膀胱PUNLMP和低分级乳头状癌的生物学比较

目的:探讨膀胱低度恶性潜能的乳头状尿路上皮肿瘤(papillary urothelial neoplasms of low malignant potential,PUNLMP)和低分级乳头状癌[low-grade(grade1)papillary carcinomas,LG]的生物学差异。方法:统计两种肿瘤的2年复发率,并利用免疫组化的方法比较34例膀胱PUNLMP和46例LG的细胞增殖指标(Ki-67)和癌基因/抑癌基因(c-erbB-2、p53)的阳性表达率。结果:PUN-LMP的2年复发率及Ki-67和p53的阳性表达率低于LG,P值分别为0.020、0.001和0.003;而c-erbB-2的阳性表达率差异无统计学意义。结论:膀胱PUNLMP和LG在生物学行为和临床预后上有较明显的差异,但PUNLMP仍需要长期随访。     

Papillary urothelial neoplasms of low malignant potential. Clinical and biologic implications

BACKGROUND: Knowledge of the long term outcomes of patients with papillary urothelial neoplasms of low malignant potential (LMP) is limited. METHODS: The authors studied 112 consecutive patients who were diagnosed with papillary urothelial neoplasms of LMP (formerly Ta, World Health Organization Grade 1 of 3 papillary urothelial carcinoma) at the Mayo Clinic between 1958 and 1963. All histologic slides were reviewed and fulfilled the diagnostic criteria of the 1998 World Health Organization/International Society of Urological Pathology classification system. RESULTS: Patient age at diagnosis ranged from 33 to 99 years (mean, 65 years). The male-to-female ratio was 3:1. The mean follow-up was 12.8 years (range, 0.1-35 years; median, 11.7 years). Twelve patients had biopsy-proven, noninvasive urothelial carcinoma; 17 patients had cystoscopically detected recurrences (all were treated by fulguration without biopsy); and 4 patients developed invasive urothelial carcinoma (including 2 with muscle-invasive carcinoma). Twelve (75%) of 16 patients with biopsy-proven recurrence or progression had cancer dedifferentiation, which resulted in a diagnosis of higher grade cancer than was indicated on initial biopsies. The mean interval from initial diagnosis to development of invasive carcinoma was 13.3 years (range, 10-14 years). Three patients died of bladder cancer. CONCLUSIONS: Patients with papillary urothelial neoplasms of LMP have increased risks of local recurrence, progression, and death from bladder carcinoma. Long term clinical follow-up may be indicated for patient management.     

Laser capture microdissection analysis reveals frequent allelic losses in papillary urothelial neoplasm of low malignant potential of the urinary bladder

BACKGROUND: In the 1999 World Health Organization classification system, papillary tumors of the urinary bladder were classified as papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), and as Grade 1, Grade 2, and Grade 3 urothelial carcinoma. The biologic potential of PUNLMP of the urinary bladder is controversial. To the authors' knowledge, information regarding the genetic changes of PUNLMP tumors of the bladder is limited. METHODS: The authors examined loss of heterogygosity (LOH) at 5 polymorphic microsatellite markers on chromosome 9q32-33 (D9S177), 9p22 (IFNA), 17p13.1 (TP53), 12q14-24 (D12S1051), and 3p25-26 (D3S3050) from 26 patients who were diagnosed with PUNLMP tumors of the urinary bladder. Tumors were microdissected from sections prepared from formalin-fixed, paraffin-processed tissue specimens using laser capture microdissection. RESULTS: LOH was found in 21 of 26 (81%) patients with PUNLMP. The rate of LOH was 41% with D9S177, 32% with IFNA, 29% with TP53, 26% with D12S1051, and 44% with D3S3050. Allelic loss of multiple chromosome loci was often present in patients with PUNLMP tumors. CONCLUSIONS: Genetic changes that commonly occur in advanced bladder carcinoma (> or = pT2) are frequently found in PUNLMP of the urinary bladder.     

膀胱低度恶性潜能乳头状泌尿上皮肿瘤的病理和临床特征

目的：探讨膀胱低度恶性潜能乳头状泌尿上皮肿瘤（papillary urothelial neoplasm of low malignant potential，PUNLMP）的病理和临床特征。方法：回顾性分析了2003年—2006年收治的41例病理证实为PUNLMP的病例，选取同时期收治的28例乳头状瘤和51例乳头状泌尿上皮低级别癌作为对照。结果：在41例PUNLMP中，男31例，女10例，年龄33—87岁，平均61．6岁。其中复发6例（15％），复发时间平均为24．6个月，复发后病理没有进展。在4例多发的患者中，有2例（50％）复发。在28例乳头状瘤中，复发1例（4％），复发后病理没有进展。在51例低级别癌中，复发18例（35％），5例（10％）有进展，肿瘤的复发率在这3者之间差异有统计学意义（P=0．002）。结论：PUNLMP有其独特的病理和临床特点，用“低度恶性潜能”来取代“癌”这一称谓是恰当的，由于有较高的复发率，手术后应当长期随访。     

Cytokeratin expression patterns in low-grade papillary urothelial neoplasms of the urinary bladder

BACKGROUND: The differential expression patterns of cytokeratin 20 (CK20) and 34betaE12 antigen in low-grade papillary urothelial tumors of the bladder are discussed. METHODS: A retrospective study of 120 patients with low-grade papillary bladder tumors (45 neoplasms of low malignant potential and 75 low-grade WHO G1 carcinomas) was performed. All tumors were graded in accordance with the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) and 1999 WHO classifications. The mean follow-up was 76.6 months (range, 36-168 mos), considering for prognostic purposes the time to first recurrence, or relapse-free interval (RFI), and the total number of recurrent patients. Immunohistochemically, normal or abnormal CK20 and 34betaE12 antigen expression patterns were determined for each patient. CK20 (clone IT-Ks) and a high-molecular weight cytokeratin (clone 34betaE12) were the monoclonal antibodies used in the immunohistochemical study. RESULTS: Seventy-seven of 120 patients (64.2%) experienced a recurrence during follow-up. In recurrence prediction, the differential expression pattern of both cytokeratins showed a high sensitivity (76.6% for CK20 and 80.5% for 34betaE12 antigen) and a high positive predictive value (85.5% for CK20 and 75.6% for 34betaE12 antigen), although specificity was higher for CK20 (76.7%) than it was for 34betaE12 antigen (53.4%). Independent of adjuvant intravesical chemotherapy, these 2 markers showed a strong statistical correlation (p < 0.001) in univariate studies with both the prediction of disease recurrences and RFI. CONCLUSIONS: CK20 and 34betaE12 antigen have proved to be strong predictive markers of disease recurrences when considering different topographic expression profiles, and, in the authors' opinion, these profiles could be incorporated into follow-up clinicopathologic strategies.     

Expression of GLUT1 is associated with increasing grade of malignancy in non-invasive and invasive urothelial carcinomas of the bladder

Glucose Transporter 1 (GLUT1) belongs to the expanding mammalian facilitative glucose transporter family. Elevated GLUT1 protein expression has been observed in the majority of urothelial carcinomas, with various effects on clinicopathological parameters. Whereas malignant cells have an accelerated metabolism with increased energy requirements, the membranous expression of GLUTs is amplified. GLUT1 protein expression was evaluated in urothelial tumours of increasing grade of malignancy, supplemented by a tumour proliferation analysis. Particular attention was paid to non-invasive precursors of urothelial carcinoma. A total of 105 paraffin-embedded samples were classified (normal urothelium, low/high-grade papillary carcinoma, carcinoma in situ and invasive carcinoma). Grading and staging were conducted using the 1998 ISUP/2004 WHO criteria. The staining intensity of GLUT1 was assessed with a standard immunoreactive score (IRS). The Ki-67 index was assessed by counting positive nuclei in representative urothelial hot spots. Results showed that an increased GLUT1-IRS and mean count of Ki-67-positive cells were significantly associated with an increased grade of malignancy (p<0.0001), particularly in non-invasive tumours. GLUT1-IRS was significantly associated with a Ki-67-labelled proliferative fraction (p<0.0001). No significant association regarding tumour grade or stage was observed within the invasive carcinoma group. GLUT1 protein expression was found to be strongly correlated with increased malignant potential, particularly in non-invasive urothelial carcinomas. The increase of GLUT1 expression may reflect a preinvasive metabolic switch in terms of enhanced cell metabolism concomitant to known genetic alterations. A further increase in invasive carcinomas may be related to hypoxic conditions.     

Gene expression profiling of progressive papillary noninvasive carcinomas of the urinary bladder.

PURPOSE: The aim of the present study was to define gene expression profiles of noninvasive and invasive bladder cancer, to identify potential therapeutic or screening targets in bladder cancer, and to define genetic changes relevant for tumor progression of recurrent papillary bladder cancer (pTa). EXPERIMENTAL DESIGN: Overall, 67 bladder neoplasms (46 pTa, 3 pTis, 10 pT1, and 8 pT2) and eight normal bladder specimens were investigated by a combination of laser microdissection and gene expression profiling. Eight of 16 patients with recurrent noninvasive papillary bladder tumors developed carcinoma in situ (pTis) or invasive bladder cancer (> or = pT1G2) in the course of time. RNA expression results of the putative progression marker cathepsin E (CTSE) were confirmed by immunohistochemistry using high-throughput tissue microarray analysis (n = 776). Univariate analysis of factors regarding overall survival, progression-free survival, and recurrence-free survival in patients with urothelial bladder cancer was done. RESULTS: Hierarchical cluster analyses revealed no differences between pTaG1 and pTaG2 tumors. However, distinct groups of invasive cancers with different gene expression profiles in papillary and solid tumors were found. Progression-associated gene profiles could be defined (e.g., FABP4 and CTSE) and were already present in the preceding noninvasive papillary tumors. CTSE expression (P = 0.003) and a high Ki-67 labeling index of at least 5% (P = 0.01) were the only factors that correlated significantly with progression-free survival of pTa tumors in our gene expression approach. CONCLUSIONS: Gene expression profiling revealed novel genes with potential clinical utility to select patients that are more likely to develop aggressive disease.     

Prognostic value of computerized DNA analysis in noninvasive papillary carcinomas of the urinary bladder

DNA parameters and a DNA status index were calculated in cases of noninvasive urothelial papillary carcinomas and apparently normal urothelium. DNA feature analysis included the measurement of basic parameters as well as those related to DNA deviation. Normal urothelium had a diploid content with a few values between 2c and 4c. The papillary lesions in the three grades showed a progressive decrease in diploid nuclei and steadily increasing percentages of tetraploid ones. One case of grade 1 papillary carcinoma and some of grade 2 showed a small proportion of aneuploid cells; the proportion quintupled in grade 3. The values of parameters related to DNA deviation increased progressively in the three grades, numerically expressing the shift from diploidy. The DNA status index is a multiparameter classification in which a single number, ranging from 0.5 to 3.7, expresses the degree of DNA deviation from a non-proliferating diploid population. The cases of normal urothelium and of grade 1 had the lowest values, from 0.5 to 1.9, whereas grade 3 cases had the highest, from 2.2 to 3.7. The index values of grade 2 cases were partly intermediate and partly in the range of the neighboring grades. The DNA status index has a prognostic significance. In fact, associated lesions and recurrences were only observed in cases with index values over 2.0.     

Strong immunohistochemical expression of fibroblast growth factor receptor 3, superficial staining pattern of cytokeratin 20, and low proliferative activity define those papillary urothelial neoplasms of low malignant potential that do not recur

BACKGROUND: Papillary urothelial neoplasm of low malignant potential (PUNLMP) is a clinically significant lesion because recurrence occurs in approximately 35% of patients. To date, it is not possible to identify those cases that will recur based on conventional histopathologic assessment. The objective of the current study was to evaluate immunohistochemically tissue expression of fibroblast growth factor receptor 3 (FGFR3), cytokeratin 20 (CK20), and MIB-1 in nonrecurrent and recurrent PUNLMP. METHODS: FGFR3, CK20, and MIB-1 were investigated by immunohistochemistry (IHC) in 80 PUNLMP cases (41 nonrecurrent and 39 recurrent), in 4 cases of normal urothelium (NU), and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). Statistics included discriminant analysis. RESULTS: NU demonstrated a weak to moderate FRFG3 staining intensity, a superficial pattern of CK20 staining, and low proliferative activity. UC was found to have FGFR3 staining similar to NU, an abnormal CK20 expression, and high proliferative activity. The nonrecurrent PUNLMP group demonstrated strong FGFR3 intensity in 80.5% of the cases (vs 56.4% of the recurrent cases), a superficial CK20 staining pattern in 53.7% of the cases (vs 28.2% of the recurrent cases), and a percentage of MIB-1-positive nuclei below the median value of all the PUNLMP cases in 61% of the cases (35.9% in the recurrent cases). The differences were statistically significant. Discriminant analysis based on these 3 features demonstrated that 67.5% of cross-validated grouped PUNLMP cases were correctly allocated, with 73.2% of the nonrecurrent and 61.5% of the nonrecurrent cases being correctly classified. The specificity and sensitivity were 73.1% and 61.5%, respectively. CONCLUSIONS: Strong immunohistochemical expression of FGFR3, a superficial staining pattern of CK20, and a low proliferative activity define those papillary urothelial neoplasms of low malignant potential that do not recur.     

Depth of invasion is the most significant histological predictor of subclinical cervical lymph node metastasis in early squamous carcinomas of the oral cavity.

AIMS: Cervical node metastasis is the single most important prognostic factor in head and neck squamous carcinomas. Taking a homogenous patient population, applying stringent selection criteria, and standard pathological evaluation methods, this retrospective study aims to establish histological predictors of subclinical cervical node metastasis in early (T1-T2/N0) squamous carcinomas of the oral cavity, thereby identifying a subset of patients who are at an increased risk for cervical node metastasis. METHODS: Forty-eight previously untreated patients with clinically T1 or T2, and N0, squamous carcinomas of the oral cavity who were treated with primary excision of the tumour and elective neck node dissection were selected. Various histological factors including T size, gross and microscopic tumour depth and thickness, grade of differentiation, pattern of invasion, inflammatory response, perineural and lymphovascular invasion were studied. The statistical significance of various parameters as predictors of subclinical node metastasis was determined using logistic regression analysis. RESULTS: Of all the parameters studied, microscopic tumour depth and thickness were the only significant factors (P value=0.026 and 0.046, respectively) which correlated with cervical node metastasis, on univariate analysis. Tumour depth emerged as a single most significant predictor on multivariate analysis. Majority of patients with node metastasis had a tumour depth of more than or equal to 5 mm. CONCLUSION: Depth is the most significant predictor of cervical node metastasis in early squamous carcinomas of the oral cavity. Patients with a tumour depth of more than or equal to 5 mm are at an increased risk of harbouring node metastasis, hence should be taken up for elective node dissection.     

An epigenetic marker panel for recurrence risk prediction of low grade papillary urothelial cell carcinoma (LGPUCC) and its potential use for surveillance after transurethral resection using urine

By a candidate gene approach, we analyzed the promoter methylation (PM) of 8 genes (ARF, TIMP3, RAR-β2, NID2, CCNA1, AIM1, CALCA and CCND2) by quantitative methylation specific PCR (QMSP) in the DNA of 17 non-recurrent and 19 recurrent noninvasive low grade papillary urothelial cell carcinoma (LGPUCC) archival tissues. Among the genes tested, by establishing an empiric cutoff value, CCND2, CCNA1, NID2, and CALCA showed higher frequency of methylation in recurrent than in non-recurrent LGPUCC: CCND2 10/19 (53%) vs. 2/17 (12%) (p=0.014); CCNA1 11/19 (58%) vs. 4/17 (23.5%) (p=0.048); NID2 13/19 (68%) vs. 3/17 (18%) (p=0.003) and CALCA 10/19 (53%) vs. 4/17 (23.5%) (p=0.097), respectively. We further analyzed PM of CCND2, CCNA1, and CALCA in urine DNA from UCC patients including LGPUCC and controls. The frequency of CCND2, CCNA1, and CALCA was significantly higher (p<0.0001) in urine of UCC cases [38/148 (26%), 50/73 (68%) and 94/148 (63.5%) respectively] than controls [0/56 (0%), 10/60 (17%) and 16/56 (28.5%), respectively)]. Most importantly we found at least one of the 3 markers were methylated positive in 25 out of 30 (83%) cytology negative LGPUCC cases. We also explored the biological function of CCNA1 in UCC. Prospective confirmatory studies are needed to develop a reliable tool for prediction of recurrence using primary LGPUCC tissues and/or urine.     

Invasive and noninvasive implants in ovarian serous tumors of low malignant potential

Ovarian serous tumors of low malignant potential ("borderline" serous tumors) are classified according to the histologic features of the primary ovarian tumor, without regard to any coexisting extraovarian disease. The peritoneal implants display a range of histologic appearances, ranging from benign glands (endosalpingiosis), to noninvasive papillary glandular proliferations resembling the ovarian neoplasms, to irregular glands associated with a desmoplastic stroma and having features of invasive disease. This review of 16 patients with histologically documented extraovarian tumor implants seen at Indiana University Medical Center, Indianapolis, and 13 patients whose tumor implants have been previously described in the literature indicates that the clinical stage of disease has much greater prognostic significance than does the implant histologic features. There is a tendency for patients with more advanced disease to have invasive implants. However, within a given clinical stage, disease progression or recurrence was not influenced by the presence or absence of invasive histologic characteristics in the tumor implants.     

Allelic loss of chromosome 17p distinguishes high grade from low grade transitional cell carcinomas of the bladder

Forty-three transitional cell carcinomas of the bladder of differing grades and stages were examined for reduction to homozygosity for chromosomes 9q, 11p, and 17p. Allelic loss of chromosome 9q was seen in 24 of 38 informative grades II, III, and IV tumors providing further evidence for a bladder tumor suppressor gene on this chromosome. In contrast to the grade-independent involvement of chromosome 9q, allelic losses of chromosomes 11p and 17p were seen only in grade III and IV tumors. The results with chromosome 17p were particularly striking and showed that 0 of 10 grade II versus 20 of 31 grade III and IV tumors had allelic losses for this chromosome harboring the p53 tumor suppressor gene often mutated in other human cancers. The data suggest that cumulative genetic damage is sustained in transitional cell carcinomas and that one of the underlying molecular mechanisms distinguishing low grade from high grade tumors involves chromosome 17p.     

High level of galectin-1 expression is a negative prognostic predictor of recurrence in laryngeal squamous cell carcinomas

Monitoring of gene-expression profiles is assumed to refine tumor characterization of laryngeal squamous cell carcinomas (LSCCs) with a therapeutic perspective. This is especially expected for adhesion/growth-regulatory effectors such as galectins, a class of endogenous lectins. Using computer-assisted microscopy, we investigated the prognostic value contributed by the quantitative determination of the immunohistochemical levels of expression of galectin-1, -3 and -7 in a series of 62 LSCCs including 42 low- and 20 high-stage LSCCs. As galectin-1 may have a key role leading to a tumor escape from immune surveillance, we also investigated whether or not the level of galectin-1 expression correlated with lymphocyte infiltration in LSCCs. The immunohistochemical determination of expression of galectin-1 is of prognostic value in human squamous laryngeal cancers. LSCCs that display high levels of galectin-1 have worse prognoses than laryngeal cancers with low levels of galectin-1 expression. Elevation of galectin-1 levels in laryngeal cancers can contribute to the process of tumor immune escape by killing the activated T-cells and other protumoral activities such as promoting motility or activity of oncogenic H-Ras proteins. The quantitative determination of galectin-1 in LSCCs is an independent prognostic marker when opposed to TNM staging. It has the potential to identify patients unlikely to benefit from T-cell-mediated immunotherapy, although the definitive effector function from its pro- and antitumoral activity profile has not been delineated.     

Neovascularisation is a prognostic factor of early recurrence in T1/G2 urothelial bladder tumours.

BACKGROUND: Of patients with superficial bladder cancer, a group are still at risk of disease recurrence, progression and death from their cancer after curative treatment. Angiogenesis is a crucial pathogenic mechanism for this type of urothelial cell carcinoma (UCC), and is a potential therapeutic target. However, the selection of the appropriate patients remains a dilemma. PATIENTS AND METHODS: Vascular endothelial growth factor (VEGF) expression and the presence of angiogenesis and occurrence of CD31, CD34, endoglin and factor VIII immunoexpression, were evaluated in 66 superficial papillary UCCs of the bladder and were correlated with classical histopathological factors and disease outcome. RESULTS: VEGF immunoreactivity was observed in 100% of cases, and more intensely in the luminal surface. The presence of microvessel clusters independently of a fibrovascular core was observed in 22.7% of cases. Of these, the T1/G2 subgroup had an independent and significantly lower recurrence-free survival (P = 0.0002). CONCLUSIONS: These results indicate that the presence of angiogenesis in tumour urothelium is a potential prognostic factor in superficial UCC, particularly in T1/G2 tumours, and may be used to select patients for anti-angiogenic treatments.     

Dominant papillary subtype is a significant predictor of the response to gefitinib in adenocarcinoma of the lung.

PURPOSE: Gefitinib (IRESSA; AstraZeneca, Osaka, Japan) shows excellent antitumor activity against advanced non-small-cell lung cancer, especially for the treatment of adenocarcinoma. However, the predictive factors for the response to gefitinib are still controversial. The aim of this study was to identify the clinicopathological and immunohistochemical features that are favorable to the use of gefitinib in adenocarcinoma patients. EXPERIMENTAL DESIGN: Between June 2002 and October 2003, 36 adenocarcinoma patients who experienced a relapse after surgical resection were treated with gefitinib at our hospital. The histologic patterns of the tumors were divided into four distinctive subtypes according to the revised World Health Organization histologic classification, and the dominant histologic subtype for the maximum cut surface of each resected specimen was documented. Association between the response to gefitinib and the clinicopathological features or immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, or c-erbB-2 were then investigated. RESULTS: A significant association between the response to gefitinib and dominant papillary subtype findings was observed (P = 0.0021); the survival time of papillary subtype patients was also significantly prolonged compared with that of non-papillary subtype patients (P = 0.03). No other clinicopathological features or the expression of EGFR, phosphorylated EGFR, or c-erbB-2 were associated with the response to gefitinib. CONCLUSIONS: The results of the present study indicate that dominant papillary subtype findings of lung adenocarcinomas can be an important predictor of the response to gefitinib. Thus, this type of adenocarcinoma might be susceptible to postoperative adjuvant treatment with gefitinib.     

Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patients

Although multiple myeloma (MM) is predominantly a disease of the elderly, few studies have focused on the identification of prognostic factors in this group of patients. Four hundred twenty five MM patients >65 years were uniformly treated with chemotherapy (MP or VCMP/VBAD). Multivariate analysis identified 4 factors with independent unfavorable prognostic influence: high percentage of S-phase bone marrow plasma cells (>2.5%); elevated beta(2) microglobulin (B2M) (>4 mg/L); age >80 years old; and LDH serum levels (above normal limit). The S-phase value was the most powerful independent prognostic factor to discriminate subgroups of patients with different prognosis. Thus, 3 main risk categories could be identified according to S-phase values: 3%, with median survivals of 34, 22 and 12 months, respectively (p < 0.0001). Our study also proved the value for elderly patients of the recently developed International Score System (ISS) based on B2M and albumin. Furthermore, the number of S-phase cells helped to subdivide the ISS III Group identifying a subset of patients with very poor prognosis defined by an additional high S-phase, who displayed a median survival of only 8 months. These results demonstrate that elderly patients can be accurately classified according to prognosis, which may be particularly valuable when comparing the efficacy of new treatment strategies. Moreover, our results underline the high prognostic value of proliferative activity of PC, a parameter that should be considered in routine laboratory investigations of MM.