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The natural course of pheochromocytomas (PCC) cannot be predicted for certain on the basis of primary histology, their malignant character can only be confirmed by the occurrence of metastases during follow-up. Based on the recently proposed PASS score for evaluation we examined 37 adrenal (36 sporadic and one familial) and six sporadic extra-adrenal paragangliomas (all designated as pheochromocytomas) with a 'malignant histology' to find additional predictive factors. Drawing upon the follow-up (18 months to 12 years, mean 5.8 years) metastasized (n ¼ 20) and nonmetastasized (n ¼ 23) courses could be distinguished. Metastasized PCC revealed significantly (P ¼ 0.03) more copy number changes on comparative genomic hybridization (CGH) (mean 8.3) than nonmetastasized tumors (mean: 4.3). The most frequent chromosomal alterations were losses on 1p (75.6%) and 3q (44%). Both were detected with identical frequency in metastasized and nonmetastasized PCC. A gain on 17q (P ¼ 0.025) was significantly predominant in malignant courses and suggests similarities in the genetic origin and progression of PCC and neuroblastomas. The proliferative activity (MIB-1 score) of metastasized PCC (n ¼ 20) was found to be significantly higher in metastasized tumors (mean 12.8% vs mean 3.5%). In contrast, the semiquantitatively scored membrane-bound staining of CD 44-S was stronger in tumors without metastases (mean 2.1 vs mean: 0.25) during the follow-up period (Po0.01). Although the results correspond to the established weight differences the tumor weight does not appear to be an independent prognostic factor. Our study suggests that CD 44-S and MIB-1 immunostaining as well as the CGH results might complement the PASS score in predicting a metastasized course of PCC. Regardless of tumor weight, tumors with a 'malignant histology' are highly prone to metastasize when more than 5% of MIB1-positive nuclei are present or CD44-S immunostaining is negative, or both. PCC with 10 or more copy number changes on CGH must be referred to as malignant tumors. The safe distinction between benign and malignant pheochromocytomas (PCC) is an unresolved dilemma beleaguering diagnostic pathology to the present day. In most cases the decision is therefore based on the occurrence of metastases as the only proof of malignancy. Recently, Thompson 1 proposed an adrenal gland scoring scale (PASS) capable of determining malignancy solely on the grounds of conventional histological criteria. Within the framework of this scoring scale, less prognostic importance is attributed to vascular and capsular invasion (with a score of 1 point each) than to growth pattern, necroses and characteristics of proliferative behavior (high cellularity, cellular monotony, more than three mitoses/10 HPF and the occurrence of atypical mitoses). These characteristics each have a score of two points).In recent reports on adrenal and extra-adrenal PCC a number of chromosomal aberrations were discussed with a view to their possible involvement

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