January 2014 - Dr. Previn Gulavita
Clinical history: 81 year old female with hypertension, tachycardia, and diaphoresis with a retroperitoneal mass.
Pheochromocytoma is a catecholamine-secreting tumour arising from neural crest-derived chromaffin cells of the sympathoadrenal system. It is relatively uncommon in surgical pathology practice, with an estimated average annual incidence of 8 per million person-years (excluding familial cases).
Pheochromocytoma has been referred to as the “10%” tumour – 10% bilateral, 10% extra-adrenal, 10% malignant, and 10% occurring in childhood – but this is only an approximation that must be correlated with other factors, such as tumor location, patient age, and familial predisposition. Over 50% of cases of familial (MEN 2a and 2b) pheochromocytoma are bilateral, and the tumour may be multicentric within the adrenal gland. The peak incidence is in the fifth decade of life, but it can occur at virtually any age. Most clinical series report a roughly equal gender incidence.
Sporadic pheochromocytoma usually forms a unicentric spherical or oval mass that is often sharply circumscribed and may appear encapsulated. Histologic sections taken at the periphery of the tumour often show a fibrous pseudocapsule or, at times, no capsule at all. Pheochromocytoma is usually firm, with a glistening gray-white surface, which may be altered by degenerative change such as congestion, hemorrhage, or necrosis, and some tumours undergo cystic change that may be marked.
Pheochromocytoma usually has an anastomosing cell cord pattern, or sometimes an alveolar or “zell-ballen” architectural growth pattern in which the neoplastic cells form rounded to oval nests that are surrounded by a delicate fibrovascular network of supporting cells, the most characteristic supporting cell being the sustentacular cell. Occasionally, tumour cells are arranged in a predominantly solid or diffuse pattern. Alterations in the supporting stroma, including sclerosis, edema and changes in the vasculature, which could create diagnostic confusion, may also be present. The cells are typically polygonal in shape with a finely granular cytoplasm that is basophilic to lightly eosinophilic. Some tumours contain cells with prominent nuclear hyperchromasia and pleomorphism, but these features alone are not useful in predicting biologic behaviour. Cytoplasmic hyaline globules can be found in some pheochromocytomas and are characteristically PAS positive and resistant to diastase predigestion. Lipid degeneration can give the cytoplasm a clear vacuolated appearance that can mimic an adrenal cortical neoplasm. Immunohistochemically, it typically expresses neuroendocrine markers, such as chromogranin A and synaptophysin. It can also express a broad array of other regulatory peptides and hormones, including somatostatin, VIP, substance P, ACTH, and calcitonin. Sustentacular cells show immunoreactivity for S100 protein.
The incidence of clinically malignant adrenal pheochromocytoma is relatively low, an it is important to consider these separately from extra-adrenal paragangliomas, which have a significantly higher incidence of malignant behaviour. It is notoriously difficult on gross and histologic evaluation to predict which tumours will prove to be malignant. The histology of benign and malignant pheochromocytoma overlaps to such an extent that the most important criterion acceptable for malignancy is the presence of metastases in sites where non-neoplastic chromaffin tissue is not normally found. However, some histologic features have been noted to be more frequently associated with malignant behaviour. These include loss of the small alveolar/nesting pattern, to be replaced by larger cell nests lacking the well formed fibrovascular supporting network; a diffuse growth pattern; tumour cell spindling; confluent tumour necrosis; increased mitotic rate (>3/10 hpf); and the presence of atypical mitotic figures. Surgical resection has been the mainstay of treatment for pheochromocytoma.