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Nonsurgical Cerebrospinal Fluid Rhinorrhea in Invasive Macroprolactinoma: Incidence, Radiological, and Clinicopathological Features

Department of Endocrinology (S.G.I.S., A.G., G.T., J.A.H.W.), Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; and Departments of Neuroradiology (J.V.B.), Neuropathology (A.G., N.S., O.A.), and Neurosurgery (S.C.), John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom

Address all correspondence and requests for reprints to: John A. H. Wass, Professor of Endocrinology, Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom. E-mail: john.wass{at}noc.anglox.nhs.uk.

Context: Macroprolactinomas (MPRLs) may result in nonsurgical (spontaneous or dopamine agonist induced) cerebrospinal fluid (CSF) rhinorrhea; however, the incidence of and mechanisms underlying this phenomenon are poorly understood.

Objective: The objective of the study was to determine the incidence of nonsurgical rhinorrhea and identify biochemical, radiological, and histopathological factors associated with leakage.

Design, Setting, and Participants: A retrospective review of MPRL patients (n = 114) was compared with patients with nonfunctioning pituitary adenoma (NFA) (n = 181) seen over a 19-yr period (1985–2004).

Main Outcome Measures: Incidence of CSF rhinorrhea, factors predictive of leakage, and differential expression of candidate markers of invasiveness were measured.

Results: Nonsurgical CSF rhinorrhea occurred in 8.7% of MPRLs (10 of 114) [2.6% spontaneous (three of 114), 6.1% dopamine agonist induced (seven of 114)], whereas no NFAs developed nonsurgical rhinorrhea. There was a clear male preponderance in MPRLs with nonsurgical rhinorrhea (males to females, 9:1, P = 0.008). Dopamine agonist resistance was more frequent in MPRLs with rhinorrhea than with MPRLs without rhinorrhea [30% (n = 10) vs. 5% (n = 104) P = 0.003]. Baseline prolactin levels, rate of prolactin decline in response to dopamine agonists, and tumor volume at diagnosis did not predict CSF leakage. Candidate markers of invasiveness, specifically the protease-activated receptor 1 and e-cadherin expression scores and tumor macrophage density, were not significantly different between groups; MPRL+CSF rhinorrhea (n = 6), MPRL without CSF rhinorrhea (n = 9), and NFAs (n = 9).

Conclusions: The incidence of nonsurgical CSF rhinorrhea in MPRL patients (8.7%) is higher than expected. Dopamine agonist resistance is more common in MPRLs with CSF rhinorrhea; however, whether this is a mechanistic relationship requires further study. Protease-activated receptor 1 expression, e-cadherin expression, and macrophage infiltration rates do not distinguish tumors with from those without CSF rhinorrhea.

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