Differences in invasiveness and recurrence rate among nonfunctioning pituitary neuroendocrine tumors depending on tumor subtype

doi:10.21203/rs.3.rs-3233446/v1

Download PDF

Research Article

Differences in invasiveness and recurrence rate among nonfunctioning pituitary neuroendocrine tumors depending on tumor subtype

https://doi.org/10.21203/rs.3.rs-3233446/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Purpose

To clarify the invasiveness to surrounding structures and recurrence rate of each subtype of nonfunctioning pituitary neuroendocrine tumor (Pit-NETs) according to the WHO 2022 classification.

Methods

This retrospective study utilized data from 292 patients with nonfunctioning Pit-NETs treated with initial transsphenoidal surgery. Recurrence was evaluated on 163 patients who were available for a magnetic resonance imaging follow-up ≥36 months. All tumors were assessed by immunohistochemical staining for Pit-1, T-PIT, and GATA3. Invasiveness to surrounding structures was evaluated based on intraoperative findings.

Results

Cavernous sinus invasion was found in 47.5% of null cell tumors, 50.0% of Pit-1 lineage tumors, 31.8% of corticotroph tumors, and 18.3% of gonadotroph tumors. Dura mater defects in the floor of sellar turcica, indicating dural invasion, were found in 44.3% of null cell tumors, 36.4% of corticotroph tumors, 16.7% of Pit-1 lineage tumors, and 17.3% of gonadotroph tumors. In logistic regression analysis, Pit-1 (OR 5.90, 95%CI 1.71–20.4, P = 0.0050) and null tumors (OR 4.14, 95%CI 1.86–9.23, P = 0.0005) were associated with cavernous sinus invasion. Recurrence was found in 8 (4.9%) patients, but without significant differences between tumor subtypes. No tumor showed immunoreactivity for hormone antibodies (8/101 vs. 0/62, P = 0.0246).

Conclusion

Among nonfunctioning Pit-NETs, Pit-1 lineage tumors tend to invade the cavernous sinus, corticotroph tumors may produce dura mater defects in the sellar turcica, and null cell tumors tend to cause both. Pit-NETs without pituitary hormone may have a higher recurrence rate.

pituitary neuroendocrine tumor

invasiveness

recurrence

cavernous sinus invasion

dura mater defect

GATA3

Pituitary neuroendocrine tumors (Pit-NETs) are the third most frequent primary brain tumors, and are relatively encountered clinically [1]. In the World Health Organization (WHO) 2022 classification, the diagnostic name changed from pituitary adenomas to Pit-NETs [2]. Although historically considered benign, 20–55% of surgically removed Pit-NETs may exhibit evidence of local invasion to the dura matter, bone, and/or surrounding structures [3]. Such “invasiveness” makes achieving surgical total resection and/or postoperative complete remission challenging, and may result in tumor recurrence at an early stage [4].

Pit-NETs are categorized as either functioning or nonfunctioning Pit-NETs, nonfunctioning Pit-NETs accounting for 14–54% of all [5]. To determine the tumor subtype as well as various hormones, the WHO 2017 classification recommends immunostaining for transcription factors [6]. Previous reports have suggested that Pit-NETs which do not show immunoreactivity to pituitary hormone antibodies or those diagnosed as null cell tumors before 2017 are more likely to invade the cavernous sinus than silent gonadotroph tumors [7]. On the other hand, most Pit-NETs diagnosed as null cell tumors before 2017 showed immunoreactivity for either T-PIT, Pit-1, or SF-1 [8]. Recently, Pit-NETs negative for all transcription factors, so-called “true null cell tumors,” have been shown to have a high rate of recurrence and cavernous sinus invasion [9]. However, the invasiveness and recurrence rate of tumors not subclassified as null cell tumors according to the latest WHO classification but diagnosed as null cell tumors before 2017 have not been clarified. Thus, this study aimed to determine the invasiveness to surrounding structures and recurrence rate for each Pit-NET subtype based on transcription factors, according to the latest WHO classification.

This retrospective study was approved by the institutional review board (E-2022), which waived the requirement for written informed consent due to the anonymous nature of the data used.

Patients

Between 2009 and 2022, 292 patients with nonfunctioning Pit-NETs underwent initial transsphenoidal surgery (TSS) at our institution. We retrieved their data from the medical records and analyzed age, sex, tumor volume, radiographical findings, operative findings, and pathological evaluations. Recurrence or regrowth was assessed on 187 patients (recurrence 163, regrowth 24) who had follow-up magnetic resonance imaging (MRI) data available for ≥ 36 months (median follow-up: 72 months, range 36–158 months).

Endocrinological studies

The basal serum/plasma thyroid stimulating hormone (TSH), free thyroxine (FT4), prolactin, luteinizing hormone (LH), follicle stimulating hormone (FSH), cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), and insulin-like growth factor 1 (IGF-1) levels were measured approximately within one month preoperatively.

Pituitary stimulation tests were performed in 242 patients 1–2 months preoperatively. Three patients who took an antiplatelet drug were excluded to prevent pituitary apoplexy. A patient with epilepsy, 17 patients with pituitary apoplexy, and 29 patients with large tumors with severe visual functional impairment were excluded as well. Patients received a combination of thyrotropin-releasing hormone (TRH) (500 µg) and LH-releasing hormone (100 µg) and underwent an insulin tolerance test (0.1 unit/kg). Patients aged ≥ 65 years old received arginine (30g) and corticotropin-releasing hormone (CRH) (100 µg) instead of insulin tolerance test.

An excessive GH secretion was identified by higher IGF-1 levels than normal and lack of GH suppression (< 0.4 ng/mL) for the 75 g oral glucose tolerance test. Patients with serum PRL > 200 ng/mL, excessive GH secretion, and inappropriate secretion of TSH were excluded from the study. Patients with both serum cortisol > 10 µg/dL and plasma ACTH > 63.3 pg/mL were evaluated with the 0.5 mg-dexamethasone-suppression-test; patients with early-morning serum cortisol not suppressed < 5 µg/dL were similarly excluded from the study.

Radiological assessment

All patients underwent 3T-MRI and head computed tomography within one month before surgery for tumor volume and shape assessment. Tumor volume (cm³) was calculated as Width × Height × Depth/2 [10]. Lateral tumor growth into the cavernous sinus was categorized according to the Knosp classification [11]. Total resection was defined as no residual tumor on MRI within three months after surgery. MRI was performed routinely at least once a year after surgery to evaluate the presence or absence of recurrence. In case of presence of residual tumor, regrowth was defined as tumor growth > 1 mm compared with the MRI performed within three months after surgery.

Surgical procedures

TSS was performed as an endoscopic procedure through one nostril as previously described [12]. For this study, invasiveness was assessed by the following surgical findings: cavernous sinus invasion defined by medial wall defect, sphenoid sinus invasion, dura matter defects in the floor of the sella turcica indicating dural invasion, and erosion of bony parts in the floor of the sellar turcica [3].

Pathological diagnosis

Tumor histology was evaluated in formalin-fixed, paraffin-embedded, hematoxylin and eosin-stained tissue by two pathologists (V.J.A and Y.T). Immunohistochemical analyses for hormonal (anti-TSH, GH, prolactin, LH, FSH, and ACTH) secretion were performed as well. Additional immunohistochemical staining for transcription factors was performed using anti-Pit-1 [1:100, mouse monoclonal, clone:D7, Santa Cruz Biotehnologies Inc, Dallas, Texas, USA SC-393943 https://www.scbt.com/ja/p/pit-1-antibody-d-7?requestFrom=search], anti-GATA3 [prediluted, mouse monoclonal, clone:L50-823, Roche diagnostics, Rotkreuz, Switzerland https://elabdoc-prod.roche.com/eLD/web/jp/en/products/RTD000922?searchTerm=GATA&catalog=ProductCatalog&orderBy=Relevance], and anti-T-PIT [1:200; Anti-TBX19/HPA072686, Atlas Antibodies, RRID: AB_2732209, AB_2732209 https://antibodyregistry.org/search?q=AB_2732209]. Pathological diagnosis was based on WHO classification, 2022 edition [2]. Tumors without immunoreactivity for any antibodies were diagnosed as null cell tumors, tumors which showed immunoreactivity for Pit-1 were defined as Pit-1 lineage tumors, those with immunoreactivity for GATA3 and no immunoreactivity for Pit-1 were diagnosed as gonadotroph tumors, and tumors with immunoreactivity for T-PIT were diagnosed as corticotroph tumors. Gonadotroph tumors are generally diagnosed using the anti-SF-1 but the combination of GATA3 and Pit-1 enables an equivalent diagnosis quality [13, 14]. Hence, we used anti-GATA3 as surrogate marker.

Statistical analyses

The Shapiro–Wilk test was used to assess data normality; continuous variables are expressed as median [interquartile range] and categorical variables are represented as frequency (%). Continuous variables were compared using the Kruskal–Wallis test and one-way ANOVA, and categorical variables were compared using the Fisher’s exact test. A P-value < 0.05 (two-tailed) was deemed significant. Bonferroni correction was used to account for multiple comparisons. A logistic regression model was used to calculate the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) to identify factors related to cavernous sinus invasion, and dura matter and bone defects in the sellar turcica. To avoid overfitting the model, seven covariates were selected for cavernous sinus invasion: age, sex, Knosp grade 3–4, tumor volume, null cell, PIT-1 and T-PIT expression, and dura matter defects in the sellar turcica: age, sex, tumor height, tumor volume, null cell, PIT-1, and T-PIT expression, respectively. Receiver operating characteristic (ROC) curves were generated to determine the sensitivity and specificity of various tumor height cutoff values for the dura matter defects in the sellar turcica. All statistical analyses were performed using JMP® version 16 (SAS Institute Inc., Cary, NC, USA).

Tumor classification

Figure 1 presents the classification of the tumors in the present study. Gonadotroph tumors were the most common (65.4%); 32.5% showed immunoreactivity for FSH and/or LH. Among 22 (7.5%) cases classified as corticotroph tumors, 13 (4.4%) showed immunoreactivity for ACTH (“totally silent” corticotroph tumors) [11]. Among 18 cases classified into Pit-1 lineage tumors, 4 (1.4%) were subclassified into somatotroph tumors, 2 (0.7%) as lactotroph tumors, and 3 (1.0%) as thyrotroph tumors. There were nine cases (3.1%) without immunoreactivity for any pituitary hormone (Supplemental Table 1). One of three patients with thyrotroph tumors had primary hypothyroidism. Of all cases, 61 (20.9%) were classified as null cell tumors.

Patient characteristics according to tumor subtype

Table 1 presents the characteristics of patients according to tumor subtype. Patients with Pit-1 lineage tumors were significantly younger than those with gonadotroph tumors (P < 0.0001) and tended to be younger than those with null cell and corticotroph tumors (P = 0.0197 and P = 0.0770). There were more male patients with gonadotroph tumors, but more female patients in the other three groups (P < 0.0001). Figure 2 shows a comparison of invasiveness between tumor subtypes. Null cell tumors showed more cavernous sinus invasion (P < 0.0001), dura mater (P < 0.0001) and bone (P < 0.0001) defects in the sellar turcica compared to gonadotroph tumors. The ratio of cavernous sinus invasion in Pit-1 lineage tumors was higher than in gonadotroph tumors (P = 0.0070), and the ratio of dura mater defects in the sellar turcica was higher in corticotroph tumors than in gonadotroph tumors (P = 0.044). No significant difference was observed in Knosp grade or the ratio of sphenoid sinus invasion. Neither was there any significant difference in total resection rate, recurrence rate, regrowth rate, or MIB-1 index.

Table 1

Patient characteristics according to tumor subtype
Subtype		Gonadotroph		Null cell		Pit-1 lineage		Corticotroph		P value
n = 292		191		61		18		22
Age at diagnosis, y.o., median	(IQR)	63	(53–71)	56	(45.5–67)	47	(39–57.5)	54.5	(47.3–66.3)	< 0.0001
Gonadotroph vs. Pit-1 lineage		63	(53–71)			47	(39–57.5)			< 0.0001
Null cell vs. Pit-1 lineage				56	(45.5–67)	47	(39–57.5)			0.0197
Pit-1 lineage vs. Corticotroph						47	(39–57.5)	54.5	(47.3–66.3)	0.0770
Sex	F:M	52:139		40:21		12:6		19:3		< 0.0001
Gonadotroph vs. Null cell		52:139		40:21						< 0.0001
Gonadotroph vs. Pit-1 lineage		52:139				12:6				0.0011
Gonadotroph vs. Corticotroph		52:139						19:3		< 0.0001
Tumor height, mm, median	(IQR)	21.0	(16.3–26.0)	20.4	(14.9–26.8)	16.5	(11.8–23.6)	19.2	(16.3–30.1)	0.3888
Tumor volume, cm³, median	(IQR)	4.33	(2.25–7.99)	5.28	(2.68–8.33)	4.07	(1.10–6.80)	3.52	(2.25–9.31)	0.4918
Knosp 0–2	(%)	144	(75.4%)	40	(65.6%)	12	(66.7%)	12	(54.6%)	0.1250
Cavernous sinus invasion	(%)	35	(18.3%)	29	(47.5%)	9	(50.0%)	7	(31.8%)	< 0.0001
Gonadotroph vs. Null cell		35	(18.3%)	29	(47.5%)					< 0.0001
Gonadotroph vs. Pit-1 lineage		35	(18.3%)			9	(50.0%)			0.0041
Sphenoid sinus invasion	(%)	6	(3.1%)	5	(8.2%)	2	(11.1%)	2	(9.1%)	0.1905
Defect of dura mater	(%)	33	(17.3%)	27	(44.3%)	3	(16.7%)	8	(36.4%)	0.0001
Gonadotroph vs. Null cell		33	(17.3%)	27	(44.3%)					< 0.0001
Gonadotroph vs. Corticotroph		33	(17.3%)					8	(36.4%)	0.0440
Defect of bone	(%)	26	(13.6%)	25	(41.0%)	4	(22.2%)	6	(27.3%)	< 0.0001
Gonadotroph vs. Null cell			(13.6%)	25	(41.0%)	4				< 0.0001
MIB-1 index, %, median	(IQR)	1.0	(1.0–2.0)	1.5	(1.0–2.0)	1.8	(1.0–2.3)	1.5	(1.0–2.0)	0.1597
Total resection on MRI	(%)	173	(90.6%)	50	(82.0%)	15	(83.3%)	18	(81.8%)	0.2272
Recurrence or regrowth	(%)	9	(7.6%)	5	(11.1%)	3	(25.0%)	3	(25.0%)	0.0973
IQR: Interquartile range, MRI: Magnetic resonance imaging.
P values between two subtype tumors showing a significant difference or tending to are shown.

Related factors of invasiveness of Pit-NETs

Table 2 shows the related factors of cavernous sinus invasion in multivariate analysis. Knosp grade 3–4, tumor volume, null cell tumor, and Pit-1 positive tumor were significantly associated with cavernous sinus invasion with adjusted ORs of 8.37 for Knosp grade 3–4 (95% CI 4.30–16.30, p < 0.0001), 4.14 for null cell tumor (95% CI 1.86–9.23, P = 0.0005), 5.90 for Pit-1 lineage tumor (95% CI 1.71–20.40, P = 0.0050), and 1.06 for tumor volume (95% CI 1.01–1.11, P = 0.0137). To exclude the tumor mass effect, cavernous sinus invasion was reassessed in 208 patients with Knosp grade 0–2. Cavernous sinus invasion was found in 33.3% of Pit-1 lineage tumors, 27.5% of null cell tumors, 9.7% of gonadotroph tumors, and in no corticotroph tumors.

Table 2

Results of multivariate logistic regression analysis on the related factors for cavernous sinus invasion
Cavernous invasion	Wald χ²	OR	95%CI	P value
Knosp 3–4	39.04	8.37	4.30–16.30	< 0.0001
Null cell	12.08	4.14	1.86–9.23	0.0005
Pit-1	7.86	5.90	1.71–20.4	0.0050
Tumor volume	5.27	1.06	1.01–1.11	0.0137
Sex, female	1.49	1.54	0.77–3.09	0.2224
Age	0.90	1.01	0.99–1.04	0.3396
T-PIT	0.01	1.06	0.31–3.66	0.9249

Table 3 shows the related factors of dura matter defects in the sellar turcica obtained in multivariate analysis. Null cell tumors and tumor height were significantly associated with dura matter defects with adjusted ORs of 4.61 for null cell tumors (95% CI 2.13–9.99, P < 0.0001), and 1.10 for tumor height (95% CI 1.03–1.18, P = 0.0052). The optimal tumor height with dura mater defects was calculated using the ROC curve (Supplemental figure). We obtained the optimal relation between sensitivity (76.06%) and specificity (67.42%) at a cutoff value of 23.02 mm (AUC = 0.75225). To reduce the effect of tumor height, we reassessed the presence or absence of dura mater defects in each group at a height ≤ 23 mm. Accordingly, dura mater defects in the sellar turcica were found in 26.7% of corticotroph tumors, 22.6% of null cell tumors, 10.0% of Pit-1 lineage tumors, and 4.6% of gonadotroph tumors (Fig. 3).

Table 3

Results of multivariate logistic regression analysis on the related factors for dura matter defects in the sellar turcica
Dura matter defect	Wald χ²	OR	95%CI	P value
Null cell	14.98	4.61	2.13–9.99	0.0001
Tumor height	7.94	1.10	1.03–1.18	0.0052
T-PIT	3.55	3.13	0.96–10.22	0.0594
Age	1.49	1.02	0.99–1.04	0.2162
Tumor volume	0.76	1.04	0.95–1.13	0.3611
Sex, female	0.29	1.21	0.61–2.43	0.5930
Pit-1	0.19	1.38	0.32–6.01	0.6671

Recurrence and regrowth

Of the 163 cases that achieved total resection, 8 (4.9%) cases showed recurrence, without significant differences among tumor subtypes (null cell tumors: 3/36, gonadotroph tumors: 3/107, Pit-1 lineage tumors: 1/10, corticotroph tumors: 1/10, P = 0.3868). However, none of the tumors showed immunoreactivity for any pituitary hormone, and no recurrence was observed in tumors showing immunoreactivity against FSH, LH, GH, PRL, TSH, and/or ACTH (8/101 cases vs. 0/62 cases, P = 0.0246). Of the 24 cases (Knosp 3–4: 19 cases, Median tumor volume: 10.0 cm3, IQR 6.5–13.8, preoperatively) with residual tumors on postoperative MRI, 12 (50.0%) cases showed regrowth but without significant differences among subtypes (null cell tumors: 2/9 cases, gonadotroph tumors: 6/11 cases, Pit-1 lineage tumors: 2/2 cases, corticotroph tumors: 2/2 cases, P = 0.0762).

In this study we evaluated patient background and tumor characteristics of nonfunctioning Pit-NETs according the WHO 2022 classification. First, we found that cavernous sinus invasion and dura mater defects in the sellar turcica occur frequently in null cell pit-NETs. Next, we showed that Pit-1 lineage tumors were common in young patients and frequently showed cavernous sinus invasion as did null cell tumors. Furthermore, we demonstrated that, similar to null cell tumors, corticotroph tumors often exhibit the dura mater defects in the sellar turcica. Due to the small number of cases, we could not find significant differences in recurrence rate and regrowth rate among subtypes. However, when tumors were divided according to immunoreactivity to the pituitary hormone, those without immunoreactivity had a high recurrence rate.

Differences in origin among Pit-NETs subtypes and invasion to surrounding structures

The majority of silent corticotroph tumors are large at the time of diagnosis and known to cause frequent invasions at multiple sites [8, 15]. We confirmed for the first time that nonfunctioning corticotroph tumors had a high rate of dura mater defects in the sellar turcica, second only to null cell tumors. From an anatomical standpoint, normal corticotroph cells comprise about 15% of anterior pituitary cells and mostly cluster in the central mucoid wedge [16]. This cellular localization may explain why the relatively small coricotroph tumors caused more dura mater defects in the sellar turcica than other subtype tumors in the present study. In addition, corticotroph tumors with TP53 mutations, which constitute 6–10% of all pituitary tumors, have been reported to be more invasive and more malignant [17], comprising up to 45% of aggressive pituitary tumors and pituitary carcinomas [18].

Asmaro and colleagues reported that 53% of Pit-1 lineage Pit-NETs caused cavernous sinus invasion, with 44% of Knosp grade 0–2 Pit-1 lineage Pit-NETs showing cavernous sinus invasion [19]. In addition, 14% of Knosp grade 0–1 acromegaly patients are reported to have histologically cavernous sinus invasion [20]. Tumors with GH secretion but without acromegaly symptoms, the so-called silent somatotroph tumors, also frequently show cavernous sinus invasion [21]. From an anatomical perspective, normal somatotroph cells are primarily located in the lateral wings of the anterior lobe [16]. As for corticotroph tumors, the features of the tumor site of origin may correspond to the localization of normal cells. Thyrotroph tumors have a high tendency to invade the cavernous sinus [22–24]. Nonetheless, thyrotroph tumors frequently have GH-TSH co-secretion [24] and may contain immature Pit-1 lineage tumors [2]. Therefore, pure thyrotroph tumors may not be highly invasive. Lactotrophs tumors are common in young women, and cavernous sinus invasion influences the decline in surgical remission [25]. Cavernous sinus invasion is more common in lactotroph tumors in males than in females, as they are less likely symptomatic and their existence is only confirmed when already large [25]. A study of medial wall resection of the cavernous sinus at Pit-NETs showed lower effects for endocrinological remission in lactotrophs tumors than in somatotrophs tumors [26]. Therefore, it is controversial that cavernous sinus invasion has been common in Lactotroph tumors as well as Somatotroph tumors. Like thyroytroph tumors, immature Pit-1 lineage tumors must also be considered about lactotrophs with cavernous sinus invasion.

There are few tumors positive solely for Pit-1 and their detail biological behaviors have not been clarified [8, 27]. In this study, half Pit-1 lineage tumors were positive solely for Pit-1. Most patients with Pit-1 solely positive tumor were young and their tumors showed cavernous sinus invasion. A more primitive differentiated tumor is possible as well [27], as the lack of hormone secretion from the tumors makes it difficult to estimate the site of origin.

Tumors with negative for pituitary hormone have been known to exhibit a propensity for invasiveness to surroundings structures [7]. In the present study, we showed that true null cell tumors, which are also negative for transcription factors, account for about one-third of tumors negative for the pituitary hormone. They also exhibited a high degree of invasiveness to surroundings structures. On the other hand, gonadotroph tumors showed less tendency of invasiveness than null cell tumors. Gonadotroph cells are scattered throughout the pars distalis, and null cells are scattered throughout the anterior pituitary [16]. Nevertheless, the fact that null cell tumors have higher invasive ability than gonadotroph tumors should be considered for factors of invasiveness other than the site of origin.

Based on the above, a combination of tumor site and subtype could result in easy invasion of surrounding structures. Therefore, nonfunctioning Pit-NETs that develop at a young age or that invade surrounding structures despite of a relatively small size should be suspected as somatotroph, corticotroph, null cell tumors, or Pit-1 only positive tumors.

Recurrence and tumors negative for pituitary hormone

Silent Pit-NETs with dedicated differentiation along the transcription factors (SF-1, T-PIT, Pit-1) may constitute primitive tumors arising from cells that initiated adenohypophyseal lineage differentiation, yet experienced an arrest in maturation before reaching the maturity required for hormone production [27]. For example, among lactotroph tumors in male, which are often aggressive with a high risk of recurrence and malignancy [6], tumors with low PRL producing ability have a low expression rate of ERα, are prone to invasion, and are poorly differentiated [28]. Transcription factors such as ERα and others may be involved in tumor upregulation and could contribute to the aggressive behavior of malignant Pit-NETs [25]. “Totally silent” Pit-NETs are more aggressive than non-silent Pit-NETs but may still be less prone to recurrence than primitive differentiated Pit-NETs negative for pituitary hormone.

Limitations

Notwithstanding the above, this study has a few limitations. First, this study was a single-center review of nonrandomized patients, which limits its generalizability. Second, the small number of cases included for evaluation of recurrence and regrowth made statistical evaluation difficult. Therefore, further multicenter trials are needed. Despite the aforementioned issues, the data on invasiveness and recurrence are interesting clinical information; we believe that this study serves to expand the knowledge in the field of pituitary tumors.

In nonfunctioning Pit-NETs, Pit-1 lineage tumors tend to invade the cavernous sinus, corticotroph tumors tend to have defect of the dura mater in the floor of the sella turcica, and null cell tumors tend to have both aspects. Pit-NETs without pituitary hormone may be prone to recurrence.

Competing Interests

All authors declare no conflict of interest.

Compliance with ethical standards

Funding

This study was supported by JSPS Grant-in-Aid for Scientific Research (C) (grant number JP23K06697).

Research involving participants and/or animals

Not applicable.

Informed consent

As patient data in this study are completely anonymized, any identification of individuals is difficult. Pertinent research content is available in the homepage of our institution.

Ethics approval

This study was conducted retrospectively, utilized data obtained for clinical purposes, and was approved by the ethics committee of Hiroshima University Hospital (E-2022, May 18, 2020).

Author contributions

Conception and design: Akira Taguchi. Acquisition of data: Akira Taguchi, Yasuyuki Kinoshita, Atsushi Tominaga. Analysis and interpretation: Akira Taguchi, Fumiyuki Yamasaki, Yasuyuki Kinoshita, Vishwa Jeet Amatya, Yukari Go. Drafting the article: Akira Taguchi. Critically revising the article: Fumiyuki Yamasaki, Yasuyuki Kinoshita, Yukio Takeshima, Nobutaka Horie. Reviewed submitted version of manuscript: all authors. Statistical analysis: Akira. Taguchi, Yasuyuki Kinoshita, Fumiyuki Yamasaki. Administrative/technical/material support: Vishwa Jeet Amatya, Atsushi Tominaga, Yukio Takeshima. Study supervision: Fumiyuki Yamasaki, Nobutaka Horie.

Acknowledgments

We gratefully acknowledge the work of past and present members of Hiroshima University Hospital. The authors would like to thank Enago (www.enago.jp) for the English language review.

Committee of Brain Tumor Registry of Japan.: Report of Barain tumor registry of Japan (2001–2004) 13th edition. Neurol. Med. Chir. (Tokyo) 54 Suppl 1, 1–102 (2014)
Asa SL, Mete O, Perry A, Osamura RY (2022) Overview of the 2022 WHO classification of pituitary tumors. Endocr Pathol 33(1):6–26. https://doi.org/10.1007/s12022-022-09703-7
Nishioka H (2023) Aggressive pituitary tumors (PitNETs). Endocr J 70(3):241–248. https://doi.org/10.1507/endocrj.EJ23-0007
Trouillas J, Roy P, Sturm N, Dantony E, Cortet-Rudelli C, Viennet G, Bonneville JF, Assaker R et al (2013) A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathol 126(1):123–135. https://doi.org/10.1007/s00401-013-1084-y
Ntali G, Wass JA (2018) Epidemiology, clinical presentation and diagnosis of non-functioning pituitary adenomas. Pituitary 21:111–118. https://doi.org/10.1007/s11102-018-0869-3
Trouillas J, Jaffrain-Rea ML, Vasiljevic A, Raverot G, Roncaroli F, Villa C (2020) How to classify the pituitary neuroendocrine tumors (PitNET)s in 2020. Cancers (Basel) 12(2):514. https://doi.org/10.3390/cancers12020514
Yamada S, Ohyama K, Taguchi M, Takeshita A, Morita K, Takano K, Sano T (2007) A study of the correlation between morphological findings and biological activities in clinically nonfunctioning pituitary adenomas. Neurosurgery 61(3):580–584. https://doi.org/10.1227/01.NEU.0000290906.53685.79
Nishioka H, Inoshita N, Mete O, Asa SL, Hayashi K, Takeshita A, Fukuhara N, Yamaguchi-Okada M, Takeuchi Y, Yamada S (2015) The complementary role of transcription factors in the accurate diagnosis of clinically nonfunctioning pituitary adenomas. Endocr Pathol 26(4):349–355. https://doi.org/10.1007/s12022-015-9398-z
Haddad AF, Young JS, Oh T, Pereira MP, Joshi RS, Pereira KM, Osorio RC, Donohue KC et al (2020) Clinical characteristics and outcomes of null-cell versus silent gonadotroph adenomas in a series of 1166 pituitary adenomas from a single institution. Neurosurg Focus 48(6):E13. https://doi.org/10.3171/2020.3.FOCUS20114
Taguchi A, Kinoshita Y, Tokumo K, Tominaga A, Kiuchi Y, Yamasaki F, Horie N (2022) Usefulness of critical flicker fusion frequency measurement and its laterality for evaluating compressive optic neuropathy due to pituitary neuroendocrine tumors. Neurosurg Rev 46(1):4. https://doi.org/10.1007/s10143-022-01915-z
Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary adenomas with invasion of the cavernous sinus space: A magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:610–617. https://doi.org/10.1227/00006123-199310000-00008
Kinoshita Y, Tominaga A, Usui S, Arita K, Sakoguchi T, Sugiyama K, Kurisu K (2016) The surgical side effects of pseudocapsular resection in nonfunctioning pituitary adenomas. World Neurosurg 93:430–435. https://doi.org/10.1016/j.wneu.2016.07.036
Turchini J, Sioson L, Clarkson A, Sheen A, Gill AJ (2020) Utility of GATA-3 expression in the analysis of pituitary neuroendocrine tumour (PitNET) transcription factors. Endocr Pathol 31(2):150–155. https://doi.org/10.1007/s12022-020-09615-4
Mete O, Kefeli M, Çalışkan S, Asa SL (2019) GATA3 immunoreactivity expands the transcription factor profile of pituitary neuroendocrine tumors. Mod Pathol 32(4):484–489. https://doi.org/10.1038/s41379-018-0167-7
Jiang S, Zhu J, Feng M, Yao Y, Deng K, Xing B, Lian W, Wang R, Bao X (2021) Clinical profiles of silent corticotroph adenomas compared with silent gonadotroph adenomas after adopting the 2017 WHO pituitary classification system. Pituitary 24(4):564–573. https://doi.org/10.1007/s11102-021-01133-8
Anat Ben-Shlomo SM (2011) : Chap. 2: Hypothalamic regulation of anterior pituitary function. In: Anat Ben-Shlomo, Shlomo Melmed. (eds.) The Pituitary (Third edition), pp. 21–45. Academic Press https://www.academia.edu/19700586/The_Pituitary_3rd_Edition. Accessed 22 June 2023
Perez-Rivas LG, Simon J, Albani A, Tang S, Roeber S, Assié G, Deutschbein T, Fassnacht M et al (2022) TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome. Acta Neuropathol Commun 10(1):139. https://doi.org/10.1186/s40478-022-01437-1
McCormack A, Dekkers OM, Petersenn S, Popovic V, Trouillas J, Raverot G, Burman P (2018) ESE survey collaborators.: Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. Eur. J. Endocrinol. 178(3), 265–276 https://doi.org/10.1530/EJE-17-0933
Asmaro K, Zhang M, Rodrigues AJ, Mohyeldin A, Vigo V, Nernekli K, Vogel H, Born DE, Katznelson L, Fernandez-Miranda JC (2023) Cytodifferentiation of pituitary tumors influences pathogenesis and cavernous sinus invasion. J Neurosurg 28:1–9. https://doi.org/10.3171/2023.3.JNS221949
Nishioka H, Fukuhara N, Horiguchi K, Yamada S (2014) Aggressive transsphenoidal resection of tumors invading the cavernous sinus in patients with acromegaly: predictive factors, strategies, and outcomes. J Neurosurg 121(3):505–510. https://doi.org/10.3171/2014.3.JNS132214
Langlois F, Woltjer R, Cetas JS, Fleseriu M (2018) Silent somatotroph pituitary adenomas: an update. Pituitary 21(2):194–202. https://doi.org/10.1007/s11102-017-0858-y
Yamada S, Fukuhara N, Horiguchi K, Yamaguchi-Okada M, Nishioka H, Takeshita A, Takeuchi Y, Ito J, Inoshita N (2014) Clinicopathological characteristics and therapeutic outcomes in thyrotropin-secreting pituitary adenomas: a single-center study of 90 cases. J Neurosurg 121(6):1462–1473. https://doi.org/10.3171/2014.7.JNS1471
Cossu G, Daniel RT, Pierzchala K, Berhouma M, Pitteloud N, Lamine F, Colao A, Messerer M (2019) Thyrotropin-secreting pituitary adenomas: a systematic review and meta-analysis of postoperative outcomes and management. Pituitary 22(1):79–88. https://doi.org/10.1007/s11102-018-0921-3
Taguchi A, Kinoshita Y, Yamasaki F, Arita K, Tominaga A (2021) Clinical characteristics and thyroid hormone dynamics of thyrotropin-secreting pituitary adenomas at a single institution. Endocrine 73(1):151–159. https://doi.org/10.1007/s12020-020-02556-2
Trouillas J, Delgrange E, Wierinckx A, Vasiljevic A, Jouanneau E, Burman P, Raverot G (2019) Clinical, pathological, and molecular factors of aggressiveness in lactotroph tumours. Neuroendocrinology 109(1):70–76. https://doi.org/10.1159/000499382
Mohyeldin A, Katznelson LJ, Hoffman AR, Asmaro K, Ahmadian SS, Eltobgy MM, Nayak JV, Patel ZM, Hwang PH, Fernandez-Miranda JC (2022) Prospective intraoperative and histologic evaluation of cavernous sinus medial wall invasion by pituitary adenomas and its implications for acromegaly remission outcomes. Sci Rep 12(1):9919. https://doi.org/10.1038/s41598-022-12980-1
Lee JC, Pekmezci M, Lavezo JL, Vogel H, Katznelson L, Fraenkel M, Harsh G, Dulai M, Perry A, Tihan T (2017) Utility of Pit-1 immunostaining in distinguishing pituitary adenomas of primitive differentiation from null cell adenomas. Endocr Pathol 28(4):287–292. https://doi.org/10.1007/s12022-017-9503-6
Lloyd RV, Landefeld TD, Maslar I, Frohman LA (1985) Diethylstilbestrol inhibits tumor growth and prolactin production in rat pituitary tumors. Am J Pathol 118(3):379–386

No competing interests reported.

supplementalfigure.tif
Supplemental figure Optimal tumor height cutoff value in cases with dura mater defects in the sellar turcica calculated by receiver operating characteristic curves; optimal relation between sensitivity (76.06%) and specificity (67.42%) at a cutoff value of 23.02 mm (AUC = 0.75225).
Supplementaltable.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

Differences in invasiveness and recurrence rate among nonfunctioning pituitary neuroendocrine tumors depending on tumor subtype

Status:

Version 1

Abstract

Figures

Introduction

Methods

Patients

Endocrinological studies

Radiological assessment

Surgical procedures

Pathological diagnosis

Statistical analyses

Results

Tumor classification

Patient characteristics according to tumor subtype

Related factors of invasiveness of Pit-NETs

Recurrence and regrowth

Discussion

Differences in origin among Pit-NETs subtypes and invasion to surrounding structures

Recurrence and tumors negative for pituitary hormone

Limitations

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1