Both invasiveness and proliferation criteria predict recurrence of non-functioning pituitary macroadenomas after surgery: a retrospective analysis of a monocentric cohort of 120 patients

in European Journal of Endocrinology
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  • 1 Department of Pathology
  • | 2 Department of Neurosurgery, University Hospital Saint-Luc, Brussels, Belgium
  • | 3 Department of Neurology, UZ Brussels, Brussels, Belgium
  • | 4 Department of Endocrinology, University Hospital Saint-Luc, Brussels, Belgium

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Introduction

Additional robust criteria to predict early postoperative recurrence of non-functioning pituitary macroadenomas (NFMAs) are needed. Recently, a new classification of pituitary tumors has been proposed, which is based on both radiological and histological criteria and allows the grading into 5 groups of different potential aggressiveness. The aim of this study was to use this classification to further characterize predictive factors of recurrence in an independent series of NFMA.

Cases and methods

120 patients operated for a NFMA were analyzed retrospectively. For each of them, the invasion of the cavernous and/or sphenoidal sinuses by the tumor was studied on the preoperative MRI and the proliferative character was based on precise histological and immunohistological examination.

Results

26% (n = 31) of the adenomas were proliferative and 57% (n = 68) were invasive. The invasive lesions were larger (P < 0.001) and their removal was complete in only 82% of the cases. The distribution of NFMAs was as follows: 32% grade 1a, 11% (proliferative) grade 1b, 42% (invasive) grade 2a and 15% (proliferative and invasive) grade 2b. Their probability of recurrence at 5 years was 20, 39, 44 and 66%, respectively. A young age, the atypical character and the presence of postoperative residual tumor were all independent risk factors of recurrence (P < 0.025).

Discussion

The new clinicopathological classification proves to be very useful in predicting the risk of recurrence of non-functioning pituitary macroadenomas after a first surgery. In particular, grade 2b lesions showed an overall likelihood of recurrence that was 8.6 times greater than those of grade 1a.

Abstract

Introduction

Additional robust criteria to predict early postoperative recurrence of non-functioning pituitary macroadenomas (NFMAs) are needed. Recently, a new classification of pituitary tumors has been proposed, which is based on both radiological and histological criteria and allows the grading into 5 groups of different potential aggressiveness. The aim of this study was to use this classification to further characterize predictive factors of recurrence in an independent series of NFMA.

Cases and methods

120 patients operated for a NFMA were analyzed retrospectively. For each of them, the invasion of the cavernous and/or sphenoidal sinuses by the tumor was studied on the preoperative MRI and the proliferative character was based on precise histological and immunohistological examination.

Results

26% (n = 31) of the adenomas were proliferative and 57% (n = 68) were invasive. The invasive lesions were larger (P < 0.001) and their removal was complete in only 82% of the cases. The distribution of NFMAs was as follows: 32% grade 1a, 11% (proliferative) grade 1b, 42% (invasive) grade 2a and 15% (proliferative and invasive) grade 2b. Their probability of recurrence at 5 years was 20, 39, 44 and 66%, respectively. A young age, the atypical character and the presence of postoperative residual tumor were all independent risk factors of recurrence (P < 0.025).

Discussion

The new clinicopathological classification proves to be very useful in predicting the risk of recurrence of non-functioning pituitary macroadenomas after a first surgery. In particular, grade 2b lesions showed an overall likelihood of recurrence that was 8.6 times greater than those of grade 1a.

Introduction

Although predominantly benign and slow growing (1, 2, 3, 4), a significant number of pituitary adenomas may be more aggressive, invading neighbor structures, growing at relatively fast rate or being resistant to conventional treatments (5, 6, 7). In 2004, the World Health Organization (WHO) introduced a new subgroup of so-called ‘atypical adenomas’ for pituitary neuroendocrine tumors with ‘borderline or uncertain behavior’ potential (8). This distinction was based on several histological criteria, namely invasive features, a high Ki67 index, an increased mitotic activity and extensive nuclear expression of p53.

However, this definition proved to be rather vague and difficult to use in practice, since only the Ki67 threshold was clearly defined (set at 3%), histological invasiveness was not systematically evaluated on routine practice and radiological criteria of invasion were not taken into account (5, 9, 10). It is therefore not surprising that the reported incidence of atypical adenoma was highly variable, ranging from 2.9% (11) to 18.7% (12). Although the criteria previously described are difficult to apply, it is however essential to identify those lesions of uncertain potential, which are at higher risk of recurrence or progression (4, 13).

In 2013, Trouillas and collaborators proposed a new five-tiered grading of pituitary adenomas based on both proliferative features of the tumor at immunohistochemistry and invasiveness criteria at preoperative imaging. They further demonstrated the prognostic value of this classification in two studies including respectively 410 and 213 pituitary adenomas of all histological types (9, 14).

Our study was aimed at confirming the reproducibility and prognostic value of this clinicopathological grading for the prediction of tumor recurrence or progression in an independent series of non-functioning pituitary macroadenomas (NFMA), which underwent their first surgery in our institution.

Subjects and methods

Patients

From October 2004 to October 2014, 376 patients underwent one or more neurosurgical resections of a pituitary adenoma in our institution. Among them, 142 (38%) had a clinically non-functioning tumor. Twenty-two patients were excluded from this study, due to the lack of sufficient clinical, radiological and/or histological information (n = 15) or in case of a pituitary apoplexy (n = 7), making immunohistochemical characterization more difficult and altering further evolution. In total, 120 patients with all relevant information could therefore be included. All patients had undergone neurosurgical removal of their pituitary macroadenoma by the same two neurosurgeons (CR and EF).

Methods

Clinical and radiological features

For each patient, medical history, baseline characteristics and symptoms at the time of diagnosis, as well as complete hormonal testing were collected and reviewed retrospectively. In each patient, the diagnosis of a functioning pituitary adenoma had been carefully ruled out, especially in the case of hormonal detection at histology (see below). The size of the pituitary tumor and its extension were evaluated by both careful reading of the preoperative magnetic resonance imaging (MRI) and revision of the protocol established by an expert neuroradiologist. The adenoma was considered invasive if it extends clearly into one or both cavernous sinuses and/or the sphenoid sinus. A cavernous sinus invasion was only considered when a grade 3 or 4 was observed according to the classification of Knosp and coworkers (15): grade 3 corresponds to a pituitary adenoma extending beyond the lateral tangent of the intracavernous and supracavernous carotid arteries and grade 4 is defined by a total encasement of the intracavernous carotid artery by the tumor. The sphenoidal infiltration was detected by imaging but only considered if confirmed by the neurosurgeon and/or by histology.

Postoperative pituitary MRI was routinely performed 3–4 months after initial surgery and annually or in case of new compression symptoms thereafter. We first recorded whether a tumor remnant was observed on the first postoperative MRI. Tumor progression (defined as the growth of a known residual tumor) and recurrence (defined as new tumor resurgence after complete gross resection) were detected on further radiological follow-up.

The immunohistochemical profile of each tumor was reviewed and confirmed by new immunohistochemistry in case of doubt. In addition, the same pathologist (JL) re-evaluated the number of mitoses and re-analyzed the expression of Ki67 and p53, so that the same antibodies were used for each sample and the evaluation was as homogeneous as possible.

Histological information

The samples were fixed in Bouin–Holland solution (from 2004 to 2010) or in formaldehyde (from January 2011 on) and paraffin-embedded. Each fragment was analyzed by routine immunohistochemistry techniques using specific antibodies for the detection of each of the major pituitary hormones, adrenocorticotropic hormone (ACTH), growth hormone (GH), prolactin (PRL), beta-follicle-stimulating hormone (FSH), beta-luteinizing hormone (LH) and beta-thyroid-stimulating hormone (TSH). Accordingly, four main subtypes of clinically non-functioning pituitary adenomas were identified in our cohort: null cell adenomas, gonadotrope adenomas, silent GH/PRL adenomas and silent ACTH adenomas.

For each tumor, proliferation markers were analyzed on new slides prepared from the embedded tumor specimen, according to previously described procedures (9). Cells from 10 representative high-power fields (HPF) of 0.30 mm2 (×400 magnification) were counted with an average count of 3000 nuclei. The mitosis counting was performed on hematoxylin-eosin staining and expressed as an absolute number/10 HPF. Immunohistochemical detection of Ki67 was carried out by counting the number of positive nuclei/10 HPF and evaluated as the percentage of the total number of nuclei counted. The detection of the p53 expression was considered positive when more than 10 nuclei/10 representative HPF showed intense immunostaining. Atypical (proliferative) adenomas were defined by the presence of at least two of the following three criteria, as proposed by Trouillas and coworkers (9): a Ki67 >1% (when fixation had been performed in Bouin–Holland) or ≥3% (when fixative was formaldehyde), a mitosis count >2 and a p53 positivity >10 cells/10 HPF (×400).

The presence of a sphenoidal sinus infiltration was also investigated histologically, based on the presence of sinusal respiratory mucosa within or close to the tumoral tissue.

Clinicopathological classification

Each tumor was classified according to the grades proposed by Trouillas and collaborators (9), taking into account invasion and extension criteria (grades 1, 2 or 3) and proliferation criteria (a or b) (Table 1). Grade 1a corresponds to a non-invasive and non-proliferative tumor, grade 1b to a non-invasive but proliferative tumor, grade 2a to an invasive but non-proliferative tumor, grade 2b to an invasive and proliferative tumor and grade 3 to a pituitary carcinoma with distant metastases (it should be noted that no non-functioning carcinoma was found in our series).

Table 1

New clinicopathological classification of pituitary adenomas (see (9).

Tumor grade based on the following criteria:
• Invasion defined as histological and/or radiological (MRI) signs of cavernous or sphenoidal invasion
• Proliferation considered on the presence of at least two of three criteria:
 Ki67: >1% (Bouin-Holland fixative) or ≥3% (formalin fixative)
 Mitoses: n >2/10 HPF
 p53: positive (>10 strongly positive nuclei/10 HPF)
The five grades are the following:
 Grade 1a: non-invasive and non-proliferative tumor
 Grade 1b: non-invasive and proliferative tumor
 Grade 2a: invasive and non-proliferative tumor
 Grade 2b: invasive and proliferative tumor
 Grade 3: metastatic tumor (cerebrospinal or systemic metastases)

HPF, high-power fields (0.30 mm2, 400× magnification).

MRI, magnetic resonance imaging.

Statistics

The statistical analyses were performed using IBM SPSS Statistics, version 23.0 software. The continuous variables were reported as mean ± s.d. or as median and (P5–P95) interval. The normality of the data was allowed for a sample size greater than or equal to 30 according to the central limit theorem or strong law of large numbers. The characteristics of patients and tumors were compared according to their invasive or proliferative character and then according to the new clinicopathological classification. The different histological subtypes were also compared. Continuous variables were compared using Student’s unpaired t-tests or nonparametric Wilcoxon tests, whereas for multiple comparisons, an analysis of variance was used. Discrete variables were compared by the chi-square test. A value of P < 0.05 was considered statistically significant. For multiple comparisons, the significance threshold was adjusted by the Bonferroni method.

In addition, a survival analysis using the Kaplan–Meier method was used to estimate the probability of recurrence or progression (considered together) over time. The patients were censored at the time of the last available imaging. The log-rank test was used for the comparison of the survival curves between subgroups. Finally, the predictive factors for recurrence or progression were determined by a multivariate logistic regression. Before conducting the multivariate analysis, a univariate analysis was carried out to select the variables (P < 0.10) to be introduced into the model.

Results

Characteristics of patients and pituitary tumors

The study population was composed of 120 patients, 68 men (57%) and 52 women (43%), with a mean age of 56.4 ± 15.0 years. The median follow-up was 48 months (extreme values: 5–187 months). Patients presented with visual alterations in 63% of the cases (mostly bitemporal hemianopsia), partial or complete pituitary hormonal insufficiency in 68%, and with headaches in 50%. Hyperprolactinemia was observed in 43% of the patients, with values ranging from 26 to 178 μg/L. All patients underwent primary neurosurgical treatment, which was a trans-nasal trans-sphenoidal surgery in all but one patient who had transcranial surgery due to a massive suprasellar extension.

An invasive adenoma was observed in 68 patients (57%). The invasion was cavernous only (single or bilateral) in 35 cases, sphenoidal only in 12 cases and mixed in 21 cases. When patients with and without an invasive tumor were compared, there was no significant difference in age and gender, while maximal tumor diameter was greater in invasive lesions (Table 2). In particular, all giant adenomas (n = 14) were invasive. On the other hand, no difference was observed in the proportion of proliferative/atypical adenomas (26% and 25% in the invasive and non-invasive groups, respectively). As expected, a greater number of patients with invasive lesions demonstrated the persistence of a postoperative residual tumor (82% vs 31%, P < 0.001).

Table 2

Baseline characteristics of patients with a proliferative or non-proliferative non-functioning pituitary macroadenoma (NFMA) and of patients with an invasive or non-invasive NFMA.

Typical pit adenomas (n = 89)Atypical pit adenomas (n = 31)P valueNon-invasive (n = 52)Invasive (n = 68)P value
Age (years)57.7 ± 13.852.5 ± 17.0NS55.4 ± 14.557.1 ± 15.1NS
Sex ratio (M/F)49/4019/12NS28/2440/28NS
Tumor height (mm)28.8 ± 10.727.3 ± 9.3NS22.9 ± 6.032.7 ± 10.9<0.001
Nb of giant tumors11/89 (12.4%)3/31 (9.7%)NS0/52 (0%)14/68 (21%)<0.001
Ki67§ (%)0.9 (0.1–3.9)3.4 (1.2–12.2)<0.0011.4 (0.1–4.6)1.2 (0.1–7.1)NS
P53 (nb positive cells/10 HPF)1 (0–9)2 (0–38)<0.012 (0–24)1 (0–16)NS
Mitoses (nb/10HPF)0 (0–2)3 (0–8)<0.0011 (0–4)1 (0–6)NS
% invasive tumors50/89 (56%)18/31 (58%)NS13/52 (25%)18/68 (26%)NS
Postoperative residue53/89 (60%)19/31 (61%)NS16/52 (22%)56/68 (82%)<0.001
Duration of follow-up (months)46 (5–235)51 (4–174)NS52 (4–208)45 (5–204)NS
Relapse22/89 (25%)16/31 (52%)0.00611/52 (29%)27/68 (40%)0.030

§Ki67 considered as positive if >1.0% with Bouin fixative or ≥3.0% with formalin fixative, as reported in Trouillas et al., Acta Neuropathol (2013) 126:123–135.

Histology and immunohistochemistry

The following histological subtypes were observed: gonadotrope adenomas in 84 patients (70%), silent GH/PRL adenomas in 7 (6%), silent ACTH adenomas in 18 (15%) and null cell adenomas in 11 (9%). There was no significant difference between these subgroups regarding age, tumor size, invasion, proliferation characteristics and postoperative residue (Supplementary Table 1, see section on supplementary data given at the end of this article). Patients with a silent GH adenoma had a younger age (45.2 ± 18.4 years) compared to patients with a gonadotrope adenoma or null cell adenoma (56.3 ± 17.0 and 57.8 ± 14.2 years, P < 0.05) and a female predominance was observed for silent GH (2M/5F) and ACTH adenomas (6M/12F) vs 51M/33F for gonadotrope adenomas and 9M/2F for null cell adenomas (P < 0.05).

Among the 120 patients, 31 (26%) had a proliferative/atypical adenoma on histological examination. High Ki67 immunoreactivity, high mitotic count and positive p53 staining were observed in 30/31 (97%), 23/31 (71%) and 9/31 tumors (29%), respectively. It is interesting to note that these markers were positive in 14 (16%), 2 (2.3%) and 0 of the 89 non-proliferative adenomas, respectively. The two subgroups were not significantly different for age, sex ratio, tumor size, proportion of invasive tumors or the percentage of patients with a postoperative residual tumor (Table 2).

Clinicopathological grade

According to the new clinicopathological classification, 32% of lesions corresponded to grade 1a (n = 39), 11% to grade 1b (n = 13), 42% to grade 2a and 15% to grade 2b (n = 18) (Fig. 1). No differences were observed between the four subgroups in terms of age and sex ratio while tumor size and the proportion of patients with a postoperative residue were increased in patients with grade 2a and 2b lesions (Table 3). Null cell adenomas showed the higher proportion of grade 1a (64%) and the lowest proportion of grade 2b lesions (9%), whereas other histological subtypes comprised at least 50% of grade 2a and 2b lesions, although these differences did not reach statistical significance (Fig. 2).

Figure 1
Figure 1

Distribution of the different grades 1a–2b according to the clinicopathological classification in the total population of non-functioning pituitary macroadenomas (n = 120).

Citation: European Journal of Endocrinology 178, 3; 10.1530/EJE-17-0965

Figure 2
Figure 2

Distribution of the different grades 1a–2b according to the clinicopathological classification of Trouillas and coworkers (2013) across the main histological sub-types of non-functioning pituitary macroadenomas.

Citation: European Journal of Endocrinology 178, 3; 10.1530/EJE-17-0965

Table 3

Baseline characteristics of patients with non-functioning pituitary macroadenomas (n = 120) subdivided in different grades (1a–2b) according to the clinicopathological classification given in (9). Values are shown as proportions, mean ± s.d. or §median (P5–P95).

Grade 1A non-prolif/non-invasiveGrade 1B prolif/non-invasiveGrade 2A non-prolif/invasiveGrade 2B prolif/invasiveP value
Number of patients (%)39 (32%)13 (11%)50 (42%)18 (15%)
Age (years)55.0 ± 14.156.5 ± 17.059.9 ± 13.449.5 ± 16.9NS
Sex ratio (M/F)21/187/628/2212/6NS
Tumor height (mm)23 ± 722 ± 533 ± 11**31 ± 10**<0.001
Nb of giant tumors0/390/1311/50**3/18**0.006
Ki67 (%)§1.1 (0.1–3.4)3.9 (1.2–8.7)**0.8 (0.1–4.9)2.3 (1.2–8.2)**<0.001
P53 (nb positive cells/10 HPF)1.0 (0–10)7.0 (0–40.9)*1.0 (0–7.0)2.0 (0–23.0)*0.015
Mitoses (nb/10HPF)0 (0–3)3 (0–6)**0 (0–2)4 (0–7)**<0.001
Postoperative residue12/39 (31%)4/13 (31%)*41/50 (82%)*15/18 (83%)**<0.001
Relapse (%)9/41 (22%)4/12 (33%)19/54 (35%)7/13 (54%)*0.007

*, **P < 0.05, 0.001 vs grade 1A.

HPF, high-power field, 400× magnification.

In order to exclude bias to the fixation technique (which in particular influences the expression of Ki67 and p53), pituitary tumors fixed in Bouin-Holland were compared with those fixed in formaldehyde. While significant differences were indeed observed in the expression of nuclear immunohistochemical markers (Ki67 and p53), the relative numbers of proliferative and invasive lesions as well as the relative proportions of grades 1a–2b were similar regardless of the type of fixative used (Supplementary Table 2).

Recurrence and progression

A significant increase in the rate of recurrence/progression was observed in the group of invasive tumors (40% vs 21% in the non-invasive lesions, P = 0.03, Table 2) and in the group of proliferative lesions (16/31, 52%) compared to non-proliferative tumors (22/89, 25%, P = 0.006, Table 2). There was also a tendency for more recurrence/progression in the group of silent GH adenomas (57%), followed by «null cell adenomas» (46%), silent ACTH adenomas (33%) and gonadotrope adenomas (27%), but these differences were not significant.

According to the clinicopathological classification, recurrence/progression rates were 22, 33, 35 and 54% in tumors of grades 1a, 1b, 2a and 2b, respectively (Table 3).

Kaplan–Meier’s analysis of recurrence/progression-free survival rates showed clear differences between grade 1a and 2b lesions, whereas grade 1b and 2a tumors had a similar intermediate profile, especially during the first 3 years following surgery (Fig. 3 and Table 4). In univariate regression analysis, compared to grade 1a tumors, grade 1b tumors had an overall 2.4-fold higher risk of recurrence, grade 2a tumors had a 2.6-fold higher risk and grade 2b tumors had a 8.6-fold higher risk (P < 0.05, <0.05 and <0.001, respectively) (Table 4).

Figure 3
Figure 3

Kaplan–Meier recurrence/progression-free survival curves of patients with a non-functioning pituitary macroadenoma (n = 120) according to the different tumor grades (1a–2b) (P = 0.026 by the Log-rank test).

Citation: European Journal of Endocrinology 178, 3; 10.1530/EJE-17-0965

Table 4

Probability of recurrence/progression of non-functioning pituitary adenomas at 1, 3 and 5 years according to the clinicopathological grade.

GradeProbability of recurrence/progressionOdds ratio§95% CI§
at 1 yearat 3 yearsat 5 years
1A3%6%20%1
1B7%18%39%2.440.57–10.57
2A5%21%44%2.581.10–7.42 *
2B12%42%66%8.622.39–31.3**

§Odds ratio and 95% confidence intervals were obtained by univariate regression analysis using the clinico-pathological grade as predictive factor of recurrence and grade 1A as control group; *, **P < 0.05, 0.001 vs grade 1A.

We also investigated the factors independently predicting progression or recurrence after NFMA surgery. In univariate analyses, young age, invasiveness, atypical character, the clinicopathological grade, the presence of a postoperative residual tumor and the duration of follow-up were each associated with an increased risk of recurrence. After multivariate analysis combining the different criteria described above (with the exception of the clinicopathological grade), a young age at diagnosis (risk ratio: −5.6% per year older), the proliferative character (risk ratio: 4.85), the presence of a postoperative residual tumor (risk ratio: 18.75) and the duration of follow-up (risk ratio: +2% per additional year of follow-up) remained independent predictors of recurrence/progression of non-functioning pituitary adenomas, whereas invasiveness was no longer significant (Table 5). However, if the multivariate analysis was repeated without including the factor ‘postoperative remnant’, invasiveness became very significant, whereas the proliferative character remained significantly associated with the risk of recurrence or progression (data not shown).

Table 5

Evaluation of predictive factors for progression/recurrence of non-functioning pituitary adenomas in a uni- and multivariate analysis.

VariableUnivariate analysisMultivariate analysis
Odds ratio95% CIP valueOdds ratio95% CIP value
Age (years)0.946(0.917–0.975)0.0010.944(0.902–0.989)0.014
Tumor height (mm)1.038(0.999–1.079)0.057NS
Invasive adenoma2.766(1.190–6.430)0.018NS
Immunohistological typeNSN/IN/IN/I
Atypical adenoma2.855(1.216–6.702)0.0164.847(1.298–18.10)0.019
Postoperative residue13.42(3.82–47.17)<0.00118.75(3.64–96.43)<0.001
Length of follow-up (years)1.022(1.013–1.032)<0.0011.019(1.007–1.031)0.001

CI, confidence interval; N/I, not included in the multivariate analysis; NS, not significant.

Finally, we also performed the same analyses in the subgroup of patients with a postoperative residual tumor (n = 72). In this group, residual proliferative adenomas progressed more frequently than non-proliferative tumors (14/19 vs 20/53, respectively; P < 0.01) and a clear difference was also observed using Kaplan–Meier’s progression-free survival curves (Supplementary Fig. 1; Log-rank test: P < 0025). By logistic regression analysis, the risk of progression for proliferative remnants was 4.62-fold higher (CI: 1.45–14.77) than for the non-proliferative adenomas with a postoperative residue (P < 0.01). A similar analysis was not possible in the 48 patients without a persistent postoperative residue as only 3 patients recurred (one with a typical adenoma and 2 with an atypical adenoma).

Discussion

Many classifications have been proposed to better characterize pituitary adenomas and their outcome. Thus, a group of adenomas with ‘borderline or uncertain behavior potential’ has been distinguished by an increased risk of recurrence and described as atypical adenomas in the 2004 WHO classification (8). According to the several definitions used and authors, these lesions show a Ki67 index greater than 3 or 4%, an increase in the number of mitoses, an extensive or intense expression of p53 and microscopic invasive features (9, 10, 11, 16, 17). However, these criteria have proved to be rather imprecise and not routinely reproducible. In addition, histological invasiveness is generally not taken into account by the pathologists. Recently, Trouillas and coworkers have proposed a new pituitary tumor classification based on precise criteria of invasion and proliferation, thus allowing a further subdivision into five distinct grades (9).

The majority of previous studies dealing with atypical pituitary adenomas have attempted to determine which proliferation markers are the most important to predict potential recurrence or progression, showing however divergent results (18, 19). Some studies have shown a significant and independent value of the Ki67 index in predicting recurrence (3, 20). However, this criterion has generally proved to have a predictive value only in association with an invasive phenotype (2, 3, 21, 22), the presence of a residual postoperative tumor (22) or depending on the histological subtype (6). So far, no study has shown a relationship between p53 expression alone and recurrence or progression (6, 10, 19). However, p53 expression has been associated with invasiveness, being increased up to 15% in invasive pituitary adenomas and up to 100% in pituitary carcinomas (23). In our study, the predictive value of each of these markers was not studied separately, but Ki67 was positive in nearly all of the proliferative adenomas, while p53 was positive in only one-third of them but never in the non-proliferative lesions.

In our series, using the same criteria described by Trouillas and coworkers (9), 26% of the lesions were considered proliferative (grade 1b and 2b lesions). This prevalence is similar to that found by the Lyon group in a total of 410 adenomas of all histological types (25%) (9). These figures differ however significantly from values obtained in other studies. Thus, Laws and coworkers described only 18 proliferative lesions (15%) out of a total of 121 (10) and Yildirim and coworkers reported 13 proliferative adenomas (9%) among 146 pituitary adenomas (16). More recently, Miermeister and coworkers identified only 121 proliferative adenomas (3%) out of a total of 4232 patients from the German pituitary adenoma registry (11), whereas Tortosa and coworkers reported a prevalence of 13% (17). These discrepancies are likely explained by technical differences in the immunohistochemical detection of proliferation marker positivity and by more strict criteria than those used in our study. This was notably the case in the German register study in which the definition of atypical adenomas was restricted to those lesions presenting at the same time a Ki67 index ≥4%, a mitotic index ≥2, an expression of p53 ≥2% and histological invasion of adjacent structures (11).

Radiological (and/or histological) evidence of cavernous or sphenoid sinus invasion was observed in 57% of the patients in this series. This frequency is similar to those reported in the literature for clinically non-functioning macroadenomas (24, 25, 26), but higher than the values of 30–45% reported for pituitary adenomas of all histological types (9, 10, 11, 17). This can however be easily explained by the fact that non-functioning pituitary adenomas are most often macroadenomas that have evolved asymptomatically for a long period of time. In addition, the definition of invasion differs from one series to the other, some also taking into account the invasion of the dura mater (27), which leads to a higher prevalence, reaching 61% (28) or even 65% (2). Similar to our population, a postoperative residual tumor is more frequently observed in invasive lesions (24, 28, 29, 30, 31, 32).

Regarding the clinicopathological classification, the proportions of grades 1a (32%), 1b (11%), 2a (42%) and 2b (15%) observed in our study are similar to the values observed by Trouillas and coworkers (9) and more recently by Raverot and coworkers (14) for all types of pituitary adenomas. They are even more similar to the proportions reported in the former study for the subtype of gonadotrope tumors specifically (35, 13, 36 and 15%, respectively). We also observed that among NFMA, grade 2b was lower for null cell adenomas and higher for other subtypes, especially silent GH adenomas, although these differences did not reach significance. This indicates that the relative proportion of invasive and proliferative adenomas likely varies according to the hormonal tumor subtype. Future larger studies are however needed to confirm this hypothesis.

Over a median follow-up period of 48 months, the recurrence/progression rates observed in our study were 22, 33, 35 and 54% for grades 1a, 1b, 2a and 2b, respectively. These values are lower than those reported in the first Lyon study, where the recurrence rates for these same subgroups were respectively 26, 58, 75 and 89% (9). Such discrepancies may be explained by differences in the type of tumors studied and by the duration of follow-up after surgery, which was longer in the previous study and which obviously influences the total number of recurrences. However, the probabilities of recurrence/progression over time were similar in both studies, being in our study 42% at 3 years and 66% at 5 years for grade 2b lesions, compared with 6% and 20%, respectively, for grade 1a tumors, while similar intermediate rates were found for grade 1b and 2a lesions The risk of recurrence/progression was 8.6-fold higher for grade 2b NFMA as compared with grade 1a tumors, a value intermediate between those found previously by Trouillas and coworkers (12-fold) and by Raverot and coworkers (3.72-fold) for the same comparison (9, 14).

We also demonstrated that a younger age, the presence of a postoperative residual tumor and the proliferative nature of the tumor were all independent factors predicting recurrence or progression of NFMA. The first two factors have already been reported in several studies (13, 22, 24, 28, 33). In particular, Kim and coworkers showed that young age and postoperative residue were the two main predictors of recurrence of non-functioning pituitary adenomas (13), and a recent Australian study showed a 4.2-fold greater risk of regrowth or relapse of the tumor in patients younger than 41 years of age (28). Interestingly, we demonstrate for the first time that the proliferative (atypical) character of non-functioning pituitary macroadenoma confers an additional risk of recurrence/progression, with an odds ratio of 4.8, independent of other well-established predictive factors. Moreover, this risk ratio remains similar (4.6) when considering only patients with a postoperative residue, who are already at a greater risk of relapse. This suggests that a very close surveillance and eventually early intervention are needed in these particular patients with a proliferative tumoral remnant.

By contrast, lesion size and invasiveness were not found to be independent risk factors of progression in our study. These results differ from those observed by Brochier and coworkers where invasiveness appeared to be a major prognostic factor of progression or recurrence (24). However, it should be noted that in our study, invasion became very significant if the analysis did not take into account the presence or absence of a postoperative residual tumor. This suggests that when proliferation markers are analyzed independently, the risk of regrowth conferred by tumor invasion is mainly related to the frequent absence of complete surgical resection.

In conclusion, we show in this study of 120 patients operated for a NFMA that a clinicopathological classification mainly based on both radiological (invasion) and histological (proliferation) criteria is useful to identify a subgroup of more aggressive adenomas (grade 2b lesions), which are at a much higher risk of progression or recurrence after initial surgery. We also show that, in addition to known risk factors such as young age at diagnosis and incomplete removal of the tumor, the atypical character of the pituitary tumor found at histology is an independent prognostic factor for predicting the risk of progression or recurrence of clinically non-functioning pituitary macroadenomas. These criteria should therefore be considered by clinicians to adapt their further surveillance and therapeutic strategy after initial surgery of any non-functioning pituitary macroadenoma.

Supplementary data

This is linked to the online version of the paper at https://doi.org/10.1530/EJE-17-0965.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • 1

    Asa L, Casar-Borota O, Chanson E, Earls P, Ezzat S, Grossman A, Ikeda H, Inoshita N, Karavitaki N & Korbonits M et al. From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International pituitary pathology club proposal. Endocrine-Related Cancer 2017 24 C5C8. (https://doi.org/10.1530/ERC-17-0004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Jaffrain-Rea ML, Di Stefano D, Minniti G, Esposito V, Bultrini A, Ferretti E, Santoro A, Faticanti Scucchi L, Gulino A & Cantore G. A critical reappraisal of MIB-1 labelling index significance in large series of pituitary tumours: secreting versus non-secreting adenomas. Endocrine-Related Cancer 2002 9 103113. (https://doi.org/10.1677/erc.0.0090103)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Righi A, Agati P, Sisto A, Frank G, Faustini-Fustini M, Agati R, Mazzatenta D, Farnedi A, Menetti F & Marucci G et al. A classification tree approach for pituitary adenomas. Human Pathology 2012 43 16271637. (https://doi.org/10.1016/j.humpath.2011.12.003)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Vasiljevic A, Jouanneau E, Trouillas J & Raverot G. Clinicopathilogical prognostic and theranostic markers in pituitary tumors. Minerva Endocrinologica 2016 41 377389.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Figarella-Branger D & Trouillas J. The new WHO classification of human pituitary tumors: comments. Acta Neuropathologica 2006 111 7172. (https://doi.org/10.1007/s00401-005-1099-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Gejman R, Swearingen B & Hedley-Whyte T. Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Human Pathology 2008 39 758766. (https://doi.org/10.1016/j.humpath.2007.10.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Di Ieva A, Rotondo F, Syro LV, Cusimano MD & Kovacs K. Aggressive pituitary adenomas: diagnosis and emerging treatments. Nature Reviews Endocrinoly 2014 10 423435. (https://doi.org/10.1038/nrendo.2014.64)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Lloyd RV, Kovacs K, Young WF Jr, Farrel WE, Asa SL, Trouillas J, Kontogeorgos G, Sano T, Scheithauer B & Hovath E. World Health Organization Classification of Tumours, chapter 1, pp 1013. Lyon : IARC Press, 2004.

    • Search Google Scholar
    • Export Citation
  • 9

    Trouillas J, Roy P, Sturm N, Dantoy E, Cortet-Rudelli C, Viennet G, Bonneville JF, Assaker R, Auger C & Brue T et al. The members of hypopronos. A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study af 410 patients with 8 years post-operative follow-up. Acta Neuropathologica 2013 126 123135. (https://doi.org/10.1007/s00401-013-1084-y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Zada G, Woodmansee W, Ramkisoon S, Amadio J, Nose V & Laws E. Atypical pituitary adenomas: incidence, clinical characteristics, and implications. Journal of Neurosurgery 2011 114 336344. (https://doi.org/10.3171/2010.8.JNS10290)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Miermeister C, Petersenn S, Buchfelder M, Fahlbush R, Lüdecke D, Hölsken A, Bergmann M, Knappe H, Hans V & Flitsch J et al. Histological criteria for atypical pituitary adenomas – data from the German pituitary adenomas registry suggests modifications. Acta Neuropathologica Communications 2015 3 50. (https://doi.org/10.1186/s40478-015-0229-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Chiloiro S, Doglietto F, Trapasso B, Iacovazzo D, Giampietro A, Di Nardo F, de Waure C, Lauriola L, Mangiola A & Anile C et al. Typical and atypical pituitary adenomas: a single-center analysis of outcome and prognosis. Neuroendocrinology 2015 101 143150. (https://doi.org/10.1159/000375448)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Kim JS, Lee YS, Jung MJ & Hong YK. The predictive value of pathologic features in pituitary adenoma and correlation with pituitary adenoma reccurence. Journal of Pathology and Translational Medicine 2016 50 419425. (https://doi.org/10.4132/jptm.2016.06.30)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Raverot G, Dantony E, Beauvy J, Vasiljevic A, Mikolasek S, Borson-Chazot F, Jouanneau E, Roy P & Trouillas J. Risk of recurrence in pituitary neuroendocrine tumors: a prospective study using a five-tiered classification. Journal of Clinical Endocrinology and Metabolism 2017 102 33683374. (https://doi.org/10.1210/jc.2017-00773)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Knosp E, Steiner E, Kitz K & Matula C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 1993 33 610617. (https://doi.org/10.1227/00006123-199310000-00008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Yildirim AE, Divanlioglu D, Nacar OA, Dursun E, Sahinoglu M, Unal T & Belen AD. Incidence, hormonal distribution and post-operative follow-up of atypical pituitary adenomas. Turkish Neurosurgery 2012 23 226231.

    • Search Google Scholar
    • Export Citation
  • 17

    Tortosa F & Webb SM. Atypical pituitary adenomas: 10 years of experience in a reference centre in Portugal. Neurologia 2015 31 97105. (https://doi.org/10.1016/j.nrl.2015.06.010)

    • Search Google Scholar
    • Export Citation
  • 18

    Asa SL. Practical pituitary pathology: What does the pathologist need to know? Pituitary Pathology 2008 132 12311240.

  • 19

    Hentschel SJ, McCutcheon IE, Moore W & Durity FA. P53 and MIB-1 immunochemistry as predictors of the clinical behaviour of non-functioning pituitary adenomas. Canadian Journal of Neurological Sciences 2003 30 215219 (https://doi.org/10.1017/S0317167100002614)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Castinetti F, Dufour H, Gaillard S, Jouanneau E, Vasiljevic A, Villa C & Trouillas J. Non-functioning pituitary adenoma: when and how to operate? What pathologic criteria for typing? Annals of Endocrinology 2015 76 220227. (https://doi.org/10.1016/j.ando.2015.04.007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Aguiar PH, Aires R, Laws ER, Isolan GR, Logullo A, Patil C & Katznelson L. Labelling index in pituitary adenomas evaluated by means of MIB-1: is there a prognostic role? A critical review. Neurological Research 2010 32 10601071. (https://doi.org/10.1179/016164110X12670144737855)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Cortet-Rudelli C, Bonneville JF, Borson-Chazot F, Clavier L, Coche Dequéant B, Desailloud R, Maiter D, Rohmer V, Sadoul JL & Sonnet E et al. Post-surgical management of non-functioning pituitary adenoma. Annals of Endocrinology 2015 76 228238. (https://doi.org/10.1016/j.ando.2015.04.003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Thapar K, Scheithauer B, Kovacs K, Pernicore P & Laws E. p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. Neurosurgery 1996 38 765771. (https://doi.org/10.1227/00006123-199604000-00027)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Brochier S, Galland F, Kujas M, Parker F, Gaillard S, Raftopoulos C, Young J, Alexopoulou O, Maiter D & Chanson P. Factors predicting relapse of non-functioning pituitary macroadenomas after neurosurgery: a study of 142 patients. European Journal of Endocrinology 2010 163 193200. (https://doi.org/10.1530/EJE-10-0255)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Ferrante E, Ferraroni M, Castrignanò T, Menicatti L, Anagni M, Reimondo G, Del Monte P, Bernasconi D, Loli P & Faustini-Fustini M et al. Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors. European Journal of Endocrinology 2006 155 8239. (https://doi.org/10.1530/eje.1.02298)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Ntali G, Capatina C, Fazal-Sanderson V, Byrne JV, Cudlip S, Grossman AB, Wass JA & Karavitaki N. Mortality in patients with non-functioning pituitary adenoma is increased: systematic analysis of 546 cases with long follow-up. European Journal of Endocrinology 2016 174 137145. (https://doi.org/10.1530/EJE-15-0967)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Meij BP, Lopes MB, Ellegala DB, Alden TD, Laws E Jr. The long-term significiance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. Journal of Neurosurgery 2002 96 195208. (https://doi.org/10.3171/jns.2002.96.2.0195)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Watts AK, Easwaran A, McNeill P, Wang WJ & Caputo C. Younger age a risk factor for regrowth and recurrence of non-funtioning pituitary macroadenomas: results from a single Australian center. Clinical Endocrinology 2017 87 264271. (https://doi.org/10.1111/cen.13365)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Hwang J, Seol HJ, Nam DH, Lee JI, Lee MH & Kong DS. Therapeutic strategy for cavernous sinus-invading non-functioning pituitary adenomas based on the modified Knosp grading system. Brain Tumors Research and Treatment 2016 4 6369. (https://doi.org/10.14791/btrt.2016.4.2.63)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Nosé V, Ezzat S, Horvath E, Kovacs K, Laws E, Lloyd R, Lopez B & Asa S. Protocol for the examination of specimens from patients with primary pituitary tumors. Archives of Pathology and Laboratory Medecine 2011 135 640646.

    • Search Google Scholar
    • Export Citation
  • 31

    Roelfsema F, Biermasz NR & Pereira AM. Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis. Pituitary 2012 15 7183. (https://doi.org/10.1007/s11102-011-0347-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Saeger W, Lüdecke DT, Buchfelder M, Fahlbusch R, Quabbe HJ & Petersem S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. European Journal of Endocrinology 2007 156 203216. (https://doi.org/10.1530/eje.1.02326)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Landeiro JA, Fonseca EO, Monnerat AL, Taboada GF, Cabral GA & Antunes F. Nonfunctioning giant pituitary adenomas : invasiveness and recurrence. Surgical Neurology international 2015 6 179. (https://doi.org/10.4103/2152-7806.170536)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

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  • View in gallery

    Distribution of the different grades 1a–2b according to the clinicopathological classification in the total population of non-functioning pituitary macroadenomas (n = 120).

  • View in gallery

    Distribution of the different grades 1a–2b according to the clinicopathological classification of Trouillas and coworkers (2013) across the main histological sub-types of non-functioning pituitary macroadenomas.

  • View in gallery

    Kaplan–Meier recurrence/progression-free survival curves of patients with a non-functioning pituitary macroadenoma (n = 120) according to the different tumor grades (1a–2b) (P = 0.026 by the Log-rank test).

  • 1

    Asa L, Casar-Borota O, Chanson E, Earls P, Ezzat S, Grossman A, Ikeda H, Inoshita N, Karavitaki N & Korbonits M et al. From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International pituitary pathology club proposal. Endocrine-Related Cancer 2017 24 C5C8. (https://doi.org/10.1530/ERC-17-0004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Jaffrain-Rea ML, Di Stefano D, Minniti G, Esposito V, Bultrini A, Ferretti E, Santoro A, Faticanti Scucchi L, Gulino A & Cantore G. A critical reappraisal of MIB-1 labelling index significance in large series of pituitary tumours: secreting versus non-secreting adenomas. Endocrine-Related Cancer 2002 9 103113. (https://doi.org/10.1677/erc.0.0090103)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Righi A, Agati P, Sisto A, Frank G, Faustini-Fustini M, Agati R, Mazzatenta D, Farnedi A, Menetti F & Marucci G et al. A classification tree approach for pituitary adenomas. Human Pathology 2012 43 16271637. (https://doi.org/10.1016/j.humpath.2011.12.003)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Vasiljevic A, Jouanneau E, Trouillas J & Raverot G. Clinicopathilogical prognostic and theranostic markers in pituitary tumors. Minerva Endocrinologica 2016 41 377389.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Figarella-Branger D & Trouillas J. The new WHO classification of human pituitary tumors: comments. Acta Neuropathologica 2006 111 7172. (https://doi.org/10.1007/s00401-005-1099-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Gejman R, Swearingen B & Hedley-Whyte T. Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Human Pathology 2008 39 758766. (https://doi.org/10.1016/j.humpath.2007.10.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Di Ieva A, Rotondo F, Syro LV, Cusimano MD & Kovacs K. Aggressive pituitary adenomas: diagnosis and emerging treatments. Nature Reviews Endocrinoly 2014 10 423435. (https://doi.org/10.1038/nrendo.2014.64)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Lloyd RV, Kovacs K, Young WF Jr, Farrel WE, Asa SL, Trouillas J, Kontogeorgos G, Sano T, Scheithauer B & Hovath E. World Health Organization Classification of Tumours, chapter 1, pp 1013. Lyon : IARC Press, 2004.

    • Search Google Scholar
    • Export Citation
  • 9

    Trouillas J, Roy P, Sturm N, Dantoy E, Cortet-Rudelli C, Viennet G, Bonneville JF, Assaker R, Auger C & Brue T et al. The members of hypopronos. A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study af 410 patients with 8 years post-operative follow-up. Acta Neuropathologica 2013 126 123135. (https://doi.org/10.1007/s00401-013-1084-y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Zada G, Woodmansee W, Ramkisoon S, Amadio J, Nose V & Laws E. Atypical pituitary adenomas: incidence, clinical characteristics, and implications. Journal of Neurosurgery 2011 114 336344. (https://doi.org/10.3171/2010.8.JNS10290)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Miermeister C, Petersenn S, Buchfelder M, Fahlbush R, Lüdecke D, Hölsken A, Bergmann M, Knappe H, Hans V & Flitsch J et al. Histological criteria for atypical pituitary adenomas – data from the German pituitary adenomas registry suggests modifications. Acta Neuropathologica Communications 2015 3 50. (https://doi.org/10.1186/s40478-015-0229-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Chiloiro S, Doglietto F, Trapasso B, Iacovazzo D, Giampietro A, Di Nardo F, de Waure C, Lauriola L, Mangiola A & Anile C et al. Typical and atypical pituitary adenomas: a single-center analysis of outcome and prognosis. Neuroendocrinology 2015 101 143150. (https://doi.org/10.1159/000375448)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Kim JS, Lee YS, Jung MJ & Hong YK. The predictive value of pathologic features in pituitary adenoma and correlation with pituitary adenoma reccurence. Journal of Pathology and Translational Medicine 2016 50 419425. (https://doi.org/10.4132/jptm.2016.06.30)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Raverot G, Dantony E, Beauvy J, Vasiljevic A, Mikolasek S, Borson-Chazot F, Jouanneau E, Roy P & Trouillas J. Risk of recurrence in pituitary neuroendocrine tumors: a prospective study using a five-tiered classification. Journal of Clinical Endocrinology and Metabolism 2017 102 33683374. (https://doi.org/10.1210/jc.2017-00773)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Knosp E, Steiner E, Kitz K & Matula C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 1993 33 610617. (https://doi.org/10.1227/00006123-199310000-00008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Yildirim AE, Divanlioglu D, Nacar OA, Dursun E, Sahinoglu M, Unal T & Belen AD. Incidence, hormonal distribution and post-operative follow-up of atypical pituitary adenomas. Turkish Neurosurgery 2012 23 226231.

    • Search Google Scholar
    • Export Citation
  • 17

    Tortosa F & Webb SM. Atypical pituitary adenomas: 10 years of experience in a reference centre in Portugal. Neurologia 2015 31 97105. (https://doi.org/10.1016/j.nrl.2015.06.010)

    • Search Google Scholar
    • Export Citation
  • 18

    Asa SL. Practical pituitary pathology: What does the pathologist need to know? Pituitary Pathology 2008 132 12311240.

  • 19

    Hentschel SJ, McCutcheon IE, Moore W & Durity FA. P53 and MIB-1 immunochemistry as predictors of the clinical behaviour of non-functioning pituitary adenomas. Canadian Journal of Neurological Sciences 2003 30 215219 (https://doi.org/10.1017/S0317167100002614)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Castinetti F, Dufour H, Gaillard S, Jouanneau E, Vasiljevic A, Villa C & Trouillas J. Non-functioning pituitary adenoma: when and how to operate? What pathologic criteria for typing? Annals of Endocrinology 2015 76 220227. (https://doi.org/10.1016/j.ando.2015.04.007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Aguiar PH, Aires R, Laws ER, Isolan GR, Logullo A, Patil C & Katznelson L. Labelling index in pituitary adenomas evaluated by means of MIB-1: is there a prognostic role? A critical review. Neurological Research 2010 32 10601071. (https://doi.org/10.1179/016164110X12670144737855)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Cortet-Rudelli C, Bonneville JF, Borson-Chazot F, Clavier L, Coche Dequéant B, Desailloud R, Maiter D, Rohmer V, Sadoul JL & Sonnet E et al. Post-surgical management of non-functioning pituitary adenoma. Annals of Endocrinology 2015 76 228238. (https://doi.org/10.1016/j.ando.2015.04.003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Thapar K, Scheithauer B, Kovacs K, Pernicore P & Laws E. p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. Neurosurgery 1996 38 765771. (https://doi.org/10.1227/00006123-199604000-00027)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Brochier S, Galland F, Kujas M, Parker F, Gaillard S, Raftopoulos C, Young J, Alexopoulou O, Maiter D & Chanson P. Factors predicting relapse of non-functioning pituitary macroadenomas after neurosurgery: a study of 142 patients. European Journal of Endocrinology 2010 163 193200. (https://doi.org/10.1530/EJE-10-0255)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Ferrante E, Ferraroni M, Castrignanò T, Menicatti L, Anagni M, Reimondo G, Del Monte P, Bernasconi D, Loli P & Faustini-Fustini M et al. Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors. European Journal of Endocrinology 2006 155 8239. (https://doi.org/10.1530/eje.1.02298)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Ntali G, Capatina C, Fazal-Sanderson V, Byrne JV, Cudlip S, Grossman AB, Wass JA & Karavitaki N. Mortality in patients with non-functioning pituitary adenoma is increased: systematic analysis of 546 cases with long follow-up. European Journal of Endocrinology 2016 174 137145. (https://doi.org/10.1530/EJE-15-0967)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Meij BP, Lopes MB, Ellegala DB, Alden TD, Laws E Jr. The long-term significiance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. Journal of Neurosurgery 2002 96 195208. (https://doi.org/10.3171/jns.2002.96.2.0195)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Watts AK, Easwaran A, McNeill P, Wang WJ & Caputo C. Younger age a risk factor for regrowth and recurrence of non-funtioning pituitary macroadenomas: results from a single Australian center. Clinical Endocrinology 2017 87 264271. (https://doi.org/10.1111/cen.13365)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Hwang J, Seol HJ, Nam DH, Lee JI, Lee MH & Kong DS. Therapeutic strategy for cavernous sinus-invading non-functioning pituitary adenomas based on the modified Knosp grading system. Brain Tumors Research and Treatment 2016 4 6369. (https://doi.org/10.14791/btrt.2016.4.2.63)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Nosé V, Ezzat S, Horvath E, Kovacs K, Laws E, Lloyd R, Lopez B & Asa S. Protocol for the examination of specimens from patients with primary pituitary tumors. Archives of Pathology and Laboratory Medecine 2011 135 640646.

    • Search Google Scholar
    • Export Citation
  • 31

    Roelfsema F, Biermasz NR & Pereira AM. Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis. Pituitary 2012 15 7183. (https://doi.org/10.1007/s11102-011-0347-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Saeger W, Lüdecke DT, Buchfelder M, Fahlbusch R, Quabbe HJ & Petersem S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. European Journal of Endocrinology 2007 156 203216. (https://doi.org/10.1530/eje.1.02326)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Landeiro JA, Fonseca EO, Monnerat AL, Taboada GF, Cabral GA & Antunes F. Nonfunctioning giant pituitary adenomas : invasiveness and recurrence. Surgical Neurology international 2015 6 179. (https://doi.org/10.4103/2152-7806.170536)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation