Home > E. Pathology by systems > Endocrine system > Adrenals > pigmented nodular adrenocortical disease

pigmented nodular adrenocortical disease

Thursday 3 February 2011

PPNAD, primary pigmented micronodular adrenal disease, pigmented micronudular dysplasia; adrenocorticotropin-independent macronodular adrenal hyperplasia; PPAD; Primary pigmented (micronodular) adrenocortical disease

Definition: Primary pigmented nodular adrenocortical disease is a rare cause of adrenocorticotropic hormone-independent Cushing syndrome.

Molecular studies have demonstrated inactivating mutations of PRKAR1A, GNAS and PDE11A4 (PDE11A), which are key components of the cAMP signaling pathway (PKA signaling pathway).

Bilateral laparoscopic adrenalectomy is the preferred treatment in these subjects.

Primary pigmented (micronodular) adrenocortical disease (PPAD) is associated with Cushing syndrome and 25% to 35% of cases have the manifestations of Carney complex with myxomas, spotty skin pigmentation, and endocrine hyperactivity.

Two affected genetic loci in this autosomal recessive disorder have been mapped to chromosomes 2p16 and 17q22,24 (PRKAR1A).

Pathologically, the adrenals are decreased, normal, or slightly increased in size.

Multiple pigmented nodules less than 4 mm in diameter occupy an otherwise atrophic appearing cortex with loss of normal zonation.

Nodules may be present in the periadrenal fat.

The enlarged cortical cells have an eosinophilic cytoplasm with abundant lipofuscin pigment.

These cells are immunoreactive for SYN but fail to stain for CHR. In this respect, the cortical nodules of PPAD react in a similar manner to adrenocortical neoplasms.

Terminology

The earlier terms used to describe this condition include primary micronodular adrenal disease, micronodular adrenal hyperplasia, pigmented adrenal micronodular dysplasia and primary adrenocortical micronodular adenomatosis.

The term PPNAD was first used by Carney in 1984 and later supported by Travis et al. The other terminologies were found inappropriate because of the frequent presence of macronodules >1 cm and atrophy of intervening cortex and the absence of hyperplasia.

Clinical synopsis

PPNAD is a rare cause of Cushing syndrome. The patients present with ACTH- independent CS. It can occur isolated or as part of CNC.

The symptoms are often mild and patients usually present much after the onset of symptoms.

The disease usually presents in the second decade, but an age range of 4–44 years has been recorded in the literature. There is a female preponderance. The hypercortisolism is resistant to the dexamethasone suppression test.

The pituitary will be normal on radiological examination. Serum ACTH levels are low or undetectable. PPNAD in children and adolescents can also manifest as variants of CS, like periodic CS (intermittent hypercortisolism) or atypical CS associated with asthenia, muscle wasting and severe osteoporosis.

The indolent and/or periodic nature of CS can lead to difficulties in clinical diagnosis.

Association

- Carney complex

  • Cushing disease, spotty cutaneous pigmentation, cutaneous and cardiac myxomas, growth hormone secreting pituitary adenomas, psammomatous melanotic schwannomas, multiple myxoid fibroadenomas of breast in females, large cell calcifying Sertoli tumors of testis in males

Macroscopy

- variable sized adrenal glands with multiple brown-black pigmented cortical nodules
- possible unilateral adrenocortical nodule (20670433)

Typically, both adrenal glands are involved. The size can vary from normal to slightly larger than normal. The typical gross appearance is of multiple nodules of varying sizes and colors studding the cortex.

The size can vary from < 1 mm to 3.0 cm and the color from yellow tan to black. In rare cases, the nodules cannot be identified grossly.

Microscopy

- sharply circumscribed nodules composed of eosinophilic lipid-poor cells similar to normal zone reticularis
- growth pattern: trabecular
- prominent lipofuscin deposits in zona fasciculata
- focal necrosis
- mitotic activity

On microscopy, the nodules are separated by atrophic or normal cortical tissue. The nodules are circumscribed, but unencapsulated and varied from small clusters of cells to large nodules filling the entire cortex. The nodules are composed of polygonal cells with eosinophilic, granular to clear cytoplasm.

The intracytoplasmic pigment varies in amount and shows staining characteristics of lipofuscin or neuromelanin, positive for PAS, Zeihl Neelsen and Masson Fontana and negative for iron stain.

Atypical histological features reported include necrosis, hyperplasia of the internodular cortex, a trabecular growth pattern, mitotic figures and a diffuse rather than a nodular arrangement of cells. These have been reported to be associated with a positive family history of PPNAD. The pathological findings can vary with age, the changes being more marked in the adult or older age group.

Associations

More than 90% of the reported PPNAD have been associated with CNC. In fact, PPNAD is one of the major criteria for the diagnosis.

Among the endocrine manifestations of CNC , PPNAD is the most frequent, seen in about 25% of the patients.

Although it may not be grossly evident, histological evidence for PPNAD has been found at autopsy in almost every patient with CNC.

Detailed investigations and careful follow-up and screening, like annual echocardiogram and thyroid and testicular ultrasound at regular intervals, is indicated to detect other manifestations of Carney complex.

Differential diagnosis

Even though primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing’s syndrome, it should be included in the differential diagnosis of adrenocorticotropic hormone-independent Cushing’s syndrome, especially because adrenal imaging can be misleading mimicking other adrenocortical diseases.

Etiology

- mutations in the PRKAR1A gene coding for the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (12424709)

Pathogenesis

Sasao et al. observed that nodules of PPNAD arise from the zona reticularis and demonstrate autonomous hypersecretion of cortisol, supporting the theory of abnormal development of the zona reticularis.

Recently, molecular studies have demonstrated inactivating mutations of the PRKAR1A gene on chromosome 17q22-23 or of the PDE11A gene, both of which are key components of the cAMP signaling pathway (PKA signaling pathway).

Treatment and management

The treatment of choice for PPNAD is bilateral adrenalectomy. Unilateral or subtotal adrenalectomy was followed by recurrence.

Bilateral adrenalectomy is indicated to avoid the morbidity associated with CS. PPNAD does not increase the risk for malignancy.

The gross and histological appearance of PPNAD is characteristic and genetic studies are not necessary for a diagnosis.

Detailed investigations and careful follow-up and screening, like annual echocardiogram and thyroid and testicular ultrasound at regular intervals, is indicated to detect other manifestations of Carney complex.

Open Access References

- Primary pigmented nodular adrenocortical disease. Manipadam MT, Abraham R, Sen S, Simon A. J Indian Assoc Pediatr Surg. 2011 Oct;16(4):160-2. PMID: 22121318 [Free]

- Primary pigmented nodular adrenocortical disease. Ngow HA, Khairina WM. Endokrynol Pol. 2011;62(3):268-70. PMID: 21717412 [Free]

- Primary pigmented nodular adrenocortical disease presenting with a unilateral adrenocortical nodule treated with bilateral laparoscopic adrenalectomy: a case report. Zografos GN, Pappa T, Avlonitis S, Markou A, Chrysikos DT, Kaltsas G, Aggeli C, Piaditis G. J Med Case Reports. 2010 Jul 29;4:230.PMID: 20670433 [Free]

- Cushing’s syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice. Sahut-Barnola I, de Joussineau C, Val P, Lambert-Langlais S, Damon C, Lefrançois-Martinez AM, Pointud JC, Marceau G, Sapin V, Tissier F, Ragazzon B, Bertherat J, Kirschner LS, Stratakis CA, Martinez A. PLoS Genet. 2010 Jun 10;6(6):e1000980. PMID: 20548949 [Free]

- Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families. Pereira AM, Hes FJ, Horvath A, Woortman S, Greene E, Bimpaki E, Alatsatianos A, Boikos S, Smit JW, Romijn JA, Nesterova M, Stratakis CA. J Clin Endocrinol Metab. 2010 Jan;95(1):338-42. PMID: 19915019 [Free]

- Inactivation of the Carney complex gene 1 (protein kinase A regulatory subunit 1A) inhibits SMAD3 expression and TGF beta-stimulated apoptosis in adrenocortical cells. Ragazzon B, Cazabat L, Rizk-Rabin M, Assie G, Groussin L, Fierrard H, Perlemoine K, Martinez A, Bertherat J. Cancer Res. 2009 Sep 15;69(18):7278-84. PMID: 19738044 [Free]

- The paradoxical increase in cortisol secretion induced by dexamethasone in primary pigmented nodular adrenocortical disease involves a glucocorticoid receptor-mediated effect of dexamethasone on protein kinase A catalytic subunits. Louiset E, Stratakis CA, Perraudin V, Griffin KJ, Libé R, Cabrol S, Fève B, Young J, Groussin L, Bertherat J, Lefebvre H. J Clin Endocrinol Metab. 2009 Jul;94(7):2406-13. PMID: 19383776 [Free]

- MicroRNA signature of primary pigmented nodular adrenocortical disease: clinical correlations and regulation of Wnt signaling. Iliopoulos D, Bimpaki EI, Nesterova M, Stratakis CA. Cancer Res. 2009 Apr 15;69(8):3278-82. PMID: 19351815 [Free]

- Mutations in regulatory subunit type 1A of cyclic adenosine 5’-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. Bertherat J, Horvath A, Groussin L, Grabar S, Boikos S, Cazabat L, Libe R, René-Corail F, Stergiopoulos S, Bourdeau I, Bei T, Clauser E, Calender A, Kirschner LS, Bertagna X, Carney JA, Stratakis CA. J Clin Endocrinol Metab. 2009 Jun;94(6):2085-91. PMID: 19293268 [Free]

- New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors. Stratakis CA. Mol Cell Endocrinol. 2009 Mar 5;300(1-2):152-7. PMID: 19063937 [Free]

- Operative management of Cushing syndrome secondary to micronodular adrenal hyperplasia. Powell AC, Stratakis CA, Patronas NJ, Steinberg SM, Batista D, Alexander HR, Pingpank JF, Keil M, Bartlett DL, Libutti SK. Surgery. 2008 Jun;143(6):750-8. PMID: 18549891 [Free]

- Expression of progesterone and estradiol receptors in normal adrenal cortex, adrenocortical tumors, and primary pigmented nodular adrenocortical disease. de Cremoux P, Rosenberg D, Goussard J, Brémont-Weil C, Tissier F, Tran-Perennou C, Groussin L, Bertagna X, Bertherat J, Raffin-Sanson ML. Endocr Relat Cancer. 2008 Jun;15(2):465-74. PMID: 18508999 [Free]

- Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions. Boikos SA, Horvath A, Heyerdahl S, Stein E, Robinson-White A, Bossis I, Bertherat J, Carney JA, Stratakis CA. Horm Metab Res. 2008 May;40(5):347-53. PMID: 18491255 [Free]

- Primary pigmented nodular adrenocortical disease and Cushing’s syndrome. Horvath A, Stratakis C. Arq Bras Endocrinol Metabol. 2007 Nov;51(8):1238-44. Review. PMID: 18209861 [Free]

- Primary pigmented nodular adrenocortical disease associated with Carney complex: case report and literature review. Gonçalves FT, Feibelmann TC, Mendes CM, Fernandes ML, Miranda GH, Gouvêa AP, Jorge PT. Sao Paulo Med J. 2006 Nov 7;124(6):336-9. PMID: 17322955 [Free]

- Primary pigmented nodular adrenocortical disease reveals insulin-like growth factor binding protein-2 regulation by protein kinase A. Shi Z, Henwood MJ, Bannerman P, Batista D, Horvath A, Guttenberg M, Stratakis CA, Grimberg A. Growth Horm IGF Res. 2007 Apr;17(2):113-21. Epub 2007 Feb 5. PMID: 17280861 [Free]

- Unravelling the mystery in a case of persistent ACTH-independent Cushing’s syndrome. Lim LC, Tan LH, Rajasoorya C. Ann Acad Med Singapore. 2006 Dec;35(12):892-6. PMID: 17219002 [Free]

References

- Familial micronodular adrenocortical disease, Cushing syndrome, and mutations of the gene encoding phosphodiesterase 11A4 (PDE11A). Carney JA, Gaillard RC, Bertherat J, Stratakis CA. Am J Surg Pathol. 2010 Apr;34(4):547-55. PMID: 20351491

- Primary pigmented nodular adrenocortical disease: a case report in a 7-year-old girl. Leka S, Kousta E, Anyfandakis K, Dolianiti M, Vakaki M, Linos D, Chrousos GP, Papathanasiou A. J Pediatr Endocrinol Metab. 2011;24(3-4):197-202. PMID: 21648292

- Choi KM, Seu JH, Kim YH, Lee EJ, KIm SJ, Baik SH, et al. Cushing’s syndrome due to primary pigmented nodular adrenocortical disease: A case report and review of literature. Korean J Intern Med. 1995;10:68–72. [7626560]

- Shenoy BV, Carpenter PC, Carney JA. Bilateral primary pigmented adrenocortical disease. Rare cause of Cushing’s syndrome. Am J Surg Pathol. 1984;8:335–44. [6329005]

- Hasleton PS, Ali HH, Anfield C, Beardwell CG, Shalet S. Micronodular adrenal disease: A light and electron microscopic diagnosis. J Clin Pathol. 1982;35:1078–85. [PMC free article] [7130419]

- Horvath A, Stratakis C. Primary pigmented nodular adrenocortical disease and Cushing’s syndrome. Arq Bras Endocrinol Metab. 2007;51:1238–44.

- Schweizer-Cagianut M, Froesch ER, Hedinger C. Familial Cushing’s syndrome with primary adrenocortical microadenomatosis (primary adrenocortical nodular dysplasia) Acta Endocrinol (Copenh) 1980;94:529–35. [6254301]

- Travis WD, Tsokos M, Doppman JL, Nieman L, Chrousos GP, Cutler GB, Jr, et al. Primary pigmented nodular adrenocortical disease. A light and electron microscopic study of eight cases. Am J Surg Pathol. 1989;13:921–30. [2679153]

- Constantine A, Stratakis Y. Mutations of the gene encoding the protein kinase A Type I alpha regulatory subunit (PRKAR1A) in patients with the complex of spotty skin pigmentation, myxomas, endocrine over activity and schwannoma (Carney complex) Ann N Y Acad Sci. 2002;968:3–21. [12119264]

- Sasano H, Miyazaki S, Sawai T, Sasano N, Nagura H, Funahashi H, et al. Primary pigmented nodular adrenocortical disease (PPNAD): Immunohistochemical and in Situ Hybridisation analysis of steroidogenic enzymes in 8 cases. Mod Pathol. 1992;5:23–9. [1542635]