Histological Prognostic Parameters Research Articles

1H MR Spectroscopy of Invasive Ductal Carcinoma: Correlations With FDG PET and Histologic Prognostic Factors

The purpose of this article is to assess the histologic prognostic relevance of choline levels obtained using (1)H MR spectroscopy with a 1.5-T MR unit in patients with invasive breast cancer and to compare the observed choline levels with the standardized uptake value obtained using FDG PET. Single-voxel (1)H MR spectroscopy and PET/CT were performed for 50 patients with invasive ductal carcinoma (1.5-3 cm in size). The normalized choline signal was calculated using an external standard method. Proton MR spectroscopy detected the presence of choline in 44 cases. The average normalized choline signal was 1.1 (range, 0-3.9). The average standardized uptake value was 6.5 (range, 1.1-23). The correlation (r) between the normalized choline signal and the standardized uptake value was 0.52 (p < 0.0001). The normalized choline signal was significantly correlated with nuclear grade (p = 0.0002), triple-negative breast cancer status (p = 0.0009), and estrogen receptor negativity (p = 0.007). The standardized uptake value was significantly correlated with nuclear grade (p = 0.0002), estrogen receptor negativity (p = 0.002), and triple-negative breast cancer status (p = 0.009). No significant differences were found between the progesterone receptor-positive and negative groups or between the human epidermal growth factor receptor 2-positive and negative groups. The choline levels obtained using (1)H MR spectroscopy with a 1.5-T unit were well correlated with the standardized uptake value obtained using PET/CT and with the histologic prognostic parameters (nuclear grade, estrogen receptor status, and triple-negative lesion status).

Prostate Tissue Composition and MR Measurements: Investigating the Relationships between ADC, T2,Ktrans,ve, and Corresponding Histologic Features

To investigate relationships between magnetic resonance (MR) imaging measurements and the underlying composition of normal and malignant prostate tissue. Twenty-four patients (median age, 63 years; age range, 44-72 years) gave informed consent to be examined for this research ethics board-approved study. Before undergoing prostatectomy, patients were examined with T2-weighted, diffusion-weighted, T2 mapping, and dynamic contrast material-enhanced MR imaging at 1.5 T. Maps of apparent diffusion coefficient (ADC), T2, volume transfer constant (K(trans)), and extravascular extracellular space (v(e)) were calculated. Whole-mount hematoxylin-eosin-stained sections were generated and digitized at histologic resolution. Percentage areas of tissue components (nuclei, cytoplasm, stroma, luminal space) were measured by using image segmentation. Corresponding regions on MR images and histologic specimens were defined by using anatomically defined segments in peripheral zone (PZ) and central gland tissue. Cancer and normal PZ regions were identified at histopathologic analysis. Each MR parameter-histologic tissue component pair was assessed by using linear mixed-effects models, and cancer versus normal PZ values were compared by using nonparametric tests. ADC and T2 were inversely related to percentage area of nuclei and percentage area of cytoplasm and positively related to percentage area of luminal space (P < or = .01). These trends were reversed for K(trans) (P < .001). K(trans) had a significantly negative (P = .01) slope versus percentage area of stroma, and v(e) had a positive (P = .008) slope versus percentage area of stroma. The v(e) was inversely proportional to the percentage area of nuclei (P = .05). All MR imaging parameters (P < or = .05) and the percentage areas of all tissue components (P < or = .001) except stroma (P > .48) were significantly different between cancer and normal PZ tissue. MR imaging-derived parameters measured in the prostate were significantly related to the proportion of specific histologic components that differ between normal and malignant PZ tissue. These relationships may help define imaging-related histologic prognostic parameters for prostate cancer.

Thrombospondin 1 expression and angiogenesis in breast carcinoma and their relation with platelet activity

This study investigates angiogenesis and the expression of thrombospondin 1 in invasive ductal carcinoma of the breast and their possible relation to platelet counts and platelet activity. The study included 20 cases of invasive ductal carcinoma. Platelet activity was evaluated by determining thromboxane B2 and cyclic guanosine monophosphate (cGMP) levels by enzyme immunoassay (EIA).Thrombospondin (TSP) 1 and CD34 expression was studied immunohistochemically. Mean platelet count of the patient group was significantly greater than the mean platelet count of the control group (P < 0.05). The platelet counts were positively correlated with tumour size (r=0.609; P < 0.01). Platelet counts were higher in the patients who had grade 3 microvessel density (P < 0.05). The mean basal platelet cGMP level in the patient group was significantly lower than it was in the control group (P < 0.05). Focal TSP immunoreactivity was detectable in 5 (20%) cases in the tumour cells, and in 9 (45%) cases in the stroma. We did not find any correlation between TSP-1 staining and angiogenesis, platelet counts, platelet activity, and the histological prognostic parameters. Our study confirms the essential role of platelets in tumour growth and angiogenesis. Decreased levels of cGMP in the patient group may cause platelet hyperreactivity. Although thrombospondin 1 may be upregulated in malignant breast tissue, this is not sufficient for tumour growth and dissemination according to our results.

Serum YKL-40 is elevated in a subgroup of patients after surgery for stage IIb-III melanoma

8574 Background: High serum YKL-40 is associated with poor prognosis in patients with adeno- and squamous cell carcinoma, glioblastoma, and stage I-II and IV melanoma. YKL-40 is secreted by cancer cells, macrophages and neutrophils. YKL-40 is a growth and differentiation factor, and plays a role in tissue remodelling and angiogenesis. The aim of our study was to compare serum YKL-40 in patients after surgery for stage IIb-III melanoma with healthy individuals and with clinical and histological prognostic parameters. Methods: YKL-40 was determined by ELISA (Quidel, CA) in serum samples from 231 patients, with stage IIb-III melanoma. The 74 women and 157 men had a median age of 50 (range 22–76 years), and they were enrolled in a Nordic adjuvant protocol, randomizing to observation or interferon therapy (1 or 2 years). Baseline samples were drawn &lt;70 days after primary biopsy, but prior to start of therapy. Results: Serum YKL-40 was increased (p=0.003) in the 231 patients (median 47 μg/l, range 20–1,416 μg/l) compared to healthy individuals (43 μg/l, range: 20–184 μg/l, n=245). Serum YKL-40 was higher than the age-corrected 95th percentile of s-YKL-40 in healthy individuals in 19% of the patients with melanoma thickness &gt;4 mm and no lymph node metastasis (n=27), in 8% with sentinel lymph node metastasis (n=89) and in 14% with clinical lymph node metastasis at time of surgery or as recurrence in the follow-up period (n=111). Comparison of serum YKL-40 in the 3 groups showed no significant differences (p=0.22). No difference was found comparing serum YKL-40 between the three groups of Breslow thickness (&lt; 1 mm, 1–2 mm, &gt; 2 mm)(p=0.66), and the two groups of Clark′s level (II-III, IV-V)(p=0.88) was found. A weak association (p=0.045) was found between s-YKL-40 and localization of primary tumor, with trunc having the highest median concentration of s-YKL-40. No association between an elevated s-YKL-40 with number of positive lymph nodes (0.36), ulceration (p=0.81), extranodal growth (p=0.56), or histologic subtype of primary tumor (p=0.48) was observed. Conclusion: Serum YKL-40 is elevated in a subgroup of melanoma patients with stage IIb-III and not associated with classical clinical and histological parameters. It is not known if the increased YKL-40 reflects the biological behaviour of the disease. No significant financial relationships to disclose.

Expression and possible role of hPTTG1/securin in cutaneous malignant melanoma

Human pituitary tumour-transforming gene 1 or hPTTG1 is a proto-oncogene that codes for securin, a protein involved in sister chromatid separation. Based on previous microarray data, we studied the expression of hPTTG1/securin in melanocytic lesions. In contrast to nevi and radial growth phase melanomas, securin was expressed by scattered cells in the vertical growth phase, suggesting a role in tumour progression. In a series of 29 nodular and 29 superficial spreading melanomas, matched for all histological prognostic parameters, securin expression was significantly correlated with the nodular subtype (P=0.018) and not related to thickness. In other cancers, hPTTG1 is involved in various oncogenic pathways, including induction of neovascularisation and aneuploidy, and inhibition of p53 activity. We found coexpression of securin with wild-type p53 in the same neoplastic cells in a minority of melanomas. Expression of securin was significantly correlated with the extent of aneuploidy but not with basic fibroblast growth factor immunoreactivity or microvessel density. DNA cytometry revealed that nuclei-overexpressing securin frequently showed tetraploidy or aneuploidy. Our data show that hPTTG1 is frequently overexpressed in nodular melanoma, and suggest that hPTTG1 may act as an oncogene in the vertical growth phase, either by inhibiting anaphase, thereby causing aneuploidy and genomic instability, or by modulating the function of p53, thereby impairing apoptosis.

Important prognostic histological parameters for patients with invasive ductal carcinoma of the pancreas

For clinicians, the orthodox histological investigation of patients with invasive ductal carcinoma (IDC) remains important for predicting prognoses. The purpose of the present study was to determine the most important of the known prognostic histological parameters (including fibrotic focus and tumor necrosis), enabling the outcomes of 101 patients with IDC of the pancreas to be predicted accurately. Furthermore, we established a scoring classification consisting of important prognostic histological parameters examined in this study. Multivariate survival analyses showed that invasive tumor size of more than 3 cm, the presence of tumor necrosis, the presence of nerve plexus invasion and lymph vessel invasion scores of 2 or 3 were important prognostic factors. Our scoring classification, consisting of the above four parameters, accurately classified the outcome of patients independent of the invasive tumor size of IDC. We concluded that invasive tumor size of 3 cm or more, the presence of tumor necrosis, the presence of nerve plexus invasion and lymph vessel invasion scores of 2 or 3 are important histological prognostic parameters for patients with IDC of the pancreas. Furthermore, the scoring system consisting of the above four histological parameters is probably a very useful prognostic histological classification for patients with IDC of the pancreas.

Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer

Extracellular-regulated kinases (ERK1, ERK2) are members of the MAPK signaling pathway, which are phosphorylated in response to extracellular stimuli and translocate to the nucleus where they can activate nuclear transcription factors. Although they have been extensively studied in vitro, little is known about their role in the behavior of tumor cells in vivo. In our present study, 148 clinical breast cancer samples (120 cases with follow-up) were studied for expression of ERK1 and ERK2 and their phosphorylated forms (p-ERK1, p-ERK2) by immunoblotting, and p-ERK1/2 expression in the corresponding paraffin sections was analyzed by immunohistochemistry (IHC). The results were correlated with clinical and histological prognostic parameters, follow-up data, and expression of 7 cell-cycle regulatory proteins which had been analyzed before. High p-ERK1 expression as determined by immunoblots correlated significantly with a low rate of recurrences or fatal outcome (p=0.007 and 0.008) and was an independent indicator of long relapse-free and overall survival in multivariate analysis. By IHC, strong p-ERK staining was associated with early stages (p=0.020), negative nodal status (p=0.003) and long recurrence-free survival (p=0.017). In contrast, expression of the unphosphorylated kinases was not associated with clinical and histological parameters except a positive correlation with estrogen receptor status. Comparison with the expression of cell-cycle proteins corroborates our conclusion that activation of ERK1 and ERK2 is not associated with enhanced proliferation of mammary carcinomas, but might be a new predictor of a favourable prognosis.

Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer

Extracellular-regulated kinases (ERK1, ERK2) play important roles in the malignant behaviour of breast cancer cells in vitro. In our present study, 148 clinical breast cancer samples (120 cases with follow-up data) were studied for the expression of ERK1, ERK2 and their phosphorylated forms p-ERK1 and p-ERK2 by immunoblotting, and p-ERK1/2 expression in corresponding paraffin sections was analysed by immunohistochemistry. The results were correlated with established clinical and histological prognostic parameters, follow-up data and expression of seven cell-cycle regulatory proteins as well as MMP1, MMP9, PAI-1 and AP-1 transcription factors, which had been analysed before. High p-ERK1 expression as determined by immunoblots correlated significantly with a low frequency of recurrences and infrequent fatal outcome (P=0.007 and 0.008) and was an independent indicator of long relapse-free and overall survival in multivariate analysis. By immunohistochemistry, strong p-ERK staining in tumour cells was associated with early stages (P=0.020), negative nodal status (P=0.003) and long recurrence-free survival (P=0.017). In contrast, expression of the unphosphorylated kinases ERK1 and ERK2 was not associated with clinical and histological prognostic parameters, except a positive correlation with oestrogen receptor status. Comparison with the expression of formerly analysed cell-cycle- and invasion-associated proteins corroborates our conclusion that activation of ERK1 and ERK2 is not associated with enhanced proliferation and invasion of mammary carcinomas.

Prognostic significance of flow cytometric deoxyribonucleic acid analysis for patients with superficial bladder cancers: a long-term follow-up study.

Flow cytometric DNA ploidy analysis for human bladder cancers may provide significant diagnostic and prognostic potential. We have previously reported that combined use of histologic and flow cytometric parameters may offer additional information regarding the clinical outcome for bladder cancer patients. However, the evaluation included both superficial and muscle-invasive tumors. In the present manuscript, we present our study on whether flow cytometric determination yields significant prognosticators beyond the classical histologic evaluation only in the patient with superficial bladder cancer. A total of 217 patients with untreated bladder cancer were evaluated, using fresh bladder tumor specimens. Tumor grading (grade 1, 2, and 3) and stage (pTa + pT1a and pT1b) served as the histologic prognostic parameters. Multiple flow cytometric parameters assessed included DNA index, percentage S-phase cells, percentage G2/M-phase cells, and hypertetraploid cell presence. Multivariate survival analysis was performed using the SAS proportional hazard regression procedure to study statistical individual prognostic values of both the histologic and the flow cytometric parameters. Clinical follow-up of more than 60 months was required, with the mean follow-up being 116.3 +/- 18.6 months. Hypertetraploid cell presence was the single most important prognostic factor (p < 0.01; risk ratio: 14.3), with the second being tumor grade (p < 0.05; risk ratio: 4.6). No other parameters, including tumor stage, the DNA index, and cell phase fractions, contributed to the model. These results indicate that hypertetraploid cell presence found by flow cytometric determination may provide additional information regarding the clinical outcome for superficial bladder cancer patients, and can be used as an indicator for decision making in treatment of superficial bladder cancer patients.

Histological prognostic parameters for adenocarcinoma of the pancreatic head. Proposal for a scoring system for prediction of outcome

To find new histopathological prognostic parameters for adenocarcinoma of the pancreatic head, 27 of these carcinomas, at stage IV according to the Japan Pancreas Society, which had been curatively resected, were histologically examined. In addition to previously recognized histological prognostic parameters, sections were examined for the following factors: fibrotic focus (FF), direct invasion of the tumor into the lymph node (DILN), and tumor necrosis (TN). Frequency of tumor recurrence or death was higher in patients with any one of the three new factors than in those without any of these factors. To develop an accurate system for predicting the outcome, the presence or absence of each factor and lymphatic permeation was given a score of 1 (present) or 0 (absent), and the total score was than calculated for each patient. All patients with a score of 0 were alive without tumor recurrence, at a mean follow-up of 20 months, whereas all seven patients with a score of 4 had experienced tumor recurrence, and six died subsequently. The results of this study demonstrated that FF, DILN, and TN are good histological parameters of ductal adenocarcinoma of the pancreatic head, and that the scoring system proposed in this paper is useful for prediction of the outcome of the disease.

Cytokeratin and vimentin expression in primary and recurrent carcinoma of the vulva: correlations with prognostic factors and the course of disease.

Radical vulvectomy for the treatment of a vulvar carcinoma inevitably entails severe psychosexual consequences for the patients. Thus, for such tumors, reliable histological prognostic parameters are needed to allow; when appropriate, the use of less radical operative measures. One possible approach to this problem might be to examine tumors immunohistochemically for the presence of cytoskeletal components. To assess the utility of this method, we applied a panel of antibodies directed against cytokeratins (CKs) and vimentin to a groups of vulvar carcinomas (62 primary and 35 recurrent tumors) and examined the results for possible correlations with the course of disease and various clinical parameters. all of the investigated CKs typical of squamous epithelia had no prognostic relevance. In contrast, the present of CKs typical of glandular differentiation as well as vimentin, suggesting early dedifferentiation, resulted in a less favorable prognosis. Thus, the procedures applied in the present study may have a role to play a decisions concerning the appropriate therapy for such tumors.

Prognostic Significance of Bromodeoxyuridine High Labeled Bladder Cancer Measured by Flow Cytometry: Does Flow Cytometric Determination Predict the Prognosis of Patients with Transitional Cell Carcinoma of the Bladder

We studied whether flow cytometric determination of proliferative cell activity estimated by the bromodeoxyuridine in vitro labeling technique provides significant prognosticators beyond the classical histological evaluation in the patient with bladder cancer. We evaluated 81 patients with transitional cell carcinoma of the bladder using fresh bladder specimens. Clinical followup of at least more than 24 months was requested, with the mean followup being 37.9 ± 10.5 months. Tumor grade and stage were the histological prognostic parameters. Flow cytometric bivariate measurements of deoxyribonucleic acid (DNA) ploidy and bromodeoxyuridine labeled cell index were evaluated. Tumors with a bromodeoxyuridine labeled cell index of more than 10.7%, which was the value of the mean plus 2 times the standard deviation obtained in grade 1 bladder tumors, were designated as high bromodeoxyuridine labeled cell index tumors. A total of 51 patients with low bromodeoxyuridine labeled cell index tumors demonstrated a 98.0% 3-year actuarial survival rate estimated by the Kaplan-Meier method, compared to 42.9% for those with high index tumors. Multivariate survival analysis was performed with Cox’s proportional regression model to study statistical individual prognostic values of histological and flow cytometric parameters. Histological tumor grade was the single most important prognostic factor (risk ratio 13.2, p <0.05), with tumor stage being the second most important (risk ratio 9.2, p <0.05), followed by bromodeoxyuridine labeled cell index status (risk ratio 6.9, p <0.05). DNA ploidy status did not influence the clinical outcome. When grade 3 tumors were classified as low and/or high bromodeoxyuridine labeled cell index tumors, 3-year actuarial survival rates were 85.7% and 27.3%, respectively. These results indicate that DNA/bromodeoxyuridine bivariate analysis can be used as an effective adjunct to histological examination for prognostication and decision-making in treatment of bladder cancer patients.

Multivariate Analysis of Flow Cytometric Deoxyribonucleic Acid Parameters and Histological Features for Prognosis of Bladder Cancer Patients

We studied whether flow cytometry provides significant prognosticators beyond the classical histological evaluation in the patient with bladder cancer. A total of 203 patients with untreated bladder cancer was evaluated using fresh bladder tumor specimens. Tumor grading and stage were the histological prognostic parameters. Deoxyribonucleic acid (DNA) index, percentage S-phase cells, percentage G2/M-phase cells and hypertetraploid cell presence were assessed as flow cytometric prognostic parameters. Multivariate survival analysis was performed using Cox’s proportional regression model to study statistical individual prognostic values of histological and flow cytometric parameters. Hypertetraploid cell presence was the single most important prognostic factor (p <0.01), with tumor grade being nearly as important (p <0.01), followed by tetraploidy (p <0.01) and tumor stage (p <0.05). No other parameters, including the DNA index or cell phase fractions, contributed to the model. These results indicated that combined use of histological and flow cytometric parameters may provide additional information regarding the clinical outcome for bladder cancer patients.