Hürthle cell carcinoma of the thyroid presenting as thyrotoxicosis

ObjectiveTo report a case of hyperthyroidism associated with Hülllnnvl-ürthle cellcarcinoma and to review the literature regarding this relationship.MethodsWe describe the clinical, biochemical, radiologic, and pathologic data of a patient with Hürthle cellcarcinoma associated with thyrotoxicosis and reversible heart failure. We discuss the mechanistic aspects and review previously reported cases of functionalHürthle cellcarcinomas.ResultsA 43-year-old womanpresented with thyrotoxicosis and nonischemic cardiomyopathy. She had a “hot” nodule inthe left lobe of the thyroid onsodium pertechnetate scan. She underwent a left hemithyroidec-tomy and isthmusectomy. Pathologic findings revealed a minimally invasive Hürthle cellcarcinoma. Onfollow-up, the dilated cardiomyopathy had resolved. The associationof thyroid carcinoma with thyrotoxicosis is rare.ConclusionsSome Hürthle cellcarcinomas canbe functionaland lead to thyrotoxicosis. To our knowledge, we present the first case of reversible dilated cardiomyopathy due to thyrotoxicosis originating from Hülll-ürthle cellcarcinoma. (Endocr Pract. 2012;18:e5-e9)     

Fine needle aspiration of poorly differentiated oxyphilic (Hürthle cell) thyroid carcinoma: a case report

BACKGROUND: Poorly differentiated oxyphilic (Hürthle cell) carcinomas are a more recently described variant of poorly differentiated thyroid carcinoma and are characterized by a prominent Hürthle cell component in a solid or trabecular arrangement. Clinically, poorly differentiated oxyphilic carcinomas behave more aggressively as compared to classic Hürthle cell carcinomas, which have a predominantly follicular pattern. Although the histology of these rare thyroid tumors has been reported in the literature, the cytologic features on fine needle aspiration biopsy have not been described before. CASE: A 73-year-old man with a long history of radioactive iodine and levothyroxine therapy for multinodular goiter presented with a painful, rapidly expanding, 6-cm, left thyroid mass with aggressive radiologic features. Fine needle aspiration biopsy of the mass yielded extremely cellular smears with a dual population of medium-sized follicular cells and numerous Hürthle cells. Subsequent thyroidectomy confirmed the malignant nature of this Hürthle cell-rich tumor, warranting a diagnosis of poorly differentiated oxyphilic (Hürthle cell) thyroid carcinoma. CONCULSION: Poorly differentiated oxyphilic thyroid carcinoma is an aggressive variant of Hürthle cell carcinomas and must enter the differential diagnosis when fine needle aspiration biopsy of a radiologically aggressive thyroid mass yields extremely hypercellular smears with a prominent Hürthle cell component.     

Fine needle aspiration biopsy of anaplastic thyroid carcinoma developing from a Hürthle cell tumor: a case report

BACKGROUND: Anaplastic thyroid carcinoma is a highly malignant tumor in elderly people with a long history of multinodular goiter and is usually associated with a rapidly fatal clinical evolution. The tumor often develops as a result of anaplastic transformation of a slowly growing papillary carcinoma or follicular neoplasm. CASE: An 85-year-old woman had a multinodular goiter and had been asymptomatic, with a normal white blood cell count and chest radiograph three months prior to her hospital admission for the treatment. The tumor presented with low grade fever, leukocytosis, multiple metastatic lung nodules and enlargement of the intrathoracic thyroid in a period of three months, causing compression of the esophagus and trachea. Despite a total thyroidectomy, the tumor recurred within one month and caused dysphagia and death. CONCLUSION: FNAB permitted the diagnosis of an anaplastic thyroid carcinoma arising from an intrathoracic Hürthle cell tumor.     

Hürthle cell Thyroid Carcinoma Presenting as A “Hot” Nodule

ObjectiveTo report an unusual clinical scenario and a rare histopathologic finding of Hürthle cell thyroid carcinoma in a patient with an autonomous thyroid nodule.MethodsWe describe the presentation and clinical course leading to the surprising histopathologic diagnosis of Hürthle cell carcinoma in a pediatric patient who was diagnosed with hyperthyroidism presenting as a solitary toxic nodule.ResultsA 13-year-old white girl presented with a recent history of a palpable thyroid nodule during a routine primary care clinic visit. She was asymptomatic, and thyroid function tests revealed a suppressed thyrotropin concentration, high-normal free thyroxine concentration, and elevated triiodothyronine concentration. The patient underwent dedicated thyroid ultrasonography revealing a 3.5-cm complex mass in the left lobe with increased central vascularity. Iodine 123 imaging of the thyroid demonstrated homogenous, hyperintense activity in the left lobe. The right lobe was not visualized. A solitary toxic nodule was diagnosed, and, considering her age, she was referred for surgical management. The patient underwent a left lobectomy with isthmusectomy. Pathologic examination revealed a 5-cm, encapsulated, well-differentiated Hürthle cell carcinoma with negative margins and no lymphovascular invasion. The patient underwent subsequent completion thyroidectomy with no evidence of residual carcinoma in the right thyroid lobe.ConclusionsMalignancy in autonomously functioning thyroid nodules is rare. Most of the thyroid nodules presenting as “hot” on radioiodine scintigraphy are benign follicular adenomas. However, this case represents a rare clinical entity, and it highlights the need for clinicians to be vigilant and aware that occasionally carcinomas can masquerade as scintigraphic “hot” nodules. (Endocr Pract. 2011;17:e68-e72)     

Spinal metastasis of a thyroglobulin-rich Hürthle cell carcinoma detected by fine needle aspiration. Light and electron microscopic study of an unusual case

A prospective diagnosis of metastatic thyroid carcinoma was made on an aspirate of a spinal mass. While the cellular component of the aspirate was compatible with a renal or hepatic neoplasm, the recognition of colloid on air-dried smears defined the cells as Hürthle cells. Biopsy of the spinal tumor and subsequent thyroidectomy revealed a Hürthle cell carcinoma. Whereas the primary tumor showed typical Hürthle cell architecture, with solid tumor nests and microfollicle formation, the metastasis contained areas of macrofollicle formation with abundant colloid production and strong immunocytochemical reactivity for thyroglobulin. This change of histologic pattern from the primary tumor to the metastasis has not been previously reported in Hürthle cell lesions. The unusual light microscopic and ultrastructural aspects of this tumor are discussed.     

Down-regulation of PKCζ in renal cell carcinoma and its clinicopathological implications

Background

Metastatic renal cell carcinoma (RCC) is highly resistant to systemic chemotherapy. Unfortunately, nearly all patients die of the metastatic and chemoresistant RCC. Recent studies have shown the atypical PKCζ is an important regulator of tumorigenesis. However, the correlation between PKCζ expression and the clinical outcome in RCC patients is unclear. We examined the level of PKCζ expression in human RCC.

Methods

PKCζ mRNA and protein expressions were examined by real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC) respectively in RCC tissues of 144 patients. Cellular cytotoxicity and proliferation were assessed by MTT.

Results

PKCζ expression was significantly higher in normal than in cancerous tissues (P < 0.0001) by real-time PCR and IHC. Similarly, PKCζ expression was down-regulated in four renal cancer cell lines compared to immortalized benign renal tubular cells. Interestingly, an increase of PKCζ expression was associated with the elevated tumor grade (P = 0.04), but no such association was found in TNM stage (P = 0.13). Tumors with higher PKCζ expression were associated with tumor size (P = 0.048). Expression of higher PKCζ found a poor survival in patients with high tumor grade. Down-regulation of PKCζ showed the significant chemoresistance in RCC cell lines. Inactivation of PKCζ expression enhanced cellular resistance to cisplatin and paclitaxel, and proliferation in HK-2 cells by specific PKCζ siRNA and inhibitor.

Conclusions

PKCζ expression was associated with tumorigenesis and chemoresistance in RCC.     

Oocyte activation and phospholipase C zeta (PLCζ): diagnostic and therapeutic implications for assisted reproductive technology

ABSTRACT: Infertility affects one in seven couples globally and has recently been classified as a disease by the World Health Organisation (WHO). While in-vitro fertilisation (IVF) offers effective treatment for many infertile couples, cases exhibiting severe male infertility (19-57%) often remain difficult, if not impossible to treat. In such cases, intracytoplasmic sperm injection (ICSI), a technique in which a single sperm is microinjected into the oocyte, is implemented. However, 1-5% of ICSI cycles still fail to fertilise, affecting over 1000 couples per year in the UK alone. Pregnancy and delivery rates for IVF and ICSI rarely exceed 30% and 23% respectively. It is therefore imperative that Assisted Reproductive Technology (ART) protocols are constantly modified by associated research programmes, in order to provide patients with the best chances of conception. Prior to fertilisation, mature oocytes are arrested in the metaphase stage of the second meiotic division (MII), which must be alleviated to allow the cell cycle, and subsequent embryogenesis, to proceed. Alleviation occurs through a series of concurrent events, collectively termed 'oocyte activation'. In mammals, oocytes are activated by a series of intracellular calcium (Ca2+) oscillations following gamete fusion. Recent evidence implicates a sperm-specific phospholipase C, PLCzeta (PLCζ), introduced into the oocyte following membrane fusion as the factor responsible. This review summarises our current understanding of oocyte activation failure in human males, and describes recent advances in our knowledge linking certain cases of male infertility with defects in PLCζ expression and activity. Systematic literature searches were performed using PubMed and the ISI-Web of Knowledge. Databases compiled by the United Nations and World Health Organisation databases (UNWHO), and the Human Fertilization and Embryology Authority (HFEA) were also scrutinised. It is clear that PLCζ plays a fundamental role in the activation of mammalian oocytes, and that genetic, molecular, or biochemical perturbation of this key enzyme is strongly linked to human infertility where oocyte activation is deficient. Consequently, there is significant scope for our understanding of PLCζ to be translated to the ART clinic, both as a novel therapeutic agent with which to rescue oocyte activation deficiency (OAD), or as a prognostic/diagnostic biomarker of oocyte activation ability in target sperm samples.     

α-Enolase: a promising therapeutic and diagnostic tumor target

α-enolase (ENOA) is a metabolic enzyme involved in the synthesis of pyruvate. It also acts as a plasminogen receptor and thus mediates activation of plasmin and extracellular matrix degradation. In tumor cells, ΕΝΟΑ is upregulated and supports anaerobic proliferation (Warburg effect), it is expressed at the cell surface, where it promotes cancer invasion, and is subjected to a specific array of post-translational modifications, namely acetylation, methylation and phosphorylation. Both ENOA overexpression and its post-translational modifications could be of diagnostic and prognostic value in cancer. This review will discuss recent information on the biochemical, proteomics and immunological characterization of ENOA, particularly its ability to trigger a specific humoral and cellular immune response. In our opinion, this information can pave the way for effective new therapeutic and diagnostic strategies to counteract the growth of the most aggressive human disease.     

Assessment of proliferative activity of thyroid Hürthle cell tumors using PCNA, Ki-67 and AgNOR methods

We have undertaken an attempt to compare the application efficacy of the proliferative activity markers in differential diagnosis of thyroid Hürthle cell tumors (HCT) using the PCNA and Ki-67 labeling and AgNOR visualisation techniques. The present work is a retrospective analysis of 78 Hürthle cell tumors: 20 Hürthle cell carcinomas (HCC), 32 Hürthle cell adenomas (HCA) and 26 hyperplastic nodules with Hurthle cell metaplasia (HCM). Five microm sections were stained according to AgNOR technique and labeled with antibodies against PCNA and Ki-67. AgNOR dot count in the nucleus and proliferative index (PI - percentage of cells expressing PCNA and Ki-67) in randomly chosen nuclei (100 in case of AgNOR and over 1000 in case of PI) were evaluated in each slide. The mean values of AgNOR dot count, PI-PCNA and PI-Ki-67 in HCC, HCA and HCM were respectively: 5.1, 61.3 and 54.9; 3.4, 42.4 and 38.6 and 2.5, 39.3 and 34.3. Statistically significant difference was found in all the proliferative activity markers between malignant and benign tumors: HCC:HCA (p<0.01) and HCC:HCM (p<0.001). There was no statistically significant difference between HCA and HCM.     

Scintigraphy with [111In]octreotide and 201Tl in a Hürthle cell thyroid carcinoma without detectable radio-iodine uptake. Report of a case and review of the literature

AIM: To describe the visualization of recurrent disease by [111In]octreotide and 201Tl scintigraphy in a patient with Hürthle cell thyroid carcinoma, increased thyroglobulin levels, and a negative radio-iodine total-body scan. METHODS: Scintigraphy with [111In]octreotide and 201Tl was performed, and a local recurrence in the thyroid bed was detected which was excised by surgery. RESULTS: On histology, the tumour proved to be a Hürthle cell carcinoma, and within the tumour somatostatin receptors were detected by RT-PCR. CONCLUSION: Scintigraphy with [111In]octreotide and 201Tl is an alternative imaging method for the detection of residual disease in patients with a differentiated thyroid carcinoma having increased thyroglobulin levels and a negative radio-iodine total-body scan.     

Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications

As a result of excessive production of angiogenic molecules, tumor vessels become abnormal in structure and function. By impairing oxygen delivery, abnormal vessels fuel a vicious cycle of non-productive angiogenesis, which creates a hostile microenvironment from where tumor cells escape through leaky vessels and which renders tumors less responsive to chemoradiation. While anti-angiogenic strategies focused on inhibiting new vessel growth and destroying pre-existing vessels, clinical studies showed modest anti-tumor effects. For many solid tumors, anti-VEGF treatment offers greater clinical benefit when combined with chemotherapy. This is partly due to a normalization of the tumor vasculature, which improves cytotoxic drug delivery and efficacy and offers unprecedented opportunities for anti-cancer treatment. Here, we overview key novel molecular players that induce vessel normalization.     

Dysfunctional HDL: A novel important diagnostic and therapeutic target in cardiovascular disease?

High density lipoprotein (HDL) has many properties, which contribute to its atheroprotective role. However, some recent clinical trials have identified subjects with the progression of atherosclerosis despite normal levels of HDL cholesterol. This raises the question if all subfractions of HDL have the same properties. Moreover, recent investigations have shown that both acute and chronic inflammation may lead to structural and functional changes of HDL, which render the particles proinflammatory. Although therapeutic agents that increase HDL levels are now quite well established it is not clear whether they influence HDL quality. We review the current state of knowledge on the properties of HDL and factors/therapeutic agents which may restrain the transformation of normal HDL into dysfunctional HDL.     

I. Cellular and molecular biology of sodium channel beta-subunits: therapeutic implications for pain? I. Cellular and molecular biology of sodium channel beta-subunits: therapeutic implications for pain?

Voltage-gated sodium channel alpha-subunits have been shown to be key mediators of the pathophysiology of pain. The present review considers the role of sodium channel auxiliary beta-subunits in channel modulation, channel protein expression levels, and interactions with extracellular matrix and cytoskeletal signaling molecules. Although beta-subunits have not yet been directly implicated in pain mechanisms, their intimate association with and ability to regulate alpha-subunits predicts that they may be a viable target for therapeutic intervention in the future. It is proposed that multifunctional sodium channel beta-subunits provide a critical link between extracellular and intracellular signaling molecules and thus have the ability to fine tune channel activity and electrical excitability.     

Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer’s disease

The mevalonate–isoprenoid–cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery that two major isoprenoids, farnesyl and geranylgeranyl pyrophosphate, are required to modify an array of proteins through a process known as protein prenylation, catalyzed by prenyltransferases. The lipophilic prenyl group facilitates the anchoring of proteins in cell membranes, mediating protein–protein interactions and signal transduction. Numerous essential intracellular proteins undergo prenylation, including most members of the small GTPase superfamily as well as heterotrimeric G proteins and nuclear lamins, and are involved in regulating a plethora of cellular processes and functions. Dysregulation of isoprenoids and protein prenylation is implicated in various disorders, including cardiovascular and cerebrovascular diseases, cancers, bone diseases, infectious diseases, progeria, and neurodegenerative diseases including Alzheimer’s disease (AD). Therefore, isoprenoids and/or prenyltransferases have emerged as attractive targets for developing therapeutic agents. Here, we provide a general overview of isoprenoid synthesis, the process of protein prenylation and the complexity of prenylated proteins, and pharmacological agents that regulate isoprenoids and protein prenylation. Recent findings that connect isoprenoids/protein prenylation with AD are summarized and potential applications of new prenylomic technologies for uncovering the role of prenylated proteins in the pathogenesis of AD are discussed.     

Can abundant colloid exclude oncocytic (Hürthle cell) carcinoma in thyroid fine needle aspiration? Cytohistological correlation of 127 oncocytic (Hürthle cell) lesions

Objective:  The objective of the present study was to find out whether the presence or absence of certain cytological features can exclude oncocytic (Hürthle cell) carcinoma in thyroid fine needle aspiration (FNA) to minimize unnecessary surgery. Methods:  Over a 17‐year period, 127 hypercellular, oncocyte‐exclusive, lymphocyte‐absent aspirates obtained via ultrasound‐guided FNA with on‐site assessment had histology slides for review. The presence or absence of six cytological features (microfollicular arrangement, discohesive single cells, small cell dysplasia, large cell dysplasia, transgressing blood vessels and colloid) and one histological feature (macrofollicular component) were determined for each case independently by two cytopathologists. Results:  Histology showed 12 (9.4%) cases of Hashimoto thyroiditis, 23 (18.1%) oncocytic adenomatoid nodules in nodular goitre, 66 (52.0%) oncocytic adenomas and 26 (20.5%) oncocytic carcinomas (13 minimally invasive without angioinvasion, six minimally invasive with angioinvasion, seven widely invasive). Histologically, a macrofollicular component was present in seven of 26 (26.9%) oncocytic carcinomas, including one case with abundant thin colloid. A microfollicular arrangement, discohesive single cells, small cell dysplasia, large cell dysplasia and transgressing vessels were present in oncocytic carcinoma, oncocytic adenoma and oncocytic adenomatoid nodules in nodular goitre. Conclusions:  A macrofollicular component is frequently present in oncocytic carcinoma, oncocytic adenoma and oncocytic adenomatoid nodules in nodular goitre. None of the cytological features studied, including abundant colloid, can exclude oncocytic carcinoma. Oncocytic carcinoma can only be excluded by thorough histological examination of thyroidectomy specimens. A molecular marker is needed to triage oncocytic lesions in thyroid FNA.     

DNA-PKcs: A promising therapeutic target in human hepatocellular carcinoma?

Hepatocellular carcinoma (HCC) is a frequent and deadly disease worldwide. The absence of effective therapies when the tumor is surgically unresectable leads to an extremely poor outcome of HCC patients. Thus, it is mandatory to elucidate the molecular pathogenesis of HCC in order to develop novel therapeutic strategies against this pernicious tumor. Mounting evidence indicates that suppression of the DNA damage response machinery might be deleterious for the survival and growth of the tumor cells. In particular, DNA dependent protein kinase catalytic subunit (DNA-PKcs), a major player in the non-homologous end-joining (NHEJ) repair process, seems to represent a valuable target for innovative anti-neoplastic therapies in cancer. DNA-PKcs levels are strongly upregulated and associated with a poor clinical outcome in various tumor types, including HCC. Importantly, DNA-PKcs not only protects tumor cells from harmful DNA insults coming either from the microenvironment or chemotherapeutic drug treatments, but also possesses additional properties, independent from its DNA repair activity, that provide growth advantages to cancer cells. These properties (metabolic and gene reprogramming, invasiveness and metastasis, resistance to apoptosis, etc.) have started to be elucidated. In the present review, we summarize the physiologic and oncogenic roles of DNA-PKcs, with a special emphasis on liver cancer. In particular, this work focuses on the molecular mechanism whereby DNA-PKcs exerts its pro-tumorigenic activity in cancer cells. In addition, the upstream regulator of DNA-PKcs activation as well as its downstream effectors thus far identified are illustrated. Furthermore, the potential therapeutic strategies aimed at inhibiting DNA-PKcs activity in HCC are discussed.     

TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants – past,present and future

Tumor Necrosis Factor (TNF), initially known for its tumor cytotoxicity, is a potent mediator of inflammation, as well as many normal physiological functions in homeostasis and health, and anti-microbial immunity. It also appears to have a central role in neurobiology, although this area of TNF biology is only recently emerging. Here, we review the basic biology of TNF and its normal effector functions, and discuss the advantages and disadvantages of therapeutic neutralization of TNF – now a commonplace practice in the treatment of a wide range of human inflammatory diseases. With over ten years of experience, and an emerging range of anti-TNF biologics now available, we also review their modes of action, which appear to be far more complex than had originally been anticipated. Finally, we highlight the current challenges for therapeutic intervention of TNF: (i) to discover and produce orally delivered small molecule TNF-inhibitors, (ii) to specifically target selected TNF producing cells or individual (diseased) tissue targets, and (iii) to pre-identify anti-TNF treatment responders. Although the future looks bright, the therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.