Corticomedullary mixed tumour resembling a small adrenal gland-involvement of cancer stem cells: case report
© The Author(s). 2017
Received: 30 September 2016
Accepted: 1 February 2017
Published: 13 February 2017
Adrenal corticomedullary mixed tumours are very rare. Its mechanism is rarely reported. Here we report the first case of a corticomedullary mixed tumour resembling a “small adrenal gland” with distinct arrangement of the cortical and medullary layers. We further hypothesize regarding the tumorigenic mechanism of this tumour.
A 58-year man had been diagnosed with diabetes and hypertension for 3 years. His 24-h urine vanillylmandelic acid (VMA) levels were slightly elevated. An abnormal circadian cortisol rhythm was noted, and his cortisol levels were not suppressed by dexamethasone. Abdominal computed tomography (CT) revealed a right adrenal gland lesion (diameter, 30 × 38 mm), while an enhanced CT showed enhancement and hypervascularization. The tumour was positive for adrenocorticotropic hormone, chromogranin A (CGA), and steroidogenic factor-1 (SF-1) on the tumour surface. Acetaldehyde dehydrogenase 1(ALDH1), CD44, CD133, Nestin, Nerve growth factor receptor (NGFR), and Sex determining region y-box 9(SOX9) staining were positive. Although administration of medications for diabetes and hypertension was stopped until surgery was performed, the blood sugar level and blood pressure were maintained after surgery.
This is the first report about a possible mechanism by which cancer stem cells induce adrenal corticomedullary tumours.
KeywordsCorticomedullary mixed tumour Tumorigenic mechanism Cancer stem cell Case report
The adrenal gland contains a cortex and medulla, which originate from different germ layers. Thus, most primary neoplasms of the adrenal gland arise from either adrenal cortical cells or chromaffin cells of the adrenal medulla, and adrenal tumours generated by more than one cell type are rare. Even if two cell types coexist in the adrenal gland, most often, two separate tumours form. Adrenal cortex and medulla lesions coexisting in the same tumour to form adrenal corticomedullary mixed tumours are rarer. In the approximately 20 cases of adrenal corticomedullary mixed tumours reported to date [1–20], tumour cells were distributed in these tumours in a random and unorganized fashion . Since cases were limited in number and little research on the subject, the tumorigenic mechanism remains unclear. We describe the first case of a corticomedullary mixed tumour resembling a “small adrenal gland” with a distinct arrangement of cortical and medullary layers, and hypothesize that tumour stem cells may contribute to its development.
The preoperative and postoperative endocrinological evaluation
LDDST Cortisol (nmol/L)
HDDST Cortisol (nmol/L)
<145(50% baseline value)
CPRT (ng/ml) 0 min
A corticomedullary mixed tumour is defined as a single adrenal tumour mass containing an intimately admixed population of both adrenal cortical cells and pheochromocytes . Corticomedullary mixed tumours are likely to occur in female , and most of them are benign with a favourable prognosis. However, some malignant tumours with a poor prognosis have been reported [16, 20]. Hence, long-term follow-up is needed.
Corticomedullary mixed tumours produce both cortisol and catecholamine, and therefore, signs and symptoms may arise from either tumour component. Hypersecretion of cortical and medullary lesions causes 40% of diabetes cases, 80% of hypertension cases, and 53.33% of Cushing’s syndrome cases . The typical clinical manifestations are easy to identify, however, the lack of specific clinical manifestations in many cases leads to them often being discovered accidentally, and ultimately a pathological diagnosis is required . Cases similar to that of our patient may manifest with subclinical Cushing’s syndrome, including cortisol rhythm abnormalities, but no typical Cushing’s syndrome appearance . Nonspecific symptoms, such as headache and flank pain, can increase the difficulty of diagnosis.
As the adrenal cortex and medulla originate from different germinal layers , cortical and medullary tumours usually develop independently, and the simultaneous development of these tumours is rare. Adrenal corticomedullary mixed tumours are rarer. The tumorigenic pathogenesis of such is different from synchronous separate adrenal collision tumours and corticomedullary mixed tumours with random, unorganized cells structure. The question of whether the cortical adenoma and pheochromocytoma components of corticomedullary mixed tumours grow independently, or whether their growth is interrelated, is difficult to resolve , therefore, the pathogenesis of corticomedullary mixed tumours remains obscure . The following mechanisms mainly have been proposed: Firstly, pheochromocytomas secreted ectopic corticotropin, which might caused adrenal cortical hyperplasia and/or adrenal cortical adenoma. Moreover, hyper-secreted catecholamines stimulated the anterior pituitary to secrete corticotropin, which may lead to similar adrenal cortical lesions . Additionally, key enzymes of catecholamine synthesis, such as beta hydroxylase, tyrosine hydroxylase, and phenylethanolamine-N-methyltransferase might be regulated by high concentrations of glucocorticoid via the intra-adrenal portal system. This induction leads to increased expression of epinephrine and norepinephrine, thus maintaining a vicious spiral . Besides, researchers speculated that some unknown mechanisms can destroy the interaction of normal cortical-chromaffin cell and result in trophic stimulation of both cells . Finally, genetic mutations in stem cells can lead to adrenal cortical tumours. Cortical tumours have excessive secretion of cortisol, and then leads to induction of the rate limiting enzyme in catecholamine synthesis, i.e. phenylethanolamine-N-methyltransferase, mediated medullary hyperplasia .
Concurrent cortical and medullary tumours present as either adrenal collision tumours, in which cortical and medullary tumours develop independently but in close proximity without admixture at the interface , or corticomedullary mixed tumours, in which the adrenal cortical and medullary tumour cells develop within the same tumour at random, forming a structurally unorganized tumour without distinct cortical and medullary layers . However, the present tumour differed from those previously described, as the cortical and medullary tumour cells were arranged in distinct layers resembling a “small adrenal gland” (Fig. 1b). The unique features of this tumour indicated that its tumorigenic mechanism might differ from that of other corticomedullary mixed tumours, it was likely derived from a single origin, which was commonly differentiated from tumor stem cell.
In summary, here we reported the first case of an adrenal corticomedullary mixed tumour with distinct layers of cortical and medullary cells resembling a “small adrenal gland”, which differed from previously reported corticomedullary mixed tumour types. We also hypothesize that tumour stem cells may contribute to the development of this tumour. Our findings provide a new insight into the tumorigenic mechanism of adrenal tumours, and may help future development in adrenal tumour interventions.
Aldehyde dehydrogenase 1
Nerve growth factor receptor
Sex determining region y-box 9
This study was supported by the grant from National Natural Science Foundations of China (NO. 81471039 and NO. 81270893) and the Natural Science Foundation Project of CQ (CSTC2014jcyjjq10006 and CSTC2012jjB10023).
Availability of data and materials
All data generated or analysed during this study are included in the article.
LD performed a literature search, clinical diagnosis and treatment. FF performed patient follow-up, and wrote the manuscript. WF, ZF, SY contributed to the clinical diagnosis and treatment. HW contributed to the clinical diagnosis and prepared the figures. ZT and ZL analysed and interpreted the data, and contributed to the critical revision of the manuscript. LD and HZ contributed to the study design, participated and supervised the clinical diagnosis and care, and wrote the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Ethics approval and consent to participate
All procedures were performed according to the Declaration of Helsinki and approved by the Ethics Committee of Xinqiao Hospital, Third Military Medical University (reference number 20130711). Written informed consent was obtained from the patient for participate in this study.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Mathison DA, Waterhouse CA. Cushing’s syndrome with hypertensive crisis and mixed adrenal cortical adenoma-pheochromocytoma. Am J Med. 1969;47:635–41.View ArticlePubMedGoogle Scholar
- Akai H, Sanoyama K, Namai K, et al. A case of adrenal mixed tumor of pheochromocytoma and adrenocortical adenoma presenting diabetes mellitus and hypertension. Nihon Naibunpi Gakkai Zasshi. 1993;69:659–69.PubMedGoogle Scholar
- Ohta TI, Motoyama T, Imai T, et al. Cortico-medullary mixed tumor (pheochromocytoma and cortical adenoma) of the adrenal gland. J Urol Pathol. 1995;3:157–64.Google Scholar
- Michal M, Havlicek F. Corticomedullary tumors of the adrenal glands. Report of two cases. Association of corticomedullary tumor with spindle cell sarcoma. Pathol Res Pract. 1996;192:1082–9.View ArticlePubMedGoogle Scholar
- Delèvaux I, Cabane J, Picard O, et al. Mixed corticomedullary tumor. Presse Med. 1998;27:1272–4.PubMedGoogle Scholar
- Wieneke JA, Thompson LD, Heffess CS. Corticomedullary mixed tumor of the adrenal gland. Ann Diagn Pathol. 2001;5:304–8.View ArticlePubMedGoogle Scholar
- Tissier F, Le Charpentier M, Guilhaume B, et al. Adrenal corticomedullary adenoma. An entity to know. Ann Pathol. 2002;22:493–4.PubMedGoogle Scholar
- Chu AY, LiVolsi VA, Fraker DL, et al. Corticomedullary mixed tumor of the adrenal gland with concurrent adrenal myelolipoma. Arch Pathol Lab Med. 2003;127:e329–32.PubMedGoogle Scholar
- Ma WY, Yang AH, Chang YH, et al. Coexistence of adrenal Cushing syndrome and pheochromocytoma in a ‘corticomedullary adenoma.’. Endocrinologist. 2007;17:341–5.View ArticleGoogle Scholar
- Lee P, Bradbury RA, Sy J, et al. Phaeochromocytoma and mixed corticomedullary tumor - a rare cause of Cushing’s syndrome and labile hypertension in a primigravid woman postpartum. Clin Endocrinol (Oxf). 2008;68:492–3.Google Scholar
- Kimura T, Usui T, Inamoto S, et al. Image in endocrinology. Pheochromocytoma with subclinical Cushing’s syndrome caused by corticomedullary mixed tumor of the adrenal gland. J Clin Endocrinol Metab. 2009;94:746–7.View ArticlePubMedGoogle Scholar
- Alexandraki KI, Michail OP, Nonni A, et al. Corticomedullary mixed adrenal tumor: case report and literature review. Endocr J. 2009;56:817–24.View ArticlePubMedGoogle Scholar
- Trimeche Ajmi S, Chadli Chaieb M, Mokni M, et al. Corticomedullary mixed tumor of the adrenal gland. Ann Endocrinol (Paris). 2009;70:473–6.View ArticleGoogle Scholar
- Singh M, Mandal S, Kakkar AK, et al. Mixed corticomedullary tumor with myelolipoma: a rare coexistence. Pathology. 2010;42:589–91.View ArticlePubMedGoogle Scholar
- Lau SK, Chu PG, Weiss LM. Mixed cortical adenoma and composite pheochromocytoma-ganglioneuroma: an unusualcorticomedullary tumor of the adrenal gland. Ann Diagn Pathol. 2011;15:185–9.View ArticlePubMedGoogle Scholar
- Turk AT, Asad H, Trapasso J, et al. Mixed corticomedullary carcinoma of the adrenal gland: a case report. Endocr Pract. 2012;18:e37–42.View ArticlePubMedGoogle Scholar
- Kaneko T, Matsushima H, Homma Y. Dopamine-secreting corticomedullary mixed tumor of the adrenal gland. Int J Urol. 2012;19:1123–4.View ArticlePubMedGoogle Scholar
- Donatini G. Editorial comment to dopamine-secreting corticomedullary mixed tumor of the adrenal gland. Int J Urol. 2012;19:1124–5.View ArticlePubMedGoogle Scholar
- Donatini G, Van Slycke S, Aubert S, et al. Corticomedullary mixed tumor of the adrenal gland-a clinical and pathological chameleon: case report and review of literature. Updates Surg. 2013;65:161–4.View ArticlePubMedGoogle Scholar
- Michalopoulos N, Pazaitou-Panayiotou K, Boudina M, et al. Mixed corticomedullary adrenal carcinoma. Surg Today. 2013;43:1232–9.View ArticlePubMedGoogle Scholar
- Ghander C, Tenenbaum F, Tissier F, et al. When adrenal Cushing’s and phaeochromocytoma meet. Lancet. 2012;380:1683.View ArticlePubMedGoogle Scholar
- Katabathina VS, Flaherty E, Kaza R, et al. Adrenal collision tumors and their mimics: multimodality imaging findings. Cancer Imaging. 2013;13:602–10.View ArticlePubMedPubMed CentralGoogle Scholar
- Young Jr WF. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356:601–10.View ArticlePubMedGoogle Scholar