as ACC and HCC.
* Declarations of interest: none.
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References
[1] Park WY, Seo HI, Choi KU, Kim A, Kim YK, Lee SJ, et al. Three cases of adrenocortical tumors mistaken for hepatocellular carcinomas/diagnostic pitfalls and differential diagnosis. Ann Diagn Pathol 2017;31:9-13.
[2] Di Tommaso L, Destro A, Seok JY, Balladore E, Terracciano L, Sangiovanni A, et al. The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for de- tection of hepatocellular carcinoma. J Hepatol 2009;50:746-54.
[3] Baumhoer D, Tornillo L, Stadlmann S, Roncalli M, Diamantis EK, Terracciano LM. Glypican 3 expression in human nonneoplastic, preneoplastic, and neoplastic tissues: a tissue microarray analysis of 4,387 tissue samples. Am J Clin Pathol 2008;129:899-906.
[4] Ibrahim TR, Abdel-Raouf SM. Immunohistochemical study of Glypican-3 and
HepPar-1 in differentiating hepatocellular carcinoma from metastatic carcinomas in FNA of the liver. Pathol Oncol Res 2015;21:379-87.
[5] Ghorab Z, Jorda M, Ganjei P, Nadji M. Melan A (A103) is expressed in adrenocortical neoplasms but not in renal cell and hepatocellular carcinomas. Appl Immunohistochem Mol Morphol 2003;11:330-3.
[6] Chivite A, Matias-Guiu X, Pons C, Algaba F, Prat J. Inhibin A expression in adrenal neoplasms. A new immunohistochemical marker for adrenocortical tumors. Appl Immunohistochem 1998;6:42-9.
Simona Lionti, Antonio Ieni, Salvatore Cannavò, Valeria Barresi* Department of Human Pathology, University of Messina, Italy E-mail address: vbarresi@unime.it
* Corresponding author at: Department of Human Pathology, Polyclinic G. Martino, Pad D, Via Consolare Valeria, 98125 Messina, Italy.