Atypical Evolution of Meningiomatosis After Discontinuation of Cyproterone Acetate: Clinical Cases and Histomolecular Characterization.

doi:10.21203/rs.3.rs-692459/v1

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Atypical Evolution of Meningiomatosis After Discontinuation of Cyproterone Acetate: Clinical Cases and Histomolecular Characterization.

https://doi.org/10.21203/rs.3.rs-692459/v1

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Purpose

Long-term use of cyproterone acetate (CPA) is associated with an increased risk of developing an intracranial meningioma. Discontinuation of CPA most often induce stabilization or regression of the tumor. The exact mechanism of regression is unknown as well as the reason why some meningiomas are still growing after CPA discontinuation.We are reporting four patients with multiple meningiomas, showing opposite tumor evolutions after stopping the CPA highlighting the underlying histologic and genetic features.

Methods

Patients presenting several meningiomaswith opposite evolutions following the discontinuation of CPA were identified. The clinical and radiological data’s were reviewed. A retrospective volumetric analysis of the meningiomas was performed. All the growing meningiomas were operated. Each tumor was characterized histopathologically and by molecular and genetic analyses.

Results

Four female withmultiple meningiomas and opposite tumor volume evolution after CPA discontinuation were identified. The histopathological results found fibroblastic meningiomas for tumorsgrowinglocated in the convexity and a morefibrousmeningioma in the skull-base tumor which decreased. Meningothelial and transitional meningiomaswere found in two skull-base growing meningiomas.The molecular characterization found twoNF2-mutations among the 4 growing meningiomas. In one patient who presented both patterns, the shrinking skull-basetumor harbored a PIK3CA-mutation whereas the growing tumor, a NF2-mutation.

Conclusion

To our knowledge, this is the first report of such an atypical tumor evolution of CPA-associated meningiomatosis after CPA discontinuation in the same patient. Underlying biological mechanisms explaining this observationespecially, the close relationship between mutational landscapes and the meningeal embryologyin CPA-related meningiomasrequire further research.

Neurology

Oncology

progestin-related meningiomas

meningioma

cyproterone acetate

PIK3CA mutation

NF2 mutation

progesterone receptors

The association between sex hormones and meningiomas is well known with arguments such asan incidence more than 2.5 times higher in women[1], tumor growth during pregnancy and regression following child birth[2], association between meningiomas and breast cancer[3], endometrial carcinoma, endometriosis[4]and, expression of progesterone receptors (PR) and oestrogene receptors (ER) in meningiomas[5].

Cyproterone acetate (CPA) is a synthetic progestin drug with strong antiandrogenic effect used for a variety of indications, mostly related to hyperandrogenization and hirsutism in women, while it is used for prostate cancer and paraphilia in men.Thesuspicion of arelationship between the use of CPA and the risk of intracranial meningiomasand, the regression after CPA discontinuation was first reported in 2008 by Froelich et al.[6] and was followed by numerous case reports or series[7–18].This increased risk and a strong dose-effect wererecently proven in a large epidemiological study in France[19]. For progestin-related meningiomas and particularly in the case of CPA, our experience and those of others showed that, when the treatment is discontinued, most of the tumors stabilize in size or decrease, avoiding the need for further surgery[7, 8, 11, 12, 15, 16, 20]. Thus, most authors now recommend careful follow-up instead of active treatment if urgent surgery is not needed. However, the long-term behaviors of regressive progestin-related meningiomas are still unknown.

Concerning the molecular standpoint, recent reports have shown that pathogenic PIK3CA/AKT1 mutations are more frequently foundin progestin-associated meningiomas[21, 22]. Meningioma mutations affecting the PIK3CA/AKT1 pathway are also more frequent in skull base location whereas meningiomas arising from the convexity or the posterior fossa harbor mutations in theNF2-gene[21, 23–25]. Distinct embryologic origins of the meninges[26]may explain some variation in the mutational landscapes of meningiomas.

We are reporting a series of CPA induced meningiomatosis with opposed tumor evolution following CPA discontinuation in the same patient,highlighting the underlying histologic and genetic features.

Patients’ selection

Since 2009, following the results of our CPA studies[7, 8, 12, 13, 20, 27], every patient presenting with a meningioma to our neurosurgical department was questioned about previous history of progestin treatment.Every newly diagnosed patient with intracranial tumor radiologically compatible with a meningioma associated with CPA intake, followed aconservative strategy starting with discontinuation of CPA and a close clinical and radiological follow-up.Surgery was onlyindicated in case of tumor growthon serial magnetic resonance imaging (MRI)or in severely symptomatic patients.

All patients with meningiomatosis (>1 meningioma), CPA exposure(>3g for six months) and opposed patterns of tumor evolution after CPA discontinuationwere included. Patients presenting prior radiation and/or meeting the clinical criteria for the diagnosis of familial schwannomatosisor type 2 neurofibromatosis were excluded. For each patient, clinical and radiological tumor characteristics, CPA history and follow-up were collected.

Files analysis and volumetric study

Patients’ charts were retrospectively studied for demographic data and clinical evolution. Carestream® software (Carestream Health Inc, Rochester NY, USA) was used to measure and compare tumor volumes on MRI. The outlining was performed by two board certified neurosurgeonsby manually contouring each meningioma on each slice on the axial reconstructions of the 3D T1 gadolinium enhanced MRI sequences, and subsequently verifiedin the sagittal and coronal planes. The contouring was then optimized with the “repulsor” tool. The volume was automatically calculated using the region of interest segmentation function.

Histopathologic review

The histological analysis was performed by two neuropathologists (H.A-B and M.P). Tumors were classified according to the 2016 WHO grading[28]. Histopathological parameterswere evaluated and immunohistochemistry studies (ABC peroxidase, DAB automate, Venta Benchmark) including antibodies directed against Ki-67 and progesterone receptors were performed for each available sample.

Biomolecular characterization (Targeted Next Generation Sequencing)

Each available tumor was analyzed for protein-coding gene mutations by targeted next-generation sequencing (NGS). The in-house NGS panel included 571 genes of interest in oncology for diagnosis, prognosis, and theranostics including meningioma genes of interest such as NF2, PIK3CA, AKT1, SMO. The library preparation was performed using the Agilent Sureselect XT HS kit according to the manufacturer protocol, and the sequencing was completed on an Illumina NovaSeq 6000 sequencer. All variants, named using Varscan2 (v2.4.3-0), that passed the following thresholds were validated: allelic ratio above 5% and population frequency lower than 0.1% in 1000 g, ESP or gnomAD.This large targeted NGS panel also allowed molecular analysis of tumors for copy number variation (CNV).

Ethics statement

All patients provided written consent for future publications for academic purposes and for translational researches. The study was approved by the local ethics committees.

Between April 2009 and August 2019, 132 patients withCPA-related meningiomaswere included in our prospective database.The mean follow-up time was 38±29 months (median,18 months).After applying inclusion and exclusion criteria, four patients with opposed patterns of meningioma growth after CPA cessation were identified. Patients had been taking CPA for a long period from 5 to 26 years (mean: 15.8 ±9.9 years). The doses of CPA ranged from 25 to 50 mg daily.In all of thesefourpatients,one meningiomawassurgically removed because of tumor growth, while others were clinically followed because decreasing in size (Fig 1). In one patient (case2), the growing and decreasing tumors were next to each other and were resected together.The targeted NGS panel with CNV status was performed for the four growing meningiomas and for one decreasing meningioma (case 2). Patients and tumor characteristics were summarized in Table 1.

Clinical, histological and molecular results

Case 1

A 45-year-old female who had been taking CPA for five years for dysmenorrhea and alopecia was referredto our department following the MRI diagnosis of two asymptomatic meningiomas (right occipital attached to the tentorium and right frontal).Both presented a homogeneous gadolinium-enhancing MRI signal.

CPA wasstopped at the time of diagnosis.Over a period of 2 years of observation,the tentorial occipital tumor continued to grow (5.3to 6.1 cm³), while the smaller frontal meningioma shrinked(0.08 to 0.03 cm³).The occipital lesion was operated. Anatomopathological examination found a fibroblasticmeningioma with a Ki-67% <1% and a level of PR >75%.ANF2 pathogenic variant (c.399C>A / p.(Cys133Ter)) was identified in this meningioma (Fig 1).

Case 2

A 62-year-old femalewho had been taking CPA for 22 years for alopecia presented with two lesions: a millimetric right frontal meningioma and a large, asymptomatic left temporal fossa meningiomaof 35 cm³. The last one was composed of two parts with distinct MRI signals after gadolinium injection:a temporal convexity part with homogeneous gadolinium-enhancementand a more medial spheno-orbital part with heterogeneous gadolinium enhancement.

The CPA was stopped,and several control MRIs were done for 11 months,showing a progression of the convexity partof the large meningioma (3.9to 7.6 cm³),although thespheno-orbital part of the tumor decreased in volume(31.1to 16.6 cm³).The other frontal meningioma completely disappeared. Given the radiological progression, a surgical treatment for the temporal fossa meningioma was considered appropriate.The histopathological examinationwas consistent with a fibroblastic meningiomafor both parts of the tumor, but a more fibrous feature for the skull-base part.The proliferation index (Ki-67) was elevated in the convexity part, superior to 12 %, while <1% in the spheno-orbital part (Fig2).The progesterone-receptor status was positive for the two components but inferior to 30 % in the growing part. Concerning the molecular standpoint, we observed a NF2 pathogenic variant (c.241-1G>A) in the convexity growing part. Loss ofchromosomes 22 and X was also identified in CNV analysis. In the spheno-orbital part of the tumor that regressed in size, a PIK3CApathogenic variant (c.1633G>A / p.(Glu545Lys)) was observed.Each component of the tumor did not harbor the mutation found in the other part.Moreover, CNV analysis confirmed the two different tumoral entities (Fig 3).

Case 3

A 53-year-old female was referred to our departmentcomplaining ofprogressivememory loss.She had been taking CPA for more than 10 years for acne. An MRI identified two small meningiomas, oneolfactory groove meningioma(0.7 cm³)and one in the left parietal region(1.1 cm³)and alopecia. Both presented a homogeneous gadolinium-enhancing MRI signal. It was therefore decided to stop CPA. During a follow-up period of 41 months, a consistent volumeincreaseofthe olfactory meningioma (0.7 to 5.2 cm3) was observed together with the regression of the left parietal tumor (1.1to 0.4 cm³). The olfactory meningioma was successfullyoperated.The anatomopathological examination showed a transitional meningioma with aKi-67<2% and aPR level >75%. No pathogenic variant was identified.

Case 4

A 42-year-old female, treated with CPA for 26 years for alopecia andoral contraception, was referred to our center following the fortuitous discovery of several asymptomatic meningiomas (tuberculum sellae, right frontal convexity, two millimetric left frontal and one millimetric left parietal). CPA was stopped, and the patient was observed. After the 15-month follow-up, the right frontal meningioma decreased in volume (13.4to 9.6 cm³)while the tuberculum sellae meningioma continued to grow (15.7 to 21 cm³) with a slight proximal and medial extension into the left optic canal. The other millimetric meningiomas of the convexity shrinked. The tuberculum meningioma was successfully removed, and the histopathological examination confirmed a meningothelial meningioma with a Ki-67 <4-5 % and a PR level >75%. No pathogenic variant was identified.

The suspicion of a link between CPA and meningiomaswas raised by our group in 2008[6]and was confirmedby numerous case seriesshowing regression or stabilization of meningioma(s) after CPA discontinuation[7, 8, 12, 13, 15, 17, 18, 27, 29–32]. Gill et al.[14]described an increased risk of meningioma(s)in patients under high dose CPA and with a longer than 1 year exposure. Recently, Weill et al.[19]proved this increased risk of meningioma(s) development with long term use of CPA and a strong dose effect[19].

CPA-related meningiomas also seem to be more often multiple and localized on the anterior or mid-skull base and the anterior convexity[21, 22].It is well known that the meninges have different embryological origins[33] depending on the anatomical site; this embryological origin might be associated with the pathophysiology of various diseases such as meningiomas[26, 34]. Recently, Okano et al[24] demonstrated that oncogenic mutations and meningioma characteristics (tumor location, histological findings) are associated with meningeal origins. Tumors from meninges originating from the neural crest more frequently harbor NF2 mutations or 22q loss[23, 24, 35], and are associated with more frequent fibrous histological type[24].Meningiomas with NF2 mutations are also associated with the posterior skull baselocation that originates from the dorsal mesoderm. The tumors arising from the meninges originating from the paraxial mesoderm harbor preferentially AKT1, SMO, KLF4 and PIK3CA mutations and are frequently associated with meningothelial meningioma type[24].

The mechanism(s) of pathogenesis of multiple sporadic meningiomas remain unclear, and two hypothesis have been raised: a monoclonal origin[36] or an independent development[36, 37] suggesting several mutational landscapes. Concerning progestin-associated meningiomas which account for almost one third of the multiple meningioma, they seem to be characterized by a specific mutational landscape. PIK3CA pathogenic mutations were identified in progestin-associated meningiomas in comparison with a control population[21, 22].

This is the first report of CPA related meningiomatosis with opposed evolution of meningiomas in the same patient after CPA discontinuation with regressing tumors while other meningiomas continued to growth. The most striking example of this differential growing pattern is case 2 in which two components exhibiting opposite behavior with volume increase of the convexity component along with a decrease in size of the skull base component. In our patients, NF2-mutations were identified in the growing tumors, although a PIK3CA mutation was only found in the tumor shrinking after CPA discontinuation.

Two mainhypotheses could be evoked to clarify this atypical phenomenon.

The first hypothesis for the opposed profile evolution of meningiomas in a same patient after cessation of CPA is the coexistence of hormone-related and not meningiomas with specific mutational landscapes.

For case 2, the hypothesis of two different meningiomas which would later unify in a single entityis plausible considering their distinct genetic profiles (Fig 3). It would imply the coexistence of two tumoral clones (hormonal or not induced) in a same patient, characterized by a different mutational landscape and probably different underlying tumorigenesismechanisms.

Furthermore, our results are in concordance with previous reports of an association between the mutational lansdscape of meningiomas and the embryological origins of the meninges from which they arise. All growing-meningiomas harboring NF2-mutations were localized in the convexity or the tentorium (who is originated from the neural crest) and were fibroblastic meningiomas. In the case 2, the spheno-orbital part of the meningioma, decreasing in volume after CPA-discontinuation, harbored a PIK3CA-mutation that is common in CPA-related meningiomas[21]. However, not only driver genetic mutations can explain the tumorigenesis of CPA-related meningiomas but also the epigenetic regulation and methylation status which is commonly implicated in tumor progression[38].

A second hypothesisthat all meningiomas were hormone-related but prolonged exposure could generate loss of progesterone receptors.

PR are found in most meningiomas[5] and are believed to play a significant role in meningioma growth[39]. Progestin exposition could induce the growth of meningeal cells through their intracellular receptors in concert with coactivators and corepressors[10]. Previous reports indicated thatloss ofPR status has been associated with a high cellular proliferation, mitotic index (Ki-67), recurrenceand high-grade tumors[40, 41]. Moreover, according to the tumor location, meningiomas express different patterns of sex hormonal receptors[42]. CPA-related meningiomas often present a higher PR expression than non-CPA meningiomas[42], and PIK3CA mutations occurred also more frequently in the presence of the hormone receptor overexpression[43].

Long-term and high-level progesterone stimulation could generate tumoral genomic alterations in CPA-meningiomas leading to progressive loss of progestin tumor receptors, thus explaining a continued growth of these tumors even after CPA withdrawal.This hypothesis refers to the mechanisms of drug resistance in patients with advanced cancers, thus selecting some clonal tumor cells. One of themincludesgenetic alterations leading to anabnormal conformation protein that impair the binding of the drug.

This hypothesis is also consistent with the pathological findings of our case 2in which we observed a PR level lower than 30% and Ki-67 at 12 % in the convexity growing part of tumor harboring a NF2-mutation. However, in the cases3 and 4, we observed in the skull base growing meningiomas a classic higher level of PR with a low Ki-67 rate as well asin the tentorial meningioma of the case 1.

If a genetic predisposition to CPA meningiomatosis exists, as suggested by familial cases[44], it must not be the only explanation considering the coexistence of two hormone response patterns. Others factors in the genesis of these tumors remain to be determinated.As the number of patients followed for progestin-related meningiomas increased significantly in the last years, it is important to understand why some meningiomas continue to grow meanwhile most of them regresses or stabilize.

In cases of CPA-related meningiomatosis, when CPA is discontinued, most of the tumors stabilize in size or evenshrink. However, as shown in this report, exceptions are possible and some meningiomas even in the same patient, continue to grow emphasizing the importance of a careful and prolonged patient follow-up.Although several hypotheses can be proposed, the underlying biological mechanisms remain unclear and deserve further studies in patients harboring opposite growth patterns, in order to predict those meningiomas that will continue to grow and improve patient counselling for newly diagnosed progestin related meningiomas.

Conflict of interest

None of the authors declare a conflict of interest

Funding

The authors did not receive support from any organization for the submitted work.

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by TP, LG, RA, JW, AP, CB, MP, HAB, ALB, JMP, EM and SF. The first draft of the manuscript was written by TP and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding on reasonable request.

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Table 1 Patients and tumor characteristics were summarized.

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