Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Pace, V.
Right arrow Articles by Germann, P.-G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pace, V.
Right arrow Articles by Germann, P.-G.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

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

Virgilio Pace

Novartis Pharma AG, Preclinical Safety, Toxicology/Pathology, Basle, Switzerland, virgilio.pace{at}dompe.it

Elias Perentes

Novartis Pharma AG, Preclinical Safety, Toxicology/Pathology, Basle, Switzerland

Paul-Georg Germann

Novartis Pharma AG, Preclinical Safety, Toxicology/Pathology, Basle, Switzerland

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.

Key Words: Pheochromocytomas • ganglioneuromas • rats • Ki-67 • peripherin • ß-tubulin • proliferating cell nuclear antigen (PCNA) • adrenal gland.

References

  • Aloe L., Levi-Montalcini R. (1979). Nerve growth factor-induced transformation of immature chromaffin cells in vivo into sympathetic neurons: Effect of antiserum to nerve growth factor. Proc Natl Acad Sci USA 76: 1246—1250.[Abstract/Free Full Text]
  • Ambros IM, Zellner A., Roald B., Amann G., Ladenstein R., Printz D., Gadner H., Ambros PF (1996). Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma. N Engl J Med 334: 1505—1511.[Abstract/Free Full Text]
  • Brady S., Lechan RM, Schwaitzberg SD, Dayal Y., Ziar J., Tischler AS (1997). Composite pheochromocytoma/ganglioneuroma of the adrenal gland associated with multiple endocrine neoplasia 2A. Am J Surg Pathol 21: 102—108.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Brown HM, Komorowski RA, Wilson SD, Demeure MJ, Zhu YR (1999). Predicting metastasis of pheochromocytomas using DNA flow cytometry and immunohistochemical markers of cell proliferation. Cancer 86(8): 1583—1589.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Capen CC, DeLellis RA, Yarrington JT (2001). Endocrine system. In: Handbook of Toxicologic Pathology, Hasek-Hock WM, Rousseaux MA, Wallig MA (eds). Academic Press, San Diego.
  • Carney JA (1992). Adrenal gland. In: Histology for Pathologists, Sternberg SS (ed). Raven Press, New York.
  • Chandra M., Riley MGI, Johnson DE (1992). Spontaneous neoplasms in aged Sprague—Dawley rats. Arch Toxicol 66: 496—502.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Chandra M., Frith CF (1992). Spontaneous neoplasms in aged control Fischer 344 rats. Cancer Lett 62: 49—56.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Clarke MR, Weyant RJ, Watson CG, Carty SE (1998). Prognostic markers in pheochromocytoma. Hum Pathol 29(5): 522—526.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cormack MJ (1989). The endocrine system. In: Ham's Textbook of Histology, 9th ed, Harper and Row, New York, pp 611—615.
  • Foley J., Witte D., Chiu FC, Parysek LM (1994). Expression of the neural intermediate filament proteins peripherin and neurofilament-66/{alpha}-internexin in neuroblastoma. Lab Invest 71(2): 193—199.[Web of Science][Medline] [Order article via Infotrieve]
  • Gilbert C., Gillman J., Loustalot P., Lute W. ( 1958). The modifying influence of diet and the physical environment on spontaneous tumor frequency in rats. Br J Cancer 12: 565—593.[Web of Science][Medline] [Order article via Infotrieve]
  • Haseman JK, Hailey JR, Morris RW (1998). Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: A National Toxicology Program update. Toxicol Pathol 26: 428— 441.[Abstract/Free Full Text]
  • Karkavelas G., Katsetos CD, Geddes JF, Herman MM, Vinores SA, Cooper HS, Provencio J., Frankfurter A. (1998). Class III ß-Tubulin isotype (ß III) in the adrenal medulla: II. Localization in primary human pheochromocytomas. Anat Rec 250: 344—350.[CrossRef][Medline] [Order article via Infotrieve]
  • Katsetos CD, Karkavelas G., Frankfurter A., Vlachos IN, Vogeley K., Schober R., Wechscler W., Urich H. (1994). The stromal Schwann cell during maturation of peripheral neuroblastomas: Immunohistochemical observations with antibodies to the neuronal class III ß-tubulin isotype (ß III), and S-100 protein. Clin Neuropathol 13: 171—180.[Web of Science][Medline] [Order article via Infotrieve]
  • Katsetos CD, Herman MM, Balin BJ, Vinores SA, Hessler RB, Arking EJ, Karkavelas G., Frankfurter A. (1998). Class III ß-Tubulin isotype (ß III) in the adrenal medulla: III. Differential expression of neuronal and glial antigens identifies two distinct populations of neuronal and glial-like (sustentacular) cells in the PC12 rat pheochromocytoma cell line maintained in a gelfoam matrix system. Anat Rec 250: 351—365.[CrossRef][Medline] [Order article via Infotrieve]
  • Katsetos CD, Karkavelas G., Herman MM, Vinores SA, Provencio J., Spano AJ, Frankfurter A. (1998). Class III ß-Tubulin isotype (ß III) in the adrenal medulla: I. Localization in the developing human adrenal medulla. Anat Rec 250: 335—343.[CrossRef][Medline] [Order article via Infotrieve]
  • Maraziotis T., Perentes E., Karamitopoulou E., Nakagawa Y., Gessaga C., Probst A. (1992). Neuron-associated class III ß-tubulin isotype, retinal S-antigen, synaptophysin, and glial fibrillary acidic protein in human medulloblastomas: A clinicopathological analysis of 36 cases. Acta Neuropathol 84: 355—363.[Medline] [Order article via Infotrieve]
  • Nakagawara A., Ikeda K., Tsuneyoshi M., Daimaru Y., Enjojj M. (1985). Malignant pheochromocytoma with ganglioneuroblastomatous elements in a patient with von Recklinghausen's disease. Cancer 55: 2794—2798.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Nakazumi H., Sasano H., Lino K. (1998). Expression of cell cycle inhibitor p27 and Ki-67 in human adrenocortical neoplasms. Mod Pathol 11: 1165— 1170.
  • Rao GN, Edmondson J., Hildebrandt PK, Bruner RH (1996). Influence of dietary protein, fat, and fiber on growth, blood chemistry, and tumor incidences in Fischer 344 rats. Nutr Cancer 25: 269—279.[Web of Science][Medline] [Order article via Infotrieve]
  • Reznik G., Ward JM, Reznik-Schuller H. (1980). Ganglioneuromas in the adrenal medulla of F344 rats. Vet Pathol 17: 614—621.[Abstract]
  • Reznik G., Germann PG (1996). In: Monographs onPathology ofLaboratory Animals, Endocrine System. Springer-Verlag, Berlin, pp 427—432.
  • Rosai J. (1996). Ackerman's Surgical Pathology, 8th ed, Vol. 1, Mosby, St. Louis, MO, pp 998—999, 1037—1042.
  • Rose D., Maddox P., Brown D. (1994). Which proliferation markers for routine immunohistology? A comparison of five antibodies. J Clin Pathol 47: 1010— 1014.
  • Rosol TJ, Yarrington JT, Latendresse J., Capen CC (2001). Adrenal gland: Structure, function, and mechanism of toxicity. Toxicol Pathol 29(1): 41—48.[Abstract/Free Full Text]
  • Russel DS, Rubinstein LJ (1989). Pathology of Tumours of the Nervous System. Arnold, London, pp 945—974.
  • Scott R., Hall P., Haldane J., Van Noorden S, Price Y., Lane D. ( 1991). A comparison of immunohistochemical markers of cell proliferation with experimentally determined growth fraction. J Pathol 165: 173—178.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Strandberg JD (1996). Hyperplasia and pheochromocytoma, adrenal medulla, rat. In: ILSI Monograph on Pathology of Laboratory Animals, Endocrine System, 2nd ed, Jones TC, Capen CC, Mohr U (eds). Springer-Verlag, Berlin/Heidelberg, pp 411—421.
  • Tischler AS, Mcclain RM, Childers H., Downing J. (1991). Neurogenic signals regulate chromaffin cell proliferation and mediate the mitogenic effect of reserpine in the adult rat adrenal medulla. Lab Invest 65: 374—376.[Web of Science][Medline] [Order article via Infotrieve]
  • Tischler AS, Ziar J., Downing J., McClain RM (1995). Sustained stimulation of rat adrenal chromaffin cell proliferation by reserpine. Toxicol Appl Pharmacol 135: 254—257.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Tischler AS, Powers JF, Downing JC, Shahsavari M., Ziar J., McClain RM (1996). Vitamin D3, lactose, and xylitol stimulate chromaffin cell proliferation in the rat adrenal medulla. Toxicol Appl Pharmacol 140: 115— 123.
  • Tischler AS, Sheldon W., Gray R. (1996). Immunohistochemical and morphological characterization of spontaneously occurring pheochromocytomas in the aging mause. Vet Pathol 33: 512—520.[Abstract]
  • Tischler AS, Dichter MD, Biales B. (1977). Neuroendocrine neoplasms and their cells of origin. N Engl J Med 296: 919—925.[Web of Science][Medline] [Order article via Infotrieve]
  • Tischler AS, Powers JF, Shahsavari M., Ziar J., Tsokas P., Downing J., McClain RM (1997). Comparative studies of chromaffin cell proliferation in the adrenal medulla of rats and mice. Fundam Appl Toxicol 35: 216—220.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Tischler AS, Powers JF, Pignatello M., Tsokas P., Downing J., McClain RM (1999). Vitamin D3-induced proliferative lesions in the rat adrenal medulla. Toxicol Sci 51: 9—18.[Abstract/Free Full Text]

Toxicologic Pathology, Vol. 30, No. 4, 492-500 (2002)
DOI: 10.1080/01926230290105668
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Toxicol PatholHome page
Y. Yasui, Y. Ohta, Y. Ueda, K. Hasegawa, T. Kihara, M. Hosoi, R. Miyajima, A. Shiga, K. Imai, and K. Toyoda
Spontaneous Ganglioneuroma Possibly Originating from the Trigeminal Ganglion in a B6C3F1 Mouse
Toxicol Pathol, April 1, 2009; 37(3): 343 - 347.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Pace, V.
Right arrow Articles by Germann, P.-G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pace, V.
Right arrow Articles by Germann, P.-G.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?