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Endocrine neoplasia represents an increasingly broad spectrum of disorders. Endocrine neoplasms range from incidental findings to potentially lethal malignancies. In this paper, we cover the impact of pathology in the interpretation of the clinic-pathological, genetic, and radiographic features underpinning these neoplasms. We highlight the critical role of multidisciplinary interactions in structuring a rational diagnostic and efficient therapeutic plan and emphasize the role of histopathological input in decision-making. In this context, standardized pathology reporting and second opinion endocrine pathology review represent relevant tools to improve the overall diagnostic workup of patients affected by endocrine tumors in every specific scenario. In fact, although a relevant proportion of cases may be correctly identified based on clinical presentation and biochemical/imaging investigations, a subset of cases presents with atypical findings that may lead to an inappropriate diagnosis and treatment plan based on a wrong pathological diagnosis if all pieces of the puzzle are not correctly considered. Pathologists have a responsibility to actively guide clinicians before and during surgical procedures to prevent unnecessary interventions. In all areas of endocrine pathology, pathologists must understand the complexity of tissue preservation and assay sensitivities and specificities to ensure the optimal quality and interpretation of diagnostic material. Finally, pathologists are central actors in tumor tissue biobanking, which is an expanding field in oncology that should be promoted while adhering to strict ethical and methodological standards.

Molecular pathology has advanced our understanding of many tumors and offers opportunities to identify novel therapies. In the pituitary, the field has uncovered several genetic mutations that predispose to pituitary neuroendocrine tumor (PitNET) development, including MEN1, CDKN1B, PRKRIα, AIP, GPR101, and other more rare events; however, these genes are only rarely mutated in sporadic PitNETs. Recurrent genetic events in sporadic PitNETs include GNAS mutations in a subset of somatotroph tumors and ubiquitin-specific peptidase mutations (e.g., USP8, USP48) in some corticotroph tumors; to date, neither of these has resulted in altered management, and instead, the prognosis and management of PitNETs still rely more on cell type and subtype as well as local growth that determines surgical resectability. In contrast, craniopharyngiomas have either CTNNB1 or BRAFV600E mutations that correlate with adamantinomatous or papillary morphology, respectively; the latter offers the opportunity for targeted therapy. DICER1 mutations are found in patients with pituitary blastoma. Epigenetic changes are implicated in the pathogenesis of the more common sporadic pituitary neoplasms including the majority of PitNETs and tumors of pituicytes.

Background: Active surveillance (AS) of small, low-risk papillary thyroid cancers (PTCs) is increasingly being considered. There is limited understanding of why individuals with low-risk PTC may choose AS over traditional surgical management. Methods: We present a mixed-methods analysis of a prospective observational real-life decision-making study regarding the choice of thyroidectomy or AS for management of localized, low-risk PTCs

In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.

Objective: Graft-versus-host disease (GVHD) is an immune phenomenon that occurs in 30 to 70% of patients after allogeneic hematopoietic stem cell transplantation (HST). Chronic GVHD is a state of immune dysregulation wherein, depending on the severity and organ involved, patients may require prolonged treatment with additional or higher corticosteroids and other immunosuppressive agents. The objective of this study was to review the endocrine manifestations following HST that can arise as a consequence of the primary disease or its treatment, including chemotherapeutic agents, corticosteroids, radiation, or GVHD. Methods: We performed a narrative review of GVHD after HST. An English-language search for relevant studies was conducted on PubMed from inception to August 1, 2018, using the following search terms: "endocrine complications," "bone marrow transplantation," "graft-versus-host disease," and "GVHD." The reference lists of relevant studies were also reviewed. Results: Chronic GVHD may be associated with considerable pediatric growth impairment and may also contribute to thyroid gland dysfunction and thyroid cancer. These patients may also be at increased risk for low bone mineral density, reduced fertility, metabolic syndrome, and suppression of the pituitary-adrenal axis with adrenal insufficiency. Conclusion: This review indicates the importance of monitoring, diagnosing, and properly treating the endocrine complications in this population. More studies are needed to investigate the independent impact of GVHD on the endocrine system and treatment for complications. Abbreviations: BMD = bone mineral density; GH = growth hormone; GVHD = graft-versus-host disease; HST = hematopoietic stem cell transplantation; IGF-1 = insulin-like growth factor 1.

Background: The potential risk of subsequent malignant neoplasms (SMNs) after radioactive iodine (RAI) treatment of thyroid cancer (TC) is an important concern. Methods: A systematic review was upd...

BackgroundThe traditional management of papillary thyroid cancer (PTC) is thyroidectomy (total or partial removal of the thyroid). Active surveillance (AS) may be considered as an alternative option for small, low risk PTC. AS involves close follow-up (including regularly scheduled clinical and radiological assessments), with the intention of intervening with surgery for disease progression or patient preference.MethodsThis is a protocol for a prospective, observational, long-term follow-up multi-centre Canadian cohort study. Consenting eligible adults with small, low risk PTC (< 2cm in maximal diameter, confined to the thyroid, and not immediately adjacent to critical structures in the neck) are offered the choice of AS or surgery for management of PTC. Patient participants are free to choose either option (AS or surgery) and the disease management course is thus not assigned by the investigators. Surgery is provided as usual care by a surgeon in an institution of the patient’s choice. Our primary objective is to determine the rate of ‘failure’ of disease management in respective AS and surgical arms as defined by: i) AS arm – surgery for progression of PTC, and ii) surgical arm - surgery or other treatment for disease persistence or progression after completing initial treatment. Secondary outcomes include long-term thyroid oncologic and treatment outcomes, as well as patient-reported outcomes.DiscussionThe results from this study will provide long-term clinical and patient reported outcome evidence regarding active surveillance or immediate surgery for management of small, low risk PTC. This will inform future clinical trials in disease management of small, low risk papillary thyroid cancer.Registration detailsThis prospective observational cohort study is registered on clinicaltrials.gov (NCT04624477), but it should not be considered a clinical trial as there is no assigned intervention and patients are free to choose either AS or surgery.

BackgroundGlucocorticoid excess in Cushing disease (CD) leads to negative feedback suppression, resulting in Crooke's hyaline change (CC) of nontumorous pituitary corticotrophs. We aimed to determine the predictive value of CC of nontumorous corticotrophs in CD.MethodsThe retrospective chart review study included patients with clinical, biochemical, radiologic and outcome data and evaluable histopathology specimens from pituitary surgery for CD. The main outcome was remission of CD, defined by clinical features, biochemical testing, and corticosteroid dependency.ResultsOf 144 CD patients, 60 (50 women, mean age 43.6±14) had clinical follow-up, biochemical data and histopathology specimens that included evaluable nontumorous adenohypophysis. Specimens from 50 patients (83.3%) demonstrated CC in nontumorous corticotrophs, and 10 (16.7%) had no CC (including 3 with corticotroph hyperplasia). One patient with CC was lost to follow-up and one without CC had equivocal outcome results. During a mean (SD) follow-up period of 74.9 months (61.0), recurrent or persistent disease was documented in 18 patients (31.0%), while 40 (69.0%) were in remission. In patients with CC, the remission rate was 73.5% (95% CI, 59.7%-83.7%) (36/49), whereas it was 44.4% (95% CI, 18.9%-73.3%) (4/9) in patients with no CC. The combination of serum cortisol >138 nmol/L within a week of surgery coupled with absence of nontumorous CC greatly improved the prediction of recurrent or persistent disease.ConclusionsCC of nontumorous corticotrophs was observed in 83% of patients with CD, and most patients with CC experienced remission. Absence of CC in nontumorous corticotrophs may serve as a predictor of reduced remission in patients with CD.

The hypothalamus is functional neuroendocrine tissue that is responsible for the synthesis and secretion of peptide hormones that regulate the pituitary and other endocrine functions. Endocrine tumors of the hypothalamus are rare but they provide a model for tumors that have both structural and functional effects. Patients with hypothalamic endocrine tumors suffer mass effects including headaches, visual disturbances, and endocrine dysfunction due to structural damage to hypothalamic nuclei, which regulate appetite, temperature, diurnal rhythms and emotions. In addition, these tumors can secrete hormones that can cause acromegaly, Cushing disease, hyperprolactinemia, and the syndrome of inappropriate antidiuresis. Morphologic classification of these tumors has provided evidence for two classes of tumors, gangliocytomas that are composed of large neurons and neurocytomas that are comprised of small cells; these resemble the variants of magnocellular and parvocellular neurons in the hypothalamic nuclei. Biomarkers are used to classify these tumors and achieve accurate structure-function correlations. While surgery remains the mainstay of therapy, novel medical and radiopharmaceutical approaches are available for patients with progressive and/or unresectable tumors.

The fibroblast growth factor receptor 4 (FGFR4)-R388 single nucleotide polymorphism has been associated with cancer risk and prognosis. Here we show that the FGFR4-R388 allele yields a receptor variant which preferentially promotes STAT3/5 signaling. This STAT activation induces Grb14 transcription in pancreatic endocrine cells to modulate insulin receptor (IR) signaling and enhance insulin secretion. Knock-in mice with the FGFR4 variant allele develop pancreatic islets that secrete more insulin, a feature that is reversed through Grb14 deletion. We also show in humans that the FGFR4-R388 allele enhances islet function and may protect against type 2 diabetes. These data support a common genetic link between cancer and hyperinsulinemia.

Pituitary neuroendocrine tumors (PitNETs) : nomenclature evolution, not clinical revolution

Differentiated thyroid carcinoma of follicular cell-derivation is the most common endocrine neoplasm with a rapidly increasing incidence. The majority represent papillary carcinomas; more rarely, they are follicular carcinomas. The vast majority have indolent behavior, however a significant proportion progress to develop lymph node metastases and a smaller proportion disseminate systemically. While common and frequent genetic events have been described to underlie the development of these neoplasms, the factors contributing to differing behaviors among tumors with similar genetic alterations remain unclear. This review focuses on epigenetic mechanisms targeting major signaling pathways that underlie the spectrum of biological behaviors and that may have potential diagnostic, prognostic and therapeutic value.

Previous studies have established the common and critical involvement of the zinc finger protein Ikaros in lymphoid and pituitary cell development and expansion. Key to the assembly of several transcriptional networks, we have demonstrated up-regulation of Ikaros and its interacting partner the C-terminal Binding Protein (CtBP) in response to hypoxia. This prompted us to explore common transcriptional targets using a chromatin immunoprecipitate (ChIP) screen of DNA from pituitary corticotroph cells. This strategy yielded a finite list of targets common to both transcription factors that included the metalloprotease ADAMTS10. In this report, we focus on validation of a second candidate target, the retrotransposon gag domain containing protein Rgag4. We identified the ability of Ikaros to bind the Rgag4 promoter, influence its transcriptional activity, and induce endogenous gene expression. Robust expression of Rgag4 was noted in the anterior lobe of the pituitary gland which was diminished in Ikaros knockout mice. Down-regulation of Rgag4 resulted in profound reduction of hormone gene expression with diminished ACTH secretion, recapitulating the effect of Ikaros deficiency in knockout mice. The results introduce Rgag4 to the repertoire of effectors serving to couple the chromatin remodeler Ikaros with the hormonal stress response.

Not applicable - this is an invited Letter to Editor response (i.e. we published a paper in Thyroid, Miyauchi et al. wrote a letter to editor, and Dr. Kebebew invited us to write a response letter).

We reported that a single nucleotide polymorphism (SNP) at codon 388 of the fibroblast growth factor receptor 4 (FGFR4-Gly388Arg) can result in distinct proteins that alter pituitary cell growth and function. Here, we examined the differential properties of the available therapeutic somatostatin analogs, octreotide and pasireotide, in pituitary tumor cells expressing the different FGFR4 isoforms. Consistent with their enhanced growth properties, FGFR4-R388-expressing cells show higher mitochondrial STAT3 serine phosphorylation driving basal and maximal oxygen consumption rate (OCR) than pituitary cells expressing the more common FGFR4-G388 isoform. While both somatostatin analogs reduce the OCR in FGFR4-G388 cells, pasireotide was more effective in decreasing OCR in cells expressing the variant FGFR4-R388 isoform. Down-regulation of somatostatin receptor 5 (SSTR5) abrogated the effect of pasireotide, demonstrating its involvement in mediating this action. The effects on OCR were recapitulated by introducing a constitutively active serine STAT3 but not by a tyrosine-active mutant. Moreover, pharmacologic inhibition demonstrated the role for the phosphatase PP2A in mediating the dephosphorylation of STAT3-S727 by pasireotide. Our data indicate that FGFR4 polymorphic isoforms mediate signaling that yields mitochondrial therapeutic targets of relevance to the actions of different somatostatin analogs.

Background: Parathyroid carcinoma is rare, representing

Background: The standard of care in management of hypothyroidism is treatment with levothyroxine (L-T4). Sometimes patients are dissatisfied with L-T4 and the combination of levo-triiodothyronine (L-T3) with L-T4 is considered. Methods: We performed a systematic review and meta-analysis of blinded randomized controlled trials (RCTs), reporting how often hypothyroid patients prefer combination L-T3/L-T4 treatment to L-T4 alone. We also explored for explanatory factors for combination therapy preference in sensitivity analyses examining trial, patient, and disease characteristics. Potential dose-response relationships were explored using meta-regression analyses. We searched 9 electronic databases (from inception until February, 2019), supplemented with a hand-search. Two reviewers independently screened abstracts and citations and reviewed full-text papers, with consensus achieved on the included studies. Two reviewers independently critically appraised the quality of included studies and abstracted the data. Random effects meta-analyses were reported for the percentage of patients preferring combination L-T3/T-T4 therapy over L-T4 alone. A binomial distribution of choices (i.e., preference of combination therapy or no preference for combination therapy) was assumed. Results: We included 7 blinded RCTs including 348 hypothyroid individuals in the primary meta-analysis. The pooled prevalence rate for preference of combination therapy over L-T4 was 46.2% (95% confidence interval 40.2%, 52.4%) (p = 0.231 for the difference from chance). There was no significant statistical heterogeneity among study results (Q = 7.32, degrees of freedom = 6, p = 0.293, I2 = 18.0%). In sensitivity analyses, combination treatment preference was explained in part by treatment effects on TSH concentration, mood and symptoms, but not quality of life nor body weight. In a secondary dose-response meta-regression analyses, a statistically significant association of treatment preference was identified for total daily L-T3 dose, but not L-T3:L-T4 dose ratio. Conclusions: In conclusion, in RCTs in which patients and investigators were blinded to treatment allocation, approximately half of participants reported preferring combination L-T3 and L-T4 therapy compared to L-T4 alone; this finding was not distinguishable from chance. An observed potential positive L-T3 dose effect on treatment preference deserves further study, with careful consideration of thyroid biochemical indices and patient reported outcomes.

Immunohistochemistry (IHC) in evaluating thyroid surgical specimens may facilitate diagnostic and prognostic evaluation, with potential therapeutic implications. We performed a systematic review and meta-analysis examining the analytic validity of IHC in detecting BRAFV600E mutations in thyroid cancer (primary or metastatic). We screened citations from three electronic databases (until December 20, 2018), supplemented by a hand search of authors' files and cross-references of reviews. Citations and full-text papers were independently reviewed in duplicate, and consensus was achieved on inclusion of papers. Two reviewers independently critically appraised and abstracted data from included papers. Random-effect meta-analyses were conducted for sensitivity and specificity estimates. We reviewed 1499 unique citations and 93 full-text articles. We included 1 systematic review and 30 original articles. The published review (from 2015) needed to be updated as there were multiple subsequent original studies. The pooled sensitivity of IHC in detecting a BRAFV600E mutation was 96.8% (95% confidence interval [CI] at 94.1%, 98.3%) (29 studies, including 2659 BRAFV600E mutant tumors). The IHC pooled specificity was 86.3% (95% CI 80.7%, 90.4%) (28 studies, including 1107 BRAFV600E wild-type specimens). These meta-analyses were subject to statistically significant heterogeneity, partly explained by antibody type (sensitivity and specificity) and tissue/tumor type (specificity). In conclusion, BRAF IHC is highly sensitive and reasonably specific in detecting the BRAFV600E mutation; however, there is some variability in analytic performance.

Pituitary carcinoma is a rare disease, defined by the presence of cerebrospinal or distant metastasis of a pituitary neuroendocrine tumor (PitNET). To review our institutional experience of pituitary carcinoma, we searched the database of the UHN Endocrine Oncology Site group and the University Health Network pathology laboratory information system from 2001 to 2016. Among 1055 PitNETs from 1169 transsphenoidal resections, we identified 4 cases of pituitary carcinoma, indicating that pituitary carcinoma represents around 0.4% of PitNETs. All four patients were women. The age at initial presentation ranged from 23 to 54 years. Two patients had Cushing disease with corticotroph tumors; one was initially a densely granulated corticotroph tumor that evolved to become sparsely granulated, while the other was a Crooke cell tumor. One patient had a functioning sparsely granulated lactotroph tumor and one had a clinically silent poorly differentiated PIT1 lineage tumor. Apart from a relatively high Ki67 labeling index (≥ 10%) in three tumors, there were no cytomorphologic features at the time of initial presentation that could predict subsequent metastatic behavior. The time from diagnosis of the pituitary neuroendocrine tumor to the diagnosis of malignancy was 3 to 14 years. Therapies included somatostatin analogs, external beam radiotherapy, chemotherapies including capecitabine/temozolomide, everolimus, sunitinib, bevacizumab, and peptide receptor radionuclide therapy (PRRT). One patient died of disease 18 years after initial diagnosis, underscoring the protracted course of this ultimately fatal neuroendocrine malignancy.

Objective: To clarify the selection of medical therapy following transsphenoidal surgery in patients with acromegaly, based on growth hormone (GH)/insulin-like growth factor 1 (IGF-1) response and glucometabolic control. Methods: We carried out a systematic literature review on three of the best studied and most practical predictive markers of the response to somatostatin analogues (SSAs): somatostatin receptor (SSTR) expression, tumor morphologic classification, and T2-weighted magnetic resonance imaging (MRI) signal intensity. Additional analyses focused on glucose metabolism in treated patients. Results: The literature survey confirmed significant associations of all three factors with SSA responsiveness. SSTR expression appears necessary for the SSA response; however, it is not sufficient, as approximately half of SSTR2-positive tumors failed to respond clinically to first-generation SSAs. MRI findings (T2-hypo-intensity) and a densely granulated phenotype also correlate with SSA efficacy, and are advantageous as predictive markers relative to SSTR expression alone. Glucometabolic control declines with SSA monotherapy, whereas GH receptor antagonist (GHRA) monotherapy may restore normoglycemia. Conclusion: We propose a decision tree to guide selection among SSAs, dopamine agonists (DAs), and GHRA for medical treatment of acromegaly in the postsurgical setting. This decision tree employs three validated predictive markers and other clinical considerations, to determine whether SSAs are appropriate first-line medical therapy in the postsurgical setting. DA treatment is favored in patients with modest IGF-1 elevation. GHRA treatment should be considered for patients with T2-hyperintense tumors with a sparsely granulated phenotype and/or low SSTR2 staining, and may also be favored for individuals with diabetes. Prospective analyses are required to test the utility of this therapeutic paradigm. Abbreviations: DA = dopamine agonist; DG = densely granulated; GH = growth hormone; GHRA = growth hormone receptor antagonist; HbA1c = glycated hemoglobin; IGF-1 = insulin-like growth factor-1; MRI = magnetic resonance imaging; SG = sparsely granulated; SSA = somatostatin analogue; SSTR = somatostatin receptor.

Parathyroid carcinoma is a rare endocrine malignancy that is typically difficult to diagnose at presentation. Here, we report a 63 year-old man who had symptomatic hypercalcemia. Investigations revealed a thyroid nodule and a lateral neck mass that was biopsied and diagnosed as “suspicious for a neuroendocrine neoplasm.” He underwent total thyroidectomy with central and left neck node dissection. Histology and immunohistochemistry revealed an intrathyroidal angioinvasive parathyroid carcinoma with lymph node metastases. The tumor showed loss of parafibromin expression; germline testing revealed no pathogenic germline variants of CDC73, suggesting either a cryptic germline variant or a sporadic malignancy. Multiple pulmonary nodules consistent with metastatic disease explained persistent hypercalcemia and the patient was treated with denosumab as well as Sorafenib resulting in early regression of the lung nodules. This case illustrates an unusual parathyroid carcinoma with respect to anatomic presentation and the importance of complete pathological workup in securing the diagnosis. The management of these rare malignancies is discussed.

Neuroendocrine tumors (NETs) are increasing in incidence yet the cause of these tumors remains unknown. Familial associations have shed light on the genetic basis of some of these tumors, but sporadic tumors seem to have primarily epigenetic dysregulation. The rarity of cell lines and animal models has been a barrier to studies of treatment modalities. We set out to develop a xenograft model of gastrointestinal NETs. Primary human NETs were collected at the time of surgery under sterile conditions and xenografted into the flanks of immunodeficient mice. Tumor growth was measured and when tumors reached 1500 mm(3), they were excised and half was re-xenografted through multiple generations. The other half was bisected; a part was frozen and a part was fixed for morphologic and immunohistochemical characterization as well as molecular validation of fidelity of a successful xenograft. Of 106 human NETs, seven were successfully engrafted of which only one tumor was successfully propagated for eight passages. Two years later, the tumor retains its neuroendocrine features and similarity to the original primary human tumor. It has retained expression of keratin as well as chromogranin A reactivity. The establishment of a NET xenograft provides a model for further study of the biological behavior of these tumors and can be used to examine the in vivo effects of various medical and targeted radiotherapeutic agents on tumor growth.

We report clinicopathological features of a large series of synchronous multiple pituitary neuroendocrine tumors (PitNETs) of different cell lineages. Retrospective review of pathology records from 2001 to 2016 identified 13 synchronous multiple PitNETs from 1055 PitNETs classified using pituitary cell-lineage transcription factors, adenohypohyseal hormones, and other biomarkers. Clinical, radiological, and histopathological features of these tumors were reviewed. The series included seven females and six males. Mean age at diagnosis was 55.23 years (range 36–73). Imaging was unavailable for four patients; among the other nine, mean tumor size was 2.23 cm (range 0.9–3.9). Five patients had acromegaly, four had Cushing disease, and four had clinically non-functional tumors. Twelve had double PitNETs; one had a triple PitNET. The most common tumor type was corticotroph (n = 8; six densely and one sparsely granulated and one Crooke cell; three densely and one sparsely granulated were clinically silent), gonadotroph tumors (n = 8), and somatotroph tumors (n = 5; four sparsely granulated and one densely granulated somatotroph) were followed by lactotroph tumors (n = 4; all sparsely granulated), poorly differentiated Pit-1 lineage tumor (n = 1), and unusual plurihormonal tumor (n = 1). A 54-year-old man with Cushing disease had MEN1-driven Crooke cell and gonadotroph tumors. The triple pitNET consisted of a multilineage plurihormonal tumor associated with a gonadotroph and a sparsely granulated lactotroph tumor. The Ki67 (available from 10 specimens) ranged from 1 to 5% in individual tumors. Radiological and biochemical follow-up was available for 10 and 11 patients, respectively. Radiological tumor persistence/recurrence was identified in three patients with double PitNETs consisting of sparsely granulated lactotroph and gonadotroph tumors (n = 1), sparsely granulated somatotroph and silent corticotroph tumors (n = 1), and gonadotroph and silent corticotroph tumors (n = 1) with cavernous sinus invasion. Biochemical persistence was noted in four patients with double PitNETs consisting of sparsely granulated somatotroph and silent corticotroph tumors (n = 2), gonadotroph and Crooke cell tumors (n = 1), and densely granulated somatotroph and silent corticotroph tumors (n = 1). Multiple PitNETs represent about 1% of PitNETs and usually have hormone excess due to at least one tumor component. Clinical manifestations may be due to the minor component, especially in patients with Cushing disease. Invasive growth and aggressive histological subtypes predicted disease persistence/recurrence. This series also highlights the importance of routine application of pituitary cell lineage transcription factors along with hormones to distinguish and subtype multiple synchronous PitNETs.

Germline mutations in Von Hippel-Lindau (VHL), succinate dehydrogenase subunit B (SDHB), SDHC, and SDHD have been detected in individuals with synchronous or metachronous pheochromocytoma/paraganglioma (PHEO/PGL) and renal cell carcinoma (RCC). Most recently, FH and TMEM127 germline mutations, which are known to cause familial PHEO/PGL, have also been identified in familial RCC. We report the first case of an individual with both a PHEO and a multilocular clear cell RCC driven by a novel germline mutation in the TMEM127 gene. Morphologically, both the PHEOs and multilocular RCC were indistinguishable from those associated with VHL disease. However, at the biochemical level, the predominant adrenergic catecholamine profile distinguishes this presentation from SDH- and VHL-related PHEOs. This case justifies the prioritization of genetic testing for germline TMEM127 in individuals with RCC and PHEO with a predominantly adrenergic phenotype.

The objective of the study is to report a rare case of pancreatic neuroendocrine tumor (pNET) producing insulin and vasopressin. We describe the clinical presentation and management of a metastatic pNET with refractory hypoglycemia and progressive severe hyponatremia. A 52-year-old patient had abdominal pain leading to the diagnosis of a tumor that was initially presumed to be splenic in origin. Investigations ultimately identified a pancreatic mass that on biopsy proved to be a pNET. Eventually, he developed extensive liver metastases, and with tumor progression, he manifested hypoglycemia and severe hyponatremia. He was managed with multiple therapies including somatostatin analogue, peptide-receptor-radionuclide-therapy (PRRT), diazoxide, and everolimus; none of these therapeutic modalities was successful in controlling functional and structural progression of the tumor. Ultimately, the pNET proved fatal and autopsy confirmed widely metastatic disease that stained strongly and diffusely for vasopressin, a feature not seen in the previous liver biopsy. This case illustrates the challenges of diagnosis and management of aggressive insulin-producing pNETs and highlights the potential concomitant ectopic production of vasopressin leading to refractory hyponatremia.

Members of the College of Physicians and Surgeons of Ontario Endocrinology and Metabolism Peer Review Network have been involved in a quality improvement project to help standardize the peer assessment of physicians practicing in endocrinology and metabolism. This has included developing state-of-the-art summaries of common endocrine problems by Canadian experts in endocrinology and metabolism. These tools have been developed in response to the educational needs, as identified by peer reviewers, of practicing endocrinologists in Ontario. These pedagogical tools aim not only to standardize the documentation of the clinical performance of endocrinologists but also to make the process more transparent and to improve the quality of patient care in Ontario. This article summarizes the project and also provides the tools developed for the endocrinology and metabolism section of the College of Physicians and Surgeons of Ontario.

Genetic mutations involving oncogenes or tumor suppressor genes are relatively uncommon in human sporadic pituitary tumors. Instead, increasing evidence has highlighted frequent epigenetic alterations including DNA methylation, histone modifications, and enhanced miRNA expression. This review covers some of this evidence as it illuminates mechanisms of tumorigenesis and highlights therapeutic opportunities.

Acromegaly has traditionally been regarded as a monomorphous disorder resulting from a benign pituitary adenoma. Increasing evidence, however, is highlighting that this disorder is associated with a spectrum of morphologically distinct pituitary tumors with variable clinical, biochemical and radiologic features and differing therapeutic outcomes that are attributed to different genetic and epigenetic changes. These data underscore the need for developing a more refined clinicopathological risk stratification system and implementing personalized targeted therapeutic approaches.

The relevance of persistent posttreatment fatigue (PPF) to thyroid cancer (TC) survivor populations is not known. This article presents a scoping review, which is an overview of published research activity. Uncontrolled data suggest that PPF is one of the most common complaints in TC survivors. Furthermore, statistically significantly worse levels of fatigue were reported in TC survivors, compared with the general population or healthy controls. There was some inconsistency among PPF risk factors. More research is needed on PPF in TC survivors, including long-term prospective cohort studies, research on fatigue severity prevalence, and randomized controlled trials of treatment strategies.

Objective To review the current literature regarding dopamine agonists (DAs) and the risk of the development of cardiac valve disease. Methods PubMed searches were performed to identify all of the available published data on DAs and valve disease in patients with hyperprolactinemia. Results Most of the available echocardiographic data from patients treated for hyperprolactinemia are from case-control studies, and prospective data are limited. The majority of the studies do not support an increased risk of clinically significant valve disease in hyperprolactinemic patients treated with cabergoline. Evidence for the use of echocardiography is needed to limit unnecessary procedures and healthcare costs. Based on the published literature describing Parkinson’s disease (PD) patients, the daily and cumulative doses of cabergoline are important factors. Considerations to minimize exposure to cabergoline, such as surgical resection of adenomas or medication withdrawal in responders, may be appropriate depending on the clinical setting. Conclusion There is no conclusive evidence that cabergoline causes clinically significant cardiac valve disease at the usual doses for the treatment of hyperprolactinemia. Although current recommendations from regulatory agencies advise routine echocardiography for patients receiving cabergoline, evidence-based criteria would be useful both to identify patients at risk and generate appropriate screening protocols. (Endocr Pract. 2014;20:608-616)

The factors associated with pituitary adenoma (PA) growth rate remain unclear.The objective of the study was to establish whether the preoperative growth and extension pattern of PA can predict postoperative growth rate and recurrence in addition to whether the PA growth rate correlates with proliferation and growth factor expression.One hundred fifty-three consecutive patients who underwent surgery for pituitary adenoma from 1999 to 2011 at Toronto Western Hospital were identified.The PA growth rate was measured both pre- and postoperatively, and its association with patient demographics, magnetic resonance imaging, and histolopathological parameters was determined.The preoperative growth rate was associated with age (P = .0001), suprasellar growth (P = .003), the presence of a cyst/hemorrhage (P = .004), the mindbomb homolog-1 (P = .005), fibroblast growth factor receptor-4 positivity (P = .047), and p27 negativity (P = .007). After surgery, there were 34.6% residual volumes, which were associated with older age (P = .038) and also with growth patterns including anterior, posterior, suprasellar, and cavernous sinus extension (P = .001); 43.3% of these residuals grew and postoperative growth rate was calculated. Pre- and postoperative growth rates were correlated (r = 0.497, P = .026). Postoperative growth rate was associated with age (P = .015) and gender (P = .017).Our data suggest that the growth rate of PAs are influenced by various patient- and tumor-specific characteristics including the age and sex of the patient, the specific subtype of PA, its hormonal activity, its immunohistochemical profile including the mindbomb homolog 1 labeling index status, and its preponderance for different growth directions relative to the pituitary fossa. Furthermore, the pre- and postoperative PA growth rates were correlated, suggesting that postoperative PA growth rates can be predicted, in part, by preoperative growth rates, thus better informing postoperative outcome.

Paragangliomas are catecholamine-secreting tumors external to the adrenal glands, most commonly arising in the head and neck, followed by the abdominal and thoracic cavities. The heart is a rare location for paragangliomas to originate from, with fewer than 50 cases as described in the literature. Functional paragangliomas of the right atrium are even more unusual, with only five cases reported to date. The investigations and therapies of a 41-year-old male presenting with a clinically functional cardiac paraganglioma are discussed. We performed a detailed pathology review of the primary cardiac tumor and a lung nodule to examine morphologic changes, along with an immunohistochemical profile (chromogranin A, tyrosine hydroxylase, MIB-1, and succinate dehydrogenase subunit B (SDHB)) of both tumors. Genetic testing of germline mutations in SDH genes was also completed. Both the 9.5-cm cardiac mass and 0.5-cm lung nodule were positive for chromogranin A and tyrosine hydroxylase and showed a global loss of SDHB expression. The MIB-1 labeling index of the smaller lesion and the bulk of the larger lesion was5 %, but there were cellular foci of the larger lesion that had a labeling index of 10%. Genetic testing yielded an intronic frameshift mutation in the SDHC gene, c.IVS 5 + 1, G A. We report the first case of a functional cardiac paraganglioma associated with an intronic frameshift SDHC gene mutation.

Silent corticotroph adenomas (SCAs) represent a distinct subset of clinically non-functioning pituitary adenomas. There are two variants of SCA; type I are densely granulated basophilic tumors and type II are sparsely granulated and chromophobic tumors. SCAs are known to be aggressive than the more common non-functioning gonadotroph adenomas (NFGAs). Cell-matrix interactions play an important role in the pathogenesis of pituitary adenomas. In this study, we compared 19 SCAs and 50 NFGAs with known fibroblast growth factor receptor-4 (FGFR4) status using semi-quantitative immunohistochemistry to localize β1-integrin, osteopontin, and matrix metalloproteinase-1 (MMP-1) as cytoplasmic, membranous, or mixed cytoplasmic-membranous staining to achieve scores of 1-4. Staining for β1-integrin was significantly higher in SCAs (100 %, score 3.3) than in NFGAs (96 %; score 2.6) (p = 0.0482); there was no statistical difference within subgroups of SCA (type II score 3.4; type I score 2.8) (p = 0.2663). Osteopontin immunoreactivity was also higher in SCAs (100 %, score 3.7) than in NFGAs (42 %, score 0.8) (p = 0.0001); there was no statistical difference within subgroups of SCA (type II score 3.6; type I score 3.9) (p = 0.2787). In contrast, MMP-1 immunoreactivity was lower in SCAs (89 %; score 2.5) than in NFGAs (98 %; score 3.6) (p = 0.0005); there was no statistical difference within subgroups of SCA (type II score 2.7; type I score 2.0) (p = 0.30704). The MMP-1 results correlated with FGFR4 expression (NFGA 96 %, type II SCA 71 %, type I SCA 40 %). Our data indicate that the biological aggressivity of SCAs compared with NFGA may be due to high osteopontin expression; in contrast, high MMP-1 is characteristic of NFGAs that also express more FGFR4. Further investigations are warranted to clarify the underlying regulatory mechanisms of these markers. The high osteopontin or FGFR4/MMP-1 expression levels in SCAs and NFGAs, respectively, indicate the potential for therapeutic strategies targeting osteopontin or FGFR4/MMP-1 for inoperable tumors of these types.

We have previously described the expression and up-regulation of the C-terminal Binding Protein (CtBP) in response to pituitary hypoxia. This co-repressor interacts with the hematopoietic factor Ikaros to target several components implicated in cellular growth and apoptotic pathways. To identify common transcriptional pituitary targets we performed promoter arrays using Ikaros and CtBP chromatin immunoprecipitated (ChIP) DNA from pituitary AtT20 cells. This approach yielded a finite list of gene targets common to both transcription factors. Of these, the metalloprotease ADAMTS10 emerged as a validated target. We show the ability of Ikaros to bind the ADAMTS10 promoter, influence its transfected activity, and induce endogenous gene expression. ADAMTS10 is expressed in primary pituitary cells and is down-regulated in Ikaros null mice. Further, knockdown of ADAMTS10 in AtT20 cells recapitulates the impact of Ikaros deficiency on POMC/ACTH hormone expression. These results uncover a novel role for the metalloprotease ADAMTS10 in the pituitary. Additionally, they position this metalloprotease as a potential functional integrator of the Ikaros-CtBP chromatin remodeling network.

In the majority of cases, Cushing’s disease is the result of a small basophilic corticotroph microadenoma with an average size of less than 5 mm. Transsphenoidal microsurgery can cure patients with Cushing’s disease; however, selective removal of the lesion requires precise preoperative localization. In this article, we present the pathological findings and clinical outcomes of four patients who underwent inferior petrosal sinus sampling (IPSS) for ACTH, pituitary imaging and subsequent transsphenoidal surgery for the diagnosis and treatment of Cushing’s disease. All patients fulfilled accepted biochemical criteria for the diagnosis of ACTH-dependent Cushing’s syndrome. Histological examination revealed a basophilic corticotroph adenoma in two patients. In one other patient, only Crooke’s hyalinization was found; however, the patient achieved a complete clinical and biochemical remission following a hemihypophysectomy based on IPSS findings. Thus, a microadenoma was assumed or proven in three patients, of whom two were cured by surgery alone. In the third patient, cortisol excess persisted following transsphenoidal surgery because of a coexistent functioning adrenal adenoma. The fourth patient developed recurrent nodular corticotroph hyperplasia following a 17-yr remission. The second transsphenoidal procedure failed to ameliorate cortisol excess, necessitating a subsequent bilateral adrenalectomy. IPSS accurately localized the site of the lesion in all four cases. Although magnetic resonance imaging (MRI) identified a distinct lesion in three cases, two of these represented false positives (a cyst in one case and a prolactinoma in the other), whereas in only one did MRI correctly match the site of the lesion. In each case, conflicting test results and/or difficult management decisions posed a challenge. Thus, successful resolution of disease requires a multidisciplinary approach to validate clinical, biochemical, and radiographic data based on morphologic findings.

A 41-yr-old patient with a history of von Hippel-Lindau (VHL) disease with previously removed bilateral pheochromocytomas and renal cell carcinoma presented with progressive obstructive jaundice due to multiple lesions in the pancreas. The pancreatectomy specimen showed a range of endocrine lesions including islet hyperplasia, nesidioblastosis, microadenomas, and endocrine carcinoma. In addition, some of the non-tumorous islets displayed peliosis. The endocrine carcinoma showed a biphasic pattern composed of typical endocrine cells and oncocytes. The oncocytic component showed widespread lymphovascular invasion and lymph node metastasis. Immunohistochemistry and electron microscopy confirmed that the oncocytic cells were endocrine. Focal areas contained cells with foamy cytoplasm, a feature that is associated with pancreatic endocrine tumors in VHL. This case expands the spectrum of lesions seen in the pancreas of VHL patients. There is some overlap with lesions encountered in multiple endocrine neoplasia type I. In addition, the endocrine lesions were composed of two main cell types (typical and oncocytic cells) with the oncocytic component invading lymphatic channels and spreading to regional lymph nodes.

The proteoglycan neuron-glial antigen 2 (NG2) is expressed by oligodendrocyte progenitors, pericytes, and some cancerous cells where it is implicated in tumor development. We examined mice with NG2-driven pRb inactivation. Unexpectedly,NG2-Cre:pRbflox/floxmice developed pituitary tumors with high penetrance. Adenohypophysial neoplasms developed initially as multifocal lesions; by 1 year, large tumors showed brain invasion. Immunohistochemistry identified these as Pit1-lineage neoplasms, with variable immunoreactivity for growth hormone, prolactin, thyrotropin, and α-subunit of glycoprotein hormones. Other than modest hyperprolactinemia, circulating hormone levels were not elevated. To determine the role of NG2 in the pituitary, we investigated NG2 expression. Immunoreactivity was identified in anterior and posterior lobes but not in the intermediate lobe of the mouse pituitary; in the adenohypophysis, folliculostellate cells had the strongest NG2 immunoreactivity but showed no proliferation in response to Rb inactivation. Pit1-positive adenohypophysial cells were positive for NG2, but corticotroph and gonadotroph cells were negative. RT-PCR revealed NG2 expression in normal human pituitary and human pituitary tumors; immunohistochemistry localized NG2 in nontumorous human adenohypophysis with strongest positivity in folliculostellate cells, and in tumors of all types except corticotrophs. Functional studies in GH4 mammosomatotrophs showed that NG2 increases prolactin (PRL), reduces growth hormone (GH) expression, and enhances cell adhesion without influencing proliferation. In conclusion, NG2-driven pRb inactivation results in pituitary tumors that mimic endocrinologically inactive Pit1-lineage human pituitary tumors. This model identifies a role for NG2 in pituitary cell-type-specific functions and unmasks a protective role from Rb inactivation in folliculostellate cells; it can be used for further research, including preclinical testing of novel therapies.

Pituitary adenomas exhibit a wide range of behaviors. The prediction of aggressive or malignant behavior in pituitary adenomas remains challenging; however, the utility of biomarkers is rapidly evolving. In this review, we discuss potential biomarkers as they relate to aggressive behavior in pituitary adenomas. While detailed histological subtyping remains the best independent predictor of aggressive behavior in the majority of cases, evidence suggests that the additional analyses of FGFR4, MMP, PTTG, Ki-67, p53, and deletions in chromosome 11 may contribute to decisions concerning management of aggressive pituitary adenomas.

Nonfunctioning pituitary adenomas (NFPA) are the most common pituitary neoplasms. There is no clinical, biochemical, or histopathological marker that would accurately predict recurrence of NFPA.The aim of this study was to evaluate a large group of NFPA for the presence of potential markers of biological behavior.A cross-sectional study using a high throughput tissue microarray technology was conducted at tertiary care centers.Seventy-four gonadotroph and null cell adenomas were included in the tissue microarray. Using highly specific antibodies and appropriate controls, we determined the expression of Ki-67, pituitary tumor transforming gene 1, the N-terminally truncated pituitary tumor-derived fibroblast growth factor receptor-4 (FGFR4), as well as somatostatin receptor subtypes 2, 3, and 5 (SSTR2, -3, and -5), in an attempt to establish correlations and/or associations with clinical characteristics of the patients.Median Ki-67 index was 1.49 (interquartile range, 0.62-2.49). Pituitary tumor transforming gene 1 nuclear immunoreactivity was found in all but one tumor (median percentage of positive nuclei, 11.44); immunopositivity for FGFR4 was found in the majority of the tumors, with variable levels of expression. The immunostaining score for SSTR2 was significantly higher than that for SSTR3 or SSTR5. FGFR4 expression correlated positively with SSTR2 and SSTR5 immunostaining scores (r = 0.59; P0.001; and r = 0.46; P0.001, respectively). Multivariate analysis revealed that the Ki-67 index was significantly associated with a tumor size greater than 3 cm (odds ratio, 2.32; 95% confidence interval, 1.17-4.58) as well as with tumor recurrence (odds ratio, 1.4; 95% confidence interval, 1.03-1.89).Ki-67 is the most consistent marker of biological behavior in NFPA. The finding of significant amounts of SSTR2 and SSTR5 may have therapeutic implications regarding the use of somatostatin analogs in preventing tumor recurrence.

Alternate splicing yields two distinct isoforms of the fibroblast growth factor (FGF) receptor FGFR2-IIIb and FGFR2-IIIc varying their extracellular structure in human thyroid cancer, in which FGFR expression is commonly dysregulated. In this study, we characterized the function of these variants in modulating thyroid cancer behavior. Enforced expression of either FGFR2-IIIb or FGFR2-IIIc in thyroid epithelial cancer cells reduced expression of fibronectin, MAGE-A3 and MMP9, while increasing p21 and enhancing Rb dephosphorylation. Consistent with these tumor-suppressive properties, FGFR2-IIIb and FGFR2-IIIc each diminished invasive behavior in vitro and reduced tumor growth and metastasis in vivo. Notably, these effects contrasted with those produced by expression of these FGFR isoforms in fibroblasts, in which they both stimulated cell growth. Moreover, in xenograft tumors generated by coimplantation of epithelial and fibroblast cells expressing that same isoform, there was no significant effect on tumor progression. Conversely, FGFR2-IIIb expression in epithelial cells yielded higher FGF4/FGF7 expression that, in the presence of FGFR2-IIIc–expressing fibroblasts, enhanced tumor progression. Together, our findings highlight the importance of cellular context in assigning growth properties to growth factor receptor isoforms. More specifically, they show how alternative splicing of FGFR2 yields heteroisoforms critical to the growth-promoting actions of FGFs that exert distinct epithelial–stromal effects in thyroid cancer. Cancer Res; 72(8); 2017–27. ©2012 AACR.