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Australasian Journal of Dermatology (2015) 56, 131–133
doi: 10.1111/ajd.12195
BRIEF REPORT
Generalised hyperpigmentation caused by ectopic adrenocorticotropic hormone syndrome with recurrent thymic neuroendocrine carcinoma Hye-Rim Moon, Chong Hyun Won, Sung Eun Chang, Mi Woo Lee, Jee Ho Choi and Kee Chan Moon Department of Dermatology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea
CASE REPORT ABSTRACT Ectopic adrenocorticotropic hormone (ACTH) syndrome is a rare cause of generalised hyperpigmentation. The clinical features are due to the excessive ectopic secretion of adenocorticotropin by diverse neuroendocrine or non-endocrine tumours. Here, we describe a rare case of ectopic ACTH syndrome developing from recurring thymic neuroendocrine carcinoma, which first presented as generalised hyperpigmentation. Key words: ACTH, ectopic ACTH syndrome, hyperpigmentation, melanogenesis, thymic neuroendocrine carcinoma.
INTRODUCTION Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours that release excessive amounts of ACTH, and occurs in approximately 20% of patients with ACTH-dependent Cushing’s syndrome (CS) and in 10% of patients with CS of any type.1 The dermatological features of EAS are similar to those of ACTH-dependent CS and include the thinning of the skin, bruising and hyperpigmentation. Generalised hyperpigmentation may present during follow up of a known tumour or prior to diagnosis of the causative tumour. In the latter case, hyperpigmentation might be an important clue to the diagnosis of occult tumours.
A 37-year-old man, previously diagnosed as skin phototype III, presented with a 1.5-month history of acute-onset hyperpigmentation over his entire body. He reported a 1-month history of facial swelling, muscle weakness and fatigue. He had previously undergone a thymomectomy for ectopic CS and had been in remission for the previous 7 years. A dermatological examination identified an intense and generalised hyperpigmentation that was more pronounced in areas exposed to sunlight, such as the face, neck and extremities, and on previously damaged areas (Fig. 1). Laboratory results revealed reduced potassium levels (2.2 mmol/L; normal, 3.5–5.5 mmol/L) and increased serum cortisol (91 μg/dL; normal, 5–25 μg/dL) and plasma ACTH (1256 pg/mL; normal, 0–60 pg/mL) levels. The results of the clinical and laboratory investigations were consistent with a diagnosis of EAS. Computed tomography (CT) revealed lobulated contoured thickening of the right ventricular side of the interventricular septum and enlarged multiple lymph nodes in the upper paratracheal region (operated on 7 years previously). Clinical and radiological findings suggested cardiac involvement of a recurrent thymic neuroendocrine carcinoma with lymph nodes metastasis. A lymph node biopsy revealed a metastatic neuroendocrine carcinoma that was positive for synaptophysin, chromogranin and cytokeratin. In addition, numerous recurrent tumour cells were present, which were strongly positive for ACTH (Fig. 2). The patient underwent a bilateral adrenalectomy to treat the uncontrolled CS symptoms and received systemic chemotherapy with ifosfamide, carboplatin, and etoposide. Abbreviations:
Correspondence: Dr Sung Eun Chang, Department of Dermatology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul 138-736, Korea. Email: [email protected] Hye-Rim Moon, MD. Chong Hyun Won, MD. Sung Eun Chang, MD. Mi Woo Lee, MD. Jee Ho Choi, MD. Kee Chan Moon, MD. Conflict of interest: none. Submitted 17 June 2013; accepted 11 April 2014. © 2014 The Australasian College of Dermatologists
ACTH CRF CS EAS MSH POMC SCLC
adrenocorticotropic hormone syndrome corticotrophin releasing factor Cushing’s syndrome ectopic adrenocorticotropic hormone syndrome melanocyte stimulating hormone pro-opiomelanocortin small cell lung carcinoma
132
H-R Moon et al.
Figure 1 Diffuse hyperpigmentation on the face (a) and anterior trunk (b), which is more pronounced in areas exposed to sunlight and on previously damaged areas.
Figure 2 Prominent recurrent tumour cells, which are stronglypositive for adrenocorticotropic hormone syndrome (ACTH; ×40).
However, despite systemic chemotherapy, his ACTH levels rose to >10 000 pg/mL and the generalised hyperpigmentation worsened.
DISCUSSION The differential diagnosis of diffuse skin hyperpigmentation with elevated ACTH is broad, encompassing Addison’s disease, Nelson’s syndrome and CS, which are caused by pituitary gland tumours and ectopic ACTH-secreting nonpituitary tumours. EAS is a rare endocrine condition affecting 20% of patients with ACTH-dependent CS and 10% of those with general CS.1 The tumours most commonly asso© 2014 The Australasian College of Dermatologists
ciated with EAS are small cell lung carcinoma (SCLC), neuroendocrine tumours, pheochromocytomas and thyroid medullary carcinoma.2 In all, 19–88% of EAS patients present with skin pigmentation.3–7 Skin hyperpigmentation, which depends on the type of ACTH-secreting tumour and the degree of ACTH increase, is generally more prominent in EAS patients with SCLC than in those with other tumours. Furthermore, the degree of skin hyperpigmentation correlates with the speed of onset and the severity of EAS. However, the duration of EAS appears not to be the major determinant of hyperpigmentation.2 ACTH regulates melanogenesis and is derived from proopiomelanocortin (POMC), which is also the common polypeptide precursor for melanocyte stimulating hormone (MSH), lipotrophins, and endorphins.8 Of these, ACTH and MSH have marked promelanogenic effects. ACTH and MSH interact with cell surface receptors expressed on melanocytes, which are linked to cAMP-dependent pathways. Receptor binding increases tyrosinase activity and melanin production and stimulates dendrite formation.9 In addition, extracellular ACTH induces both increased melanogenesis and the production of neuroendocrine peptides.10 Melanocytes respond to UVB by producing corticotrophin releasing factor (CRF) and by expressing CRF receptors. CRF stimulates the production of POMC and, ultimately, the production of ACTH and MSH. These hormones are produced in a manner analogous to the classical neuroendocrine axis (e.g., the hypothalamic-pituitaryadrenal axis).11 Here, we report a case of recurrent thymic neuroendocrine ACTH-secreting carcinoma presenting as acuteonset skin hyperpigmentation caused by a rapid increase in ACTH secretion. The tumour had remained in remission for 7 years after the initial thymomectomy. Because EAS in
Hyperpigmentation caused by thymic NEC patients with highly malignant tumours presents as a paraneoplastic syndrome, such patients are usually seen in endocrinology or oncology departments. Although these EAS patients are not usually seen by dermatologists, most present with acute-onset hyperpigmentation, which can be the initial symptom of EAS. Therefore, dermatologists presented with a patient showing acute-onset hyperpigmentation should suspect EAS and look for occult malignant tumours. In conclusion, dermatologists should consider this rare syndrome during the differential diagnosis of acuteonset hyperpigmentation.
4.
5.
6.
7. 8.
REFERENCES 1. 2.
3.
Newell-Price J, Bertagna X, Grossman AB et al. Cushing’s syndrome. Lancet 2006; 367: 1605–17. Isidori AM, Kaltsas GA, Pozza C et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J. Clin. Endocrinol. Metab. 2006; 91: 371–7. Doi M, Sugiyama T, Izumiyama H et al. Clinical features and management of ectopic ACTH syndrome at a single institute in Japan. Endocr. J. 2010; 57: 1061–9.
9.
10. 11.
133
Wajchenberg BL, Mendonca BB, Liberman B et al. Ectopic adrenocorticotropic hormone syndrome. Endocr. Rev. 1994; 15: 752–87. Ilias I, Torpy DJ, Pacak K et al. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J. Clin. Endocrinol. Metab. 2005; 90: 4955–62. Salgado LR, Fragoso MC, Knoepfelmacher M et al. Ectopic ACTH syndrome: our experience with 25 cases. Eur. J. Endocrinol. 2006; 155: 725–33. Beuschlein F, Hammer GD. Ectopic pro-opiomelanocortin syndrome. Endocrinol. Metab. Clin. North Am. 2002; 31: 191–234. Mains RE, Eipper BA, Ling N. Common precursor to corticotropins and endorphins. Proc. Natl. Acad. Sci. U. S. A. 1977; 74: 3014–8. Slominski A, Tobin DJ, Shibahara S et al. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol. Rev. 2004; 84: 1155–228. Slominski A, Wortsman J. Neuroendocrinology of the skin. Endocr. Rev. 2000; 21: 457–87. Slominski A. Neuroendocrine activity of the melanocyte. Exp. Dermatol. 2009; 18: 760–3.
© 2014 The Australasian College of Dermatologists
Australasian Journal of Dermatology (2015) 56, 131–133
doi: 10.1111/ajd.12195
BRIEF REPORT
Generalised hyperpigmentation caused by ectopic adrenocorticotropic hormone syndrome with recurrent thymic neuroendocrine carcinoma Hye-Rim Moon, Chong Hyun Won, Sung Eun Chang, Mi Woo Lee, Jee Ho Choi and Kee Chan Moon Department of Dermatology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea
CASE REPORT ABSTRACT Ectopic adrenocorticotropic hormone (ACTH) syndrome is a rare cause of generalised hyperpigmentation. The clinical features are due to the excessive ectopic secretion of adenocorticotropin by diverse neuroendocrine or non-endocrine tumours. Here, we describe a rare case of ectopic ACTH syndrome developing from recurring thymic neuroendocrine carcinoma, which first presented as generalised hyperpigmentation. Key words: ACTH, ectopic ACTH syndrome, hyperpigmentation, melanogenesis, thymic neuroendocrine carcinoma.
INTRODUCTION Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours that release excessive amounts of ACTH, and occurs in approximately 20% of patients with ACTH-dependent Cushing’s syndrome (CS) and in 10% of patients with CS of any type.1 The dermatological features of EAS are similar to those of ACTH-dependent CS and include the thinning of the skin, bruising and hyperpigmentation. Generalised hyperpigmentation may present during follow up of a known tumour or prior to diagnosis of the causative tumour. In the latter case, hyperpigmentation might be an important clue to the diagnosis of occult tumours.
A 37-year-old man, previously diagnosed as skin phototype III, presented with a 1.5-month history of acute-onset hyperpigmentation over his entire body. He reported a 1-month history of facial swelling, muscle weakness and fatigue. He had previously undergone a thymomectomy for ectopic CS and had been in remission for the previous 7 years. A dermatological examination identified an intense and generalised hyperpigmentation that was more pronounced in areas exposed to sunlight, such as the face, neck and extremities, and on previously damaged areas (Fig. 1). Laboratory results revealed reduced potassium levels (2.2 mmol/L; normal, 3.5–5.5 mmol/L) and increased serum cortisol (91 μg/dL; normal, 5–25 μg/dL) and plasma ACTH (1256 pg/mL; normal, 0–60 pg/mL) levels. The results of the clinical and laboratory investigations were consistent with a diagnosis of EAS. Computed tomography (CT) revealed lobulated contoured thickening of the right ventricular side of the interventricular septum and enlarged multiple lymph nodes in the upper paratracheal region (operated on 7 years previously). Clinical and radiological findings suggested cardiac involvement of a recurrent thymic neuroendocrine carcinoma with lymph nodes metastasis. A lymph node biopsy revealed a metastatic neuroendocrine carcinoma that was positive for synaptophysin, chromogranin and cytokeratin. In addition, numerous recurrent tumour cells were present, which were strongly positive for ACTH (Fig. 2). The patient underwent a bilateral adrenalectomy to treat the uncontrolled CS symptoms and received systemic chemotherapy with ifosfamide, carboplatin, and etoposide. Abbreviations:
Correspondence: Dr Sung Eun Chang, Department of Dermatology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul 138-736, Korea. Email: [email protected] Hye-Rim Moon, MD. Chong Hyun Won, MD. Sung Eun Chang, MD. Mi Woo Lee, MD. Jee Ho Choi, MD. Kee Chan Moon, MD. Conflict of interest: none. Submitted 17 June 2013; accepted 11 April 2014. © 2014 The Australasian College of Dermatologists
ACTH CRF CS EAS MSH POMC SCLC
adrenocorticotropic hormone syndrome corticotrophin releasing factor Cushing’s syndrome ectopic adrenocorticotropic hormone syndrome melanocyte stimulating hormone pro-opiomelanocortin small cell lung carcinoma
132
H-R Moon et al.
Figure 1 Diffuse hyperpigmentation on the face (a) and anterior trunk (b), which is more pronounced in areas exposed to sunlight and on previously damaged areas.
Figure 2 Prominent recurrent tumour cells, which are stronglypositive for adrenocorticotropic hormone syndrome (ACTH; ×40).
However, despite systemic chemotherapy, his ACTH levels rose to >10 000 pg/mL and the generalised hyperpigmentation worsened.
DISCUSSION The differential diagnosis of diffuse skin hyperpigmentation with elevated ACTH is broad, encompassing Addison’s disease, Nelson’s syndrome and CS, which are caused by pituitary gland tumours and ectopic ACTH-secreting nonpituitary tumours. EAS is a rare endocrine condition affecting 20% of patients with ACTH-dependent CS and 10% of those with general CS.1 The tumours most commonly asso© 2014 The Australasian College of Dermatologists
ciated with EAS are small cell lung carcinoma (SCLC), neuroendocrine tumours, pheochromocytomas and thyroid medullary carcinoma.2 In all, 19–88% of EAS patients present with skin pigmentation.3–7 Skin hyperpigmentation, which depends on the type of ACTH-secreting tumour and the degree of ACTH increase, is generally more prominent in EAS patients with SCLC than in those with other tumours. Furthermore, the degree of skin hyperpigmentation correlates with the speed of onset and the severity of EAS. However, the duration of EAS appears not to be the major determinant of hyperpigmentation.2 ACTH regulates melanogenesis and is derived from proopiomelanocortin (POMC), which is also the common polypeptide precursor for melanocyte stimulating hormone (MSH), lipotrophins, and endorphins.8 Of these, ACTH and MSH have marked promelanogenic effects. ACTH and MSH interact with cell surface receptors expressed on melanocytes, which are linked to cAMP-dependent pathways. Receptor binding increases tyrosinase activity and melanin production and stimulates dendrite formation.9 In addition, extracellular ACTH induces both increased melanogenesis and the production of neuroendocrine peptides.10 Melanocytes respond to UVB by producing corticotrophin releasing factor (CRF) and by expressing CRF receptors. CRF stimulates the production of POMC and, ultimately, the production of ACTH and MSH. These hormones are produced in a manner analogous to the classical neuroendocrine axis (e.g., the hypothalamic-pituitaryadrenal axis).11 Here, we report a case of recurrent thymic neuroendocrine ACTH-secreting carcinoma presenting as acuteonset skin hyperpigmentation caused by a rapid increase in ACTH secretion. The tumour had remained in remission for 7 years after the initial thymomectomy. Because EAS in
Hyperpigmentation caused by thymic NEC patients with highly malignant tumours presents as a paraneoplastic syndrome, such patients are usually seen in endocrinology or oncology departments. Although these EAS patients are not usually seen by dermatologists, most present with acute-onset hyperpigmentation, which can be the initial symptom of EAS. Therefore, dermatologists presented with a patient showing acute-onset hyperpigmentation should suspect EAS and look for occult malignant tumours. In conclusion, dermatologists should consider this rare syndrome during the differential diagnosis of acuteonset hyperpigmentation.
4.
5.
6.
7. 8.
REFERENCES 1. 2.
3.
Newell-Price J, Bertagna X, Grossman AB et al. Cushing’s syndrome. Lancet 2006; 367: 1605–17. Isidori AM, Kaltsas GA, Pozza C et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J. Clin. Endocrinol. Metab. 2006; 91: 371–7. Doi M, Sugiyama T, Izumiyama H et al. Clinical features and management of ectopic ACTH syndrome at a single institute in Japan. Endocr. J. 2010; 57: 1061–9.
9.
10. 11.
133
Wajchenberg BL, Mendonca BB, Liberman B et al. Ectopic adrenocorticotropic hormone syndrome. Endocr. Rev. 1994; 15: 752–87. Ilias I, Torpy DJ, Pacak K et al. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J. Clin. Endocrinol. Metab. 2005; 90: 4955–62. Salgado LR, Fragoso MC, Knoepfelmacher M et al. Ectopic ACTH syndrome: our experience with 25 cases. Eur. J. Endocrinol. 2006; 155: 725–33. Beuschlein F, Hammer GD. Ectopic pro-opiomelanocortin syndrome. Endocrinol. Metab. Clin. North Am. 2002; 31: 191–234. Mains RE, Eipper BA, Ling N. Common precursor to corticotropins and endorphins. Proc. Natl. Acad. Sci. U. S. A. 1977; 74: 3014–8. Slominski A, Tobin DJ, Shibahara S et al. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol. Rev. 2004; 84: 1155–228. Slominski A, Wortsman J. Neuroendocrinology of the skin. Endocr. Rev. 2000; 21: 457–87. Slominski A. Neuroendocrine activity of the melanocyte. Exp. Dermatol. 2009; 18: 760–3.
© 2014 The Australasian College of Dermatologists
