Molecular analysis and literature-based hypothesis of an immunonegative prostate small cell carcinoma causing ectopic ACTH syndrome

Abstract

Ectopic ACTH syndrome (EAS) due to a prostate small cell carcinoma (SCC) is very rare with only 26 cases reported to date and has a poor prognosis. We here describe another case of this disorder that was clinically typical based on prior reports as it showed hypercortisolemia and severe hypokalemia with multiple metastasis. However, our current case of prostate SCC causing EAS is the first to display negative immunostaining for ACTH despite detectable POMC mRNA expression in the primary lesion. ACTH immunonegativity is thought to be associated with a more aggressive disease course and a poorer prognosis although there are few studies of the underlying mechanisms. We explored two possibilities for this finding in our current patient: aberrant POMC processing prevented immunodetection with an anti-ACTH antibody; and the ACTH content per cell was below the threshold for immunodetection due to its rapid secretion or low synthesis. The aberrant processing theory was thought to be less likely because of immunonegative findings even using anti-POMC/ACTH antibodies. As the plasma ACTH levels in our patient were comparable with those reported for previous immunopositive prostate EAS cases, we speculated that the depletion of ACTH may be caused not only by rapid secretion but also by low production levels as a sign of de-differentiation. De-differentiation may therefore explain the mechanism underlying the negative correlation between immunoreactivity for ACTH in EAS and disease aggressiveness. We believe that our present findings will be of use in future prospective studies aimed at confirming the mechanism of immunonegativity.

Current trend of worsening prognosis of prostate small cell carcinoma: A population‐based study

“…Once the symptomatic, including obstructive, neurological or systemic symptoms like paracancerous syndrome, bone pain, hydronephrosis, abdominal pain, bloody stools, tumor has usually already evolved to a terminal stage. [2][3][4] Thus, the prognosis of patients diagnosed with prostate SCC is typically poor. Another reason for the poor prognosis is its aggressive behavior.…”

“…Previous studies have reported that prostate SCC patients lack specific clinical symptoms in the early stage. Once the symptomatic, including obstructive, neurological or systemic symptoms like paracancerous syndrome, bone pain, hydronephrosis, abdominal pain, bloody stools, tumor has usually already evolved to a terminal stage . Thus, the prognosis of patients diagnosed with prostate SCC is typically poor.…”

Case report: A challenging case of severe Cushing’s syndrome in the course of metastatic thymic neuroendocrine carcinoma with a synchronous adrenal tumor

“…Moreover, the diagnosis of EAS is not ruled out in the case of primary tumor negative ACTH IHC staining. Less differentiated neuroendocrine tumors are believed to secrete ACTH rapidly and might also lose the ability to store ACTH in the secretory granules, thus leaving for typical techniques insufficient ACTH amounts stored to be stained ( 39 , 40 ). In addition, the tumor might secrete various biologically active ACTH precursors that are negative on IHC.…”