Search

Technetium-99 m sestamibi parathyroid scintigraphy (MIBI scan) has been used to localize abnormal glands in patients with primary hyperparathyroidism to guide parathyroidectomy. This series aimed to identify the biochemical and histopathological correlates of MIBI scan findings in patients with parathyroid adenoma. A total of 378 patients with histologically and biochemically proven parathyroid adenoma were included. The results of MIBI scan, histopathological (gland volume and weight, oxyphil cell ratio), biochemical (blood and 24 h urine calcium, creatinine, glomerular filtration rate, parathormone, alkaline phosphate, and vitamin D3) variables were recorded. A positive uptake on the MIBI scan referred to a localized adenoma. Among histological variables, a cutoff of 30% was applied to define parathyroid adenomas with low (≤ 30%) and high (> 30%) oxyphil cell content. Statistical analyses were performed to assess the relationship among variables. MIBI scan localized the adenoma in 306 patients. Parathyroid gland volume and weight, and oxyphil ratio were significantly higher in the MIBI scan-positive group. Among the biochemical variables, only PTH was found to be significantly increased in the MIBI scan-positive group. Binary logistic regression models identified statistically significant cutoffs for the gland volume (1700 mm3), gland weight (1.3 g) and PTH levels (170 pg/mL) that can be used to predict the MIBI scan positivity. In addition to PTH levels, this series underscored the impact of cellular composition along with the parathyroid gland volume and weight, both of which correlate with sestamibi positivity in patients with benign uniglandular parathyroid disease.

Summay Complete resection of adrenal cortical carcinoma (ACC) with or without adjuvant therapy offers the best outcome. Recurrence is common, and in individual cases, the long-term outcome is difficult to predict, making it challenging to personalize treatment options. Current risk stratification approaches are based on clinical and conventional surgical pathology assessment. Rigorous and uniform pathological assessment may improve care for individual patients and facilitate multi-institutional collaborative studies. The International Collaboration on Cancer Reporting (ICCR) convened an expert panel to review ACC pathology reporting. Consensus recommendations were made based on the most recent literature and expert opinion. The data set comprises 23 core (required) items. The core pathological features include the following: diagnosis as per the current World Health Organization classification, specimen integrity, greatest dimension, weight, extent of invasion, architecture, percentage of lipid-rich cells, capsular invasion, lymphatic invasion, vascular invasion, atypical mitotic figures, coagulative necrosis, nuclear grade, mitotic count, Ki-67 proliferative index, margin status, lymph node status, and pathological stage. Tumors were dichotomized into low-grade ( 20 mitoses per 10 mm2) ones. Additional noncore elements that may be useful in individual cases included several multifactorial risk assessment systems (Weiss, modified Weiss, Lin-Weiss-Bisceglia, reticulin, Helsinki, and Armed Forces Institute of Pathology scores/algorithms). This data set is now available through the ICCR website with the hope of better standardizing pathological assessment of these relatively rare but important malignancies.

Approximately one-tenth of the general population exhibit adrenal cortical nodules, and the incidence has increased. Afflicted patients display a multifaceted symptomatology-sometimes with rather spectacular features. Given the general infrequency as well as the specific clinical, histological, and molecular considerations characterizing these lesions, adrenal cortical tumors should be investigated by endocrine pathologists in high-volume tertiary centers. Even so, to distinguish specific forms of benign adrenal cortical lesions as well as to pinpoint malignant cases with the highest risk of poor outcome is often challenging using conventional histology alone, and molecular genetics and translational biomarkers are therefore gaining increased attention as a possible discriminator in this context. In general, our understanding of adrenal cortical tumorigenesis has increased tremendously the last decade, not least due to the development of next-generation sequencing techniques. Comprehensive analyses have helped establish the link between benign aldosterone-producing adrenal cortical proliferations and ion channel mutations, as well as mutations in the protein kinase A (PKA) signaling pathway coupled to cortisol-producing adrenal cortical lesions. Moreover, molecular classifications of adrenal cortical tumors have facilitated the distinction of benign from malignant forms, as well as the prognostication of the individual patients with verified adrenal cortical carcinoma, enabling high-resolution diagnostics that is not entirely possible by histology alone. Therefore, combinations of histology, immunohistochemistry, and next-generation multi-omic analyses are all needed in an integrated fashion to properly distinguish malignancy in some cases. Despite significant progress made in the field, current clinical and pathological challenges include the preoperative distinction of non-metastatic low-grade adrenal cortical carcinoma confined to the adrenal gland, adoption of individualized therapeutic algorithms aligned with molecular and histopathologic risk stratification tools, and histological confirmation of functional adrenal cortical disease in the context of multifocal adrenal cortical proliferations. We herein review the histological, genetic, and epigenetic landscapes of benign and malignant adrenal cortical neoplasia from a modern surgical endocrine pathology perspective and highlight key mechanisms of value for diagnostic and prognostic purposes.

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.

The clinical significance of multifocal pulmonary neuroendocrine proliferation (MNEP), including tumorlets and pulmonary neuroendocrine cell hyperplasia, in association with typical carcinoid (TC), is still debated.We evaluated a retrospective series of TC with long-term follow-up data prospectively collected from 2 institutions and compared the outcome between TC alone and MNEP plus TC. Several baseline covariates were imbalanced between the MNEP plus TC and TC groups; therefore, we conducted 1:1 propensity score matching and inverse probability of treatment weighting in the full sample. In the matched group, the association of clinical, respiratory, and work-related factors with the group was determined through univariable and multivariable conditional logistic regression analysis.A total of 234 TC patients underwent surgery: 41 MNEP plus TC (17.5%) and 193 TC alone (82.5%). In the MNEP plus TC group, older age (P.001), peripheral tumors (P = .0032), smaller tumor size (P = .011), and lymph node spread (P = .02) were observed compared with the TC group. Relapses occurred in 8 patients in the MNEP plus TC group (19.5%) and 7 in the TC group (3.6%). After matching, in 36 pairs of patients, a significantly higher 5-year progression-free rate was observed for the TC group (P.01). Similar results were observed using inverse probability of treatment weighting in the full sample. The odds of being in the MNEP plus TC group was higher for those with work-related exposure to inhalant agents (P = .008), asthma or bronchitis (P = .002), emphysema, fibrosis, and inflammatory status (P = .032), or micronodules on the chest computed tomography scan and respiratory insufficiency (P = .036).The association with MNEP seems to represent a clinically and prognostic relevant factor in TC. Hence, careful preoperative workup, systematic pathologic evaluation, including nontumorous lung parenchyma, and long-term postoperative follow-up should be recommended in these patients.

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.

Characterization of adrenal cortical proliferations requires integration of dynamic endocrine tests with imaging and histopathological characteristics. While pathologists are more frequently exposed to adrenalectomy specimens from patients with presumed adrenal cortical neoplasms, pre-operative biopsy specimens from non-functional adrenal lesions have also expanded the clinical tasks of pathologists. Confirmation of the adrenal cortical origin and distinction of benign cortical proliferations from adrenal cortical carcinomas are well-defined clinical responsibilities of pathologists. However, application of immunohistochemical and/or molecular biomarkers in adrenal cortical neoplasia and careful correlation of morphological features with laboratory findings and disease pathogenesis have evolved the impact of pathologist's role in the multidisciplinary team of endocrine disorders. This review provides an overview of what surgical pathologists need to know about the clinical, morphological, immunohistochemical and molecular features of various forms of adrenal cortical neoplasms (ACNs) in order to advance the clinical care.

Oncocytes are cells that have abundant eosinophilic cytoplasm due to the accumulation of mitochondria; they are also known as oxyphils. In the thyroid they have been called Hürthle cells but this is a misnomer, since Hürthle described C cells; for this reason, we propose the use of “oncocyte” as a scientific term rather than an incorrect eponym. Oncocytic change occurs in nontumorous thyroid disorders, in benign and malignant tumors of thyroid follicular cells, in tumors composed of thyroid C cells, and intrathyroidal parathyroid proliferations as well as in metastatic lesions. The morphology of primary oncocytic thyroid tumors is similar to that of their non-oncocytic counterparts but also is complicated by the cytologic features of these cells that include both abundant eosinophilic cytoplasm and large cherry red nucleoli. The molecular alterations in oncocytic thyroid tumors echo those of their non-oncocytic counterparts but in addition feature mitochondrial DNA mutations as well as chromosomal gains and losses. In this review we emphasize the importance of recognition of the spectrum of oncocytic thyroid pathology. The cell of origin, morphologic features including architecture, nuclear atypia and invasive growth, as well as high grade features such as mitoses and necrosis, enable accurate classification of these lesions. The molecular alterations underlying the pathological entity are associated with genetic alterations associated with oncocytic change. The arbitrary cut-off of 75% oncocytic change to classify a lesion as an oncocytic variant brings another complexity to the classification scheme of tumors that frequently have mixed oncocytic and non-oncocytic components. This controversial and often confusing area of thyroid pathology requires thoughtful and cautious investigation to clarify accurate diagnosis, prognosis and prediction for patients with oncocytic thyroid lesions.

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.

Silent corticotroph tumors are composed of corticotroph cells, but do not manifest any biochemical or clinical evidence of hypercortisolism. A choristoma is a benign, congenital proliferation of histologically mature tissue elements normally not present at the site of occurrence. The existence of adrenocortical cells within the pituitary gland, which can be explained as a choristoma, is a very rare entity, and the co-occurrence of these two entities have only been reported in few cases. In the present case, we report an 11-year-old boy with central hypothyroidism. In his cranial magnetic resonance imaging a pituitary tumor was detected, and histopathological studies led to a diagnosis of an adrenal choristoma and a silent corticotroph tumor in the pituitary gland. The presence of adrenocortical cells were confirmed with positive calretinin, inhibin and Melan A staining, and the corticotroph cells with adrenocorticotropic hormone immunohistochemistry. Herein, we report the fourth and the youngest case of silent corticotroph tumor with adrenocortical choristoma in the literature. Even though the underlying mechanism is not fully understood, suggested mechanisms are discussed in the paper.

Thoracic (pulmonary and thymic) neuroendocrine tumors are well-differentiated epithelial neuroendocrine neoplasms that are classified into typical and atypical carcinoid tumors based on mitotic index cut offs and presence or absence of necrosis. This classification scheme is of great prognostic value but designed for surgical specimens, only. Deep molecular characterization of thoracic neuroendocrine tumors highlighted their difference with neuroendocrine carcinomas. Neuroendocrine tumors of the lung are characterized by a low mutational burden, and a high prevalence of mutations in chromatin remodeling and histone modification-related genes, whereas mutations in genes frequently altered in neuroendocrine carcinomas are rare. Molecular profiling divided thymic neuroendocrine tumors into three clusters with distinct clinical outcomes and characterized by a different average of copy number instability. Moreover, integrated histopathological, molecular and clinical evidence supports the existence of a grey zone category between neuroendocrine tumors (carcinoid tumors) and neuroendocrine carcinomas. Indeed, cases with well differentiated morphology but mitotic/Ki-67 indexes close to neuroendocrine carcinomas have been increasingly recognized. These are characterized by specific molecular profiles and have an aggressive clinical behavior. Finally, thoracic neuroendocrine tumors may arise in the background of genetic susceptibility, being MEN1 syndrome the well-defined familial form. However, pathologists should be aware of rarer germline variants that are associated with the concurrence of neuroendocrine tumors of the lung or their precursors (such as DIPNECH) with other neoplasms, including but not limited to breast carcinomas. Therefore, genetic counseling for all young patients with thoracic neuroendocrine neoplasia and/or any patient with pathological evidence of neuroendocrine cell hyperplasia-to-neoplasia progression sequence or multifocal disease should be considered.

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.

Although growth hormone (GH)–producing pituitary neuroendocrine tumors are by far the most common neoplastic cause of acromegaly and gigantism, other neoplastic causes exist, including hypothalamic tumors, which secrete eutopic GH-releasing hormone (GHRH) as well as a number of other tumor types throughout the body, which may secrete GHRH or GH in an ectopic fashion. This chapter is devoted to these less common but equally important entities and focuses on their clinical, radiological, biochemical, and pathological characteristics, in addition to diagnostic challenges that may be encountered when dealing with these interesting neoplasms.

High-grade neuroendocrine neoplasms (HG-NENs) are clinically aggressive diseases, the classification of which has recently been redefined. They now include both poorly differentiated NENs (neuroendocrine carcinoma, NECs) and high proliferating well-differentiated NENs (called grade 3 neuroendocrine tumors, G3 NETs, in the digestive system). In the last decade, the "molecular revolution" that has affected all fields of medical oncology has also shed light in the understanding of HG NENs heterogeneity and has provided new diagnostic and therapeutic tools, useful in the management of these malignancies. Considering the kaleidoscopic aspects of HG NENs in various anatomical sites, this review systematically addresses the genomic landscape of such neoplasm throughout the more common thoracic and digestive locations, as well as it will consider other rare but not exceptional primary sites, including the skin, the head and neck, and the urogenital system. The revision of the available literature will then be oriented to understand the translational relevance of molecular data, by analyzing conceptual issues, clinicopathological correlations, and unmet needs in this field.

Inherited neuroendocrine neoplasms (NENs) represent a heterogeneous group of disorders that often present with subtle clinical or biochemical features. The well-recognized entities include a spectrum of associated neoplasms harboring various degrees of biologic aggressiveness, which often show variable degrees of genotype-phenotype correlations and penetrance. The rate of germline susceptibility in endocrine neoplasms is generally underestimated as most healthcare providers do not routinely consider the possibility of germline disease in a seemingly sporadic presentation in adults over the age of 50–60 years. Variations in disease penetrance and de novo pathogenic variants can lead to late-onset manifestations of inherited NENs that can simulate sporadic disease in the absence of family history. Some of these also manifest with a non-syndromic presentation as seen in patients with familial isolated hyperparathyroidism (FIHP), familial isolated pituitary adenoma (FIPA), as well as in a subset of multiple endocrine neoplasia type 2 (MEN2) patients manifesting only with medullary thyroid carcinoma (formerly known as familial isolated medullary thyroid carcinoma syndrome). The suspicion of an underlying germline susceptibility for NENs should be based on tumor multifocality and morphology including non-tumorous parenchyma, identification of hyperplasia-to-neoplasia progression sequence, early-onset, and coexistence of synchronous or asynchronous endocrinopathies, including endocrine neoplasias. The delivery of genetic care for hereditary inherited disorders is multifaceted and involves multiple healthcare practitioners, including laboratory geneticists, physician geneticists, and genetic counsellors.

Paragangliomas, including the intra-adrenal forms known as pheochromocytomas, are nonepithelial neuroendocrine neoplasms that produce catecholamines as their principal hormonal product. Clinically and biochemically they are divided into two categories. Parasympathetic paragangliomas that make dopamine include head and neck paragangliomas such as carotid body tumors and jugulotympanic tumors, sympathetic paragangliomas that produce epinephrine and norepinephrine occur mainly in the abdomen, most commonly in the adrenal and the organ of Zuckerkandl. Paragangliomas also occur in unusual locations, including the sella turcica, paranasal sinuses, larynx, thyroid and parathyroid glands, mediastinum, heart and lungs, gallbladder, liver, gut, pancreas, and mesentery. These tumors have a characteristic morphology. They are composed of nests known as “Zellballen” and the tumor cells tend to be large polygonal neuroid cells with abundant granular basophilic cytoplasm; rarely they are eosinophilic, chromophobic, or amphophilic epithelioid cells or elongated and spindle-shaped cells. They stain for chromogranin and synaptophysin but are negative for keratins; they express the nuclear transcription factor GATA3 and the enzymes involved in catecholamine synthesis including tyrosine hydroxylase that is a valuable tool for confirmation of the diagnosis, and phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, and can be used to distinguish tumors that make epinephrine. S100 protein accentuates sustentacular stromal cells that also express SOX10. These tumors are familial in about 40% of cases, leading to multifocal tumors and in some, adrenal medullary hyperplasia. There is a long list of genes that are mutated in kindred with these tumors. Some familial tumors have specific morphologic features and molecular immunohistochemistry can be used to identify tumors associated with SDHx, VHL, and FH-related disease. Rarely these tumors can be the source of ectopic production of other peptide hormones. All paragangliomas have malignant potential; therefore, they are not classified as benign or malignant but rather only as primary and metastatic. Metastasis must be distinguished from multifocal primary disease. Prognosis is dependent on resectability.

The thyroid is the location of neuroendocrine C cells that produce calcitonin. The most common thyroid neuroendocrine neoplasm is medullary thyroid carcinoma (MTC) that is composed of C cells. Rare other thyroid neuroendocrine neoplasms include mixed neuroendocrine and non-neuroendocrine neoplasms (MiNENs) that represent a composite MTC and thyroid follicular neoplasm, usually papillary thyroid carcinoma, as well as occasional paragangliomas, intrathyroidal parathyroid tumors, NENs originating from intrathyroidal thymic remnants and metastatic neuroendocrine neoplasms.

Pituitary neuroendocrine tumors are a complex family of lesions that show a spectrum of differentiation based on their developmental regulatory transcription factors and hormone expression. They can cause a number of clinical syndromes such as acromegaly, Cushing disease, hyperprolactinemia, and hyperthyroidism or they may be clinically silent. Their morphology is variable and of clinical importance to predict therapy and prognosis.

Virtually all neuroendocrine neoplasms (NENs) have metastatic potential, and up to 20% of cases present as metastasis from an occult primary. The identification of the primary site is an important step toward the correct management of the patient, particularly when dealing with a well-differentiated neuroendocrine tumor (NET), as therapeutic approach may vary depending on the site and cell type. Thorough morphological and immunohistochemical analyses can provide important clues to the recognition of the site of origin of a metastatic NET. The liver represents the most frequent location of metastatic NENs; lymph nodes, peritoneum, bone, and lung represent other common secondary sites. However, virtually any body organ including those that can give rise to primary NENs may host metastatic NENs, including breast, ovary, thyroid, pancreas, and pituitary. Thus, it becomes evident that the diagnosis of a metastatic NEN gives rise to two orders of problems: (i) the identification of the occult primary site and (ii) the distinction from a putative primary NEN of the organ in which the lesion is present. Both challenges are of crucial importance in the management of the patients, and the pathologist should be aware of the diagnostic tools to approach them and of the entities which enter in the differential diagnosis. Careful interpretation of clinical, morphologic, and immunohistochemical findings using a panel approach combining cytokeratins along with anatomic site-related transcription factors, hormones, and other biomarkers can assist identifying the origin of a metastatic NEN and distinguishing metastatic from primary and multifocal tumors. The power of this approach is limited in the setting of poorly differentiated NECs.

The parathyroid glands are the site of common benign neuroendocrine tumors, including adenomas and lipoadenomas. Metastatic disease is very rare, and local growth does not usually have significant sequelae; even large non-metastatic tumors are easily resected. The diagnosis of parathyroid carcinoma has been assisted by the development of biomarkers that can reduce the use of “atypical” for tumors that show unusual features, which are frequently attributed to prior manipulation. There has been significant progress in understanding the genetics of these tumors and their association with familial endocrinopathies.

The hypothalamus is now recognized to be the location where signals from the internal milieu and external stimuli are integrated to regulate endocrine homeostasis. Neuroendocrine tumors that arise from neurons in and around the hypothalamus give rise to clinical manifestations of mass effect as well as hormonal activity. These rare tumors include gangliocytomas and neurocytomas that produce hormones and are associated with endocrinopathies.

Context Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors. Objective To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors. Methods Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants. Results Family A has multiple individuals with PC (including bilateral and metastatic disease) and 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone–releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (IGF-1). A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss of heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss of function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. Conclusion Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.

The traditional approach to the diagnosis of primary adenohypophyseal cell proliferations uses hormone immunohistochemistry to classify pituitary neuroendocrine tumors (PitNETs). The routine application of immunolocalization of pituitary transcription factors (SF1, PIT1, TPIT, ERα, and recently GATA3) along with adenohypophyseal hormones has taught us critical lessons that are discussed in this communication. We point out that appropriate patient care requires accurate diagnosis and is critical in the era of precision medicine. A misdiagnosis can result in far greater health care costs than the cost of accurate tumor classification and may have other unintended consequences. We provide additional insights about confusing findings in genomic studies, emphasizing that high-quality pathology is essential for strong science and translational research.

The expression of programmed death-ligand 1 (PD-L1) is an established prerequisite for the administration of checkpoint inhibitor therapy and is of prognostic value in several cancer types. Data concerning the potential effect of PD-L1 on the prognosis of thyroid carcinoma are limited. Therefore, this study aimed to provide a systematic review of the published data on this topic. The literature was reviewed to gather and quantify evidence on the prognostic role of PD-L1 in follicular epithelial derived thyroid carcinomas and determine its association with clinicopathological parameters. A meta-analysis was performed using the DerSimonian-Laird random-effects model. The quality of studies was evaluated with the Newcastle-Ottawa Scale and a modified GRADE approach used to rate the quality of evidence. Out of 445 papers, 18 were included and 15 provided adequate data for meta-analysis. The quality of evidence ranged from low to high. PD-L1 expression was significantly associated with a reduced disease-free survival (DFS) (RR 1.63, CI 1.04–2.56, p = 0.03, I2 68%, τ2 0.19 and HR 1.90, CI 1.33–2.70, p

A Case of Acromegaly Secondary to Ectopic Growth Hormone-Releasing Hormone (GHRH) Secretion from a Bronchial Neuroendocrine Tumour Background Acromegaly due to ectopic GHRH secretion is a rare disorder and only accounts for less than 1% of all cases of acromegaly. Case We present the case of a 42-year old female with acromegaly from a bronchial neuroendocrine tumour (NET) secreting GHRH. The patient presented with gradual onset of dyspnea and wheezing. Subsequent imaging (chest X-ray, CT chest) revealed a large left-sided thoracic mass. Bronchoscopy was performed and a biopsy was taken from the mass. Initial histological examination reported small cell lung carcinoma (SCLC). Therefore, she underwent chemoradiotherapy. The patient was concurrently experiencing increased digital girth, weight gain, and enlarged tongue and was therefore referred to our endocrinology clinic for evaluation of acromegaly. Investigations revealed normal ACTH, markedly elevated IGF-1 (1031 μg/L, normal 63–215 μg/L), and non-suppressed GH levels following a 75g oral glucose tolerance test. The remainder of the pituitary panel, including TSH, prolactin, FSH, LH were all normal. An MRI sella showed a completely normal pituitary and pineal gland with no evidence of brain metastasis. She thus met clinical and biochemical criteria for acromegaly but a pituitary source could not be identified. Given her history, a paraneoplastic process or ectopic GHRH-producing tumour was suspected. Further workup showed a significantly elevated circulating GHRH levels of 73 pg/mL (normal 5 – 18 pg/mL). Subsequently, a second pathologist with expertise in NETs reviewed the same biopsy specimen. The specimen was found to be a GHRH-producing well differentiated pulmonary NET with a Ki67 index of 1.5%, and thus not a SCLC. Furthermore, a somatostatin receptor scintigraphy study was done which showed evidence of a somatostatin avid receptor rich lesion in the lung, corresponding to the known tumour. Thus, what initially appeared to be a SCLC was subsequently found to be a GHRH-secreting NET, illustrating the challenges of diagnosing these rare tumours. She was treated with intramuscular sandostatin 20mg q28days and then underwent a left pneumonectomy, resulting in biochemical resolution of her acromegaly (IGF-1 219 μg/L). Genetic testing for MEN1 was also completed as there is an association between ectopic GHRH NETs and MEN-1; however, genetic testing revealed no pathogenic variants and exon deletions or duplications suggestive of MEN-1. Learning points Diagnosis of acromegaly due to ectopic GHRH secretion requires high clinical suspicion by the treating clinicians (e.g., endocrinologist, oncologist) as well as review of histology by expert pathologists. Our case highlights that ectopic GHRH secretion is a rare but important cause of acromegaly, which should always be suspected when a clear pituitary cause is not identified.

Primary hyperparathyroidism is a condition that occurs infrequently in children. Parathyroid carcinoma, as the underlying cause of hyperparathyroidism in this age group, is extraordinarily rare, with only a few cases reported in the literature. We present a 13‐year‐old boy with musculoskeletal pain who was found to have brown tumors from primary hyperparathyroidism caused by parafibromin‐immunodeficient parathyroid carcinoma. Our patient had no clinical, biochemical, or radiographic evidence of pituitary adenomas, pancreatic tumors, thyroid tumors, pheochromocytoma, jaw tumors, renal abnormalities, or testicular lesions. Germline testing for AP2S1, CASR, CDC73/HRPT2, CDKN1B, GNA11, MEN1, PTH1R, RET, and the GCM2 gene showed no pathological variants, and a microarray of CDC73/HRPT2 did not reveal deletion or duplication. He was managed with i.v. fluids, calcitonin, pamidronate, and denosumab prior to surgery to stabilize hypercalcemia. After removal of a single parathyroid tumor, he developed severe hungry bone syndrome and required 3 weeks of continuous i.v. calcium infusion, in addition to oral calcium and activated vitamin D. Histopathological examination identified an angioinvasive parathyroid carcinoma with global loss of parafibromin (protein encoded by CDC73/HRPT2).HRpQCT and DXA studies were obtained prior to surgery and 18‐months postsurgery. HRpQCT showed a resolution of osteolytic lesions combined with structural improvement of cortical porosity and an increase in both cortical thickness and density compared with levels prior to treatment. These findings highlight the added value of HRpQCT in primary hyperparathyroidism. In addition to our case, we have provided a review of the published cases of parathyroid cancer in children. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

WOS: 000519375300005 PubMed: 31912298 Medullary thyroid carcinomas display cytologic and architectural features that can simulate various primary and metastatic neoplasms. PAX8 immunoexpression in neuroendocrine neoplasms yielded antibody-dependent findings. Since the data regarding the expression profile of monoclonal PAX8 (MRQ-50) antibody is limited in large series of medullary thyroid carcinomas, this study investigated the expression profile of PAX8 (MRQ-50) in a series of 45 medullary thyroid carcinomas. PAX8 (MRQ-50) expression was noted in the thyroid follicular epithelial cells surrounding the tumor and was negative in all medullary thyroid carcinomas. In addition, twenty medullary thyroid carcinomas showed scattered entrapped thyroid follicular epithelial cells at the periphery of the tumor. Entrapped follicular epithelial cells were positive for PAX8 and thyroglobulin, and were negative for monoclonal CEA and calcitonin. A panel approach combining monoclonal antibodies to transcription factors, hormones and cell-specific peptides often assist diagnosticians in the workup of the cellular origin of a neuroendocrine neoplasm. Since PAX8 immunostaining is dependent on the antibody characteristics in neuroendocrine neoplasms, pathologists should be aware of the details of the PAX8 antibody used in a particular case.

Hyperparathyroidism, commonly observed in asymptomatic middle-aged women, with mild hypercalcemia, is usually caused by a benign adenoma. Some cases present with more severe manifestation and greater hypercalcemia. Within this spectrum, several familial/genetic associations have been discovered. While the majority are caused by benign disease, adenomas, or hyperplasia, a small proportion (

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

Recent studies have reported the prevalence of pituitary tumors to be ~1/1000 population. Many are prolactin-producing tumors that are managed medically, however, the epidemiology of surgically resected pituitary adenohypophysial neuroendocrine tumors has not been reported in a large series with detailed characterization. We reviewed 1055 adenohypophysial tumors from 1169 transsphenoidal resections from the pathology files of University Health Network, Toronto, 2001-2016. Tumors were characterized by immunohistochemical localization of transcription factors (Pit-1, ERα, SF-1, Tpit), hormones (adrenocorticotropin, growth hormone, prolactin, β-thyrotropin, β-folliculotropin, β-luteotropin, α-subunit), and other biomarkers (keratins, Ki67, p27, FGFR4). Electron microscopy was used only for unusual lesions. In this cohort, 51.3% of patients were female; the average age was 51 years. Gonadotroph tumors represented 42.5%. Pit-1-lineage-tumors represented 29.9%; these were subclassified as growth-hormone-predominant (somatotroph/mammosomatotroph/mixed; 53%), prolactin-predominant (lactotroph/acidophil-stem-cell; 28%), thyrotrophs (2%), plurihormonal (14%), and not-otherwise-specified (3%). Corticotroph tumors represented 17.1%. Only 4.5% were null cell tumors and 0.5% were unusual plurihormonal tumors. In 5.5% the tumor was not characterized for technical reasons (sample size, fixation, necrosis or other artifact). All corticotroph and plurihormonal tumors were positive for keratins; others tumors showed variable negativity with highest rates in gonadotroph (37.1%) and null cell tumors (28.2%). Tumors with a Ki67 ≥ 3% comprised 60% of this cohort. Global loss of p27 was most frequent in corticotroph neoplasms, specifically those associated with elevated glucocorticoid levels. Corticotroph and lactotroph tumors were more common among females; gonadotroph tumors were more common among males. Younger patients had mainly corticotroph and Pit-1-lineage neoplasms, whereas older patients harbored mainly gonadotroph tumors. This represents one of the largest surgical series of morphologically characterized pituitary tumors reported to date and the first to include the routine use of transcription factors for tumor classification. The data provide the basis for clinicopathologic correlations that are helpful for prognostic and predictive patient management.

Context Papillary thyroid carcinoma (PTC) is a common malignancy in adolescence and is molecularly and clinically distinct from adult PTC. Mutations in the DICER1 gene are associated with thyroid abnormalities, including multinodular goiter and differentiated thyroid carcinoma. Objective In this study, we sought to characterize the prevalence of DICER1 variants in pediatric PTC, specifically in tumors without conventional PTC oncogenic alterations. Patients Patients (N = 40) who underwent partial or total thyroidectomy and who were

Tall-cell variant (TCV) is widely believed to be a more aggressive subtype of papillary thyroid carcinoma (PTC). Despite the significance of TCV with respect to risk stratification and therapeutic decision making, its diagnosis is subject to inter-observer variability. This study aimed to determine the level of agreement among expert pathologists in the identification and reporting of TCV.Seventeen surgical resections for thyroid cancer containing the diagnostic term "tall cell" in their pathology reports and 22 cases diagnosed as classical PTC were selected. Cases were digitalized, and 14 expert pathologists reviewed the scanned slides blinded to the original interpretation. Each pathologist designated each case as TCV or not and answered multiple questions about diagnostic histopathologic features of TCV.The overall strength of agreement for identifying TCV was fair (Fleiss kappa 0.34), and the proportion of observed agreement was 0.70. Of 22 cases originally diagnosed as PTC classical variant, 15 (68%) were reclassified as TCV by at least one expert pathologist. It was noted that four different definitions for TCV were used by the participants based on various combinations of cell height to width (H:W) ratio and the percentage of tumor cells showing that specific ratio. All pathologists agreed that the diagnosis of TCV does not rely solely on a specific H:W ratio.Pathologic reporting of TCV varies among pathologists. This disagreement is a result of the lack of unanimous diagnostic criteria and variation in individual pathologists' interpretations. These discrepancies lead to over- and under-diagnosis of TCV, which has significant implications in patient management. It is imperative to understand this variability in diagnosis TCV as it relates to risk stratification and interpretation of clinical studies related to this histologic subtype of PTC. Further studies are needed to reach consensus on the diagnostic criteria of TCV.

Selection was initially site-dependent, which then evolved into a partially voluntary basis, made in collaboration with the Post-Graduate Medical Education Office (PGME), AP Residency Program Committee, and the AP resident body. Resident representatives noted that these were due to technical reasons such as lack of appropriate hardware, spotty connectivity, and the inconsistent use of different devices ranging from smartphones to desktop computers. [...]in-person teaching with glass slides became challenging as sign-outs using multiheaded microscopes were discontinued across most training sites. A recent review on the psychological impacts of COVID-19 on health care workers found that depression, anxiety, and other psychological distresses affect a quarter to a third of health care workers.4 Our program widely promoted and supported formal and informal wellness initiatives, including online wellness resources, a virtual trivia night, distribution of jackets with the U of T AP logo to all trainees, physically distanced outdoor and virtual parties for incoming and graduating residents, and a wellness photo social media competition. Carlo Hojilla, MD, PhD1,2;Susan Armstrong, MD, PhD1;Cherry Pun, MD1;Tyler Bruce Malcolm Hickey, MD, PhD1,3;Ozgur Mete, MD14;Rachel Han, MD1;Elan Hahn, MD1;Sameer Shivji, MD2;Susan Done, MA, MB, BChir MBA, PhD1,4;Fang-I Lu, MD1,5 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada;2Department of Pathology & Laboratory Medicine, Sinai Health System, Toronto, Ontario, Canada;3Ontario Forensic Pathology Service, Toronto, Ontario, Canada;4Laboratory Medicine Program, Department of Anatomical Pathology, University Health Network, Toronto, Ontario, Canada;5Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada Accepted for publication April 8, 2021.

Renaming encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently suggested to prevent the overtreatment, cost and stigma associated with this low-risk entity. The purpose of this study is to document the incidence and further assess the clinical outcomes of reclassifying EFVPTC to NIFTP. We searched synoptic pathologic reports from a high-volume academic endocrine surgery hospital from 2004 to 2013. The standard of surgical pathology practice was based on complete submission of malignant thyroid nodules along with the nontumorous thyroid parenchyma. Rigid morphological criteria were used for the diagnosis of noninvasive EFVPTC, currently known as NIFTP. A retrospective chart review was conducted looking for evidence of malignant behavior. One hundred and two patients met the strict inclusion criteria of NIFTP. The incidence of NIFTP in our cohort was 2.1% of papillary thyroid cancer cases during the studied time period. Mean follow-up was 5.7 years (range 0–11). Five patients were identified with nodal metastasis and one patient with distant metastasis. Overall, six patients showed evidence of malignant behavior representing 6% of patients with NIFTP. Our study demonstrates that the incidence of NIFTP is significantly lower than previously thought. Furthermore, evidence of malignant behavior was seen in a significant number of NIFTP patients. Although the authors fully support the de-escalation of aggressive treatment for low-risk thyroid cancers, NIFTP behaves as a low-risk thyroid cancer rather than a benign entity and ongoing surveillance is warranted.

While the vast majority of pancreatic neuroendocrine tumours (pNETs) are sporadic, the recognition of an inherited pNET represents an evolving clinical responsibility of practising pathologists in the era of personalized medicine. The initially well-defined inherited pNET syndromes includes multiple endocrine neoplasia type 1 (MEN-1), von Hippel Lindau disease (VHL), neurofibromatosis type 1 (NF) and tuberous sclerosis (TS). Over the past decade, the spectrum of inherited pNETs has been expanded by the inclusion of new presentations such as multiple endocrine neoplasia type 4 (MEN-4), glucagon cell adenomatosis (Mahvash disease) along with germline mutations in DNA repair genes (MUTYH, BRCA2, and CHEK2) in a subset of seemingly sporadic looking pNETs as well as isolated case reports of succinate dehydrogenase deficient (SDH)- and mismatch repair deficient-pNETs occurring in the setting of SDH-related familial paraganglioma syndrome and Lynch syndrome, respectively. The findings have pointed out that the spectrum of inherited pNETs is indeed larger than what most physicians generally anticipate, likely reaching a rate greater than 15% of the overall presentations. From a morphological perspective, the identification of multifocal pNET should prompt the attention of pathologists to the possibility of an underlying genetic susceptibility. Since not all inherited pNETs manifest with multifocal disease, careful morphological assessment of the tumour and the non-tumorous pancreas, and application of immunohistochemical biomarkers are essential in the prediction of inherited pNETs. In order to facilitate the recognition of inherited pNETs, this review is aimed to provide a practical overview of pancreatic endocrine manifestations of MEN-1, MEN-4, VHL, NF-1, TS and glucagon cell adenomatosis.

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.

Xanthomatous hypophysitis is a rare inflammatory disease of the pituitary gland that can mimic a neoplastic lesion clinically and radiologically. Its pathogenesis remains largely unknown, although recent evidence suggests that pituitary inflammation may occur as a secondary reaction to mucous content released from a ruptured cyst. In a series of 1221 pituitary specimens, we identified seven cases of xanthomatous hypophysitis. Six patients had complete radiological and biochemical workup preoperatively: a cystic-appearing pituitary mass was identified in all six patients (100%) with a mean size of 2.0 cm (range 1.4-2.5 cm) on imaging, and pituitary endocrine dysfunction was noted in five patients (83.3%). In all cases, the pituitary mass was resected through an endoscopic transsphenoidal approach. Pathological examination revealed the presence of foamy macrophages admixed with variable amounts of giant cells and chronic inflammatory cells, confirming the diagnosis of xanthomatous hypophysitis. Additionally, all cases presented with concurrent findings of ruptured Rathke's cleft cyst, with the exception of one patient who had previous surgery for a Rathke's cleft cyst, followed by recurrence and diagnosis of xanthomatous hypophysitis. While accurate distinction of hypophysitis from a pituitary neoplasm can be problematic in the preoperative setting, the identification of a cystic lesion in the sella turcica should raise the possibility of such an entity in the clinical and radiological differential diagnosis. The current series provides further evidence that xanthomatous hypophysitis predominantly occurs as a secondary reaction to a ruptured Rathke's cleft cyst; thus, it is best classified as a secondary (reactive) hypophysitis.

Adrenocortical tumors range from primary bilateral micronodular or macronodular forms of adrenocortical disease to conventional adrenocortical adenomas and carcinomas. Accurate classification of these neoplasms is critical given the varied pathogenesis, clinical behavior, and outcome of these different lesions. Confirmation of adrenocortical origin, diagnosing malignancy, providing relevant prognostic information in adrenocortical carcinoma, and correlation of laboratory results with clinicopathologic findings are among the important responsibilities of pathologists who evaluate these lesions. This article focuses on a practical approach to the evaluation of adrenocortical tumors with an emphasis on clinical and imaging findings, morphologic characteristics, and multifactorial diagnostic schemes and algorithms.

The 2017 World Health Organization classification of pituitary tumors redefined pituitary null cell adenomas (NCAs) by restricting this diagnostic category to pituitary tumors that are negative for pituitary transcription factors and adenohypophyseal hormones. The clinical behavior of this redefined entity has not been widely studied, and this is a major shortcoming of the classification. This study evaluated the imaging and clinical features of NCAs from two pituitary centers and compared them with those of gonadotroph adenomas (GAs). Imaging, pathologic, and clinical characteristics of NCAs and GAs were retrospectively reviewed. Tumor immunohistochemistry was performed to confirm absence of adenohypophyseal hormones and pituitary transcription factor expression. Thirty-one NCAs were compared with 38 GAs. NCAs were more likely to invade the cavernous sinus (15/31 [48%] vs. 5/38 [13%], P = .003) and had a higher proliferative index (i.e., MIB-1 > 3%, 11/31 [35%] vs. 5/38 [13%], P = .04). Gross total resection was less likely in the NCA group (19/31 [61%] vs. 33/38 [87], P = .02). Progression-free survival was worse in the NCA cohort (5-year progression-free survival, 0.70 vs. 1.00; P = .011, by log-rank test). Compared with GAs, NCAs are more invasive at the time of presentation and have a more aggressive clinical course. This study provides evidence that NCAs represent a distinct clinicopathologic entity with behavior that differs adversely from that of GAs. This may inform clinical decision-making, including frequency of postoperative tumor surveillance and timing of adjunctive treatments.

Background: Parathyroid carcinoma is rare, representing

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.