Follicular Cell-derived Cancer Research Articles

Thyroid Cancer Epidemic: A Peril or an Alarm?

Thyroid Cancer Epidemic: A Peril or an Alarm?

Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases.

Radioiodine (RAI) remains the mainstay of therapy for RAI-avid (RAIA) distant metastatic thyroid carcinoma. We previously demonstrated that RAI-refractory distant metastatic thyroid cancers commonly harbor BRAF mutations. However, the molecular profile of RAIA metastatic thyroid cancer is unknown. Here we describe the mutational profile of thyroid tumors from follicular cell-derived cancer (FCDTC) patients presenting with RAIA distant metastases. In addition, we aimed to correlate clinical outcomes of RAI therapy with clinicopathological factors and tumor mutational status. We retrospectively identified 43 patients with FCDTC who had RAI uptake in the lungs and/or bones on their initial ¹³¹I postablation scan. Primary tumors were genotyped for known mutations in thyroid cancer genes. Structural response to RAI was assessed 6-18 months after each administered RAI activity and at the end of follow-up. RAS, BRAF, RET/PTC, and PIK3CA mutations were found in 42, 23, 10, and 2% of tumors, respectively, and the remaining 23% were wild type. None of these patients achieved cure after repeat RAI therapies, and most patients (54%) experienced disease progression despite repeated RAI administration. There was an increased prevalence of RAS mutations in these RAIA tumors. RAS-mutant cancers were more likely to concentrate iodine on diagnostic whole body scans. Despite this, structural response to RAI was not influenced by tumor genotype. RAIA metastatic FCDTC are overrepresented with RAS mutations, whereas RAI refractory metastatic thyroid cancers are enriched with BRAF mutations. Despite a seemingly preserved ability to concentrate iodine, RAI therapy is ineffective in achieving cure in most patients with RAIA metastatic FCDTC, even in RAS-mutant disease. These poor outcomes may be improved based on recent evidence that pretreatment with MAPK kinase 1/2 inhibitors enhances responses to RAI, particularly in patients with RAS-mutant tumors.

Classification of follicular cell-derived thyroid cancer by global RNA profiling

The incidence of thyroid cancer is increasing worldwide and thyroid nodules are a frequent clinical finding. Diagnosing follicular cell-derived cancers is, however, challenging both histopathologically and especially cytopathologically. The advent of high-throughput molecular technologies has prompted many researchers to explore the transcriptome and, in recent years, also the miRNome in order to generate new molecular classifiers capable of classifying thyroid tumours more accurately than by conventional cytopathological and histopathological methods. This has led to a number of molecular classifiers that may differentiate malignant from benign thyroid nodules. Molecular classification models based on global RNA profiles from fine-needle aspirations are currently being evaluated; results are preliminary and lack validation in prospective clinical trials. There is no doubt that molecular classification will not only contribute to our biological insight but also improve clinical and pathological examinations, thus advancing thyroid tumour diagnosis and ultimately preventing superfluous surgery. This review evaluates the status of classification and biological insights gained from molecular profiling of follicular cell-derived thyroid cancers.

Chromosomal rearrangements and the pathogenesis of differentiated thyroid cancer

The majority of thyroid cancers arise from the follicular cells of the thyroid gland, which yield a wide variety of distinct morphotypes, ranging from relatively indolent lesions to the most malignant forms of cancer known. The remaining primary thyroid cancers arise from C cells within the gland and result primarily from mutations of the RET protooncogene, germ line mutations of which give rise to the various forms of multiple endocrine neoplasia. The most common of the follicular cell-derived cancers are papillary carcinomas, (PTC), followed by follicular carcinomas (FTC) and its Hurthle cell variant (HCC) and finally anaplastic carcinomas (ATC). The pathogenesis of many thyroid cancers, of both PTC and FTC morphotype, involves chromosomal translocations. Rearrangements of the RET protoconcogene are known to be involved in the pathogenesis of ca. 50% of PTC. A similar proportion of FTC have been associated with a t(2;3)(q13;p25) translocation, fusing the thyroid-specific transcription factor PAX8 with the peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor, a ubiquitously expressed transcription factor. These rearrangements have analogy with translocations in erythropoetic cells, which form the only other known group of human malignancies that are largely the result of chromosomal translocation events. In this review we compare and contrast the oncogenic properties of thyroid and erythroid chromosomal transformations and speculate on mechanisms leading to their formation.

The Coming of Age of Ultrasound-Guided Percutaneous Ethanol Ablation of Selected Neck Nodal Metastases in Well-Differentiated Thyroid Carcinoma

The majority of patients with well-differentiated thyroid cancer (WDTC), whether derived from the follicular cell or the C-cell, present with a focal, often palpable, intrathyroidal primary lesion, but at initial diagnosis, many such tumors have already spread to regional lymph nodes, mainly in the neck (1). The prevalence of such neck nodal metastases (NNM) at presentation varies significantly among the various histological subtypes of WDTC but approaches 40% (2) in both papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC). A significant number of WDTC patients, despite potentially curative primary surgery, are also found to have NNM discovered at months to years after the date of the initial operation. Historically, postoperative “recurrence” within 30 postoperative years occurs in NNM, despite apparently complete primary surgical resection, in 9–20% of PTC and about 25% of MTC patients (2, 3). As detection limits of tumor markers progressively diminish, and high-resolution ultrasound (US) allows the identification of NNM as small as 2–3 mm diameter, increasing numbers of tiny NNM are being confirmed (4) by USguided biopsy (USGB). What to do with such nonthreatening disease is a dilemma increasingly faced by thyroidologists in contemporary clinical practice (5, 6). Clearly, radioiodine remnant ablation (RRA) rarely prevents the discovery of postoperative NNM in follicular cell-derived cancers (FCDC), and reoperative compartment-oriented surgery, recommended by most clinical management guidelines (5, 6) produces a biochemical remission in PTC only 30–50% of the time (7–9). Stereotactic radiotherapy has recently been employed in Korea to treat recurrent NNM in WDTC, but follow-up in these patients (7 PTC; 2 MTC) has been short, and new metastases in 4 of 9 patients developed in “nontarget regional nodes” (10). In this issue of JCEM, a study from Norway (11) describes the latest chapter in a series of papers (12– 15) describing the efficacy of ultrasound-guided percutaneous ethanol ablation (UPEA) in treating NNM in WDTC. Ultrasound-guided percutaneous ethanol injections (UPEI) have been employed since the 1980s for the palliative treatment of small hepatocellular carcinomas. In 1988, UPEI was successfully employed by Charboneau and Hay at the Mayo Clinic (16) to ablate a parathyroid adenoma, which had resulted in persistent hyperparathyroidism in an elderly patient considered unsuitable for neck re-exploration. By 1990, UPEI was being employed in many European centers to treat autonomously functioning thyroid adenomas (17), and it had also been used to treat an inoperable FCDC (18). UPEA was first used at the Mayo Clinic in 1991 to treat two left central compartment NNM (9 mm and 1.1 cm diameter) in a 46-yr-old psychiatrist with stage IV MTC who had undergone three prior neck surgeries, had previously undergone transection of his right recurrent laryngeal nerve and was facing a possible tracheostomy, if he were to undergo further surgical resection. His two injected level VI nodes disappeared on careful US scanning within 10 months and did not recur after 20 yr of follow-up (Hay, I. D., and J. W. Charboneau, unpublished data).

Growth inhibition of thyroid follicular cell-derived cancers by the opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis

BackgroundCarcinoma of the thyroid gland is an uncommon cancer, but the most frequent malignancy of the endocrine system. Most thyroid cancers are derived from the follicular cell. Follicular carcinoma (FTC) is considered more malignant than papillary thyroid carcinoma (PTC), and anaplastic thyroid cancer (ATC) is one of the most lethal human cancers. Opioid Growth Factor (OGF; chemical term - [Met5]-enkephalin) and its receptor, OGFr, form an inhibitory axis regulating cell proliferation. Both the peptide and receptor have been detected in a wide variety of cancers, and OGF is currently used clinically as a biotherapy for some non-thyroid neoplasias. This study addressed the question of whether the OGF-OGFr axis is present and functional in human thyroid follicular cell - derived cancer.MethodsUtilizing human ATC (KAT-18), PTC (KTC-1), and FTC (WRO 82-1) cell lines, immunohistochemistry was employed to ascertain the presence and location of OGF and OGFr. The growth characteristics in the presence of OGF or the opioid antagonist naltrexone (NTX), and the specificity of opioid peptides for proliferation of ATC, were established in KAT-18 cells. Dependence on peptide and receptor were investigated using neutralization studies with antibodies and siRNA experiments, respectively. The mechanism of peptide action on DNA synthesis and cell survival was ascertained. The ubiquity of the OGF-OGFr axis in thyroid follicular cell-derived cancer was assessed in KTC-1 (PTC) and WRO 82-1 (FTC) tumor cells.ResultsOGF and OGFr were present in KAT-18 cells. Concentrations of 10-6 M OGF inhibited cell replication up to 30%, whereas NTX increased cell growth up to 35% relative to cultures treated with sterile water. OGF treatment reduced cell number by as much as 38% in KAT-18 ATC in a dose-dependent and receptor-mediated manner. OGF antibodies neutralized the inhibitory effects of OGF, and siRNA knockdown of OGFr negated growth inhibition by OGF. Cell survival was not altered by OGF, but DNA synthesis as recorded by BrdU incorporation was depressed by 28% in OGF-treated cultures compared to those exposed to sterile water. The OGF-OGFr axis was detected and functional in PTC (KTC-1) and FTC (WRO 82-1) cell lines.ConclusionThese data suggest that OGF and OGFr are present in follicular-derived thyroid cancers, and that OGF serves in a tonically active inhibitory manner to maintain homeostasis of cell proliferation. These results may provide a biotherapeutic strategy in the treatment of these cancers.

New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy

Well-differentiated thyroid cancer has in general terms a very good outcome. It has a very slow growth rate and, although it metastasizes at a relatively high frequency, it has very high survival rates. Whereas the prevalence of nodular thyroid disease worldwide is high, malignant conversion from benign thyroid nodules is rare. Treatment of thyroid cancer is usually successful, but we still do not have effective therapies for patients with invasive or metastatic thyroid cancer if the disease does not concentrate radioiodine and it is not surgically resectable. On the other hand, from the same thyroid cell, one of the most aggressive human tumours can arise--undifferentiated or anaplastic thyroid carcinoma--leading to death in a few months. What features of this malignancy account for such paradoxical behaviour? The most common type of thyroid cancer--papillary thyroid carcinoma--stands out among solid tumours because many of the tumour-initiating events have been identified. All of them function in a single pathway--the RTK/RAS/RAF/MAPK pathway--and obey an 'exclusivity principle': one and only one component of the pathway is mutated in a single tumour. This highlights the requirement of this signal transduction pathway for the transformation to thyroid cancer and paves the way to targeted therapies against a tumour with a mutation in a known gene or any gene upstream of the target. However, it is also interesting to underscore the differences among the tumours arising from the different mutations. Studies in vitro and in vivo, including genomic profiling and genetically engineered mouse models, have clearly shown that each oncoprotein exerts its own oncogenic drive, conferring a distinct biological behaviour on thyroid tumours. In this review, we attempt to summarise the most recent advances in thyroid follicular cell-derived cancers research and their potential clinical impact that may change the management of thyroid cancer in the near future.

Chromosomal rearrangements and the pathogenesis of differentiated thyroid cancer

The majority of thyroid cancers arise from the follicular cells of the thyroid gland, which yield a wide variety of distinct morphotypes, ranging from relatively indolent lesions to the most malignant forms of cancer known. The remaining primary thyroid cancers arise from C cells within the gland and result primarily from mutations of the RET protooncogene, germ line mutations of which give rise to the various forms of multiple endocrine neoplasia. The most common of the follicular cell-derived cancers are papillary carcinomas, (PTC), followed by follicular carcinomas (FTC) and its Hurthle cell variant (HCC) and finally anaplastic carcinomas (ATC). The pathogenesis of many thyroid cancers, of both PTC and FTC morphotype, involves chromosomal translocations. Rearrangements of the RET protoconcogene are known to be involved in the pathogenesis of ca. 50% of PTC. A similar proportion of FTC have been associated with a t(2;3)(q13;p25) translocation, fusing the thyroid-specific transcription factor PAX8 with the peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor, a ubiquitously expressed transcription factor. These rearrangements have analogy with translocations in erythropoetic cells, which form the only other known group of human malignancies that are largely the result of chromosomal translocation events. In this review we compare and contrast the oncogenic properties of thyroid and erythroid chromosomal transformations and speculate on mechanisms leading to their formation.

Selective use of radioactive iodine in the postoperative management of patients with papillary and follicular thyroid carcinoma

Radioiodine remnant ablation (RRA) was developed in the 1960s to "complete a thyroidectomy" in the initial management of papillary and follicular thyroid cancer. By the 1990s, it was claimed that RRA diminished recurrence rates in follicular cell-derived cancer (FCDC) patients and decreased the cause-specific mortality (CSM) in patients more than 40 years old at initial surgery. The international trend for the past decade has been towards routine RRA in most FCDC patients. Clinical guidelines have been produced by many societies, promoting such an aggressive stance. Since 1997, many papers have reported improved outcome in FCDC, when patients were subjected to RRA after bilateral lobar resection. However, during the same time-period, it has been recognized that most FCDC patients are truly at "low-risk" of developing life-threatening recurrences. Accordingly, it has been suggested that rational therapy selection should lead to restricting aggressive therapy to those "high-risk" FCDC patients, more predisposed to CSM. To date, no prospective controlled trials exist. Presently available outcome data is based on single institutional or multicenter retrospective studies. This article summarizes the available relevant reported data, and concludes that a selective use of RRA in the postoperative management of FCDC patients is rational, and should actually be encouraged.

Surgical treatment of thyroid carcinoma

BACKGROUND: Thyroid cancer is usually of follicular cell origin, but medullary thyroid cancer (MTC) arises from the parafollicular or C-cells. The annual incidence of thyroid cancer varies from 3–7 per 100.000 population in Austria and constitutes 1.36 % of all malignant tumours. METHODS: The current surgical treatment of thyroid carcinoma is reviewed with respect to the endemic epidemiology. RESULTS: Four distinct histological types of follicular cell-derived cancers are recognized, approximately two-thirds are papillary, one-third is follicular, some are oxyphilic cancers and the anaplastic type has become rare lately. The first three types are summed up as differentiated thyroid carcinomas (DTCs). MTC is rare and constitutes 6–7 % of thyroid cancers, of which approximately 75 % are sporadic and 25 % are hereditary. There are no prospective, randomised trials to determine the "optimal treatment" of the various thyroid carcinomas. The "failed TNM classification" in its sixth edition again demolished studies over a longer period, as the fifth and sixth editions were only five years apart and classification does not match. At least in endemic areas surgery should be more radical, as tumour biology seems to be more aggressive and the patients are mainly in the higher risk groups. Therefore total thyroidectomy is the operation of choice for pre- or intraoperatively diagnosed DTCs and MTCs. Less than radical surgery should only be performed for tumours smaller than 10 mm without obvious multicentricity. Central cervical lymph node dissection is mandatory in all operations with pre- or intraoperatively determined cancer. If there is evidence of clinical or pathological central lymph node metastases, an uni- or bilateral neck dissection should be accomplished. Only in patients with occult or incidentally found papillary carcinomas of less than 10 mm completion thyroidectomy and lymph node dissection can be omitted. CONCLUSIONS: As there are no controlled randomized studies, developing guidelines is difficult, especially as data from other parts of the world do not necessarily apply for endemic regions, such as Austria. It is generally agreed that patients with DTC and MTC should be treated by total thyroidectomy with adequate lymph node dissection. Patients can usually be discharged after 2 or 3 days after these procedures, and morbidity for RLNP and postoperative hypoparathyroidism is low when thyroidectomy is performed by an experienced thyroid surgeon. As age >45 years and increasing tumour size predict poor prognosis in DTCs, new means of diagnosis for earlier treatment are therefore necessary. Hereditary MTCs should only be treated in multidisciplinary study groups according to their genetic risk.

Children with Differentiated Thyroid Cancer Achieve Adequate Hyperthyrotropinemia within 14 Days of Levothyroxine Withdrawal

The preparation for radioiodine administration recommended by the current pediatric literature is a 6-wk withdrawal that typically includes the transient administration of T3. Compared with adults, T4 clearance rates and serum TSH to free T4 ratios are higher in children, implying that pediatric patients can achieve adequate hyperthyrotropinemia with shorter levothyroxine withdrawals. The objective of this study was to determine whether children with differentiated thyroid cancer achieve adequate hyperthyrotropinemia using an abbreviated levothyroxine withdrawal protocol. The study design was a retrospective analysis of 15 consecutive levothyroxine withdrawals performed without T3 at Children's Hospital Boston. Eleven children with differentiated thyroid cancer were included. The average age at the time of withdrawal was 12.5 +/- 0.8 yr. Serum TSH concentrations obtained after the discontinuation of levothyroxine were analyzed to determine the time interval required to achieve a serum TSH level greater than 25 microU/ml for each patient. Adequate hyperthyrotropinemia was documented in all children tested by d 14. The mean interval required to achieve a serum TSH level above 25 microU/ml from a suppressed serum TSH was 12.3 +/- 0.7 d. Shorter withdrawals minimize hypothyroid morbidity and the theoretical risk of decreased 131micro)I residence time from excessive hyperthyrotropinemia. These benefits are amplified in children due to their high incidence of distant metastases. We propose an abbreviated 2-wk withdrawal protocol to facilitate the adjunctive therapy and surveillance of children with follicular cell-derived cancers.