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Horm Metab Res 2017; 49(10): 786-792
DOI: 10.1055/s-0043-116385
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Lipofuscin Accumulation in Cortisol-Producing Adenomas With and Without PRKACA Mutations

Anna Angelousi
1   Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA
,
Eva Szarek
1   Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA
,
Vincent Shram
2   Microscopy and Imaging Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA
,
Electron Kebebew
3   Endocrine Surgery, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA
,
Martha Quezado
4   Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA
,
Constantine A Stratakis
1   Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA
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Publikationsverlauf

received 15. April 2017

accepted 05. Juli 2017

Publikationsdatum:
23. August 2017 (online)

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Abstract

The adrenal cortex accumulates lipofuscin granules with age. Lipofuscin accumulation is also seen in adrenocortical tumors associated with Cushing syndrome (CS), particularly those with PRKAR1A mutations, such as in primary pigmented nodular adrenocortical disease (PPNAD). We investigated the presence of lipofuscin in cortisol-producing adenomas (CPAs) responsible for CS with and without the PRKACA (pLeu206Arg) somatic mutation. Ten paraffin-embedded sections of CPAs from cases with overt CS with (n=4) and without (n=6) a PRKACA mutation were microscopically examined through three detection methods, the hematoxylin-Eosin (H & E) staining, the Fontana Masson (FM) staining using light microscopy, and lipofuscin autofluorescence, using confocal laser scanning microscopy (CLSM). Sections were examined quantitatively according to the intensity of the pigmentation, as well as qualitatively based on the total number of granular pigments at all visual fields per tissue slide. Tissues from CPAs were compared to peritumoral adjacent tissues (n=5), to Conn adenomas (n=4), and PPNAD (n=3). CPAs had significantly higher number of lipofuscin-pigment granules compared to peritumoral adrenal tissue and Conn adenomas (46.9±9.5 vs. 3.8±4.8, p=0.0001). The presence of the PRKACA mutation did not increase the chances of pigmentation in the form of lipofuscin granules within CPAs associated with CS. Thus, all CPAs leading to CS accumulate lipofuscin, which presents like pigmentation sometimes seen macroscopically but always detected microscopically. PPNAD caused by PRKAR1A mutations is the best known adrenal lesion leading to CS associated with intense lipofuscin pigmentation and this was confirmed here; CPAs harboring PRKACA mutations did not have statistically significantly more pigmentation than CPAs without mutation, but a larger study might have shown a difference.

Key words

lipofuscin - Cushing syndrome - adrenal adenoma - cortisol - Conn adenoma - PPNAD
 

  • References

  • 1 Cheng B, Tserng KY, Kowal J. et al. Characterization and identification of an adrenal age-related nonpolar fluorescent substance. Endocrinology 1996; 137: 2447-2456
    CrossrefPubMedSuche in Google Scholar
  • 2 Cheng B, Hornick TR, Hassan MO. et al. Effects of prolonged ACTH-stimulation on adrenocortical accumulation of lipofuscin granules in aged rats. Tissue Cell 1999; 31: 594-604
    CrossrefPubMedSuche in Google Scholar
  • 3 Terman A, Brunk UT. Lipofuscin: mechanisms of formation and increase with age. APMIS: Acta pathologica, microbiologica, et immunologica Scandinavica 1998; 106: 265-276
    CrossrefPubMedSuche in Google Scholar
  • 4 Kovacs K, Horvath E, Feldman PS. Pigmented adenoma of adrenal cortex associated with Cushing’s syndrome: Light and electron microscopic study. Urology 1976; 7: 641-645
    CrossrefPubMedSuche in Google Scholar
  • 5 Odanaka M, Katabami T, Inoue M. et al. Adrenal black adenoma associated with preclinical Cushing’s syndrome. Pathol Int 2003; 53: 796-799
    CrossrefPubMedSuche in Google Scholar
  • 6 Tirosh A, Lodish MB, Papadakis GZ. et al. Diurnal plasma cortisol measurements utility in differentiating various etiologies of endogenous cushing syndrome. Horm Metab Res 2016; 48: 677-681
    Thieme ConnectPubMedSuche in Google Scholar
  • 7 Lindholm J, Juul S, Jorgensen JO. et al. Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001; 86: 117-123
    PubMedSuche in Google Scholar
  • 8 Stratakis CA. E pluribus unum? The main protein kinase A catalytic subunit (PRKACA), a likely oncogene, and cortisol-producing tumors. J Clin Endocrinol Metab 2014; 99: 3629-3633
    CrossrefPubMedSuche in Google Scholar
  • 9 Beuschlein F, Fassnacht M, Assie G. et al. Constitutive activation of PKA catalytic subunit in adrenal cushing’s syndrome. N Engl J Med 2014; 370: 1019-1028
    CrossrefPubMedSuche in Google Scholar
  • 10 Carney JA, Lyssikatos C, Lodish MB. et al. Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes. Hum Pathol 2015; 46: 40-49
    CrossrefPubMedSuche in Google Scholar
  • 11 Erem C, Hacihasanoglu A, Cinel A. et al. Adrenal black adenoma associated with Cushing’s syndrome. Endocrine 2004; 25: 253-257
    CrossrefPubMedSuche in Google Scholar
  • 12 Fischer AH, Jacobson KA, Rose J. et al. Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc 2008; 1: 2008 pdb prot4986
    PubMedSuche in Google Scholar
  • 13 Markelic M, Velickovic K, Golic I. et al. The origin of lipofuscin in brown adipocytes of hyperinsulinaemic rats: The role of lipid peroxidation and iron. Histol Histopathol 2013; 28: 493-503
    PubMedSuche in Google Scholar
  • 14 Inomoto C, Sato H, Kanai G. et al. Black adrenal adenoma causing preclinical Cushing’s syndrome. Tokai J Exp Clin Med 2010; 35: 57-61
    PubMedSuche in Google Scholar
  • 15 Damron TA, Ward WG, Stewart A. Osteosarcoma, chondrosarcoma, and Ewing’s sarcoma: National Cancer Data Base Report. Clinical orthopaedics and related research 2007; 459: 40-47
    CrossrefPubMedSuche in Google Scholar
  • 16 Lucksch F. Uber pigmentierte Adenome der Nebennieren. Beitr. z. Pathol. Anat. u.z. allg. Pathol. 1916; Bd. 215
    PubMedSuche in Google Scholar
  • 17 Baker MR. A pigmented adenoma of the adrenal. Arch Pathol 1938; 26: 845-852
    PubMedSuche in Google Scholar
  • 18 Robinson MJ, Pardo V, Rywlin AM. Pigmented nodules (black adenomas) of the adrenal. An autopsy study of incidence, morphology, and function. Hum Pathol 1972; 3: 317-325
    CrossrefPubMedSuche in Google Scholar
  • 19 Tseng CH, Chang GK, Wong QY. et al. Cushing’s syndrome and functioning adrenal black adenoma. South Med J 1978; 71: 1166-1168
    CrossrefPubMedSuche in Google Scholar
  • 20 Zaniewski M, Sheeler LR. Cushing’s syndrome associated with functional black adenoma of the adrenal cortex. South Med J 1980; 73: 1410-1412
    CrossrefPubMedSuche in Google Scholar
  • 21 Ueda Y, Tanaka H, Murakami H. et al. A functioning black adenoma of the adrenal gland. Intern Med 1997; 36: 398-402
    CrossrefPubMedSuche in Google Scholar
  • 22 Caplan RH, Virata RL. Functional black adenoma of the adrenal cortex. A rare cause of primary aldosteronism. Am J Clin Pathol 1974; 62: 97-103
    PubMedSuche in Google Scholar
  • 23 Shimokawa I, Higami Y, Horiuchi S. et al. Advanced glycosylation end products in adrenal lipofuscin. J Gerontol A Biol Sci Med Sci 1998; 53: 49-51
    PubMedSuche in Google Scholar
  • 24 Kamalanathan S, Mahesh DM, Muruganandham K. et al. Black adrenal adenoma: Distinction from PPNAD. BMJ Case Rep 2012; 3: 2012
    PubMedSuche in Google Scholar
  • 25 Mochizuki Y, Park MK, Mori T. et al. The difference in autofluorescence features of lipofuscin between brain and adrenal. Zoolog Sci 1995; 12: 283-288
    CrossrefPubMedSuche in Google Scholar
  • 26 Bahu RM, Battifora H, Shambaugh 3rd G. Functional black adenoma of the adrenal gland. Light and electron microscopical study. Arch Pathol 1974; 98: 139-142
    PubMedSuche in Google Scholar
  • 27 Balazs M. Functioning “black adenoma” of the adrenal gland with emphasis on ultrastructural studies. Zentralbl Pathol 1991; 137: 151-156
    PubMedSuche in Google Scholar
  • 28 Bourdeau I, Lacroix A, Schürch W. et al. Primary pigmented nodular adrenocortical disease: paradoxical responses of cortisol secretion to dexamethasone occur in vitro and are associated with increased expression of the glucocorticoid receptor. J Clin Endocrinol Metab 2003; 88: 3931-3937
    CrossrefPubMedSuche in Google Scholar