Stage-independent Prognostic Factor Research Articles

P-234 Association between tumor differentiation grade and TNM staging in colorectal cancer

The tumor differentiation grade has been shown by several studies to be a stage-independent prognostic factor in colorectal cancer (CRC) 1. It is a factor that accounts for the tumor biology and is considered as an indicator of potential tumor growth and spread. The aim of this study was to analyze the importance of differentiation grade and how it relates to TNM staging system. 1. Mori T, Hirota T, Ohashi Y, Kodaira S. Significance of histologic type of primary lesion and metastatic lymph nodes as a prognostic factor in stage III colon cancer. Dis Colon Rectum 2006;49:982–92. The study was a retrospective single-centre analysis conducted at the University Clinic of Gastroenterology, University Hospital Center Mother Teresa, Tirana, Albania during the period 2014-2017. The clinical parameters and pathology data of cancer stage and differentiation grade were included. Tumor staging was done according to TNM system, AJCC (American Joint Committee on Cancer) 7th edition. The differentiation grade was correlated with demography, tumor location and overall TNM stage. They were further divided into low tumor grade (G1+G2) and high tumor grade (G3+G4) according to tumor differentiation. Data analysis was performed using the SPSS statistical package version 23.0. A total number of 237 patients were included in the study, mean age 62.7 ± 11.0 years, 133 (56.1%) male and 104 (43.9%) female. The tumor differentiation grade correlated significantly with the overall TNM stage (p = 0.001). A higher grade was more likely to correspond with a worse overall stage. High tumor grade (G3+G4) was diagnosed more frequently in stage III-IV than in stage I-II (71.6% vs 9.6%). The grade significantly correlated with the risk of having lymph node metastasis where the high grade tumors (G3/4) had a markedly increased risk of having positive nodes (p < 0.001). There were found no correlations between the differentiation grade and age or gender. Tumor differentiation grade is an important prognostic component, which correlates strongly with TNM classification system of CRC. Higher grade may have a higher malignant potential and be associated with worse clinical outcomes.

Clinical significance of elevated antinuclear antibodies in patients with diffuse large B-cell lymphoma: A single center study.

To investigate the potential diagnostic and prognostic values of antinuclear autoantibodies (ANAs) in diffuse large B-cell lymphoma (DLBCL). Eighty-two DLBCL patients and 120 healthy controls were selected from the Department of Hematology, Jincheng Dayi Hospital between 2005 and 2014. We examined the expression of ANA in the sera of the 82 DLBCL patients at different Ann-Arbor stages (15 at Stage I, 22 at Stage II, 27 at Stage III, and 18 at Stage IV). ANA detection was performed by immunofluorescence, and the results were confirmed by Western blotting analysis. ANAs were more frequently detected in DLBCL patients than in controls (P < 0.001), with 25 (30.5%) DLBCL patients and 9 (7.5%) controls displaying elevated ANA levels. However, the majority of DLBCL patients in which ANA were detected did not develop autoimmune diseases, suggesting that ANA in DLBCL might not be correlated autoimmune diseases. Furthermore, no correlation was observed between the expression of ANA and the clinical stages of DLBCL. However, ANA-positive DLBCL patients had a better survival rate (P < 0.05). ANA in DLBCL may be a stage-independent prognostic factor rather than an indication for autoimmune diseases and may represent an effective immune response to the tumor.

Primary Tumor Location Is a Useful Predictor for Lymph Node Metastasis and Prognosis in Lung Adenocarcinoma

IntroductionWe examined the value of tumor location in predicting the clinicopathologic features, survival, and metastases of pulmonary adenocarcinoma. Patients and MethodsA total of 417 cases of pulmonary adenocarcinoma were included in the present study. The tumors with invasion of the segmental and/or lobar bronchus were classified as central adenocarcinoma and those without as peripheral adenocarcinoma. Histologic grade, cytologic features, and adenocarcinoma type (terminal respiratory unit [TRU] type vs. non-TRU type) were compared between the 2 groups. The prognostic factors for disease-free survival (DFS) were analyzed using univariate and multivariate analyses. ResultsCentral adenocarcinoma was associated with lymphatic and/or vascular invasion (P = .011), necrosis (P < .001), high histologic grade (P = .004), and advanced stage (P < .001). For lung adenocarcinoma 1 to 4 cm in size, central adenocarcinoma was linked to a greater rate of nodal metastasis than peripheral adenocarcinoma. However, for lung adenocarcinoma of other sizes, central and peripheral adenocarcinoma had no differences in the rates of nodal metastasis. For nuclear features, central adenocarcinoma showed high mitotic counts, advanced nuclear atypia, and larger nuclei (P < .001, P < .001, P < .001, respectively). More peripheral adenocarcinomas than central adenocarcinomas were TRU type (229 of 281 [81.5%] vs. 58 of 136 [42.6%]; P < .001). Multivariate survival analyses of DFS showed that tumor location (central vs. peripheral, hazard ratio, 1.744; P < .001) was a stage-independent prognostic factor. ConclusionCentral adenocarcinoma is associated with a high potential for regional lymph node metastases, even at a small size. The results of our study showed that tumor location is an important factor for choosing treatment strategies and predicting DFS.

A novel diagnostic biosensor for distinguishing immunoglobulin mutated and unmutated types of chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), the immunoglobulin heavy-chain variable (IgVH) region may be mutated (Ig-mutated CLL) or unmutated (Ig-unmutated CLL); and the presence or absence of mutations in this region of CLL cells distinguishes two clinically distinct forms. It is important for physicians to distinguish between patients with Ig-unmutated CLL, where typically have more indolent disease with median survivals close to 25 years, and Ig-mutated CLL, where have more aggressive disease with median survivals around eight years. In this work, a biosensor capable of diagnosis and distinguishing between these two types of CLL was reported. The biosensor was fabricated by modifying a gold electrode with gold nanoparticles (AuNPS) followed by coating of ZAP70 oligonucleotide probe on the surface to detect specific sequence of ZAP70 gene. ZAP70 could predict the IgVH mutation status and is a good marker for differentiating Ig-mutated and Ig-unmutated CLL and serve as prognostic marker. First, we focused on achieving hybridization between probe and its complementary sequence. Hybridization between probe and target was determined with electrochemical impedance spectroscopy (EIS). Then, our efforts turned to optimize the conditions for the detection of any point mutation and also to maximize the selectivity. Under optimal conditions, the biosensor has a good calibration range between 2.0 × 10(-14) and 1.0 × 10(-9)molL(-1), with ZAP70 DNA sequence detection limit of 4.0 × 10(-15)molL(-1). We successfully detect hybridization first in synthetic samples, and ultimately in blood samples from patients. Experimental results illustrated that the nanostructured biosensor clearly discriminates between mutated and non-mutated CLL and predict the IgVH mutation status, which it has been considered as the single most informative stage independent prognostic factor in CLL.

Expression of Bile Duct Transcription Factor HNF1β Predicts Early Tumor Recurrence and Is a Stage-Independent Prognostic Factor in Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) frequently exhibits biliary differentiation, which is typically overlooked. Hepatocyte nuclear factor 1β (HNF1β), a bile duct-specific transcription factor expressed in bile ducts but not in the normal hepatocytes, is also expressed in HCC. Materials and MethodsThe expression of HNF1β and the biliary differentiation marker cytokeratin 19 (CK19) were retrospectively evaluated using immunohistochemistry in 159 surgically resected primary HCCs. ResultsA significant correlation was observed between HNF1β protein expression and younger age (p = 0.0293), high serum α-fetoprotein levels (p = 6 × 10−4), and high tumor grade (p = 0.0255). However, HNF1β expression exhibited no correlation with tumor stage. Patients with HCCs and HNF1β expression were more likely to exhibit early tumor recurrence (ETR; p = 0.0048) and a lower 5-year survival rate (p = 0.0001). A multivariate analysis indicated HNF1β expression as an independent prognostic factor in HCC (p = 0.0048). A combinatorial analysis revealed additive adverse effects of HNF1β when concomitant with CK19 expression and p53 mutation. Furthermore, HNF1β expression can predict poor prognosis in patients with ETR. ConclusionOur results indicated that HNF1β expression is a crucial predictor of poor prognosis in HCC and is independent of tumor stage. Moreover, concomitant HNF1β and CK19 expressions exhibited additive adverse effects in HCC, confirming that HCC with biliary differentiation has a poor prognosis.

Tumour differentiation grade is associated with TNM staging and the risk of node metastasis in colorectal cancer

Aim. The tumour differentiation grade has been shown by numerous multivariate analyses to be a stage-independent prognostic factor in colorectal cancer. The aim of this study was to explore the importance of differentiation grading for the staging of colorectal cancer and how it relates to the components of the TNM system. Material and methods. The study was a retrospective single-centre analysis of all patients undergoing surgical resection for colorectal cancer during the period 2002–2007 (n = 1239). The clinical parameters and pathology data of overall stage, differentiation grade, local tumour (T)-stage and metastasis status (M-stage) were included as well as the lymph node count of both assessed and metastatic nodes. The differentiation grade was correlated with demography, overall stage and each component of the TNM staging system. The correlation between differentiation grade and N-stage was also explored for the separate T-stages. Results. The tumour differentiation grade correlated significantly with the overall TNM stage (p < 0.0001). The grade significantly correlated with the T-stage and the risk of having lymph node metastasis (p < 0.0001). A high grade was associated with a higher positive lymph node count in stage III disease (p < 0.0002). For the T-stages, the risk of node metastasis was significantly linked to the tumour grade. A low grade (G1) T2 had a 17% risk of lymph node metastasis compared to a 44% risk for a high grade (G4) T2. Conclusion. Tumour differentiation is an important prognostic factor. It correlates significantly with the overall stage of the TNM system and also to each of its components. The risk of having lymph node metastasis for each T-stage also correlates with the tumour grade. The findings can be of importance in postoperative risk assessment or when considering local resection procedures like TEM.

Lymphovascular Invasion in Colorectal Cancer

Lymphovascular invasion (LVI) in colorectal cancer (CRC) is considered a strong stage-independent prognostic factor and influences decisions regarding adjuvant chemotherapy in patients with stage II tumors. However, the degree of interobserver agreement among pathologists for LVI in CRC is largely unknown. This study was undertaken to examine such interobserver variability, and we hypothesized that the use of immunohistochemical markers for vascular and lymphatic channels could improve interobserver agreement. Fifty cases of American Joint Committee on Cancer stage II moderately differentiated CRC from 1990 to 2005 from the pathology archives were selected; mucinous, medullary, and other recognized special subtypes were excluded. Fifty hematoxylin and eosin (H&E) slides (1 from each case) were circulated to 6 gastrointestinal pathologists, who independently assessed small and large vessel invasion. No diagnostic guidelines were given to the participating pathologists; each was instructed to apply the criteria for LVI that he or she used in daily practice. Immunohistochemistry (IHC) for D2-40 and CD31 was performed on corresponding paraffin blocks. The IHC slides were randomized, recirculated, and rescored for LVI. Results were analyzed by kappa (kappa) statistics, which correct for agreement by chance, and for percentage agreement. The average kappa values were determined for the H&E slides (large and small vessel), CD31 (small vessel), and D2-40 (small vessel) (Fig. 1). Agreement was fair for H&E small vessel invasion [kappa=0.28; 95% confidence interval (CI): 0.22-0.34]. The least agreement was seen in interpretation of H&E large vessel invasion (kappa=0.18; 95%CI: 0.11-0.26). Agreement was not improved by use of immunohistochemical stains: CD31 (large vessel, kappa=0.42, 95%CI: 0.20-0.63, small vessel, kappa=0.26, 95%CI: 0.10-0.42) and D2-40 (kappa=0.32, 95%CI: 0.21-0.42). Interobserver variability in diagnosis of LVI was substantial on H&E slides and did not improve upon use of IHC. Agreement in evaluation of large vessel invasion was only slightly higher than would be seen by chance alone. This study highlights the need for criteria in evaluation of LVI, as this assessment may impact patient prognosis and thus change the course of clinical treatment.

Protocol for the Examination of Specimens From Patients With Primary Carcinomas of the Colon and Rectum

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the “Surgical Pathology Cancer Case Summary (Checklist)” portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice. The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.

Overexpression of tumour-associated trypsin inhibitor (TATI) enhances tumour growth and is associated with portal vein invasion, early recurrence and a stage-independent prognostic factor of hepatocellular carcinoma

Tumour-associated trypsin inhibitor (TATI) overexpresses in various tumours, but its clinicopathological significance in hepatocellular carcinoma (HCC) is unclear. Differential display analysis revealed expression of TATI in HCC. By RT-PCR in the linear range, TATI was found to be overexpressed in 176 of 258 unifocal primary HCCs (68%). TATI overexpression correlated with high-stage HCC (stage IIIB to IV) with portal vein (PV) invasion ( p = 0.00014), early tumour recurrence (ETR; p = 0.00002), and a lower 5-year survival ( p = 0.000001), in both low- and high-stage HCC ( p = 0.033 and p = 0.00036, respectively). Ectopic expression of TATI led to enhanced anchorage-independent tumour cell growth in vitro. To determine its potential as a part of a group of combined diagnostic markers, we analysed 235 HCCs for three genes encoding secretory proteins known to be overexpressed in HCC; these were TATI, AFP and osteopontin; 202 of the tumours (86%) overexpressed one or more of these genes. Further, HCC with a greater number of gene overexpressions produced bigger tumours ( p = 0.0024), had a higher rate of PV invasion ( p= 1 × 10 −8), had a higher ETR ( p = 1 × 10 −8), and showed a lower 5-year survival ( p = 0.000001). We conclude that TATI overexpression contributes to cell growth advantage, enhances the metastatic potential of tumours and leads to advanced HCC with PV invasion. Thus, it is a stage-independent prognostic factor for HCC and a useful predictor for ETR. Moreover, it should be possible to use TATI, AFP and osteopontin as combined markers for molecular staging, the detection of HCC and for the prediction of ETR.

The longitudinal relationship between circulating concentrations of C-reactive protein, interleukin-6 and interleukin-10 in patients undergoing resection for renal cancer

The systemic inflammatory response, as evidenced by elevated circulating concentrations of C-reactive protein, is a stage-independent prognostic factor in patients undergoing curative nephrectomy for localised renal cancer. However, it is not clear whether the systemic inflammatory response arises from the tumour per se or as a result of an impaired immune cytokine response. The aim of the present study was to examine C-reactive protein, interleukin-6 and interleukin-10 concentrations before and following curative resection of renal cancer. Sixty-four patients with malignant renal disease and 12 with benign disease, undergoing resection were studied. Preoperatively, a blood sample was collected for routine laboratory analysis with a further sample stored before analysis of interleukin-6 and interleukin-10 using an enzyme-linked immunosorbent assay (ELISA) technique. The blood sampling procedure and analyses were repeated at approximately 3 months following resection. Circulating concentrations of both interleukin-6 and interleukin (P⩽0.01) were higher and a greater proportion were elevated (P<0.05) in malignant compared with benign disease. The renal cancer patients were grouped according to whether they had evidence of a systemic inflammatory response. In the inflammatory group T stage was higher (P<0.01), both interleukin-6 and interleukin-10 concentrations were higher (P<0.001) and elevated (P<0.10) compared with the non-inflammatory group. Tumour volume was weakly correlated with C-reactive protein (r2=0.20, P=0.002), interleukin-6 (r2=0.20, P=0.002) and interleukin-10 (r2=0.24, P=0.001). Following nephrectomy the proportion of patients with elevated C-reactive protein, interleukin-6 and interleukin-10 concentrations did not alter significantly. An elevated preoperative C-reactive protein was associated with increased tumour stage, interleukin-6 and interleukin-10 concentrations. However, resection of the primary tumour did not appear to be associated with significant normalisation of circulating concentrations of C-reactive protein, interleukin-6 or interleukin-10. Therefore, the presence of systemic inflammatory response is unlikely to be solely be determined by the tumour itself, but may be as a result of an impaired immune cytokine response in patients with renal cancer.

Bone marrow histology and flow cytometry (FCM) as staging procedures in follicular lymphoma (FL)

In chronic lymphocytic leukemia (CLL), the immunoglobulin heavy-chain variable (IgVH) region may be mutated (Ig-mutated CLL) or unmutated (Ig-unmutated CLL); and the presence or absence of mutations in this region of CLL cells distinguishes two clinically distinct forms. It is important for physicians to distinguish between patients with Ig-unmutated CLL, where typically have more indolent disease with median survivals close to 25 years, and Ig-mutated CLL, where have more aggressive disease with median survivals around eight years. In this work, a biosensor capable of diagnosis and distinguishing between these two types of CLL was reported. The biosensor was fabricated by modifying a gold electrode with gold nanoparticles (AuNPS) followed by coating of ZAP70 oligonucleotide probe on the surface to detect specific sequence of ZAP70 gene. ZAP70 could predict the IgVH mutation status and is a good marker for differentiating Ig-mutated and Ig-unmutated CLL and serve as prognostic marker. First, we focused on achieving hybridization between probe and its complementary sequence. Hybridization between probe and target was determined with electrochemical impedance spectroscopy (EIS). Then, our efforts turned to optimize the conditions for the detection of any point mutation and also to maximize the selectivity. Under optimal conditions, the biosensor has a good calibration range between 2.0×10−14 and 1.0×10−9 mol L−1, with ZAP70 DNA sequence detection limit of 4.0×10−15 mol L−1. We successfully detect hybridization first in synthetic samples, and ultimately in blood samples from patients. Experimental results illustrated that the nanostructured biosensor clearly discriminates between mutated and non-mutated CLL and predict the IgVH mutation status, which it has been considered as the single most informative stage independent prognostic factor in CLL.

Antineural and antinuclear autoantibodies are of prognostic relevance in non-small cell lung cancer

Background. Autoantibodies against nervous system structures have been proven to be a prognostic factor in small cell lung cancer. However, little is known about humoral autoimmunity in non-small cell lung cancer (NSCLC) and its prognostic significance.Methods. We examined antineural antibodies (AnAb) and antinuclear antibodies (ANA) in the sera of 61 patients with NSCLC (histologically: 29 adenocarcinoma, 32 squamous cell carcinoma). Twenty-one patients had stage I NSCLC, 11 stage II, and 29 patients stage III. Autoantibody detection was done by immunofluorescence test; Western blotting was used as a confirmation test.Results. Of the NSCLC patients, 27.8% were antineural antibody positive, and 32.7% had ANA. No differences were found between the histological groups. AnAb-positive patients showed a better survival in all patients (p = 0.005). There was also a higher survival of ANA-positive patients, but this was only significant in stage III (p = 0.0025). Cox regression analysis showed that antineural and antinuclear antibodies are a stage-independent prognostic factor in NSCLC.Conclusions. Antineural and antinuclear autoantibodies are a stage-independent prognostic factor in patients with NSCLC and may represent an effective immune response to the tumor.