ALK fusions are found in various tumors, including thyroid cancer, and serve as a diagnostic marker and therapeutic target. Spectrum and outcomes of ALK fusions found in thyroid nodules and cancer are not fully characterized. We report a series of 44 ALK-translocated thyroid neoplasms, including 31 identified preoperatively in thyroid fine-needle aspirates (FNA). The average patients’ age was 43 years (range, 8–76 years); only one with radiation history. All 19 resected thyroid nodules with ALK fusion identified preoperatively were malignant. Among nodules with known surgical pathology (n = 32), 84% were papillary thyroid carcinomas (PTCs) and 16% poorly differentiated thyroid carcinomas (PDTCs). PTCs showed infiltrative growth with follicular architecture seen exclusively (30%) or in combination with papillary and/or solid growth (37%). Tumor multifocality was seen in 10 (31%) PTC cases. Most PDTC had a well-differentiated PTC component. Lymph node metastases were identified in 10/18 (56%) patients with neck dissection. The most common ALK fusion partners were STRN (n = 22) and EML4 (n = 17). In five cases, novel ALK fusion partners were discovered. All five PDTCs carried STRN-ALK fusion. On follow-up, ten patients were free of disease at 2–108 months, whereas two patients with PDTC died of disease. In summary, ALK fusion-positive thyroid carcinomas are typically infiltrative PTC with common follicular growth, which may show tumor dedifferentiation associated with increased mortality. Compared to EML4-ALK, STRN-ALK may be more common in PDTC, and ~10% of ALK fusions occur to rare gene partners. When ALK fusion is detected preoperatively in FNA samples, malignancy should be expected.
Federica Panebianco, Alyaksandr V Nikitski, Marina N Nikiforova, Cihan Kaya, Linwah Yip, Vincenzo Condello, Abigail I Wald, Yuri E Nikiforov and Simion I Chiosea
David Taïeb, Abhishek Jha, Giorgio Treglia and Karel Pacak
In recent years, advancement in genetics has profoundly helped to gain a more comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas and paragangliomas (PPGLs). Newly discovered molecular targets, particularly those that target cell membranes or signaling pathways have helped move nuclear medicine in the forefront of PPGL precision medicine. This is mainly based on the introduction and increasing experience of various PET radiopharmaceuticals across PPGL genotypes quickly followed by implementation of novel radiotherapies and revised imaging algorithms. Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis and staging of PPGLs and in selecting patients for PRRT as a potential alternative to 123/131I-MIBG theranostics. PRRT using 90Y/177Lu-DOTA-SSAs has shown promise for treatment of PPGLs with improvement of clinical symptoms and/or disease control. However, more well-designed prospective studies are required to confirm these findings, in order to fully exploit PRRT’s antitumoral properties to obtain the final FDA approval. Such an approval has recently been obtained for high‐specific-activity 131I-MIBG for inoperable/metastatic PPGL. The increasing experience and encouraging preliminary results of these radiotherapeutic approaches in PPGLs now raises an important question of how to further integrate them into PPGL management (e.g. monotherapy or in combination with other systemic therapies), carefully taking into account the PPGLs locations, genotypes, and growth rate. Thus, targeted radionuclide therapy (TRT) should preferably be performed at specialized centers with an experienced interdisciplinary team. Future perspectives include the introduction of dosimetry and biomarkers for therapeutic responses for more individualized treatment plans, α-emitting isotopes, and the combination of TRT with other systemic therapies.
Moray J Campbell
The 3D organization of the genome within the cell nucleus has come into sharp focus over the last decade. This has largely arisen because of the application of genomic approaches that have revealed numerous levels of genomic and chromatin interactions, including topologically associated domains (TADs). The current review examines how these domains were identified, are organized, how their boundaries arise and are regulated, and how genes within TADs are coordinately regulated. There are many examples of the disruption to TAD structure in cancer and the altered regulation, structure and function of TADs are discussed in the context of hormone responsive cancers, including breast, prostate and ovarian cancer. Finally, some aspects of the statistical insight and computational skills required to interrogate TAD organization are considered and future directions discussed.
Livia Lamartina, Sophie Leboulleux, Marie Terroir, Dana Hartl and Martin Schlumberger
Low-risk papillary cancers, which represent the vast majority of thyroid cancers diagnosed today, do not require aggressive treatment or follow-up. Initial treatment consists of a total thyroidectomy without prophylactic lymph node dissection. A hemithyroidectomy is an alternative in some patients with an intrathyroidal tumor and with a normal contralateral lobe at pre-operative neck ultrasonography. The use of post-operative radioiodine should be restricted to selected patients. Follow-up at 6–18 months is based on serum thyroglobulin (Tg), Tg-antibody determination and neck ultrasonography. In the absence of any abnormality (excellent response to treatment), the risk of recurrence is extremely low and follow-up may consist of serum TSH monitoring that is maintained in the normal range, and a Tg and Tg-antibody titer determination every year. There is no need for referral to a specialized center. In patients with detectable serum Tg or detectable Tg antibodies, the trend over time of these markers on levothyroxine treatment will dictate subsequent follow-up: a decreasing trend is reassuring, but an increasing trend should lead to imaging, starting with neck ultrasonography.
Dimitra A Vassiliadi and Stylianos Tsagarakis
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression from the rarely encountered severe forms, regarding both cortisol excess and adrenal enlargement, to mild forms of asymptomatic or oligosymptomatic cases with less impressive imaging phenotypes. Activation of cAMP/PKA pathway, either due to alterations of the different downstream signaling pathways or through aberrantly expressed G-protein-coupled receptors, relates to both cortisol secretion and adrenal growth. Germline ARMC5 mutations are a frequent genetic defect. The diagnostic approach consists of both imaging and hormonal characterization. Imaging characterization should be done separately for each lesion. Endocrine evaluation in cases with clinically overt Cushing’s syndrome (CS) is similar to that applied for all forms of CS. In incidentally detected PBMAH, hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1 mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism, ACTH levels should be measured in order to establish ACTH independency. At variance with other forms of CS, PBMAH may be characterized by a distinct pattern of inefficient steroidogenesis. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with severe CS. Unilateral adrenalectomy might be considered in selected patients. In cases where the regulation of cortisol secretion is mediated by aberrant receptors there is some potential for medical therapy.
Fabian Pitoia and Fernando Jerkovich
The stratification of patients with differentiated thyroid cancer based on their initial risk of recurrence, according to specific clinical, histopathological and perioperative data, is an important starting point for tailoring the follow-up during the first 1–2 years after initial therapy (surgery with or without radioiodine ablation). However, risk of recurrence re-stratification based on new clinical data that becomes available after considering the response to treatment (dynamic risk assessment) provides a more accurate prediction of the status at final follow-up and a more individualized approach. In this review, we summarized the available data regarding dynamic risk of recurrence and the suggested management of differentiated thyroid cancer patients according to the response to treatment. The use of this strategy is crucial to avoid overtreatment and intensive follow-up of the vast majority of patients who will have a very good prognosis and, on the other hand, focus therapeutic efforts on those patients who will have a worse prognosis. In the future, molecular biology analysis of the tumors and well-designed prospective studies will probably refine the risk of recurrence prediction.
Monia Zidane, Jean-Baptiste Cazier, Sylvie Chevillard, Catherine Ory, Martin Schlumberger, Corinne Dupuy, Jean-François Deleuze, Anne Boland, Nadia Haddy, Fabienne Lesueur and Florent de Vathaire
The first study establishing exposure to ionizing radiations (IRs) as a risk factor for differentiated thyroid cancer (DTC) was published 70 years ago. Given that radiation exposure causes direct DNA damage, genetic alterations in the different DNA repair mechanisms are assumed to play an important role in long-term IR-induced DNA damage prevention. Individual variations in DNA repair capacity may cause different reactions to damage made by IR exposure. The aim of this review is to recapitulate current knowledge about constitutional genetic polymorphisms found to be significantly associated with DTC occurring after IR exposure. Studies were screened online using electronic databases – only fully available articles, and studies performed among irradiated population or taking radiation exposure as adjustment factors and showing significant results are included. Nine articles were identified. Ten variants in/near to genes in six biological pathways, namely thyroid activity regulations, generic transcription, RET signaling, ATM signaling and DNA repair pathways were found to be associated with radiation-related DTC in these studies. Only seven variants were found to be in interaction with IR exposure in DTC risk. Most of these variants are also associated to sporadic DTC and are not specific to IR-related DTC. In the published studies, no data on children treated with radiotherapy is described. In conclusion, more studies carried out on larger cohorts or on case–control studies with well-documented individual radiation dose estimations are needed to get a comprehensive picture of genetic susceptibility factors involved in radiation-related DTC.
Cathy B Moelans, Joep de Ligt, Petra van der Groep, Pjotr Prins, Nicolle J M Besselink, Marlous Hoogstraat, Natalie D ter Hoeve, Miangela M Lacle, Robert Kornegoor, Carmen C van der Pol, Wendy W J de Leng, Ellis Barbé, Bert van der Vegt, John Martens, Peter Bult, Vincent T H B M Smit, Marco J Koudijs, Isaac J Nijman, Emile E Voest, Pier Selenica, Britta Weigelt, Jorge S Reis-Filho, Elsken van der Wall, Edwin Cuppen and Paul J van Diest
Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes. The landscape of mutations and copy number alterations was compared to that of publicly available estrogen receptor (ER)-positive female breast cancers (smFBCs) and correlated to prognosis. From the 135 MBCs, 90% showed ductal histology, 96% were ER-positive, 66% were progesterone receptor (PR)-positive, and 2% HER2-positive, resulting in 50, 46 and 4% luminal A-like, luminal B-like and basal-like cases, respectively. Five patients had Klinefelter syndrome (4%) and 11% of patients harbored pathogenic BRCA2 germline mutations. The genomic landscape of MBC to some extent recapitulated that of smFBC, with recurrent PIK3CA (36%) and GATA3 (15%) somatic mutations, and with 40% of the most frequently amplified genes overlapping between both sexes. TP53 (3%) somatic mutations were significantly less frequent in MBC compared to smFBC, whereas somatic mutations in genes regulating chromatin function and homologous recombination deficiency-related signatures were more prevalent. MDM2 amplifications were frequent (13%), correlated with protein overexpression (P = 0.001) and predicted poor outcome (P = 0.007). In conclusion, despite similarities in the genomic landscape between MBC and smFBC, MBC is a molecularly unique and heterogeneous disease requiring its own clinical trials and treatment guidelines.
Ryan K Orosco, Timon Hussain, Julia E Noel, David C Chang, Chrysoula Dosiou, Erik Mittra, Vasu Divi and Lisa A Orloff
Radioactive iodine (RAI) is a key component in the treatment of differentiated thyroid cancer. RAI has been recommended more selectively in recent years as guidelines evolve to reflect risks and utility in certain patient subsets. In this study we sought to evaluate the survival impact of radioactive iodine in specific thyroid cancer subgroups. Nationwide retrospective cohort study of patients using the National Cancer Database (NCDB) from 2004 to 2012 and Surveillance, Epidemiology, and End Results (SEER) database from 1992 to 2009 examining patients with differentiated thyroid cancer treated with or without RAI. Primary outcomes included all-cause mortality (NCDB and SEER), and cancer-specific mortality (SEER). Cox multivariate survival analyses were applied to each dataset, and in 135 patient subgroups based on clinical and non-clinical parameters. A total of 199,371 NCDB and 77,187 SEER patients were identified. RAI was associated with improved all-cause mortality (NCDB: RAI hazard ratio (HR) 0.55, P < 0.001; SEER: HR 0.64, P < 0.001); and cancer-specific mortality (SEER: HR 0.82, P = 0.029). Iodine therapy showed varied efficacy within each subgroup. Patients with high-risk disease experienced the greatest benefit in all-cause mortality, followed by intermediate-risk, then low-risk subgroups. Regarding cancer-specific mortality, radioactive iodine therapy was protective in high-risk patients, but did not achieve statistical significance in most intermediate-risk subgroups. Low-risk T1a subgroups demonstrated an increased likelihood of cancer-specific mortality with iodine therapy. The efficacy of RAI in patients with differentiated thyroid cancer varies by disease severity. A negative cancer-specific survival association was identified in patients with T1a disease. These findings warrant further evaluation with prospective studies.
Adwitiya Kar, Yu Zhang, Betelehem W Yacob, Jordan Saeed, Kenneth D Tompkins, Stacey M Bagby, Todd M Pitts, Hilary Somerset, Stephen Leong, Margaret E Wierman and Katja Kiseljak-Vassiliades
Adrenocortical carcinoma (ACC) is an aggressive orphan malignancy with less than 35% 5-year survival and 75% recurrence. Surgery remains the primary therapy and mitotane, an adrenolytic, is the only FDA-approved drug with wide-range toxicities and poor tolerability. There are no targeted agents available to date. For the last three decades, H295R cell line and its xenograft were the only available preclinical models. We recently developed two new ACC patient-derived xenograft mouse models and corresponding cell lines (CU-ACC1 and CU-ACC2) to advance research in the field. Here, we have utilized these novel models along with H295R cells to establish the mitotic PDZ-binding kinase (PBK) as a promising therapeutic target. PBK is overexpressed in ACC samples and correlates with poor survival. We show that PBK is regulated by FOXM1 and targeting PBK via shRNA decreased cell proliferation, clonogenicity and anchorage-independent growth in ACC cell lines. PBK silencing inhibited pAkt, pp38MAPK and pHistone H3 altering the cell cycle. Therapeutically, targeting PBK with the small-molecule inhibitor HITOPK032 phenocopied PBK-specific modulation of pAkt and pHistone H3, but also induced apoptosis via activation of JNK. Consistent with in vitro findings, treatment of CU-ACC1 PDXs with HITOPK032 significantly reduced tumor growth by 5-fold (P < 0.01). Treated tumor tissues demonstrated increased rates of apoptosis and JNK activation, with decreased pAkt and Histone H3 phosphorylation, consistent with effects observed in ACC cell lines. Together these studies elucidate the mechanism of PBK in ACC tumorigenesis and establish the potential therapeutic potential of HITOPK032 in ACC patients.