A Clinicopathologic Study on the Role of Estrogen, Progesterone, and Their Classical and Nonclassical Receptors in Cutaneous Neurofibromas of Individuals With Neurofibromatosis 1

Abstract

Objectives To evaluate the expression of progesterone receptor (PR), estrogen receptor (ER), and G protein–coupled estrogen receptor 1 (GPER-1) in cutaneous neurofibromas (cNFs) and their correlation with demographic, clinical, and laboratory data of individuals with neurofibromatosis 1 (NF1). The association of PROGINS polymorphism and PR expression in cNFs, as well as the serum steroidal hormones and the number of cNFs, was investigated. Methods The sample comprised 80 large and 80 small cNFs from 80 individuals with NF1. PR, ER, GPER-1, and Ki-67 expression were investigated by immunohistochemistry in tissue micro- and macroarrays and quantified using a digital computer-assisted method. The number of cNFs, the levels of serum 17β estradiol and progesterone, and the PROGINS polymorphism were identified. Results Twelve (8.5%) small cNFs were weakly positive for ER, 131 (92.3%) cNFs expressed PR, and all (100%) cNFs expressed GPER-1. Large cNFs showed a higher expression of PR (P < .0001) and GPER-1 (P = .019) and had a higher intensity of staining for these receptors (P < .0001). The cell proliferation index was positively correlated with PR (P = .001). Persons with more cNFs had higher serum levels of progesterone (P = .001). Conclusions These findings emphasize the role of estrogen and progesterone in cNF development and suggest that these hormones may act on cNF cells via a noncanonical pathway through GPER-1.

Turner Syndrome and Neurofibromatosis 1: Rare Co-Existence with Important Clinical Implications

“…26 Gonadal hormones may lead to neurofibroma development, acting via a noncanonical pathway through GPER-1. 27 Case reports also demonstrate increased tumour growth in girls receiving depot progesterone preparations, but not in those receiving combined oral contraceptive pills. 27,28 Since the effects of progesterone are more established in girls and women with TS and NF1, use of progesterone should preferably be restricted to a maximum of ten days every month rather than a daily combined estrogen plus progesterone pill.…”

“…27 Case reports also demonstrate increased tumour growth in girls receiving depot progesterone preparations, but not in those receiving combined oral contraceptive pills. 27,28 Since the effects of progesterone are more established in girls and women with TS and NF1, use of progesterone should preferably be restricted to a maximum of ten days every month rather than a daily combined estrogen plus progesterone pill. Close monitoring is warranted in these women for any increase in the number and size of neurofibroma, any new appearance or worsening of neurologic symptoms and worsening of visual acuity due to progression of optic glioma.…”

Neurofibromatosis type 1: Factors associated with flare‐ups of cutaneous neurofibromas at puberty

“…An increased progesterone receptor expression is associated with more cNFs and an increased proliferation index. 6 The absence of an association with male gender might indicate a lower impact of male hormonal changes on the growth of cNFs. We also found that a pubertal flare of cNFs was associated with the risk of having more than 100 neurofibromas.…”