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Purpose <p>Differentiating prolactinomas from non-functional pituitary adenomas (NFPAs) with stalk effect relies on biochemical thresholds that assume a linear relationship between tumor size and prolactin secretion. We applied a pathology-informed Prolactin Secretory Efficiency (PSE) framework to characterize diagnostic overlap between prolactinomas and NFPAs and evaluate the limitations of current prolactin thresholds.</p> Methods <p>Retrospective study of 425 patients undergoing first-time surgery for pituitary adenomas: 115 pathology-confirmed lactotroph adenomas, 291 NFPAs, and 19 mammosomatotrophs. Patients with clinical or biochemical evidence of ACTH- or GH-secreting tumors were excluded. PSE was calculated as the serum prolactin-to-tumor volume ratio <InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(\:(\frac{\text{n}\text{g}}{\text{m}\text{L}\bullet\:{\text{m}\text{m}}^{3}}\)</EquationSource> </InlineEquation>). Primary outcomes included PSE-based group separation and diagnostic accuracy of the 200 ng/mL threshold.</p> Results <p>While no NFPA exceeded 200 ng/mL, 42% of pathology-confirmed macroprolactinomas and 49% of macro-NFPAs fell within the diagnostic grey zone (ULN &lt; prolactin &lt; 200 ng/mL). PSE achieved superior group separation versus raw prolactin, yet a paradox emerged: high-efficiency stalk effect in some NFPAs produced PSE values exceeding those of low-efficiency macroprolactinomas.</p> Conclusions <p>Rigid biochemical thresholds fail to capture the full spectrum of lactotroph adenoma biology. Significant secretory ambiguity exists for macroadenomas below 200 ng/mL, creating risk of misclassification. D2-agonist trials may serve as a low-risk diagnostic probe in this grey zone, ensuring low-efficiency prolactinomas receive appropriate first-line medical management.</p>

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Disentangling secretory ambiguity and the limitations of classical thresholds in defining prolactinomas

  • 期刊论文

  • 发表日期：

    2026年7月23日

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  • Maya Harary,
  • Mishek Thapa,
  • Stuart D. Harper,
  • Ines Donangelo,
  • Anthony P. Heaney,
  • Won Kim,
  • Marvin Bergsneider

摘要

Purpose

Differentiating prolactinomas from non-functional pituitary adenomas (NFPAs) with stalk effect relies on biochemical thresholds that assume a linear relationship between tumor size and prolactin secretion. We applied a pathology-informed Prolactin Secretory Efficiency (PSE) framework to characterize diagnostic overlap between prolactinomas and NFPAs and evaluate the limitations of current prolactin thresholds.

Methods

Retrospective study of 425 patients undergoing first-time surgery for pituitary adenomas: 115 pathology-confirmed lactotroph adenomas, 291 NFPAs, and 19 mammosomatotrophs. Patients with clinical or biochemical evidence of ACTH- or GH-secreting tumors were excluded. PSE was calculated as the serum prolactin-to-tumor volume ratio \(\:(\frac{\text{n}\text{g}}{\text{m}\text{L}\bullet\:{\text{m}\text{m}}^{3}}\) ). Primary outcomes included PSE-based group separation and diagnostic accuracy of the 200 ng/mL threshold.

Results

While no NFPA exceeded 200 ng/mL, 42% of pathology-confirmed macroprolactinomas and 49% of macro-NFPAs fell within the diagnostic grey zone (ULN < prolactin < 200 ng/mL). PSE achieved superior group separation versus raw prolactin, yet a paradox emerged: high-efficiency stalk effect in some NFPAs produced PSE values exceeding those of low-efficiency macroprolactinomas.

Conclusions

Rigid biochemical thresholds fail to capture the full spectrum of lactotroph adenoma biology. Significant secretory ambiguity exists for macroadenomas below 200 ng/mL, creating risk of misclassification. D2-agonist trials may serve as a low-risk diagnostic probe in this grey zone, ensuring low-efficiency prolactinomas receive appropriate first-line medical management.