Lectin-like Transcript-1 (LLT1) Expression in Oral Squamous Cell Carcinomas: Prognostic Significance and Relationship with the Tumor Immune Microenvironment.

Lectin-like transcript-1 (LLT1) expression is detected in different cancer types and is involved in immune evasion. The present study investigates the clinical relevance of tumoral and stromal LLT1 expression in oral squamous cell carcinoma (OSCC), and relationships with the immune infiltrate into the tumor immune microenvironment (TIME). Immunohistochemical analysis of LLT1 expression was performed in 124 OSCC specimens, together with PD-L1 expression and the infiltration of CD20+, CD4+, and CD8+ lymphocytes and CD68+ and CD163+-macrophages. Associations with clinicopathological variables, prognosis, and immune cell densities were further assessed. A total of 41 (33%) OSCC samples showed positive LLT1 staining in tumor cells and 55 (44%) positive LLT1 in tumor-infiltrating lymphocytes (TILs). Patients harboring tumor-intrinsic LLT1 expression exhibited poorer survival, suggesting an immunosuppressive role. Conversely, positive LLT1 expression in TILs was significantly associated with better disease-specific survival, and also an immune-active tumor microenvironment highly infiltrated by CD8+ T cells and M1/M2 macrophages. Furthermore, the combination of tumoral and stromal LLT1 was found to distinguish three prognostic categories (favorable, intermediate, and adverse; p = 0.029, Log-rank test). Together, these data demonstrate the prognostic relevance of tumoral and stromal LLT1 expression in OSCC, and its potential application to improve prognosis prediction and patient stratification.

Tumor-Infiltrating CD20+ B Lymphocytes: Significance and Prognostic Implications in Oral Cancer Microenvironment.

Immunohistochemical analysis of stromal/tumoral CD20+ B lymphocytes was performed in 125 OSCC patients. Correlations with immune profiles CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocytes (TILs), tumoral PD-L1, and stem-related factors NANOG and SOX2 were assessed, and also associations with clinical data and patient survival. There was a strong positive correlation between the infiltration of CD20+ B lymphocytes and other immune profiles (i.e., CD4+, CD8+, and FOXP3+ TILs, and CD68+ and CD163+ macrophages) both in stroma and tumor nests. Strikingly, CD20+ TILs were inversely correlated with NANOG/SOX2 expression. Stromal CD20+ TILs were significantly associated with T classification and second primary tumors. A stratified survival analysis showed that tumoral CD20+ TILs were significantly associated with prognosis in male and younger patients, with tobacco or alcohol consumption, high tumoral CD8+ TILs, low tumoral infiltration by CD68+ macrophages, positive PD-L1 expression, and negative NANOG/SOX2. Multivariate Cox analysis further revealed clinical stage and tumoral CD20+ TILs independently associated with disease-specific survival (HR = 2.42, p = 0.003; and HR = 0.57, p = 0.04, respectively). In conclusion, high CD20+ TIL density emerges as an independent good prognostic factor in OSCC, suggesting a role in antitumor immunity. This study also uncovered an inverse correlation between CD20+ TILs and CSC marker expression.

Prognostic Relevance of CD4+, CD8+ and FOXP3+ TILs in Oral Squamous Cell Carcinoma and Correlations with PD-L1 and Cancer Stem Cell Markers.

This study investigates the relevance of tumor-infiltrating lymphocytes (TILs) in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis of stromal/tumoral CD4+, CD8+ and FOXP3+ TILs is performed in 125 OSCC patients. Potential relationships with the expression of tumoral PD-L1 and cancer stem cell (CSC) markers (NANOG, SOX2, OCT4, Nestin and Podoplanin (PDPN)) are assessed. CD4+ and CD8+ TILs are significantly associated with smoking and alcohol habits. CD4+ and CD8+ TILs show an inverse relationship with NANOG and SOX2 expression, and FOXP3+ TILs is significantly correlated with Nestin and PDPN expression. High infiltration of CD4+ and CD8+ TILs and a high tumoral CD8+/FOXP3+ ratio are significantly associated with tumors harboring positive PD-L1 expression. Infiltration of stromal/tumoral FOXP3+ TILs and a low stromal CD8+/FOXP3+ ratio are significantly associated with better disease-specific survival. Multivariate analysis reveals that the stromal CD8+/FOXP3+ TILs ratio is a significant independent prognostic factor. Regarding OSCC patient survival, the CD8+/FOXP3+ TILs ratio is an independent prognostic factor. TILs may act as biomarkers and potential therapeutic targets for OSCC.

Macrophages in Oral Carcinomas: Relationship with Cancer Stem Cell Markers and PD-L1 Expression.

Tumor-associated macrophages (TAMs) can be polarized into antitumoral M1 and protumoral and immunosuppressive M2 macrophages. This study investigated the clinical relevance of TAM infiltration in oral squamous cell carcinoma (OSCC), evaluating CD68 (M1 and M2 macrophage marker) and CD163 expression (M2 macrophage marker) in the tumor nests and surrounding stroma. Immunohistochemical analysis of both stromal/tumoral CD68+ and CD163+ TAMs was performed in paraffin-embedded tissue specimens from 125 OSCC patients, and correlated with clinical data. Potential relationships with the expression of cancer stem cell (CSC) markers and PD-L1 in the tumors were also assessed. Stromal CD163+ infiltration was significantly associated with the tumor location in the tongue, and stromal and tumoral CD68+ and CD163+-infiltrating TAMs were more abundant in nonsmokers and non-alcohol-drinkers. Strikingly, this study uncovers an inverse relationship between CD68+ and CD163+ TAMs and CSC marker expression (NANOG and SOX2) in OSCC. High infiltration of CD163+ TAMs in both tumor and stroma was strongly and significantly correlated with the absence of NANOG expression. Moreover, infiltration of both CD68+ and CD163+ TAMs was also significantly associated with high tumor expression of PD-L1. Our results suggest that there is a link between TAM infiltration and immune escape in OSCC.

AA amyloidosis associated with morbid obesity (clinical case).

We present the case of a 45-year-old woman who was hospitalized due to severe macrocytic anemia and renal failure. The patient presented a morbid obesity. The immunological study showed anti-ENA anti-SSA (Ro52) positive, with negative antinuclear antibodies. Also in the proteinogram (serum immunofixation) the presence of monoclonal bands IgG lambda and IgG kappa, monoclonal component 7.2% (4.68g/L), with elevation of free light chains (kappa 95.94mg/L (3.3-19.4), evidenced, lambda 145.17mg/L (5.71-26.3)). The bone marrow study showed an infiltration of 5% of plasma cells and positive for AA amyloid. Finally, a percutaneous renal biopsy was performed, which again showed amyloid infiltration. In the genetic study, 2 mutations of the family Mediterranean fever gene (MEFV) have been identified. Secondary AA amyloidosis has been described associated with obesity, in addition to a percentage of cases of unknown etiology.

The usefulness of new serum tumor markers in head and neck squamous cell carcinoma.

OBJECTIVE: To determine the usefulness of specific and reliable serum biomarkers to predict cervical lymph node metastasis. METHODS: A cross-sectional study of cases and controls. Thirty-nine serum samples of head and neck squamous cell carcinoma were collected from patients during neoplasm resection. Another 10 serum samples were collected from healthy individuals as a control group. Selected serum biomarkers were E-cadherin, MMP-2, MMP-9, active MMP-13, and p53 autoantibodies. RESULTS: We found a correlation between active MMP-13 (>685 pg/mL; ROC curve analysis 95% CI for sensitivity 79.6-99.3; specificity 49.2-95.1; positive predictive value 65-100; and negative predictive value 36-100) as well as the presence of p53 autoantibodies and lymph node metastasis. Multimarker analysis using MMP-13 and p53 autoantibodies together provided better sensitivity (76%) and specificity (100%). CONCLUSIONS: The combined determination of active MMP-13 and p53 autoantibodies could improve diagnosis of lymphatic metastasis in head and neck squamous cell carcinoma and aid therapeutic decision making.

Distinct Expression and Clinical Significance of Zinc Finger AN-1-Type Containing 4 in Oral Squamous Cell Carcinomas.

Zinc finger AN1-type containing 4 (ZFAND4) has emerged as a promising prognostic marker and predictor of metastasis for patients with oral squamous cell carcinoma (OSCC). However, further validation is fundamental before clinical implementation. Hence, this study evaluated the expression pattern of ZFAND4 protein expression by immunohistochemistry using an independent cohort of 125 patients with OSCC, and correlations with the clinicopathologic parameters and disease outcome. Remarkably, ZFAND4 expression, while negligible in normal epithelium, exhibited two distinct expression patterns in tumors that did not overlap. A gross granular staining was characteristic of the undifferentiated cells at the invasive front of tumors, whereas the most differentiated cells located at the center of the tumor nests showed diffuse non-granular staining. ZFAND4 staining was higher in undifferentiated than in differentiated areas of tumors. High ZFAND4 expression in differentiated cells was significantly associated to well-differentiated (p = 0.04) and non-recurrent tumors (p = 0.04), whereas ZFAND4 expression in undifferentiated cells correlated with tumor location (p = 0.005). No correlations between the ZFAND4 expression and patient survival were found. These data question the clinical relevance of ZFAND4 expression as a prognostic biomarker in OSCC, and also reveal distinct ZFAND4 expression patterns depending on the differentiation areas of tumors that should be evaluated separately.

Serum ferritin as prognostic marker in classical Hodgkin lymphoma treated with ABVD-based therapy.

Ferritin levels might correlate with disease activity in classical Hodgkin lymphoma (cHL). We analyzed the prognostic significance of the ferritin value at diagnosis in 173 cHL patients treated with ABVD between 2003 and 2013. The 5-year overall survival (OS) and progression-free survival (PFS) probabilities were 80% and 64%, respectively. Patients with ferritin ≥ 350 µg/l [high ferritin group (HF), n = 62] were more likely to have advanced stage disease, B-symptoms and higher International Prognostic Score (IPS) compared with patients with ferritin < 350 µg/l [low ferritin group (LF), n = 111]. The complete remission (CR) rate and 5-year PFS and OS probabilities were lower in HF vs. LF patients (69% vs. 89%, p = 0.025; 40% vs. 78%, p < 0.001; 61% vs. 90%, p = 0.001; respectively). Multivariate analysis revealed that advanced stage (p = 0.001) and ferritin levels ≥ 350 µg/l (p = 0.002) were independent predictors for PFS. In conclusion, the ferritin level at diagnosis is a useful prognostic marker for cHL.

Renal translocation carcinoma with expression of TFEB: presentation of a case with distinctive histological and immunohistochemical features.

The authors describe a case of renal cell carcinoma with t(6; 11) (p21; q12) in a 22-year-old man. The tumor showed typical histological features of this neoplasm with 2 types of cells and hyaline nodules surrounded by small cells. Characteristically, the tumor showed cystic lumina with hyaline-papillary structures inside and in some areas large and irregular intratumoral vessels. On immunohistochemical study, the tumoral cells were positive for melanocytic markers and transcription factor EB, as also for AE1-AE3 and Cam5.2 anticytokeratin antibodies. The expression of epithelial markers in this neoplasm is uncommon, and we think it is an important finding because otherwise, if melanocytic markers such as HMB45 or Melan A are not used, some renal cell carcinomas with the t(6; 11) (p21; q12) may be mistaken for other more common renal cell carcinomas.

Combined Papillated Bowen Disease and Clear Cell Atypical Fibroxanthoma.

We describe a case of papillated Bowen disease (PBD), associated with a clear cell atypical fibroxanthoma (CCAFXA). The epidermal lesion showed a bowenoid papillomatous growth pattern with histologic features suggestive of infection by human papilloma virus (HPV). In the dermis a neoplasm made up by spindled or polygonal cells with wide clear cytoplasm and moderate nuclear pleomorphism was found. Immunohistochemical characteristics of these two lesions were clearly different. The atypical cells of the intraepidermal proliferation were positive for AE1-AE3 anticytokeratin antibody, EMA, p16, p53 and p63. The dermal tumor was positive for vimentin, CD10, CD68, CD99, alpha-1-antitrypsin and c-kit. Histological features and immunohistochemical profile of the dermal tumor corresponded to a CCAFXA, a very uncommon neoplasm of which only 10 cases have been reported. In situ hybridization for numerous types of HPVs was negative in both lesions.

AA amyloidosis associated with morbid obesity (clinical case) / Amiloidosis AA asociada a la obesidad mórbida (caso clínico)

We present the case of a 45-year-old woman who was hospitalized due to severe macrocytic anemia and renal failure. The patient presented a morbid obesity. The immunological study showed anti-ENA anti-SSA (Ro52) positive, with negative antinuclear antibodies. Also in the proteinogram (serum immunofixation) the presence of monoclonal bands IgG lambda and IgG kappa, monoclonal component 7.2% (4.68g/L), with elevation of free light chains (kappa 95.94mg/L (3.3-19.4), evidenced, lambda 145.17mg/L (5.71-26.3)). The bone marrow study showed an infiltration of 5% of plasma cells and positive for AA amyloid. Finally, a percutaneous renal biopsy was performed, which again showed amyloid infiltration. In the genetic study, 2 mutations of the family Mediterranean fever gene (MEFV) have been identified. Secondary AA amyloidosis has been described associated with obesity, in addition to a percentage of cases of unknown etiology

Presentamos el caso de una mujer de 45 años que fue hospitalizada debido a una anemia macrocítica severa e insuficiencia renal. El paciente presentaba una obesidad mórbida. El estudio inmunológico mostró positividad para anti-ENA, anti-SSA (Ro52) y negatividad para anticuerpos antinucleares. También en el proteinograma (inmunofijación sérica) se detectó la presencia de bandas monoclonales IgG lambda e IgG kappa, con un componente monoclonal del 7,2% (4,68g/l) y la elevación de cadenas ligeras libres (kappa 95,94mg/l [3,3-19,4]; lambda 145,17mg/l [5,71-26,3]). El estudio de biopsia de médula ósea mostró una infiltración del 5% de células plasmáticas y positividad para amiloide AA. Finalmente, se realizó una biopsia renal que nuevamente mostró infiltración amiloide. En el estudio genético se identificaron 2 mutaciones del gen de la fiebre mediterránea familiar (MEFV). La amiloidosis secundaria AA se ha descrito asociada a la obesidad, además de un porcentaje de casos de etiología desconocida