Pheochromocytomas and Ganglioneuromas in the Aging Rats: Morphological and Immunohistochemical Characterization

Abstract

We investigated, morphologically and immunohistochemically, 74 medullary adrenal tumors, including 64 pheochromocytomas (14 malignant and 50 benign), 9 ganglioneuromas, and 1 malignant schwannoma. The tumors were detected in 2-year-old Wistar and Sprague-Dawley rats from carcinogenicity studies. Morphologically, benign pheochromocytomas were characterized by monomorphic, small, basophilic cells with almost absence of mitoses. Malignant pheochromocytomas presented a low grade of pleomorphism, higher rate of mitoses, necrosis, infiltrative growth and in 1 case metastases in the lung. Ganglioneuromas were characterized by ganglion and neuron-like cells embedded in an eosinophilic matrix containing neurites, Schwann cells, and scant fibrovascular elements. All pheochromocytomas were strongly immunoreactive for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Subpopulations of chromaffin cells expressed chromogranin A (CGA) positivity. Matrix and Schwann cells were positive for S-100 and for glial fibrillary acidic protein (GFAP). In focal areas of the tumors, ganglion cells and axons were positive for neurofilament proteins (NFP) and synaptophysin. Ganglion cells exhibited peripherin and ß-tubulin. Proliferative activity of the tumors was assessed by immunostaining the endogenous cell proliferation associated-antigen Ki-67 and the proliferating cell nuclear antigen (PCNA). As expected, cell proliferation indeces were much higher in malignant pheochromocytomas than in benign, yet ganglioneuromas remained immunonegative. Considering that Ki-67 antigen is more specific for cell proliferation, it should be regarded as marker of choice for supporting the differential diagnosis between benign and malignant pheochromocytomas.

A Spontaneous Ganglioneuroma in the Adrenal Medulla of a Young Wistar Hannover Rat

“…These tumors rarely occur (0.05-0.5%) in the adrenal medulla in rats, whereas pheochromocytoma is common (Haseman et al 1998;Pace et al 2002;Reznik et al 1980). As far as we know, the earliest appearance of a ganglioneuroma in the adrenal medulla in rats was observed in a fifty-eight-month-old Fischer rat (Reznik et al 1980).…”

“…This was thought to be an extremely rare case, especially because of the young age of this animal, considering the very low spontaneous occurrence of ganglioneuroma in older rats such as those in two-year carcinogenicity studies (Haseman et al 1998;Pace et al 2002;Reznik et al 1980).…”

“…Chromaffin cells and ganglion cells are generated from a common undifferentiated cell, the sympathoadrenal cell (Huber et al 2009), and dedifferentiation or differentiation into another cell sharing the same cell lineage is known to occur in tumors. In fact, almost all of the ganglioneuromas in the rat adrenal are accompanied by pheochromocytoma cells (Glaister et al 1997;Pace et al 2002;Reznik et al 1980). These previous reports and our results suggest that the ganglion cells in ganglioneuroma originate from dedifferentiated and differentiated atypical chromaffin cells of the adrenal medulla in rats.…”

Spontaneous Ganglioneuroma Possibly Originating from the Trigeminal Ganglion in a B6C3F1 Mouse

“…We found GFAP-positive neuropil-like elements resembling cells of the neurohypophysis located at the edge of the tumor mass. Schwann cells, satellite cells, and glial cells of ganglioneuromas have been demonstrated to express GFAP in human and animal cases (Pace et al 2002;Porter et al 2007;Scheithauer et al 1997). Glial fibrillary acidic proteinpositive neuropil-like elements in the present case may have represented one of the components of the tumor tissue rather than of the neurohypophysis.…”

Ganglion-Like Cells in Relation to C-cell Proliferation of the Thyroid Gland in Rats

“…GL cells also appear in the adrenal medullary tumor. A tumor in the adrenal medulla is diagnosed as ganglioneuroma when it consists of GL cells exclusively [6][7][8] . Accordingly, it is also appropriate to diagnose a tumor in the thyroid gland as ganglioneuroma when it is the ganglioneuroma type C-cell adenoma composed of GL cells exclusively.…”