Primary Thyroid Neoplasm with Fetal Morphology Associated with DICER1 Mutations: Expanding the Diagnostic Profile of Thyroblastoma.

Introduction: Thyroblastoma, a primary thyroid neoplasm with histological features of primitive thyroid tissue has recently been described and is included as a distinct entity in the most recent edition of the World Health Organization (WHO) Classification of Tumors (5th edition). In this study, we expand the clinical, morphological, and molecular profile of this aggressive neoplasm. Patient Findings: The patients are females, 19 and 45 years of age, referred for large thyroid nodules. Tumor morphology is biphasic, composed of nests and follicles of epithelial cells, some with colloid-like secretions reminiscent of fetal thyroid follicles intertwined with a primitive stromal spindle cell component. By immunohistochemistry, the epithelial component is diffusely positive for PAX8 and TTF1 markers. Molecular studies showed DICER1 aberrations. Conclusion: A primary primitive thyroid malignancy reminiscent of early fetal embryology with no teratoid element, recently reported as thyroblastoma represents a unique entity, novel in its description, and is likely underdiagnosed.

Parathyroid Pathology.

Proliferative pathologic lesions of parathyroid glands encompass a spectrum of entities ranging from benign hyperplastic processes to malignant neoplasia. This review article outlines the pathophysiologic classification of parathyroid disorders and describes histologic, immunohistochemical, and molecular features that can be assessed to render accurate diagnoses.

A Guide to Pheochromocytomas and Paragangliomas.

Pheochromocytomas and extra-adrenal paragangliomas are rare neuroendocrine neoplasms with characteristic histologic and immunohistochemical features. These tumors can arise in several anatomic locations, necessitating that their diagnostic recognition extends beyond the realm of endocrine disorders. A practical and reproducible risk stratification system for these tumors is still in development. In this rapidly evolving era of molecular medicine, it is essential for pathologists to equip themselves with a framework for understanding the classification of paragangliomas and pheochromocytomas and be informed of how they might advise their colleagues with regard to prognostication and appropriate follow-up.

Placental 11ß-HSD2 and Cardiometabolic Health Indicators in Infancy.

OBJECTIVE: Fetal excessive exposure to glucocorticoids may program cardiometabolic risk. Placental 11 ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) serves as a barrier to prevent fetal overexposure to maternal glucocorticoids. It has not been explored whether placental 11ß-HSD2 levels are associated with cardiometabolic health in postnatal life. RESEARCH DESIGN AND METHODS: In a prospective birth cohort study of 246 mother-infant pairs, we measured placental 11ß-HSD2 expression and maternal (32-35 weeks of gestation) and cord plasma cortisol concentrations. The primary outcomes were HOMA of insulin resistance (IR) and blood pressure (BP) in infants at age 1 year. Other outcomes included fasting insulin, HOMA ß-cell function, carotid intima-media thickness, weight z score, and skinfold thickness (triceps and subscapular) at age 1 year. RESULTS: Placental 11ß-HSD2 expression was negatively correlated with HOMA-IR (r = -0.17, P = 0.021) and fasting insulin (r = -0.18, P = 0.017) and marginally negatively correlated with systolic BP (r = -0.16, P = 0.057) but was not correlated with HOMA of ß-cell function, diastolic BP, carotid intima-media thickness, and skinfold thickness (all P > 0.1) in infants at age 1 year. Cord plasma cortisol was negatively correlated to skinfold thickness (r = -0.20, P = 0007) but was not correlated with other outcomes at age 1 year. Maternal plasma cortisol was positively correlated with maximal carotid intima-media thickness (r = 0.20, P = 0.03) but was not correlated with other outcomes. Adjusting for maternal and infant characteristics, the associations were similar. CONCLUSIONS: The study is the first to show that higher placental 11ß-HSD2 expression is associated with lower IR in infancy. Independent cohort studies are required to confirm this novel finding.

Paraneoplastic syndromes and other systemic disorders associated with neuroendocrine neoplasms.

Neuroendocrine paraneoplastic syndromes (PNS) consist of metabolic disorders that accompany benign and malignant neoplasms but remain unrelated to mass effects or invasion by the primary tumor or its metastases. The underlying pathogenesis responsible for PNS usual clinical presentation relies on aberrant production of protein hormones, proteins and other substances by the tumor. Prompt recognition of characteristic signs and symptoms combined with serological identification of key substances may result in early diagnosis of PNS and its underlying malignancy. For these reasons, healthcare professionals should familiarize themselves with tumor-induced hypercalcemia, syndrome of inappropriate antidiuretic hormone, carcinoid syndrome, virilisation syndrome, gynecomastia, acromegaly, Cushing syndrome, osteogenic osteomalacia, tumor-induced hypoglycemia, necrolytic migratory erythema, and watery diarrhea, hypokalemia and achlorydria syndrome. Medical awareness for PNS can improve patient outcomes through earlier administration of cancer therapy and treatment, better symptomatic relief and prolong overall survival.

High-Grade Sinonasal Carcinoma: Classification Through Molecular Profiling.

High-grade sinonasal carcinomas are a cohort of malignant epithelial neoplasms arising in the sinonasal cavities with distinct, ominous morphologic features or lacking well-differentiated features that might otherwise classify them as less biologically worrisome. Recent advances in molecular profiling have led to the identification of several distinct tumor entities previously grouped together. These molecularly distinct lesions include NUT (midline) carcinoma, INI1 (SMARCB1)-deficient carcinoma, SMARCA4-deficient sinonasal carcinoma, and novel IDH-mutant sinonasal undifferentiated carcinoma, in addition to the previously described lymphoepithelial carcinoma that may also be included in the differential diagnosis. The discovery of these distinct molecular tumor profiles may have significant clinical impact as targeted molecular-based therapeutics continue to evolve, and they may offer some respite for patients who have these highly aggressive cancers.

Neoplasms of the Neuroendocrine Pancreas: An Update in the Classification, Definition, and Molecular Genetic Advances.

This review focuses on discussing the main modifications of the recently published 2017 WHO Classification of Neoplasms of the Neuroendocrine Pancreas (panNEN). Recent updates separate pancreatic neuroendocrine tumors into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), and incorporates a new subcategory of "well-differentiated high-grade NET (G3)" to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. In addition, these neuroendocrine neoplasms are capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes. These functioning tumors include, insulinomas, glucagonomas, somatostatinomas, gastrinomas, VIPomas, serotonin-producing tumors, and ACTH-producing tumors. Although most panNENs arise as sporadic diseases, a subset of these heterogeneous tumors present as parts on inherited genetic syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1, tuberous sclerosis, and glucagon cell hyperplasia and neoplasia syndromes. Characteristic clinical and morphologic findings for certain functioning and syndromic panNENs should alert both pathologists and clinicians as appropriate patient management and possible genetic counseling may be necessary.

Novel gene fusions in secretory carcinoma of the salivary glands: enlarging the ETV6 family.

Secretory carcinoma (SC) of the salivary gland is a low-grade malignancy associated with a well-defined clinical, histologic, immunohistochemical, and cytogenetic signature. Although the t(12;15) (p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion is well documented, advances in molecular profiling in salivary gland tumors have led to the discovery of RET as another ETV6 gene fusion partner in SC. Here, we applied an RNA-based next-generation sequencing (NGS) approach for fusion detection on 14 presumed SC. The cases included 7 SC with classic ETV6-NTRK3 gene fusion and 3 SC harboring ETV6-RET gene fusion. In addition, 2 cases revealed a NCOA4-RET gene fusion and were subsequently reclassified as intraductal carcinomas. One case with an unusual dual-pattern morphology revealed a novel translocation involving ETV6, NTRK3, and MAML3 gene rearrangements. Interestingly, no ETV6-NTRK3 or ETV6-RET SC was ever documented to have this unique dual-pattern morphology or harbor a MAML3 mutation. The remaining case had no detected chromosomal abnormalities. Advances in molecular profiling of SC have led to the discovery of novel fusion partners such as RET and now MAML3. Further molecular characterization of salivary gland neoplasms is needed as these mutations may present alternative therapeutic targets in patients with these tumors.

Hereditary and familial thyroid tumours.

The worldwide incidence of thyroid malignancies has been increasing rapidly. Sensitive imaging modalities and early detection of thyroid lesions have made thyroid cancers the most rapidly increasing cancers in the USA in 2017 (SEER Cancer Facts, 2017). Clinical awareness of potential risk factors, such as inherited thyroid cancers, has allowed earlier recognition of more vulnerable population clusters. Hereditary thyroid neoplasms arising from calcitonin-producing C cells are known as familial medullary thyroid carcinomas (FMTCs), and include well-documented syndromes such as multiple endocrine neoplasia IIA or IIB, and pure familial medullary thyroid carcinoma syndrome. Familial thyroid cancers arising from follicular cells are referred to as familial non-medullary thyroid carcinoma (FNMTC), or familial follicular cell-derived carcinoma. Clinicopathological correlations have resulted in the further subclassification of FNMTCs into two groups. Among the first group are found syndromes characterised by a predominance of non-thyroidal tumours, including familial adenomatous polyposis, Cowden syndrome, Werner syndrome, Carney complex, and Pendred syndrome. The second group encompasses a spectrum of familial syndromes characterised by a predominance of non-medullary thyroid tumours, such as pure familial papillary thyroid carcinoma with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary carcinoma with multinodular goitre. Most familial thyroid cancers have been described as being more aggressive than sporadic thyroid cancers, with a predisposition for lymph node metastasis, extrathyroidal invasion, and a younger age of onset. The distinct thyroid pathology in some of these syndromes should alert the pathologist to a possible familial cancer syndrome.

Four PTEN-targeting co-expressed miRNAs and ACTN4- targeting miR-548b are independent prognostic biomarkers in human squamous cell carcinoma of the oral tongue.

The purpose of this study was to determine the prognostic value and oncogenic pathways associated to miRNA expression in squamous cell carcinoma of the oral tongue and to link these miRNA candidates with potential gene targets. We performed a miRNA screening within our institutional cohort (n = 58 patients) and reported five prognostic targets including a cluster of four co-expressed miRNAs (miR-18a, miR-92a, miR-103, and miR-205). Multivariate analysis showed that expression of miR-548b (p = 0.007) and miR-18a (p = 0.004, representative of co-expressed miRNAs) are independent prognostic markers for squamous cell carcinoma of the oral tongue. These findings were validated in The Cancer Genome Atlas (TCGA) cohort (n = 131) for both miRNAs (miR-548b: p = 0.027; miR-18a: p = 0.001). Bioinformatics analysis identified PTEN and ACTN4 as direct targets of the four co-expressed miRNAs and miR-548b, respectively. Correlations between the five identified miRNAs and their respective targeted genes were validated in the two merged cohorts and were concordantly significant (miR-18a/PTEN: p < 0.0001; miR-92a/PTEN: p = 0.0008; miR-103/PTEN: p = 0.008; miR-203/PTEN: p = 0.019; miR-548b/ACTN4: p = 0.009).

Malignant Rhabdoid Tumor of Soft Tissue.

Introduction Malignant rhabdoid tumor (MRT) is defined as a high-grade sarcoma derived from an uncertain cell of origin. Its diagnosis is associated with poor prognosis and patient's life expectancy is greatly reduced. Material and method Here, we describe a unique case of 9-month-old boy who presented with a large MRT arising from the soft tissue of the neck. Following intensive multimodal treatment, the patient benefited from a 25 years' remission until the discovery of multiple liver metastases. Conclusion MRT of soft tissue needs to be distinguished from other soft tissue neoplasms, as MRT is highly aggressive and is usually associated with a poor outcome. In addition, this is the longest remission time reported in a patient with soft tissue MRT and this might be related to the use of early intensive multimodal treatments.

Ultrastructural Characterization of Mammary Analogue Secretory Carcinoma of the Salivary Glands: A Distinct Entity from Acinic Cell Carcinoma?

Mammary analogue secretory carcinoma (MASC) of the salivary glands is a recently described neoplasm of the salivary glands with a characteristic morphology complemented by a specific cytogenetic translocation and gene rearrangements. Although immunophenotypic and cytogenetic differences allow for a more reliable distinction, ultrastructural features can also provide important information about the relationship between MASC, classic acinic cell carcinoma (AciCC), and AciCC intercalated duct cell-predominant variant. Following approval from the hospital's institutional review board, 7 cases of MASC, 8 cases of classic AciCC, and 4 cases of AciCC intercalated duct cell-predominant variant were retrieved from the pathology files of Massachusetts General Hospital from 2012 to 2015. Electron microscopy was performed using formalin-fixed, paraffin-embedded tissue. Ultrastructural features of all 19 neoplasms of the salivary glands were recorded. The predominant cell-types observed in MASC are those with intercalated/striated duct cell differentiation. These features include prominent invaginations of the cell surface studded with microvilli, and some intra- and intercellular lumina also with a microvillous surface. Classic AciCC dominant cell-type recapitulates acinar cell differentiation. These cells contain large intracytoplasmic zymogen-like granules. AciCC intercalated duct cell-predominant variant showed both cell populations in various proportions with the intercalated/striated duct cell type usually being the dominant one. MASC presents with distinctive ultrastructural features that allows its proper differentiation from classic AciCC. However, significant ultrastructural features overlaps between both AciCC intercalated duct cells-predominant and classic AciCC and MASC. These findings indicate a very close proximity between these tumors.