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

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 17ß 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.

Receptor of ghrelin is expressed in cutaneous neurofibromas of individuals with neurofibromatosis 1.

BACKGROUND: Multiple cutaneous neurofibromas are a hallmark of neurofibromatosis 1 (NF1). They begin to appear during puberty and increase in number and volume during pregnancy, suggesting a hormonal influence. Ghrelin is a hormone that acts via growth hormone secretagogue receptor (GHS-R), which is overexpressed in many neoplasms and is involved in tumorigenesis. We aimed to investigate GHS-R expression in NF1 cutaneous neurofibromas and its relationship with tumors volume, and patient's age and gender. RESULTS: Sample comprised 108 cutaneous neurofibromas (55 large and 53 small tumors) from 55 NF1 individuals. GHS-R expression was investigated by immunohistochemistry in tissue micro and macroarrays and quantified using a digital computer-assisted method. All neurofibromas expressed GHS-R, with a percentage of positive cells ranging from 4.9% to 76.1%. Large neurofibromas expressed more GHS-R than the small ones. The percentage of GHS-R-positive cells and intensity of GHS-R expression were positively correlated with neurofibromas volume. GHS-R expression was more common in female gender. CONCLUSIONS: GHS-R is expressed in cutaneous neurofibromas. Larger neurofibromas have a higher percentage of positive cells and higher GHS-R intensity. Based on our results we speculate that ghrelin may have an action on the tumorigenesis of cutaneous neurofibromas. Future studies are required to understand the role of ghrelin in the pathogenesis of NF1-associated cutaneous neurofibroma.

Validity and interexaminer reliability of a new method to quantify skin neurofibromas of neurofibromatosis 1 using paper frames.

BACKGROUND: Skin neurofibromas represent one of the main clinical manifestations of neurofibromatosis 1, and their number varies greatly between individuals. Quantifying their number is an important step in the methodology of many clinical studies, but counting neurofibromas one by one in individuals with thousands of tumors is arduous, time-consuming, and subject to intra and interexaminer variability. We aimed to evaluate the efficacy of a new methodology for skin neurofibromas quantification using paper frames. METHODS: The sample comprised 92 individuals with NF1. Paper frames, with a central square measuring 100 cm2, were placed on the back, abdomen and thigh. Images were taken, transferred to a computer and two independent examiners counted the neurofibromas. The average number of neurofibromas/100 cm2 of skin was obtained from the mean of the three values. The differences in the quantity of neurofibromas counted by two examiners were evaluated with Intraclass correlation coefficient (ICC), paired t-test, Bland-Altman and survival-agreement plots. To evaluate the predictive value of the method in obtaining the total number of neurofibromas, 49 participants also had their tumors counted one by one. Reproducibility was assessed with Pearson's correlation coefficients and simple linear regression model. RESULTS: There was excellent agreement between examiners (ICC range 0.992-0.997) and the total number of skin neurofibromas could be predicted by the adhesive frames technique using a specific formula (P < 0.0001). CONCLUSIONS: In this article we describe a reliable, easy and rapid technique using paper frames to quantify skin neurofibromas that accurately predicts the total number of these tumors in patients with NF1. This method may be a useful tool in clinical practice and clinical research to help achieve an accurate quantitative phenotype of NF1.