Endocrine System

Adrenal Gland, Cortex - Hypertrophy

Narrative
Comment:
Adrenal cortical hypertrophy refers to an increased cell size without an appreciable increase in cell numbers. Hypertrophic cortical cells have increased amounts of cytoplasm, which may be pale to brightly eosinophilic (Figure 1, Figure 2, Figure 3, and Figure 4) but may also be clear, vacuolated, and/or basophilic. The nucleus is frequently enlarged. Small numbers of nuclei in a focus of hypertrophy may have features of atypia. If a large proportion of the hypertrophic cells are atypical, then atypia should be diagnosed rather than hypertrophy (see Adrenal Gland - Cortex - Cellular Atypia ). Cortical hypertrophy may be focal or diffuse. Focal hypertrophy (Figure 1, Figure 2, Figure 3, and Figure 4) most often involves the zona fasciculata. Small hypertrophic foci are generally noncompressive, but larger focal lesions may cause variable compression of the adjacent cortical parenchyma (Figure 3).

Diffuse cortical hypertrophy (Figure 5 and Figure 6) often results in pronounced widening of the cortex and overall gland enlargement compared with unaffected normal adrenal glands (Figure 7 and Figure 8).

Cortical hypertrophy (of the zona fasciculata) in rats and mice usually results from elevated levels of adrenocorticotropic hormone (ACTH), which in turn can be elevated due to various causes, such as primary hypothalamic or pituitary disease or decreased glucocorticoid feedback regulation caused by adrenal cortical toxic or degenerative lesions. Diffuse, bilateral, and often prominent hypertrophy in the zona fasciculata can also be a sequela to stress from various causes, a finding that is especially common in rats.

Hypertrophy (and hyperplasia) of zona glomerulosa cells can result from derangements of the renin-angiotensin system that result in elevated angiotensin II.

Whether focal or diffuse, cortical hypertrophy is generally not considered to be a preneoplastic change. However, cortical hypertrophy (increased cell size) and hyperplasia (increased cell numbers) can often be concurrent lesions in the same gland or even in the same focus. Thus, as a practical matter, determining which change is predominant in a given lesion and/or gland can be very difficult. Cortical hypertrophy can also be confused with the cortical cell enlargement that occurs in many cases of cytoplasmic vacuolization.
Recommendations:
Adrenal cortical hypertrophy should be diagnosed and assigned a severity grade and appropriate distribution modifier (i.e., focal, diffuse). The modifier "bilateral" should be used when hypertrophy is present in both glands. An attempt should be made to distinguish cortical hypertrophy from hyperplasia, though the frequent superimposition of both changes in the same lesion can make this determination very challenging. In cases where both findings are concurrent in the same focus, only hyperplasia should be recorded, with the hypertrophy feature described in the pathology narrative. If there are a small number of atypical cells in the focus of hypertrophy, they should be described in the narrative. However, if the pathologist feels there is a large enough proportion of atypical cells, cellular atypia should be diagnosed (see Adrenal Gland - Cortex - Cellular Atypia ).
Related Links:
Adrenal Gland - Cortex - Cellular Atypia
References:

Brix AE, Nyska A, Haseman JK, Sells DM, Jokinen MO, Walker NJ. 2005. Incidences of selected lesions in control female Harlan Sprague-Dawley rats from two-year studies performed by the National Toxicology Program. Toxicol Pathol 33:477-483.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/16036865

Dunn TB. 1970. Normal and pathologic anatomy of the adrenal gland of the mouse, including neoplasms. J Natl Cancer Inst 44:1323-1389.

Abstract: http://jnci.oxfordjournals.org/content/44/6/1323.abstract

Ferreira JC, Cruz CD, Neves D, Pignatelli D. 2007. Increased extracellular signal regulated kinases phosphorylation in the adrenal gland in response to chronic ACTH treatment. J Endocrinol 192:647-658.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/17332532

Frith CH, Botts S, Jokinen MP, Eighmy JJ, Hailey JR, Morgan SJ, Chandra M. 2000. Non-proliferative lesions of the endocrine system in rats, E-1. In: Guides for Toxicologic Pathology. STP/ARP/AFIP, Washington, DC.

Full Text: https://www.toxpath.org/docs/SSNDC/EndocrineNonprolifRat.pdf

Hamlin MH, Banas DA. 1990. Adrenal gland. In: Pathology of the Fischer Rat: Reference and Atlas (Boorman GA, Eustis SL, Elwell MR, Montgomery CA, MacKenzie WF, eds). Academic Press, San Diego, 501-518.

Abstract: https://www.ncbi.nlm.nih.gov/nlmcatalog/9002563

Harvey PW, Sutcliffe C. 2010. Adrenocortical hypertrophy: Establishing cause and toxicological significance. J Appl Toxicol 30:617-626.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/20687119

Mazzocchi G, Rebuffat P, Belloni AS, Robba C, Nussdorfer GG. 1980. An ultrastructural stereologic study of the effects of angiotensin II on the zona glomerulosa of the rat adrenal cortex. Acta Endocrinol 95:523-527.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/7006292

McEwan PE, Lindop GB, Kenyon CJ. 1996. Control of cell proliferation in the rat adrenal gland in vivo by the renin-angiotensin system. Am J Physiol (Endocrinol Metab) 34:E192-E198.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/8760097

National Toxicology Program. 2006. NTP TR-520. Toxicology and Carcinogenesis Studies of 3,3',4,4',5-Pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in Female Harlan Sprague-Dawley Rats (Gavage Studies). NTP, Research Triangle Park, NC.

Abstract: https://ntp.niehs.nih.gov/go/9301

National Toxicology Program. 2013. NTP TR-578. Toxicology and Carcinogenesis Studies of Gingko biloba Extract in F344/N Rats and B6C3F1 Mice (Gavage Studies). NTP, Research Triangle Park, NC.

Abstract: https://ntp.niehs.nih.gov/go/37193

Nyska A, Maronpot RR. 1990. Adrenal gland. In: Pathology of the Mouse: Reference and Atlas (Maronpot RR, Boorman GA, Gaul BW, eds). Cache River Press, Vienna, IL, 509-536.

Ulrich-Lai YM, Figueiredo HF, Ostrander MM, Choi DC, Engeland WC, Herman JP. 2006. Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am J Physiol (Endocrinol Metab) 291:E965-E973.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/16772325
  • Image of hypertrophy in the adrenal gland cortex from a female Sprague-Dawley rat in a chronic study

    Adrenal gland, Cortex - Hypertrophy in a female Sprague-Dawley rat from a chronic study. There is a well-demarcated, noncompressive focal area in which the cells are enlarged (FH). C = cortex, M = medulla.

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<p>Adrenal gland, Cortex - Hypertrophy in a female Sprague-Dawley rat from a chronic study. There is a well-demarcated, noncompressive focal area in which the cells are enlarged (FH). C = cortex, M = medulla.</p>

Adrenal gland, Cortex - Hypertrophy in a female Sprague-Dawley rat from a chronic study. There is a well-demarcated, noncompressive focal area in which the cells are enlarged (FH). C = cortex, M = medulla.
<p>Adrenal gland, Cortex - Hypertrophy in a female Sprague-Dawley rat from a chronic study (higher magnification of Figure 1). The cells in this focus of hypertrophy (FH) have increased amounts of pale eosinophilic cytoplasm.</p>

Adrenal gland, Cortex - Hypertrophy in a female Sprague-Dawley rat from a chronic study (higher magnification of Figure 1). The cells in this focus of hypertrophy (FH) have increased amounts of pale eosinophilic cytoplasm.
<p>Adrenal gland, Cortex - Hypertrophy in a male B6C3F1/N/N mouse from a chronic study. There is a focus of enlarged cells (arrows) in the cortex that slightly compresses the adjacent parenchyma; there is also subcapsular hyperplasia (SCH).</p>

Adrenal gland, Cortex - Hypertrophy in a male B6C3F1/N/N mouse from a chronic study. There is a focus of enlarged cells (arrows) in the cortex that slightly compresses the adjacent parenchyma; there is also subcapsular hyperplasia (SCH).
<p>Adrenal gland, Cortex - Hypertrophy in a male B6C3F1/N/N mouse from a chronic study (higher magnification of Figure 3). The cells in this focus of hypertrophy (FH) have increased amounts of pale eosinophilic cytoplasm and slightly enlarged nuclei.</p>

Adrenal gland, Cortex - Hypertrophy in a male B6C3F1/N/N mouse from a chronic study (higher magnification of Figure 3). The cells in this focus of hypertrophy (FH) have increased amounts of pale eosinophilic cytoplasm and slightly enlarged nuclei.
<p>Adrenal gland, Cortex - Hypertrophy in a male F344/N rat from a chronic study. Diffuse cortical hypertrophy results in pronounced overall gland enlargement. M = medulla.</p>

Adrenal gland, Cortex - Hypertrophy in a male F344/N rat from a chronic study. Diffuse cortical hypertrophy results in pronounced overall gland enlargement. M = medulla.
<p>Adrenal gland, Cortex - Hypertrophy in a male F344/N rat from a chronic study (higher magnification of Figure 5). The hypertrophic cortical cells (arrows) have increased cytoplasmic volume.</p>

Adrenal gland, Cortex - Hypertrophy in a male F344/N rat from a chronic study (higher magnification of Figure 5). The hypertrophic cortical cells (arrows) have increased cytoplasmic volume.
<p>Adrenal gland, Cortex - Normal in a male F344/N rat from a chronic study. A normal adrenal gland at the same magnification as Figure 5 6 is shown for comparison. M = medulla.</p>

Adrenal gland, Cortex - Normal in a male F344/N rat from a chronic study. A normal adrenal gland at the same magnification as Figure 5 6 is shown for comparison. M = medulla.
<p>Adrenal gland, Cortex - Normal in a male F344/N rat from a chronic study. A normal adrenal gland at the same magnification as Figure 6 is shown for comparison.</p>

Adrenal gland, Cortex - Normal in a male F344/N rat from a chronic study. A normal adrenal gland at the same magnification as Figure 6 is shown for comparison.

Authors

Mark J. Hoenerhoff, DVM, PhD, DACVP
Associate Professor
Veterinary Pathologist, In Vivo Animal Core
Unit for Laboratory Animal Medicine
University of Michigan
Ann Arbor, MI

Georgette D. Hill, D.V.M., Ph.D.
Toxicologic Pathologist/Assistant Pathology Program Manager
Comparative Molecular Pathology Division
Integrated Laboratory Systems, Inc.
Research Triangle Park, NC

Margarita M. Gruebbel, DVM, PhD, DACVP
Senior Pathologist
Experimental Pathology Laboratories, Inc.
Research Triangle Park, NC

Reviewers

Thomas J. Rosol, DVM, PhD, DACVP
Professor of Veterinary Biosciences
Senior Advisor, Life Sciences, Technology Commercialization and Knowledge Transfer
The Ohio State University
Columbus, OH

Gordon Flake, MD
Staff Scientist
NTP Pathologist
Cellular and Molecular Pathology Branch
National Institute of Environmental Health Sciences
Research Triangle Park, NC