Immunohistochemical expression of bcl-2 protein in squamous cell carcinoma and basaloid carcinoma of the esophagus

In the present study, the expression of bcl-2 protein in esophageal squamous cell carcinoma (SCC) and basaloid carcinoma (BC) was immunohistochemically examined, and its relation to tumor progression and postoperative survival was determined in SCC.A total of 42 SCC and 4 BC tumor samples were fixed with formalin, embedded in paraffin, and stained using monoclonal bcl-2 protein antibody, clone 124. Immunoreactivity was semiquantitatively scored, and the staining results were compared with the pathologic features and survival rates. The cytoplasm of basal cells from the normal esophageal epithelium was stained. In some well- and moderately differentiated SCCs, bcl-2 protein-positive reaction was observed in the peripheral part of the tumor cord, but in poorly differentiated SCC, the cells were weakly or hardly stained. However, in BC, the cells were strongly stained. The immunoreactivity was positive in 45.2% of the SCCs and all of the BCs. There were no significant differences in pathological features or patient survival between the bcl-2 protein-positive and protein-negative SCCs. In conclusion, the expression was not related to tumor progression and had no prognostic significance in SCC. Conversely, BC had strong immuno-histochemical expression, probably associated with the differentiation of carcinoma cells simulating the basal cells of the esophagus.     

Invasive Squamous Cell Carcinoma of the Skin: Defining a High-Risk Group

Background Unlike its more common non-invasive form, invasive squamous cell carcinoma (SCC) of the skin can be biologically aggressive and is prone to recur. The objectives of this study were to identify relevant clinicopathologic prognostic factors associated with the outcomes of patients with invasive SCC in order to define a high-risk group. Methods We retrospectively reviewed the records of patients with invasive cutaneous SCC of the trunk or extremities who received surgical treatment at a tertiary care cancer center over the past 10 years. We examined the patterns of presentation, all known clinical and histological risk factors for recurrence, and their association with survival. Results 136 patients were identified, of whom 102 (74%) were male. Patterns of presentation included primary (n = 91), locally recurrent (n = 16), regional nodal (n = 24), and distant (n = 5) disease. Univariate analysis identified poorly differentiated carcinomas (hazard ratio [HR] = 2.92, P = .016), scar carcinomas (HR = 3.12, P = .008), tumor size > 2 cm (HR = 3.79, P = .006), and regional nodal disease (HR = 5.77, P < .0001) as significant risk factors for recurrence or death. On multivariate analysis, however, only regional nodal disease at presentation (HR = 7.64, P < .0001) was found to be significant. Conclusions Patients with invasive SCCs metastatic to regional nodes constitute a group at high risk for recurrence and death. Such patients should be considered for adjuvant therapy trials.     

Immunohistochemical studies of vascular volume and proliferative activity in squamous cell carcinoma of the esophagus

For immunohistochemical investigation and clarification of the relationship between the vascular volume in esophageal carcinoma and the proliferative activity of its tumor cells, we examined surgical specimens of squamous cell carcinoma (SCC) of the esophagus from 15 patients. The vascular volume was evaluated by immunostaining for platelet-endothelial cell adhesion molecule-1 with monoclonal antibody JC70, and the proliferative activity of the carcinoma cells was evaluated by immunostaining for proliferating cell nuclear antigen (PCNA) with antibody 19A2. The ratio of the vascular area to the tumor area and the labeling index (LI) for PCNA in the carcinoma cells was then calculated. The antibody JC70 was useful for immunohistochemically detecting blood microvessels in esophageal carcinoma. The vascular volume, expressed as the ratio mentioned above, was higher in well-and moderately differentiated SCCs than in poorly differentiated SCC (P<0.01), and the PCNA LI did not depend on the degree of differentiation. However, there was a significantly inverse relationship between the ratio of the vascular area to that of carcinoma and the PCNA LI of the carcinoma cells (P<0.01). These findings show that angiogenesis is greater in esophageal carcinomas with little proliferative activity.     

HPV-Related Nonkeratinizing Squamous Cell Carcinoma of the Oropharynx: Utility of Microscopic Features in Predicting Patient Outcome

Human papilloma virus (HPV) is an etiologic agent in a subset of oropharyngeal squamous cell carcinomas (SCCs). The aim of this study was to sub-classify SCC of the oropharynx based upon histologic features into nonkeratinizing (NK) SCC, keratinizing (K) SCC, and hybrid SCC, and determine the frequency of HPV and patient survival in each group. Patients with oropharyngeal SCC with a minimum of 2 years of clinical follow-up were identified from radiation oncology databases from 1997 to 2004. All patients received either up front surgery with postoperative radiation or definitive radiation based therapy. In situ hybridization (ISH) for high-risk HPV subtypes and immunohistochemistry for p16, a protein frequently up-regulated in HPV-associated carcinomas, were performed. Overall and disease-specific survival were assessed. Of 118 cases, 46.6% were NK SCC, 24.6% K SCC and 28.8% hybrid SCC. NK SCC occurred in slightly younger patients that were more often male. It more frequently presented with lymph node metastases and was surgically resected compared to K SCC. NK SCC was significantly more likely to be HPV and p16 positive than KSCC (P < 0.001) and to have better overall and disease-specific survival (P = 0.0002; P = 0.0142, respectively). Hybrid SCC was also more likely than K SCC to be HPV and p16 positive (P = 0.003; P = 0.002, respectively) and to have better overall survival (P = 0.0105). Sub-classification of oropharyngeal SCC by histologic type provides useful clinical information. NK SCC histology strongly predicts HPV-association and better patient survival compared to K SCC. Hybrid SCC appears to have an intermediate frequency of HPV-association and patient survival.     

Role of fibroblast growth factor in squamous cell carcinoma of the bladder: Prognostic biomarker and potential therapeutic target

BackgroundWe evaluated the association of fibroblast growth factor (FGF2) expression with pathologic features and clinical outcomes of squamous cell carcinoma (SCC) of the urinary bladder.MethodsImmunohistochemistry of FGF2 was performed on radical cystectomy specimens with pure SCC from 1997 to 2003. The relationship between FGF2 and pathologic parameters and oncological outcome was assessed.ResultsThe study included 151 patients with SCC (98 men) with a median age of 52 years (range: 36–74 y). Schistosomal infection was found in 81% of patients. Pathologic category was T2 and T3 in 88% of patients and the grade was low in>50%. Lymph node invasion and lymphovascular invasion were found in 30.5% and 16%. Altered FGF2 was associated with tumor grade (P = 0.014), lymph node invasion, and lymphovascular invasion (P = 0.042). Altered FGF2 was associated with both disease recurrence and cancer-specific mortality (P≤0.001) in Kaplan-Meier analyses and was an independent predictor of cancer recurrence (hazard ratio = 2.561, P = 0. 009) and cancer-specific mortality (hazard ratio = 2.679, P = 0. 033) in multivariate Cox regression analyses. Adding FGF2 to a model including standard clinicopathologic prognostics (pathologic T category, lymph node status, and grade) showed a significant improvement (6%) in accuracy of prediction poor oncological outcome.ConclusionsFGF2 overexpression is associated with aggressive pathologic features and worse outcomes after radical cystectomy for SCC, suggesting a good prognostic and possible therapeutic role.     

Angiogenesis and skin carcinomas with skull base invasion: a case-control study

BACKGROUND: Some skin carcinomas may be very aggressive. Intensity of angiogenesis, measured by intratumoral vessel density using expression of CD34, has been associated with tumor aggressiveness. In this study, the expression of CD34 in basal cell carcinomas ( BCCs) and squamous cell carcinomas (SCCs) with skull base invasion was compared with that in tumors with good outcome. METHODS: Expression of CD34 was graded as mild, moderate, and intense, in 24 BCCs and 11 SCCs with skull base invasion. The control group included 23 BCCs and 10 SCCs. RESULTS: Intense expression of CD34 was noted in 25.00% of BCCs with skull base invasion, compared with 4.35% in the control group (p =.058). Regarding SCCs, intense expression of CD34 was found in 54.55% of aggressive tumors, compared with 10.00% in the control group (p =.133). CONCLUSIONS: A trend toward denser microvascular angiogenesis was observed in both BCCs and SCCs with skull base invasion compared with less aggressive controls.     

Expression of CD44 protein in bilharzial and non-bilharzial bladder cancers

OBJECTIVES: To investigate the expression of CD44 protein in bilharzial and non-bilharzial bladder carcinomas, and to relate the results of immunohistochemistry to the established prognostic factors, as studies clearly show that altered adhesive function of tumour cells is important in the metastatic process and CD44 is assumed to be critical in the malignant progression of many human tumours. PATIENTS AND METHODS: The study included 55 patients with bladder carcinoma confirmed by cystoscopy and biopsy. Of the 33 patients with transitional cell carcinoma (TCC), 19 were bilharzial and 14 non-bilharzial, and of 22 with squamous cell carcinoma (SCC), 12 were bilharzial and 10 non-bilharzial. CD44 expression was measured by immunohistochemical analysis of paraffin-embedded tissue obtained from these patients after appropriate treatment (transurethral resection, partial or radical cystectomy). RESULTS: There was significantly less CD44 expression in invasive TCC than in normal urothelium and pre-invasive TCC (P = 0.05). The expression of CD44 was inversely related to the tumour grade and depth of invasion (P = 0.05). However, there was no such relation for SCC; there was no significant difference between CD44 expression in metaplastic squamous epithelium, pre-invasive and invasive SCC. The presence or absence of bilharzial ova had no apparent effect on the expression of CD44, with no significant difference between CD44 expression in bilharzial and non-bilharzial bladder carcinomas. CONCLUSIONS: These data confirm that there is a reduction in CD44 expression with increasing tumour grade and stage of TCC, and may provide an additional aid in predicting the progression of this tumour. There was no such relationship with SCC, and no difference between CD44 expression in bilharzial and non-bilharzial bladder carcinomas.     

Multimodality treatments with endoscopic mucosal resection of esophageal squamous cell carcinoma with submucosal invasion

Background and study aims: A standard treatment for esophageal squamous cell carcinoma (SCC) with submucosal invasion is considered to be radical resection at present. In this study, we evaluated the efficacy of multimodality treatments with endoscopic mucosal resection (EMR) of esophageal SCC with submucosal invasion. Method: Eighteen cases of SCC with submucosal invasion were treated with EMR. Lymphatic invasion was found in 11 cases (67%), and there were no cases of blood vessel invasion. EMR was performed prior to any other treatment. Chemotherapy and/or radiotherapy were added if indicated by the histopathological features. Results: There were no cases of local recurrence. Lymph-node recurrence was detected in 1 case treated with EMR alone. There were no cases of cancer death. The overall survival rate was 83% in all patients.Conclusions: Multimodality treatments with EMR were effective in treating esophageal SCC with submucosal invasion.     

Clinical significance and prognostic value of apoptosis related proteins in superficial esophageal squamous cell carcinoma

Background: The purpose of the present study was to examine the expression of cell cycle regulators [p53, p21^WAF1/CIP1 (p21), and Rb] and apoptosis related proteins Bax and Bcl-X_L and to evaluate the relationship between their expressions and clinicopathological findings in patients with superficial squamous cell carcinomas of the esophagus.Methods: We immunohistochemically investigated the expression of p53, p21, Rb, Bax, and Bcl-X_L in 79 patients with superficial esophageal carcinoma.Results: p21 overexpression was found in mucosal carcinoma (P = 0.05) and a high Bcl-X_L score was observed for submucosal carcinoma (P = 0.03). The patients with high Bcl-X_L score had more frequent lymphatic invasion and lymph node metastasis than did those with low Bcl-X_L score (P < 0.05). Univariate analysis revealed significantly shorter survival in patients with high Bcl-X_L expression than in those with low Bcl-X_L expression, but Bcl-X_L expression was not identified as an independent prognostic factor by multivariate analysis.Conclusions: Because Bcl-Xl expression correlated well with depth of tumor invasion, lymphatic invasion, and lymph node metastasis, examination of Bcl-X_L expression will help to estimate the properties in superficial squamous cell carcinoma of the esophagus.     

Bladder Squamous Cell Carcinomas Express Psoriasin and Externalize it to the Urine

Purpose

To report a single biomarker, psoriasin (Mr 11.0 kd, pI 6.2), a calcium binding protein which is expressed largely by stratified squamous epithelia and is externalized to the urine of bladder squamous cell carcinoma (SCC) bearing patients.

Materials and Methods

Protein expression profiles of SCCs obtained immediately after surgery were analyzed by two-dimensional gel electrophoresis and Coomassie blue staining. Protein identity was determined by microsequencing and immunoblotting. Protein expression in cryosections was studied by immunofluorescence.

Results

Four patients with SCC were identified from 100 samples of patients with suspected transitional cell carcinoma (TCC). The protein profiles of the 4 SCCs (56-1, grade III, T4; 181-1, grade I, T3; 219-1, grade III, T3 and 239-1, grade not determined, T2-4) resembled that of keratinocytes, suggesting that these cells express an early developmental pattern of gene expression. Besides expressing markers characteristic of keratinizing stratified squamous epithelia, the SCCs exhibited psoriasin, a protein externalized to the medium by keratinocytes. Immunohistochemistry of 3 of the SCCs with psoriasin antibodies showed that the positive cells were confined chiefly to the “squamous pearls.” The presence of psoriasin in the urine of the 4 SCC patients was demonstrated by two-dimensional gel immunoblotting. Similar analysis of 43 urines from patients with bladder tumors other than SCC revealed 7 positives, some of which may reflect squamous differentiation. Analysis of the urine of 13 control individuals (12 males matched by age and a 42-year-old female) revealed 2 positives. Immunoblotting of the SCC patients' serum proteins with psoriasin antibodies failed to reveal the protein.

Conclusion

The results point towards psoriasin, alone or as part of a biomarker profile, as a potential marker for the noninvasive follow-up of patients with SCC.     

Hypercalcemia associated with parathyroid hormone-related protein at the terminal stage of uncomplicated squamous cell carcinoma in the head and neck region.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) is mainly responsible for hypercalcemia in squamous cell carcinomas (SCCs). METHODS: We retrospectively checked the appearance of hypercalcemia among 33 patients who died with head and neck SCC. Serum concentrations of C-terminal region of PTHrP (C-PTHrP) were measured in 15 of them. The intracellular PTHrP expression was immunohistochemically stained in 42 SCC sections obtained from the 33 before the appearance of hypercalcemia. RESULTS: Hypercalcemia appeared in 24 of the 33, and increased serum C-PTHrP levels were confirmed in 11 of 12 hypercalcemic patients. PTHrP was identified in all SCC sections, and a stronger intensity than in normal squamous epithelia was observed in 50% of those obtained within 1 year before the onset of hypercalcemia. CONCLUSION: A high incidence of PTHrP-induced hypercalcemia was shown among patients dying with head and neck SCCs. The intracellular increase in PTHrP might be observed preceding hypercalcemia.     

Inducible nitric oxide synthase expression in laryngeal neoplasia: correlation with angiogenesis.

BACKGROUND: The nitric oxide (NO) pathway plays a relevant role in angiogenesis and tumor progression in squamous cell carcinoma (SCC) of the head and neck. The aim of this study was to assess whether the NO pathway may be correlated with angiogenesis in the transition from laryngeal dysplasia to invasive carcinoma. METHODS: We investigated the expression of the inducible NO synthase (iNOS) in 26 laryngeal precancerous lesions and 35 squamous cell carcinomas with respect to microvessel density. In addition, we determined iNOS activity and cGMP levels in specimens from SCCs. RESULTS: There was a significant increase of iNOS levels detected immunohistochemically passing from hyperplastic/mild dysplastic to moderate/severe dysplastic lesions to SCC (p =.04). Accordingly, Northern and Western analyses demonstrated higher iNOS mRNA and protein levels in SCCs than dysplastic mucosa. iNOS expression was significantly correlated with microvessel counts both in the group of preneoplastic lesions (p =.02) and in the group of SCCs (p =.01). In addition, iNOS activity was correlated with iNOS immunohistochemical expression (p =.1) and was significantly associated with increased vascularization (p =.03) in SCCs. Similarly, iNOS expression was significantly correlated with cGMP levels in SCC (p =.02) and increased tumor vascularization correlated with higher cGMP levels (rs =.4; p =.01). CONCLUSIONS: Our data indicate that the NO pathway may play a relevant role in the angiogenesis associated with the progression from laryngeal dysplasia to laryngeal SCC.     

Expression of Human Leukocyte Antigen G (HLA-G) Correlates with Poor Prognosis in Gastric Carcinoma

Objective We had previously demonstrated that human leukocyte antigen G (HLA-G) was expressed in a majority of primary colorectal carcinomas and that the detection of HLA-G expression had a strong and independent prognostic value for that cancer. Currently, we investigate whether or not HLA-G is also expressed in patients with gastric carcinoma and whether the expression has any clinical application value. Methods The expression of HLA-G was investigated immunohistochemically in 160 patients with gastric carcinoma. The correlation between HLA-G status and various clinicopathological parameters was analyzed with the levels of HLA-G expression used to compare the survival length amongst patients. Results HLA-G protein expression was observed in 71% (113 of 160) of the primary site of gastric carcinomas, but not in the normal stomach tissues. HLA-G expression in the tumors was significantly correlated with the tumor location, histological grade, depth of invasion, lymph nodal metastasis, clinical stages of the disease, and host immune response (P = .012, .008, .001, .038, .030, and .016, respectively). Patients with HLA-G positive tumors had a significantly shorter survival time than those patients with tumors that were HLA-G negative (P = .001). As well, in multivariate analysis, HLA-G demonstrated an independent prognostic factor (P = .0001, relative risk 9.08; 95% confidence interval, 3.44–24.0). Conclusions Overall, our results indicated that the expression of HLA-G is a characteristic feature of gastric carcinoma and that immunostaining by anti-HLA-G antibody may be a potentially useful prognostic indicator.     

Maspin expression in stage I and II oral tongue squamous cell carcinoma.

BACKGROUND: A relatively high failure rate in the therapy of patients with early oral tongue squamous cell carcinomas (SCCs) is evidenced by untreated clinically negative neck lymph node metastasis. It is important to predict the malignant potential of oral tongue SCC in stage I and II patients, because the development of lymph node metastasis directly affects the prognosis of the patients. METHODS: We evaluated maspin expression immunohistochemically in patients with stage I and II oral tongue SCCs and determined whether the expression level may be a useful factor in predicting metastatic potential and prognosis of these SCCs. RESULTS: Clinical follow-up data showed a longer disease-free interval and overall survival periods for tumors immunohistochemically positive for maspin than for tumors negative for maspin, with the difference in disease-free interval being statistically significant (p =.01). The absence of maspin expression was found more frequently in cases of subsequent cervical lymph node metastasis than in cases without metastasis (p =.03). CONCLUSIONS: Decreased maspin expression may be a significant factor associated with the metastatic potential of stage I and II oral tongue SCCs.     

Improved Surgical Results in Thoracic Esophageal Squamous Cell Carcinoma: A 40-year Analysis of 792 Patients

Extensive lymphadenectomy, including upper mediastinum, for thoracic esophageal carcinoma was introduced at the beginning of 1980s. However, the efficacy has not been analyzed in large series at a single institute. We evaluated factors potentially related to improved surgical results in patients with thoracic esophageal squamous cell carcinoma (SCC). From 1959 to 1998, a total of 792 patients with thoracic esophageal SCC underwent R0 surgery. A variety of clinicopathological factors were compared among patients treated from 1990 to 1998 (recent group, n = 164) and 1959 to 1989 (former group, n = 628). The recent group showed significantly better survival than the former group (5-year survival rates: 51 versus 17%, P < 0.01), partly because earlier stage disease was included in the recent group than in the former group. Multivariable analysis, using the Cox regression analysis, indicated the time period of surgery, age, tumor location, the number of positive nodes (>5), venous invasion, and tumor–node–metastasis stage. Upper mediastinum lymphadenectomy was also an independent factor to improve survival of patients with thoracic esophageal SCC. Based on multivariate analysis of 792 cases during 40-years experience on thoracic esophageal cancer surgery at Chiba University Hospital, upper mediastinum lymphadenectomy was found to be one of the independent prognostic factors to improve patient’s overall survival.     

TGF-ALPHA IMMUNOREACTIVITY IN LARYNGEAL CARCINOMA: LACK OF PROGNOSTIC VALUE AND CORRELATION TO EGF-RECEPTOR EXPRESSION

Background : Transforming growth factor alpha (TGF-α) is a polypeptide that is structurally similar to epidermal growth factor (EGF) that binds to the epidermal growth factor receptor (EGFR) and has been implicated in the development of several types of human tumours. Methods : The expression of TGF-α is examined in laryngeal squamous cell carcinoma (SCC) (n= 24) and non-neoplastic polyps (n = 7) using streptavidin-biotin immunohistochemistry and a monoclonal antibody to the TGF-α protein. These cases had been previously characterized for EGFR immunoreactivity. The carcinomas were classified as well differentiated (n = 2). moderately differentiated (n = 16) and poorly differentiated (n= 6). Tissues from metastatic tumour deposits in lymph nodes (n = 5) were also studied. Results : TGF-α overexpression was defined as intense immunoreactivity in more than two-thirds of tumour cells immunostained for TGF-a and was present in the majority of the SCC cases (n= 15; 63%) and metastatic turnour deposits (n = 4; 80%). In contrast, although some of the vocal cord polyps showed weak (n= 2) to moderate (n = 5) immunostaining, none had evidence of strong TGF-a immunoreactivity. The differences in TGF-α immunoreactivity were significant between primary laryngeal SCC and vocal cord polyps (P= 0.013; x² test with continuity correction), and between metastatic laryngeal SCC and vocal cord polyps (P = 0.023; x² test with continuity correction). There was no significant difference in TGF-α expression between the different grades of carcinomas (P= 0.92, x² test) or between non-metastatic and metastatic carcinomas (P= 0.82; x² test with continuity correction). No significant correlation was found between TGF-α expression and patient survival or tumour recurrence (r = 0.077, r²= 0.006, P = 0.75; simple regression analysis), or between TGF-α expression and EGFR immunoreactivity (r = 0.325. r'= 0.106, P = 0.0851). Conclusions : In conclusion, increased TGF-α immunoreactivity is present in most cases of laryngeal SCC with no specific relationship to tumour grade, suggesting that it may be important in the development of laryngeal carcinomas but not in its progression. No significant correlation was found between TGF-a and EGFR expression in laryngeal tumours and TGF-a immunoreactivity is of no prognostic value.     

Prognostic value of apoptotic markers in squamous cell carcinoma of the urinary bladder

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Apoptotic pathways are important in carcinogenesis. Many studies, involving small numbers of patients, have found an association between one or two apoptotic markers and some of the pathological features of squamous cell carcinoma (SCC). This study included a large number of patients who had undergone radical cystectomy (RC) for SCC with long‐term follow‐up, allowing us to study biomarker alterations and their prognostic role. This is the first study on the prognostic role of a panel of apoptotic‐related markers in SCC of the urinary bladder, introducing the novel concept of a prognostic marker score based on the number of altered markers. We found that apoptotic markers can improve prediction of oncological outcomes after RC for SCC and might potentially help in patient selection for adjunct therapies.

OBJECTIVE

• ? To evaluate the association of cleaved caspase‐3 (CC‐3), Bax, COX‐2, and p53 expression with pathological features and clinical outcomes in patients with squamous cell carcinoma (SCC) of the urinary bladder.

METHODS

• ? Immunohistochemistry for CC‐3, Bax, COX‐2, and p53 was performed on tissue microarray sections of radical cystectomy specimens with pure SCC from 1997 to 2003. The relationship between the expression of these markers and pathological features was assessed.
• ? A prognostic marker score (PS) was defined as favourable if ≤2 biomarkers were altered and unfavourable if >2 biomarkers were altered and the association of the PS with oncological outcomes was examined.

RESULTS

• ? The study included 151 patients, of whom 98 were men and 53 were women, with a mean age of 52 years. SCC was associated with schistosomiasis (bilharziasis) in 122 (81%) patients.
• ? Pathological stage was T2 in 50%, T3 in 38%, T1 in 6% and T4 in 6% of patients. Tumours were low grade in 53%, lymph node metastasis was found in 30.5% and lymphovascular invasion was found in 16% of patients.
• ? Median follow‐up was 63.2 months.
• ? Advanced stage was associated with COX‐2, p53 and CC‐3 alterations and high grade was associated with COX‐2 alterations (P < 0.05). The total number of altered markers and unfavourable PS were associated with both disease recurrence and bladder cancer‐specific mortality in Kaplan–Meier analyses (P < 0.05). Unfavourable PS was an independent predictor of disease recurrence (hazard ratio [HR] 2.694, 95% confidence interval [CI] 1.386–5.235, P= 0. 003) and bladder cancer‐specific mortality (HR 2.868, 95% CI 1.209–6.802, P= 0. 017) in multivariable Cox regression analysis.

CONCLUSION

• ? Markers of apoptosis pathways may play an important role in the prognosis of SCC of the bladder. An increased number of altered markers and an unfavourable PS may identify patients who might benefit from multimodal therapies.

     

Prediction of Lymph Node Status in Superficial Esophageal Carcinoma

Background  Esophageal carcinoma is among the cancers with the worst prognosis. Real chances for cure depend on both early recognition and early treatment. The ability to predict lymph node involvement allows early curative treatment with less invasive approaches. Aims  To determine clinicohistopathological criteria correlated with lymph node involvement in patients with early esophageal cancer (T1) and to identify the best candidate patients for local endoscopic or less invasive surgical treatments. Methods  A total of 98 patients with pT1 esophageal cancer [67 with squamous cell carcinomas (SCC) and 31 with adenocarcinomas (ADK)] underwent Ivor–Lewis or McKeown esophagectomy in the period between 1980 and 2006 at our institution. Based on the depth of invasion, lesions were classified as m1, m2, or m3 if mucosal, and sm1, sm2, or sm3 if submucosal. Results  The rates of lymph node metastasis were 0% for the 27 mucosal carcinomas (T1m) and 28% for the 71 submucosal (T1sm) carcinomas (P < 0.001). Sm1 carcinomas were associated with a lower rate of lymph-node metastasis (8.3% versus 49 % sm2/3, P  = 0.003). As for histotype, the rates of lymph node metastasis for sm1 were 0% for ADK and 12.5% for SCC; for sm2/3 there were no significant differences. On multivariate analysis, depth of infiltration, lymphocytic infiltrate, angiolymphatic and neural invasion were significantly associated with lymph node involvement. Neural invasion was the single parameter with the greatest accuracy (82%); depth of infiltration and angiolymphatic invasion had 75% accuracy. Altogether these three parameters had an accuracy of 97%. Five-year survival rate was 56.7% overall: 77.7% for T1m and 53.3% for T1sm (P  = 0.048). Conclusions  The most important factors for predicting lymph node metastasis in early esophageal cancer are depth of tumor infiltration, angiolymphatic invasion, neural invasion and grade of lymphocytic infiltration. The best candidates for endoscopic therapy are tumors with high-grade lymphocytic infiltration, no angiolymphatic or neural invasion, mucosal infiltration or sm1 (only for ADK), and tumor <1 cm in size. For sm SCC and sm2/3 ADK the treatment of choice remains esophagectomy with standard lymphadenectomy.     

Hypermethylation of the thrombospondin-1 gene is associated with poor prognosis in penile squamous cell carcinoma

OBJECTIVE

To evaluate the presence of human papillomavirus (HPV) infection, the methylation status in the promoter region of thrombospondin‐1 (TSP‐1), RAS association domain family 1A (RASSF1‐A) and p16 genes, and the expression of TSP‐1, CD31, p16 and p53 proteins in patients diagnosed with penile cancer, and the possible associations between these variables and clinical and pathological features.

PATIENTS AND METHODS

HPV types, gene promoter hypermethylation and protein expression were analysed by reverse line blot, methylation‐specific polymerase chain reaction, and immunohistochemistry, respectively, in 24 penile squamous cell carcinomas.

RESULTS

HPV infection was detected in 11 of 24 cases (46%), and TSP‐1, RASSF1‐A and p16 genes were hypermethylated in 46%, 42% and 38% of the tumours, respectively. TSP‐1 hypermethylation was associated with unfavourable histological grade (grade 3; P = 0.033), vascular invasion (P = 0.023), weak expression of TSP‐1 protein (P = 0.041), and shorter overall survival (P = 0.04). TSP‐1 expression was not associated with microvessel density. However, RASSF1‐A hypermethylation was more frequent in T1 tumours (P = 0.01), and p16 hypermethylation was not associated with any of the tested variables except for absence of p16 expression (P = 0.022).

CONCLUSION

In summary, the epigenetic inactivation of TSP‐1 and RASSF1‐A genes is associated with pathological variables and seems to be of prognostic significance in penile cancer.