Breast cancer is the most common invasive cancer in women of reproductive age. In young women, chemotherapy may induce amenorrhea: it is still uncertain how to assess menopausal status in these patients despite the importance of its definition for choosing appropriate endocrine treatment. In the development of sensitive biomarkers for fertility and ovarian reserve, anti-Müllerian hormone (AMH) is considered a promising marker of ovarian reserve. The clearest data regarding a clinical use of AMH are related to the measurement of the ovarian pool in women who undergo IVF: the available data, also in breast cancer patients, seem to suggest that AMH measurement, before gonadotropin administration, can be a useful marker for the prediction of women at risk for poor-response or no response to ovarian stimulation. The utility of AMH as a potential marker of chemotherapy-induced ovarian follicular depletion and an early plasma marker of chemotherapy-induced gonadal damage has been evaluated both in young women after treatment for cancer in childhood and in young survivors of hematological malignancies and solid tumors. Several studies have demonstrated a potential utility of AMH, inhibin, or follicle-stimulating factor as biomarkers predicting infertility risk in breast cancer patients, but the studies conducted so far are not conclusive. Further studies are needed in order to define the regimen-specific action of chemotherapy on AMH levels, the percentage of post-treatment recovery of plasma levels of the hormone, and the relationship between menopausal status and AMH.
Claudia Bozza, Fabio Puglisi, Matteo Lambertini, Etin-Osa Osa, Massimo Manno, and Lucia Del Mastro
Susanne Singer, Susan Jordan, Laura D Locati, Monica Pinto, Iwona M Tomaszewska, Cláudia Araújo, Eva Hammerlid, E Vidhubala, Olga Husson, Naomi Kiyota, Christine Brannan, Dina Salem, Eva M Gamper, Juan Ignacio Arraras, Georgios Ioannidis, Guy Andry, Johanna Inhestern, Vincent Grégoire, Lisa Licitra, and on behalf of the EORTC Quality of Life Group, the EORTC Head and Neck Cancer Group, and the EORTC Endocrine Task Force
The purpose of the study was to pilot-test a questionnaire measuring health-related quality of life (QoL) in thyroid cancer patients to be used with the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire EORTC QLQ-C30. A provisional questionnaire with 47 items was administered to patients treated for thyroid cancer within the last 2 years. Patients were interviewed about time and help needed to complete the questionnaire, and whether they found the items understandable, confusing or annoying. Items were kept in the questionnaire if they fulfilled pre-defined criteria: relevant to the patients, easy to understand, not confusing, few missing values, neither floor nor ceiling effects, and high variance. A total of 182 thyroid cancer patients in 15 countries participated (n = 115 with papillary, n = 31 with follicular, n = 22 with medullary, n = 6 with anaplastic, and n = 8 with other types of thyroid cancer). Sixty-six percent of the patients needed 15 min or less to complete the questionnaire. Of the 47 items, 31 fulfilled the predefined criteria and were kept unchanged, 14 were removed, and 2 were changed. Shoulder dysfunction was mentioned by 5 patients as missing and an item covering this issue was added. To conclude, the EORTC quality of life module for thyroid cancer (EORTC QLQ-THY34) is ready for the final validation phase IV.
M M Muresan, P Olivier, J Leclère, F Sirveaux, L Brunaud, M Klein, R Zarnegar, and G Weryha
The presence of distant metastases from differentiated thyroid carcinoma decreases the 10-year survival of patients by 50%. Bone metastases represent a frequent complication especially of follicular thyroid cancer and severely reduce the quality of life causing pain, fractures, and spinal cord compression. Diagnosis is established by correlating clinical suspicion with imaging. Imaging is essential to detect, localize, and assess the extension of the lesions and should be used in conjunction with clinical evidence. Bone metastases are typically associated with elevated markers of bone turnover, but these markers have not been evaluated in differentiated thyroid cancer. Skeletal and whole-body magnetic resonance imaging and fusion 2-deoxy-2-[18F]fluoro-d-glucose whole-body positron emission tomography/computed tomography (PET/CT) are the best anatomic and functional imaging techniques available in specialized centers. For well-differentiated lesions, iodine-PET scan combined 124I-PET/CT is the newest imaging development and 131I is the first line of treatment. Bisphosphonates reduce the complications rate and pain, alone or in combination with radioiodine, radionuclides, or external beam radiotherapy and should be employed. Surgery and novel minimally invasive consolidation techniques demand an appropriate patient selection for best results on a multimodal approach. Basic research on interactions between tumor cells and bone microenvironment are identifying potential novel targets for future more effective therapeutic interventions for less differentiated tumors.
Feng Wu, Fuxingzi Li, Xiao Lin, Feng Xu, Rong-Rong Cui, Jia-Yu Zhong, Ting Zhu, Su-Kang Shan, Xiao-Bo Liao, Ling-Qing Yuan, and Zhao-Hui Mo
Tumour-derived exosomes under hypoxic conditions contain informative miRNAs involved in the interaction of cancer and para-carcinoma cells, thus contributing to tissue remodelling of the tumour microenvironment (TME). Exosomes isolated from hypoxic papillary thyroid cancer cells, BCPAP cells and KTC-1 cells enhanced the angiogenesis of human umbilical vein endothelial cells (HUVECs) compared with exosomes isolated from normal thyroid follicular cell line (Nthy-ori-3-1), normoxic BCPAP or KTC-1 cells both in vitro and in vivo. miR-21-5p was significantly upregulated in exosomes from papillary thyroid cancer BCPAP cells under hypoxic conditions, while the exosomes isolated from hypoxic BCPAP cells with knockdown of miR-21-5p attenuated the promoting effect of angiogenesis. In addition, our experiment revealed that miR-21-5p directly targeted and suppressed TGFBI and COL4A1, thereby increasing endothelial tube formation. Furthermore, elevated levels of exosomal miR-21-5p are found in the sera of papillary thyroid cancer patients, which promote the angiogenesis of HUVECs. Taken together, our study reveals the cell interaction between hypoxic papillary thyroid cancer cells and endothelial cells, elucidating a new mechanism by which hypoxic papillary thyroid cancer cells increase angiogenesis via exosomal miR-21-5p/TGFBI and miR-21-5p/COL4A1 regulatory pathway.
Shih-Ping Cheng, Chien-Liang Liu, Ming-Jen Chen, Ming-Nan Chien, Ching-Hsiang Leung, Chi-Hsin Lin, Yi-Chiung Hsu, and Jie-Jen Lee
CD74, the invariant chain of major histocompatibility complex class II, is also a receptor for macrophage migration inhibitory factor (MIF). CD74 and MIF have been associated with tumor progression and metastasis in hematologic and solid tumors. In this study, we found that 60 and 65% of papillary thyroid cancers were positive for CD74 and MIF immunohistochemical staining respectively. Anaplastic thyroid cancer was negative for MIF, but mostly positive for CD74 expression. Normal thyroid tissue and follicular adenomas were negative for CD74 expression. CD74 expression in papillary thyroid cancer was associated with larger tumor size (P=0.043), extrathyroidal invasion (P=0.021), advanced TNM stage (P=0.006), and higher MACIS score (P=0.026). No clinicopathological parameter was associated with MIF expression. Treatment with anti-CD74 antibody in thyroid cancer cells inhibited cell growth, colony formation, cell migration and invasion, and vascular endothelial growth factor secretion. In contrast, treatment with recombinant MIF induced an increase in cell invasion. Anti-CD74 treatment reduced AKT phosphorylation and stimulated AMPK activation. Our findings suggest that CD74 overexpression in thyroid cancer is associated with advanced tumor stage and may serve as a therapeutic target.
Zhenying Guo, Heather Hardin, and Ricardo V Lloyd
Thyroid cancer is one of the most rapidly increasing malignancies. The reasons for this increase is not completely known, but increases in the diagnosis of papillary thyroid microcarcinomas and follicular variant of papillary thyroid carcinomas along with the enhanced detection of well-differentiated thyroid carcinomas are probably all contributing factors. Although most cases of well-differentiated thyroid carcinomas are associated with an excellent prognosis, a small percentage of patients with well-differentiated thyroid carcinomas as well as most patients with poorly differentiated and anaplastic thyroid carcinomas have recurrent and/or metastatic disease that is often fatal. The cancer stem-like cell (CSC) model suggests that a small number of cells within a cancer, known as CSCs, are responsible for resistance to chemotherapy and radiation therapy, as well as for recurrent and metastatic disease. This review discusses current studies about thyroid CSCs, the processes of epithelial-to-mesenchymal transition (EMT), and mesenchymal-to-epithelial transition that provide plasticity to CSC growth, in addition to the role of microRNAs in CSC development and regulation. Understanding the biology of CSCs, EMT and the metastatic cascade should lead to the design of more rational targeted therapies for highly aggressive and fatal thyroid cancers.
Pedro Weslley Rosario, Gabriela Franco Mourão, Maurício Buzelin Nunes, Marcelo Saldanha Nunes, and Maria Regina Calsolari
Recently, it was proposed that some papillary thyroid carcinomas (PTC) will no longer be termed ‘cancer’ and are christened as ‘noninvasive follicular thyroid neoplasm with papillary-like nuclear features’ (NIFTP). As this is a recent definition, little information is available about NIFTP. The objective of this study was to report the frequency, ultrasonographic appearance, cytology result and long-term evolution of cases of NIFTP seen at our institution. We excluded tumours ≤1 cm. The sample consisted of 129 patients. Sixty-four patients were submitted to total thyroidectomy and 65 to lobectomy. These patients with NIFTP did not receive radioiodine. NIFTP corresponded to 15% of cases diagnosed as PTC >1 cm. An ultrasonographic appearance considered to be of low suspicion for malignancy was common in NIFTP (32.5%), whereas a highly suspicious appearance was uncommon (5%). NIFTP frequently exhibited indeterminate cytology (62%), while malignant cytology was uncommon (4%). The patients were followed up for 12–146 months (median 72 months) after surgery. None of the patients developed structural disease during follow-up. Comparing the concentrations of thyroglobulin (Tg) and anti-Tg antibodies (TgAb) obtained 6–12 months after surgery and in the last assessment, none of the patients exhibited an increase in these markers.
Catherine Ory, Nicolas Ugolin, Céline Levalois, Ludovic Lacroix, Bernard Caillou, Jean-Michel Bidart, Martin Schlumberger, Ibrahima Diallo, Florent de Vathaire, Paul Hofman, José Santini, Bernard Malfoy, and Sylvie Chevillard
Both external and internal exposure to ionizing radiation are strong risk factors for the development of thyroid tumors. Until now, the diagnosis of radiation-induced thyroid tumors has been deduced from a network of arguments taken together with the individual history of radiation exposure. Neither the histological features nor the genetic alterations observed in these tumors have been shown to be specific fingerprints of an exposure to radiation. The aim of our work is to define ionizing radiation-related molecular specificities in a series of secondary thyroid tumors developed in the radiation field of patients treated by radiotherapy. To identify molecular markers that could represent a radiation-induction signature, we compared 25K microarray transcriptome profiles of a learning set of 28 thyroid tumors, which comprised 14 follicular thyroid adenomas (FTA) and 14 papillary thyroid carcinomas (PTC), either sporadic or consecutive to external radiotherapy in childhood. We identified a signature composed of 322 genes which discriminates radiation-induced tumors (FTA and PTC) from their sporadic counterparts. The robustness of this signature was further confirmed by blind case-by-case classification of an independent set of 29 tumors (16 FTA and 13 PTC). After the histology code break by the clinicians, 26/29 tumors were well classified regarding tumor etiology, 1 was undetermined, and 2 were misclassified. Our results help shed light on radiation-induced thyroid carcinogenesis, since specific molecular pathways are deregulated in radiation-induced tumors.
J L Reverter, S Holgado, N Alonso, I Salinas, M L Granada, and A Sanmartí
The effect of subclinical hyperthyroidism on bone mineral density is controversial and could be significant in patients with differentiated thyroid carcinoma who receive suppressive doses of levothyroxine (LT4). To ascertain whether prolonged treatment with LT4 to suppress thyrotropin had a deleterious effect on bone mineral density and/or calcium metabolism in patients thyroidectomized for differentiated thyroid cancer we have performed a cross-sectional study in a group of 88 women (mean ± SD age: 51 ± 12 years) treated with LT4 after near-total thyroidectomy and in a control group of 88 healthy women (51 ± 11 years) matched for body mass index and menopausal status. We determined calcium metabolism parameters, bone turnover marker N-telopeptide and bone mass density by dual-energy X-ray absorptiometry. No differences were found between patients and controls in calcium metabolism parameters or N-telopeptide except for PTH, which was significantly increased in controls. No differences were found between groups in bone mineral density in femoral neck (0.971 ± 0.148 gr/cm2 vs 0.956 ± 0.130 gr/cm2 in patients and controls respectively, P = 0.5). In lumbar spine, bone mineral density values were lower in controls than in patients (1.058 ± 0.329 gr/cm2 vs 1.155 ± 0.224 gr/cm2 respectively, P<0.05). When premenopausal (n = 44) and postmenopausal (n = 44) patients were compared with their respective controls, bone mineral density was similar both in femoral neck and lumbar spine. The proportion of women with normal bone mass density, osteopenia and osteoporosis in patient and control groups was similar in pre- and postmenopausal women. In conclusion, long-term suppressive LT4 treatment does not appear to affect skeletal integrity in women with differentiated thyroid carcinoma.
Ying Ni, Spencer Seballos, Shireen Ganapathi, Danielle Gurin, Benjamin Fletcher, Joanne Ngeow, Rebecca Nagy, Richard T Kloos, Matthew D Ringel, Thomas LaFramboise, and Charis Eng
Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC.