Spatial Distribution of Macrophage and Lymphocyte Subtypes within Tumor Microenvironment to Predict Recurrence of Non-Muscle-Invasive Papillary Urothelial Carcinoma after BCG Immunotherapy.

Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette-Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses in about 30% of patients despite the treatment, raising the need for better risk stratification. We explored the potential of spatial distributions of immune cell subtypes (CD20, CD11c, CD163, ICOS, and CD8) within the tumor microenvironment to predict NMIPUC recurrence following BCG immunotherapy. Based on analyses of digital whole-slide images, we assessed the densities of the immune cells in the epithelial-stromal interface zone compartments and their distribution, represented by an epithelial-stromal interface density ratio (IDR). While the densities of any cell type did not predict recurrence, a higher IDR of CD11c (HR: 0.0012, p-value = 0.0002), CD8 (HR: 0.0379, p-value = 0.005), and ICOS (HR: 0.0768, p-value = 0.0388) was associated with longer recurrence-free survival (RFS) based on the univariate Cox regression. The history of positive repeated TUR (re-TUR) (HR: 4.93, p-value = 0.0001) and T1 tumor stage (HR: 2.04, p-value = 0.0159) were associated with shorter RFS, while G3 tumor grade according to the 1973 WHO classification showed borderline significance (HR: 1.83, p-value = 0.0522). In a multivariate analysis, the two models with a concordance index exceeding 0.7 included the CD11c IDR in combination with either a history of positive re-TUR or tumor stage. We conclude that the CD11c IDR is the most informative predictor of NMIPUC recurrence after BCG immunotherapy. Our findings highlight the importance of assessment of the spatial distribution of immune cells in the tumor microenvironment.

Thyroglobulin Antibodies and Tumor Epitope-Specific Cellular Immunity in Papillary Thyroid Cancer.

Papillary thyroid carcinoma (PTC) is characterized by T cell infiltration and frequently by the presence of anti-thyroglobulin antibodies (TgAbs). The role of cellular immunity and of TbAbs in this context is a matter of debate. The aim of our study was to correlate the presence of TgAbs, tumor epitope-specific T cells and the clinical outcome of PTC patients. We studied n=183 consecutive patients with a diagnosis of PTC which were treated with total thyroidectomy plus 131I ablation. During a follow-up of in mean 97 months, most of the PTC patients had no signs of tumor relapse (n=157 patients). In contrast, one patient had serum Tg levels above the detection limit and<1 ng/ml, two patients Tg serum levels≥1 ng/ml and<2 ng/ml and n=23 patients had Tg serum levels≥2 ng/ml. Morphological signs of tumor recurrence were seen in 14 patients; all of these patients had serum Tg levels≥2 ng/ml. Importantly, with the exception of one patient, all TgAb positive PTC patients (n=27) had no signs of tumor recurrence as the serum Tg levels were below the assays functional sensitivities. Tetramer analyses revealed a higher number of tumor epitope-specific CD8+T cells in TgAb positive patients compared to TgAb negative PTC patients. In summary, we show that the occurrence of TgAbs may have an impact on the clinical outcome in PTC patients. This might be due to a tumor epitope-specific cellular immunity in PTC patients.

Checkpoint inhibitors in metastatic papillary renal cell carcinoma.

Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) and a distinct entity, although heterogenous, associated with poor outcomes. The treatment landscape of metastatic pRCC (mpRCC) relied so far on targeted therapies, mimicking previous developments in metastatic clear-cell renal cell carcinoma. However, antiangiogenics as well as mTOR inhibitors retain only limited activity in mpRCC. As development of immune checkpoint inhibitors (ICI) is now underway in patients with mpRCC, we aimed at discussing early activity data and potential for future therapeutic strategies in monotherapy or combination. Expression of immune checkpoints such as PD-L1 and infiltrative immune cells in pRCC could provide insights into their potential immunogenicity, although this is currently poorly described. Based on retrospective and prospective data, efficacy of ICI as single agent remains limited. Combinations with tyrosine-kinase inhibitors, notably with anti-MET inhibitors, harbor promising response rates and may enter the standard of care in untreated patients. Collaborative work is needed to refine the molecular and immune landscape of pRCC, and pursue efforts to set up predictive biomarker-driven clinical trials in these rare tumors.

Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study.

BACKGROUND: Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0-2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0-40·7). 39 (41%; 95% CI 30·7-51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related. INTERPRETATION: Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population. FUNDING: Merck Sharp & Dohme.

The diagnostic predictive value of neutrophil-to-lymphocyte ratio in thyroid cancer adjusted for tumor size.

The role of systemic inflammation has not been clearly defined in thyroid cancers. There have been conflicting reports on whether systemic inflammatory markers have predictive value for thyroid cancers. We aimed to evaluate the association between systemic inflammatory markers and clinicopathological factors in thyroid cancers and to assess their predictive value for thyroid cancers in detail. Five hundred thirty-one patients who underwent surgery for thyroid nodules were included. The patient population consisted of 99 individuals (18.6%) with benign thyroid nodules and 432 individuals (81.4%) with thyroid cancers. In 432 patients with thyroid cancers, neutrophil-to-lymphocyte ratio (NLR) was significantly higher in the cases with tumors greater than 2 cm than in those with tumors less than 2 cm. (p = 0.027). NLR and platelet-to-lymphocyte ratio (PLR) were significantly higher in cases with lateral lymph node metastasis (LNM) than in those without LNM (p = 0.007 and 0.090, respectively). The nodule size was significantly higher in benign thyroid nodules than in thyroid cancers (p < 0.001). When the cases were stratified by tumor size, NLR was a significant predictor of thyroid cancers in cases with nodules greater than 2 cm (Exp(B) = 1.85, 95% CI = 1.15-2.97, p = 0.011), but not in those with nodules less than 2 cm. In thyroid cancers, preoperative NLR was associated with pathological prognosticators such as tumor size and lateral lymph node metastasis. When the size difference between thyroid cancers and benign thyroid nodules was adjusted, NLR could be a significant predictor of thyroid cancers.

[Diagnostic Utility of LEF1 Immunostain in Cytology Specimens of Solid Pseudopapillary Neoplasm of Pancreas].

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm. Diagnosis of SPN requires an integrated approach with aid of radiology, biopsy, cytology, and immunohistochemical stains. Although morphological features in combination with nuclear positivity of ß-catenin IHC have been the gold standard of SPN diagnosis, but overlapping morphology and immunohistochemical findings with other entities in differential diagnoses such as pancreatic neuroendocrine tumors and pancreatic ductal adenocarcinoma make the diagnosis of SPN difficult particularly in limited cytology specimens. Lymphoid enhancer-binding factor 1 (LEF1), a key player in the Wnt signaling pathway, has shown promising diagnostic utility in SPN in recent literatures. METHODS: In this retrospective study, we evaluated the diagnostic utility of LEF1 IHC in SPN in cytology specimens. LEF1 IHC was performed and compared with ß-catenin, synaptophysin, and chromogranin immunostains in 13 SPN and 23 pancreatic neuroendocrine tumors (PanNETs) cytology cases with retrievable cell blocks. RESULTS: LEF1 was positive in 13 of 13 (100%) SPNs and was negative in all PanNETs (0%). CONCLUSION: LEF1 shows 100% sensitivity and specificity in cytology specimens for SPN and can be valuable immuno-stain in the diagnosis of SPN in cytology cell blocks.

Identification and validation of L Antigen Family Member 3 as an immune-related biomarker associated with the progression of papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is heterogeneous cancer with many different immune cells involved in its pathogenesis. L Antigen Family Member 3 (LAGE3) is an ESO/LAGE gene family member that has not been extensively studied in PTC. METHODS: Comprehensive bioinformatics analyses of LAGE3 were based on The Cancer Genome Atlas, Gene Expression Omnibus, and Genomics of Drug Sensitivity in Cancer (GDSC) databases. We also performed RNA-sequencing on 78 paired samples from local PTC patients. RESULTS: We observed that LAGE3 was significantly up-regulated in most solid tumor types, including PTC compared with corresponding normal tissues. The high level of LAGE3 was also significantly associated with advanced malignancy. LAGE3 expression was significantly associated with cancer-related pathways, biochemical metabolism, and immune-related terms. Further, tumor microenvironment analysis indicated LAGE3 was positively correlated with different immune cells infiltrating levels and the activity of different steps of the cancer-immunity cycle. Analyses based on the GDSC database revealed that low levels of LAGE3 might be resistant to WZ3105, I-BET-762, and PHA-793887. In addition, the experimental results validated that knocking down LAGE3 could affect proliferation, migration, and invasion in the PTC cell lines. CONCLUSION: This study discloses that LAGE3 plays an oncogenic and cancer-immunological role, also providing novel PTC biological and clinical implications.

Serum antithyroglobulin antibody levels are not a good predictive factor on detection of disease activity in patients with papillary thyroid carcinoma.

OBJECTIVE: Thyroglobulin antibodies (TgAb) are detected in thyroid cancer patients up to 25%. We investigated the prognostic value of TgAb positivity in patients with papillary thyroid carcinoma (PTC) after initial therapy. PATIENTS AND METHODS: A database of 109 consecutive patients who underwent total thyroidectomy and therapeutic lateral neck dissection followed by remnant ablation for PTC between January 1989 and December 2014 was reviewed We recorded the patients' all serum Tg and TgAb levels over time to establish changing trends. Patients were classified as either positive or negative according to serum TgAb levels. The recurrence or persistence rates in both groups were compared. RESULTS: Of the 109 patients enrolled 14 patients had TgAb positivity. Thirty-two (29.3%) showed disease recurrence or persistent disease during 101 months of follow-up. Twenty-seven of 95 patients (28.4%) with negative TgAb had persistent or recurrent disease, whereas 5 of 14 patients (35.7%) with positive TgAb had persistence or recurrence (P = 0.57). No significant difference in disease-free survival (115.3 ± 10.8 vs. 224.1 ± 16.6 months, P = 0.78) and overall survival (P = 0.59) was observed between TgAb positive and TgAb negative patients. CONCLUSIONS: TgAb status is not useful as a prognostic and predictive factor for clinical outcomes in patients with PTC in our experience.

Mechanisms of the Impact of Hashimoto Thyroiditis on Papillary Thyroid Carcinoma Progression: Relationship with the Tumor Immune Microenvironment.

BACKGROUND: The relationship between Hashimoto thyroiditis (HT) and papillary thyroid carcinoma (PTC) remains uncertain. We assessed the impact of HT on the tumor immune microenvironment (TIME) in PTC. METHODS: Thirty patients with PTC (group 1) and 30 patients with PTC and HT (group 2) were enrolled in this pilot study. The distribution and number of CD8+ lymphocytes, plasma cells (CD138+), regulatory T cells (forkhead box P3 [FOXP3+)], mast cell tryptase (MCT+), and M2 macrophages (CD163+) were evaluated. To test the hypothesis that HT impacts PTC development via signal transducer and activator of transcription 6 (STAT6) activation and M2 macrophage polarization, we investigated STAT6 expression in tumor and stromal cells. We also evaluated vascular endothelial growth factor (VEGF) expression by lymph node metastasis (LNM) status. RESULTS: TIME showed significant between-group differences. Group 1 patients demonstrated immune desert or immune-excluded immunophenotypes, while an inflamed phenotype with more CD8+ cells (P<0.001) predominated in group 2. Immune-excluded TIME was associated with the highest LNM rate. In PTC, LNM was associated with more numerous CD163+ cells. Moreover, LNM in group 1 was associated with increased numbers of mast cells peritumorally and FOXP3+ cells intratumorally and peritumorally. Group 2 demonstrated higher STAT6 but not higher VEGF expression in tumor cells. High VEGF expression was associated with LNM regardless of HT status. CONCLUSION: Concomitant HT impacted PTC signaling via STAT6 and TIME by increasing the number of CD8+ cells. LNM is associated with increases in CD163+ cells and VEGF expression in PTC, whereas HT affected LNM through different mechanisms.

Serum Anti-p53 Antibody Can Serve as a Predictive Marker for Histological Grade of Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVE: The aim of the study was to clarify the diagnostic impact of measuring serum anti-p53 antibody (S-p53Ab) in predicting the histological grades of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. METHODS: We compared the measured values and positive prevalence of S-p53Ab across the different histological grades of 111 resected IPMN cases. We also evaluated the TP53 alterations using immunohistochemistry and next-generation sequencing. RESULTS: Serum anti-p53 antibody were detected in 6 of 111 cases, all of their histological grades were high-grade dysplasia (HGD) and invasive carcinoma (INV). Positive prevalence of S-p53Ab was higher in cases with INV (4/35 cases, 11.4%) than those with HGD (2/38 cases, 5.3%), whereas S-p53Abs were undetectable in cases with low-grade dysplasia. Measured S-p53Ab values were not correlated with either carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA 19-9). In 4 of 6 S-p53Ab-positive cases, the TP53 alterations-somatic pathogenic mutations or aberrant immunoreactivity-were identified in their IPMN lesions. A combination assay of S-p53Ab, CEA, and CA 19-9 revealed a 38.4% sensitivity and 81.6% specificity for predicting HGD/INV. CONCLUSIONS: Serum anti-p53 antibody can serve as a surrogate marker for TP53 alterations and help predict the presence of HGD/INV in cases with IPMN, in combination with CEA and CA 19-9.

Markers of immune activation: novel biomarkers to predict the early-warning indicator of patients with papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is an indolent tumor that is exploding with increasing thyroid nodules (TN). Environmental carcinogens, lifestyle changes increased the incidence of thyroid carcinoma. With the development of B-ultrasound imaging, more and more thyroid cancer has been found. There has been a debate about whether thyroid cancer is overtreated. METHODS: The expression of T cell subsets and plasma cytokines in 191 patients, including 79 patients with PTC (PTC group), 58 patients with thyroid nodules (TN group) and 54 healthy individuals (HP group) were analyzed by flow cytometry. RESULTS: High levels of natural killer cells (NK) were detected in PTC and TN groups than in HP group. High activities of CD8+HLA-DR+ and CD8+CD38+ showed a gradual upward trend from HP group to PTC group. The rise in the levels of TNF-α in PTC patients' was evident when compared with HP group. CD8+CD38+ showed a significant correlation with lymph node metastasis. CD8+CD38+ co-expression was higher in Nx stage than N0 stage, while the proportion of IL-10 was dramatically decreased in the Nx stage. CONCLUSIONS: These results indicated that CD8+CD38+ might act as a biomarker of PTC lymph node metastasis. The combination of CD8+HLA-DR+, CD8+CD38+ and TNF-α can be used as useful biomarkers for the early-warning indicator of PTC.

Immunomorphological Pattern of Molecular Chaperones in Normal and Pathological Thyroid Tissues and Circulating Exosomes: Potential Use in Clinics.

The thyroid is a major component of the endocrine system and its pathology can cause serious diseases, e.g., papillary carcinoma (PC). However, the carcinogenic mechanisms are poorly understood and clinical useful biomarkers are scarce. Therefore, we determined if there are quantitative patterns of molecular chaperones in the tumor tissue and circulating exosomes that may be useful in diagnosis and provide clues on their participation in carcinogenesis. Hsp27, Hsp60, Hsp70, and Hsp90 were quantified by immunohistochemistry in PC, benign goiter (BG), and normal peritumoral tissue (PT). The same chaperones were assessed in plasma exosomes from PC and BG patients before and after ablative surgery, using Western blotting. Hsp27, Hsp60, and Hsp90 were increased in PC in comparison with PT and BG but no differences were found for Hsp70. Similarly, exosomal levels of Hsp27, Hsp60, and Hsp90 were higher in PC than in BG, and those in PC were higher before ablative surgery than after it. Hsp27, Hsp60, and Hsp90 show distinctive quantitative patterns in thyroid tissue and circulating exosomes in PC as compared with BG, suggesting some implication in the carcinogenesis of these chaperones and indicating their potential as biomarkers for clinical applications.

Increased cytoplasmatic expression of cancer immune surveillance receptor CD1d in anaplastic thyroid carcinomas.

BACKGROUND: Anaplastic thyroid carcinomas are associated with rapid tumor growth, short survival time and without any promising therapy to improve the poor prognosis. In this study, expression of immunoregulative receptor CD1d and lymphocyte infiltration in different thyroid tumors as well as in healthy tissue were analyzed in order to find new targets for an immunotherapeutic approach. METHODS: CD1d immunohistochemistry was performed in samples of 18 anaplastic, 17 follicular, 27 papillary, and 4 medullary thyroid carcinomas as well as in 19 specimens from normal thyroid tissue and additionally in 10 samples of sarcoma, seven malignant melanoma and three spindle-cell lung carcinoma. Furthermore, thyroid samples were stained with antibodies against CD3, CD20, CD56, CD68, and LCA in order to analyze lymphocyte infiltration. RESULTS: For the first time CD1d receptor expression on normal thyroid tissue could be demonstrated. Moreover, anaplastic thyroid carcinomas showed significantly higher expression levels compared to other thyroid samples. Most astonishingly, CD1d expression disappeared from the cellular surface and was detected rather in the cytoplasm of anaplastic thyroid carcinoma cells. In addition, histologically similar tumors to anaplastic carcinoma like sarcoma and malignant melanoma revealed distinct CD1d staining patterns. Furthermore, infiltration of T cells, B cells, and macrophages in anaplastic thyroid carcinomas was different when compared to normal thyroid tissue and all other thyroid carcinomas. CONCLUSIONS: Anaplastic thyroid carcinomas show significantly higher expression of CD1d, a receptor for NKT cells, which are subject of several anticancer therapy studies. These results may offer a novel approach to explore immunotherapeutic treatment options.

Immune infiltration in renal cell carcinoma.

Immune infiltration of tumors is closely associated with clinical outcome in renal cell carcinoma (RCC). Tumor-infiltrating immune cells (TIICs) regulate cancer progression and are appealing therapeutic targets. The purpose of this study was to determine the composition of TIICs in RCC and further reveal the independent prognostic values of TIICs. CIBERSORT, an established algorithm, was applied to estimate the proportions of 22 immune cell types based on gene expression profiles of 891 tumors. Cox regression was used to evaluate the association of TIICs and immune checkpoint modulators with overall survival (OS). We found that CD8+ T cells were associated with prolonged OS (hazard ratio [HR] = 0.09, 95% confidence interval [CI].01-.53; P = 0.03) in chromophobe carcinoma (KICH). A higher proportion of regulatory T cells was associated with a worse outcome (HR = 1.59, 95% CI 1.23-.06; P < 0.01) in renal clear cell carcinoma (KIRC). In renal papillary cell carcinoma (KIRP), M1 macrophages were associated with a favorable outcome (HR = .43, 95% CI .25-.72; P < 0.01), while M2 macrophages indicated a worse outcome (HR = 2.55, 95% CI 1.45-4.47; P < 0.01). Moreover, the immunomodulator molecules CTLA4 and LAG3 were associated with a poor prognosis in KIRC, and IDO1 and PD-L2 were associated with a poor prognosis in KIRP. This study indicates TIICs are important determinants of prognosis in RCC meanwhile reveals potential targets and biomarkers for immunotherapy development.

CD1d- and PJA2-related immune microenvironment differs between invasive breast carcinomas with and without a micropapillary feature.

BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is characterized by its unique morphology and frequent nodal metastasis. However, the mechanism for development of this unique subtype has not been clearly elucidated. The aim of this study was to obtain a better understanding of IMPC. METHODS: Using representative cases of mixed IMPC, mRNA expression in the micropapillary area and usual invasive area was compared. Then, immunohistochemical analyses for 294 cases (76 invasive carcinomas with a micropapillary feature [ICMF] and 218 invasive carcinomas without a micropapillary feature [ICNMF]) were conducted. Clinicopathological analyses were also studied. RESULTS: DNA microarray analyses for mixed IMPC showed that BC-1514 (C21orf118) was commonly upregulated in the micropapillary area. CAMK2N1, CD1d, PJA2, RPL5, SAMD13, TCF4, and TXNIP were commonly downregulated in the micropapillary area. Immunohistochemically, we confirmed that BC-1514 was more upregulated in ICMF than in ICNMF. CD1d and PJA2 were more downregulated in ICMF than ICNMF. All patients with cases of PJA2 overexpression survived without cancer recurrence during the follow-up period, although the differences for disease-free (p = 0.153) or overall survival (p = 0.272) were not significant. CONCLUSIONS: The CD1d- and PJA2-related tumour microenvironment might be crucial for IMPC. Further study of the immune microenvironment and micropapillary features is warranted.

CD200 expression is a feature of solid pseudopapillary neoplasms of the pancreas.

CD200 has been recently indicated as a robust marker of well-differentiated neuroendocrine neoplasms. Here, we evaluate its role in differential diagnosis of solid pancreatic neoplasms. We immunostained for CD200 22 solid pseudopapillary neoplasms (SPNs), 8 acinar carcinomas (ACs), 2 pancreatoblastomas (PBs), 138 neuroendocrine tumors (PanNETs), and 48 ductal adenocarcinomas. All SPNs showed strong cytoplasmic and membranous staining for CD200, while only one case of AC had focal positivity. The two PBs showed focal CD200 positivity, mainly located in squamoid nests. The vast majority of PanNETs (96%) showed strong cytoplasmic and membranous staining for CD200, whereas all PDACs were negative. As both PanNETs and SPNs express CD200, it has no role in the differential diagnosis between these two entities.

Unusual Papillary Squamous Cell Carcinoma of the Tip of Tongue Presenting in a Patient Status Post Heart Transplant.

Oral papillary squamous cell carcinoma (PSCC) is an unusual variant of squamous cell carcinoma with a better prognosis. The most common location of PSCC in the oral cavity is the gingiva and buccal mucosa, and it is exceedingly rare in the tongue. Herein, we present a case of PSCC in an 85-year-old male with a history of heart transplant and long-term use of immunosuppression medication. A verrucous pedunculated mass measuring 3.5 cm in the greatest dimension was present on the tip of tongue and a partial glossectomy was performed. Histological diagnosis was well differentiated PSCC with focal and minimal stalk invasion. No vascular nor perineural invasion was identified. Based on the current WHO and AJCC oral cancer staging system, the tumor stage was T2N0M0. The tumor cells were focally positive for p16, but in situ hybridization was negative for low-risk HPV (types 6 and 11) and high-risk HPV (types 16, 18, 31, 33 and 51). To the best of our knowledge, this is the first documented case of PSCC present on the tip of tongue in patients with long-term immune suppression. The pathogenesis, stage and prognosis of this entity are discussed. More case studies with long-term follow up are needed to achieve an accurate tumor stage and definite prognosis.

Changing Trend of Thyroglobulin Antibodies in Patients With Differentiated Thyroid Cancer Treated With Total Thyroidectomy Without 131I Ablation.

BACKGROUND: Thyroglobulin (Tg) antibodies (TgAb) can interfere with Tg measurement and can be used as "Tg surrogate" in patients with differentiated thyroid cancer (DTC) treated with total thyroidectomy (TTx) and radioiodine remnant ablation (RRA). In contrast, few data, and in patients usually followed for a short-term follow-up, have been reported about the changes of TgAb levels in patients treated with TTx but without RRA. The aims of this study were to evaluate the changes of TgAb levels in DTC patients treated with TTx but not RRA and to identify the factors that influence these changes. METHODS: The change in TgAb levels in 107 DTC (<1 cm) patients submitted to TTx but not RRA was evaluated. Patients were followed for a median of 6.3 years, and all had at least three determinations of TgAb and neck ultrasound (nUS). RESULTS: TgAb levels showed a progressive decrease during follow-up. Initial TgAb levels and degree of lymphocytic infiltration influenced the time but not the rate of TgAb disappearance. No influence on time and rate of the decrease in TgAb was observed when the association with thyroperoxidase antibodies (TPOAb) levels were considered. A TgAb cutoff value of 61.9 IU/mL at first postoperative evaluation was a good indicator for disappearance of the TgAb within six years. No tumor recurrence was observed in the series. In one case, the progressive increase in TgAb anticipated the reappearance of benign thyroid tissue with lymphocytic infiltration. CONCLUSIONS: TgAb levels decline in the majority of DTC patients treated with TTx but not ablated with radioiodine. The levels decrease rapidly after the surgical treatment and continue to decrease over time. The time of disappearance is influenced by the initial TgAb levels and the degree of lymphocytic infiltration. No influence of the actual TPOAb levels has been observed. An increase in TgAb levels should not be overlooked, since it can indicate the presence or reappearance of either normal thyroid tissue or tumor recurrence.

Anti-Podocalyxin Monoclonal Antibody 47-mG2a Detects Lung Cancers by Immunohistochemistry.

Lung cancer is one of the leading causes of cancer-related deaths in the world. Regardless of the advances in lung cancer treatments, the prognosis is still poor. Podocalyxin (PODXL) is a highly glycosylated type I transmembrane protein that is expressed in normal tissues, including the heart, pancreas, and breast. It is also found and used as a diagnostic marker in many cancers, such as renal, brain, breast, oral, and lung cancers. We previously developed specific and sensitive anti-PODXL monoclonal antibodies, PcMab-47 (mouse IgG1, kappa) and its mouse IgG2a-type (47-mG2a), both of which were suitable for immunohistochemical analyses of oral cancers. In this study, we investigated the utility of PcMab-47 and 47-mG2a for the immunohistochemical analyses of lung cancers. PcMab-47 stained 51/70 (72.9%) cases of lung cancer, whereas 47-mG2a stained 59/70 (84.3%) cases, indicating that the latter antibody is more sensitive and is useful for detecting PODXL in lung cancers.

Predictive relevance of programmed cell death protein 1 and tumor-infiltrating lymphocyte expression in papillary thyroid cancer.

BACKGROUND: Co-signaling molecule programmed cell death 1 ligand 1 has been shown to induce potent inhibition of T cell-mediated antitumoral immunity. Our study aimed to investigate the prognostic value of programmed cell death 1 ligand 1 expression and tumor-infiltrating lymphocyte density as biomarkers in specimens from patients with papillary thyroid cancer. METHODS: We retrospectively analyzed the data and tissue samples of 75 patients with papillary thyroid cancer. Stained cells were counted manually and analyzed for clinical and histopathologic correlations and disease-free survival. RESULTS: Programmed cell death 1 ligand 1 expression was significantly correlated with increased incidence of lymphovascular invasion (P = .038), extrathyroidal extension (P = .026), and concurrent lymphocytic thyroiditis (P = .003). Patients with low CD8+ and CD3+ expression presented with a significantly higher incidence of lymph node metastasis (P = .042) and extrathyroidal extension (P = .015). The subgroup of cases with positive programmed cell death 1 ligand 1 expression and low CD8+ T cell infiltration demonstrated a significantly increased incidence of lymph node metastasis (P = .031). Univariate and multivariate analysis confirmed that a high CD8+ T cell density was significantly associated with favorable disease-free survival (P = .017). Subanalysis revealed that the shortest disease-free survival was evident in the programmed cell death 1 ligand 1+/CD8low group (P = .004). CONCLUSION: Our findings indicate that CD8+ tumor-infiltrating lymphocyte density and programmed cell death 1 ligand 1 expression may serve as valuable predictive biomarkers in patients with papillary thyroid cancer.