Areas Of Poor Differentiation Research Articles

Responses to the First Radioactive Iodine Treatment After Targeted Therapy for Aggressive Papillary Thyroid Cancers

Introduction: Tall cell variant (TCV) and columnar cell variant (CCV) are aggressive variants of papillary thyroid cancer (PTC) and they are overrepresented in radioactive iodine (RAI) refractory cases. Studies have reported using BRAF and/or MEK inhibitors to restore iodine avidity in patients with iodine refractory disease. There is much less experience of using targeted therapy pre-emptively to enhance iodine uptake for aggressive variants and advanced disease prior to the first RAI treatment (RAI-T). We present three patients with these variants and describe their responses to the first RAI-T after targeted therapy. Case 1: 64-year-old male with CCV-PTC and areas of poor differentiation (pT3aN1bM1) has somatic BRAF V600E, TERT and AJUBA mutations. Thyroglobulin (TG) 6 weeks post surgery was 21 ug/L, with negative TG antibodies (TGAb). PET-CT revealed FDG avid superior mediastinal lymphadenopathy and lung metastases. He received dabrafenib for 6 weeks followed by his first RAI -T(153 mCi) after thyroid hormone withdrawal (THW). Pre- and post-therapy scans showed uptake in the neck, right superior mediastinum and lung metastases. Three months post RAI, TG decreased to 5.1 ug/L. Chest CT revealed stable mediastinal lymphadenopathy and decreased size of lung metastases. Case 2: 41-year-old male with TCV-PTC containing areas of focal squamous differentiation and poor differentiation (pT4aN1bM1) has somatic BRAF V600E and TP53 mutations. PET-CT showed FDG avid neck lymph nodes and lung metastases. TG 8 weeks after surgery was 1.5 ug/L, TGAb 31.19 IU/L. He was treated with dabrafenib and trametinib for 4 weeks followed by his first RAI-T (150mCi) after THW. Pretreatment scan showed uptake in the thyroid bed and cervical lymph nodes. Post-therapy scan revealed additional uptake in the lung metastases. Chest CT 3 and 9 months after RAI-T revealed stable paratracheal lymph node and lung metastases. TGAb decreased to 7.04 IU/L; TG was 2.2 ug/L. Case 3: 33-year-old female with invasive TCV-PTC (pT3bN1aM1) has a somatic BRAF V600E mutation. CT chest showed multiple scattered lung nodules up to 4mm. Ten weeks post surgery, TG was 0.1 ug/L, TGAb 5.21 IU/ml. Patient received 1 month of dabrafenib and trametinib followed by his first RAI-T(125 mCi) after THW. Pre- and post-therapy scans revealed uptake in the neck and left supraclavicular areas, without uptake in lung nodules. Three months post RAI, chest CT revealed stable lung nodules. TG was 0.1 ug/L, and TGAb was 5.16 IU/L. Neck ultrasound showed no disease. Conclusion: These three patients with aggressive variants of PTC have advanced disease, and all were found to have a BRAFV600E mutation on genomic analysis. They tolerated BRAF targeted inhibition as an attempt to enhance iodine uptake preemptively with various responses to their first RAI-T. More studies will be needed to determine if this strategy will improve outcomes for these patients.

Prognostic Impact of Focal Poorly Differentiated Areas in Follicular Differentiated Thyroid Cancer: Is It a Distinct Entity from Poorly Differentiated Thyroid Cancer?

Poorly differentiated thyroid cancer (PDC) and especially poorly differentiated areas (PDA) within follicular cell-derived differentiated thyroid cancer are ill-defined clinicopathological entities. We report our experience on their comparative prognostic outcomes This is a retrospective study of 61 patients (PDC = 29; PDA = 32) from Endocrine and Metabolic Surgery Department (2009 to 2017). Clinical and follow-up details are collected and digitally tabulated from departmental database. Gender ratio was M:F = 1:1.3 and 1:1.6. Mean age was 51 ± 12years (16-76) and 54 ± 10.5years (36-81) in PDA and PDC, respectively. Mean tumour size (4.6 ± 0.9cm; 4.9 ± 1.2cm), extrathyroidal invasion (59%; 73%) and regional lymphadenopathy were 50% and 55% in PDA and PDC, respectively. Total thyroidectomy was possible in 94% of PDA and in only 77% of PDC. Radioiodine ablation was utilised in 65% (PDA); 29% (PDC). With mean follow-up of 64 ± 23.5months (12-103) in PDA and 37 ± 22months (6-94) in PDC, nodal recurrence (PDC = 29%; PDA = 22%) and systemic metastasis was 41% in PDC (synchronous = 24%; metachronous = 17%); 19% in PDA (synchronous = 16%; metachronous = 3%). Five-year event-free survival (EFS) and overall survival (OS) was 90% and 93% in PDA, and 42% and 44% in PDC, respectively. Our study shows that PDA is a separate clinicopathological entity with significantly positive prognosis compared to PDC.

Loss of INI1 expression in colorectal carcinoma is associated with high tumor grade, poor survival, BRAFV600E mutation, and mismatch repair deficiency

SMARCB1 is a tumor suppressor gene that encodes for the protein INI1. SMARCB1 is commonly inactivated and INI1 correspondingly shows loss of expression in a range of malignant neoplasms including rhabdoid tumors, renal medullary carcinomas, and epithelioid sarcomas. Loss of INI1 expression has recently been reported in occasional gastrointestinal adenocarcinomas. We sought to investigate the incidence and clinicopathological significance of INI1 loss in colorectal adenocarcinoma (CRC). Immunohistochemistry for INI1 was performed in tissue microarray (TMA) format on a well-characterized and unselected cohort of CRCs undergoing surgical resection. If staining was negative or equivocal in the TMA sections, immunohistochemistry was repeated on whole sections. Focal or widespread negative staining for INI1 was identified in whole sections from 14 (0.46%) of 3051 CRCs. In 7 (50%) of 14 negative cases, the loss of staining was focal, whereas the remainder were characterized by negative staining in all neoplastic cells in whole sections. In the cases with focal staining, loss of staining was frequently found in areas of poor differentiation. Global or focal INI1 loss was strongly associated with higher histological grade, larger tumor size and poor overall survival (P<.001). We conclude that INI1 loss occurs rarely (0.46% when screened by TMA) in CRC, where it is associated with higher grade, larger tumor size, poorer survival, mismatch repair deficiency, and BRAFV600E mutation.

Distinct mechanisms for opposite functions of homeoproteins Cdx2 and HoxB7 in double-strand break DNA repair in colon cancer cells

Homeobox genes, involved in embryonic development and tissues homeostasis in adults, are often deregulated in cancer, but their relevance in pathology is far from being fully elucidated. In colon cancers, we report that the homeoproteins HoxB7 and Cdx2 exhibit different heterogeneous patterns, Cdx2 being localized in moderately altered neoplasic glands in contrast to HoxB7 which predominates in poorly-differentiated areas; they are coexpressed in few cancer cells. In human colon cancer cells, both homeoproteins interact with the DNA repair factor KU70/80, but functional studies reveal opposite effects: HoxB7 stimulates DNA repair and cell survival upon etoposide treatment, whereas Cdx2 inhibits both processes. The stimulatory effect of HoxB7 on DNA repair requires the transactivation domain linked to the homeodomain involved in the interaction with KU70/80, whereas the transactivation domain of Cdx2 is dispensable for its inhibitory function, which instead needs the homeodomain to interact with KU70/80 and the C-terminal domain. Thus, HoxB7 and Cdx2 respectively use transcription-dependent and -independent mechanisms to stimulate and inhibit DNA repair. In addition, in cells co-expressing both homeoproteins, Cdx2 lessens DNA repair activity through a novel mechanism of inhibition of the transcriptional function of HoxB7, whereby Cdx2 forms a molecular complex with HoxB7 and prevents it to recognize its target in the chromatin. These results point out the complex interplay between the DSB DNA repair activity and the homeoproteins HoxB7 and Cdx2 in colon cancer cells, making the balance between these factors a determinant and a potential indicator of the efficacy of genotoxic drugs.

The PLK1 Inhibitor GSK461364A Is Effective in Poorly Differentiated and Anaplastic Thyroid Carcinoma Cells, Independent of the Nature of Their Driver Mutations

Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are the most aggressive forms of thyroid cancer. Despite their low incidence, they account for a disproportionate number of thyroid cancer-related deaths because of their resistance to most therapeutic approaches. We have generated mouse models that develop ATC ([Pten, p53](thyr-/-) mice) and follicular thyroid cancer with areas of poor differentiation (Pten(thyr-/-),Kras(G12D) mice). Comparative gene expression profiling of human and mouse ATCs reveals a common "mitotic signature" in which mitotic kinases, including Polo-like kinase-1 (PLK1), are found deregulated in both species. Most genes from this signature are also upregulated in poorly differentiated tumors developing in Pten(thyr-/-),Kras(G12D) mice. PLK1 is a crucial driving force for normal mitotic spindle formation, centrosome maturation, and separation, and its overexpression has been demonstrated in a wide range of tumors. Human and mouse ATC and PDTC cell lines were treated with the PLK1 inhibitor GSK461364A, and proliferation, apoptosis, and mitotic spindle alterations were analyzed. Furthermore, immunocompetent mice were injected in the flank with mouse ATC cells, and treated with placebo or GSK461364A. We show that the PLK1 inhibitor GSK461364A inhibits cell proliferation and induces cell death in both mouse ATC- and PDTC-derived cell lines and in several human ATC cell lines carrying different driver mutations. Dose-dependent changes in chromosome alignment and spindle assembly during mitosis are observed after treatment, together with changes in the mitotic index. FACS analysis reveals a G2/M phase arrest, followed by apoptosis, and mitotic slippage in cells with PI3K activation. GSK461364A is also effective in vivo, in an allograft model of ATC. Taken together, these data suggest that PLK1 targeting is a promising and effective therapeutic approach against PDTC cells and undifferentiated thyroid carcinoma cells.

Molecular and Clinicopathological Findings in a Tonsillar Synovial Sarcoma. A Case Study and Review of the Literature

Synovial sarcoma (SS), 3-5% of which occurs in the head and neck region, has generally been regarded as high grade sarcoma. Recent analysis of clinical, morphological, and molecular characteristics of SS, however, identified low and high risk group of patients, resulting in important implications for the treatment of patients diagnosed with SS. We describe the case of a 31-year-old male who presented with biphasic SS with poorly differentiated areas (clinical stage IIA) in a palatine tonsil, an extremely rare site of SS. Molecular analyses revealed typical t(X;18) translocation of the SYT gene and a SYT/SSX1 fusion type. The tumor was surgically resected with free margins. Adjuvant radiotherapy or chemotherapy was not considered indicated. To date, the patient has remained free of tumor for 4 years after surgery. Literature review reveals that primary tonsillar HNSS has previously been documented only in three patients. In all of these patients the tumor was histologically biphasic; however only one published case and the case presented here showed areas of poor differentiation. We discuss the relevance of the presented findings with regard to prognostic and therapeutic considerations in SS in the head and neck region.

Lectins in the vulva. II. Vulvar intraepithelial neoplasia and squamous cell carcinoma.

This study used lectins as histologic probes to determine the cell surface oligosaccharide expression in different grades and types of vulvar intraepithelial neoplasia (VIN). Lectin binding patterns in metastasizing and non-metastasizing squamous cell carcinomas (SCCs) of the vulva were also compared to correlate lectin binding patterns with metastatic potential and other clinical/tumor characteristics. Twenty cases each of VIN epithelium, metastasizing SCC, and non-metastasizing vulvar carcinoma were randomly chosen from the pathology archives. Sixteen lectins were used to probe individual terminal oligosaccharide residues in formalin-fixed, paraffin-embedded tissue specimens from these cases through an indirect immunohistochemical technique. There were no differences in lectin binding patterns between the different histologic subtypes of VIN. In addition, there were no consistent differences between metastasizing and non-metastasizing primary tumors and no major differences in staining patterns between nodal metastases and the corresponding primary tumors. Furthermore, there was no identifiable correlation between lectin binding patterns and subsequent survival or local or regional recurrence; however, lectin staining of invasive tumor cells did appear to be related to local invasiveness. In addition, positive PNA binding was found to be a constant finding in each of the VIN and invasive SCC cases, confirming that the T-antigen becomes unmasked during the process of vulvar carcinogenesis. However, poorly-differentiated areas consistently showed absent lectin binding, suggesting loss of specific glycosyl transferase activities. In addition, the blood group "A" antigen appears to be lost during the process of tumorgenesis, although the blood group "O" antigen appears to be preserved.

Cancer volume and site of origin of adenocarcinoma in the prostate: Relationship to local and distant spread

Biologic aggressive behavior in adenocarcinoma of the prostate is proposed to be a direct function of cancer volume. In an autopsy series, distant metastasis was found only in cancers that had both volume greater than 5 cc and areas of poor differentiation (Gleason grades 4 and 5). In subsequent study of over 200 radical prostatectomy specimens, cancers were found to originate both in the peripheral zone (PZ) and in the normally small anteromedial transition zone (TZ) where benign nodular hyperplasia also develops. Anatomic TZ and PZ cancers were nearly equivalent to clinical stage A and B cancers, respectively. Transition zone cancers showed much less capsule penetration and seminal vesicle invasion than PZ cancers of comparable volume because the TZ boundary provided a barrier to cancer spread through the PZ. In PZ carcinomas, capsule penetration depended largely on facilitated spread along perineural spaces, and its distribution was determined by the location of superior and inferior nerve pedicles. Capsule penetration, seminal vesicle invasion, and positive surgical margins were all strongly correlated with cancer volume. Tumors smaller than 4 cc had all morphologic variables favorable; tumors larger than 12 cc tended to have all variables unfavorable. Lymph node metastasis in radical prostatectomy cases was most strongly predicted by a combination of cancer volume plus percentage of high-grade tumor. Cancers with more than 3.2 cc of grade 4 and/or 5 component showed a 100-fold increase in proportion of cases with nodal spread.

Immunocytochemical Analysis of Intermediate Filaments in Human Ependymal Tumors

The peroxidase anti-peroxidase technique was used for localization of glial fibrillary acidic protein (GFAP) and vimentin (VM) in 19 ependymal tumors in order to determine if a unique pattern of intermediate filament (IF) expression could be demonstrated. Cytokeratin (CK) immunoreactivity was examined in a subgroup of 7 tumors with papillary pattern. Nineteen non-ependymal neuroectodermal tumors were used as controls. Ependymomas, subependymomas and astrocytomas were positive for both IF. Oligodendrogliomas, oligodendroglial portions of mixed gliomas and the majority of medulloblastomas were negative for GFAP and VM. Areas of poor differentiation in all tumors demonstrated little expression of any IF. A composite ependymoma/choroid plexus papilloma showed the presence of GFAP, VM and CK in the papillomatous portion only. Four papillary ependymomas were negative for CK. This study emphasizes the parallel distribution of GFAP and VM in well differentiated ependymomas and other glial tumors and casts doubt upon the concept of VM as a marker for de-differentiation in neuroectodermal neoplasia.