Sylvia L. Asa

Isolation of a Murine Homologue of the Drosophila neuralized Gene, a Gene Required for Axonemal Integrity in Spermatozoa and Terminal Maturation of the Mammary Gland

ABSTRACT The Drosophila neuralized gene shows genetic interactions with Notch, Enhancer of split, and other neurogenic genes and is thought to be involved in cell fate specification in the central nervous system and the mesoderm. In addition, a human homologue of the Drosophila neuralizedgene has been described as a potential tumor suppressor gene in malignant astrocytomas. We have isolated a murine homologue of theDrosophila and human Neuralized genes and, in an effort to understand its physiological function, derived mice with a targeted deletion of this gene. Surprisingly, mice homozygous for the introduced mutation do not show aberrant cell fate specifications in the central nervous system or in the developing mesoderm. This is in contrast to mice with targeted deletions in other vertebrate homologues of neurogenic genes such as Notch, Delta, andCbf-1. Male Neuralized null mice, however, are sterile due to a defect in axoneme organization in the spermatozoa that leads to highly compromised tail movement and sperm immotility. In addition, female Neuralized null animals are defective in the final stages of mammary gland maturation during pregnancy.

The Breast Cancer Susceptibility Gene Product Fibroblast Growth Factor Receptor 2 Serves as a Scaffold for Regulation of NF-κB Signaling

ABSTRACT Fibroblast growth factor (FGF) receptor 2 (FGFR2) has been identified in genome-wide association studies to be associated with increased breast cancer risk; however, its mechanism of action remains unclear. Here we show that the two major FGFR2 alternatively spliced isoforms, FGFR2-IIIb and FGFR2-IIIc, interact with IκB kinase β and its downstream target, NF-κB. FGFR2 inhibits nuclear RelA/p65 NF-κB translocation and activity and reduces expression of dependent transcripts, including interleukin-6. These interactions result in diminished STAT3 phosphorylation and reduced breast cancer cell growth, motility, and invasiveness. FGFR2 also arrests the epithelial cell-to-mesenchymal cell transition (EMT), resulting in attenuated neoplastic growth in orthotopic xenografts of breast cancer cells. Our studies provide strong evidence for the protective effects of FGFR2 on tumor progression. We propose that FGFR2 serves as a scaffold for multiple components of the NF-κB signaling complex. Through these interactions, FGFR2 isoforms can respond to tissue-specific FGF signals to modulate epithelial cell-stromal cell communications in cancer progression.

Immunohistochemical Biomarkers in Thyroid Pathology

The application of immunohistochemistry to the diagnosis of thyroid lesions has increased as new biomarkers have emerged. In this review, we discuss the biomarkers that are critical for accurate diagnosis, prognosis, and management. Immunohistochemical markers are used to confirm that an unusual tumor in the thyroid is indeed of thyroid origin, either of follicular epithelial or C-cell differentiation; the various mimics include nonthyroidal lesions such as parathyroid tumors, paragangliomas, thymic neoplasms, and metastatic malignancies. Tumors of thyroid follicular epithelial cells can be further subclassified using a number of immunohistochemical biomarkers that can distinguish follicular-derived from C-cell lesions and others that support malignancy in borderline cases. The use of mutation-specific antibodies can distinguish papillary carcinomas harboring a BRAFV600E mutation from RAS-like neoplasms. Immunostains have been developed to further identify molecular alterations underlying tumor development, including some rearrangements. Altered expression of several biomarkers that are known to be epigenetically modified in thyroid cancer can be used to assist in predicting more aggressive behavior such as a propensity to develop locoregional lymphatic spread. Immunohistochemistry can assist in identifying lymphatic and vascular invasion. Biomarkers can be applied to determine dedifferentiation and to further classify poorly differentiated and anaplastic carcinomas. The rare tumors associated with genetic predisposition to endocrine neoplasia can also be identified using some immunohistochemical stains. The application of these ancillary tools allows more accurate diagnosis and better understanding of pathogenesis while improving prediction and prognosis for patients with thyroid neoplasms.

A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal

The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.

Epidemiology and biomarker profile of pituitary adenohypophysial tumors

Recent studies have reported the prevalence of pituitary tumors to be ~1/1000 population. Many are prolactin-producing tumors that are managed medically, however, the epidemiology of surgically resected pituitary adenohypophysial neuroendocrine tumors has not been reported in a large series with detailed characterization. We reviewed 1055 adenohypophysial tumors from 1169 transsphenoidal resections from the pathology files of University Health Network, Toronto, 2001-2016. Tumors were characterized by immunohistochemical localization of transcription factors (Pit-1, ERα, SF-1, Tpit), hormones (adrenocorticotropin, growth hormone, prolactin, β-thyrotropin, β-folliculotropin, β-luteotropin, α-subunit), and other biomarkers (keratins, Ki67, p27, FGFR4). Electron microscopy was used only for unusual lesions. In this cohort, 51.3% of patients were female; the average age was 51 years. Gonadotroph tumors represented 42.5%. Pit-1-lineage-tumors represented 29.9%; these were subclassified as growth-hormone-predominant (somatotroph/mammosomatotroph/mixed; 53%), prolactin-predominant (lactotroph/acidophil-stem-cell; 28%), thyrotrophs (2%), plurihormonal (14%), and not-otherwise-specified (3%). Corticotroph tumors represented 17.1%. Only 4.5% were null cell tumors and 0.5% were unusual plurihormonal tumors. In 5.5% the tumor was not characterized for technical reasons (sample size, fixation, necrosis or other artifact). All corticotroph and plurihormonal tumors were positive for keratins; others tumors showed variable negativity with highest rates in gonadotroph (37.1%) and null cell tumors (28.2%). Tumors with a Ki67u2009≥u20093% comprised 60% of this cohort. Global loss of p27 was most frequent in corticotroph neoplasms, specifically those associated with elevated glucocorticoid levels. Corticotroph and lactotroph tumors were more common among females; gonadotroph tumors were more common among males. Younger patients had mainly corticotroph and Pit-1-lineage neoplasms, whereas older patients harbored mainly gonadotroph tumors. This represents one of the largest surgical series of morphologically characterized pituitary tumors reported to date and the first to include the routine use of transcription factors for tumor classification. The data provide the basis for clinicopathologic correlations that are helpful for prognostic and predictive patient management.

Immunohistochemical Biomarkers in Pituitary Pathology

Pituitary pathology is one area of endocrine pathology that is highly dependent on immunohistochemistry. There is a wide range of disorders that occur in and around the sella turcica, and the distinction of tumor-like lesions from neoplasms requires careful evaluation. The diagnosis, prognosis, and predictive features of neoplasms in the sellar region are all dependent on the application and interpretation of biomarkers of cell differentiation, hormonal activity, subcellular morphology, and proliferation. As in hematopathology, the number of biomarkers has increased dramatically and continues to increase. Fortunately, some of the biomarkers provide information that was initially dependent on electron microscopy; therefore, the need for this additional technology has been reduced to only rare unusual tumors. In this review, we provide a simple approach to understanding the importance of the various biomarkers that are used to ensure the correct diagnosis and provide the treating clinicians with tools to guide appropriate patient management and surveillance.

Immunohistochemical Biomarkers of Adrenal Cortical Neoplasms

Careful morphological evaluation forms the basis of the workup of an adrenal cortical neoplasm. However, the adoption of immunohistochemical biomarkers has added tremendous value to enhance diagnostic accuracy. The authors provide a brief review of immunohistochemical biomarkers that have been used in the confirmation of adrenal cortical origin and in the detection of the source of functional adrenal cortical proliferations, as well as diagnostic, predictive, and prognostic biomarkers of adrenal cortical carcinoma. In addition, a brief section on potential novel theranostic biomarkers in the prediction of treatment response to mitotane and other relevant chemotherapeutic agents is also provided. In the era of precision and personalized medical practice, adoption of combined morphology and immunohistochemistry provides a new approach to the diagnostic workup of adrenal cortical neoplasms, reflecting the evolution of clinical responsibility of pathologists.

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): Trading Six for a Risky Half Dozen: Reply

Since the term noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) was introduced, its existence has been controversial. The resultant debate has left clinicians confused as to how to counsel and follow their patients diagnosed with this entity. The authors would like to thank Dr. Rosàrio for his support with respect to our recent article on the clinical safety of renaming encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) [1]. The authors believe that a continued academic discourse as well as further research on the topic is necessary to clarify the ongoing uncertainty. After Nikiforov et al. [2] published their article suggesting that the nomenclature for the low-risk thyroid cancer variant EFVPTC be changed to NIFTP, the authors found that the experience at the University Health Network was significantly different with respect to both incidence and malignant potential [1]. In addition to Parente et al., there have been several studies indicating that EFVPTC has both malignant potential and a low incidence [1, 3, 4]. The authors certainly support the de-escalation of treatment of these low-risk thyroid cancers including the use of thyroid lobectomy and more selective radioactive iodine ablation. However, the avoidance of the term ‘‘cancer’’ for an entity with malignant potential may result in undertreatment or inappropriate lack of surveillance of patients with these tumors. In this regard, change in terminology is not a substitute for meaningful patient education and multidisciplinary discussion to highlight the low-risk nature of these cancers. Until future research can clarify the current controversy in the literature, clinicians should continue to follow and counsel patients about this low-risk malignant entity. Furthermore, ongoing capture of this diagnostic category by Cancer Registries is essential for both quality improvement and investigational study.

The Diagnosis and Clinical Significance of Paragangliomas in Unusual Locations

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.

Synchronous Multiple Pituitary Neuroendocrine Tumors of Different Cell Lineages

We report clinicopathological features of a large series of synchronous multiple pituitary neuroendocrine tumors (PitNETs) of different cell lineages. Retrospective review of pathology records from 2001 to 2016 identified 13 synchronous multiple PitNETs from 1055 PitNETs classified using pituitary cell-lineage transcription factors, adenohypohyseal hormones, and other biomarkers. Clinical, radiological, and histopathological features of these tumors were reviewed. The series included seven females and six males. Mean age at diagnosis was 55.23xa0years (range 36–73). Imaging was unavailable for four patients; among the other nine, mean tumor size was 2.23xa0cm (range 0.9–3.9). Five patients had acromegaly, four had Cushing disease, and four had clinically non-functional tumors. Twelve had double PitNETs; one had a triple PitNET. The most common tumor type was corticotroph (nxa0=u20098; six densely and one sparsely granulated and one Crooke cell; three densely and one sparsely granulated were clinically silent), gonadotroph tumors (nu2009=u20098), and somatotroph tumors (nxa0=u20095; four sparsely granulated and one densely granulated somatotroph) were followed by lactotroph tumors (nxa0=u20094; all sparsely granulated), poorly differentiated Pit-1 lineage tumor (nxa0=u20091), and unusual plurihormonal tumor (nu2009=u20091). A 54-year-old man with Cushing disease had MEN1-driven Crooke cell and gonadotroph tumors. The triple pitNET consisted of a multilineage plurihormonal tumor associated with a gonadotroph and a sparsely granulated lactotroph tumor. The Ki67 (available from 10 specimens) ranged from 1 to 5% in individual tumors. Radiological and biochemical follow-up was available for 10 and 11 patients, respectively. Radiological tumor persistence/recurrence was identified in three patients with double PitNETs consisting of sparsely granulated lactotroph and gonadotroph tumors (nxa0=u20091), sparsely granulated somatotroph and silent corticotroph tumors (nu2009=u20091), and gonadotroph and silent corticotroph tumors (nu2009=u20091) with cavernous sinus invasion. Biochemical persistence was noted in four patients with double PitNETs consisting of sparsely granulated somatotroph and silent corticotroph tumors (nxa0=u20092), gonadotroph and Crooke cell tumors (nxa0=u20091), and densely granulated somatotroph and silent corticotroph tumors (nu2009=u20091). Multiple PitNETs represent about 1% of PitNETs and usually have hormone excess due to at least one tumor component. Clinical manifestations may be due to the minor component, especially in patients with Cushing disease. Invasive growth and aggressive histological subtypes predicted disease persistence/recurrence. This series also highlights the importance of routine application of pituitary cell lineage transcription factors along with hormones to distinguish and subtype multiple synchronous PitNETs.