Publications by authors named "Shereen Ezzat"

222 Publications

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

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 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

Prolactin, a potential biomarker for chronic GVHD activity.

Eur J Haematol 2021 Feb 26;106(2):158-164. Epub 2020 Oct 26.

Section of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Introduction: The polypeptide prolactin (PRL) is a peptide hormone and a cytokine mostly secreted from the anterior pituitary gland. PRL is also synthesized in extra pituitary tissues including thymocytes and T lymphocytes. Considering the need for chronic GVHD (cGVHD) biomarkers, we explored the relationship between hyperprolactinemia and active cGVHD in a cohort of long-term post-alloHCT survivors.

Methods: Three-hundred sixteen adults underwent alloHCT between 2010 and 2016, survived more than 1 year and were included. All patients underwent a regular annual assessment that includes a hormone profile with serum PRL levels.

Results: Overall, 236 (74.7%) patients had cGVHD, and in 199 (63%), the grade was moderate or severe. Sixty-five (21%) recipients had active cGVHD at the time of the annual evaluation, and hyperprolactinemia was documented in 63 (19.9%) patients. Hyperprolactinemia correlated with cGVHD activity (Odds Ratio 6.9 (95% CI; 3.6-13.1); P < .001) in the multivariate analysis. In conclusion, patients with hyperprolactinemia were 6.4 times more likely to have active cGVHD in comparison with those patients with normal levels of PRL (P < .001).

Conclusion: Prolactin may serve as a biomarker for cGVHD activity. Further studies are required to confirm these findings, and to explore if hyperprolactinemia has an impact on cGVHD severity and prognosis.
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http://dx.doi.org/10.1111/ejh.13531DOI Listing
February 2021

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

Subclinical hypothyroidism.

Minerva Endocrinol 2020 Aug 3. Epub 2020 Aug 3.

Endocrinology Unit-Northern Area, Azienda USL Modena, Modena, Italy -

Subclinical hypothyroidism - i.e., a condition characterized by serum TSH concentrations above the normal reference range in the presence of normal serum T4 levels - affects 4 to 20% of the population living in iodine-sufficient areas. The present work reviews the clinical challenges regarding, on the one hand, the signs and symptoms possibly related to subclinical hypothyroidism, and on the other hand, the most recent guideline recommendations to treatment.
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http://dx.doi.org/10.23736/S0391-1977.20.03176-4DOI Listing
August 2020

Response to Miyauchi re: "A Prospective Mixed-Methods Study of Decision Making on Surgery or Active Surveillance for Low-Risk Papillary Thyroid Cancer".

Thyroid 2020 10 2;30(10):1542-1543. Epub 2020 Jul 2.

Department of Otolaryngology and Head and Neck Surgery, University Health Network and University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1089/thy.2020.0495DOI Listing
October 2020

A Prospective Mixed-Methods Study of Decision-Making on Surgery or Active Surveillance for Low-Risk Papillary Thyroid Cancer.

Thyroid 2020 07 8;30(7):999-1007. Epub 2020 Apr 8.

Department of Otolaryngology-Head and Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Canada.

Active surveillance (AS) of small, low-risk papillary thyroid cancers (PTCs) is increasingly being considered. There is limited understanding of why individuals with low-risk PTC may choose AS over traditional surgical management. We present a mixed-methods analysis of a prospective observational real-life decision-making study regarding the choice of thyroidectomy or AS for management of localized, low-risk PTCs <2 cm in maximum diameter (NCT03271892). Patients were provided standardized medical information and were interviewed after making their decision (which dictated disease management). We evaluated patients' levels of decision-self efficacy (confidence in medical decision-making ability) at the time information was presented and their level of decision satisfaction after finalizing their decision (using standardized questionnaires). We asked patients to explain the reason for their choice and qualitatively analyzed the results. We enrolled 74 women and 26 men of mean age 52.4 years, with a mean PTC size of 11.0 mm (interquartile range 9.0, 14.0 mm). Seventy-one patients (71.0% [95% confidence interval 60.9-79.4%]) chose AS over surgery. Ninety-four percent (94/100) of participants independently made their own disease management choice; the rest shared the decision with their physician. Participants had a high baseline level of decision self-efficacy (mean 94.3, standard deviation 9.6 on a 100-point scale). Almost all (98%, 98/100) participants reported high decision satisfaction. Factors reported by patients as influencing their decision included the following: perceived risk of thyroidectomy or the cancer, family considerations, treatment timing in the context of life circumstances, and trust in health care providers. In this Canadian study, ∼7 out of 10 patients with small, low-risk PTC, who were offered the choice of AS or surgery, chose AS. Personal perceptions about cancer or thyroidectomy, contextual factors, family considerations, and trust in health care providers strongly influenced patients' disease management choices.
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http://dx.doi.org/10.1089/thy.2019.0592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374636PMC
July 2020

The Clinicopathological Spectrum of Acromegaly.

J Clin Med 2019 Nov 13;8(11). Epub 2019 Nov 13.

Department of Endocrine Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.

Background: Acromegaly results from a persistent excess in growth hormone with clinical features that may be subtle or severe. The most common cause of acromegaly is a pituitary tumor that causes excessive production of growth hormone (GH), and rare cases are due to an excess of the GH-releasing hormone (GHRH) or the ectopic production of GH.

Objective: Discuss the different diseases that present with manifestations of GH excess and clinical acromegaly, emphasizing the distinct clinical and radiological characteristics of the different pathological entities.

Methods: We performed a narrative review of the published clinicopathological information about acromegaly. An English-language search for relevant studies was conducted on PubMed from inception to 1 August 2019. The reference lists of relevant studies were also reviewed.

Results: Pituitary tumors that cause GH excess have several variants, including pure somatotroph tumors that can be densely or sparsely granulated, or plurihormonal tumors that include mammosomatotroph, mixed somatotroph-lactotroph tumors and mature plurihomonal Pit1-lineage tumors, acidophil stem cell tumors and poorly-differentiated Pit1-lineage tumors. Each tumor type has a distinct pathophysiology, resulting in variations in clinical manifestations, imaging and responses to therapies.

Conclusion: Detailed clinicopathological information will be useful in the era of precision medicine, in which physicians tailor the correct treatment modality to each patient.
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http://dx.doi.org/10.3390/jcm8111962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912315PMC
November 2019

The Clinicopathological Spectrum of Parathyroid Carcinoma.

Front Endocrinol (Lausanne) 2019 23;10:731. Epub 2019 Oct 23.

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

Parathyroid carcinoma is rare, representing <1% of primary hyperparathyroidism cases. Retrospective data of patients referred for evaluation of parathyroid disease between 2001 and 2018 were reviewed. The goal was to describe the clinical presentation, histopathologic characteristics, and treatment outcomes of parathyroid carcinoma. We identified 8 cases of parathyroid carcinoma from the outpatient practice of a quaternary care Endocrine Oncology practice in Toronto, Canada. The clinical presentation was as follows: 5/8 cases (62.5%) of symptomatic hypercalcemia and 3/8 cases (37.5%) of a suspicious thyroid nodule. Hypercalcemia was evident in all 7 cases with pre-operative calcium measurements. Histopathologic features included: vascular invasion in 7/8 cases (87.5%) and immunohistochemical loss of either parafibromin, retinoblastoma, or p27 in all 8 cases. Additional treatment included: external beam radiotherapy in 5/8 cases (62.5%), chemotherapy for 2/8 patients (25%), and additional surgery for 3/8 patients (37.5%). Only 2 patients (25%) had long-term remission following surgical treatment, and the others had either persistent (3 patients) or recurrent disease (3 patients). Five patients developed metastatic disease, all involving lung. In one of two patients treated with Sorafenib there was evidence of regression of lung metastases. One patient died of disease progression. In this series of patients with parathyroid carcinoma largely presenting with symptomatic hypercalcemia and angioinvasive disease, only a minority achieved a durable remission. Lung was the most common site of distant metastasis. Surgery led to remission in two cases, but none of the six patients with persistent or recurrent disease ultimately achieved disease remission.
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http://dx.doi.org/10.3389/fendo.2019.00731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819433PMC
October 2019

Co-occurrence of breast cancer and neuroendocrine tumours: New genetic insights beyond Multiple Endocrine Neoplasia syndromes.

Endocrinol Diabetes Metab 2019 Oct 8;2(4):e00092. Epub 2019 Sep 8.

Division of Endocrinology and Metabolism Department of Medicine University Health Network University of Toronto Toronto Ontario Canada.

Objective: Age-standardized incidence of female breast cancer is 145.1 per 100000/year and 5.86 per 100000/year for neuroendocrine tumours (NET) in Canada. Evidence is scarce about gene variants that may predispose patients to develop both neoplasms. The objective of this study was to identify germline gene variants associated with this combination of tumours.

Design And Patients: A retrospective chart review (2007-2018) in a tertiary NET referral centre was completed. A series of 9 female patients with concurrent breast cancer and NET is presented. All patients underwent a 37 gene hereditary cancer next-generation sequencing panel.

Results: Mean age was 61.4 years (35-85) at breast cancer diagnosis and 63.4 years (51-89) at NET diagnosis. Four patients had a pancreatic, three had a small bowel and two had a lung NET. Two patients were known cases of and one patient was found to harbour a pathogenic variant in and a variant of unknown significance (VUS) in . A second patient was found to harbour a pathogenic variant in . A third patient was found to carry a pathogenic variant in as well as a VUS in and . Another patient was found to harbour a VUS in . One patient was found to carry a pathogenic variant in .

Conclusion: The first cases of a , an and a pathogenic variants in patients with both breast cancer and NET were presented. NGS testing should be considered in specific patients with this combination of neoplasms, as certain germline variants beyond , have important implications for cancer surveillance.
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http://dx.doi.org/10.1002/edm2.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775469PMC
October 2019

Management of Small Bowel Neuroendocrine Tumors.

Cancers (Basel) 2019 Sep 18;11(9). Epub 2019 Sep 18.

Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University of Toronto, Toronto M5G2C1, ON, Canada.

Several important landmark trials have reshaped the landscape of non-surgical management of small bowel neuroendocrine tumors over the last few years, with the confirmation of the antitumor effect of somatostatin analogue therapy in PROMID and CLARINET trials as well as the advent of therapies with significant potential such as mammalian target of rapamycin inhibitor (mTor) everolimus (RADIANT trials) and peptide receptor radionuclide therapy (PRRT) with 177-Lutetium (NETTER-1 trial). This narrative summarizes the recommended management strategies of small bowel neuroendocrine tumors. We review the main evidence behind each recommendation as well as compare and contrast four major guidelines, namely the 2016 Canadian Consensus guidelines, the 2017 North American Neuroendocrine Tumor Society guidelines, the 2018 National Comprehensive Cancer Network guidelines, and the 2016 European Neuroendocrine Tumor Society guidelines. Different clinical situations will be addressed, from loco-regional therapy to metastatic unresectable disease. Carcinoid syndrome, which is mostly managed by somatostatin analogue therapy and the serotonin antagonist telotristat etiprate for refractory diarrhea, as well as neuroendocrine carcinoma will be reviewed. However, several questions remain unanswered, such as the optimal management of neuroendocrine carcinomas or the effect of combining and sequencing of the aforementioned modalities where more randomized controlled trials are needed.
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http://dx.doi.org/10.3390/cancers11091395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770692PMC
September 2019

A Systematic Review and Meta-Analysis of Patient Preferences for Combination Thyroid Hormone Treatment for Hypothyroidism.

Front Endocrinol (Lausanne) 2019 24;10:477. Epub 2019 Jul 24.

Division of Endocrinology, University Health Network and University of Toronto, Toronto, ON, Canada.

The standard of care in management of hypothyroidism is treatment with levothyroxine (L-T4). Sometimes patients are dissatisfied with L-T4 and the combination of levo-triiodothyronine (L-T3) with L-T4 is considered. We performed a systematic review and meta-analysis of blinded randomized controlled trials (RCTs), reporting how often hypothyroid patients prefer combination L-T3/L-T4 treatment to L-T4 alone. We also explored for explanatory factors for combination therapy preference in sensitivity analyses examining trial, patient, and disease characteristics. Potential dose-response relationships were explored using meta-regression analyses. We searched 9 electronic databases (from inception until February, 2019), supplemented with a hand-search. Two reviewers independently screened abstracts and citations and reviewed full-text papers, with consensus achieved on the included studies. Two reviewers independently critically appraised the quality of included studies and abstracted the data. Random effects meta-analyses were reported for the percentage of patients preferring combination L-T3/T-T4 therapy over L-T4 alone. A binomial distribution of choices (i.e., preference of combination therapy or no preference for combination therapy) was assumed. We included 7 blinded RCTs including 348 hypothyroid individuals in the primary meta-analysis. The pooled prevalence rate for preference of combination therapy over L-T4 was 46.2% (95% confidence interval 40.2%, 52.4%) ( = 0.231 for the difference from chance). There was no significant statistical heterogeneity among study results (Q = 7.32, degrees of freedom = 6, = 0.293, = 18.0%). In sensitivity analyses, combination treatment preference was explained in part by treatment effects on TSH concentration, mood and symptoms, but not quality of life nor body weight. In a secondary dose-response meta-regression analyses, a statistically significant association of treatment preference was identified for total daily L-T3 dose, but not L-T3:L-T4 dose ratio. In conclusion, in RCTs in which patients and investigators were blinded to treatment allocation, approximately half of participants reported preferring combination L-T3 and L-T4 therapy compared to L-T4 alone; this finding was not distinguishable from chance. An observed potential positive L-T3 dose effect on treatment preference deserves further study, with careful consideration of thyroid biochemical indices and patient reported outcomes.
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http://dx.doi.org/10.3389/fendo.2019.00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667836PMC
July 2019

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients.

Clin Genet 2019 11 6;96(5):461-467. Epub 2019 Aug 6.

Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.
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http://dx.doi.org/10.1111/cge.13613DOI Listing
November 2019

A Systematic Review and Meta-Analysis of the Diagnostic Performance of BRAF V600E Immunohistochemistry in Thyroid Histopathology.

Endocr Pathol 2019 Sep;30(3):201-218

Division of Endocrinology, University Health Network and University of Toronto, Toronto, Canada.

Immunohistochemistry (IHC) in evaluating thyroid surgical specimens may facilitate diagnostic and prognostic evaluation, with potential therapeutic implications. We performed a systematic review and meta-analysis examining the analytic validity of IHC in detecting BRAFV600E mutations in thyroid cancer (primary or metastatic). We screened citations from three electronic databases (until December 20, 2018), supplemented by a hand search of authors' files and cross-references of reviews. Citations and full-text papers were independently reviewed in duplicate, and consensus was achieved on inclusion of papers. Two reviewers independently critically appraised and abstracted data from included papers. Random-effect meta-analyses were conducted for sensitivity and specificity estimates. We reviewed 1499 unique citations and 93 full-text articles. We included 1 systematic review and 30 original articles. The published review (from 2015) needed to be updated as there were multiple subsequent original studies. The pooled sensitivity of IHC in detecting a BRAFV600E mutation was 96.8% (95% confidence interval [CI] at 94.1%, 98.3%) (29 studies, including 2659 BRAFV600E mutant tumors). The IHC pooled specificity was 86.3% (95% CI 80.7%, 90.4%) (28 studies, including 1107 BRAFV600E wild-type specimens). These meta-analyses were subject to statistically significant heterogeneity, partly explained by antibody type (sensitivity and specificity) and tissue/tumor type (specificity). In conclusion, BRAF IHC is highly sensitive and reasonably specific in detecting the BRAFV600E mutation; however, there is some variability in analytic performance.
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http://dx.doi.org/10.1007/s12022-019-09585-2DOI Listing
September 2019

Treatment Options for Pancreatic Neuroendocrine Tumors.

Cancers (Basel) 2019 Jun 14;11(6). Epub 2019 Jun 14.

Department of Endocrine Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 1Z5, Canada.

The management of pancreatic neuroendocrine tumors (PanNETs) involves classification into non-functional or functional PanNET, and as localized or metastatic PanNET. In addition, while most PanNETs are sporadic, these endocrine neoplasms can also be manifestations of genetic syndromes. All these factors may assist in forming a risk stratification system permitting a tailored management approach. Most PanNETs are classified as non-functional because they are not associated with clinical sequelae of hormone excess. They are characterized by non-specific symptoms, such as abdominal pain or weight loss, resulting from mass effect related to the pancreatic tumor or secondary to distant metastases. Accurate staging of the disease is essential for determining the appropriate approach to therapy. As cure is only potentially possible with surgical resection of the tumor, it is recommended to remove all localized and limited metastatic disease. However, many patients present with metastatic and/or advanced local disease. In such instances, the goal of therapy is to control tumor growth and/or decrease tumor burden, lengthen survival, and palliate local symptoms and those of hormone excess. This typically requires a multimodal approach, including surgery, liver-directed treatment, and systemic medical therapy.
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http://dx.doi.org/10.3390/cancers11060828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628351PMC
June 2019

Papillary Thyroid Cancers with Focal Tall Cell Change are as Aggressive as Tall Cell Variants and Should Not be Considered as Low-Risk Disease.

Ann Surg Oncol 2019 Aug 21;26(8):2533-2539. Epub 2019 May 21.

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

Background: The tall cell variant of papillary thyroid carcinoma (PTC) is as an aggressive histological variant. The proportion of tall cells needed to influence prognosis is debated.

Methods: Patients with PTC and tall cells, defined as having a height-to-width ratio of ≥ 3:1, seen at a high-volume center between 2001 and 2015, were reviewed. Specimens were classified as (1) focal tall cell change, containing < 30% of tall cells; (2) tall cell variant, ≥ 30% of tall cells; and (3) control cases selected from infiltrative classical PTCs without adverse cytologic features. Univariate, sensitivity, and multivariate analyses were performed with persistent/recurrent disease as the primary outcome.

Results: We identified 96 PTCs with focal tall cell change, 35 with the tall cell variant and 104 control cases. Factors associated with poor clinical prognosis were significantly greater in those with focal tall cell change and tall cell variants. Regarding primary outcome, hazard ratios were 2.3 (95% confidence interval [CI] 1.0-5.7) for focal tall cell change, and 3.4 (95% CI 1.2-8.7) for tall cell variants compared with controls. Five-year disease-free survival was higher for the control group (92.7%, CI 87.4-98.0) compared with focal tall cell change (76.3%, CI 66.1-86.5) and the tall cell variant (62.2%, CI 43.2-81.2). When stratified in groups consisting of tall cell proportions (< 10%, 10-19%, 20-29% and ≥ 30%), identification of ≥ 10% tall cell change was associated with worse outcome (p = 0.002).

Conclusions: PTCs with ≥ 10% tall cell change have worse prognosis than those without tall cells. Our data indicate that thyroid cancer management guidelines should consider PTCs with focal tall cell change outside of the low-risk classification.
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http://dx.doi.org/10.1245/s10434-019-07444-2DOI Listing
August 2019

A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial.

Br J Cancer 2019 06 20;120(12):1113-1119. Epub 2019 May 20.

Department of Medical Oncology and Haematology Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.

Background: Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited.

Methods: A multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL. Patients received 50 mg orally for 4-6 weeks.

Results: Between May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 (64%) prior surgery. The DCR was 83% (95% CI: 61-95%) and median PFS 13.4 (95% CI: 5.3-24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1-88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment.

Conclusion: Although the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.
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http://dx.doi.org/10.1038/s41416-019-0474-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738062PMC
June 2019

Cognitive functioning in thyroid cancer survivors: a systematic review and meta-analysis.

J Cancer Surviv 2019 04 4;13(2):231-243. Epub 2019 Apr 4.

Division of Endocrinology, University of Toronto, Toronto, Canada.

Background: Some thyroid cancer (TC) survivors experience cognitive symptoms.

Purpose: The purpose of this study is to perform a systematic literature review and meta-analysis comparing cognitive performance in TC survivors to controls.

Methods: We performed a seven-database electronic search and hand-search. We performed duplicate independent reviews and data abstraction. Random effects meta-analyses reported standardized mean differences (SMDs) with 95% confidence intervals (CIs), where a negative value implies worse performance in the TC group.

Results: We reviewed 1174 unique citations and 10 full-text papers. We included seven studies of 241 treated TC survivors and 273 controls. Cognitive function was statistically significantly worse in TC survivors in the following domains: Attention and Concentration (Digit Span Forwards) SMD - 0.37 (95% CI - 0.62, - 0.13, p = 0.003, four studies), Speed of Processing (Trail Making A) SMD - 0.36 (95% CI - 0.66, - 0.05, p = 0.022, four studies), and Language (Controlled Oral Word Association [COWAT]-Categories) SMD - 0.97 (95% - 1.31, - 0.64, p < 0.001, two studies). Executive Function results varied: COWAT-Letters SMD - 0.60 (95% CI - 0.94, - 0.27, p < 0.001, two studies), Digit Span Backwards SMD - 0.40 (95% CI - 0.64, - 0.15, p = 0.002, four studies), and Trail Making B test SMD - 0.20 (95% CI - 0.51, 0.10, p = 0.191, four studies). Statistical heterogeneity limited the COWAT-Categories and Digit Span Backwards meta-analyses.

Conclusions: Cognitive function was worse in TC survivors in multiple domains. Limitations included few studies, potential confounding, and lack of prospective data.

Implications For Cancer Survivors: TC survivors may experience impairments in cognitive function and should report cognitive concerns to healthcare practitioners.
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http://dx.doi.org/10.1007/s11764-019-00745-1DOI Listing
April 2019

An Institutional Experience of Tumor Progression to Pituitary Carcinoma in a 15-Year Cohort of 1055 Consecutive Pituitary Neuroendocrine Tumors.

Endocr Pathol 2019 Jun;30(2):118-127

Department of Medicine, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Ontario, Canada.

Pituitary carcinoma is a rare disease, defined by the presence of cerebrospinal or distant metastasis of a pituitary neuroendocrine tumor (PitNET). To review our institutional experience of pituitary carcinoma, we searched the database of the UHN Endocrine Oncology Site group and the University Health Network pathology laboratory information system from 2001 to 2016. Among 1055 PitNETs from 1169 transsphenoidal resections, we identified 4 cases of pituitary carcinoma, indicating that pituitary carcinoma represents around 0.4% of PitNETs. All four patients were women. The age at initial presentation ranged from 23 to 54 years. Two patients had Cushing disease with corticotroph tumors; one was initially a densely granulated corticotroph tumor that evolved to become sparsely granulated, while the other was a Crooke cell tumor. One patient had a functioning sparsely granulated lactotroph tumor and one had a clinically silent poorly differentiated PIT1 lineage tumor. Apart from a relatively high Ki67 labeling index (≥ 10%) in three tumors, there were no cytomorphologic features at the time of initial presentation that could predict subsequent metastatic behavior. The time from diagnosis of the pituitary neuroendocrine tumor to the diagnosis of malignancy was 3 to 14 years. Therapies included somatostatin analogs, external beam radiotherapy, chemotherapies including capecitabine/temozolomide, everolimus, sunitinib, bevacizumab, and peptide receptor radionuclide therapy (PRRT). One patient died of disease 18 years after initial diagnosis, underscoring the protracted course of this ultimately fatal neuroendocrine malignancy.
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http://dx.doi.org/10.1007/s12022-019-9568-5DOI Listing
June 2019

PREDICTIVE MARKERS FOR POSTSURGICAL MEDICAL MANAGEMENT OF ACROMEGALY: A SYSTEMATIC REVIEW AND CONSENSUS TREATMENT GUIDELINE.

Endocr Pract 2019 Apr 18;25(4):379-393. Epub 2019 Jan 18.

To clarify the selection of medical therapy following transsphenoidal surgery in patients with acromegaly, based on growth hormone (GH)/insulin-like growth factor 1 (IGF-1) response and glucometabolic control. We carried out a systematic literature review on three of the best studied and most practical predictive markers of the response to somatostatin analogues (SSAs): somatostatin receptor (SSTR) expression, tumor morphologic classification, and T2-weighted magnetic resonance imaging (MRI) signal intensity. Additional analyses focused on glucose metabolism in treated patients. The literature survey confirmed significant associations of all three factors with SSA responsiveness. SSTR expression appears necessary for the SSA response; however, it is not sufficient, as approximately half of SSTR2-positive tumors failed to respond clinically to first-generation SSAs. MRI findings (T2-hypo-intensity) and a densely granulated phenotype also correlate with SSA efficacy, and are advantageous as predictive markers relative to SSTR expression alone. Glucometabolic control declines with SSA monotherapy, whereas GH receptor antagonist (GHRA) monotherapy may restore normoglycemia. We propose a decision tree to guide selection among SSAs, dopamine agonists (DAs), and GHRA for medical treatment of acromegaly in the postsurgical setting. This decision tree employs three validated predictive markers and other clinical considerations, to determine whether SSAs are appropriate first-line medical therapy in the postsurgical setting. DA treatment is favored in patients with modest IGF-1 elevation. GHRA treatment should be considered for patients with T2-hyperintense tumors with a sparsely granulated phenotype and/or low SSTR2 staining, and may also be favored for individuals with diabetes. Prospective analyses are required to test the utility of this therapeutic paradigm. = dopamine agonist; = densely granulated; = growth hormone; = growth hormone receptor antagonist; = glycated hemoglobin; = insulin-like growth factor-1; = magnetic resonance imaging; = sparsely granulated; = somatostatin analogue; = somatostatin receptor.
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http://dx.doi.org/10.4158/EP-2018-0500DOI Listing
April 2019

ENDOCRINE COMPLICATIONS IN PATIENTS WITH GVHD.

Endocr Pract 2019 May 18;25(5):485-490. Epub 2019 Jan 18.

Graft-versus-host disease (GVHD) is an immune phenomenon that occurs in 30 to 70% of patients after allogeneic hematopoietic stem cell transplantation (HST). Chronic GVHD is a state of immune dysregulation wherein, depending on the severity and organ involved, patients may require prolonged treatment with additional or higher corticosteroids and other immunosuppressive agents. The objective of this study was to review the endocrine manifestations following HST that can arise as a consequence of the primary disease or its treatment, including chemotherapeutic agents, corticosteroids, radiation, or GVHD. We performed a narrative review of GVHD after HST. An English-language search for relevant studies was conducted on PubMed from inception to August 1, 2018, using the following search terms: "endocrine complications," "bone marrow transplantation," "graft-versus-host disease," and "GVHD." The reference lists of relevant studies were also reviewed. Chronic GVHD may be associated with considerable pediatric growth impairment and may also contribute to thyroid gland dysfunction and thyroid cancer. These patients may also be at increased risk for low bone mineral density, reduced fertility, metabolic syndrome, and suppression of the pituitary-adrenal axis with adrenal insufficiency. This review indicates the importance of monitoring, diagnosing, and properly treating the endocrine complications in this population. More studies are needed to investigate the independent impact of GVHD on the endocrine system and treatment for complications. = bone mineral density; = growth hormone; = graft-versus-host disease; = hematopoietic stem cell transplantation; = insulin-like growth factor 1.
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http://dx.doi.org/10.4158/EP-2018-0529DOI Listing
May 2019

Intrathyroidal Parathyroid Carcinoma: An Atypical Thyroid Lesion.

Front Endocrinol (Lausanne) 2018 1;9:641. Epub 2018 Nov 1.

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

Parathyroid carcinoma is a rare endocrine malignancy that is typically difficult to diagnose at presentation. Here, we report a 63 year-old man who had symptomatic hypercalcemia. Investigations revealed a thyroid nodule and a lateral neck mass that was biopsied and diagnosed as "suspicious for a neuroendocrine neoplasm." He underwent total thyroidectomy with central and left neck node dissection. Histology and immunohistochemistry revealed an intrathyroidal angioinvasive parathyroid carcinoma with lymph node metastases. The tumor showed loss of parafibromin expression; germline testing revealed no pathogenic germline variants of , suggesting either a cryptic germline variant or a sporadic malignancy. Multiple pulmonary nodules consistent with metastatic disease explained persistent hypercalcemia and the patient was treated with denosumab as well as Sorafenib resulting in early regression of the lung nodules. This case illustrates an unusual parathyroid carcinoma with respect to anatomic presentation and the importance of complete pathological workup in securing the diagnosis. The management of these rare malignancies is discussed.
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http://dx.doi.org/10.3389/fendo.2018.00641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230986PMC
November 2018

Re: Quality of life and symptom impact of thyroid cancer: A cross-sectional survey of Canadian patients.

Surgery 2019 11 29;166(5):948-949. Epub 2018 Oct 29.

Clinical Endocrinology Fellowship, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology, Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.surg.2018.09.018DOI Listing
November 2019

Hypothalamic Vasopressin-Producing Tumors: Often Inappropriate Diuresis But Occasionally Cushing Disease.

Am J Surg Pathol 2019 02;43(2):251-260

Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Tumors of hypothalamic neurons that produce vasopressin are rare. We retrieved all cases of vasopressin-positive tumors in the sellar region from the database of the Department of Pathology. Five cases fulfilled the selection criteria, representing the first series of such tumors. Clinical, radiologic, and pathologic features were reviewed. Four tumors classified as neurocytomas were identified in 3 females and 1 male patient; the ages at onset of symptoms ranged from 17 to 40 years. All were large sellar masses with suprasellar extension and/or invasion of the parasellar sinuses. Three patients had the syndrome of inappropriate antidiuresis; in one of these, a 6-year history was initially considered to be idiopathic. One patient died of progressive disease; 3 had incomplete resections and are being followed. In contrast to these patients with neurocytoma, a 65-year-old woman had Cushing disease and a 0.8 cm mass that was completely resected at transsphenoidal surgery; this tumor was a gangliocytoma producing vasopressin associated with corticotroph hyperplasia. We postulate that the small amount of vasopressin secreted by this mature gangliocytic tumor was locally bound to corticotrophs, resulting in hyperplasia and Cushing disease, without sufficient overproduction to cause systemic effects of vasopressin excess. Hypothalamic neurocytoma is a tumor that can mimic pituitary neuroendocrine tumors and olfactory neuroblastoma but is distinguished by positivity for neurofilaments, NeuN, and TTF-1 and negative staining for adenohypophysial biomarkers. Our cases illustrate that neurocytoma and gangliocytoma are 2 variants of tumors of hypothalamic neurons that can produce vasopressin. The morphologic and proliferative features of these 2 tumor types represent 2 ends of a spectrum; their function also can result in divergent clinical manifestations, one characterized by reduced urine output and the other by the more insidious features of glucocorticoid excess.
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http://dx.doi.org/10.1097/PAS.0000000000001185DOI Listing
February 2019

A Systematic Review and Meta-Analysis of Subsequent Malignant Neoplasm Risk After Radioactive Iodine Treatment of Thyroid Cancer.

Thyroid 2018 12 27;28(12):1662-1673. Epub 2018 Nov 27.

Department of Endocrinology, University Health Network, Toronto, Canada.

The potential risk of subsequent malignant neoplasms (SMNs) after radioactive iodine (RAI) treatment of thyroid cancer (TC) is an important concern. A systematic review was updated comparing the risk of SMNs in TC patients treated with RAI to TC patients without RAI. Six electronic databases were searched (up to March, 2018), supplemented with a hand search. Two reviewers independently screened citations, reviewed full-text papers, and critically appraised/abstracted data. Random-effects meta-analyses were conducted using crude data and data statistically adjusted for confounders. The outcomes were any SMN and specific SMNs for which sufficient data were available. In total, 3506 unique electronic search citations and 93 full-text papers were examined, including 17 studies (3 systematic reviews and 14 original studies). Published knowledge syntheses were limited by inclusion of small numbers of studies, with two systematic reviews suggesting an increased risk of any SMN and one meta-analysis suggesting a reduced risk of breast SMN after RAI treatment. In a meta-analysis of crude data, the risk ratio of any SMN in RAI-treated TC patients was 0.98 ([confidence interval (CI) 0.76-1.27];  = 10 studies of 65,539 individuals, heterogeneity Q = 64.26, degrees of freedom [df] = 9,  < 0.001,  = 85.99). The pooled risk ratio for any SMN, adjusted for confounders, was 1.16 ([CI 0.97-1.39];  = 6 studies, data from at least 11,241 TC patients,  = 10.86, df = 5,  = 0.054,  = 53.96). In secondary analyses examining specific SMNs, although relatively rare, the risk of subsequent leukemia was increased, but the risk of multiple myeloma was reduced in RAI-treated TC patients. There was no significant increased relative risk of breast cancer, salivary cancer, or combined hematologic malignancies according to RAI treatment status. The body of evidence on whether I treatment of thyroid cancer is associated with the primary outcome of any SMN is highly heterogeneous and complex. More research examining the long-term risk of specific SMNs after I treatment is needed.
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http://dx.doi.org/10.1089/thy.2018.0244DOI Listing
December 2018

The Diagnosis and Clinical Significance of Paragangliomas in Unusual Locations.

J Clin Med 2018 Sep 13;7(9). Epub 2018 Sep 13.

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

Paragangliomas are neuroendocrine neoplasms, derived from paraganglia of the sympathetic and parasympathetic nervous systems. They are most commonly identified in the head and neck, being most frequent in the carotid body, followed by jugulotympanic paraganglia, vagal nerve and ganglion nodosum, as well as laryngeal paraganglia. Abdominal sites include the well-known urinary bladder tumors that originate in the Organ of Zuckerkandl. However, other unusual sites of origin include peri-adrenal, para-aortic, inter-aortocaval, and paracaval retroperitoneal sites, as well as tumors in organs where they may not be expected in the differential diagnosis of neuroendocrine neoplasms, such as thyroid, parathyroid, pituitary, gut, pancreas, liver, mesentery, lung, heart and mediastinum. The distinction of these lesions from epithelial neuroendocrine neoplasms is critical for several reasons. Firstly, the determination of clinical and biochemical features is different from that used for epithelial neuroendocrine tumors. Secondly, the genetic implications are different, since paragangliomas/pheochromocytomas have the highest rate of germline susceptibility at almost 40%. Finally, the characterization of metastatic disease is unique in these highly syndromic lesions. In this review, we summarize updated concepts by outlining the spectrum of anatomic locations of paragangliomas, the importance of morphology in establishing the correct diagnosis, the clinical implications for management, and the impact of genetics on the distinction between multifocal primary tumors compared with malignant disease.
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http://dx.doi.org/10.3390/jcm7090280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162705PMC
September 2018