The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: A North American validation

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Abstract

Background

A reclassification of the International Union Against Cancer (UICC) staging system for adrenocortical carcinoma (ACC) patients has recently been proposed by the European Network for the Study of Adrenal Tumors (ENSAT) to better discriminate between cancer-specific mortality (CSM) risk strata. We formally tested the validity of the modified staging system in a large North American population-based cohort.

Methods

Kaplan–Meier survival curves depicted CSM rates in the overall population and after stratification according to the 2004 UICC or the 2008 ENSAT-staging system. Cox regression models addressing CSM tested the prognostic value of respectively the UICC or the ENSAT-staging system. Harrell’s concordance index quantified the accuracy of the standard versus the modified staging system.

Results

In the overall population (n = 573), the CSM-free survival rates at 1, 3, and 5 years were, respectively, 62.9%, 47.0%, and 38.1%. No statistically significant differences in survival were recorded between 2004 UICC stages II and III patients (p = 0.1). Conversely, a statistically significant difference was observed between 2008 ENSAT stage II and stage III patients (p < 0.001). The 2008 ENSAT-staging system showed higher accuracy (83.0%) in predicting 3-year CSM rates, relative to the 2004 UICC-staging system (79.5%) (p < 0.001).

Conclusion

Our study corroborates the superior accuracy of the ENSAT-staging system for ACC relative to the 2004 UICC-staging system. In consequence, the 2008 ENSAT-staging system may warrant consideration in the next update of staging manuals.

Introduction

Adrenocortical carcinoma (ACC) is a rare solid tumour, with an estimated incidence of 0.5–2.0 per million population.1, 2, 3 ACC is characterised by a poor prognosis, with 5-year cancer-specific mortality (CSM) free survival rates between 16% and 38%.1, 3, 4 The prognostic stratification of patients with ACC is crucial, since the survival of those patients may be very different.2, 3, 5, 6, 7 To date, only tumour stage has been consistently found as an independent predictor of CSM.6, 7, 8, 9, 10, 11, 12, 13, 14 Nonetheless, other variables, such as patient age,7, 8, 12 type of treatment9, 10, 12, 13 and tumour grade7, 11, 13 emerged as CSM predictors in select studies.

The first tumour, node and metastasis (TNM) classification was proposed in 2004 by the International Union Against Cancer (UICC).15 This scheme was largely based on the classification systems proposed by Macfarlane16 and Sullivan.17 It classifies tumours  5 centimeters (cm) as stage I (T1N0M0) and tumours > 5 cm as stage II (T2N0M0) if these do not fulfill the criteria for stages III and IV. Stage III ACC infiltrates the surrounding adipose tissue (T3N0M0) or invades at least one lymph node (T1–2N1M0). Stage IV ACC indicates infiltration of surrounding adipose tissue and at least one positive lymph node (T3N1M0), tumour invasion into adjacent organs (T4N0–1M0) or the presence of distant metastases (T1–4N0–1M1) (Table 1).

Recently, Fasschnat et al. showed that the stratification based on the 2004 UICC-staging system failed to accurately discriminate between the prognoses of stages II and III patients.18 To circumvent this limitation, the European Network for the Study of Adrenal Tumors (ENSAT) proposed a modification of the 2004 UICC-staging system.18 The derived 2008 ENSAT-staging system reclassified stage III and stage IV ACC.18 The 2008 ENSAT stage III denotes the presence of nodal metastases, irrespective of T stage (T1–4N1M0), or tumour extension into surrounding adipose tissue, or invasion of adjacent organs (T3–4N0M0). Conversely, the 2008 ENSAT stage IV ACC only includes tumours with established distant metastases (T1–4N0–1M1) (Table 1).

Although the prognostic discrimination was better when the ENSAT cohort was used for a head-to-head comparison of the modified ENSAT versus the standard 2004 UICC-staging system, no external validation has been performed to prove the value of the 2008 ENSAT-staging system in an independent cohort. To address this limitation, we formally tested the prognostic ability of the 2008 ENSAT-staging system using Harrell’s concordance index (c-index) and we compared it with the 2004 UICC-staging system.

Section snippets

Study population

Within 16 Surveillance, Epidemiology and End Results (SEER) registries, patients with ACC were identified using the International Classification of Diseases for Oncology codes (second and third edition). Specifically, primary tumour location codes (ICD-O-2 C74.0 and C74.9 codes) and histology codes (ICD-O-3: 8010, 8140 and 8370) were used for patients diagnosed between the years 1988 and 2006,19 which resulted in the identification of 1206 patients affected by adrenocortical carcinoma. The 16

Results

The study population consisted of 573 patients diagnosed with ACC between 1988 and 2006 within 16 SEER registries (Table 2). The majority was female (55.7%) and Caucasian (86.0%). The mean and median tumour size was 11.8 and 11.0 cm. Overall, 65.6%, 5.3% and 29.1% of patients were, respectively, treated with surgery only, surgery and adjuvant radiotherapy, and without surgery. The majority of patients (43.6%) were diagnosed in the most contemporary year tertile (2001–2006).

In the overall

Discussion

Prognostication in any malignancy is important for initial treatment selection, adjuvant or salvage therapy, type and frequency of follow-up, as well as for the interest of the patients and the treating physicians.22, 23 In ACC, only two treatment modalities may affect the natural history of the disease. Surgery for patients with non-metastatic disease represents the mainstay therapy.2, 3, 4, 9, 10, 24, 25, 26 Those with locally advanced disease may benefit from adjuvant systemic mitotane.25

Conflict of interest statement

None declared.

Acknowledgements

Dr. Pierre I. Karakiewicz is partially supported by the University of Montreal Urology Associates, Fonds de la Recherche en Santé du Québec, the University of Montreal Department of Surgery and the University of Montreal Foundation.

References (32)

  • L. Ng et al.

    Adrenocortical carcinoma: diagnosis, evaluation and treatment

    J Urol

    (2003)
  • B.L. Paton et al.

    Outcomes of adrenal cortical carcinoma in the United States

    Surgery

    (2006)
  • J.E. Lee et al.

    Surgical management, DNA content, and patient survival in adrenal cortical carcinoma

    Surgery

    (1995)
  • B.L. Wajchenberg et al.

    Adrenocortical carcinoma: clinical and laboratory observations

    Cancer

    (2000)
  • B. Allolio et al.

    Clinical review: adrenocortical carcinoma: clinical update

    J Clin Endocrinol Metab

    (2006)
  • A.P. Dackiw et al.

    Adrenal cortical carcinoma

    World J Surg

    (2001)
  • R. Vassilopoulou-Sellin et al.

    Adrenocortical carcinoma. Clinical outcome at the end of the 20th century

    Cancer

    (2001)
  • K.Y. Bilimoria et al.

    Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors

    Cancer

    (2008)
  • J.P. Luton et al.

    Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy

    New Engl J Med

    (1990)
  • P. Icard et al.

    Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group

    World J Surg

    (2001)
  • A. Stojadinovic et al.

    Adrenocortical carcinoma: clinical, morphologic, and molecular characterization

    J Clin Oncol

    (2002)
  • G. Abiven et al.

    Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients

    J Clin Endocrinol Metab

    (2006)
  • E. Kebebew et al.

    Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress?

    World J Surg

    (2006)
  • G. Assie et al.

    Prognostic parameters of metastatic adrenocortical carcinoma

    J Clin Endocrinol Metab

    (2007)
  • R.A. De Lellis et al.

    Pathology and genetics of tumors of endocrine organs

    (2004)
  • D.A. Mcfarlane

    Cancer of the adrenal cortex: the natural history, prognosis and treatment in the study of fifty cases

    Ann R Coll Surg Engl

    (1958)
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