Prior literature suggests that cancer patients with hyperglycemia and type 2 diabetes mellitus (DM) exhibit worse oncologic and overall outcomes. Tumor metabolism and anabolism pathophysiology may explain this association, although this has not been adequately studied in adrenocortical carcinoma (ACC). We hypothesized that DM would be associated with worse oncological outcomes in ACC, and we utilized data from a national database and institutional sources for multimodal analysis.
Both a multi-institutional database (the Collaborative Endocrine Surgery Quality Improvement Program or CESQIP) and a single-center longitudinal cohort (Dana Farber Cancer Institute or DFCI) were queried as unique retrospective cohorts to identify patients with ACC. Patient demographics, tumor characteristics, DM-specific variables, and oncologic outcome data were assessed. Results were analyzed via univariate analysis and multivariable linear regression analysis. Statistical significance was defined as p < 0.05.
Forty-eight CESQIP patients met inclusion criteria; 16 (33.0%) had DM. DM patients had a higher frequency of recurrence on longitudinal follow-up (12.5% v 0.0%, p = 0.04). Persistent disease was observed in 68.8% of DM patients and 40.6% of non-DM patients (p = 0.06). Patients in the DFCI cohort with lower average glucose values (< 110 mg/dL) had a significant survival benefit (p < .0001). A mean serum glucose > 110 mg/dL had increased risk (HR 36.3, 95% confidence interval 1.6, 831.3) for all-cause mortality.
This multi-institutional, multimodal analysis suggests that patients with DM have worse oncologic and overall outcomes for ACC. While further study is warranted, consideration should be given among clinicians to optimize glycemic control as part of their ACC management.
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Data is available via CESQIP.org and by written request. These data were previously presented in limited fashion at the virtual CESQIP session hosted by the American Association of Endocrine Surgeons (AAES) on May 18, 2020.
Collaborative Endocrine Surgery Quality Improvement Program
Dana Farber Cancer Institute
American Association of Endocrine Surgeons
Body mass index
Beuschlein F, Weigel J, Saeger W, Kroiss M, Wild V, Daffara F, Libé R, Ardito A, al Ghuzlan A, Quinkler M, Oßwald A, Ronchi CL, de Krijger R, Feelders RA, Waldmann J, Willenberg HS, Deutschbein T, Stell A, Reincke M, Papotti M, Baudin E, Tissier F, Haak HR, Loli P, Terzolo M, Allolio B, Müller HH, Fassnacht M (2015) Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab 100(3):841–849. https://doi.org/10.1210/jc.2014-3182
Papathomas TG, Pucci E, Giordano TJ, Lu H, Duregon E, Volante M, Papotti M, Lloyd RV, Tischler AS, van Nederveen FH, Nose V, Erickson L, Mete O, Asa SL, Turchini J, Gill AJ, Matias-Guiu X, Skordilis K, Stephenson TJ, Tissier F, Feelders RA, Smid M, Nigg A, Korpershoek E, van der Spek PJ, Dinjens WNM, Stubbs AP, de Krijger RR (2016) An international Ki67 reproducibility study in adrenal cortical carcinoma. Am J Surg Pathol 40(4):569–576. https://doi.org/10.1097/PAS.0000000000000574
Terzolo M, Boccuzzi A, Bovio S, Cappia S, de Giuli P, Alì A, Paccotti P, Porpiglia F, Fontana D, Angeli A (2001) Immunohistochemical assessment of Ki-67 in the differential diagnosis of adrenocortical tumors. Urology. 57:176–182
Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L (2005) Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 12:657–666
Li W, Zhang X, Sang H, Zhou Y, Shang C, Wang Y, Zhu H (2019) Effects of hyperglycemia on the progression of tumor diseases. J Exp Clin Cancer Res 38:327
Joshi S, Lie M, Turner N (2015) Diabetes and its link with cancer: providing the fuel and spark to launch an aggressive growth regimen. Biomed Res Int 2015:390863
Hou Y, Zhou M, Xie J et al (2017) High glucose levels promote the proliferation of breast cancer cells through GTPases. Breast Cancer (Dove Med Press) 9:429–436
Han L, Ma Q, Li J, Liu H, Li W, Ma G, Xu Q, Zhou S, Wu E (2011) High glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. PLoS One 6:e27074
Talutis SD, Drake FT, Sachs T, Rao SR, McAneny D (2019) Evacuation of postoperative hematomas after thyroid and parathyroid surgery: an analysis of the CESQIP database. Surgery. 165(1):250–256. https://doi.org/10.1016/j.surg.2018.04.087
Homepage to the Collaborative Endocrine Surgery Quality Improvement Program. https://cesqip.org Site accessed May 13, 2020
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 371(9612):569–578. https://doi.org/10.1016/S0140-6736(08)60269-X
Warburg O (1956) On the origin of cancer cells. Science. 123(3191):309–314. https://doi.org/10.1126/science.123.3191.309
Langbein S, Zerilli M, Zur Hausen A et al (2006) Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer 94(4):578–585. https://doi.org/10.1038/sj.bjc.6602962
Zhou S, Wang S, Wu Q, Fan J, Wang Q (2008) Expression of glucose transporter-1 and -3 in the head and neck carcinoma--the correlation of the expression with the biological behaviors. ORL J Otorhinolaryngol Relat Spec 70(3):189–194. https://doi.org/10.1159/000124293
Smith TA (1999) Facilitative glucose transporter expression in human cancer tissue. Br J Biomed Sci 56(4):285–292
Reske SN, Grillenberger KG, Glatting G, Port M, Hildebrandt M, Gansauge F, Beger HG (1997) Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma. J Nucl Med 38(9):1344–1348
Fenske W, Völker HU, Adam P, Hahner S, Johanssen S, Wortmann S, Schmidt M, Morcos M, Müller-Hermelink HK, Allolio B, Fassnacht M (2009) Glucose transporter GLUT1 expression is an stage-independent predictor of clinical outcome in adrenocortical carcinoma. Endocr Relat Cancer 16:919–928
Tsujimoto T, Kajio H, Sugiyama T (2017) Association between hyperinsulinemia and increased risk of cancer death in nonobese and obese people: a population-based observational study. Int J Cancer 141(1):102–111. https://doi.org/10.1002/ijc.30729
Puglisi S, Perotti P, Pia A, Reimondo G, Terzolo M (2018) Adrenocortical carcinoma with hypercortisolism. Endocrinol Metab Clin N Am 47(2):395–407. https://doi.org/10.1016/j.ecl.2018.02.003
Margonis GA, Kim Y, Tran TB, Postlewait LM, Maithel SK, Wang TS, Glenn JA, Hatzaras I, Shenoy R, Phay JE, Keplinger K, Fields RC, Jin LX, Weber SM, Salem A, Sicklick JK, Gad S, Yopp AC, Mansour JC, Duh QY, Seiser N, Solorzano CC, Kiernan CM, Votanopoulos KI, Levine EA, Poultsides GA, Pawlik TM (2016) Outcomes after resection of cortisol-secreting adrenocortical carcinoma. Am J Surg 211(6):1106–1113. https://doi.org/10.1016/j.amjsurg.2015.09.020
Berruti A, Fassnacht M, Haak H, Else T, Baudin E, Sperone P, Kroiss M, Kerkhofs T, Williams AR, Ardito A, Leboulleux S, Volante M, Deutschbein T, Feelders R, Ronchi C, Grisanti S, Gelderblom H, Porpiglia F, Papotti M, Hammer GD, Allolio B, Terzolo M (2014) Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer. Eur Urol 65(4):832–838. https://doi.org/10.1016/j.eururo.2013.11.006
Ronchi CL, Sbiera S, Leich E, Tissier F, Steinhauer S, Deutschbein T, Fassnacht M, Allolio B (2012) Low SGK1 expression in human adrenocortical tumors is associated with ACTH-independent glucocorticoid secretion and poor prognosis. J Clin Endocrinol Metab 97(12):E2251–E2260. https://doi.org/10.1210/jc.2012-2669
Dekkers OM, Horváth-Puhó E, Jørgensen JO et al (2013) Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab 98(6):2277–2284. https://doi.org/10.1210/jc.2012-3582
el-Kebbi IM, Ziemer DC, Gallina DL, Phillips LS (1998) Diabetes in urban African-Americans. VI. Utility of fasting or random glucose in identifying poor glycemic control. Diabetes Care 21(4):501–505. https://doi.org/10.2337/diacare.21.4.501
Gill GV, Hardy KJ, Patrick AW, Masterson A (1994) Random blood glucose estimation in type 2 diabetes: does it reflect overall glycaemic control? Diabet Med 11(7):705–708. https://doi.org/10.1111/j.1464-5491.1994.tb00337.x
The authors would like to thank the AAES research committee of CESQIP, particularly Dr. Dave Schneider for making these data available. We would like to thank Lia Wrenn MD for her critical appraisal of the manuscript and for her support.
Conflict of interest
The authors declare that they have no conflict of interest.
This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
This article does not contain any studies with animals performed by any of the authors.
Given the retrospective nature of this research, a waiver of informed consent was obtained by the Institutional Review Board.
“CESQIP and the hospitals participating in CESQIP are the source of the data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors. The conclusions, findings, and opinions expressed by the authors do not necessarily reflect the official position of the AAES or CESQIP. Use of CESQIP data does not imply endorsement by any of the groups named above.”
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Wrenn, S.M., Pandian, T.K., Gartland, R.M. et al. Diabetes mellitus and hyperglycemia are associated with inferior oncologic outcomes in adrenocortical carcinoma. Langenbecks Arch Surg (2021). https://doi.org/10.1007/s00423-020-02061-0
- Adrenal gland
- Adrenocortical carcinoma
- Endocrine surgery
- Surgical metabolism
- Diabetes mellitus
- Warburg effect