Poorly differentiated thyroid cancer (PDTC) is a rare but clinically highly significant entity because it accounts for most fatalities from non-anaplastic follicular cell-derived thyroid cancer. Due ...to the relative rarity of the disease and heterogeneous diagnostic criteria, studies on PDTC have been limited. In light of the evolution of ultra-deep next-generation sequencing technologies and through correlation of clinicopathologic and genomic characteristics of PDTC, an improved understanding of the biology of PDTC has been facilitated. Here, the diagnostic criteria, clinicopathologic characteristics, management, and outcomes in PDTC, as well as genomic drivers in PDTC reported in recent next-generation sequencing studies, are reviewed. In addition, future prospects in improving the outcomes in PDTC patients are reviewed.
PDTC patients tend to present with adverse clinicopathologic characteristics: older age, male predominance, advanced locoregional disease, and distant metastases. Surgery with clearance of all gross disease can achieve satisfactory locoregional control. However, the majority of PDTC patients die of distant disease. Five-year disease-specific survival for PDTC patients has been reported at 66%. On multivariate analysis, reported predictors of poor survival in PDTC patients have been older age (>45 years), T4a pathological stage, extrathyroidal extension, high mitotic rate, tumor necrosis, and distant metastasis at presentation. BRAF
or RAS mutations (27% and 24% of cases, respectively) remain mutually exclusive main drivers in PDTC. TERT promoter mutations represent the most common alteration in PDTC (40%). Mutation in translation initiation factor EIF1AX (11%) and tumor suppressor TP53 (16%) have also been reported in PDTC. High rates of novel mutations (MED12 and RBM10) have been reported in fatal PDTC (15% and 12%, respectively). Chromosome 1q gains represent the most common arm-level alterations in PDTC, and those patients show worse survival rates. Chromosome 22q losses are also found in PDTC and show strong association with RAS mutation.
These new insights into the clinicopathologic and molecular characteristics of PDTC, together with further advancement in ultra-deep sequencing technologies, will be conducive in narrowing the focus in order to develop novel targeted therapies and improve the outcomes in PDTC patients.
•2082 patients with OSCC operated at a tertiary cancer care center from 1985 to 2015 were studied.•Age, comorbidity, margin, vascular and perineural invasion, T, N were independent predictors of ...OS.•Alcohol use, margin, vascular and perineural invasion, T, and N were independent predictors of DSS.•pN was the single most powerful and consistent predictor of outcome in patients with OSCC.
To present treatment results of oral squamous cell carcinoma (OSCC) at a tertiary cancer care center from 1985 to 2015.
A total of 2082 patients were eligible for this study. Main outcomes measured were overall survival (OS) and disease specific survival (DSS). Prognostic variables were identified with bivariate analyses using Kaplan-Meier curves and log-rank testing for comparison. A p-value < 0.05 was considered statistically significant and significant factors were entered into multivariate analysis. Median age was 62 years (16–100), 56% were men, 66% reported a history of tobacco use and 71% of alcohol consumption. The most common subsite was tongue (51%). Seventy-three percent of patients had cT1-2 and 71% had clinically negative necks (cN0). Surgery alone was performed in 1348 patients (65%), adjuvant postoperative radiotherapy in 608 patients (29%) and postoperative chemoradiation in 126 patients (6%). Neck dissection was performed in 920 patients with cN0, and in 585 patients with a clinically involved neck. The median follow-up was 37.6 months (range 1–382).
The 5-year OS and DSS were 64.4% and 79.3%, respectively. Age, comorbidities, margin status, vascular invasion, perineural invasion, AJCC 8th edition pT, and pN were independent prognostic factors of OS (p < 0.05). History of alcohol consumption, margin status, vascular invasion, perineural invasion, pT, and pN were independent prognostic factors of DSS (p < 0.05).
pN stage is the most powerful and consistent predictor of outcome in patients with OSCC treated with primary surgery and appropriate adjuvant therapy.
Hürthle cell tumors (HCT), including Hürthle cell adenomas (HCA) and Hürthle cell carcinomas (HCCs), arise in the thyroid gland and are defined in part by an accumulation of mitochondria. These ...neoplasms were long considered a subtype of follicular neoplasm, although HCT is now generally considered a distinct entity. HCTs exhibit overlapping but distinct clinical features compared to follicular tumors, and several studies have demonstrated that HCTs harbor distinct genomic alterations compared to other forms of thyroid cancer. Two studies recently reported the most complete characterization of the HCC genome to date. These studies assessed complementary cohorts of HCC specimens. The study by Ganly et al. consisted of a large panel of primary HCCs, including 32 widely invasive and 24 minimally invasive primary tumors. Exome and RNA sequencing of material isolated from fresh-frozen tumor specimens was performed. The study by Gopal et al. utilized exome and targeted sequencing to characterize the nuclear and mitochondrial genomes of 32 primary tumors and 38 resected regional and distant metastases using DNA isolated from formalin-fixed paraffin-embedded tissues. Here, HCC is briefly reviewed in the context of these studies.
Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization.
We ...performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC).
Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation.
These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality.
This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.
Background
Minor salivary gland carcinomas of the head and neck are rare cancers with variable clinical behavior. This study explored the incidence, pathology, clinical behavior, and factors ...predictive of outcomes in a large cohort of patients treated at Memorial Sloan Kettering Cancer Center over a 30‐year period (1985‐2015).
Methods
Clinical, pathological, treatment, and outcome data were collected. Unadjusted and adjusted hazard ratios for each variable were calculated with univariate and multivariable Cox regression for survival and recurrence outcomes.
Results
Four hundred fifty patients were included: 55% were female, 56% were younger than 60 years, and the median follow‐up was 74 months (range, 1‐364 months). The most common site was the oral cavity with 305 tumors (68%), which was followed by the oropharynx with 96 (21%), the sinonasal cavity with 38 (8%), the trachea with 7 (2%), and the larynx with 4 (1%). The most common histological types were mucoepidermoid carcinoma (180 tumors 40%), adenoid cystic carcinoma (141 tumors 31%), and polymorphous low‐grade adenocarcinoma (54 tumors 12%). The 5‐year predicted overall survival rate was 86%, and the disease‐specific survival rate was 94% at 5 years. Pathology and tumor stage were significant variables on multivariate analysis for overall survival, disease‐specific survival, recurrence‐free survival, local recurrence–free survival, regional recurrence–free survival, and distant recurrence–free survival.
Conclusions
American Joint Committee on Cancer stage and pathology were the most predictive variables across all outcomes. Tumor site, postoperative radiotherapy, and margin status were not statistically significant variables after tumor stage and pathology were controlled for in most outcomes.
This is a large retrospective study of 450 minor salivary gland tumors of the head and neck. The tumor stage and histological type are the most predictive variables of survival and recurrence.
Background:
TERT encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thus enabling cell replication. Telomerase activity is required for cell ...immortalization. Somatic TERT promoter mutations modifying key transcriptional response elements were recently reported in several cancers, such as melanomas and gliomas.
Objectives:
The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC.
Methods:
TERT promoter was PCR-amplified and sequenced in 42 thyroid cancer cell lines and 183 tumors: 80 papillary thyroid cancers (PTCs), 58 poorly differentiated thyroid cancers (PDTCs), 20 anaplastic thyroid cancers (ATCs), and 25 Hurthle cell cancers (HCCs).
Results:
TERT promoter mutations were found in 98 of 225 (44%) specimens. TERT promoters C228T and C250T were mutually exclusive. Mutations were present in 18 of 80 PTCs (22.5%), in 40 of 78 (51%) advanced thyroid cancers (ATC + PDTC) (P = 3 × 10−4 vs PTC), and in widely invasive HCCs (4 of 17), but not in minimally invasive HCCs (0 of 8). TERT promoter mutations were seen more frequently in advanced cancers with BRAF/RAS mutations compared to those that were BRAF/RAS wild-type (ATC + PDTC, 67.3 vs 24.1%; P < 10−4), whereas BRAF-mutant PTCs were less likely to have TERT promoter mutations than BRAF wild-type tumors (11.8 vs 50.0%; P = .04).
Conclusions:
TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression.
Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong ...need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.
Background There remains controversy over the type of surgery appropriate for T1T2N0 well differentiated thyroid cancers (WDTC). Current guidelines recommend total thyroidectomy for all but the ...smallest lesions, despite previous evidence from large institutions suggesting that lobectomy provides similar excellent results. The objective of this study was to report our experience of T1T2N0 WDTC managed by either thyroid lobectomy or total thyroidectomy. Methods Eight hundred eighty-nine patients with pT1T2 intrathyroid cancers treated surgically between 1986 and 2005 were identified from a database of 1810 patients with WDTC. Total thyroidectomy was carried out in 528 (59%) and thyroid lobectomy in 361 (41%) patients. Overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) were determined by the Kaplan-Meier method. Factors predictive of outcome by univariate and multivariate analysis were determined using the log rank test and Cox proportional hazards method respectively. Results With a median follow-up of 99 months, the 10-yr OS, DSS, and RFS for all patients were 92%, 99%, and 98% respectively. Univariate analysis showed no significant difference in OS by extent of surgical resection. Multivariate analysis showed that age over 45 yr and male gender were independent predictors for poorer OS, whereas T stage and type of surgery were not. Comparison of the thyroid lobectomy group and the total thyroidectomy group showed no difference in local recurrence (0% for both) or regional recurrence (0% vs 0.8%, P = .96). Conclusion Patients with pT1T2 N0 WDTC can be safely managed by thyroid lobectomy alone.
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