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Introduction Endoscopic endonasal approaches (EEAs) provide improved access and operative visualization for resection of pituitary adenomas. Although the technique has gained wide acceptance, there is a paucity of data regarding late recurrence. Objective We aim to assess long-term outcomes of patients with nonfunctioning pituitary adenomas (NFPAs) who underwent EEA. Methods We reviewed 269 patients operated on for an NFPA between 2005 and 2015. Clinical and radiologic factors including those potentially related to higher chances of recurrence were analyzed. Progression-free survival was analyzed using the Kaplan-Meier method, and univariate and multivariate survival were analyzed using a Cox regression model. Results The study included 269 patients. The gross total resection rate was 46.0% (n = 124) but cavernous sinus involvement was present in almost half the patients (n = 115). The probability of recurrence at 5 years and 10 years was 22.0% and 47.2%, respectively. The median time to recurrence was 10 years for patients without cavernous sinus involvement and 6 years for those with cavernous sinus involvement. Univariate and multivariate analysis showed that tumor size, cavernous sinus invasion, anterior skull base extensions, and residual tumor were significantly associated with recurrence. Conclusions Recurrence rate of NFPA remains high despite the better visualization offered by EEA, especially in those tumors involving the cavernous sinus and/or previously operated on. Repeat surgery is adequate for tumor debulking and decompression of the optic apparatus but is unlikely to achieve gross total resection if a successful previous EEA has been performed. Radiation therapy is an effective option for management of recurrent tumors.

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.

INTRODUCTION The polypeptide prolactin (PRL) is a peptide hormone and a cytokine mostly secreted from the anterior pituitary gland. PRL is also synthesized in extra pituitary tissues including thymocytes and T lymphocytes. Considering the need for chronic GVHD (cGVHD) biomarkers, we explored the relationship between hyperprolactinemia and active cGVHD in a cohort of long-term post-alloHCT survivors. METHODS Three-hundred sixteen adults underwent alloHCT between 2010 and 2016, survived more than 1 year and were included. All patients underwent a regular annual assessment that includes a hormone profile with serum PRL levels. RESULTS Overall, 236 (74.7%) patients had cGVHD, and in 199 (63%), the grade was moderate or severe. Sixty-five (21%) recipients had active cGVHD at the time of the annual evaluation, and hyperprolactinemia was documented in 63 (19.9%) patients. Hyperprolactinemia correlated with cGVHD activity (Odds Ratio 6.9 (95% CI; 3.6-13.1); P

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

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.

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.

Some thyroid cancer (TC) survivors experience cognitive symptoms. The purpose of this study is to perform a systematic literature review and meta-analysis comparing cognitive performance in TC survivors to controls. We performed a seven-database electronic search and hand-search. We performed duplicate independent reviews and data abstraction. Random effects meta-analyses reported standardized mean differences (SMDs) with 95% confidence intervals (CIs), where a negative value implies worse performance in the TC group. We reviewed 1174 unique citations and 10 full-text papers. We included seven studies of 241 treated TC survivors and 273 controls. Cognitive function was statistically significantly worse in TC survivors in the following domains: Attention and Concentration (Digit Span Forwards) SMD − 0.37 (95% CI − 0.62, − 0.13, p = 0.003, four studies), Speed of Processing (Trail Making A) SMD − 0.36 (95% CI − 0.66, − 0.05, p = 0.022, four studies), and Language (Controlled Oral Word Association [COWAT]-Categories) SMD − 0.97 (95% − 1.31, − 0.64, p

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 classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.

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 diagnosis of neuroendocrine tumors is based on the recognition of signs and symptoms of the structural and functional effects of these tumors. The structural impact depends on the location of the tumor; in some, such as the pituitary, the structural impact can be significant because of mass effects in a small enclosed and critical area, whereas in others, such as distal pancreas or retroperitoneal sites like adrenal, tumors can grow to be very large without major mass effects. The functional aspects of these tumors involve biochemical confirmation that can be very complex. In this chapter, the various hormone excess syndromes are discussed, along with the specific structural considerations at the common sites of neuroendocrine tumors. The wide array of clinical manifestations of neuroendocrine tumors emphasizes the importance of careful clinical history, sophisticated biochemical investigations, and thoughtful consideration of the potential for germline predisposition syndromes that are common in these disorders.

Neuroendocrine neoplasms arise in tissues of the endocrine system, including pituitary, thyroid, parathyroid, pancreas, respiratory system, gastrointestinal tract, and adrenal glands and rarely in other unusual sites. Surgery is the first line of treatment in many of these cases and can include a complete removal of the organ (i.e., total thyroidectomy or adrenalectomy), partial removal (i.e., hemithyroidectomy or distal pancreatectomy), or removal of only the tumor (i.e., pituitary tumor). Medical treatment is frequently used, and while this is usually reserved as adjuvant treatment to control symptoms or tumor growth in cases of residual disease following surgical intervention, it is sometimes used as a treatment of choice (i.e., prolactinoma), sometimes as neoadjuvant before surgery to improve outcomes (i.e., treatment to control growth hormone or cortisol excess before surgery), or as the sole primary treatment in patients who are poor candidates for surgery. Other treatment options can include radiotherapy and peptide receptor radionuclide therapy (PRRT); in some patients, additional therapies are intended for symptom control. Additional data on the molecular basis of neuroendocrine neoplasms may lead to providing treatment sequences personalized for each patient, based on the tumor biology and molecular and genetic patterns. Immunotherapy with immune checkpoint inhibitors may prove to be a successful option for selected neuroendocrine neoplasms.

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

Medullary thyroid cancer is a rare type of neuroendocrine tumour that arises from the parafollicular cells (C cells) of the thyroid gland. It accounts for 3%&ndash, 5% of thyroid cancer cases. Close to 25% of cases are familial, and 75% are considered sporadic. Familial cases are associated with a germline RET mutation, 43%&ndash, 65% of sporadic cases harbour a somatic event in the gene. Germline RET mutations are associated with the autosomal-dominant inherited multiple endocrine neoplasia (men) 2a and 2b syndromes and the isolated familial medullary thyroid cancer syndrome. More than 100 RET codon mutations have been reported to date, with genotype&ndash, phenotype correlations that include the extent and aggressiveness of the medullary thyroid cancer and the presence of other features of the men2 syndromes. The latter include pheochromocytoma&ndash, paraganglioma, hyperparathyroidism, cutaneous lichen amyloidosis, and Hirschsprung disease.

Background Medullary thyroid carcinoma (mtc) is a rare malignancy of the thyroid gland, and raising awareness of the recommended diagnostic workup and pathologic characteristics of this malignancy is therefore important. Methods We reviewed the current clinical practice guidelines and recent literature on mtc, and here, we summarize the recommendations for its diagnosis and workup. We also provide an overview of the pathology of mtc. Results A neuroendocrine tumour, mtc arises from parafollicular cells (“C cells”), which secrete calcitonin. As part of the multiple endocrine neoplasia (men) type 2 syndromes, mtc can occur sporadically or in a hereditary form. This usually poorly delineated and infiltrative tumour is composed of solid nests of discohesive cells within a fibrous stroma that might also contain amyloid. Suspicious nodules on thyroid ultrasonography should be assessed with fine-needle aspiration (fna). If a diagnosis of mtc is made on fna, patients require baseline measurements of serum calcitonin and carcinoembryonic antigen. Calcitonin levels greater than 500 pg/mL or clinical suspicion for metastatic disease dictate the need for further imaging studies. All patients should undergo dna analysis for RET mutations to diagnose men type 2 syndromes, and if positive, they should be assessed for possible pheochromocytoma and hyperparathyroidism. Summary Although the initial diagnosis of a suspicious thyroid nodule is the same for differentiated thyroid carcinoma and mtc, the remainder of the workup and diagnosis for mtc is distinct.

Aggressive fibromatosis (AF) is a rare benign tumor, which occurs in the deep part of bone and muscle fibrous tissue. Clinical and pathological features can be challenging for definitive diagnosis. Here, we report a rare case of a large AF in the axilla. Interestingly, 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography showed significant increase in standard uptake value. Surgical resection yielded a spindle cell tumor likely of fibromatosis origin which was positive for β-catenin expression.

Occult breast cancer is defined by the presence of axillary metastases without an identifiable primary breast tumor. Here, we report a rare case of a male occult breast cancer with dermatomyositis. We performed a modified radical mastectomy consisting of whole breast mastectomy and axillary lymph node dissection. Immunohistochemistry and fluorescent in situ hybridization analyses demonstrated an adenocarcinoma likely of breast origin, which was an occult triple-negative breast cancer. Interestingly, the patient's previously noted periorbital dermatomyositis resolved promptly following surgical excision.

Radioactive iodine-resistant differentiated thyroid cancer (RAIRTC) is an aggressive form of thyroid cancer that is uncommon and heterogeneous in its clinical behavior. With the emergence of more effective systemic therapy, the need for guidance in decision-making was recognized and a consensus committee of national experts was assembled. The consensus committee consisted of 13 clinicians involved in treating RAIRTC from across Canada and included endocrinologists, nuclear medicine physicians, surgeons, and radiation and medical oncologists. Domains of interest were identified by consensus, and evidence gathered using systematic reviews. Consensus recommendations for the diagnosis and management of RAIRTC were developed. It was recognized that the rarity of RAIRTC in practice and heterogeneous patterns of thyroid cancer care could limit access to effective therapy for some RAIRTC patients. This document offers guidance to manage RAIRTC patients in a multidisciplinary manner.

An excess of growth hormone (GH) results in accelerated growth and in childhood, the clinical manifestation is gigantism. When GH excess has its onset after epiphyseal fusion at puberty, the overgrowth of soft tissue and bone results in acromegaly. Persistent GH excess in gigantism also causes acromegalic features that become evident in the adult years. The causes of GH excess are primarily lesions in the pituitary, which is the main source of GH. In this review, we provide an update on the clinical, radiological and pathologic features of the various types of pituitary neuroendocrine tumors (PitNETs) that produce GH. These tumors are all derived from PIT1-lineage cells. Those composed of somatotrophs may be densely granulated, resembling normal somatotrophs, or sparsely granulated with unusual fibrous bodies. Those composed of mammosomatotrophs also produce prolactin; rare plurihormonal tumors composed of cells that resemble mammosomatotrophs also produce TSH. Some PitNETs are composed of immature PIT1-lineage cells that do not resemble differentiated somatotrophs, mammosomatotrophs, lactotroph or thyrotrophs; these tumors may cause GH excess. An unusual oncocytic PIT1-lineage tumor known as the acidophil stem cell tumor is predominantly a lactotroph tumor but may express GH. Immature PIT1-lineage cells that express variable amounts of hormones alone or in combination can sometimes cause GH excess. Unusual tumors that do not follow normal lineage differentiation may also secrete GH. Exceptional examples of acromegaly/gigantism are caused by sellar tumors composed of hypothalamic GHRH-producing neurons, alone or associated with a sparsely granulated somatotroph tumor. Each of these various tumors has distinct clinical, biochemical and radiological features. Data from careful studies based on morphologic subtyping indicate that morphologic classification has both prognostic and predictive value.

We present a series of nonectopic pituitary adenomas presenting as polypoid sinonasal or nasopharyngeal masses. Thirteen cases diagnosed by biopsies from the nasal cavity, sinuses, or nasopharynx were identified from a series of 1288 surgical pituitary specimens. The patients included 5 men and 8 women ranging from 29 to 69 years of age. The presentations included nasal obstruction (4 cases), headaches (3), visual defects (2), recurrent nose bleeds (1), rhinorrhea (1), sepsis (1), fatigue (1), and hyperthyroidism (1). All patients had large tumors involving the sella and extending inferiorly to involve the sphenoid sinus in 10 cases, ethmoid in 8, nasopharynx in 3, nasal cavity in 6, maxillary and frontal sinuses in 1 case each. In 3 patients, the biopsy was from the nasopharynx, in 4 from the nasal cavity, in 4 from the sphenoid sinus, and in 2 from the ethmoid sinus. The correct diagnosis of pituitary adenoma was initially made in 10 cases. In 3 cases the initial diagnosis was incorrect; 2 tumors were classified as olfactory neuroblastoma, one of those was reclassified as neuroendocrine carcinoma, and 1 case was initially diagnosed as neuroendocrine carcinoma with aberrant adrenocorticotrophic hormone expression. Clinical follow-up (2 to 25 y) and treatment information was available in 10 cases. All 10 patients were alive, either free of disease (4 cases) or with disease (6 cases). In 2 cases, the wrong diagnoses led to incorrect treatment with significant morbidity. These cases illustrate that pituitary adenomas can invade nasopharynx and sinonasal cavities and when they do, they present a possible diagnostic pitfall with potentially serious consequences. We demonstrate the need to always consider this entity when encountering a nasopharyngeal or sinonasal tumor with neuroendocrine features.

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).

Objective Age‐standardized incidence of female breast cancer is 145.1 per 100000/year and 5.86 per 100000/year for neuroendocrine tumours (NET) in Canada. Evidence is scarce about gene variants that may predispose patients to develop both neoplasms. The objective of this study was to identify germline gene variants associated with this combination of tumours. Design and patients A retrospective chart review (2007‐2018) in a tertiary NET referral centre was completed. A series of 9 female patients with concurrent breast cancer and NET is presented. All patients underwent a 37 gene hereditary cancer next‐generation sequencing panel. Results Mean age was 61.4 years (35‐85) at breast cancer diagnosis and 63.4 years (51‐89) at NET diagnosis. Four patients had a pancreatic, three had a small bowel and two had a lung NET. Two patients were known cases of MEN1, and one patient was found to harbour a pathogenic variant in MEN1 and a variant of unknown significance (VUS) in ATM. A second patient was found to harbour a pathogenic variant in APC. A third patient was found to carry a pathogenic variant in PALB2 as well as a VUS in FANCM, MLH1 and STK11. Another patient was found to harbour a VUS in MSH2. One patient was found to carry a pathogenic variant in NTHL1. Conclusion The first cases of a PALB2, an APC and a NTHL1 pathogenic variants in patients with both breast cancer and NET were presented. NGS testing should be considered in specific patients with this combination of neoplasms, as certain germline variants beyond MEN1, have important implications for cancer surveillance.

Background: Acromegaly results from a persistent excess in growth hormone with clinical features that may be subtle or severe. The most common cause of acromegaly is a pituitary tumor that causes excessive production of growth hormone (GH), and rare cases are due to an excess of the GH-releasing hormone (GHRH) or the ectopic production of GH. Objective: Discuss the different diseases that present with manifestations of GH excess and clinical acromegaly, emphasizing the distinct clinical and radiological characteristics of the different pathological entities. Methods: We performed a narrative review of the published clinicopathological information about acromegaly. An English-language search for relevant studies was conducted on PubMed from inception to 1 August 2019. The reference lists of relevant studies were also reviewed. Results: Pituitary tumors that cause GH excess have several variants, including pure somatotroph tumors that can be densely or sparsely granulated, or plurihormonal tumors that include mammosomatotroph, mixed somatotroph-lactotroph tumors and mature plurihomonal Pit1-lineage tumors, acidophil stem cell tumors and poorly-differentiated Pit1-lineage tumors. Each tumor type has a distinct pathophysiology, resulting in variations in clinical manifestations, imaging and responses to therapies. Conclusion: Detailed clinicopathological information will be useful in the era of precision medicine, in which physicians tailor the correct treatment modality to each patient.

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.

The management of pancreatic neuroendocrine tumors (PanNETs) involves classification into non-functional or functional PanNET, and as localized or metastatic PanNET. In addition, while most PanNETs are sporadic, these endocrine neoplasms can also be manifestations of genetic syndromes. All these factors may assist in forming a risk stratification system permitting a tailored management approach. Most PanNETs are classified as non-functional because they are not associated with clinical sequelae of hormone excess. They are characterized by non-specific symptoms, such as abdominal pain or weight loss, resulting from mass effect related to the pancreatic tumor or secondary to distant metastases. Accurate staging of the disease is essential for determining the appropriate approach to therapy. As cure is only potentially possible with surgical resection of the tumor, it is recommended to remove all localized and limited metastatic disease. However, many patients present with metastatic and/or advanced local disease. In such instances, the goal of therapy is to control tumor growth and/or decrease tumor burden, lengthen survival, and palliate local symptoms and those of hormone excess. This typically requires a multimodal approach, including surgery, liver-directed treatment, and systemic medical therapy.

Background: Autonomous glucocorticoid excess in patients with Cushing disease (CD) may lead to negative feedback suppression, resulting in Crooke's hyaline change (CC) of the non-tumorous corticotrophs in the pituitary. Objective: To determine the prognostic implication of evidence of CC on histopathology examination following pituitary surgery for CD. Methods: This was a retrospective review of patients from a single clinic with preoperative diagnosis of CD, who had pituitary surgery and pathology specimens that were reviewed by two pathologists for the presence of CC in non-tumorous adenohypophysis. Results: The cohort included 47 patients (37 female) with at least one available pathology sample for evaluation; 11 patients had two samples. Evaluation of CC was not possible in 15 pathology samples from 13 patients, mainly due to lack of non-tumorous pituitary tissue (8 samples), crush artifact (4 samples), or other reason (3 samples). Among 34 patients with adequate pathology sample for evaluation of CC, in 28 patients (82%) there was evidence of CC and in 6 patients (18%) the samples were negative for CC; 2 of these had corticotroph hyperplasia. During the mean (SD) follow-up of 62 months (40), recurrent or persistent disease was evident in 14 cases, while 18 patients were in remission; 2 cases with CC were lost to follow-up. Remission rates were lower in patients with no histological evidence of CC (2/6 patients, 33%), compared to those with CC (16/26 patients, 62%). Repeat pituitary surgery was completed in 7 patients (27%) with CC, 4 cases (67%) without CC, and one case (31%) with no data regarding CC. Conclusions: In most patients with clinical suspicion of CD there is CC in the non-tumorous corticotrophs. The absence of CC may point to increased risk of persistent or recurrent disease. While in some cases this may be attributed to corticotroph hyperplasia, in others this may reflect altered cellular feedback regulation in the non-tumorous corticotrophs. Further studies are required to determine the molecular pathogenesis of these findings with respect to various clinical conditions manifesting with ACTH excess.

Background: In Ontario, age-standardized incidence of female breast cancer was 145.1 per 100000/year in 2012. Neuroendocrine tumors (NET) are less common, with an incidence of 5.86 per 100000/year in 2009 in the same population. Evidence is scarce about the possible genetic mutations that may predispose patients with NET to develop breast cancer. Clinical cases: We report a series of 9 cases of co-occurrence of breast cancer and NET. All patients (n=9) were female, with a mean age of 61.4 years (35-85) at breast cancer diagnosis and 63.4 years (51-89) at NET diagnosis. Six patients had a lumpectomy, 2 had a mastectomy and one was not a surgical candidate. Five tumors were invasive ductal carcinomas, one was a ductal carcinoma in situ and two were lobular carcinomas. Seven tumors were ER+, 5 were PR+ and only one was HER-2 neu +. Mean tumor size was 1.1 cm (0.4-2.0). Three tumors had a histologic grade 2 and one had a grade 3. All tumors were Stage 1a. Three patients had locoregional recurrence. Two patients developed breast cancer metastases, one in cervical lymph nodes and bone metastases and one had liver metastases. In terms of adjuvant therapy, two patients received chemotherapy, four received radiotherapy, 6 received an aromatase inhibitor and one received trastuzumab. Mean follow-up time for the breast cancer was 7.44 years (2-26). Of the 9 patients, 4 had a pancreatic NET, 3 had a small bowel NET and two had a lung NET. Five patients had surgical resection of the primary tumor, three were not surgical candidates and one was followed by active surveillance. Mean tumor size was 5.2 cm (1.9-8.1); one patient had Stage 1, two had Stage 2 and one had Stage 3 disease. One pancreatic NET was an insulinoma. Mean Ki-67 index was 12.6 % (1.0-33.0). One NET had a Grade 1, 6 had a Grade 2 and 1 had a Grade 3. Five tumors developed metastases during follow-up, 5 to the liver, two to mesenteric lymph nodes, two to bones. 6 were treated with a somatostatin analogue and 4 with everolimus. Two received capecitabine-temozolomide chemotherapy, which targets both malignancies, one received peptide receptor radionuclide therapy (PRRT with 177-Lutetium) and three are currently being considered for PRRT. Two patients had hepatic metastasectomy. Mean NET follow-up time was 5.67 years (1-10). Two patients were known cases of Multiple Endocrine Neoplasia type 1 harboring pathogenic MEN1 variants. At time of submission, we are awaiting germline candidate gene mutational analyses including MEN1, MEN4/CDKN1B, BRCA1/2, MUTYH, CHEK2 and Lynch syndrome. Conclusion: This case series serves as a reminder that patients with one malignancy are more often predisposed to develop a second neoplasm, prompting clinicians to consider this possibility when new lesions appear during follow-up. In particular, NET patients maybe at increased risk of breast cancer, the underlying basis of which remains to be determined .

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.

Pituitary adenohypophysial tumors range from small indolent incidental findings to progressive neoplasms that invade the base of the brain. This chapter focuses on biomarkers that have been examined to help distinguish between these differing behaviors. This is particularly relevant in childhood cases where treatment and surveillance plans can have far-reaching implications. We review the familial syndromes that predispose to tumor development. We emphasize the histological subtypes that can be diagnosed using morphologic and immunophenotyping techniques. We then review candidate biomarkers including proliferation markers, metalloproteinases, growth factors and their receptors, as well as hormone and cytokine receptors. We conclude with larger chromosomal aberrations and microRNAs that have been implicated in epigenetic dysregulation. These data provide an integrated approach to formulate a risk stratification system for patients with pituitary tumors.

Tumors of hypothalamic neurons that produce vasopressin are rare. We retrieved all cases of vasopressin-positive tumors in the sellar region from the database of the Department of Pathology. Five cases fulfilled the selection criteria, representing the first series of such tumors. Clinical, radiologic, and pathologic features were reviewed. Four tumors classified as neurocytomas were identified in 3 females and 1 male patient; the ages at onset of symptoms ranged from 17 to 40 years. All were large sellar masses with suprasellar extension and/or invasion of the parasellar sinuses. Three patients had the syndrome of inappropriate antidiuresis; in one of these, a 6-year history was initially considered to be idiopathic. One patient died of progressive disease; 3 had incomplete resections and are being followed. In contrast to these patients with neurocytoma, a 65-year-old woman had Cushing disease and a 0.8 cm mass that was completely resected at transsphenoidal surgery; this tumor was a gangliocytoma producing vasopressin associated with corticotroph hyperplasia. We postulate that the small amount of vasopressin secreted by this mature gangliocytic tumor was locally bound to corticotrophs, resulting in hyperplasia and Cushing disease, without sufficient overproduction to cause systemic effects of vasopressin excess. Hypothalamic neurocytoma is a tumor that can mimic pituitary neuroendocrine tumors and olfactory neuroblastoma but is distinguished by positivity for neurofilaments, NeuN, and TTF-1 and negative staining for adenohypophysial biomarkers. Our cases illustrate that neurocytoma and gangliocytoma are 2 variants of tumors of hypothalamic neurons that can produce vasopressin. The morphologic and proliferative features of these 2 tumor types represent 2 ends of a spectrum; their function also can result in divergent clinical manifestations, one characterized by reduced urine output and the other by the more insidious features of glucocorticoid excess.

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.

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.

Paragangliomas are neuroendocrine neoplasms, derived from paraganglia of the sympathetic and parasympathetic nervous systems. They are most commonly identified in the head and neck, being most frequent in the carotid body, followed by jugulotympanic paraganglia, vagal nerve and ganglion nodosum, as well as laryngeal paraganglia. Abdominal sites include the well-known urinary bladder tumors that originate in the Organ of Zuckerkandl. However, other unusual sites of origin include peri-adrenal, para-aortic, inter-aortocaval, and paracaval retroperitoneal sites, as well as tumors in organs where they may not be expected in the differential diagnosis of neuroendocrine neoplasms, such as thyroid, parathyroid, pituitary, gut, pancreas, liver, mesentery, lung, heart and mediastinum. The distinction of these lesions from epithelial neuroendocrine neoplasms is critical for several reasons. Firstly, the determination of clinical and biochemical features is different from that used for epithelial neuroendocrine tumors. Secondly, the genetic implications are different, since paragangliomas/pheochromocytomas have the highest rate of germline susceptibility at almost 40%. Finally, the characterization of metastatic disease is unique in these highly syndromic lesions. In this review, we summarize updated concepts by outlining the spectrum of anatomic locations of paragangliomas, the importance of morphology in establishing the correct diagnosis, the clinical implications for management, and the impact of genetics on the distinction between multifocal primary tumors compared with malignant disease.

Background: The tall cell variant of papillary thyroid carcinoma (PTC) is as an aggressive histological variant. The proportion of tall cells needed to influence prognosis is debated. Methods: Patients with PTC and tall cells, defined as having a height-to-width ratio of ≥ 3:1, seen at a high-volume center between 2001 and 2015, were reviewed. Specimens were classified as (1) focal tall cell change, containing < 30% of tall cells; (2) tall cell variant, ≥ 30% of tall cells; and (3) control cases selected from infiltrative classical PTCs without adverse cytologic features. Univariate, sensitivity, and multivariate analyses were performed with persistent/recurrent disease as the primary outcome. Results: We identified 96 PTCs with focal tall cell change, 35 with the tall cell variant and 104 control cases. Factors associated with poor clinical prognosis were significantly greater in those with focal tall cell change and tall cell variants. Regarding primary outcome, hazard ratios were 2.3 (95% confidence interval [CI] 1.0–5.7) for focal tall cell change, and 3.4 (95% CI 1.2–8.7) for tall cell variants compared with controls. Five-year disease-free survival was higher for the control group (92.7%, CI 87.4–98.0) compared with focal tall cell change (76.3%, CI 66.1–86.5) and the tall cell variant (62.2%, CI 43.2–81.2). When stratified in groups consisting of tall cell proportions (< 10%, 10–19%, 20–29% and ≥ 30%), identification of ≥ 10% tall cell change was associated with worse outcome (p = 0.002). Conclusions: PTCs with ≥ 10% tall cell change have worse prognosis than those without tall cells. Our data indicate that thyroid cancer management guidelines should consider PTCs with focal tall cell change outside of the low-risk classification.

Pituitary tumors are common and exhibit a wide spectrum of hormonal, proliferative and invasive behaviors. Traditional classifications consider them malignant only when they exhibit metastasis. Patients who suffer morbidity and mortality from aggressive tumors classified as "adenomas" are denied support provided to patients with "cancers" and in many jurisdictions, these tumors are considered curiosities that do not warrant reporting in health registries. We propose use of the term "tumor" rather than "adenoma" to align with other neuroendocrine tumors. The features that can serve as diagnostic, prognostic and predictive markers are reviewed. Clinico-pathological and radiographic classifications provide important information and to date, no single biomarker has been able to offer valuable insight to guide the management of patients with pituitary tumors.

Objective: To report the role of liver transplantation in the management of refractory carcinoid syndrome. Methods: We describe the clinical course, biochemical, radiographic, and histopathologic features of a patient with severe refractory carcinoid syndrome due to a metastatic well-differentiated enterochromaffin cell neuroendocrine tumor of the jejunum. We also review and summarize the literature on liver transplantation in this setting. Results: An 18-year-old patient presented with a 3-year history of progressive palpitations, flushing, abdominal pain, and diarrhea. Initial imaging studies demonstrated multiple cystic liver lesions; biochemistry confirmed elevated 24-hour urinary 5-hydroxy-indolacetic acid (5-HIAA) levels. She was managed with somatostatin analogues followed by a partial small-bowel resection. Five sessions of liver embolization and escalating somatostatin analogues failed to control her symptoms or normalize urinary 5-HIAA levels. Cross-sectional imaging detected disease only in the liver. Due to progressively worsening symptoms, liver transplantation was offered as a therapeutic option at age 21 years. One year following the procedure, her condition improved clinically and biochemically with minimal disease outside the liver. Conclusion: Liver transplantation represents a potential therapeutic option in selected patients with refractory carcinoid syndrome.