Arthur S. Tischler, MD
Professor of Pathology
Tufts University School of Medicine
Tufts Medical Center
800 Washington Street, Box 802
Boston, MA 02111
Phone 617 636-1038
Fax 617 636-8302

Ronald R. de Krijger, MD, PhD
Reinier de Graaf Hospital
Reinier de Graafweg 7
2625 AD Delft
The Netherlands
Phone: +31-15-2604547
Fax: +31-15-2604532


Pheochromocytomas (PCC) are neuroendocrine tumours of the adrenal medulla. Their extra-adrenal counterparts are called paragangliomas (PGL), which are usually sympathetic in the abdomen and chest, and parasympathetic in the head and neck region. Sympathetic PGL and PCC usually secrete catecholamines and are treated by surgery. Parasympathetic PGL usually do not produce catecholamines and treatment may be surgical, but a conservative approach is also frequently employed to avoid damage to cranial nerves and other vital structures in the head and neck area.

The task of pathology is to make the diagnosis of PCC or PGL and to give an indication of the potential clinical behaviour of tumours. Whilst the diagnosis is frequently straightforward in the typical setting (PCC in the adrenal medulla with proven catecholamine synthesis), this may not be so evident outside the adrenal gland. Apart from the typical histology (nested pattern of large cells with granular amphophilic cytoplasm, growing in so-called ôZellballen), additional immunostaining with chromogranin A, synaptophysin and tyrosine hydroxylase (TH) is helpful. If chromogranin A (CgA) is negative, the diagnosis is in doubt. However, head and neck PGL can show only focal staining for CgA and are often negative for TH. Keratin stains are typically negative.

The prediction of clinical behaviour is difficult. Despite extensive research there do not currently appear single markers or combinations thereof that allow the prediction of clinical behaviour with certainty. A number of seminal studies have been done in the past (1-3) that have put forward scoring systems based on combinations of markers (see table 1 and 2 below), but use has not gained universal acceptance and has not been recommended by official bodies. Nonetheless, some markers are shared by the major scoring systems, suggesting that their presence might eventually assist in risk stratification.


  1. to provide patients and clinicians with the latest developments in the field of pathology
  2. to provide clinicians with potential new immunohistochemical or molecular markers for the distinction of benign and malignant PCC and PGL
  3. to implement findings in other areas of (neuroendocrine tumour) research in the field of PCC and PGL pathology


Both PCC and PGL should preferably be reported by specialist pathologists, as surgery is more and more concentrated in tertiary centres. Such reporting should be done in a standardized way using a template. Examples of such templates have been published in the literature, recently by Mete et al. (4; including several members of this working group). However, aside from minimal reporting elements required for any tumor (e.g. location, size, invasiveness, adequacy of resection and presence of unusual features) there is not yet a consensus on what else must be included. Reports tend to vary according to institutional preferences.

So far, there does not seem to be a place for the use of classification systems for PCC and PGL for the distinction of benign and malignant tumours.


  1. Linnoila RI, Keiser HR, Steinberg SM, Lack EE. Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologic features. Hum Pathol. 1990 Nov;21(11):1168-80.
  2. Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol. 2002 May;26(5):551-66.
  3. Kimura N, Watanabe T, Noshiro T, Shizawa S, Miura Y. Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol. 2005 Spring;16(1):23-32.
  4. Mete O, Tischler AS, de Krijger R, McNicol AM, Eisenhofer G, Pacak K, Ezzat S, Asa SL. Protocol for the examination of specimens from patients with pheochromocytomas and extra-adrenal paragangliomas. Arch Pathol Lab Med. 2014 Feb;138(2):182-8.