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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

5092 Background: ACC is a rare endocrine malignancy. Patients with metastatic disease at diagnosis are often treated palliatively with systemic therapy. It is unclear if neoadjuvant cytoreduction with chemotherapy can render metastatic or previously resected but locally recurrent patients become surgical candidates and impact overall survival (OS). Methods: A retrospective single institution review (2002-2019) of metastatic ACC patients was performed. Descriptive statistics were used and OS was estimated by Kaplan-Meier method. Results: Out of 84 patients with metastatic ACC [30 (20.7%) upfront and 54 (37.2%) after definitive therapy], 51 received systemic therapy with mitotane and etoposide-doxorubicin-cisplatin (EDP) as standard 1st line regimen and varied subsequent lines of therapy. Two patients were excluded as they were lost to follow-up. Among the included 49 patients, 29 were females (59.2%) and 26 patients (53.1%) had functional tumors at baseline. Out of 33 patients who had information available on tumor grade, 26 (78.8%) were high grade. Nine pts (18.4%) underwent surgery after receiving systemic therapy (eight after EDP in first line and one after pembrolizumab in third line). These patients were younger (median age 39 years compared to 52.5 years for those receiving only chemotherapy), had locally recurrent disease (all nine patients) with four having evidence of progressive liver metastasis. Median number of EDP cycles delivered before surgery was 4 (range 3-7). The patient who underwent surgery after pembrolizumab received nine cycles of preoperative pembrolizumab. Five pts (55.5%) had partial response, three (33.3%) had disease progression and one (11.1%) had stable disease prior to surgery. Patients underwent surgery after a mean interval of 3.1 months (m) (1.1-5.1) after systemic therapy. Six patients had no evidence of disease (NED) (five with disease limited to adrenal bed) after surgery. Eight out of nine patients recurred after surgery with a median time of 6.1 m (4.4-7.8). The median OS for the entire cohort was 26 m (95% CI 22.3-35.2). This was not significantly better for patients undergoing surgery [median OS 31.2 m (95% CI 21.4-63.3) vs 24.7 m (95% CI 17.7-35.2) p = 0.48]. Patients rendered NED after surgery had numerically better OS than those with residual disease or those receiving only chemotherapy [median OS 39.6 m (24.8.-NR), vs 23.5 m (21.4-NR) vs 24.7 m (17.7-35.2), p = 0.271]. Higher Ki-67 predicted for inferior OS in the entire cohort with no effect of age, gender, tumor grade or functional status. Conclusions: Attempting to downstage patients with metastatic or locally recurrence with systemic therapy does not seem to prolong OS in patients with ACC. Selected patients with limited disease burden, who can be rendered disease free by surgery, may be suitable for this approach.

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...

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.

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.

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.

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.

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).

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: 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.

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.

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.

Originally classified as a variant of silent corticotroph adenoma, silent subtype 3 adenomas are a distinct histologic variant of pituitary adenoma of unknown cytogenesis. We reviewed the clinical, biochemical, radiological, immunohistochemical and ultrastructural features of 31 silent subtype 3 adenomas to clarify their cellular origin. Among 25 with clinical and/or radiological data, all were macroadenomas; there was cavernous sinus invasion in 30% of cases and involvement of the clivus in 17% of cases. Almost 90% of patients were symptomatic; 67% had mass effect symptoms, 37% were hypogonadal and 8% had secondary adrenal insufficiency. Significant hormonal excess in 29% of cases included hyperthyroidism in 17%, acromegaly in 8% and hyperprolactinemia above 150 μg/l in 4%. Two individuals with hyperprolactinemia who were younger than 30 years had multiple endocrine neoplasia type 1. Immunohistochemically, all 31 tumors were diffusely positive for the pituitary lineage-specific transcription factor Pit-1. Although three only expressed Pit-1, others revealed variable positivity for one or more hormones of Pit-1 cell lineage (growth hormone, prolactin, thyroid-stimulating hormone), as well as alpha-subunit and estrogen receptor. Most tumors exhibited perinuclear reactivity for keratins with the CAM5.2 antibody; scattered fibrous bodies were noted in five (16%) tumors. The mean MIB-1 labeling index was 4% (range, 1-9%). Fourteen cases examined by electron microscopy were composed of a monomorphous population of large polygonal or elongated cells with nuclear spheridia. Sixty-five percent of patients had residual disease after surgery; after a mean follow-up of 48.4 months (median 41.5; range=2-171) disease progression was documented in 53% of those cases. These data identify silent subtype 3 adenomas as aggressive monomorphous plurihormonal adenomas of Pit-1 lineage that may be associated with hyperthyroidism, acromegaly or galactorrhea and amenorrhea. Our findings argue against the use of the nomenclature 'silent' for these tumors. To better reflect the characteristics of these tumors, we propose that they be classified as 'poorly differentiated Pit-1 lineage adenomas'.

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.

Fibroblast growth factor (FGF) receptor 2 (FGFR2) has been identified in genome-wide association studies to be associated with increased breast cancer risk; however, its mechanism of action remains unclear. Here we show that the two major FGFR2 alternatively spliced isoforms, FGFR2-IIIb and FGFR2-IIIc, interact with IκB kinase β and its downstream target, NF-κB. FGFR2 inhibits nuclear RelA/p65 NF-κB translocation and activity and reduces expression of dependent transcripts, including interleukin-6. These interactions result in diminished STAT3 phosphorylation and reduced breast cancer cell growth, motility, and invasiveness. FGFR2 also arrests the epithelial cell-to-mesenchymal cell transition (EMT), resulting in attenuated neoplastic growth in orthotopic xenografts of breast cancer cells. Our studies provide strong evidence for the protective effects of FGFR2 on tumor progression. We propose that FGFR2 serves as a scaffold for multiple components of the NF-κB signaling complex. Through these interactions, FGFR2 isoforms can respond to tissue-specific FGF signals to modulate epithelial cell-stromal cell communications in cancer progression.