Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study.

BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥ 50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥ 20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.

Developing treatment for adrenocortical carcinoma.

Cancer of the adrenal cortex (ACC) is a rare endocrine malignancy with limited treatment options. Patients typically present with autonomous hormonal overproduction and/or a large abdominal mass. Hormonal assays and medical imaging can be diagnostic, but urinary steroid profiling might be a more sensitive technique to assess malignancy in adrenal tumours. The stage of the disease at diagnosis is the most important prognostic factor. The current staging system needs refinement, especially to separate aggressive from indolent disease in stage IV patients and to select patients who need adjuvant treatment after complete surgical resection. Regarding the latter, assessing the proliferation index Ki-67 seems the best tool currently available. Genomic profiling is expected to become of clinical relevance in the future. Medical therapy is centred on the adrenolytic drug mitotane, which carries considerable toxicity and is not easy to manage. Its tolerability and long plasma level build-up phase may be improved by therapeutic drug monitoring based on pharmacokinetic modelling and intensive counselling of patients. Current chemotherapy regimens can offer disease stabilization in about 50% of patients, but an objective response should be expected in <25%. Research on targeted therapy and immunotherapy is difficult in this rare disease with often heavily pre-treated patients and has not yet been successful. Quality of care should be ensured by treating patients in centres with established experience in multidisciplinary oncologic care, who adhere to prevailing guidelines and state-of-the-art in diagnostic and treatment concepts. International collaboration in fundamental research and clinical trials is the key to further elucidate the pathogenesis and to improve patient care.

Disappearing adrenal masses.

Adrenal incidentalomas are a common finding due to the increasing use and improved technology of imaging studies. The majority of these enlargements are non-functional and irreversible. Publications on reversible adrenal enlargement are sparse. Our patient, a 66-year-old man, was admitted to the hospital due to abdominal discomfort. He was treated for rectal carcinoma 3 years before, and was now free of disease. Computed tomography (CT) scan showed no abnormalities other than the incidental finding of bilateral adrenal enlargement. Metastasis was suspected. The CEA-level, however, was within normal range and there was no evidence of hormonal overproduction. After 1 month the patient was reviewed. Physical examination and laboratory testing were normal. Surprisingly, the CT-scan showed a decreased size of both adrenals and after 3 months even showed completely normalized adrenals. Reversible adrenal enlargements are rare. Commonly described causes of adrenal enlargement are haematomas, cystic lesions and infections of the adrenal glands. The patient in this case did not show any clinical, laboratory or radiological signs of any of these diagnoses. The current existing differential diagnosis for bilateral adrenal enlargement is not sufficient to explain the findings in our patient.

Response to radiation therapy in adrenocortical carcinoma.

INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare disease which is considered resistant to many treatments. The role of radiotherapy in ACC remains unclear. In general radiotherapy is thought to be ineffective for the treatment of ACC, and therefore not often used. However, recent reports suggest the opposite. The aim of this study was to perform a retrospective analysis to evaluate the application of radiotherapy in Dutch ACC patients, and to determine the occurrence of response. MATERIALS AND METHODS: The Dutch ACC Registry (no.=159) was screened for patients who had received radiotherapy between 1990 and 2008. Tumor response evaluation was performed according to the Response Evaluation Criteria In Solid Tumors (RECIST). RESULTS: Only 13 patients (8% of registered patients) had received radiation therapy of whom 6 were irradiated for the palliation of painful bone metastases. In all patients this radiation resulted in pain relief. Three patients received adjuvant tumor bed radiation after resection. Four patients were radiated on irresectable tumor recurrence or tumor metastases. Two patients died soon after radiation therapy and therefore follow-up information regarding tumor response after radiation therapy of 2 patients was available. Interestingly, partial tumor response according to RECIST criteria, was observed in both patients. CONCLUSION: ACC can be sensitive to radiotherapy and should be considered in the treatment of advanced ACC, particularly in worrisome lesions. The role of radiotherapy in advanced ACC is to complement a systemic treatment such as mitotane or classic cytotoxic agents.

Extremely long survival in six patients despite recurrent and metastatic adrenal carcinoma.

OBJECTIVE: Adrenal cortical carcinoma (ACC) is an aggressive tumour with a high mortality. We describe six patients living 12-28 years despite recurrent and/or metastatic ACC. PATIENTS: The first patient presented in 1979 with an ACC of 8 cm. After resection, she developed seven recurrences for which she was treated with resection and/or mitotane (o,p'-DDD) treatment. The patient is still alive 28 years after diagnosis. The second patient presented with an ACC of 9 cm. After resection, the patient developed liver metastases, which were treated with o,p'-DDD. The patient is still alive 25 years after diagnosis. The third patient presented with an ACC of 12 cm. The tumour was resected followed by o,p'-DDD treatment. She had a local recurrence that was completely resected. She is still alive 18 years after diagnosis. The fourth patient presented with an ACC of 14 cm. After resection, adjuvant o,p'-DDD was started. Subsequently, the patient developed two recurrences, which were resected. He is still alive 17 years after the initial diagnosis. The fifth patient presented with an ACC of 10 cm. After diagnosis, she developed lung metastasis, which were treated with o,p'-DDD and chemotherapy. The patient is still alive with slowly progressive disease 12 years after diagnosis. The sixth patient presented with an ACC of 7 cm. After resection, she developed four recurrences, which were resected. The patient is still alive 28 years after diagnosis. CONCLUSION: Some patients can have an extremely long survival of ACC, despite recurrent disease and metastases. The mainstay of therapy in our patients was repeated surgery and o,p'-DDD.