Progression Free -survival According to Simpson Grade Resection and Histological Types of Meningiomas in the Mexican Population Progression Free-survival of Meningiomas in the Mexican Population


 Introduction: Meningiomas are the most common primary central nervous system (CNS) tumors, with an incidence of 8.14 per 100,000 habitants. They represent 30% of all adult primary brain tumor diagnoses in the United States in contrast to Latin America with 50%. In Mexico, there are no epidemiological trends of meningiomas or other CNS tumors. Simpson resection grade and WHO grade are the prognostic factors with the greatest effect. In this paper, we describe the correlation between the survival free of disease and the gross total resection with its histological type according to Simpson’s grading scale. Materials and methods: A descriptive, analytical, retrospective, case-control study was conducted in two public third -level hospitals and three second- level hospitals in two cities of Mexico, (Mexico City and Guadalajara, Jalisco in a period of 10 years (2010-2020). An analysis of measures of central tendency was performed for age, sex, location, histological type, and postsurgical Simpson grade.Results: 26 patients of 179 had recurrence. Among the total recurrences, 15.4% were Simpson 1, 69.2%Simpson 2, and 15.4%Simpson 3. The survival for Simpson 1 was 142.0 months, Simpson 2 90.32 months, and Simpson 3 69.13 months. According to the histological type, the meningiomas with the lowest survival were the microcystic ones with 60 months, followed by the atypical ones with 90.4 months, and the psammomatous ones with 99.8 months. Conclusion: Surgical resection and the histological type are factors that affect progression free -survival. The Mexican population presents characteristics similar to those described in world literature.Importance of the study: This is the first study of its kind in the Mexican population and lays the foundations for future studies in the Latin American population.


Introduction
Meningiomas are the most common primary central nervous system (CNS) tumors. The Central Brain Tumor Registry of the United States (CBTRUS) reported an incidence of 6.0 per 100,000 inhabitants . 1 Meanwhile Moreau et al 2 , reported in 2020 an incidence of 8.14 per 100,000 inhabitants. The estimated prevalence ranges between 1 and 2,7%, and about 85% are diagnosed as screening. 3 In The United States, represent 30% of all adult primary brain tumors. By the side, in Latin America, the meningiomas represent 50% of cases associated with primary brain tumors. 4,5 Several studies have associated the appearance of meningiomas with a family history of some cancers, such as bladder cancers, thyroid cancer, leukemia, breast cancer, and melanoma. 6 Meningiomas represent approximately 20% of all intracranial tumors in men and 38% for women. 7 Almost all the meningiomas are considered histologically benign (92.8%), only 5% are de ned as malignant. Also, there are 2.2% considered as uncertain or atypical 7 and these are slightly predominantly in male. 8 The most frequent location of meningiomas is supratentorial (parafalcin, cavernous sinus, sphenoid bone, olfactory sulcus and parasillar). 9 The most frequent symptoms are: motor de cit, headache, and dizziness. 10 Negative prognostic factors in meningiomas include young age, male gender, low Karnofsky, functional status, high grade, high mitotic index, subtotal surgical resection, and optic nerve involvement. 11 In 1957, Simpson 12 published his article in which he demonstrated a signi cant correlation between the degree of resection of the meningioma and the recurrence of this tumor. The extent of the resection is classi ed according to Simpson, using a 5-level scale. Complete surgical excision is the treatment of choice for all meningiomas. 7 In 2012, Heros et al. 12 noted that many brain surgeons had begun to consider "gross total resection" to refer to Simpson grades 1, 2, and 3, ruling out possible differences between the grades of resection. 12 The term recurrence is used in the clinical sense to imply progression directly due to tumor growth after a disease-free period. 13 The incidence of recurrence varies somewhat with the surgeon's experience and even more with his judgment of what constitutes an appropriate operation. 13 In Mexico, there are no epidemiological trends of meningiomas or other CNS tumors. 4 In this paper, we describe the correlation between the progression free-survival disease and the gross total resection with its histological type according Simpson to grading scale.

Materials And Methods
A descriptive, analytical, retrospective, case-control study was conducted in two public third-level hospitals and three second -level hospitals in two cities of Mexico, (Mexico City and Guadalajara, Jalisco) in a period of 10 years (2010-2020).All the patients were operated on for a single intra-or extracranial meningioma. Also, had at least 6 months of clinical follow-up for the inclusion. All the patients with no surgical procedure, even if they had the diagnosis of intra or extracranial meningioma were excluded. By the side, patients with no follow-up after surgery and, those with the diagnosis of a genetic disease (i.e. neuro bromatosis type 2, Carney complex and others) associated with meningiomas or meningiomatosis.
Ethics statements: The National Code on Clinical Trials has declared that ethics approval is not necessary for real retrospective studies.
Data collectionAll the post -surgical follow -up records were obtained from the virtual media system of electronic clinical les. The recurrence was determined in patients with T1 hyperintense or isointense lesion after the systematic analysis of a neurosurgeon with expertise in the topic. Also, evidence of lesions including new brain areas was eliminated from the nal analysis of the study.
Statistic analysisAn analysis of measures of central tendency was performed for age, sex, location, histological type, and postsurgical Simpson grade. The analysis was completed as Kaplan Meyer survival curves for the total population studied and modi ed for each Simpson grade. In other words, global recurrence-free survival was analyzed for all patients and later modi ed by the degree of resection achieved. We consider only patients with satisfactory resection at Simpson 1, 2, and 3. Patients with Simpson 4 and 5 were eliminated from the survival analysis, which we do not consider as total resection.

Results
A total of 186 patients were obtained. Four were excluded from the analysis due to concomitant diagnosis of Neuro bromatosis type 2 and meningiomatosis, and 3 patients due to lack of data for the follow-up during the postoperative period. The nal analysis was carried out with 179 patients.
Only 141 patients were considered at the end for their survival analysis. There were no cases registered for papillary, lymphoblastic, and secretory histological subtypes Relationship between Simpson grade and recurrence Twenty -six patients had a recurrence. The Simpson grade 2 resection was two times more frequent in women than men. The results are shown in Table 1.

Survival analysis, Survival curves
There is overall recurrence-free survival of 120,996 months, with a typical error of 6.3 months, (95% CI 108.63-133.361).

Discussion
Despite the relatively high prevalence of meningiomas, only a few studies describe their epidemiology, analyze demographics, and investigate risk factors for developing such lesions. 14 In this study we reported the clinical and demographics features for meningiomas in a Mexican population.
The 2016 World Health Organization (WHO) classi cation of tumors affecting the central nervous system (CNS) recognizes three grades of meningioma. In absolute numbers, those known as benign meningiomas (grade I) are much more common than borderline malignant or malignant meningiomas (grade II-III). 15,16 The current global prevalence for meningiomas is estimated three times higher for females. Also is reported an incidence peak between 30 and 59 years old. It could be due to the in uence of hormonal factors. 2,9 In this study, we obtained similar results in our population.
Also, there was a close correlation between the Simpson grade and the risk of recurrence. 17 Here we reported a major recurrence (24.7%) for Simpson 2 meningiomas after surgical resection. Meanwhile, the recurrence was 6.8% for meningiomas Simpson I, 2 and 44.4% in the case of Simpson III. These results are slightly higher in comparison to the original results reported by Simpson. 13 It is known that subtotal resection (STR) often leads to progression and subsequently often to new invasive procedures. Consequently, gross total resection (GTR) has always been considered the aim to pursue. On the other hand, the increasing mean age of patients with meningiomas imposes less aggressive surgical interventions due to the risk of morbidity or injury to neurovascular structures in locations such as parasagittal, skull base, or tentorium. 12,18 In locations with low surgical risk, such as convexity, Simpson grade I resection should continue to be the main objective. 12 In general, higher WHO grading has been associated with the poor prognosis of meningiomas. 19 World while, WHO grade III meningiomas show extremely aggressive behavior and high rates of recurrence. 20 In our study, in accordance to the histological type, the microcystic meningiomas (WHO I) had a surveillance rate of 60 months (lowest) in contrast with transitional (WHO I) with 122 months (highest). For the non-graphed variants, not enough censored data were obtained, so no data was obtained from them. For the WHO grade classi cation, in our study, the most frequent was grade I. It is in accordance with current medical literature. 2 Also, the Simpson grade II was the 40.8% of the postsurgical resection histopathological report, two times more in women than men.
Tumor recurrence after complete surgical resection could be due to local persistence of tumor cells with clonogenic capacity due to tumor seeding during surgery, microinvasion of lymphatic vessels and other tissues, or incomplete microscopic resection of the tumor. 21 Finally, the extent of surgical resection re ected by the Simpson grade seems to be closely associated with the risk of recurrence in association to the histological type. 17 For example WHO grade I tumors with features of atypia are more likely to progress than those without features of atypia. 22 Recent Mexican papers lay the foundations for future studies on the differentiation and typing of meningiomas, regardless of the histological grade to which they belong. 23 Tumor size, location, and bone in ltration were reported as prognostic factors although these factors were not associated with the poor prognosis of recurrent meningioma. 17,19 Strengths and Limitations of the Study The strength of this study is that this is the one of the largest case series that analyzes postoperative survival in Mexican population. However, this study is limited by its retrospective nature. Our variables are just limited to the available data in the medical centers that participate in this job.

Conclusion
Surgical resection and the histological type of meningiomas are a factor that affects survival. The Mexican population presents characteristics similar to those described in the world literature.

Declarations
Funding: This research did not receive any speci c grant from funding agencies in the public, commercial, or not-for-pro t sectors.  Figure 1 Global recurrence free -survival curve and free recurrence survival adjusted to Simpson 1, 2 and 3.

Figure 2
Free recurrence survival adjusted to Histological type.