Anaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with
-wild type disease. As part of a phase I/II study ...in patients with advanced/metastatic solid tumors, patients with anaplastic thyroid carcinoma were treated with spartalizumab, a humanized monoclonal antibody against the programmed death-1 (PD-1) receptor.
We enrolled patients with locally advanced and/or metastatic anaplastic thyroid carcinoma in a phase II cohort of the study. Patients received 400 mg spartalizumab intravenously, once every 4 weeks. The overall response rate was determined according to RECIST v1.1.
Forty-two patients were enrolled. Adverse events were consistent with those previously observed with PD-1 blockade. Most common treatment-related adverse events were diarrhea (12%), pruritus (12%), fatigue (7%), and pyrexia (7%). The overall response rate was 19%, including three patients with a complete response and five with a partial response. Most patients had baseline tumor biopsies positive for PD-L1 expression (n = 28/40 evaluable), and response rates were higher in PD-L1-positive (8/28; 29%) versus PD-L1-negative (0/12; 0%) patients. The highest rate of response was observed in the subset of patients with PD-L1 ≥ 50% (6/17; 35%). Responses were seen in both
-nonmutant and
-mutant patients and were durable, with a 1-year survival of 52.1% in the PD-L1-positive population.
To our knowledge, this is the first clinical trial to show responsiveness of anaplastic thyroid carcinoma to PD-1 blockade.
Viruses are known drivers of head and neck squamous cell carcinomas (HNSCC), particularly Epstein-Barr virus (EBV) and human papillomavirus (HPV). Both EBV-positive nasopharyngeal carcinoma (EBVNPC) ...and HPV-positive oropharyngeal SCC (OPSCC) can have overlapping histomorphology and molecular signatures, including nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB) pathway mutations. A recent study showed that NFKB activation in EBVNPC drives somatostatin receptor 2 (SSTR2) expression that is detectable by immunohistochemistry and by imaging with 68-Gadolinium-DOTA-peptide radioconjugate. However, whether a similar NFKB-SSTR2 signaling mechanism exists for other virus-positive HNSCC, namely HPV-positive sinonasal carcinomas and OPSCC, remains unclear. Here we examined SSTR2 expression in a cohort of EBV-positive, HPV-positive, and virus-negative HNSCC with immunohistochemistry. SSTR2 immunohistochemistry was performed on our cohort of primary and/or metastatic EBVNPC, HPV-positive sinonasal SCC, OPSCC, HPV-negative sinonasal and oral cavity SCC, and benign tonsil and adenoid tissue. For SSTR2 staining, the extent was categorized as focal, multifocal, or diffuse, and the intensity was categorized as weak, moderate, or strong. Multifocal/diffuse SSTR2 staining of any intensity was considered positive. Among primary, recurrent, and/or undifferentiated NPC, 90% showed multifocal to diffuse strong SSTR2 expression. One HPV-positive sinonasal carcinoma showed patchy SSTR2 staining. None of the remaining HPV-positive sinonasal carcinomas, OPSCC, or oral cavity HNSCC showed significant SSTR2 staining. Overall, SSTR2 is highly sensitive and specific for EBVNPC and could represent a surrogate biomarker. Among HNSCC assessed here, we recommend testing primary NPC for SSTR2 because of its relevance for diagnosis, associated imaging modalities, and its therapeutic implications for patient care.
•Somatostatin receptor 2 expression is expressed in EBV-associated nasopharyngeal carcinoma (NPC).•Expression of SSTR2 is detectable with 68-Gadolinium-DOTA-peptide radioconjugate for tumor imaging.•SSTR2 expression is unique among EBV-associated NPC over other head and neck squamous cell carcinomas.•SSTR2 expression may be documented in EBV-associated NPC using immunohistochemistry.•SSTR2 expression in EBV-associated NPC provides a mechanism for imaging-based surveillance and rational therapeutics.
Hürthle cell carcinoma of the thyroid (HCC) is a form of thyroid cancer recalcitrant to radioiodine therapy that exhibits an accumulation of mitochondria. We performed whole-exome sequencing on a ...cohort of primary, recurrent, and metastatic tumors, and identified recurrent mutations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter. Parallel analysis of mtDNA revealed recurrent homoplasmic mutations in subunits of complex I of the electron transport chain. Analysis of DNA copy-number alterations uncovered widespread loss of chromosomes culminating in near-haploid chromosomal content in a large fraction of HCC, which was maintained during metastatic spread. This work uncovers a distinct molecular origin of HCC compared with other thyroid malignancies.
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•HCC is driven by unique alterations of the nuclear and mitochondrial genomes•Early widespread loss of chromosomes leads to a stable near-haploid state in HCC•mtDNA mutations in complex I of the electron transport chain are enriched in HCC•DAXX, TERT, TP53, NRAS, NF1, CDKN1A, and ARHGAP35 are recurrently altered in HCC
Gopal et al. identify recurrent alterations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter, as well as in mtDNA-encoding complex I of the electron transport chain, in Hürthle cell carcinomas (HCC). Many HCCs harbor widespread chromosomal loss culminating in a near-haploid state.
Purpose
To explore whether targeted next generation sequencing (NGS) of liquid biopsy in advanced non-small cell lung cancer (NSCLC) could potentially overcome the innate problems that arise with ...standard tissue biopsy, like intratumoral heterogeneity and the inability to obtain adequate samples for analysis.
Methods
The Scopus, Cochrane Library, and MEDLINE (via PubMed) databases were searched for studies with matched tissue and liquid biopsies from advanced NSCLC patients, analyzed with targeted NGS. The number of mutations detected in tissue biopsy only, liquid biopsy only, or both was assessed and the positive percent agreement (PPA) of the two methods was calculated for every clinically relevant gene.
Results
A total of 644 unique relevant articles were retrieved and data were extracted from 38 studies fulfilling the inclusion criteria. The sample size was composed of 2000 mutations tested in matched tissue and liquid biopsies derived from 1141 patients. No studies analyzed circulating tumor cells. The calculated PPA rates were 53.6% (45/84) for ALK, 53.9% (14/26) for BRAF, 56.5% (13/23) for ERBB2, 67.8% (428/631) for EGFR, 64.2% (122/190) for KRAS, 58.6% (17/29) for MET, 54.6% (12/22) for RET, and 53.3% (8/15) for ROS1. We additionally recorded data for 65 genes that are not recommended by current guidelines for mutational testing. An extra category containing results of unspecified genes was added, with a PPA rate of 55.7% (122/219).
Conclusion
Despite many advantages, liquid biopsy might be unable to fully substitute its tissue counterpart in detecting clinically relevant mutations in advanced NSCLC patients. However, it may serve as a helpful tool when making therapeutic decisions. More studies are needed to evaluate its role in everyday clinical practice.
Salivary duct carcinoma (SDC) is an aggressive subtype of primary salivary gland carcinoma, often with an advanced stage at presentation and high rates of metastasis and recurrence. It most commonly ...arises in the parotid gland of older men and microscopically resembles high‐grade breast ductal carcinoma. While 50 years have lapsed since the first report of this entity, recent intensive studies have shed light on its biologic, genetic, and clinical characteristics. The diagnosis of SDC is aided by the immunohistochemical expression of androgen receptor (AR) coupled with its characteristic histomorphology. Fine‐needle aspiration typically reveals cytologic features of high‐grade carcinoma, and ancillary studies using cell block material can facilitate the specific diagnosis of SDC. In surgical specimens, certain histologic features are important prognostic factors, including nuclear pleomorphism, mitotic counts, vascular invasion, and the morphology at the invasion front. Several clinical studies have shown promising results using targeted therapy for AR and human epidermal growth factor receptor 2 (HER2), and the latest version of the National Comprehensive Cancer Network guidelines recommends the evaluation of AR and HER2 status before treatment. Recent molecular analyses have revealed multiple heterogeneous alterations in well‐known oncogenes and tumor suppressor genes, including TP53, HRAS, PIK3CA, PTEN, and BRAF. Clinical trials of drugs targeting these genes may broaden the treatment options for SDC in the near future.
Salivary duct carcinoma is the most aggressive subtype of primary salivary gland carcinoma. Recent studies have clarified the biology and clinicopathological features of this entity, in turn leading to the introduction of new therapies.
Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and ...there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF -mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf ⱽ⁶⁰⁰ᴱ mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.
Genetic profiling has caused an explosion in the subclassification of sinonasal malignancies. Distinguishing several of these tumor types by histomorphology alone has been quite challenging, and ...although pathologic classification aims to be as specific as possible, it remains to be seen if this recent move toward tumor speciation bears clinical relevance, most particularly focused on subtyping for the sake of prognostication and treatment. One such recently described cohort, predominantly lumped under the moniker of sinonasal undifferentiated carcinoma (SNUC) is IDH2 -mutated sinonasal carcinoma, a high-grade carcinoma associated with mutations in the isocitrate dehydrogenase-2 ( IDH2 ) gene. A hotspot mutation in the R172 codon has been described in 50% to 80% of the tumors classified as SNUC, large cell neuroendocrine carcinomas, and rarely in cases classified as olfactory neuroblastoma. The use of immunohistochemical and molecular approaches is required to correctly identify this subset of sinonasal tumors, with further study necessary to elucidate their unique pathophysiology, ultimately determining whether a revision is required toward the current therapeutic approach.
Here, we provide an overview of the IDH2- mutated sinonasal tumors, discuss histopathologic and clinical features, and focus on molecular diagnostics and novel immunohistochemical markers.
A review of the literature reveals 82 reported cases with IDH2 -mutated sinonasal tumors (IST), confirmed either by molecular studies or diagnostic immunohistochemical markers. The mean patient age is 60 years (female/male: 1/1.4), the median tumor size is 5 cm (range: 2.5 to 7.0 cm), and the most common location is the nasal cavity (81%). IST displays tumor necrosis and increased mitotes. Histopathologically, IST shows SNUC-like, large cell neuroendocrine carcinomas-like, or poorly differentiated carcinoma-like features (77%, 12%, and 9%, respectively). The molecular hotspot alterations in mitochondrial IDH2 are: R172S (61%), R172T (19%), R172G (7%), and R172M (3%). Sixty-five percent of tumors are surgically resectable, and all patients received chemotherapy, radiation therapy, or both. Rates of locoregional recurrence and distant metastasis are 60% and 40%, respectively. One-, 3- and 5-year survival rates are 83%, 50%, and 43%, respectively. In all but 1 study, IST is associated with better outcomes than IDH2 wild-type tumors and SMARCB1 -deficient sinonasal tumors.
High-grade sinonasal carcinomas are a cohort of malignant epithelial neoplasms arising in the sinonasal cavities with distinct, ominous morphologic features or lacking well-differentiated features ...that might otherwise classify them as less biologically worrisome. Recent advances in molecular profiling have led to the identification of several distinct tumor entities previously grouped together. These molecularly distinct lesions include
(midline) carcinoma,
(
)-deficient carcinoma,
-deficient sinonasal carcinoma, and novel
-mutant sinonasal undifferentiated carcinoma, in addition to the previously described lymphoepithelial carcinoma that may also be included in the differential diagnosis. The discovery of these distinct molecular tumor profiles may have significant clinical impact as targeted molecular-based therapeutics continue to evolve, and they may offer some respite for patients who have these highly aggressive cancers.
Thyroid nodules are quite common, and the determination of a nodule of concern is complex, involving serum testing, radiology and, in some cases, pathological evaluation. For those nodules that raise ...clinical concern of neoplasia, fine needle aspiration biopsy is the gold standard for evaluation; however, in up to 30% of cases, results are indeterminate for malignancy, and further testing is needed. Advances in molecular testing have shown it to be of benefit for both diagnostic and prognostic purposes, and its use has become an integral part of thyroid cancer management in the United States and in several global nations. After The Cancer Genome Atlas (TCGA) consortium published its molecular landscape of papillary thyroid carcinoma (PTC) and reduced the "black matter" in PTC from 25% to 3.5%, further work ensued to clarify the remaining fraction not neatly attributed to the
-like or
-like phenotypes of the TCGA. Over the past decade, commercial molecular platforms have been refined as data accrues, and they increasingly cover most genetic variants of thyroid carcinomas. Molecular reporting focuses on the nodule tested, including related clinical information for that nodule (size of nodule, Bethesda category, etc.). This results in a comprehensive report to physicians that may also include patient-directed, clear language that facilitates conversations about nodule management. In cases of advanced or recurrent disease, molecular testing may become essential for devising an individual therapeutic plan. In this review, we focus on the evolution of integrated molecular testing in thyroid nodules, and how our understanding of tumor genetics, combined with histopathology, is driving the next generation of rational patient management, particularly in the context of emerging small, targetable therapeutics.
Hürthle cell lesions have been a diagnostic conundrum in pathology since they were first recognized over a century ago. Controversy as to the name of the cell, the origin of the cell, and even which ...cells in particular may be designated as such still challenge pathologists and confound those treating patients with a diagnosis of "Hürthle cell" anything within the diagnosis, especially if that anything is a sizable mass lesion. The diagnosis of Hürthle cell adenoma (HCA) or Hürthle cell carcinoma (HCC) has typically relied on a judgement call by pathologists as to the presence or absence of capsular and/or vascular invasion of the adjacent thyroid parenchyma, easy to note in widely invasive disease and a somewhat subjective diagnosis for minimally invasive or borderline invasive disease. Diagnostic specificity, which has incorporated a sharp increase in molecular genetic studies of thyroid tumor subtypes and the integration of molecular testing into preoperative management protocols, continues to be challenged by Hürthle cell neoplasia. Here, we provide the improving yet still murky state of what is known about Hürthle cell tumor genetics, clinical management, and based upon what we are learning about the genetics of other thyroid tumors, how to manage expectations, by pathologists, clinicians, and patients, for more actionable, precise classifications of Hürthle cell tumors of the thyroid.
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