Clinical review: Adrenocortical carcinoma: clinical update

CONTEXT: Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with incompletely understood pathogenesis and poor prognosis. Patients present with hormone excess (e.g. virilization, Cushing's syndrome) or a local mass effect (median tumor size at diagnosis > 10 cm). This paper reviews current diagnostic and therapeutic strategies in ACC. EVIDENCE ACQUISITION: Original articles and reviews were identified using a PubMed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) covering the time period up until November 2005. The following search terms were used in varying combinations: adrenal, adrenocortical, cancer, carcinoma, tumor, diagnosis, imaging, treatment, radiotherapy, mitotane, cytotoxic, surgery. EVIDENCE SYNTHESIS: Tumors typically appear inhomogeneous in both computerized tomography and magnetic resonance imaging with necroses and irregular borders and differ from benign adenomas by their low fat content. Hormonal analysis reveals evidence of steroid hormone secretion by the tumor in the majority of cases, even in seemingly hormonally inactive lesions. Histopathology is crucial for the diagnosis of malignancy and may also provide important prognostic information. In stages I-III open surgery by an expert surgeon aiming at an R0 resection is the treatment of choice. Local recurrence is frequent, particularly after violation of the tumor capsule. Surgery also plays a role in local tumor recurrence and metastatic disease. In patients not amenable to surgery, mitotane (alone or in combination with cytotoxic drugs) remains the treatment of choice. Monitoring of drug levels (therapeutic range 14-20 mg/liter) is mandatory for optimum results. In advanced disease, the most promising therapeutic options (etoposide, doxorubicin, cisplatin plus mitotane, and streptozotocin plus mitotane) are currently being compared in an international phase III trial (www.firm-act.org). Adjuvant treatment options after complete tumor removal (e.g. mitotane, radiotherapy) are urgently needed because postoperative disease-free survival at 5 yr is only around 30%, but options have still not been convincingly established. National registries, international cooperations, and trials provide important new structures for patients but also for researchers aiming at systematic and continuous progress in ACC. However, future advances in the management of ACC will mainly depend on a better understanding of the molecular pathogenesis facilitating the use of modern cancer treatments (e.g. tyrosine kinase inhibitors).     

Adrenocortical carcinoma

Adrenocortical carcinoma is a rare disease with a poor prognosis. Patients can present with a hormonal syndrome or with general symptoms from an abdominal mass. The pathogenesis is unknown. Sometimes the adrenocortical carcinoma is associated with tumour syndromes such as the Beckwith-Wiedemann and Li-Fraumeni syndrome; however, most tumours are sporadic. Using one of the international classification methods, histopathological research can in almost all cases distinguish between adrenocortical adenoma and carcinoma. complete surgical resection is the treatment of choice for adrenocortical carcinoma. Mitotane is given when surgery is not possible, after incomplete resection or for metastatic disease. Frequently used chemotherapeutic combinations are etoposide, doxorubicin, cisplatin and mitotane (EDP/M) and streptozotocin and mitotane (SZ/M). International and national cooperation has resulted in a randomised trial aimed at determining a standard therapy in advanced adrenocortical carcinoma. The Dutch Adrenal Network is a national cooperation of endocrinologists, pathologists and oncologists from all eight academic centres and Máxima Medical centre. The network combines knowledge and expertise and gives patients the opportunity to receive optimal treatment in their own district.     

Adrenocortical carcinoma: Impact of surgical treatment

Compared to benign adrenal lesions, secreting or otherwise, malignant adrenocortical carcinoma is rare. Overall prognosis is poor, with < 50% 5-year survival. Various prognostic factors have been identified, some tumor-related and others directly linked to surgical treatment. Surgery is the only possible curative treatment, and is decided upon in a multidisciplinary medical-surgical team meeting. Surgical approach (laparotomy vs. laparoscopy) remains a matter of debate. In the light of a recent literature search, the present review reassesses the prognostic criteria of surgical resection, the quality of which determines overall and recurrence-free survival.     

Adrenocortical carcinoma: Report of two cases

Adrenocortical carcinoma (ACC) is a rare neoplasm with a slight predilection for female patients. We report two cases of ACC. The first case was of a 7-year-old girl who presented with clitoromegaly. The second case was of a 22-Year-old female who presented with a lump in the abdomen and features of Cushing's syndrome with virilization.The clinical, biochemical, histological features along with differential diagnosis are discussed. These cases are presented because of their rarity, and also to highlight the importance of differentiating ACC from an adenoma particularly in pediatric patients.     

Adrenocortical carcinoma producing 11-deoxycorticosterone: a rare cause of mineralocorticoid hypertension

A 37-yr-old man presented with the classic signs of mineralocorticoid excess hypertension and hypokalemia. The cause was not aldosterone excess, but elevation of plasma 11-deoxycorticosterone (DOC). Computed tomography (CT) scans showed a large right adrenal mass without signs of metastatic disease. The tumor was removed by open laparotomy, and histology revealed an adrenocortical carcinoma. Two yr after diagnosis, the patient is in good general condition and there is no sign of recurrence or metastatic disease, despite the large tumor size. DOC producing adrenocortical carcinomas causing mineralocorticoid hypertension are very rare, so far only 10 cases have been described in the literature.     

Alcoholic hepatitis: a clinician's guide

Alcoholic hepatitis is a frequent reason for admission and a common consultation request for hepatologists and gastroenterologists. Although it seems to occur acutely, it is usually subacute and often superimposed on underlying alcoholic cirrhosis. Typically patients have a background of drinking on a daily basis, but, in response to a life crisis, patients have started drinking massively.     

Colorectal carcinoma: an update

During the last decade important advances have occurred in the fields of understanding genesis, molecular biology, detection of "precancerous data", intervention, and metastatic behaviour of colorectal cancer. An important step forward has been made in adjuvant therapy. Better understanding of 5-fluorouracil metabolism has led to advances in the treatment of metastatic colon cancer. In this review these recent developments as well as future directions are discussed.     

Adrenocortical stem and progenitor cells: implications for adrenocortical carcinoma

The continuous centripetal repopulation of the adrenal cortex is consistent with a population of cells endowed with the stem/progenitor cell properties of self-renewal and pluripotency. The adrenocortical capsule and underlying undifferentiated cortical cells are emerging as critical components of the stem/progenitor cell niche. Recent genetic analysis has identified various signaling pathways including Sonic Hedgehog (Shh) and Wnt as crucial mediators of adrenocortical lineage and organ homeostasis. Shh expression is restricted to the peripheral cortical cells that express a paucity of steroidogenic genes but give rise to the underlying differentiated cells of the cortex. Wnt/β-catenin signaling maintains the undifferentiated state and adrenal fate of adrenocortical stem/progenitor cells, in part through induction of its target genes Dax1 and inhibin-α, respectively. The pathogenesis of ACC, a rare yet highly aggressive cancer with an extremely poor prognosis, is slowly emerging from studies of the stem/progenitor cells of the adrenal cortex coupled with the genetics of familial syndromes in which ACC occurs. The frequent observation of constitutive activation of Wnt signaling due to loss-of-function mutations in the tumor suppressor gene APC or gain-of-function mutation in β-catenin in both adenomas and carcinomas, suggests perhaps that the Wnt pathway serves an early or initiating insult in the oncogenic process. Loss of p53 might be predicted to cooperate with additional genetic insults such as IGF2 as both are the most common genetic abnormalities in malignant versus benign adrenocortical neoplasms. It is unclear whether other factors such as Pod1 and Pref1, which are implicated in stem/progenitor cell biology in the adrenal and/or other organs, are also implicated in the etiology of adrenocortical carcinoma. The rarity and heterogeneous presentation of ACC makes it difficult to identify the cellular origin and the molecular progression to cancer. A more complete understanding of adrenocortical stem/progenitor cell biology will invariably aid in characterization of the molecular details of ACC tumorigenesis and may offer new options for therapeutic intervention.     

Pancreatic carcinoma: imaging update 2001

This paper discusses the most recent advances in imaging of pancreatic carcinomas. The specific modalities discussed include helical computed tomography (HCT) with combined CT angiography, magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP), and positron emission tomography (PET). Endoscopic ultrasound is discussed in other papers. HCT is believed to be the most efficacious modality for initial detection and staging of pancreatic carcinomas. It has an accuracy rate of about 95-97% for the detection of carcinomas and of virtually 100% for staging unresectable carcinomas. The accuracy for CT staging of a resectable tumor is about 80-85%, with small surface metastases to liver and peritoneum being the most often missed findings. MRI and MRCP are best used for evaluation of patients that cannot receive intravenous contrast media for HCT and of patients who have equivocal HCT findings. PET imaging may be useful for detection of extrapancreatic nodal metastases.     

Adrenocortical carcinoma manifesting pure primary aldosteronism: a case report and analysis of steroidogenic enzymes

Adrenocortical carcinoma manifesting pure hyperaldosteronism is extremely rare. We report here a 61-year-old woman with biochemically proven primary aldosteronism due to right adrenocortical carcinoma. Computed tomographic scan showed 4.5x5.3 cm lobulated mass with tiny calcification, while there was no significant uptake of 131I-iodomethyl norcholesterol in the tumor. Immunohistochemical analysis demonstrated expression of steroidogenic enzymes in the tumor tissue: P-450scc, P-45c21, 3beta-hydroxysteroid dehydrogenase, P450(17alpha), and P-450(11beta). In addition, we could demonstrate mRNA expression of aldosterone synthase (P-450aldo:CYP11B2) in the tumor by specific ribonuclease protection assay. This is the first report of a case of primary aldosteronism due to adrenocortical carcinoma, in which expression of all sets of steroidogenic enzymes required for aldosterone synthesis was proven.     

Rocky Mountain spotted fever: a clinician's dilemma

Rocky Mountain spotted fever is still the most lethal tick-vectored illness in the United States. We examine the dilemmas facing the clinician who is evaluating the patient with possible Rocky Mountain spotted fever, with particular attention to the following 8 pitfalls in diagnosis and treatment: (1) waiting for a petechial rash to develop before diagnosis; (2) misdiagnosing as gastroenteritis; (3) discounting a diagnosis when there is no history of a tick bite; (4) using an inappropriate geographic exclusion; (5) using an inappropriate seasonal exclusion; (6) failing to treat on clinical suspicion; (7) failing to elicit an appropriate history; and (8) failing to treat with doxycycline. Early diagnosis and proper treatment save lives.     

Benzene-induced acute myeloid leukemia: a clinician's perspective

Benzene-induced acute myeloid leukemia (AML) is considered a secondary form of AML, based both in theory and on limited cohort observations. Its latency, cytogenetic aberrations, and clinical features are thought similar to, or identical with, AML resulting from the use of modern day cytotoxic agents for chemotherapy and immunotherapy. Although distinction between secondary AML and the far more common de novo AML is difficult to establish with certainty in any given case, latency from toxic therapeutic and environmental exposure and certain clinical and pathological features generally separate these two entities. AML is the only human neoplasm proven to be potentially caused by benzene, which actually is an obsolete form of chemotherapy. Despite many years of environmental regulation, alleged toxic exposure to this ubiquitous chemical has become an expanding area of litigation. A review of benzene-induced AML suggests that, in developed countries, this entity should no longer merit serious consideration among workers in the modern petrochemical industry and related fields.