# Recurrence Rate and Exploration of Clinical Factors after Pituitary Adenoma Surgery: A Systematic Review and Meta-Analysis based on Computer Artificial Intelligence System

Authors: Xianghe Zhang; Fan Yang; Nianchen Han
Journal: Computational Intelligence and Neuroscience
 (2022)

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## Abstract

Background. The first-line treatment for patients with any type of pituitary adenoma is trans-sphenoidal surgery. Considering the prevalence of the condition globally, the treatment is quite common. The recurrence of pituitary adenoma is a recognized occurrence in the medical field; however, there is limited comprehensive research and analysis of the predictive factors of recurrence rates and the clinical factors impacting relapse rates. Identifying the recurrence rates of pituitary adenomas and the clinical factors associated with them could help increase the remission rate by increasing focus on the specific aspects for early diagnosis and improved treatment. Objective. The objective of the current systematic review and meta-analysis is to assess the recurrent rates based on previous studies and to explore the clinical factors after pituitary surgery. Methods. A search was performed on PubMed, APA PsycINFO, Scopus, CENTRAL, and Google Scholar databases for English articles published from 1st January 2010 to 1st August 2022. Systematic reviews, meta-analysis, evidence syntheses, editorials, commentaries, preclinical studies, abstracts, theses, and preprints were excluded. Meta XL statistical software was used to conduct a prevalence meta-analysis. Results. PubMed, PsycINFO, and Medline databases were searched. All of the articles were written between 2012 and 2022. In the beginning, 612 items were recognized. After removing duplicates and analyzing the remaining articles in terms of inclusion and exclusion criteria, 31 articles remained. Conclusion. There is a relationship between recurrence rates and the follow-up period. There were conflicting results about the clinical factors after pituitary adenoma surgery, specifically age and tumor size. Some included studies that there was an association between macroadenomas and high recurrence rates. No study reported that gender was a clinical factor affecting pituitary adenoma surgery outcomes or the recurrence rate. Studies also reported that there was a correlation between the remnant tumor factor and the recurrence rates; adenoma remnants after surgery increased the risk of recurrence rates for patients.


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## Body

## 1. Introduction

Trans-sphenoidal surgery is one of the available treatments for patients with pituitary adenoma [1]. There are many types of pituitary adenomas including prolactinoma, acromegaly, and Cushing’s disease [2]. Pituitary surgery is common for patients with acromegaly and prolactinoma; the treatment is known for quick relief of adenoma signs and symptoms. Unfortunately, despite the fact that the surgery is among the best treatment options, it does not guarantee high remission [3]. Recurrence of the tumor can occur in some cases. Some predictive factors are known in association with recurrence of pituitary adenomas, but very few clinical factors are explored after the surgery [4].A common type of pituitary adenoma is silent corticotroph adenoma which is characterized by positive immunostaining for adrenocorticotropic hormone; it stems from a rise in adenohypophyseal cells of Tpit lineage [5]. It accounts for approximately 3%–19% of nonfunctioning adenoma, which shows that it is quite prevalent. There are two categories of pituitary adenomas including macroadenoma (greater than 1 centimeter) and microadenoma (smaller than 1 centimeter). Cushing’s disease, a pituitary adenoma [6], is mostly attributed to microadenoma and stems from prior exposure to dangerously high cortisol levels for a prolonged period. The benign tumor of the pituitary gland in those with Cushing’s disease produces a very high amount of adrenocorticotropic hormone that stimulates the adrenal glands to release more cortisol [7]. Endogenous Cushing’s syndrome is rare. “Endogenous” means something inside your body is causing disorder rather than something outside your body, such as medicine. However, estimates vary, ranging from 40 to 70 people out of every million. There is a strong association with the development of pituitary adenomas [8].Patients with pituitary adenomas who do not show hypersecretory symptoms, such as hyperprolactinemia, acromegaly, or Cushing’s syndrome, have nonfunctioning adenomas. Cushing’s disease is a rare kind of pituitary adenoma characterized by excessive adrenocorticotropic hormone release, which causes hypertension, weight gain, morbidity, extreme tiredness, diabetes, and osteoporosis. The recurrence rate of pituitary surgery varies greatly based on a variety of variables. The present systematic review and meta-analysis aims to quantify recurrence rates based on prior research and to investigate clinical variables after pituitary surgery [9, 10].


### 1.1. Objectives and Research Questions

Despite the fact that trans-sphenoidal surgery is the first-line treatment for patients with pituitary adenoma, there is limited research on the recurrence rates of treatments, the clinical factors affecting them, and significant aspects after surgery. Therefore, the objective of the current systematic review is as follows:(i)
Assess the recurrent rates of pituitary surgery(ii)
Explore the clinical factors after pituitary surgerySome characteristics of patients included in the study are shown in Tables1 and 2.


### 1.2. Research Question

The research question for the current analysis was structured according to the PICO model.Population: people with pituitary adenomaIntervention: treatment using pituitary adenoma surgeryComparison: no comparisonOutcome: recurrence rateQuestion: what are the recurrent rates and the clinical factors after pituitary surgery?


## 1.1. Objectives and Research Questions

Despite the fact that trans-sphenoidal surgery is the first-line treatment for patients with pituitary adenoma, there is limited research on the recurrence rates of treatments, the clinical factors affecting them, and significant aspects after surgery. Therefore, the objective of the current systematic review is as follows:(i)
Assess the recurrent rates of pituitary surgery(ii)
Explore the clinical factors after pituitary surgerySome characteristics of patients included in the study are shown in Tables1 and 2.


## 1.2. Research Question

The research question for the current analysis was structured according to the PICO model.Population: people with pituitary adenomaIntervention: treatment using pituitary adenoma surgeryComparison: no comparisonOutcome: recurrence rateQuestion: what are the recurrent rates and the clinical factors after pituitary surgery?


## 2. Search Methods

### 2.1. Search Criteria and Information Sources

The current systematic review was reported by following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Numerous online databases were searched based on computer artificial intelligence system, including PubMed, MEDLINE, and APA PsycINFO. A search string was developed and applied in the databases; the results from each database are shown.


### 2.2. Inclusion Criteria

All articles had to have been published within the past twenty years and authored in English. The study designs included randomized controlled trials, case series, prospective analysis, retrospective analysis, controlled trials, comparative studies, and experimental studies. No grey literature was included in the analysis. Only peer-reviewed articles were included. All articles had to have been published through proper channels. The participants in the included studies had to be 18 years or older. The articles had to be relevant to the research topic focusing on the recurrence rate and clinical factors affecting exploration of clinical factors after pituitary adenoma surgery. Different categories of pituitary adenoma were included for the analysis such as silent corticotroph adenoma, Cushing’s disease/syndrome, acromegaly, hypercortisolism, prolactinoma, and nonfunctioning pituitary adenoma. All the studies included had to focus exclusively on pituitary adenoma surgery; any other treatments such as radiotherapy were not allowed. The follow-up period had to be more than 12 months. The included studies also had to focus on primary pituitary adenoma surgery.


### 2.3. Exclusion Criteria

All articles published before 2010 (the past twelve years) were excluded from the systematic review and meta-analysis. As mentioned, no grey literature or articles published through unknown/unconventional channels were included in the current systematic review. All articles that were not peer-reviewed were also excluded. Any studies that were irrelevant to the research topic were not included. Studies focusing on secondary pituitary adenoma surgery or a combination of both primary and secondary surgeries were excluded since the objective of the systematic review and meta-analysis was to assess recurrence rates and clinical factors after the treatment. Systematic reviews, meta-analysis, evidence syntheses, editorials, commentaries, and preclinical studies that were authored before 2010 were also excluded. Studies that included radiotherapy intricately were excluded considering the fact that although the treatment may help in tumor control, it does not impact recurrence rates [11, 12]. The articles included also had to be available online; the source was excluded when only the abstract was available. Studies with participants less than 18 years such as cases of pediatric Cushing’s disease were not included.


### 2.4. Data Extraction

The data and findings from the included studies that passed the eligibility criteria are shown in Table2. The extracted data included author, year of publication, study design, pituitary adenoma, follow-up period, and recurrence rates and clinical factors. The follow-up period was the mean/average since some studies failed to report on the exact follow-up period related to the remission rate.


## 2.1. Search Criteria and Information Sources

The current systematic review was reported by following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Numerous online databases were searched based on computer artificial intelligence system, including PubMed, MEDLINE, and APA PsycINFO. A search string was developed and applied in the databases; the results from each database are shown.


## 2.2. Inclusion Criteria

All articles had to have been published within the past twenty years and authored in English. The study designs included randomized controlled trials, case series, prospective analysis, retrospective analysis, controlled trials, comparative studies, and experimental studies. No grey literature was included in the analysis. Only peer-reviewed articles were included. All articles had to have been published through proper channels. The participants in the included studies had to be 18 years or older. The articles had to be relevant to the research topic focusing on the recurrence rate and clinical factors affecting exploration of clinical factors after pituitary adenoma surgery. Different categories of pituitary adenoma were included for the analysis such as silent corticotroph adenoma, Cushing’s disease/syndrome, acromegaly, hypercortisolism, prolactinoma, and nonfunctioning pituitary adenoma. All the studies included had to focus exclusively on pituitary adenoma surgery; any other treatments such as radiotherapy were not allowed. The follow-up period had to be more than 12 months. The included studies also had to focus on primary pituitary adenoma surgery.


## 2.3. Exclusion Criteria

All articles published before 2010 (the past twelve years) were excluded from the systematic review and meta-analysis. As mentioned, no grey literature or articles published through unknown/unconventional channels were included in the current systematic review. All articles that were not peer-reviewed were also excluded. Any studies that were irrelevant to the research topic were not included. Studies focusing on secondary pituitary adenoma surgery or a combination of both primary and secondary surgeries were excluded since the objective of the systematic review and meta-analysis was to assess recurrence rates and clinical factors after the treatment. Systematic reviews, meta-analysis, evidence syntheses, editorials, commentaries, and preclinical studies that were authored before 2010 were also excluded. Studies that included radiotherapy intricately were excluded considering the fact that although the treatment may help in tumor control, it does not impact recurrence rates [11, 12]. The articles included also had to be available online; the source was excluded when only the abstract was available. Studies with participants less than 18 years such as cases of pediatric Cushing’s disease were not included.


## 2.4. Data Extraction

The data and findings from the included studies that passed the eligibility criteria are shown in Table2. The extracted data included author, year of publication, study design, pituitary adenoma, follow-up period, and recurrence rates and clinical factors. The follow-up period was the mean/average since some studies failed to report on the exact follow-up period related to the remission rate.


## 3. Results

### 3.1. Search Results

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist 2020 guidelines were applied. The initial search in the online databases using the earlier mentioned keywords identified 612 studies. After the removal of duplicates, only 436 studies were left. The abstracts and titles of 274 studies were scanned to determine their significance for the systematic review. After elimination, 132 articles remained; they were scrutinized based on the eligibility criteria. Finally, 31 articles were identified that effectively passed the predefined eligibility criteria. Figure1 shows the process of study selection presented in a flowchart (Figure 1and Tables 1–3).Figure 1
PRISMA flowchart diagram.Table 1
Patient characteristics.
CharacteristicsPatients overall registeredFemale,n (%)1378Age (y), mean ± SD51.3 ± 16.1Age group (y), n (%)18–2425125–3420235–4430845–54498Diagnosed with,∗n (%)Neck and back pain995Diabetes736Asthma/chronic obstructive418Pulmonary diseaseMental health problems383Hearing or vision loss370Cancer153Lung disease86Stroke80Epilepsy53Table 2
Generalised features of patients.
CharacteristicsGenderMale/female44/5Median age at treatment (years)59 (43–75)Performance status (PS)Small-cell carcinoma/others51/0StageNumber of first-line chemotherapy courses1/2/3/4/5/61/4/3/38/2/1Median (range)5(0–3)Number of regimens after progressionAfter first-line chemotherapy0/1/2/3/4/55/18/13/8/3/2Median (range)3 (2–6)Median sum of target lesion diameters99(61–305)(mm) (range)Table 3
Data extraction results.
Author and yearStudy designRecurrence rate (95% CI)Adenoma typePopulationFollow-upClinical factorsLanglois et al. (2018)Retrospective single-center study36% for silent corticotroph adenomas, 10% for silent gonadotroph adenomas,P=0.001Silent corticotroph adenomas versus silent gonadotroph adenomas814 pituitary surgeries>5 yearsWatts et al. (2017)Retrospective analysis12.5% (6/48;P=0.003)Nonfunctioning pituitary macroadenomas143 patients12 monthsJahangiri et al. (2013)Retrospective analysis34% for strongly ACTH-positive type I SCAs, 10% for weakly ACTH-positive type II SCAsSilent corticotroph adenomas75 patients>3 yearsAlahmadi et al. (2012)Retrospective analysis14% for silent corticotroph adenomas, 10% for nonfunctioning pituitary macroadenomasSilent corticotroph adenomas nonfunctioning pituitary macroadenomas20 patients41 monthsIoachimescu et al. (2012)Retrospective cohort study6.0%Silent corticotroph adenomas3342.5 monthsReddy et al. (2011)Comparative study23.1% (5 years), 46.7% (10 years) 67.9% (15 years)Nonfunctioning pituitary adenomas (NFAs)155 patients6.5 yearsPituitary tumor remnant after the first postoperative scan (P≤0.001) younger age at initial surgery (P=0.034)Cho et al. (2010)Comparative study25.0% for silent corticotroph adenomas and 26.9% for nonsilent corticotroph adenomas (P=0.839)Silent corticotroph adenomas28 patients5.2 yearsYoung patients had a higher frequency of multiple and late recurrences with more aggressive tumor behaviorCooper et al. (2010)Cohort analysis54% for SCAs 17% for nonfunctioning adenomas (P<0.025)Silent corticotroph adenomas and nonfunctioning adenomas25 SCA 84 nonfunctioning adenomas1–15 yearsBrochier et al. (2010)Retrospective study24% for those who initially had complete macroscopic resection, 47% for initial surgical remnantNonfunctioning adenomas142 patients6.9 yearsInitial complete macroscopic resection, initial surgical treatmentRaverot et al. (2010)Cohort study20%Pituitary tumor94 patients138 ± 46 monthsLindsay et al. (2011)Retrospective analysis12%Cushing’s disease331 patients10.5 ± 0.3 yearsChang et al. (2010)Retrospective analysis8%Inactive pituitary macroadenomas (EIA)81 patients5 yearsBrady et al. (2021)Retrospective analysis3%Cushing’s disease39 patients24 monthsJang et al. (2016)Retrospective analysis19%Pituitary adenoma331 patients68.5 monthsCiric et al. (2012)Retrospective study9.67%Cushing’s disease136 patients>12 monthsRecurrence rates increased with the passage of time, mean immediate postoperative plasma cortisol (IPPC) of >2.0μg/dLJung et al. (2012)Retrospective study32.4% (5 years) 54.6% (10 years)Cushing’s disease54 patients50.7 monthsRecurrence rate increases with time and possibly increases the preoperative serum cortisol level and pathologic confirmation of adenomaBarbot et al. (2013)Retrospective analysis42.11% (40 months)Cushing’s disease57 patients40 monthsAlwani et al. (2010)Retrospective analysis20%Cushing’s disease79 patients84 monthsAmmini et al. (2011)Prospective study18.5%Cushing’s disease97 patients2.9 ± 2.1 yearsAmbrogio et al. (2017)Prospective study23%Cushing’s disease56 patientsMost patients who had successful adenomectomy did not respond to desmopressin after surgeryEspinosa-de-Los-Monteros et al. (2017)Retrospective cohort study26%Cushing’s disease84 patients6.3 yearsMayberg et al. (2018)Single-center retrospective cohort analysis9.5%Cushing’s disease69 patients43.5 monthsImmediate reoperation is associated with low recurrence ratesShirvani et al. (2016)Retrospective analysis21.9%Cushing’s disease96 patients44 monthsAge, preoperative basal cortisol levels, and follow-up duration influenced recurrence (there was a significant negative correlation between the patient’s age and the follow-up period)Johnston et al. (2017)Prospective analysis7%Cushing’s disease101 patients4.33 yearsPresence of macroadenoma and tumor extension beyond the pituitary and sella were predictive of risk of late recurrenceAlmeida et al. (2020)Retrospective study34% for GTR 39.5% for subtotal resectionPituitary adenoma98 patientsMedian 144 monthsDimopoulou et al. (2014)Retrospective analysis34% (54 months)Cushing’s disease85 patients79 monthsHigher recurrence rates of CD after first TSSBou et al. (2011)Retrospective analysis20.8%Cushing’s disease101 patients44.7 monthsA positive response to vasopressin analogs and/or CRH tests occurs early in recurrenceFeng et al. (2018)Single-center retrospective analysis2.42%Cushing’s disease197 patients12 to 36 monthsMaletkovic et al. (2019)Retrospective analysis9.4%Nonfunctioning pituitary Tumors85 patientsBansal et al. (2017)Retrospective analysis32%Cushing’s disease151 patients74 ± 61.1 monthsChandler et al. (2016)Retrospective analysis17% (4 years)Cushing’s disease219 patients4 years


### 3.2. Follow-Up Periods and Recurrence Rates

Figure2 shows findings from two studies by Jung et al. [2012] and Reddy et al. [13] that showed follow-up periods and their recurrence rates. As shown in Table 4, nonfunctioning pituitary adenomas have the highest recurrent rates.Figure 2
Correlation between follow-up periods and recurrence rates.Table 4
Highest recurrence rates.
AuthorRecurrence rate >30%Pituitary adenomaLanglois et al. (2018)36%Silent corticotroph adenomaJahangiri et al. (2013)34%Silent corticotroph adenomaReddy et al. (2011)67.9% (highest after 15 years)Nonfunctioning pituitary adenomaCooper et al. (2010)54%Silent corticotroph adenomaJung et al. (2012)54.6%Cushing’s diseaseBarbot et al. (2013)42.11%Cushing’s diseaseBansal et al. (2017)32%Cushing’s diseaseDimopoulou et al. (2014)34%Cushing’s disease


### 3.3. Statistical Analysis

Figure3 shows a meta-analysis of the studies that focused exclusively on silent corticotroph adenoma. IR (95% CI) figures are highlighted in the analysis.Figure 3
IR for silent corticotroph adenoma.


### 3.4. Cushing’s Disease

The mean recurrence rate for Cushing’s disease was 18.888% for the included studies. The total number of participants was 2021. The average recurrence rate (95% CI) was found to be 18.88 (11.11–28.38), as shown in Figure4.Figure 4
The mean recurrence rate for Cushing’s disease.


### 3.5. Recurrence Rate

As shown in the figure, the recurrence rate for Cushing’s disease has fluctuated through the years but continues to decrease through the past few years; there is no distinct way to forecast future recurrence, as shown in Figure5.Figure 5
Recurrence rates through the years for Cushing’s disease.


## 3.1. Search Results

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist 2020 guidelines were applied. The initial search in the online databases using the earlier mentioned keywords identified 612 studies. After the removal of duplicates, only 436 studies were left. The abstracts and titles of 274 studies were scanned to determine their significance for the systematic review. After elimination, 132 articles remained; they were scrutinized based on the eligibility criteria. Finally, 31 articles were identified that effectively passed the predefined eligibility criteria. Figure1 shows the process of study selection presented in a flowchart (Figure 1and Tables 1–3).Figure 1
PRISMA flowchart diagram.Table 1
Patient characteristics.
CharacteristicsPatients overall registeredFemale,n (%)1378Age (y), mean ± SD51.3 ± 16.1Age group (y), n (%)18–2425125–3420235–4430845–54498Diagnosed with,∗n (%)Neck and back pain995Diabetes736Asthma/chronic obstructive418Pulmonary diseaseMental health problems383Hearing or vision loss370Cancer153Lung disease86Stroke80Epilepsy53Table 2
Generalised features of patients.
CharacteristicsGenderMale/female44/5Median age at treatment (years)59 (43–75)Performance status (PS)Small-cell carcinoma/others51/0StageNumber of first-line chemotherapy courses1/2/3/4/5/61/4/3/38/2/1Median (range)5(0–3)Number of regimens after progressionAfter first-line chemotherapy0/1/2/3/4/55/18/13/8/3/2Median (range)3 (2–6)Median sum of target lesion diameters99(61–305)(mm) (range)Table 3
Data extraction results.
Author and yearStudy designRecurrence rate (95% CI)Adenoma typePopulationFollow-upClinical factorsLanglois et al. (2018)Retrospective single-center study36% for silent corticotroph adenomas, 10% for silent gonadotroph adenomas,P=0.001Silent corticotroph adenomas versus silent gonadotroph adenomas814 pituitary surgeries>5 yearsWatts et al. (2017)Retrospective analysis12.5% (6/48;P=0.003)Nonfunctioning pituitary macroadenomas143 patients12 monthsJahangiri et al. (2013)Retrospective analysis34% for strongly ACTH-positive type I SCAs, 10% for weakly ACTH-positive type II SCAsSilent corticotroph adenomas75 patients>3 yearsAlahmadi et al. (2012)Retrospective analysis14% for silent corticotroph adenomas, 10% for nonfunctioning pituitary macroadenomasSilent corticotroph adenomas nonfunctioning pituitary macroadenomas20 patients41 monthsIoachimescu et al. (2012)Retrospective cohort study6.0%Silent corticotroph adenomas3342.5 monthsReddy et al. (2011)Comparative study23.1% (5 years), 46.7% (10 years) 67.9% (15 years)Nonfunctioning pituitary adenomas (NFAs)155 patients6.5 yearsPituitary tumor remnant after the first postoperative scan (P≤0.001) younger age at initial surgery (P=0.034)Cho et al. (2010)Comparative study25.0% for silent corticotroph adenomas and 26.9% for nonsilent corticotroph adenomas (P=0.839)Silent corticotroph adenomas28 patients5.2 yearsYoung patients had a higher frequency of multiple and late recurrences with more aggressive tumor behaviorCooper et al. (2010)Cohort analysis54% for SCAs 17% for nonfunctioning adenomas (P<0.025)Silent corticotroph adenomas and nonfunctioning adenomas25 SCA 84 nonfunctioning adenomas1–15 yearsBrochier et al. (2010)Retrospective study24% for those who initially had complete macroscopic resection, 47% for initial surgical remnantNonfunctioning adenomas142 patients6.9 yearsInitial complete macroscopic resection, initial surgical treatmentRaverot et al. (2010)Cohort study20%Pituitary tumor94 patients138 ± 46 monthsLindsay et al. (2011)Retrospective analysis12%Cushing’s disease331 patients10.5 ± 0.3 yearsChang et al. (2010)Retrospective analysis8%Inactive pituitary macroadenomas (EIA)81 patients5 yearsBrady et al. (2021)Retrospective analysis3%Cushing’s disease39 patients24 monthsJang et al. (2016)Retrospective analysis19%Pituitary adenoma331 patients68.5 monthsCiric et al. (2012)Retrospective study9.67%Cushing’s disease136 patients>12 monthsRecurrence rates increased with the passage of time, mean immediate postoperative plasma cortisol (IPPC) of >2.0μg/dLJung et al. (2012)Retrospective study32.4% (5 years) 54.6% (10 years)Cushing’s disease54 patients50.7 monthsRecurrence rate increases with time and possibly increases the preoperative serum cortisol level and pathologic confirmation of adenomaBarbot et al. (2013)Retrospective analysis42.11% (40 months)Cushing’s disease57 patients40 monthsAlwani et al. (2010)Retrospective analysis20%Cushing’s disease79 patients84 monthsAmmini et al. (2011)Prospective study18.5%Cushing’s disease97 patients2.9 ± 2.1 yearsAmbrogio et al. (2017)Prospective study23%Cushing’s disease56 patientsMost patients who had successful adenomectomy did not respond to desmopressin after surgeryEspinosa-de-Los-Monteros et al. (2017)Retrospective cohort study26%Cushing’s disease84 patients6.3 yearsMayberg et al. (2018)Single-center retrospective cohort analysis9.5%Cushing’s disease69 patients43.5 monthsImmediate reoperation is associated with low recurrence ratesShirvani et al. (2016)Retrospective analysis21.9%Cushing’s disease96 patients44 monthsAge, preoperative basal cortisol levels, and follow-up duration influenced recurrence (there was a significant negative correlation between the patient’s age and the follow-up period)Johnston et al. (2017)Prospective analysis7%Cushing’s disease101 patients4.33 yearsPresence of macroadenoma and tumor extension beyond the pituitary and sella were predictive of risk of late recurrenceAlmeida et al. (2020)Retrospective study34% for GTR 39.5% for subtotal resectionPituitary adenoma98 patientsMedian 144 monthsDimopoulou et al. (2014)Retrospective analysis34% (54 months)Cushing’s disease85 patients79 monthsHigher recurrence rates of CD after first TSSBou et al. (2011)Retrospective analysis20.8%Cushing’s disease101 patients44.7 monthsA positive response to vasopressin analogs and/or CRH tests occurs early in recurrenceFeng et al. (2018)Single-center retrospective analysis2.42%Cushing’s disease197 patients12 to 36 monthsMaletkovic et al. (2019)Retrospective analysis9.4%Nonfunctioning pituitary Tumors85 patientsBansal et al. (2017)Retrospective analysis32%Cushing’s disease151 patients74 ± 61.1 monthsChandler et al. (2016)Retrospective analysis17% (4 years)Cushing’s disease219 patients4 years


## 3.2. Follow-Up Periods and Recurrence Rates

Figure2 shows findings from two studies by Jung et al. [2012] and Reddy et al. [13] that showed follow-up periods and their recurrence rates. As shown in Table 4, nonfunctioning pituitary adenomas have the highest recurrent rates.Figure 2
Correlation between follow-up periods and recurrence rates.Table 4
Highest recurrence rates.
AuthorRecurrence rate >30%Pituitary adenomaLanglois et al. (2018)36%Silent corticotroph adenomaJahangiri et al. (2013)34%Silent corticotroph adenomaReddy et al. (2011)67.9% (highest after 15 years)Nonfunctioning pituitary adenomaCooper et al. (2010)54%Silent corticotroph adenomaJung et al. (2012)54.6%Cushing’s diseaseBarbot et al. (2013)42.11%Cushing’s diseaseBansal et al. (2017)32%Cushing’s diseaseDimopoulou et al. (2014)34%Cushing’s disease


## 3.3. Statistical Analysis

Figure3 shows a meta-analysis of the studies that focused exclusively on silent corticotroph adenoma. IR (95% CI) figures are highlighted in the analysis.Figure 3
IR for silent corticotroph adenoma.


## 3.4. Cushing’s Disease

The mean recurrence rate for Cushing’s disease was 18.888% for the included studies. The total number of participants was 2021. The average recurrence rate (95% CI) was found to be 18.88 (11.11–28.38), as shown in Figure4.Figure 4
The mean recurrence rate for Cushing’s disease.


## 3.5. Recurrence Rate

As shown in the figure, the recurrence rate for Cushing’s disease has fluctuated through the years but continues to decrease through the past few years; there is no distinct way to forecast future recurrence, as shown in Figure5.Figure 5
Recurrence rates through the years for Cushing’s disease.


## 4. Discussion

The objective of the current systematic review was to analyze the recurrence rate and explore clinical factors after pituitary adenoma surgery. The highest recurrence rates were recorded in patients with nonfunctioning adenoma as shown in Table3 in comparison to Cushing’s disease and silent corticotroph adenomas. As proposed by Shirvani et al. [2016] and Jung et al. [2012], there is a direct correlation between the follow-up period and recurrence rates; a comparison shown in Figure 2 highlights the relationship.Some studies reported that age, gender, and tumor size impacted the recurrence rate, while some studies suggested the opposite. According to Shirvani et al. [2016], age influenced the recurrence rate; additionally, there was a significant negative correlation between the follow-up period and patient’s age in the same study. Additionally, in the study conducted by Cho et al. [14], younger patients had a higher frequency of numerous and late recurrences with more aggressive tumor behavior [15]. In a similar study conducted by Reddy et al., there was an increase in the recurrence rates for younger patients at initial surgery (P=0.034) [16, 17]. Conversely, some previous studies found that the age factor did not affect the recurrence rate such as the study by Losa et al. [18]. The same findings reported by Watts et al. [19] showed that younger age was the predictor of recurrence/relapse in patients with nonfunctional pituitary adenomas; the recurrence rate was diminished every year by approximately 3% each increase in the age of the patient after surgery. However, in reference to previous studies, the question of age as a prognostic factor remains quite controversial and conflicted. None of the included studies in the systematic review and meta-analysis showed that gender influenced the recurrence rates [20, 21].Johnston et al. [2017] found that macroadenoma (a benign tumor with glandular tissue more than 10 mm) presence and tumor extension beyond the pituitary and sella were predictive of risk of late recurrence [22, 23]; this shows that size of the tumor may be a clinical factor that impacts the recurrence rate. The same findings had been echoed by Amar et al. [4] who found that the probability of long-term chemical cure was much higher (91) for patients with microadenomas than those with macroadenomas (33%).Pituitary tumor remnant after the primary pituitary adenoma surgery is an additional clinical factor that could impact the recurrence and remission rates [18, 24]. According to the study by Reddy et al. [13], pituitary tumor remnant after the first postoperative scan (P≤0.001) increases the risk of relapse or recurrence of pituitary adenoma. Brochier et al. [10] recorded a very high recurrence rate of 47% after initial surgical remnant. No studies reported any relationships between remnant tumors and recurrence or remission rates.The number of trans-sphenoidal surgeries/pituitary adenoma surgeries may be a clinical factor that may impact the treatment outcome. According to a study conducted by Dimopoulou et al. [16], higher recurrence rates of Cushing’s disease were recorded after first trans-sphenoidal surgery; this means that revision pituitary surgeries could report higher remission rates and lower recurrence rates [10, 16]. Additionally, immediate reoperation of patients with pituitary adenoma was associated with low recurrence rates (Mayberg et al., 2018). There were some predicting factors of recurrence of pituitary adenomas highlighted by different studies. Bou et al. [9] found that a predictive factor of early recurrence was a positive response to CRH tests and/or vasopressin analogs.According to Ambrogio et al. [5], a significant percentage of patients that had successful adenomectomy failed to respond to desmopressin after pituitary adenoma surgery. Therefore, the test could be used as a predictive factor of the recurrence of the condition if the treatment was unsuccessful. Ciric et al. [2012] also found that the mean immediate plasma cortisol (IPPC) after pituitary adenoma surgery should not exceed 2.0 μg/dL; a higher level shows that the operation was not fully successful and adenoma may recur after an unknown period. Such predictive factors are very significant in defining the follow-up period and possibly the behavior of adenoma after recurrence. At the same time, the control of surgical infection is also crucial. Therefore, the effects of commonly used anti-infective drugs, such as amoxicillin and ornidazole, should also be concerned [25–27].


## 5. Conclusion

All the studies included in the current systematic review and meta-analysis reported different recurrence rates depending on pituitary adenoma [13, 19]. As shown in the analysis, there is a relationship between the recurrence rates and the follow-up period. Therefore, the highest value recorded by the analysis (67.9%) for nonfunctioning adenoma may be due to a follow-up period of 15 years. Other than the relationship between the two aspects, there was no distinct factor in relation to the distinct factor. There were conflicting results about the clinical factors after pituitary adenoma surgery. Some studies suggested that age and tumor size impacted the recurrence rate, while others found no evidence of existence of such a relationship; some studies reported the correlation of macroadenomas with high recurrence rates. No study reported that gender was a clinical factor affecting pituitary adenoma surgery outcomes or the recurrence rate. The most significant factor reported by studies with no conflicting results was the remnant tumor factor. According to the findings, initial surgical remnant adenomas increased the probability of low remission rates and high recurrence rates for patients. Additionally, some studies reported that the recurrence rates were lower for patients undergoing revision pituitary adenoma surgery than patients going through it for the first time.


### 5.1. Limitations

A significant limitation of the studies that passed the eligibility criteria for pituitary surgery was their noncomparative nature, restricting the analysis of within-study confounders. Additionally, there was a very high heterogeneity degree among the reported recurrence rates. Previous reports have attributed this heterogeneity to variations in the length of follow-up and criteria used to define remission and recurrence. Unfortunately, there were very few studies that highlighted numerous recurrence rates of different pituitary adenomas during the same follow-up period; this means that it was difficult to carry out a statistical analysis to analytically define the relationship between the follow-up period and the recurrence rates. The eligibility criteria were a significant limitation considering that few studies met the inclusion criteria. Some studies that failed to meet the inclusion criteria contained important data that could have helped to solve the existing conflicting results in relation to some clinical aspects such as the impact of age and tumor size. For instance, there have been few studies relevant to the research topic that have been published within the last twelve years (2010–2022). The findings from the current systematic review will form a foundation for future research into the treatment of pituitary adenomas. Future research should focus on highlighting clinical factors after pituitary adenoma surgery, especially conflicting aspects such as gender, age, and tumor size; additionally, they should consider highlighting more predictive factors of recurrence.


## 5.1. Limitations

A significant limitation of the studies that passed the eligibility criteria for pituitary surgery was their noncomparative nature, restricting the analysis of within-study confounders. Additionally, there was a very high heterogeneity degree among the reported recurrence rates. Previous reports have attributed this heterogeneity to variations in the length of follow-up and criteria used to define remission and recurrence. Unfortunately, there were very few studies that highlighted numerous recurrence rates of different pituitary adenomas during the same follow-up period; this means that it was difficult to carry out a statistical analysis to analytically define the relationship between the follow-up period and the recurrence rates. The eligibility criteria were a significant limitation considering that few studies met the inclusion criteria. Some studies that failed to meet the inclusion criteria contained important data that could have helped to solve the existing conflicting results in relation to some clinical aspects such as the impact of age and tumor size. For instance, there have been few studies relevant to the research topic that have been published within the last twelve years (2010–2022). The findings from the current systematic review will form a foundation for future research into the treatment of pituitary adenomas. Future research should focus on highlighting clinical factors after pituitary adenoma surgery, especially conflicting aspects such as gender, age, and tumor size; additionally, they should consider highlighting more predictive factors of recurrence.



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