Publications by authors named "Ozgur Mete"

184 Publications

Middle Ear "Adenoma": a Neuroendocrine Tumor with Predominant L Cell Differentiation.

Endocr Pathol 2021 May 27. Epub 2021 May 27.

Department of Pathology, University Health Network, University of Toronto, Ontario, M5G 2C4, Toronto, Canada.

This morphological and immunohistochemical study demonstrates that tumors currently known as "middle ear adenomas" are truly well-differentiated epithelial neuroendocrine tumors (NETs) composed of cells comparable to normal intestinal L cells, and therefore, these tumors resemble hindgut NETs. These tumors show consistent expression of glucagon, pancreatic polypeptide, PYY, and the transcription factor SATB2, as well as generic neuroendocrine markers and keratins. The same L cell markers are expressed by cells within the normal middle ear epithelium. These markers define a valuable immunohistochemical profile that can be used for differential diagnosis of middle ear neoplasms, particularly in distinguishing epithelial NETs from paragangliomas. The discovery of neuroendocrine cells expressing the same markers in non-neoplastic middle ear mucosa opens new areas of investigation into the physiology of the normal middle ear and the pathophysiology of middle ear disorders.
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http://dx.doi.org/10.1007/s12022-021-09684-zDOI Listing
May 2021

Cribriform-Morular Thyroid Carcinoma Is a Distinct Thyroid Malignancy of Uncertain Cytogenesis.

Endocr Pathol 2021 May 21. Epub 2021 May 21.

Department of Pathology, University Health Network, Toronto, ON, Canada.

Tumors with papillary cribriform and morular architecture were initially considered to be variants of papillary thyroid carcinoma; however, recent observations have challenged this view. In this study, we reviewed the demographical, histopathological, and immunohistochemical features of the largest case series, consisting of 33 tumors. The age at time of pathological diagnosis ranged from 18 to 59 (mean 33) years, and all patients except one were female. Sixteen patients had multifocal and fifteen had unifocal disease. The status of focality was unavailable in two patients. Tumors were well-circumscribed, ranging in size from 0.1 to 8.0 cm. The cribriform component was admixed with morulae in the majority, except seven had a cribriform-predominant architecture and two had predominantly solid growth. Variable degrees of nuclear enlargement, elongation, overlapping, and grooves were seen but florid nuclear convolution, intranuclear pseudoinclusions, and optically clear nuclei due to chromatin margination were not appreciated. There was no or little colloid material within the cribriform spaces. Two solid tumors had high-grade features. Immunohistochemical studies showed beta-catenin nuclear and cytoplasmic positivity in all cases. The cribriform component was positive for TTF1 and negative for thyroglobulin. PAX8 was absent in half of these tumors and focal in the remainder. Morulae were positive for keratin 5 and CD5 and negative for p63, p40, TTF1, and PAX8. Molecular studies revealed germline APC mutations in 12 tumors and were negative in 5 sporadic tumors in a subset of tested tumors. Irrespective of the antibody used in this cohort, all cribriform-morular carcinomas express TTF1; however, PAX8 immunoreactivity is weak, focal or negative, and all tumors lack thyroglobulin reactivity; these findings raise questions about tumor cell origin and may indicate that these are not of thyroid follicular epithelial differentiation. We postulate that morulae may represent divergent thymic/ultimobranchial pouch-related differentiation. Given their unique cytomorphology, immunohistochemical profiles, and genetic features that have little overlap with traditional follicular cell-derived thyroid carcinomas, we propose that these tumors represent a distinct form of thyroid carcinoma unrelated to other neoplasms of thyroid follicular cells.
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http://dx.doi.org/10.1007/s12022-021-09683-0DOI Listing
May 2021

Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification.

Mod Pathol 2021 May 21. Epub 2021 May 21.

Department of Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1038/s41379-021-00820-yDOI Listing
May 2021

A Holistic Approach to Pathology Education During the Coronavirus Disease 2019 (COVID-19) Pandemic.

Arch Pathol Lab Med 2021 May 20. Epub 2021 May 20.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.

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http://dx.doi.org/10.5858/arpa.2020-0668-LEDOI Listing
May 2021

Oncocytic Change in Thyroid Pathology.

Front Endocrinol (Lausanne) 2021 3;12:678119. Epub 2021 May 3.

Department of Pathology, University Health Network, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.3389/fendo.2021.678119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127945PMC
May 2021

Follicular Cells in Pituitary Neuroendocrine Tumors.

Hum Pathol 2021 May 12. Epub 2021 May 12.

Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH USA, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA. Electronic address:

Follicular cells (FCs) are thought to be agranular, non-hormone producing stellate cells distributed throughout the adenohypophysis, occasionally arranged around colloid-filled follicles, and thought to be more prominent in the vicinity of necrosis and apoptotic cells. A distinct but similar cell type, the folliculostellate cell (FSC), is a sustentacular cell that is negative for keratins and stains for S100, GFAP and SOX10. While several studies have examined FSCs in pituitary neuroendocrine tumors (PitNETs), the distribution and derivation of FCs in these lesions is unclear. We examined the presence and distribution of FCs in 104 PitNETs obtained by trans-sphenoidal surgery, using immunohistochemistry for keratins as well as the full complement of immunohistochemical stains for tumor characterization. The tumors included 9 somatotroph, 5 mammosomatotroph, 7 lactotroph, 7 immature PIT1-lineage, 2 acidophil stem cell, 17 corticotroph, 53 gonadotroph, 2 null cell and 2 unusual plurihormonal tumors. CK-positive FCs were only identified in gonadotroph PitNETs and were found in 12 (23%) of those tumors; all other tumor types were negative for FCs. FCs express keratins identified by CAM5.2, AE1/AE3, CK18 and CK19 antibodies. FCs were identified scattered singly among hormone-producing neuroendocrine cells, in small clusters of 3-5 cells and surrounding colloid-filled follicles, as well as linearly along intratumoral blood vessels. Sequential stains showed that FCs express nuclear SF1 and GATA3, transcription factors of gonadotrophs, and multiplex immunohistochemistry confirmed colocalization of SF1 In the nucleus of keratin-positive FCs. In this series, FCs were exclusively found in gonadotroph PitNETs and occurred in 23% of those tumors. Co-expression of gonadotroph transcription factors in FCs supports the concept of cellular plasticity and transformation of neoplastic hormone-producing neuroendocrine cells to FCs. Further studies are required to determine if and why gonadotrophs alone undergo this transformation, the function of these cells and whether they have prognostic value.
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http://dx.doi.org/10.1016/j.humpath.2021.05.002DOI Listing
May 2021

Prognostic Significance of Pulmonary Multifocal Neuroendocrine Proliferation with Typical Carcinoid.

Ann Thorac Surg 2021 Apr 5. Epub 2021 Apr 5.

Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, ITALY. Electronic address:

Background: Clinical significance of multifocal pulmonary neuroendocrine proliferation (MNEP), including tumorlets and pulmonary neuroendocrine cell hyperplasia, in association with Typical Carcinoid (TC), is still debated.

Methods: A retrospective series of TC with long-term follow-up data prospectively collected from two institutions was evaluated, and the outcome comparison between TC alone and MNEP+TC was investigated. Several baseline covariates were imbalanced between the MNEP+TC and TC groups, therefore, we have conducted 1:1 propensity score matching and inverse probability of treatment weighting (IPTW) in the full sample. In the matched group, association of clinical, respiratory and work-related factors with group was determined through univariable and multivariable conditional logistic regression analysis.

Results: 234 TC patients have undergone surgery: 41 MNEP+TC(17.5%) and 193 TC alone(82.5%). In the MNEP+TC group older age(p<0.001), peripheral tumors(p=0.0032), smaller tumor size(p=0.011) and lymph-nodal spread(p=0.02) were observed in comparison with TC group. Relapses occurred in 8 patients (19.5%) of MNEP+TC group and in 7(3.6%) of TC group. After matching, in 36 pairs of patients a significantly higher 5-years progression-free rate was observed for TC group(p<0.01). Similar results were observed using IPTW in the full sample. Odds of being in the MNEP+TC group was higher with work-related exposure to inhalant agents(p=0.008), asthma/bronchitis(p=0.002), emphysema, fibrosis and inflammatory status(p=0.032), micronodules on the chest CT scan and respiratory insufficiency(p=0.036).

Conclusions: The association with MNEP seems to represent a clinically and prognostic relevant factor in TC. Hence, careful pre-operative workup, systematic pathological evaluation, including non-tumorous lung parenchyma, and long-term postoperative follow-up should be recommended in these patients.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.069DOI Listing
April 2021

Significance of Alpha-inhibin Expression in Pheochromocytomas and Paragangliomas.

Am J Surg Pathol 2021 Apr 8. Epub 2021 Apr 8.

Department of Pathology, University Health Network Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada Endocrine Oncology Site, The Princess Margaret Cancer Centre Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes Department of Pathology, University of Michigan, Ann Arbor, MI Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH.

Alpha-inhibin expression has been reported in pheochromocytomas and paragangliomas (PPGLs). We analyzed alpha-inhibin immunohistochemistry in 77 PPGLs (37 pheochromocytomas [PCCs] and 40 paragangliomas) and correlated the results with catecholamine profile, tumor size, Ki-67 labeling index, succinate dehydrogenase B subunit and carbonic anhydrase IX (CAIX) staining, and genetic pathogenesis. PPGLs were classified as pseudohypoxic cluster 1 disease with documented VHL mutation or SDHx mutation or biochemical phenotype, whereas NF1-driven and RET-driven PPGLs and those with a mature secretory (adrenergic or mixed adrenergic and noradrenergic) phenotype were classified as cluster 2 disease. The Cancer Genome Atlas data on INHA expression in PPGLs was examined. Alpha-inhibin was positive in 43 PPGLs (56%). Ki-67 labeling indices were 8.07% and 4.43% in inhibin-positive and inhibin-negative PPGLs, respectively (P<0.05). Alpha-inhibin expression did not correlate with tumor size. Alpha-inhibin was expressed in 92% of SDHx-related and 86% of VHL-related PPGLs. CAIX membranous staining was found in 8 of 51 (16%) tumors, including 1 SDHx-related PCC and all 5 VHL-related PCCs. NF1-driven and RET-driven PPGLs were negative for alpha-inhibin and CAIX. Alpha-inhibin was expressed in 77% of PPGLs with a pseudohypoxia signature, and 20% of PPGLs without a pseudohypoxia signature (P<0.05). PPGLs with a mature secretory phenotype were negative for CAIX. The Cancer Genome Atlas data confirmed higher expression of INHA in cluster 1 than in cluster 2 PPGLs. This study identifies alpha-inhibin as a highly sensitive (90.3%) marker for SDHx/VHL-driven pseudohypoxic PPGLs. Although CAIX has low sensitivity, it is the most specific biomarker of VHL-related pathogenesis. While alpha-inhibin cannot replace succinate dehydrogenase B subunit immunohistochemistry for detection of SDHx-related disease, it adds value in prediction of cluster 1 disease. Importantly, these data emphasize that alpha-inhibin is not a specific marker of adrenal cortical differentiation, as it is also expressed in PCCs.
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http://dx.doi.org/10.1097/PAS.0000000000001715DOI Listing
April 2021

Significance of Crooke's Hyaline Change in Nontumorous Corticotrophs of Patients With Cushing Disease.

Front Endocrinol (Lausanne) 2021 18;12:620005. Epub 2021 Mar 18.

Department of Endocrine Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.

Background: Glucocorticoid 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.

Methods: The 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.

Results: Of 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.

Conclusions: CC 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.
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http://dx.doi.org/10.3389/fendo.2021.620005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013723PMC
March 2021

The Pangenomic Classification of Pituitary Neuroendocrine Tumors: Quality Histopathology is Required for Accurate Translational Research.

Endocr Pathol 2021 Mar 3. Epub 2021 Mar 3.

Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA.

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http://dx.doi.org/10.1007/s12022-021-09671-4DOI Listing
March 2021

Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know?

Endocr Pathol 2021 Mar 27;32(1):154-168. Epub 2021 Feb 27.

Dept. of Medicine and Surgery, University of Insubria, Varese, Italy.

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.
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http://dx.doi.org/10.1007/s12022-021-09668-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960615PMC
March 2021

Special Issue on Molecular Pathology of Endocrine Neoplasms: Understanding the Basis of Endocrine Pathology Practice.

Authors:
Ozgur Mete

Endocr Pathol 2021 Mar;32(1):1-2

Department of Pathology, University Health Network, Toronto, ON, Canada.

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http://dx.doi.org/10.1007/s12022-021-09670-5DOI Listing
March 2021

SILENT CORTICOTROPH TUMOR WITH ADRENOCORTICAL CHORISTOMA IN AN ELEVEN-YEAR-OLD BOY.

J Clin Res Pediatr Endocrinol 2021 Feb 15. Epub 2021 Feb 15.

Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey.

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.
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http://dx.doi.org/10.4274/jcrpe.galenos.2021.2020.0258DOI Listing
February 2021

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics.

Endocr Pathol 2021 Mar 3;32(1):102-133. Epub 2021 Feb 3.

Department of Pathology, University Health Network, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1007/s12022-021-09667-0DOI Listing
March 2021

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates.

Endocr Pathol 2021 Mar 25;32(1):77-101. Epub 2021 Jan 25.

Department of Pathology and Laboratory Medicine, Perelmann School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.

Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be "sporadic" is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease.
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http://dx.doi.org/10.1007/s12022-020-09661-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960606PMC
March 2021

Genomics of High-Grade Neuroendocrine Neoplasms: Well-Differentiated Neuroendocrine Tumor with High-Grade Features (G3 NET) and Neuroendocrine Carcinomas (NEC) of Various Anatomic Sites.

Endocr Pathol 2021 Mar 12;32(1):192-210. Epub 2021 Jan 12.

Department of Oncology, University of Turin, Torino, Italy.

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.
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http://dx.doi.org/10.1007/s12022-020-09660-zDOI Listing
March 2021

Genomics and Epigenomics of Pituitary Tumors: What Do Pathologists Need to Know?

Endocr Pathol 2021 Mar 12;32(1):3-16. Epub 2021 Jan 12.

Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada.

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 BRAF 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.
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http://dx.doi.org/10.1007/s12022-021-09663-4DOI Listing
March 2021

Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?

J Clin Endocrinol Metab 2021 Mar;106(4):1163-1182

Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, Woolloongabba, Australia.

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.
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http://dx.doi.org/10.1210/clinem/dgaa957DOI Listing
March 2021

Endoscopic Endonasal Pituitary Surgery For Nonfunctioning Pituitary Adenomas: Long-Term Outcomes and Management of Recurrent Tumors.

World Neurosurg 2021 Feb 22;146:e341-e350. Epub 2020 Oct 22.

University Health Network, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1016/j.wneu.2020.10.083DOI Listing
February 2021

Cytokeratin profiles in pituitary neuroendocrine tumors.

Hum Pathol 2021 Jan 21;107:87-95. Epub 2020 Oct 21.

Department of Pathology, University Health Network, Toronto, M5G 2C4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5G 2C4, Canada.

The presence and patterns of keratins are critical in the classification of pituitary neuroendocrine tumors. A large body of literature has included information about the staining patterns of pituitary tumors and tissues with the CAM 5.2 antibody. During an antibody validation for clinical use, we carried out staining of a series of 29 surgically resected pituitary cases containing 31 pituitary neuroendocrine tumors that were tested for CAM 5.2 as well as for cytokeratin (CK) 7, 18, 19, and 20 and the pan-keratin cocktail AE1/AE3. The results showed an almost identical staining pattern for CK18 and CAM 5.2; however, CAM 5.2 yielded more intense staining, whereas CK18 provided more delicate results. Staining results using AE1/AE3 were satisfactory but generally less intense; however, this marker was more specific, identifying keratin expression in one tumor that was negative with CAM 5.2. CK19 is expressed in nontumorous adenohypophysis but was less frequently positive in tumors; somatotroph and corticotroph tumors were negative for CK19, but CK19 antibody highlighted follicular cells in some gonadotroph tumors. CK7 and CK20 were negative in all pituitary tissues tested. Our findings underscore the role for CAM 5.2 and CK18 as the most valuable to identify specific alterations in adenohypophysial cells and their tumors; there is also a role for AE1/AE3 to verify the epithelial nature of pituitary neuroendocrine tumors that are negative for CAM 5.2 and CK18.
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http://dx.doi.org/10.1016/j.humpath.2020.10.004DOI Listing
January 2021

Data set for reporting of carcinoma of the adrenal cortex: explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting.

Hum Pathol 2021 Apr 12;110:50-61. Epub 2020 Oct 12.

University of Sydney, Sydney, New South Wales, 2006, Australia; Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia. Electronic address:

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 mm) and high-grade (>20 mitoses per 10 mm) 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.
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http://dx.doi.org/10.1016/j.humpath.2020.10.001DOI Listing
April 2021

Structure, Function, and Morphology in the Classification of Pituitary Neuroendocrine Tumors: the Importance of Routine Analysis of Pituitary Transcription Factors.

Endocr Pathol 2020 Dec 19;31(4):330-336. Epub 2020 Aug 19.

Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA.

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.
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http://dx.doi.org/10.1007/s12022-020-09646-xDOI Listing
December 2020

International Histopathology Consensus for Unilateral Primary Aldosteronism.

J Clin Endocrinol Metab 2021 Jan;106(1):42-54

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Germany.

Objective: Develop a consensus for the nomenclature and definition of adrenal histopathologic features in unilateral primary aldosteronism (PA).

Context: Unilateral PA is the most common surgically treated form of hypertension. Morphologic examination combined with CYP11B2 (aldosterone synthase) immunostaining reveals diverse histopathologic features of lesions in the resected adrenals.

Patients And Methods: Surgically removed adrenals (n = 37) from 90 patients operated from 2015 to 2018 in Munich, Germany, were selected to represent the broad histologic spectrum of unilateral PA. Five pathologists (Group 1 from Germany, Italy, and Japan) evaluated the histopathology of hematoxylin-eosin (HE) and CYP11B2 immunostained sections, and a consensus was established to define the identifiable features. The consensus was subsequently used by 6 additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, United Kingdom, United States) for the assessment of all adrenals with disagreement for histopathologic diagnoses among group 1 pathologists.

Results: Consensus was achieved to define histopathologic features associated with PA. Use of CYP11B2 immunostaining resulted in a change of the original HE morphology-driven diagnosis in 5 (14%) of 37 cases. Using the consensus criteria, group 2 pathologists agreed for the evaluation of 11 of the 12 cases of disagreement among group 1 pathologists.

Conclusion: The HISTALDO (histopathology of primary aldosteronism) consensus is useful to standardize nomenclature and achieve consistency among pathologists for the histopathologic diagnosis of unilateral PA. CYP11B2 immunohistochemistry should be incorporated into the routine clinical diagnostic workup to localize the likely source of aldosterone production.
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http://dx.doi.org/10.1210/clinem/dgaa484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765663PMC
January 2021

Programmed Death-Ligand 1 (PD-L1) Is a Potential Biomarker of Disease-Free Survival in Papillary Thyroid Carcinoma: a Systematic Review and Meta-Analysis of PD-L1 Immunoexpression in Follicular Epithelial Derived Thyroid Carcinoma.

Endocr Pathol 2020 Sep;31(3):291-300

Department of Pathology and Diagnostics, University and Hospital Trust of Verona, P.le Stefani n. 1, 37126, Verona, Italy.

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, I 68%, τ 0.19 and HR 1.90, CI 1.33-2.70, p< 0.001, I 0%, τ 0.00); however, no association was found with the overall survival (OS). Furthermore, a significant association was found with respect to underlying chronic lymphocytic thyroiditis and BRAFV600E mutation status in papillary thyroid carcinomas. In the subgroup analysis, the association of PD-L1 and DFS remained strong in papillary thyroid carcinoma when compared with dedifferentiated thyroid carcinomas (anaplastic and poorly differentiated thyroid carcinomas) that failed to demonstrate a significant association with respect to PD-L1. These findings underscore the role of PD-L1 immunohistochemistry as a potential prognostic biomarker of disease recurrence in patients with papillary thyroid carcinoma.
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http://dx.doi.org/10.1007/s12022-020-09630-5DOI Listing
September 2020

Immunohistochemical Analysis of the Metabolic Phenotype of Adrenal Cortical Carcinoma.

Endocr Pathol 2020 Sep;31(3):231-238

Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G 2C4, Canada.

Metabolic reprogramming is a cellular process contributing to carcinogenesis. However, it remains poorly understood in adrenal cortical carcinoma (ACC), an aggressive malignancy with overall poor prognosis and limited therapeutic options. We characterized the metabolic phenotype of ACC, by examining the immunoprofile of key proteins involved in glucose metabolism, hexokinase (HK1), pyruvate kinase (PKM1, PKM2), succinate dehydrogenase (SDHB), and phospho-S6 ribosomal protein (pS6), in a tissue microarray of 137 adrenal cortical tissue samples. Protein expression was compared between ACC (n = 42), adrenal cortical adenoma (ACA; n = 50), and normal adrenal cortical tissue samples (n = 45). Cytoplasmic expression of HK1 and PKM2 was significantly higher in ACC than in ACA (p < 0.001 and p = 0.014, respectively) or normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). Expression of HK1 and PKM2 was also higher in ACA than in normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). PKM1 expression was overall low in ACC, ACA, and normal samples, although expression of PKM1 was higher in ACC than in ACA (p = 0.027). There was no loss of cytoplasmic granular SDHB expression in our cohort of adrenal cortical tumors, and cytoplasmic expression of pS6 was lower in ACC than in ACA (p = 0.003) or normal adrenal cortical tissue samples (p = 0.008). Significantly, HK1 expression correlated with pyruvate kinase isoform (PKM2 and PKM1) expression (p < 0.001 and p = 0.007, respectively). Although functional validation was not performed, this study provides further evidence that metabolic reprogramming and altered glucose metabolism may occur in a subset of ACC through overexpression of intracellular glycolytic enzymes, notably HK1 and PKM2. The possibility of utilizing the reprogrammed glucose metabolism in ACC for novel therapeutic strategies should be explored in future studies.
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http://dx.doi.org/10.1007/s12022-020-09624-3DOI Listing
September 2020

Thyroid Tumor Capsular Invasion: the Bottom Line or Much Ado About Nothing?

Endocr Pathol 2020 06;31(2):141-142

Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G 2C4, Canada.

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http://dx.doi.org/10.1007/s12022-020-09621-6DOI Listing
June 2020

Severe Primary Hyperparathyroidism Caused by Parathyroid Carcinoma in a 13-Year-Old Child; Novel Findings From HRpQCT.

JBMR Plus 2020 Mar 2;4(3):e10324. Epub 2020 Jan 2.

Department of Pediatrics, Division of Endocrinology Toronto Canada.

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 , , , , , , and the gene showed no pathological variants, and a microarray of 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 )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. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059826PMC
March 2020

Do You Know the Details of Your PAX8 Antibody? Monoclonal PAX8 (MRQ-50) Is Not Expressed in a Series of 45 Medullary Thyroid Carcinomas.

Endocr Pathol 2020 Mar;31(1):33-38

Department of Pathology, University Health Network, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1007/s12022-019-09603-3DOI Listing
March 2020