Ovarian mucinous tumor with mural nodules of anaplastic carcinoma:Three case reports

BACKGROUND Anaplastic carcinoma mural nodules in ovarian mucinous tumors are very rare.This study aimed to report the morphological characteristics,molecular detection results,clinical treatment and prognosis of three ovarian mucinous tumors with mural nodules of anaplastic carcinoma.CASE SUMMARY The pathomorphological features,molecular detection results,clinical treatment and prognosis of anaplastic carcinoma mural nodules were described in three cases.In case 1,sarcoma-like mural nodules(SLMNs)coexisted with anaplastic carcinoma mural nodules.No mutation was found in mucinous tumors.KRAS mutation was found in anaplastic carcinoma nodules and heterotypic cells were found in SLMNs.In case 2,KRAS mutation occurred in the mucinous epithelium and BRAF mutation occurred in mural nodules.In case 3,both mural nodules and mucinous tumors had the same KRAS mutation and a morphological transition between them was observed.All three patients died within 2 years,whether receiving chemotherapy or not.CONCLUSION Anaplastic carcinoma mural nodules may develop from dedifferentiation of mucinous tumors or are unrelated to mucinous tumors.

An overview of the contemporary diagnosis and management approaches for anaplastic thyroid carcinoma

Thyroid carcinoma is a complex disease with several types,the most common being well-differentiated and undifferentiated.The latter,“undifferentiated carcinoma”,also known as anaplastic thyroid carcinoma(ATC),is a highly aggr-essive malignant tumor accounting for less than 0.2%of all thyroid carcinomas and carries a poor prognosis with a median survival of 5 months.BRAF gene mutations are the most common molecular factor associated with this type of thyroid carcinoma.Recent advances in targeted biological agents,immuno-therapy,stem cell therapy,nanotechnology,the dabrafenib/trametinib com-bination therapy,immune checkpoint inhibitors(ICI)and artificial intelligence offer novel treatment options.The combination therapy of dabrafenib and tra-metinib is the current standard treatment for patients with BRAF-V600E gene mutations.Besides,the dabrafenib/trametinib combination therapy,ICI,used alone or in combination with targeted therapies have raised some hopes for improving the prognosis of this deadly disease.Younger age,earlier tumor stage and radiotherapy are all prognostic factors for improved outcomes.Ultimately,therapeutic regimens should be tailored to the individual patient based on surveillance and epidemiological data,and a multidisciplinary approach is ess-ential.

Current status of anaplastic thyroid carcinoma

In this editorial we comment on the article by Pavlidis et al,published in the recent issue of the World Journal of Oncology.We focus on the recent contributions in the management of anaplastic thyroid carcinoma,highlighting the importance of surgery and radiotherapy as first line therapies in its management and the introduction of new systemic therapies beyond chemotherapy,focused on molecular alterations,an essential step in the diagnosis and included in clinical guidelines for the selection of the ideal treatment.In contrast to other neoplasms,immunotherapy,is still beginning in studies of this pathology with encouraging results.Therefore,multimodal management of the pathology together with new drugs seems to be the logical step to increase the survival of this neoplasm.

Update on current diagnosis and management of anaplastic thyroid carcinoma

Well-differentiated thyroid carcinoma has a favorable prognosis with a 5-year survival rate of over 95%.However,the undifferentiated or anaplastic type accounting for<0.2%,usually in elderly individuals,exhibits a dismal prognosis with rapid growth and disappointing outcomes.It is the most aggressive form of thyroid carcinoma,with a median survival of 5 mo and poor quality of life(airway obstruction,dysphagia,hoarseness,persistent pain).Early diagnosis and staging are crucial.Diagnostic tools include biopsy(fine needle aspiration,core needle,open surgery),high-resolution ultrasound,computed tomography,magnetic resonance imaging,[(18)F]fluoro-D-glucose positron emission tomography/computed tomography,liquid biopsy and microRNAs.The BRAF gene(BRAF-V600E and BRAF wild type)is the most often found molecular factor.Others include the genes RET,KRAS,HRAS,and NRAS.Recent management policy is based on surgery,even debulking,chemotherapy(cisplatin or doxorubicin),radiotherapy(adjuvant or definitive),targeted biological agents and immunotherapy.The last two options constitute novel hopeful management modalities improving the overall survival in these otherwise condemned patients.Anti-programmed death-ligand 1 antibody immunotherapy,stem cell targeted therapies,nanotechnology achievements and artificial intelligence implementation provide novel promising alternatives.Genetic mutations determine molecular pathways,thus indicating novel treatment strategies such as anti-BRAF,anti-vascular endothelial growth factor-A,and anti-epidermal growth factor receptor.Treatment with the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has been approved by the Food and Drug Administration in cases with BRAF-V600E gene mutations and is currently the standard care.This neoadjuvant treatment followed by surgery ensures a twoyear overall survival of 80%.Prognostic factors for improved outcomes have been found to be younger age,earlier tumor stage and radiation therapy.A multidisciplinary approach is necessary,and the therapeutic plan should be individu alized based on surveillance and epidemiology end results.

Combined targeted therapy and immunotherapy in anaplastic thyroid carcinoma with distant metastasis: A case report

BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and is the leading cause of death from malignant thyroid tumors.The one-year survival rate is 20%,with a median overall survival(OS)of only 5 mo[2].The aim of this report is to provide our experience in the diagnosis and treatment of ATC.CASE SUMMARY A patient with a thyroid mass underwent surgical treatment after developing symptoms of hoarseness.The resected tumor was pathologically diagnosed as ATC.Imaging examination revealed organ and lymph node metastasis.After multiple cycles of chemotherapy and local radiotherapy,the metastases were not relieved and gradually increased in size and new metastases appeared.The patient immediately received immunotherapy combined with targeted therapy.During treatment,immune-related adverse reactions occurred,which were improved after symptomatic treatment,and tolerated by the patient.The OS of the patient was more than 30 mo after immunotherapy combined with targeted therapy.CONCLUSION For metastatic ATC,surgical treatment,radiotherapy and chemotherapy have no significant effect on remission of the disease.However,immunotherapy has made a breakthrough in the treatment of ATC。

TMEM158 May Serve as a Diagnostic Biomarker for Anaplastic Thyroid Carcinoma:An Integrated Bioinformatic Analysis

Anaplastic thyroid carcinoma(ATC)is a rare but extremely lethal malignancy.However,little is known about the pathogenesis of ATC.Given its high mortality,it is critical to improve our understanding of ATC pathogenesis and to find new diagnostic biomarkers.In the present study,two gene microarray profiles(GSE53072 and GSE65144),which included 17 ATC and 17 adjacent non-tumorous tissues,were obtained.Bioinformatic analyses were then performed.Immunohistochemistry(IHC)and receiver operating characteristic(ROC)curves were then used to detect transmembrane protein 158(TMEM158)expression and to assess diagnostic sensitivity.A total of 372 differentially expressed genes(DEGs)were identified.Through protein-protein interaction(PPI)analysis,we identified a significant module with 37 upregulated genes.Most of the genes in this module were related to cell-cycle processes.After co-expression analysis,132 hub genes were selected for further study.Nine genes were identified as both DEGs and genes of interest in the weighted gene co-expression network analysis(WGCNA).IHC and ROC curves confirmed that TMEM158 was overexpressed in ATC tissue as compared with other types of thyroid cancer and normal tissue samples.We identified 8 KEGG pathways that were associated with high expression of TMEM158,including aminoacyl-tRNA biosynthesis and DNA replication.Our results suggest that TMEM158 may be a potential oncogene and serve as a diagnostic indicator for ATC.

Invasive ductal carcinoma of the pancreas showing exophytic growth

BACKGROUND:Invasive pancreatic carcinoma generally appears as poorly defined mass reflecting the infiltrative growth.We aimed to identify the histological and immunohistochemical features in a rare case of pancreatic carcinoma showing exophytic growth. METHODS:A 67-year-old woman presented with a mass of 5.0 cm in diameter in the pancreatic head.Preoperative computed tomography revealed a well-demarcated, primarily solid mass with a central low-density area. Magnetic resonance cholangiopancreatography revealed neither encasement nor dilation of the main pancreatic duct.An incorrect preoperative diagnosis was made of solid pseudopapillary tumor of the pancreas.Elevated serum carcinoembryonic antigen(CEA)levels and abnormal FDG positron emmission tomography accumulation suggested that the tumor had malignant potential requiring a pancreatoduodenectomy. RESULTS:The head of the pancreas contained a well- circumscribed encapsulated mass of 5.0 cm in diameter, comprising 50%adenocarcinoma,with mucinous carci- noma in the center and anaplastic carcinoma at the periphery.The anaplastic carcinoma comprised pleo- morphic cells(PCs)and pleomorphic giant cells(PGCs). The PGCs phagocytozed mononuclear PCs and lymphocytes adjacent to the capsule without infiltrating the capsule itself.Immunohistochemistry revealed that the anaplastic carcinoma cells including PGCs were positive for the tumor antigen Mucin 1 and CEA but negative for vimentin. CONCLUSION:Our observations suggest anaplastic carcinoma components in the present tumor have a ductal origin and that the exophytic tumor growth is associated with the phagocytotic activity of PGCs.

Aberrant DNA repair as a potential contributor for the clonal evolution in subsets of anaplastic thyroid carcinomas arising through dedifferentiation: implications for future therapeutic algorithms?

Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy.Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC),of which especially the latter has an exceptionally poor patient outcome.The underlying genetics responsible for this tumor progression is only partly understood,and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable,pre-existing WDTC.Even so,recent advances using next generation sequencing(NGS)techniques have identified a genetic link between WDTCs and ATCs,suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases.In this Commentary,recent findings from an NGS study on synchronous FTC,PDTC,and ATC tumor components from the same patient are highlighted.By using whole-genome data,clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair,with sub-clones in each tumor component that were identified also in the less differentiated,neighboring tumor.Moreover,mutational signatures suggested a general mismatch repair(MMR)deficiency along with microsatellite instability.These findings support the chained progression model of dedifferentiation in thyroid cancer,and pinpoint a central role for defective DNA repair.Since effective treatment modalities for ATCs are urgently needed,studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.

Capsaicin restores sodium iodine symportermediated radioiodine uptake through bypassing canonical TSH–TSHR pathway in anaplastic thyroid carcinoma cells

Anaplastic thyroid cancer(ATC)is a rare but highly lethal disease.ATCs are resistant to standard therapies and are extremely difficult to manage.The stepwise cell dedifferentiation results in the impairment of the iodine-metabolizing machinery and the infeasibility of radioiodine treatment in ATC.Hence,reinducing iodine-metabolizing gene expression to restore radioiodine avidity is considered as a promising strategy to fight against ATC.In the present study,capsaicin(CAP),a natural potent transient receptor potential vanilloid type 1(TRPV1)agonist,was discovered to reinduce ATC cell differentiation and to increase the expression of thyroid transcription factors(TTFs including TTF-1,TTF-2,and PAX8)and iodine-metabolizing proteins,including thyroidstimulating hormone receptor(TSHR),thyroid peroxidase,and sodium iodine symporter(NIS),in two ATC cell lines,8505C and FRO.Strikingly,CAP treatment promoted NIS glycosylation and its membrane trafficking,resulting in a significant enhancement of radioiodine uptake of ATC cells in vitro.Mechanistically,CAP-activated TRPV1 channel and subsequently triggered Ca2þinflux,cyclic adenosine monophosphate(cAMP)generation,and cAMP-responsive element-binding protein(CREB)signal activation.Next,CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription.Moreover,the TRPV1 antagonist CPZ,the calcium chelator BAPTA,and the PKA inhibitor H-89 effectively alleviated the redifferentiation exerted by CAP,demonstrating that CAP might improve radioiodine avidity through the activation of the TRPV1–Ca2þ/cAMP/PKA/CREB signaling pathway.In addition,our study indicated that CAP might trigger a novel cascade to redifferentiate ATC cells and provide unprecedented opportunities for radioiodine therapy in ATC,bypassing canonical TSH–TSHR pathway.