Publications by authors named "Sylvia L Asa"

337 Publications

Single cell transcriptome and genome analysis: a much needed tool for pituitary neuroendocrine tumor studies.

Neuro Oncol 2021 Sep 4. Epub 2021 Sep 4.

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

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http://dx.doi.org/10.1093/neuonc/noab205DOI Listing
September 2021

XB130 deficiency causes congenital hypothyroidism in mice due to disorganized apical membrane structure and function of thyrocytes.

Thyroid 2021 Sep 2. Epub 2021 Sep 2.

University of Toronto, 7938, Surgery, 101 College Street, Toronto, Ontario, Canada, M5S 1L7.

Background: Congenital hypothyroidism is often caused by genetic mutations that impair thyroid hormone (TH) production, resulting in growth and development defects. XB130 (actin filament associated protein 1 like 2) is an adaptor/scaffold protein that plays important roles in cell proliferation, migration, intracellular signal transduction, and tumorigenesis. It is highly expressed in thyrocytes, however, its function in the thyroid remains largely unexplored.

Methods: Xb130-/- mice and their littermates were studied. Post-natal growth and Gh levels were measured, and responses to low or high iodine diet, and levothyroxine treatment were examined. TH and TSH in the serum and TH in the thyroid glands were quantified. Structure and function of thyrocytes in embryos and postnatal life were studied with histology, immunohistochemistry, immunofluorescent staining, western blotting and quantitative RT-PCR.

Results: Xb130-/- mice exhibited transient growth retardation postnatally, due to congenital hypothyroidism with reduced TH synthesis and secretion, which could be rescued by exogenous thyroxine supplementation. The thyroid glands of Xb130-/- mice displayed diminished thyroglobulin iodination and release at both embryonic and early postnatal stages. XB130 was found mainly on the apical membrane of thyroid follicles. Thyroid glands of embryonic and postnatal Xb130-/- mice exhibited disorganized apical membrane structure, delayed folliculogenesis and abnormal formation of thyroid follicle lumina.

Conclusion: XB130 critically regulates folliculogenesis by maintaining apical membrane structure and function of thyrocytes, and its deficiency leads to congenital hypothyroidism. .
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http://dx.doi.org/10.1089/thy.2021.0195DOI Listing
September 2021

Nasopharyngeal neuroendocrine neoplasms: Systematic review of the literature and case presentation.

J Neuroendocrinol 2021 Aug 3;33(8):e13005. Epub 2021 Aug 3.

Department of Medicine, Division of Hematology and Medical Oncology, Seidman Cancer Center, University Hospitals, Case Western Reserve University, Cleveland, OH, USA.

Most of neuroendocrine neoplasms (NENs) are located in the gastrointestinal tract and lung, and they are rarely found on the upper aero-digestive tract, which limit the current literature about nasopharyngeal NENs. This systemic review will summarize the clinical, pathological features and optimal diagnosis and management of different types of nasopharyngeal NENs (NP NENs). In-addition, we herein report an EBV negative TP53-mutated/ Rb-wild type nasopharyngeal neuroendocrine carcinoma (NEC) in a young man in which touch preparation cytology studies were integral to establishing a definitive diagnosis. To our knowledge, only very few cases of primary neuroendocrine carcinoma of the nasopharynx have been reported in the literature and the reports of these cases have not included detailed description of different types and how to optimally diagnose and manage them. In this abstract, we also highlighted the evidence about the safety of using growth factors in patients with sickle cell anemia who are receiving cytotoxic chemotherapy.
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http://dx.doi.org/10.1111/jne.13005DOI Listing
August 2021

Pendred Syndrome with C Cell Hyperplasia.

Endocr Pathol 2021 Sep 27;32(3):427-428. Epub 2021 Jul 27.

Departments of Pathology, University Hospitals Cleveland Medical Center, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH, 44106, USA.

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http://dx.doi.org/10.1007/s12022-021-09690-1DOI Listing
September 2021

Pituitary corticotroph tumour with adrenocortical cells: A distinct clinicopathologic entity with unique morphology and methylation profile.

Neuropathol Appl Neurobiol 2021 Jul 23. Epub 2021 Jul 23.

Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.

We describe a rare TPIT-positive corticotroph PitNET that is admixed with SF1-positive adrenocortical cells. This dimorphous population of cells showed no colocalisation between TPIT and SF1 by immunofluorescence, and an adrenocortical choristoma was favoured. Methylation array analysis revealed a novel methylation profile in relation to other pituitary neoplasms.
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http://dx.doi.org/10.1111/nan.12754DOI Listing
July 2021

Hypothalamic hormone-producing tumors.

Handb Clin Neurol 2021 ;181:67-74

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

The hypothalamus is functional neuroendocrine tissue that is responsible for the synthesis and secretion of peptide hormones that regulate the pituitary and other endocrine functions. Endocrine tumors of the hypothalamus are rare but they provide a model for tumors that have both structural and functional effects. Patients with hypothalamic endocrine tumors suffer mass effects including headaches, visual disturbances, and endocrine dysfunction due to structural damage to hypothalamic nuclei, which regulate appetite, temperature, diurnal rhythms and emotions. In addition, these tumors can secrete hormones that can cause acromegaly, Cushing disease, hyperprolactinemia, and the syndrome of inappropriate antidiuresis. Morphologic classification of these tumors has provided evidence for two classes of tumors, gangliocytomas that are composed of large neurons and neurocytomas that are comprised of small cells; these resemble the variants of magnocellular and parvocellular neurons in the hypothalamic nuclei. Biomarkers are used to classify these tumors and achieve accurate structure-function correlations. While surgery remains the mainstay of therapy, novel medical and radiopharmaceutical approaches are available for patients with progressive and/or unresectable tumors.
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http://dx.doi.org/10.1016/B978-0-12-820683-6.00006-3DOI Listing
July 2021

An Update on Pituitary Neuroendocrine Tumors Leading to Acromegaly and Gigantism.

J Clin Med 2021 May 22;10(11). Epub 2021 May 22.

Department of Medicine, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada.

An excess of growth hormone (GH) results in accelerated growth and in childhood, the clinical manifestation is gigantism. When GH excess has its onset after epiphyseal fusion at puberty, the overgrowth of soft tissue and bone results in acromegaly. Persistent GH excess in gigantism also causes acromegalic features that become evident in the adult years. The causes of GH excess are primarily lesions in the pituitary, which is the main source of GH. In this review, we provide an update on the clinical, radiological and pathologic features of the various types of pituitary neuroendocrine tumors (PitNETs) that produce GH. These tumors are all derived from PIT1-lineage cells. Those composed of somatotrophs may be densely granulated, resembling normal somatotrophs, or sparsely granulated with unusual fibrous bodies. Those composed of mammosomatotrophs also produce prolactin; rare plurihormonal tumors composed of cells that resemble mammosomatotrophs also produce TSH. Some PitNETs are composed of immature PIT1-lineage cells that do not resemble differentiated somatotrophs, mammosomatotrophs, lactotroph or thyrotrophs; these tumors may cause GH excess. An unusual oncocytic PIT1-lineage tumor known as the acidophil stem cell tumor is predominantly a lactotroph tumor but may express GH. Immature PIT1-lineage cells that express variable amounts of hormones alone or in combination can sometimes cause GH excess. Unusual tumors that do not follow normal lineage differentiation may also secrete GH. Exceptional examples of acromegaly/gigantism are caused by sellar tumors composed of hypothalamic GHRH-producing neurons, alone or associated with a sparsely granulated somatotroph tumor. Each of these various tumors has distinct clinical, biochemical and radiological features. Data from careful studies based on morphologic subtyping indicate that morphologic classification has both prognostic and predictive value.
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http://dx.doi.org/10.3390/jcm10112254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196981PMC
May 2021

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 Sep 21;32(3):327-335. 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
September 2021

Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification.

Mod Pathol 2021 09 21;34(9):1634-1650. 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
September 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 Aug 12;114:1-8. Epub 2021 May 12.

Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, 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
August 2021

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.

Pancreas 2021 04;50(4):469-493

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract: This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma held on October 2 and 3, 2019. The panelists consisted of endocrinologists, medical oncologists, surgeons, radiologists/nuclear medicine physicians, nephrologists, pathologists, and radiation oncologists. The panelists performed a literature review on a series of questions regarding the medical management of metastatic and unresectable pheochromocytoma and paraganglioma as well as questions regarding surveillance after resection. The panelists voted on controversial topics, and final recommendations were sent to all panel members for final approval.
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http://dx.doi.org/10.1097/MPA.0000000000001792DOI Listing
April 2021

Challenges in the Diagnosis of Pituitary Neuroendocrine Tumors.

Authors:
Sylvia L Asa

Endocr Pathol 2021 Jun 17;32(2):222-227. Epub 2021 Apr 17.

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

Detailed analysis of cytodifferentiation and hormone production has classified pituitary neuroendocrine tumors (PitNETs) in a formal system that reflects the lineage differentiation of nontumorous adenohypophysial cells as well as subtypes of tumors that have predictive value. In addition, tumors composed of cells that lack terminal differentiation are well characterized. To comply with the proposal to create an overarching classification of neuroendocrine neoplasia, these tumors are now called PitNETs rather than adenomas. The next important step will be to relinquish the term "pituitary carcinoma" for metastatic PitNETs that remain well differentiated, and to alter the terminology used for tumors that are not terminally differentiated to reflect only their immature lineage. The existence of mixed neuroendocrine and non-neuroendocrine neoplasms (MiNENs) similar to those at other body sites is proven by mixed craniopharyngiomas with PitNETs. As with other NETs, these neoplasms should be reported with synoptic data that guide completeness of reporting. A formal system of grading should be created, but not only based on proliferation, as these tumors have shown the prognostic value of cytodifferentiation. A formal system of staging should also be devised to complement grade in the thorough and accurate diagnosis of tumors that arise from adenohypophysial cells.
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http://dx.doi.org/10.1007/s12022-021-09678-xDOI Listing
June 2021

Significance of Alpha-inhibin Expression in Pheochromocytomas and Paragangliomas.

Am J Surg Pathol 2021 09;45(9):1264-1273

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
September 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 Sep 3;32(3):415-417. 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
September 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

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors.

Endocr Pathol 2021 Mar 18;32(1):169-191. Epub 2021 Jan 18.

Green Templeton College, University of Oxford and ENETS Centre of Excellence, Royal Free Hospital, London, UK.

Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.
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http://dx.doi.org/10.1007/s12022-021-09662-5DOI 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

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

World Neurosurg 2021 02 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

Issues to Consider When Implementing Digital Pathology for Primary Diagnosis.

Arch Pathol Lab Med 2020 11;144(11):1297

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

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http://dx.doi.org/10.5858/arpa.2020-0168-LEDOI Listing
November 2020

Cytokeratin profiles in pituitary neuroendocrine tumors.

Hum Pathol 2021 01 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

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

Molecular profiling confirms historical immunohistochemistry in acromegaly.

Endocr Relat Cancer 2020 10;27(10):L1-L2

Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1530/ERC-20-0260DOI Listing
October 2020

Characterization of pathological thyroid tissue using polarization-sensitive second harmonic generation microscopy.

Lab Invest 2020 10 31;100(10):1280-1287. Epub 2020 Jul 31.

Department of Physics, University of Toronto, Toronto, ON, Canada.

Polarization-sensitive second harmonic generation (SHG) microscopy is an established imaging technique able to provide information related to specific molecular structures including collagen. In this investigation, polarization-sensitive SHG microscopy was used to investigate changes in the collagen ultrastructure between histopathology slides of normal and diseased human thyroid tissues including follicular nodular disease, Grave's disease, follicular variant of papillary thyroid carcinoma, classical papillary thyroid carcinoma, insular or poorly differentiated carcinoma, and anaplastic or undifferentiated carcinoma ex vivo. The second-order nonlinear optical susceptibility tensor component ratios, χ'/χ' and χ'/χ', were obtained, where χ'/χ' is a structural parameter and χ'/χ' is a measure of the chirality of the collagen fibers. Furthermore, the degree of linear polarization (DOLP) of the SHG signal was measured. A statistically significant increase in χ'/χ' values for all the diseased tissues except insular carcinoma and a statistically significant decrease in DOLP for all the diseased tissues were observed compared to normal thyroid. This finding indicates a higher ultrastructural disorder in diseased collagen and provides an innovative approach to discriminate between normal and diseased thyroid tissues that is complementary to standard histopathology.
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http://dx.doi.org/10.1038/s41374-020-0475-7DOI Listing
October 2020

Images in Endocrine Pathology: Progressive Loss of Sustentacular Cells in a Case of Recurrent Jugulotympanic Paraganglioma over a Span of 5 years.

Endocr Pathol 2020 Sep;31(3):310-314

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

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http://dx.doi.org/10.1007/s12022-020-09632-3DOI Listing
September 2020

Perithyroidal Salivary Gland Acinic Cell Carcinoma: Morphological and Molecular Attributes of a Unique Lesion.

Head Neck Pathol 2021 Jun 9;15(2):628-637. Epub 2020 Jun 9.

Department of Breast, Endocrine Tumors and Sarcoma, Karolinska University Hospital, Stockholm, Sweden.

Rarely, salivary gland tumors such as mucoepidermoid carcinoma, mammary analogue secretory carcinoma and mucinous carcinoma arise as primary tumors from ectopic or metaplastic salivary gland tissue adjacent to or within the thyroid gland. We report for the first time a case of primary salivary acinic cell carcinoma (AcCC) adjacent to the thyroid gland in a 71-year-old female patient with Crohns disease and a previous history of malignant melanoma. Following the development of a nodule adjacent to the left thyroid lobe, a fine-needle aspiration biopsy was reported as consistent with a follicular lesion of undetermined significance (Bethesda III). A left-sided hemithyroidectomy was performed. A circumscribed lesion measuring 33 mm was noted adjacent to the thyroid and trapping parathyroid, it was composed of solid nests and glands with microcystic and follicular patterns. The tumor was negative for thyroid, parathyroid and paraganglioma markers, but positive for pan-cytokeratins, CK7, CD10, CD117, androgen receptor and HNF-beta. A metastasis of a thyroid-like renal cell carcinoma was suspected but ruled out, and the patient had no evident lesions on extensive radiology of the urogenital, pulmonary and GI tracts. Based on the morphology, a diagnosis of AcCC was suggested, and confirmed with DOG1 and PAS-diastase staining. Molecular analyses pinpointed a constitutional ASXL1 variant of uncertain significance, but no fusion events. The patient had no radiological or clinical evidence of parotid, submandibular or sublingual tumors postoperatively, and the excised lesion was therefore assumed to be a primary tumor. We here detail the morphological and immunophenotypic profile of this previously undescribed perithyroidal tumor.
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http://dx.doi.org/10.1007/s12105-020-01187-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134583PMC
June 2021

Data set for the reporting of pheochromocytoma and paraganglioma: explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting.

Hum Pathol 2021 04 11;110:83-97. Epub 2020 May 11.

Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, USA. Electronic address:

Background And Objectives: The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each anatomic site, to be used throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to improved patient management and enhanced epidemiological research.

Methods: Pheochromocytoma and paraganglioma are uncommon and are frequently overlooked in registry data sets. Malignant criteria have previously been defined only when there was metastatic disease.

Results: With recent recognition of a significant inheritance association and the development of risk stratification tools, this data set was created in order to obtain more meaningful outcomes and management data, using similar criteria across the global pathology community. Issues related to key core and non-core elements, especially clinical hormonal status, familial history, tumor focality, proliferative fraction, adverse or risk stratification features, and ancillary techniques, are discussed in the context of daily application to these types of specimens.

Conclusions: The ICCR data set, developed by an international panel of endocrine organ specialists, establishes a pathology-standardized reporting guide for pheochromocytoma and paraganglioma.
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http://dx.doi.org/10.1016/j.humpath.2020.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655677PMC
April 2021
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