A proposed clinical classification for pituitary neoplasms to guide therapy and prognosis.

No comprehensive classification system that guides prognosis and therapy of pituitary adenomas exists. The 2022 WHO histopathology-based classification system can only be applied to lesions that are resected, which represent few clinically significant pituitary adenomas. Many factors independent of histopathology provide mechanistic insight into causation and influence prognosis and treatment of pituitary adenomas. We propose a new approach to guide prognosis and therapy of pituitary adenomas by integrating clinical, genetic, biochemical, radiological, pathological, and molecular information for all adenomas arising from anterior pituitary cell lineages. The system uses an evidence-based scoring of risk factors to yield a cumulative score that reflects disease severity and can be used at the bedside to guide pituitary adenoma management. Once validated in prospective studies, this simple manageable classification system could provide a standardised platform for assessing disease severity, prognosis, and effects of therapy on pituitary adenomas.

Stereotactic radiosurgery for the treatment of a distant recurrence of ependymoma on the optic nerve: illustrative case.

BACKGROUND: Ependymomas rarely disseminate to other central nervous system areas distant from the original site. Stereotactic radiosurgery (SRS) provides high control rates for recurring ependymomas. The treatment of optic nerve tumors carries high morbidity, but SRS is an acceptable option to manage these cases to reduce risks. OBSERVATIONS: The authors report the case of a 31-year-old male with a cervical spinal ependymoma who had a disseminated pattern of recurrence including the optic nerve after initial resection of the cervical lesion. The optic nerve tumor was treated with SRS, and the authors discuss the technical aspects of the treatment and its outcomes. At the last follow-up, the optic nerve tumor was controlled with SRS, and visual function was preserved. LESSONS: High-grade ependymomas such as the one in the presented case can have unpredictable patterns of recurrence. SRS provides excellent control of the distant recurring ependymoma with a low complication profile given the location of the tumor in this case.

Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide.

PURPOSE: The purpose of this study was to determine the safety, feasibility, and immunologic responses of treating grade 4 astrocytomas with multiple infusions of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed T cells (EGFR BATs) in combination with radiation and chemotherapy. METHODS: This phase I study used a 3 + 3 dose escalation design to test the safety and feasibility of intravenously infused EGFR BATs in combination with radiation and temozolomide (TMZ) in patients with newly diagnosed grade 4 astrocytomas (AG4). After finding the feasible dose, an expansion cohort with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) tumors received weekly EGFR BATs without TMZ. RESULTS: The highest feasible dose was 80 × 109 EGFR BATs without dose-limiting toxicities (DLTs) in seven patients. We could not escalate the dose because of the limited T-cell expansion. There were no DLTs in the additional cohort of three patients with unmethylated MGMT tumors who received eight weekly infusions of EGFR BATs without TMZ. EGFR BATs infusions induced increases in glioma specific anti-tumor cytotoxicity by peripheral blood mononuclear cells (p < 0.03) and NK cell activity (p < 0.002) ex vivo, and increased serum concentrations of IFN-γ (p < 0.03), IL-2 (p < 0.007), and GM-CSF (p < 0.009). CONCLUSION: Targeting AG4 with EGFR BATs at the maximum feasible dose of 80 × 109, with or without TMZ was safe and induced significant anti-tumor-specific immune responses. These results support further clinical trials to examine the efficacy of this adoptive cell therapy in patients with MGMT-unmethylated GBM. CLINICALTRIALS: gov Identifier: NCT03344250.

Co-occurrence of Functional Gonadotroph Adenoma and Lactotroph Adenoma: A Case Report and Literature Review.

Background/Objective: Functional gonadotroph adenomas (FGAs) are adenomas producing active gonadotropins, follicle-stimulating hormone or luteinizing hormone. Double pituitary adenomas are 2 distinct adenomas occurring in an individual. This report aimed to present an extremely rare case of an FGA, itself an uncommon disorder, co-occurring with a lactotroph adenoma. Case Report: A 33-year-old woman presented with menorrhagia and was found to have ovarian enlargement, large uterine leiomyomas, and bitemporal hemianopsia. Initially, the levels of follicle-stimulating hormone, luteinizing hormone, estradiol, and prolactin were 73.3 mIU/mL (midcycle peak, 2.3-20.9 mIU/L), 3.74 mIU/L (midcycle peak, 8.7-76.3 mIU/L), 1071 pg/mL (midcycle peak 38-649 pg/mL), and 402 ng/mL (2-30 ng/mL), respectively. Pituitary magnetic resonance imaging demonstrated a single sellar mass (2.0 × 2.2 cm). Two months of cabergoline did not reverse visual field deficits; therefore, transsphenoidal resection was performed. Diagnosis of 2 separate adenomas, a gonadotroph and lactotroph adenoma, was confirmed on pathology. Discussion: In this case, gonadotropins did not suppress in response to hyperprolactinemia. Although marked hyperprolactinemia has been associated with functional and clinically silent gonadotroph adenomas in prior cases, this is the first case to confirm an FGA co-occurring with a lactotroph adenoma. Conclusion: In patients who present with elevated gonadotropin levels despite hyperprolactinemia, we suggest considering FGA. Further research is needed to clarify whether there is underdiagnosis of lactotroph adenomas co-occurring with gonadotroph adenomas.

Impact of histopathological classification of non-functioning adenomas on long term outcomes: comparison of the 2004 and 2017 WHO classifications.

PURPOSE: Outcomes of patients with non-functioning pituitary adenomas categorized using the 2004 and 2017 WHO classification systems are understudied. We report outcomes from the University of Virginia of patients with non-functioning pituitary adenomas categorized using both systems. METHODS: We constructed a database from all 239 patients who underwent resection of a non-functioning pituitary adenoma between 2003 and 2015 and had at least 5 years of follow-up. Pathologic diagnosis was determined under both the 2004 and 2017 WHO classification systems. We compared the rates of recurrence and progression between subtypes using univariate and multivariate Cox regression analyses. RESULTS: Nearly 30% of the tumors in our database were classified as null cell adenomas under the 2004 classification system, whereas only 10% of the tumors were classified as null cell adenomas using the 2017 classification system. Most of these tumors were reclassified as either corticotroph or gonadotroph adenomas. Despite our relatively large cohort and average follow-up of nearly 9 years, we did not detect a significant difference in recurrence and progression between subtypes. CONCLUSIONS: The majority of null cell adenomas diagnosed under the 2004 WHO classification system are reclassified as gonadotroph or corticotroph adenomas under the 2017 WHO classification system. Rates of progression and recurrence between subtypes are not as different as previously believed at our institution and require a larger cohort to further investigate.

Gamma-Aminobutyric Acid A Receptor Subunit Expression and Cellular Localization in the Human Parkinsonian Globus Pallidus.

BACKGROUND: The gamma-aminobutyric acid A (GABAA) receptor is an important mediator of cellular signaling in the globus pallidus and might be implicated in the pathophysiology of Parkinson disease (PD). The goal of the present study was to characterize GABAA receptor subunit expression in the normal and parkinsonian human globus pallidus. METHODS: Postmortem brain specimens were obtained from 8 patients with pathological evidence of PD at autopsy and from 4 control patients without such evidence. These tissues were exposed to primary antibodies directed against the α1 and α3 subunits of the GABAA receptor and were visualized and quantified using fluorescence microscopy. RESULTS: No differences were found in the pallidal neuronal density in the control versus PD tissues. Projection neurons strongly expressed the α1, α3, and ß2 GABAA receptor subunits. After normalizing the immunofluorescence intensities in the globus pallidus to those in the adjacent structures, no significant differences were found in GABAA receptor subunit expression in the globus pallidus between the PD specimens and the control specimens. CONCLUSIONS: Compensatory changes in GABAA receptor α1 and α3 subunit expression in response to PD-related signaling abnormalities in the globus pallidus did not occur in our PD cohort.

Clinical Biology of the Pituitary Adenoma.

All endocrine glands are susceptible to neoplastic growth, yet the health consequences of these neoplasms differ between endocrine tissues. Pituitary neoplasms are highly prevalent and overwhelmingly benign, exhibiting a spectrum of diverse behaviors and impact on health. To understand the clinical biology of these common yet often innocuous neoplasms, we review pituitary physiology and adenoma epidemiology, pathophysiology, behavior, and clinical consequences. The anterior pituitary develops in response to a range of complex brain signals integrating with intrinsic ectodermal cell transcriptional events that together determine gland growth, cell type differentiation, and hormonal production, in turn maintaining optimal endocrine health. Pituitary adenomas occur in 10% of the population; however, the overwhelming majority remain harmless during life. Triggered by somatic or germline mutations, disease-causing adenomas manifest pathogenic mechanisms that disrupt intrapituitary signaling to promote benign cell proliferation associated with chromosomal instability. Cellular senescence acts as a mechanistic buffer protecting against malignant transformation, an extremely rare event. It is estimated that fewer than one-thousandth of all pituitary adenomas cause clinically significant disease. Adenomas variably and adversely affect morbidity and mortality depending on cell type, hormone secretory activity, and growth behavior. For most clinically apparent adenomas, multimodal therapy controlling hormone secretion and adenoma growth lead to improved quality of life and normalized mortality. The clinical biology of pituitary adenomas, and particularly their benign nature, stands in marked contrast to other tumors of the endocrine system, such as thyroid and neuroendocrine tumors.

Intracranial mesenchymal tumors with FET-CREB fusion are composed of at least two epigenetic subgroups distinct from meningioma and extracranial sarcomas.

'Intracranial mesenchymal tumor, FET-CREB fusion-positive' occurs primarily in children and young adults and has previously been termed intracranial angiomatoid fibrous histiocytoma (AFH) or intracranial myxoid mesenchymal tumor (IMMT). Here we performed genome-wide DNA methylation array profiling of 20 primary intracranial mesenchymal tumors with FET-CREB fusion to further study their ontology. These tumors resolved into two distinct epigenetic subgroups that were both divergent from all other analyzed intracranial neoplasms and soft tissue sarcomas, including meningioma, clear cell sarcoma of soft tissue (CCS), and AFH of extracranial soft tissue. The first subgroup (Group A, 16 tumors) clustered nearest to but independent of solitary fibrous tumor and AFH of extracranial soft tissue, whereas the second epigenetic subgroup (Group B, 4 tumors) clustered nearest to but independent of CCS and also lacked expression of melanocytic markers (HMB45, Melan A, or MITF) characteristic of CCS. Group A tumors most often occurred in adolescence or early adulthood, arose throughout the neuroaxis, and contained mostly EWSR1-ATF1 and EWSR1-CREB1 fusions. Group B tumors arose most often in early childhood, were located along the cerebral convexities or spinal cord, and demonstrated an enrichment for tumors with CREM as the fusion partner (either EWSR1-CREM or FUS-CREM). Group A tumors more often demonstrated stellate/spindle cell morphology and hemangioma-like vasculature, whereas Group B tumors more often demonstrated round cell or epithelioid/rhabdoid morphology without hemangioma-like vasculature, although robust comparison of these clinical and histologic features requires future study. Patients with Group B tumors had inferior progression-free survival relative to Group A tumors (median 4.5 vs. 49 months, p = 0.001). Together, these findings confirm that intracranial AFH-like neoplasms and IMMT represent histologic variants of a single tumor type ('intracranial mesenchymal tumor, FET-CREB fusion-positive') that is distinct from meningioma and extracranial sarcomas. Additionally, epigenomic evaluation may provide important prognostic subtyping for this unique tumor entity.

Melanoma brain metastasis mimicking cortical laminar necrosis.

Background: Metastatic lesions to the brain are common in patients with melanoma. Imaging characteristics can support the diagnosis of metastatic melanoma, but alternative diagnoses should be considered. Case Description: Here, we present a case of a 57-year-old man in whom a metastatic melanoma initially mimicked the imaging characteristics of cortical laminar necrosis. Conclusion: This comprises the first report of melanoma brain metastasis presenting with these imaging characteristics and emphasizes the importance of maintaining a high index of suspicion for metastatic lesions in patients with known cancer.

Genetic and epigenetic characterization of posterior pituitary tumors.

Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.

Predictors of early, recurrent, and intractable seizures in low-grade glioma.

BACKGROUND: Seizures are common among patients with low-grade glioma (LGG) and can significantly affect morbidity. We sought to determine the association between the clinical and molecular factors with seizure incidence and refractoriness in LGG patients. METHODS: We conducted a retrospective review at the University of Virginia in patients with LGG (World Health Organization, WHO Grade II) evaluated between 2002 and 2015. Descriptive statistics were calculated for variables of interest, and the Kaplan-Meier method was used to estimate survival curves, which were compared with the log-rank test. RESULTS: A total of 291 patients were included; 254 had molecular testing performed for presence of an isocitrate dehydrogenase (IDH) mutation and/or 1p/19q codeletion. Sixty-eight percent of patients developed seizures prior to LGG diagnosis; 41% of all patients had intractable seizures. Using WHO 2016 integrated classification, there was no significant difference in seizure frequency during preoperative and postoperative periods or in developing intractable seizures, though a trend toward increased preoperative seizure incidence among patients with the IDH mutation was identified (P = .09). Male sex was significantly associated with higher seizure incidence during preoperative (P < .001) and postoperative periods (P < .001); men were also more likely to develop intractable seizures (P = .01). CONCLUSIONS: Seizures are common among patients with LGG. Differences in preoperative or postoperative and intractable seizure rates by WHO 2016 classification were not detected. Our data showed a trend toward higher seizure incidence preoperatively in patients with IDH-mutant LGG. We describe a unique association between male sex and seizure incidence and intractability that warrants further study.

Fluid attenuation in non-contrast-enhancing tumor (nCET): an MRI Marker for Isocitrate Dehydrogenase (IDH) mutation in Glioblastoma.

PURPOSE: The WHO 2016 update classifies glioblastomas (WHO grade IV) according to isocitrate dehydrogenase (IDH) gene mutation status. We aimed to determine MRI-based metrics for predicting IDH mutation in glioblastoma. METHODS: This retrospective study included glioblastoma cases (n = 199) with known IDH mutation status and pre-operative MRI (T1WI, T2WI, FLAIR, contrast-enhanced T1W1 at minimum). Two neuroradiologists determined the following MRI metrics: (1) primary lobe of involvement (frontal or non-frontal); (2) presence/absence of contrast-enhancement; (3) presence/absence of necrosis; (4) presence/absence of fluid attenuation in the non-contrast-enhancing tumor (nCET); (5) maximum width of peritumoral edema (cm); (6) presence/absence of multifocal disease. Inter-reader agreement was determined. After resolving discordant measurements, multivariate association between consensus MRI metrics/patient age and IDH mutation status was determined. RESULTS: Among 199 glioblastomas, 16 were IDH-mutant. Inter-reader agreement was calculated for contrast-enhancement (ĸ = 0.49 [- 0.11-1.00]), necrosis (ĸ = 0.55 [0.34-0.76]), fluid attenuation in nCET (ĸ = 0.83 [0.68-0.99]), multifocal disease (ĸ = 0.55 [0.39-0.70]), and primary lobe (ĸ = 0.85 [0.80-0.91]). Mean difference for peritumoral edema width between readers was 0.3 cm [0.2-0.5], p < 0.001. Multivariate analysis uncovered significant associations between IDH-mutation and fluid attenuation in nCET (OR 82.9 [19.22, ∞], p < 0.001), younger age (OR 0.93 [0.86, 0.98], p = 0.009), frontal lobe location (OR 11.08 [1.14, 352.97], p = 0.037), and less peritumoral edema (OR 0.15 [0, 0.65], p = 0.044). CONCLUSIONS: Conventional MRI metrics and patient age predict IDH-mutation status in glioblastoma. Among MRI markers, fluid attenuation in nCET represents a novel marker with high inter-reader agreement that is strongly associated with Glioblastoma, IDH-mutant.

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.

Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.

Automated apparent diffusion coefficient analysis for genotype prediction in lower grade glioma: association with the T2-FLAIR mismatch sign.

PURPOSE: The prognosis of lower grade glioma (LGG) patients depends (in large part) on both isocitrate dehydrogenase (IDH) gene mutation and chromosome 1p/19q codeletion status. IDH-mutant LGG without 1p/19q codeletion (IDHmut-Noncodel) often exhibit a unique imaging appearance that includes high apparent diffusion coefficient (ADC) values not observed in other subtypes. The purpose of this study was to develop an ADC analysis-based approach that can automatically identify IDHmut-Noncodel LGG. METHODS: Whole-tumor ADC metrics, including fractional tumor volume with ADC > 1.5 × 10-3mm2/s (VADC>1.5), were used to identify IDHmut-Noncodel LGG in a cohort of N = 134 patients. Optimal threshold values determined in this dataset were then validated using an external dataset containing N = 93 cases collected from The Cancer Imaging Archive. Classifications were also compared with radiologist-identified T2-FLAIR mismatch sign and evaluated concurrently to identify added value from a combined approach. RESULTS: VADC>1.5 classified IDHmut-Noncodel LGG in the internal cohort with an area under the curve (AUC) of 0.80. An optimal threshold value of 0.35 led to sensitivity/specificity = 0.57/0.93. Classification performance was similar in the validation cohort, with VADC>1.5 ≥ 0.35 achieving sensitivity/specificity = 0.57/0.91 (AUC = 0.81). Across both groups, 37 cases exhibited positive T2-FLAIR mismatch sign-all of which were IDHmut-Noncodel. Of these, 32/37 (86%) also exhibited VADC>1.5 ≥ 0.35, as did 23 additional IDHmut-Noncodel cases which were negative for T2-FLAIR mismatch sign. CONCLUSION: Tumor subregions with high ADC were a robust indicator of IDHmut-Noncodel LGG, with VADC>1.5 achieving > 90% classification specificity in both internal and validation cohorts. VADC>1.5 exhibited strong concordance with the T2-FLAIR mismatch sign and the combination of both parameters improved sensitivity in detecting IDHmut-Noncodel LGG.

World Health Ozganization 2017 Classification of Pituitary Tumors.

The 2017 (fourth edition) World Health Organization Classification of Endocrine Tumors has recommended major changes in classification of tumors of the pituitary gland and region. In addition to the accurate tumor subtyping, assessment of the tumor proliferative potential (mitotic and/or Ki-67 index) and other clinical parameters such as tumor invasion is strongly recommended in individual cases for consideration of clinically aggressive adenomas. It is expected that this new WHO classification will establish more uniform biologically and clinically groups of pituitary tumors and contribute to understanding of clinical outcomes for patients harboring pituitary tumors.

Liver metastases from pituitary carcinomas mimicking visceral well-differentiated neuroendocrine tumors: a series of four cases.

BACKGROUND: Pathologists frequently encounter neuroendocrine tumors (NETs) presenting as multiple liver masses in routine practice. Most often, these are well-differentiated tumors with characteristic histologic features. In contrast, pituitary carcinoma is very rare, and there is limited data on its natural history and pathologic characterization. METHODS: The aim of this study was to describe clinical characteristics, histomorphology, immunophenotype and follow-up of pituitary carcinoma involving the liver and mimicking well-differentiated NETs of visceral origin. We selected a group of well-differentiated NETs of the pancreas to use as immunophenotypic controls. We identified 4 patients (age range, 51 to 73) with pituitary corticotroph carcinoma with liver metastases. Three patients presented with Cushing syndrome. RESULTS: All cases histologically resembled well-differentiated NETs of visceral origin with Ki-67 proliferation indices of 5-42% and expression of T-PIT; metastatic tumors were not immunoreactive with CDX2, Islet 1 or TTF-1. CONCLUSIONS: Frequently, these cases display adrenocorticotropic hormone (ACTH) secretion and pituitary-specific transcription factor immunohistochemistry may be used as a reliable marker to distinguish metastatic pituitary carcinoma from NETs of visceral origin in addition to delineating a corticotroph carcinoma from somatotroph, lactotroph, thyrotroph, and gonadotroph lineage. Although rare, the differential diagnosis of pituitary carcinoma should be considered in metastatic well-differentiated NETs in which the site of origin is uncertain. In summary, pituitary corticotroph carcinoma can metastasize to the liver and mimic well-differentiated NET.

Pathology of prolactinomas: any predictive value?

Lactotroph adenomas, also called prolactinomas and prolactin-secreting adenomas, constitute nearly 80% of functioning pituitary tumors and about 30-50% of all adenomas in the clinical practice. Lactotroph adenomas occur in the general population at a prevalence of 45/100,000, are more common in women, but also involve men and children of both sexes. Most lactotroph adenomas are microadenomas occurring in reproductive-age women who present with oligo/amenorrhea, galactorrhea, and infertility. In men and elderly women, lactotroph adenomas are usually macroadenomas and are most commonly associated with symptoms of a tumoral mass, including headaches, neurologic defects, and visual loss. Although clinical and laboratory features may differ depending on patient's gender and age, the histopathology of the tumors is similar. Lactotroph adenomas are histologically classified into three subtypes: the common sparsely granulated lactotroph adenoma, and the rare densely granulated lactotroph adenoma and acidophilic stem cell adenoma. We will review the main pathological features of the lactotroph adenomas and some of their characteristics that may predict biological behavior and responsiveness to treatment.