Silent Gonadotroph Adenomas Research Articles

SURG-56. TRANSCRIPTION FACTOR CELL LINEAGE DETERMINES AGGRESSIVE BEHAVIOR AMONG NONFUNCTIONAL PITUITARY ADENOMAS

Abstract INTRODUCTION Pituitary neuroendocrine tumors (PitNETs) are the second most common intracranial neoplasm. Silent or non-functional PitNETs represent a common neuro-oncological challenge due to their size and unpredictable invasion of parasellar structures. This makes their complete surgical resection difficult and puts patients at higher risk for recurrence. OBJECTIVE To characterize differences in tumor volume, cavernous sinus invasion, and recurrence in nonfunctional PitNETs. METHODS Out of 615 transsphenoidal surgeries from 2012 to 2024, there were 309 overall PitNETs and 181 nonfunctional PitNETs. Based on new WHO criteria for transcription factor profiling (PIT-1, TPIT, and SF-1), there were 98 silent gonadotroph adenomas (SGA), 31 silent corticotroph adenomas (SCA), 10 silent pleurihormonal tumors (PHT), and 2 null cell adenomas. Tumor volume was calculated using (AxBxC/2). Knosp grade was calculated. Cavernous sinus invasion was defined as Knosp ≥ 3. Residual disease at 3 months postoperative was recorded and surgical intervention for growing residual disease was captured. RESULTS Average tumor volume of PHT (18.08 cm3) was significantly higher than SGA (8.44 cm3, p=0.007) and similar to SCA (10.33 cm3, p=0.11). Percentage of cavernous sinus invasion was significantly different between SCA (31.82%) and SGA (10.20%, p=0.003), but not PHT (33.33%; p>0.05). There was a significantly higher residual rate in SCA compared to SGA (31.71% vs. 11.22%, p=0.006). There were significantly more reoperations in the SCA group compared to SGA and PHT. CONCLUSIONS Despite similar tumor volume between SCA and SGA, there was a significantly higher rate of cavernous sinus invasion and residual disease among SCA. This has important neuro-oncological implications regarding surgical technique, postoperative surveillance, and need for adjuvant therapy to mitigate aggressive recurrent disease.

8209 Silent Somatotroph Adenoma Unmasked as Pituitary Apoplexy, Disguised as Subarachnoid Hemorrhage

Abstract Disclosure: P. Vemparala: None. S. Challagulla: None. Introduction - Pituitary apoplexy is a rare and potentially life-threatening complication associated with pituitary adenomas, particularly in cases of nonfunctioning macroadenomas. Silent somatotroph adenomas, characterized by the presence of growth hormone (GH) immunoreactivity without manifesting signs and symptoms of acromegaly, are uncommon. This case report presents a distinctive instance where pituitary apoplexy served as the initial manifestation of a GH-immunoreactive tumor. CASE PRESENTATION- A 45-year-old male with a medical history of hypertension, sleep apnea, and hypogonadism sought emergency medical attention following a syncopal episode. Post-syncope, he reported severe headache and neck pain, with no other associated symptoms. Imaging revealed a subarachnoid hemorrhage and a sellar/suprasellar mass measuring approximately 2.8 x 3.6 x 4.2 cm. CT angiography ruled out an aneurysm or vascular malformation. The subarachnoid hemorrhage was attributed to hemorrhage within the sellar mass. Treatment with Nimodipine and levetiracetam was initiated. Laboratory investigations indicated normal insulin-like growth factor 1 (IGF-1) levels. Brain MRI revealed a 4.2 x 2.3 x 2.6 cm heterogeneous enhancing cystic sellar/suprasellar lesion causing mass effect on the hypothalamus and third ventricle. The patient underwent endoscopic transsphenoidal hypophysectomy, revealing a tumor that was diffusely positive for GH and synaptophysin immunostaining and negative for prolactin and ACTH. Ki67 was less than 5%, with no apparent mitotic activity, atypia, or tumor necrosis. The postoperative course was uneventful, and the patient was discharged on oral steroids. Conclusion- Silent somatotroph adenomas constitute a small percentage (2-4.2%) of pituitary adenomas. In contrast to silent gonadotroph adenomas, these tumors are more prevalent in women, tend to present earlier and exhibit higher recurrence rates. This case emphasizes the potential of silent somatotroph adenomas to manifest initially as pituitary apoplexy. It underscores the importance of vigilant post-surgical follow-up due to the possibility of recurrence. Additionally, recognizing pituitary apoplexy as subarachnoid hemorrhage is crucial for timely intervention and appropriate management. Presentation: 6/2/2024

A rare case of silent Gonadotroph Adenoma presenting with secondary infertility, oligomenorrhea in a female patient with a history of polycystic ovarian syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Differences in Menin Expression in Pituitary Adenomas in Multiple Endocrine Neoplasia Type 1, Its Phenocopies and Sporadic Acromegaly

Introduction: Multiple endocrine neoplasia type 1 syndrome (MEN 1) is caused by mutations in MEN1 gene, encoding menin protein. A combination of pituitary adenomas (PA) and primary hyperparathyroidism (PHPT) in patients without MEN1 mutations is defined as MEN 1 phenocopy. The aim of the study is to find if there are any differences in menin expression in PA of patients with genetically confirmed MEN 1, MEN 1 phenocopies and sporadic acromegaly.Materials and Methods: Formalin-fixed paraffin-embedded PA tissues were obtained from 9 genetically confirmed MEN 1 patients (group 1), 12 patients with MEN 1 phenocopies (a combination of PA and PHPT) (group 2) and 14 patients with sporadic acromegaly (group 3). The integrity of the tissues was tested by immunohistochemistry (IHC) using antibodies against the nuclear protein Pit-1. MEN1 mutations were confirmed or excluded by Sanger sequencing or by NGS (NextSeq550, Illumina, USA). Expression of menin was assessed using IHC (Anti-Menin antibody — ChIP Grade, Abcam, UK).Results: The distribution of PA by the type of secretion in group 1 was: 3 — ACTH-secreting, 2 — PRL-secreting, 2 — GH+PRL, 1 — TSH+PRL, 1 — ACTH+PRL, 1 — silent gonadotroph adenoma. All 12 PA from group 2 were GH-secreting. All 14 PA in group 3 were GH-secreting without mixed secretion. The median age at the moment of transsphenoidal surgery in group 1 was 35 years [27; 47], in group 2 — 59 years [56; 65], in group 3 — 56 years [53; 62]. There were 2 men and 7 women in group 1; 2 men and 10 women in group 2; 4 men and 10 women in group 3. In group 1 patients did not receive somatostation analogues (SSA), 7 patients received cabergoline. In group 2 seven patients received SSA, in group 3 — 4 patients received SSA, 2 patients received cabergoline. The results of menin staining were (negative staining/positive cytoplasmic staining/positive nuclear staining): group 1 — 4/4/0; group 2 — 0/11/1; group 3 — 1/7/6. Phenocopy group showed significantly more cytoplasmic expression of menin than in MEN 1 group (p<0.008). MEN 1 group also differed from sporadic acromegaly group by nuclear expression of menin (p<0.015). No statistical significance between sporadic and phenocopy groups was found (p=0.07). Although there were no differences among these groups, the group 2 showed weak nuclear expression only in one case, while in group 3 the menin staining was present both in the nucleus and cytoplasm in equal proportions.Conclusion: Menin expression is generally preserved in PA in MEN 1 phenocopies and sporadic acromegaly, though with different pattern of nuclear and cytoplasmic expression, while its expression varies in PA in MEN 1. These findings suggest that pathogenesis of PA in MEN 1 phenocopies and sporadic acromegaly may have similarities. The mechanisms of co-occurrence of PA and PHPT in MEN 1 phenocopies are poorly understood and epigenetic modifications downstream menin interacting pathways could play a role.

Immunohistochemical Profile of Nonfunctioning Pituitary Adenomas

Background: Nonfunctioning pituitary adenomas (NFPAs) are neuro-endocrine tumors without clinical and laboratory signs of anterior pituitary hormonal hypersecretion. The recent World Health Organization classification is based on the adenohypophyseal cell lineages and requires immunohistochemical evaluation of adenohypophyseal hormones and pituitary transcription factors. There are few data regarding the age and sex prevalence of different cell-types nonfunctioning adenomas and clinical data correlations. Objective: To discover the immunohistochemical profile of large cohort of NFPAs. Materials and Methods: The study includes 100 consecutive cases of endoscopically transsphenoidally removed nonfunctional pituitary adenomas, immunohistochemically assessed for anterior pituitary hormones and transcription factors. Clinical presentation, imaging, laboratory hormonal data and immunohistochemical staining features have been analyzed. All patients (64 women and 36 men) have been divided into four age groups: 20-34 (A) years old, 35-44 (B) years old, 45-59 (C) years old, 60-70 (D) years old. Peculiarities of immunohistochemical profile have been statistically analyzed in those age groups. Results: Most tumors (97%) were macroadenomas with mass effect symptoms. In the groups of silent corticotroph and Pit-1 adenomas most of the patients had subclinical symptoms of hormonal hypersecretion. The proportions of silent gonadotroph adenomas have appeared to be increased with age with predominant prevalence in group D (60%) in women and group C (78, 6%) in men. The proportions of silent Pit-1 adenomas decreased with age with maximum rate in group A (77,8%) in women and in group A (50%) in men. The incidence of silent corticotroph adenomas was different: increasing with age in women with maximum (36,8%) in group C and decreasing from young age (30%-0%) in men age groups B-D respectively. Plurihormonal pituitary adenomas from different cell lineages were found only in women, with maximum incidence rate (17,6%) in group B. The incidence of “null cell” adenomas didn’t differ in men and women in group B and C but was much more higher in men in groups A and D (16,7% vs 0% and 33% vs 6,6% respectively). Conclusions: The different age and sex prevalence of NFPAs, revealed in our study, may be helpful in diagnosing and optimal treatment of NFPAs.

Clinical profiles of silent corticotroph adenomas compared with silent gonadotroph adenomas after adopting the 2017 WHO pituitary classification system.

Silent corticotroph adenomas (SCAs) can be redefined according to the 2017 World Health Organization pituitary classification system with the introduction of T‑PIT, a transcription factor. We studied the clinical features of these redefined SCAs. We compared 112 patients with SCAs and 198 patients with silent gonadotroph adenomas (SGAs) who underwent surgery from January 2019 to May 2020. The prevalence of SCAs increased from 21.3 to 30.2% under the new classification rules. T-PIT-positive, adrenocorticotropic hormone-negative SCAs and T-PIT-positive, adrenocorticotropic hormone-positive SCAs exhibited similar clinical features. SCAs exhibited significant female preponderance (90.2% vs. 29.8%, P < 0.0001); more frequent invasion (36.6% vs. 7.6%, P < 0.0001), especially multiple-site invasion (P < 0.0001); and marked cystic changes on imaging compared with SGAs (54.5% vs. 19.2%, P < 0.0001). SCAs had a softer tumor consistency (89.2% vs. 61.1%, P < 0.0001). Gross total resection was achieved in 66.1% of SCAs and 66.2% of SGAs (P > 0.9999). The overall recurrence/progression rates of SCAs and SGAs were 9.8% and 6.6% at 14.1 and 13.5 months of follow-up, respectively (P = 0.3765). The proportion of patients with more than two recurrences requiring multiple surgeries and radiation was similar between SCAs and SGAs (7.1% vs. 3.0%, P = 0.1514). However, multiple recurrences of SCAs affected younger patients than SGAs (39.0 vs. 53.5 years, P = 0.0433). The prevalence of SCAs increased with the introduction of T-PIT. SCAs and SGAs exhibited comparable size and recurrence/progression rates, but SCAs showed increased invasion and more marked cystic change. Aggressive SCAs tended to affect younger patients. Close long-term monitoring for SCA recurrence/progression is required.

Clinical Relevance and Immunohistochemical Patterns of Silent Pituitary Adenomas: 10 Years of Single-centre Experience

Background:Silent pituitary adenomas are clinically non-functional (i.e., without clinically evident pituitary hormone production).Introduction:The aim of this study was to investigate subjects with silent pituitary adenomas for possible variations in their clinical status.Methods:A total of 102 patients who had undergone surgery for pituitary adenoma and had been diagnosed with silent pituitary adenoma was included in the study. The patients’ preoperative and postoperative hormonal parameters and magnetic resonance imaging (MRI) features were collected, and pathological specimens were re-evaluated.Results:Immunohistochemistry results of the 102 patients were as follows: hormone-negative adenomas (n=35) 35.5%; FSH+LH-positivity (n=32) 31.3%; ACTH-positivity (n=11) 10.7%; α-subunit- positivity (n= 9) 8.8%; prolactin-positivity (n=8) 7.8%; GH-positivity (n=6) 5.4%; and plurihormonal adenoma (n=1). The mean sizes of SGA, SGHA, and SCA were 28.0±12.7, 30.0±16.0, and 27.7±8.9mm (p&gt;0.05), respectively. With the exception of silent gonadotroph adenomas (SGAs), female gender dominance was shown in patients with silent growth hormone adenoma (SGHA) and silent corticotroph adenoma (SCA). Although no clinical relevance was observed in relation to hormonal excess, preoperative GH (4.21±4.6, vs. 0.27±0.36 p=0.00) was slightly more elevated in SGHA than in GH-negative adenomas. Additionally, preoperative basal ACTH values (47.3±28.7 vs. 23.9±14.4, p=0.003) were also higher in SCA compared to the other types. Our findings revealed SCAs to be of more aggressive behaviour than SGHAs and SGAs due to invasiveness in radiological imaging, their elevated re-operation, and postoperative ACTH values.Conclusion:Silent pituitary adenomas represent a challenging diagnostic tumour group. Careful initial evaluation of patients with pituitary adenomas should consider any mild signs and symptoms of functionality, particularly in cases of GH- and ACTH-secreting adenomas.

Adenomas hipofisarios y adenomas hipofisarios no funcionantes

Pituitary adenomas (PA) are a rare and heterogeneous group, mainly benign, of central nervous system lesions. Non-functioning pituitary adenomas (NFPAs) account for 25-35% of PA; in adulthood macroadenomas are the commonest. Silent gonadotroph adenomas are the most frequent AH's subtype (70-90% of all NFPAs). Symptoms are related with mass effects of the tumor on the surrounding tissues or with hypopituitarism. AHs are diagnosed by imaging tests, mainly contrast magnetic resonance imaging. In order to discard hormone disorders, endocrine analysis has to be performed. Neuro-ophthalmological study has to be carried out in adenomas involving optic chiasm and/or cavernous sinuses, as well as in patients with visual symptoms. Trans-sphenoidal surgery is the primary treatment for symptomatic or large NFPA.

Nonfunctioning pituitary adenomas in pediatric and adolescent patients: a clinical analysis of a series of 14 patients.

Nonfunctional pituitary adenomas (NFPAs) in pediatric and adolescent age are extremely rare. This study aimed to report a series of 14 pediatric and adolescent NFPAs to assist in its clinical management. A total of 14 consecutive patients pathologically diagnosed with NFPAs (age ≤ 20years) were retrospectively examined, and the clinical data were analyzed. NFPA is uncommon in pediatric and adolescent patients (0.4%). The most common clinical symptoms were a headache (6/14, 42.9%) and visual loss (4/14, 28.6%). Ten patients (71.4%) had preoperative hypopituitarism. All patients were diagnosed with macroadenoma including 8 (57.1%) invasive tumors, and the average tumor diameter was 2.8cm. All patients underwent transsphenoidal surgery, and a near-total resection was achieved in nine (64.3%) patients. Postoperative visual acuity improved in three patients (75%). The results of immunohistochemistry showed 6 silent plurihormonal adenomas (42.9%), 3 null cell adenomas (21.4%), 3 silent lactotroph adenomas (21.4%), 1 silent gonadotroph adenoma (7.1%) and 1 silent corticotroph adenoma (7.1%). The mean follow-up was 54.8months, and five patients had tumor recurrence. Tumors with Ki-67 ≧ 2% (28.6%) showed higher recurrence rate than those with lower index (P = 0.001). Two patients received secondary surgery and radiation for recurrent tumors suffered from panhypopituitarism. Pediatric and adolescent NFPA is clinically rare, and shows potential invasiveness. The silent plurihormonal adenoma is the most frequent phenotype. Transsphenoidal surgery is as safe and effective as in adults. However, individualized care and teamwork of neurosurgeons, pediatricians, endocrinologists, and radiation oncologists are important, especially for recurrent diseases.

Nonfunctioning Pituitary Adenoma Recurrence and Its Relationship with Sex, Size, and Hormonal Immunohistochemical Profile

Tumor recurrence or incomplete resection in nonfunctioning pituitary adenomas (NFPAs) is relatively common. However, predictive factors of tumor recurrence in NFPAs are not well established. We evaluated possible factors related to tumor recurrence in a large cohort of NFPAs at a single pituitary neurosurgery center. A retrospective analysis was conducted of 410 medical records of patients with NFPAs treated by transsphenoidal surgery between 2000 and2014. Among the participants, 210 were female (51.0%). A total of 14.1% had giant adenomas. Null-cell pituitary adenomas (n= 239; 58.9%) were the most frequent, followed by silent gonadotroph adenomas (n= 112; 27.3%). Null-cell adenomas were more frequent in women (P= 0.008) and silent gonadotroph adenomas were more frequent in men (P= 0.004). Recurrence was not related to sex or age. Tumor recurrence occurred more often among silent corticotropic adenomas and giant adenomas (hazard ratio 2.45; P < 0.0001 and hazard ratio 2.35; P= 0.001, respectively). Silent thyrotrophic adenoma presented a comparable frequency of recurrence of silent corticotropic adenomas, despite having borderline significance (P= 0.07). NFPA tumors have a high heterogeneous hormonal profile and may have prognostic importance. Silent corticotropic adenomas and giant adenomas present a high rate of recurrence.

Clinical profile of silent growth hormone pituitary adenomas; higher recurrence rate compared to silent gonadotroph pituitary tumors, a large single center experience

Study and comparison of characteristics of silent growth hormone adenomas (SGHA), silent corticotroph adenomas (SCA), and silent gonadotroph adenomas (SGA) in a single institution cohort of surgically treated pituitary adenomas. Retrospective analysis of SGHA surgically resected over 10 years: SGHA was defined as no clinical or biochemical evidence of acromegaly and positive GH immunostaining. Of 814 pituitary surgeries; 2.1% (n = 17) were SGHA, 4.5% (n = 37) SCA, and 18.9% (n = 70/371; 2011-2016) SGA. Mean age at SGHA diagnosis was 43 years, with a large female predominance (82%). Mean tumor size and cavernous/sphenoid sinus invasiveness for SGHA, SCA, and SGA were 1.5 ± 1.0 cm and 25%, 2.5 ± 1.2 cm and 43%, 2.9 ± 2.0 cm and 41%, respectively (tumor size p = 0.009, SGHA vs. SGA, and invasion p; not-significant). During mean follow-up of 3.9 years, two patients (11%) developed elevated insulin-like growth factor-1 and five patients (29%) required a second surgery for tumor recurrence. Rate of surgical reintervention was similar to SCA (31%), but higher than SGA (10%) (p = 0.035, SGHA vs. SGA), and 18% underwent radiation therapy, similar to SCA (19%, p; not-significant) but higher than SGA (2.9%, p = 0.018). This is the largest single center study characterizing SGHA behavior with SGA and SCA control groups in a cohort of surgically resected pituitary adenomas. SGHA present mostly in young females, and should be closely followed due to their higher likelihood of recurrence and potential of progression to clinical acromegaly. We propose that a complete hormonal staining panel be routinely performed for all pituitary adenomas.

Null cell adenomas of the pituitary gland: an institutional review of their clinical imaging and behavioral characteristics.

The aim of the study was to establish if the null cell adenoma (NCA) forms a distinct subgroup with unique clinicopathological characteristics within the nonfunctioning pituitary adenoma group particularly in relation to the silent gonadotroph adenomas (SGAs). We identified 31 patients with the pathological diagnosis of NCA verified by routine histology and immunohistochemistry with distinct differentiation from SGAs by an established negative testing for SF-1 at the Toronto Western Hospital between December 2004 and August 2010. We reviewed their demographic data, clinical features, magnetic resonance imaging, and the histologic variables: MIB-1, FGFR4, and P27. We compared these to 63 SGAs identified within the same period. All the NCAs were macroadenomas with diameter ranging from 15-57 mm and tumor volumes between 1.95-53.5 mm(3). Preoperative cavernous sinus tumor growth was able to predict the presence of a residual after surgery (p = 0.023). Furthermore, preoperative cavernous sinus extension (p = 0.002) and negative P27 expression (p = 0.035) were able to independently predict the subsequent growth of the postoperative tumor residual. Comparing the NCA to SGA, we found that MIB-1 was higher in NCA (mean ± SD = 3.43 ± 2.76 %) compared to SGAs (mean ± SD = 2.49 ± 1.41 %) (p = 0.044). The preoperative and postoperative tumor volume doubling times (TVDTs) displayed a negative correlation in the SGA (r = -0.855, p = 0.002) while in the NCA, a positive correlation was evident (r = 0.718, p = 0.029). Our study suggests that the NCAs are a distinct group with differing behavioral characteristics from the SGAs. It also appears that the finding of cavernous sinus extension on preoperative imaging and a negative P27 expression on immunohistochemistry in NCAs may be valuable tools in predicting residual tumor growth which may impact on postoperative care.

Clinicopathological analysis of nonfunctioning pituitary adenomas in patients younger than 25 years of age

The authors evaluated the pathological and clinical characteristics of young patients with clinically nonfunctioning pituitary adenomas (NFPAs). Twenty-one patients (13 males and 8 females) with NFPAs who were 25 years of age or younger (mean 20 years, range 13-25 years) were retrospectively investigated. The following factors were examined: results of conventional light microscopy, immunohistochemistry, and electron microscopy; clinical symptoms; tumor size and invasion on MRI; and clinical course after therapeutic procedures such as surgery and adjuvant radiotherapy. Two major significant findings in young patients with NFPAs were noted. First, silent subtype 3 adenomas were common, whereas silent gonadotroph adenomas were rare. Second, silent subtype 3 adenomas in young patients tended to be clinically and radiologically aggressive. To correct the morphological diagnosis, NFPAs in young patients should be examined by immunohistochemical analysis and electron microscopy, as well as by light microscopy. The authors' results provide information that will be useful when making decisions regarding the treatment of young patients with NFPAs.

A Silent Follicle-Stimulating Hormone-Producing Pituitary Adenoma in a Teenage Male

An 18-year-old male was referred to Toranomon Hospital seeking reoperation for recurrent clinically nonfunctioning pituitary adenoma. A pituitary macroadenoma was first suspected at age 15 due to intractable headaches. Endocrine data were unremarkable except slightly elevated serum follicle-stimulating hormone (FSH). Transsphenoidal surgery done at another hospital achieved partial tumor removal but the remaining tumor regrew 2 years after surgery. The recurrent tumor was completely and selectively removed on repeat surgery at Toranomon Hospital. Pathological examination confirmed a silent FSH-producing pituitary adenoma. Forty-five patients less than 20 years old underwent transsphenoidal surgery for pituitary adenoma at Toranomon Hospital between 1993 and 2010. Of the 45 patients, 36 (80.0%) had clinically functioning adenomas and the other 9 (20.0%) had clinically non-functioning adenomas. No patients, other than the present case, had a silent gonadotroph adenoma. In contrast, among 579 patients over 20 years old undergoing surgery for nonfunctioning pituitary adenomas between 2006 and 2010 at Toranomon Hospital, 304 (52.3%) had silent gonadotroph adenomas. Gonadotroph adenomas are more common with aging: for example, 37 (61.7%) of 60 patients more than 70 years old at the time of operation had gonadotroph adenomas. In conclusion, gonadotroph adenomas, especially silent gonadotroph adenomas, are extremely rare in childhood and adolescence.

Silent Familial Isolated Pituitary Adenomas: Histopathological and Clinical Case Report

Familial isolated pituitary adenoma (FIPA) is a rare condition independent of Carney Complex or MEN1. An international multicenter study recently described 28 nonfunctioning pituitary adenomas in 26 families with only two homogeneous nonsecreting phenotype families consistent of silent GH and silent gonadotroph adenomas, respectively. We present the clinical, genetic, and morphological analysis of two silent pituitary adenomas occurring in a man and his daughter, and discuss the differential diagnosis associated with their histological, immunohistochemical, and ultrastructural features. The patients developed invasive nonsecreting macroadenomas manifesting only with compressive symptoms. Genetic analysis in the father showed no MEN-1 germ-line mutation. Tissue samples obtained after paraseptal trans-sphenoidal surgery were studied by immunohistochemistry for adenohypophyseal hormones, low molecular weight cytokeratins (CAM 5.2), proliferation markers, and anterior pituitary transcription factors (Pit-1 and SF-1) and by electron microscopy for secretory granules. The clinical, histological, and immunohistochemical features of the lesions posed a differential diagnosis between a null cell adenoma and a silent corticotroph adenoma (Type II); on the basis of immunohistochemical stains for cytokeratin and adenohypophysis cell lineage markers, tumor behavior and ultrastructural studies we concluded for the second. The reported cases represent an as yet undescribed example of homogeneous family with silent corticotroph adenomas (Type II). Our observations support the trend for more aggressive behavior in nonsecreting FIPAs as compared with sporadic adenomas.

A STUDY OF THE CORRELATION BETWEEN MORPHOLOGICAL FINDINGS AND BIOLOGICAL ACTIVITIES IN CLINICALLY NONFUNCTIONING PITUITARY ADENOMAS

The aims of this study are to review the histology of the clinically nonfunctioning pituitary adenomas (CNFPAs) we have observed and to determine whether or not the frequency of cavernous sinus invasion is different among each type of morphology. In addition, several proliferative markers, including Ki67, p53, E-cadherin, matrix metallo-proteinase 9 and pituitary tumor derived fibroblast growth factor receptor 4 (ptd-FGFR4), were also investigated in invasive and non-invasive tumors. Our consequent 213 CNFPAs were diagnosed as follows: 64% were silent gonadotroph adenomas, 18% were null cell adenomas, 12% were silent corticotroph adenomas, 4% were silent Subtype 3 adenomas, and 1% were other types of adenomas. Female patients or younger patients showed a significant preponderance in silent corticotroph adenomas and in silent Subtype 3 adenomas, respectively. Cavernous sinus invasion occurs most frequently in silent corticotroph adenomas (85%) followed by Subtype 3 adenomas (67%), null cell adenomas (38%), and silent gonadotroph adenomas (11%). There were no significant differences in the Ki67, p53, E-cadherin, matrix metallo-proteinase 9, and ptd-FGFR4 expression between tumors with and without cavernous sinus invasion. From a clinical standpoint, it is quite important to differentiate morphological type in CNFPAs to aid the clinician in assessing the clinical behavior and prognosis of the tumor. Therefore, we suggest that all CNFPAs be examined not only by conventional light microscopy but also by immunohistochemistry, preferably by electron microscopy, to achieve a correct morphological diagnosis.

Gene expression of adrenomedullin, leptin, their receptors and neuropeptide Y in hormone-secreting and non-functioning pituitary adenomas, meningiomas and malignant intracranial tumours in humans.

The aim of this study was to assess human intracranial tumours for their gene expression pattern of the vasoactive peptide adrenomedullin (AM), its receptor (AM-R) and leptin, which exerts multiple biological effects including proliferation and angiogenesis via the leptin receptor (OB-Rb). Gene activity of neuropeptide Y (NPY) was monitored additionally. We investigated whether there was a characteristic gene expression pattern of AM and leptin in different intracranial tumours, depending on their proliferation activity and biological behaviour. We investigated 35 non-functioning pituitary adenomas (including eight null cell, four silent plurihormonal, 23 silent gonadotroph adenomas), seven somatotropinomas, seven prolactinomas, eight meningiomas, five astrocytomas, two glioblastoma multiformes and unaffected temporal lobe (n = 8). Quantitative reverse transcriptase-polymerase chain reaction (TaqMan RT-PCR) was performed. AM mRNA was detectable in all tumour specimens. AM/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) ratio was significantly higher in somatotropinomas, as was AM/CD31 ratio in prolactinomas, compared with inactive adenomas (P < 0.05). AM-R mRNA was found in all tumour subgroups in small quantities but, in general, higher in tumours than in temporal lobe tissue, respectively. AM-R/CD31 ratio was significantly higher in prolactinomas than in inactive adenomas (P < 0.05). Leptin was detectable in very low quantities in each subgroup. OB-Rb gene expression was found in all tumour subgroups, OB-Rb/GAPDH ratio was highest for meningiomas (P < 0.0001, compared with temporal lobe). NPY mRNA was detectable in temporal lobe in higher quantities than in tumours (P < 0.0001), and almost undetectable in prolactinomas and astrocytomas. Our data demonstrate that AM and AM-R, NPY, as well as leptin and OB-Rb, are expressed in various intracranial tumours in humans but their particular function has to be elucidated further. At present, there is no evidence for a cross-talk on transcriptional level between the peptidergic vasodilative system AM and the putative angiogenic and proliferation affecting factor leptin.

Clinically nonsecreting pituitary adenomas in childhood and adolescence.

Clinically nonsecreting pituitary adenomas are rare in childhood and adolescence. We analyzed five cases of clinically nonsecreting pituitary adenomas in patients (4 male and 1 female patient) under 20 years of age at surgery (0.22%), identified by a review of 2288 patients with pituitary adenomas treated from 1970 to 1996 at the Hamburg University. Patient age at the onset of symptoms ranged from 8 to 13 years (mean, 10.8 yr), and age at surgery ranged from 12.5 to 19.5 years (mean, 15.5 yr). Two patients presented with endocrine symptoms, two with headache only, and one with a visual field defect. Endocrinological examinations showed pituitary insufficiency in two patients with endocrine symptoms. The serum prolactin level was normal in all patients. Radiological investigations demonstrated resectable macroadenomas with ring enhancement in four patients and a nonresectable macroadenoma with parasellar extension in one. Transnasal explorations achieved radical tumor resection except in one patient. The latter underwent a transcranial resection and radiotherapy because of parasellar tumor rest. Surgical morbidity consisted of left oculomotor nerve palsy after transcranial exploration. In two patients, normal pituitary function was preserved by transnasal surgery. Follow-up duration was 2 to 23 years (mean, 10.9 yr). There was no recurrence except for one parasellar adenoma. Immunohistological diagnosis was null cell adenoma in two patients, silent prolactinoma in two, and silent gonadotroph adenoma in one. The proliferative activity measured by Ki-67 (as the antibody MIB-1) and p53 expression revealed a positive reaction in one adenoma with parasellar extension. Clinically nonsecreting pituitary adenomas in childhood and adolescence cause different endocrine symptoms from those in adults. They caused pubertal and growth delay and/or primary amenorrhea in the patients investigated in this study. Transnasal surgery in childhood and adolescence is as safe as in adults. The characteristics of nonsecreting pituitary adenomas in this age group, including 20 patients cited from the literature, do not differ from those in adults.

Clinically Non-Functioning Human Pituitary Adenomas

Clinically non-functioning pituitary adenomas are morphologically classified into two groups, those which have hormone immunoreactivity and ultrastructural features of known adenohypophysial cell types but are clinically silent, and those composed of cells that do not resemble nontumorous adenohypophysial cell types. Among the former are the silent somatotroph adenomas, silent corticotroph adenomas and silent gonadotroph adenomas; the latter include the silent type III adenomas, null cell adenomas and oncocytomas. We review their histological, immunohistochemical and ultrastructural features, the results of in situ hybridization to determine hormone synthesis by these tumors and data obtained from tissue culture characterizing their hormone release in vitro. Non-functioning adenomas represent a heterogeneous group. The discrepancies between morphology, immunoreactivity and lack of endocrine activity of silent adenomas are not clear. Oncocytomas are variants of null cell adenomas. We suggest that null cell adenomas and oncocytomas originate in uncommitted pluripotent precursor cells capable of undergoing multidirectional differentiation. The progenitor cells differentiate most frequently toward FSH/alpha-subunit producing cells; the mechanism of preferential differentiation is obscure.

Morphological study of clinically nonsecreting pituitary adenomas in patients under 40 years of age

Clinically nonsecreting pituitary adenomas removed at surgery from 69 patients under 40 years of age were studied by histological, immunocytochemical, and transmission electron microscopic examination. By morphological analysis, 19 tumors were found to be null-cell adenomas, 17 silent gonadotroph adenomas, 14 silent subtype 3 adenomas of unknown cellular origin, 13 silent subtype 1 or subtype 2 corticotroph adenomas, three oncocytomas, and three silent thyrotroph adenomas. These results indicate that the incidence of null-cell adenomas and oncocytomas, which are known to be the most common types of nonsecreting pituitary adenomas in patients over 40 years of age, is relatively low in younger patients. This trend is even more obvious in patients younger than 30 years of age. It can be concluded that clinically nonsecreting pituitary adenomas represent a heterogeneous group morphologically, and that the incidence of the different tumor types varies depending on the patient's age. These findings underline the importance of careful morphological studies. It is proposed that, in order for the correct morphological diagnosis to be made, tumors removed surgically from patients with clinically nonsecreting pituitary adenomas (especially younger patients) should be investigated not only by histological means but also by immunocytochemical and electron microscopic examination. The information obtained from such analysis may be useful in assessing prognosis and deciding on the appropriate treatment.