Thyroid Cancer: Molecular and Modern Advances

Over the last decade, surgeons have witnessed dramatic changes in surgical practice as a result of the introduction of new technological advancement. Some of these changes include reﬁnement of techniques in thyroid cancer surgery. The development of various endoscopic thyroidectomy techniques, the addition of the da Vinci robot, and the use of operative adjuncts in thyroid surgery, such as intraoperative neuromonitoring and quick intraoperative parathyroid hormone, have made thyroid cancer surgery not only safer and better accepted by patients with thyroid cancer but also o ﬀ er them more surgical treatment options. Background . The results of video-assisted thyroidectomy (VAT) were evaluated in a large series of patients with papillary thyroid carcinoma (PTC), especially in terms of completeness of the surgical resection and short-to-medium term recurrence. Methods . The medical records of all patients who underwent video-assisted thyroidectomy for PTC between June 1998 and May 2009 were reviewed. Results . Three hundred ﬁfty-nine patients were included. One hundred twenty-six patients underwent concomitant central neck node removal. Final histology showed 285 pT1, 26 pT2, and 48 pT3 PTC. Lymph node metastases were found in 27 cases. Follow-up was completed in 315 patients. Mean postoperative serum thyroglobulin level o ﬀ levothyroxine was 5.4ng/mL. Post operative ultrasonography showed no residual thyroid tissue in all the patients. Mean post-operative 131 I uptake was 1.7%. One patient developed lateral neck recurrence. No other recurrence was observed. Unilateral vocal fold paralysis (UVFP) is one of the most serious problems in conducting surgery for thyroid cancer. Di ﬀ erent treatments are available for the management of UVFP including intracordal injection, type I thyroplasty, arytenoid adduction, and laryngeal reinnervations. The e ﬀ ects of immediate recurrent laryngeal nerve (RLN) reconstruction during thyroid cancer surgery with or without UVFP before the surgery were evaluated with videostroboscopic, aerodynamic, and perceptual analyses. All subjects experienced postoperative improvements in voice quality. Particularly, aerodynamic analysis showed that the values for all patients entered normal ranges in both patients with and without UVFP before surgery. Immediate RLN reconstruction has the potential to restore a normal or near-normal voice by returning thyroarytenoid muscle tone and bulk seen with vocal fold denervation. Immediate RLN reconstruction is an e ﬃ cient and e ﬀ ective approach to the management of RLN resection during surgery for thyroid cancer. Glycosylation is one of the most common posttranslational modiﬁcation reactions and nearly half of all known proteins in eukaryotes are glycosylated. In fact, changes in oligosaccharides structures are associated with many physiological and pathological events, including cell growth, migration and di ﬀ erentiation, and tumor invasion. Therefore, functional glycomics, which is a comprehensive study of the structures and functions of glycans, is attracting the increasing attention of scientists in various ﬁelds of life science. In cases of thyroid cancer, the biological characters and prognosis are completely di ﬀ erent in each type of histopathology, and their oligosaccharide structures as well as the expression of glycosyltransferases are also di ﬀ erent. In this review, we summarized our previous papers on oligosaccharides and thyroid cancers and discussed a possible function of oligosaccharides in the carcinogenesis in thyroid cancer. Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid. An accurate cytological diagnosis is based on distinctive cytological features in combination with immunocytochemistry. Methods . A number of 83 ﬁne needle aspirations, positive for papillary thyroid cancer (44 from thyroid nodules and 39 from cervical lymph nodes), were studied using Thin Layer Cytology. A panel of the immunomarkers Cytokeratin-19, Galectin-3, HBME1, CD-44, CD-56, and E-Cadherin was performed. Results . Positive expression of CK-19 was observed in 77 cases (92.7%), of Galectin-3 in 74 cases (89.1%), of HBME1 in 65 (78.3%), and of CD-44 in 72 cases (86.7%). Loss of expression of CD-56 was observed in 80 cases (96.4%) and of E-cadherin in 78 (93.9%). Conclusions . Our data suggest that Thin Layer Cytology increases the diagnostic accuracy in papillary carcinoma and seems to be a promising technique for further investigation of thyroid lesions permitting the possibility to use archive material. Positive immunoexpression of CK-19, Galectin-3, HBME-1, and CD-44 improves the diagnostic accuracy of papillary thyroid cancer. Furthermore, loss of E-cadherin and of CD-56 expression is a feature of malignancy. Familial thyroid cancer has become a well-recognized entity in patients with thyroid cancer originating from follicular cells, that is, nonmedullary thyroid carcinoma. The diagnosis of familial thyroid cancer provides an opportunity for early detection and possible prevention in family members. Understanding the syndromes associated with familial thyroid cancer allows clinicians to evaluate and treat patients for coexisting pathologic conditions. About ﬁve percents of patients with well-di ﬀ erentiated thyroid carcinoma have a familial disease. Patients with familial non-medullalry thyroid cancer have more aggressive tumors with increased rates of extrathyroid extension, lymph node metastases, and frequently show the phenomenon of “anticipation” (earlier age at disease onset and increased severity in successive generations). So far, four predisposition loci have been identiﬁed in relatively rare extended pedigrees, and association studies have identiﬁed multiple predisposing variants for di ﬀ erentiated thyroid cancer. This suggests that there is a high degree of genetic heterogeneity and that the development of this type of tumor is a multifactorial and complex process in which predisposing genetic variants interact with a number of incompletely understood environmental risk factors. A 68-year-old woman with solid/trabecular follicular thyroid carcinoma inside of an autonomously functioning thyroid nodule is described in this paper. The patient was referred to our clinic for swelling of the neck and an increased pulse rate. Ultrasonography showed a slightly hypoechoic nodule in the right lobe of the thyroid. Despite suppressed TSH levels, the 99m Tc-pertechnetate scan showed a hot area corresponding to the nodule with a suppressed uptake in the remaining thyroid tissue. Histopathological examination of the nodule revealed a solid/trabecular follicular thyroid carcinoma. To the best of our knowledge, this is the ﬁrst case of hyperfunctioning follicular solid/trabecular carcinoma reported in the literature. Even if a hyperfunctioning thyroid carcinoma is an extremely rare malignancy, careful management is recommended so that a malignancy will not be overlooked in the hot thyroid nodules. An understanding of the mutations of the proto-oncogenes and tumor suppressor genes that occur in thyroid cancers should eventually explain the diverse clinical characteristics of these tumors and also direct therapy. Some insights have already emerged in the last decade; some abnormalities in tumor genes are consistently associated with speciﬁc clinical and pathologic ﬁndings. These genetic abnormalities usually represent somatic mutations in tumors of follicular epithelial origin, as opposed to inherited mutations in medullary thyroid cancers of parafollicular C cells origin because most thyroid tumors are sporadic and not familial. This is di ﬀ erent from the multiple endocrine neoplasia syndromes in which the primary tumorigenic gene mutations are inherited. This improved understanding of the molecular basis of these diseases has led to the development of novel targeted therapeutic approaches which will be discussed in this paper. Up to now, there are no curative therapies available for the subset of metastasized undi ﬀ erentiated/anaplastic thyroid carcinomas. This review describes the possible use of immunocompetent cells which may help to restore the antitumor immune recognition for treating an existing tumor or preventing its recurrence. The most prominent experimental strategy is the use of dendritic cells (DCs) which are highly potent in presenting tumor antigens. Activated DCs subsequently migrate to draining lymph nodes where they present antigens to na¨ıve lymphocytes and induce cytotoxic T cells (CTL). Alternatively to DC therapy, adoptive cell transfer may be performed by either using natural killer cells or ex vivo maturated CTLs. Within this review article we will focus on recent advances in the understanding of anti-tumor immune responses, for example, in thyroid carcinomas including the advances which have been made for the identiﬁcation of potential tumor antigens in thyroid malignancies.

Thyroid cancer is the most common endocrine malignancy and accounts for approximately 44,670 cases and 1,690 deaths in 2010 per the ACS. The purpose of this special issue is to provide an update on recent advances in the understanding of thyroid tumorigenesis and their implications in clinical practice and new surgical approaches to thyroid cancer and to the adoption of techniques used successfully in other tumor types for use in patients with thyroid cancer. Invited papers addressed several of the above topics.
Advances in surgery promise to allow expanded surgical treatment options and potentially make thyroid cancer surgery safer and better accepted by patients. Lang et al. provide a detailed overview of refinement in surgical techniques including endoscopic thyroidectomy techniques, the addition of the da Vinci robot, and the use of operative adjuncts in thyroid surgery such as intraoperative neuromonitoring and quick intraoperative parathyroid hormone. They also outline the clinical studies needed to better analyze the use of this new technology and its relative benefits and risks. Lombardi et al. present their review of a large series of patients with papillary thyroid cancer who underwent video-assisted thyroidectomy (VAT) for completeness of the surgical resection and short-to-medium term recurrence. Their results, while retrospective, seem to indicate that VAT is feasible and safe and may be a valid alternative to conventional surgery for small PTC. No surgical approach is without its concomitant risks-in thyroid surgery, this includes injury to one or both recurrent laryngeal nerves which can result in poor voice quality and the potential for recurrent aspiration. Sanuki et al. discuss their findings of immediate reconstruction of the recurrent laryngeal nerve during thyroid cancer surgery in terms of voice outcomes using videostroboscopic, aerodynamic, and perceptual analyses. While their numbers were small, it addresses an important question often raised in surgery as to whether immediate or delayed reconstruction should be performed.
Advances in genomics have offered exciting insights into the biology of thyroid cancer. While much attention has been focused on the traditional nucleic acids, the study of proteins and their function has been relatively neglected, in part due to the difficulty of the techniques required. The paper by Miyoshi et al. provides a comprehensive overview of the vital role of glycosylation and functional glycomics in thyroid cancer.
As clinicians well know, an accurate cytological diagnosis is key to the treatment approach for patients with thyroid nodules; this diagnosis is based on distinctive cytological features in combination with immunocytochemistry. Pazaitou-Panayiotou and colleagues present here their study of 83 thyroid cancer fine needle aspirations using Thin Layer Cytology. They present data on a panel of immunomarkers (including Cytokeratin-19, Galectin-3, HBME1, CD-44, CD-56, and E-Cadherin) and describe this promising new technique to improve diagnostic accuracy.
Early detection is a key component of familial thyroid cancer; Bonora et al. provide us with an excellent review of the familial syndromes, genetic abnormalities, and risk factors proposed to increase the likelihood of this type of neoplasia. Giovanella et al. present a very interesting case example of a rare functioning trabecular tumor of the thyroid gland which serves as a reminder to us that we must not overlook the potential for malignancy in the high-uptake pertechnetate positive nodule.
While the most extensively studied pathway for targeted therapy in thyroid cancer is RAS/RAF/MEK, clinical trials targeting therapies in this pathway are relatively new. The review by Poon and Tai provides us with a comprehensive update of known genomic changes in thyroid cancer and how this information is being used in clinical trials to improve targeted therapy.
Treatment of certain subtypes of thyroid cancer has been limited in part due to a dearth in therapeutic strategies. In a seminal paper, Dr. Steven Rosenberg proposed the concept that the body's immune system could be manipulated for cancer therapy. (Rosenberg SA (Jan 1984). "Adoptive immunotherapy of cancer: accomplishments and prospects". Cancer Treat Rep 68 (12): 233-55). Since then, a wide variety of immunotherapeutic approaches have been tested in clinical trials, in particular using either cell-based therapy or immunomodulators. These have led to fairly modest improvements in patient outcomes and a number of therapeutic challenges. This initial work has set the basis for a vigorous research effort to better understand the complex relationship and numerous intersecting pathways which regulate the body's response not only to cancer but to therapy for cancer as well. In their excellent review of dendritic cell-based immunotherapy for the subset of advanced, metastatic, or undifferentiated and anaplastic thyroid carcinoma, Papewalis et al. provide us with a focus on understanding the advances of antitumor immune response in thyroid carcinoma and well summarizes the rationale for adoptive dendritic cell transfer including the technical approach to this interesting new modality of treatment.
We hope that this special issue will educate, stimulate, and inspire support for participation in clinical trials and new research in the field of thyroid cancer. The development of new surgical approaches, effective targeted therapies, and better preventive interventions will assist in improving treatment and outcome in patients with thyroid cancer.

Jennifer E. Rosen Steven K. Libutti
Stephanie L. Lee