• Rare pancreatic neuroendocrine neoplasm producing adrenocorticotrophic hormone (ACTH)
• ACTH can also rarely be produced by acinar cell carcinoma or pancreatoblastoma (Am J Surg Pathol 2015;39:374)

• Rare lesion mostly described in case reports
• Patients develop Cushing syndrome clinically
• Aggressive, with poor prognosis

• Recognized by IARC: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017 as “ACTH producing tumor with Cushing syndrome”

• ICD-10: E24.3 - Ectopic ACTH syndrome

• Responsible for about 15% of cases of ectopic Cushing syndrome

• May be more common in tail of pancreas

• Mean age 42 years, with a female predominance (Am J Surg Pathol 2015;39:374)
• Causes Cushing syndrome: central obesity, muscle weakness, glucose intolerance, hypertension
• One-third of patients also have Zollinger-Ellison syndrome
• Ten year survival is roughly 15% (Am J Surg Pathol 2015;39:374)

• Determined clinically, not by immunohistochemical positivity for ACTH

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• Surgical excision

• Firm, gray-white, well circumscribed lesions that may measure up to 5 cm

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• ACTH (though this does not establish the diagnosis), beta-endorphin, galectin3
• Ki67 usually 3 - 20%, as these lesions are typically WHO grade 2

• Non ACTH secreting pancreatic neuroendocrine tumor: must be determined on clinical grounds, though ACTH positivity by immunohistochemistry is rare in these
• Pancreatic acinar cell carcinoma
• Pancreatoblastoma

A 45 year old woman presents with complaints of weight gain, increased facial hair, striae on her arms and easy bruising. An abdominal CT scan shows a 4 cm mass in the tail of her pancreas. What hormone is the tumor likely secreting?


1. ACTH
2. Cortisol
3. Gastrin
4. Glucagon

A. ACTH. The patient is presenting with Cushing syndrome, secondary to ACTH production by her pancreas lesion (likely a neuroendocrine tumor), which leads to increased cortisol production by the adrenal glands. Pancreatic tumors do not themselves secrete cortisol.

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Which of the following is often seen microscopically in well differentiated pancreatic neuroendocrine tumors that secrete ACTH?


1. Abundant necrosis
2. Grade 3 mitotic rate
3. Lymphocytic infiltration
4. Perineural invasion

D. Perineural invasion. These tumors, which are commonly WHO grade 2, often show lymphovascular and perineural invasion. Focal necrosis may sometimes be seen.

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