Preoperative Diagnostic Strategy for Parotid Gland Tumors Using Diffusion-Weighted MRI and Technetium-99m Pertechnetate Scintigraphy: A Prospective Study

Objective

Fine needle aspiration cytology (FNAC) for diagnosis of a parotid gland tumor is widely used but its sensitivity is low and non-diagnostic rate is relatively high. In contrast, core needle biopsy (CNB) has a higher sensitivity and lower rate of sampling errors but has a higher risk of injury to adjacent organs such as facial nerve than FNAC. Screening of patients with parotid gland tumors to identify cases of pleomorphic adenoma (PA) and Warthin tumor (WT) may allow CNB to be confined to patients without PA and WT. We established an algorithm for preoperative diagnosis and management of parotid gland tumor using diffusion-weighted MRI and ^99mTc pertechnetate scintigraphy. This algorithm was developed with the goal of maximal reduction of the number of patients in whom CNB is required. The purpose of the study is to validate our algorithm prospectively.

Methods

A prospective study was conducted in 71 cases who were newly diagnosed with parotid gland tumor and 53 cases were enrolled in the study. In the algorithm, PA (high apparent diffusion coefficient (ADC) _mean≥1.5×10⁻³ mm²/s) and non-PA (low ADC_mean<1.5×10⁻³ mm²/s) cases are first distinguished based on the ADC_mean on diffusion-weighed MRI. Second, among suspected non-PA cases, WT and non-WT are distinguished using technetium-99m pertechnetate scintigraphy. CNB is then performed only in probable non-PA and non-WT cases.

Results

Although CNB was only required in 40% (21/53) of all cases, we made a preoperative histopathological diagnosis with an accuracy of 87% (46/53) and we correctly diagnosed whether a tumor was benign or malignant with an accuracy of 96% (51/53). Preoperative surgical planning had to be changed during surgery in only one case (2%)

Conclusions

Our algorithm is valuable in terms of clinical practice with highly potential for preoperative diagnosis and with less risk of CNB procedure.     

CT联合肿瘤标志物与MRI联合肿瘤标志物对于直肠癌患者术前诊断 的准确率与特异性的研究

目的:探讨CT联合肿瘤标志物与MRI联合肿瘤标志物对于直肠癌患者术前诊断的准确率与特异性,为大肠癌的术前诊断提供一定的理论依据。方法:选取我院在2015年01月至2016年01月间收治的86例直肠癌患者以及64例肠道良性病变患者分别作为观察组I组和观察II组的研究对象,另外选取来我院进行健康体检的80例人员作为对照组研究,分别分析CT联合肿瘤标志物与MRI联合肿瘤标志物(CEA、CA125、CA199、CA242、CA724)对大肠癌患者诊断的准确率与特异性之间的差别。结果:观察I组肿瘤标志物水平要明显高于观察II组和对照组,差异显著,具有统计学意义;肿瘤标志物CEA、CA125、CA199、CA242、CA724对大肠癌患者检测的阳性率分别为67.44%(58/86)、26.74%(23/86)、84.88%(73/86)、72.09%(62/86)、33.72%(29/86),肿瘤标志物并联检测对大肠癌的阳性检测率为94.19%(81/86)。CT联合肿瘤标志物对大肠癌的准确率为97.67%(84/86),特异性为94.44%(136/144);MRI联合肿瘤标志物对大肠癌的阳性检测率为100.00%(86/86),特异性为98.61%(142/144)。结论:CT联合肿瘤标志物对大肠癌诊断的准确率与特异性均不如MRI联合肿瘤标志物,因此MRI联合肿瘤标志物可作为大肠癌除病理学鉴定外最佳的诊断方式。     

MRI在喉癌术前分期中的临床应用价值

目的:探讨MRI在喉癌术前诊断、分期中的临床应用价值。方法:对114例行电子喉镜检查并经病理学证实为喉癌的患者行术前MRI扫描,根据图像资料判断肿瘤侵及范围及判断有无淋巴结转移;同时进行术前分期、分型,并与术后病理分期、分型对照研究。结果:术前MRI T1期27例,其中25例经病理证实为T1期,2例为T2期,准确率为92.6%;术前MRI T2期39例,其中经病理证实35例为T2期,3例T1期,1例T3期,准确率为89.7%;术前MRI T3期29例,其中经病理证实25例为T3期,4例T2期,准确率为86.2%;术前MRI T4期17例,其中经病理证实15例为T4期,2例T3期,准确率为88.2%;MRI术前T分期总准确率为87.7%。N1期准确率为81.8%,N2期准确率为94.1%。结论:MRI图像能很好地显示喉癌肿块的侵及范围及淋巴结转移等,对喉癌的术前分期、分型及制定合理的手术方案具有指导意义。     

Treatment-independent miRNA signature in blood of wilms tumor patients

ABSTRACT: BACKGROUND: Blood-born miRNA signatures have recently been reported for various tumor diseases. Here, we compared themiRNA signature in Wilms tumor patients prior and after preoperative chemotherapy according to SIOPprotocol 2001. RESULTS: We did not find a significant difference between miRNA signature of both groups. However both, Wilmstumor patients prior and after chemotherapy showed a miRNA signature different from healthy controls. Thesignature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5% and of patients afterchemotherapy an accuracy of 97.0%, each as compared to healthy controls. CONCLUSION: Our results provide evidence for a blood-born Wilms tumor miRNA signature largely independent of fourweeks preoperative chemotherapy treatment.     

Prediction of Nodal Involvement in Primary Rectal Carcinoma without Invasion to Pelvic Structures: Accuracy of Preoperative CT,MR, and DWIBS Assessments Relative to Histopathologic Findings

Objective

To investigate the accuracy of preoperative computed tomography (CT), magnetic resonance (MR) imaging and diffusion-weighted imaging with background body signal suppression (DWIBS) in the prediction of nodal involvement in primary rectal carcinoma patients in the absence of tumor invasion into pelvic structures.

Methods and Materials

Fifty-two subjects with primary rectal cancer were preoperatively assessed by CT and MRI at 1.5 T with a phased-array coil. Preoperative lymph node staging with imaging modalities (CT, MRI, and DWIBS) were compared with the final histological findings.

Results

The accuracy of CT, MRI, and DWIBS were 57.7%, 63.5%, and 40.4%. The accuracy of DWIBS with higher sensitivity and negative predictive value for evaluating primary rectal cancer patients was lower than that of CT and MRI. Nodal staging agreement between imaging and pathology was fairly strong for CT and MRI (Kappa value = 0.331 and 0.348, P<0.01) but was relatively weaker for DWIBS (Kappa value = 0.174, P<0.05). The accuracy was 57.7% and 59.6%, respectively, for CT and MRI when the lymph node border information was used as the criteria, and was 57.7% and 61.5%, respectively, for enhanced CT and MRI when the lymph node enhancement pattern was used as the criteria.

Conclusion

MRI is more accurate than CT in predicting nodal involvement in primary rectal carcinoma patients in the absence of tumor invasion into pelvic structures. DWIBS has a great diagnostic value in differentiating small malignant from benign lymph nodes.     

La pratique de l’IRM mammaire au centre hospitalier de Chambéry

ObjectiveTo determine indications, technique and results of breast MRI performed at Chambery hospital (CH).Patients and methodsAnalytical retrospective study of 12 months, conducted at CH. It involved the analyzing of 100 breast MRI examinations performed in 84 patients using a brand device Siemens Magneton Area^®.ResultsThe mean age of patients was 56.2 years. The indications for breast MRI were the assessment of local and regional extension of breast cancer (28%), the results of monitoring of neoadjuvant chemotherapy (22%), the research of local recurrence after conservative treatment (14%) and cases of diagnostic discrepancies (13%). The most commonly used sequences were axial T1 ES (91%), axial T2 STIR (91%) and axial T1 with gadolinium injection (97%). The assessment of locoregional extension revealed multifocal invasion in 14 cases, pectoral in 3 cases, lymph node in 7 cases and skin in 4 cases. Concerning the monitoring of neoadjuvant chemotherapy, tumor involution was found in 10 patients and stability in 3 others. The distinction between tumor recurrence and postoperative scar showed 10 negative cases and 4 cases of tumor recurrence.ConclusionBreast MRI is an excellent non-invasive method for studying fully and satisfactorily within. It is mainly practiced in the CH to the extension of cancer and monitoring neoadjuvant chemotherapy balance.     

原发性骨恶性纤维组织细胞瘤24例临床特征及预后分析

摘要 目的：总结原发性骨恶性纤维组织细胞瘤（PBMFH）的临床特征和预后。方法：回顾性分析我院2000年10月至2011年1月收治的24例PBMFH患者的术前影像学资料、诊断依据、治疗方案和随访资料。结果：24例患者全部通过术后病理确诊,穿刺准确率为75.00%.胸部X线检查结果显示：2例发现肺部转移灶,22例未发现肺部转移灶。肿瘤局部X线检查结果显示：3例出现骨质溶解性破坏,1例出现肿块影,20例表现为骨膜反应。MRI检查结果显示：4例MRI检查肿瘤局部情况时发现3例T1WI等信号、T2WI稍高信号,1例T1WI低信号、T2WI低信号。本研究中行放化疗18例,有6例（33.33%）发生转移,转移时间为6~45个月,中位转移时间为（25.30±6.24）个月,单纯手术治疗6例中有5例发生转移（83.33%）,转移发生时间为3~6月,中位转移时间为（5.00±0.24）个月。结论：PBMFH患者单纯手术出现转移多发生于术后5月,根治性手术辅以放化疗出现转移多发生于术后25月。由此可见,术前穿刺活检病理有助于疾病诊断,术后辅助化疗有助于降低PBMFH的复发率和转移率。     

磁共振检查对复杂性肛瘘手术治疗患者的指导价值及术后复发的危险因素分析

目的:探讨磁共振成像技术(MRI)对复杂性肛瘘诊断和术前评估的指导意义及术后复发的危险因素。方法:前瞻性选取2015年6月至2017年12月到我院诊断并接受手术治疗的359例复杂性肛瘘患者,将其随机分为观察组182例和对照组177例。对照组患者术前未行MRI检查,术中行亚甲蓝染色指导手术治疗。观察组术前行MRI检查,术中给予亚甲蓝染色结合术前评估行手术治疗,以术中探查结果为金标准,统计MRI术前检查复杂性肛瘘的准确率,Kappa检验评估MRI检查结果与术中探查结果的一致性,经1-2年的随访统计所有患者复发情况,单因素和多因素Logistic回归分析术后复发的危险因素。结果:观察组术中探查共发现瘘管内口281个,合并肛周脓肿57例,多发瘘管及支管151例,MRI术前检查瘘管内口、合并肛周脓肿、多发瘘管及支管的准确率分别为98.22%(276/281)、85.96%(49/57)、96.03%(145/151),观察组中MRI结果与术中探查结果对患者Parks分型通过一致性检验显示,两结果一致性较好(k=0.890,P=0.001)。单因素分析结果显示,肛瘘位置、内口位置、合并肛周脓肿、既往肛瘘手术史及术前是否行MRI检查均会影响复发率(均P0.05),Logistic回归多因素分析显示,术前未进行MRI检查、高位肛瘘、内口位于后正中线、既往肛瘘手术史是复杂性肛瘘术后复发的危险因素(均P0.05)。结论:MRI检查复杂性肛瘘能够术前明确瘘管及内口数量,可较为精确地识别瘘管Parks分型,有助于提高手术疗效,合并肛周脓肿、术前未进行MRI检查、高位肛瘘、内口位于后位、既往肛瘘手术史是复杂性肛瘘术后复发的危险因素。     

CT和MRI鉴定腹膜后间隙脂肪肉瘤与组织病理学特征相关

本研究选取2012年1月至2018年1月在我院治疗的腹膜后间隙脂肪肉瘤患者33例,分析患者术前CT、MRI图像及术后病理结果,旨在探讨不同类型腹膜后间隙脂肪肉瘤病理学及影像学特征。研究结果表明:33例患者中术后病理诊断为高分化脂肪肉瘤19例,去分化脂肪肉瘤7例,黏液性脂肪肉瘤7例;不同病理分型脂肪肉瘤病灶大小比较差异无统计学意义(p>0.05);高分化脂肪肉瘤其CT密度同皮下脂肪,CT值-10～-110 Hu,肿瘤内可见不规则增厚的间隔;去分化脂肪肉瘤部分区域呈脂肪密度(CT值-70～30 Hu),部分区域呈软组织肿块(CT值为30～50 Hu);黏液性脂肪肉瘤CT密度接近水,增强扫描时肿块呈网状、片状、延迟强化,CT值20～40 Hu;高分化脂肪肉瘤MRI信号同皮下脂肪;黏液性脂肪肉瘤MRI呈长T1,长T2信号,与水相似;CT和MRI诊断腹膜后间隙脂肪瘤准确率分别为69.70%和73.33%,差异比较无统计学意义(p>0.05)。本研究得出初步结论,不同病理类型腹膜后间隙脂肪肉瘤的CT、MRI表现有所差异;CT和MRI术前诊断腹膜后间隙脂肪肉瘤准确性相似。     

Papillary carcinoma of the thyroid gland. Analysis of 94 cases with preoperative fine needle aspiration cytologic examination

From 1979 to 1983, 94 papillary carcinomas of the thyroid gland were examined histologically in our institute after a preoperative cytologic examination. Material for cytologic examination was obtained using fine needle aspiration (FNA) biopsy. Eighty-five (90.4%) of the 94 examined cytologic smears were representative. Among these 85 cases suspicion for malignancy or malignancy itself was found in 64 cases (75.3%). The remaining 21 smears, classified as cytologically not as suspect for malignancy, were reclassified and the previous diagnosis had to be revised in one case. In the other 20 cases no clue for malignancy could be demonstrated even after reexamination. In the 85 cases with representative cytologic findings, tumor size was determined on surgical material, in order to establish how many carcinomas with a diameter less than 3 cm could not be reached by FNA biopsy. Except for one case, all carcinomas with negative preoperative cytologic findings had a diameter less than or equal to 3 cm. The question arising is the possibility of improving the accuracy of FNA biopsy in tumor detection within cold nodules of the thyroid by combined use of scintigraphy and ultrasound-guided FNA biopsy.     

Salivary gland tumors with a prominent oncocytic component. Cytologic findings and differential diagnosis of oncocytomas and Warthin's tumor on fine needle aspirates

OBJECTIVE: To review aspirates from histologically documented oncocytomas and Warthin's tumor (WT) to highlight the cytomorphologic findings and determine the difficulties encountered in typing oncocytepredominant aspirates. STUDY DESIGN: Over a 19-year period (1982-2000) we reviewed aspirates from 45 cases with an oncocyte preponderance. In 24 of them tissue for histologic examination was available (5 oncocytomas and 19 WT). RESULTS: In 4 of the 5 histologically documented oncocytomas the aspirates were cellular, with oncocytic epithelial cells in sheets, papillary fragments and singly. Epithelial atypia was minimal and lymphoid component absent, though scant proteinaceous material with a sprinkling of lymphocytes was seen. In WT moderate (35%) to abundant (28%) oncocytic epithelial cells were seen predominantly in a sheetlike arrangement with occasional papillary fragments and single cells. A variable quantity of lymphoid component was seen in 90% of the aspirates, with 88% of them showing a proteinaceous background accompanied by necrotic debris in 43% of cases. Squamous metaplasia was identified in 30% of cases, with 3 showing atypical squamous cells. In four cases the lymphoid component was scant and oncocytes abundant, and both possibilities were entertained. CONCLUSION: Fine needle aspiration cytology is fairly accurate in the preoperative diagnosis of WT. When the lymphoid component, mucus and necrotic background are minimal or absent, the tumors can be confused with oncocytoma. In oncocytoma, the oncocytic epithelial cells are more often seen in papillary fragments, acini and singly in comparison to WT, where sheets of oncocytic cells are observed. Some degree of epithelial atypia can be seen in oncocyte-predominant benign lesions. Squamous metaplasia, especially if accompanied by atypia and necrosis, can prove challenging.     

Potentialities of low-field magnetic resonance tomography in the diagnosis and treatment of invasive cancer of cervix uteri

The aim of the study was to evaluate the efficiency of low-field (0.14 T) magnetic resonance imaging (MRI) in the diagnosis and treatment of cancer of the cervix uteri. MATERIALS AND METHODS: Low-field MRI was performed in 39 patients with cancer of the cervix uteri to define the stage of the tumor and to follow up the outcomes of their treatment. Particular emphasis was laid on the determination of the size of the tumor and the presence of parametral invasion and on metastatic lesions of lymph nodes. MRI data were compared with clinical, morphological, and surgical staging results. In detecting the stage of cancer of the cervix uteri, the accuracy of MRI was 72% whereas that of clinical study was 51%. In determining parametral invasion, the accuracy of clinical study and low-field MRI was 71 and 90%, respectively. The sensitivity and specificity of MRI were 83 and 92%, respectively. The anterioposterior tumor size was an important prognostic factor in following up the outcomes of treatment as there was its close association and the incidence of tumor recurrences. The present study has indicated that the high efficiency of low-field MRI in detecting the stage of invasive cancer of cervix uteri makes it the method of choice in planning treatment and monitoring the outcomes of combined radiation therapy.     

Significant reduction of WT1 gene expression,possibly due to epigenetic alteration in Wilms' tumor

WT1 at 11p13 is a tumor suppressor gene, an aberration of which causes Wilms' tumor (WT). Since WT1 expression is reduced in a certain proportion of WTs and its mutation is found only in 10-20% of WTs, we examined WT1 gene silencing due to epigenetic alteration in a total of 22 WTs. WT1 expression was significantly reduced in half of WTs without any mutation in the WT1 gene itself, suggesting that the reduction of expression was possibly epigenetic. We found promoter hypermethylation in one WT with loss of heterozygosity (LOH) and showed that promoter methylation reduced reporter gene activity by a reporter assay. These data suggested that methylation was an epigenetic mechanism leading to WT1 silencing and that the expression-reduced allele by hypermethylation combined with LOH was consistent with the revised two-hit model. In addition, as the beta-catenin mutation is frequently associated with the WT1 mutation, the association of WT1 silencing with the beta-catenin mutation was also investigated. beta-catenin mutated in only one WT without WT1 silencing, suggesting that the beta-catenin mutation was not associated with the reduction of WT1 expression.     

3.0 T高分辨磁共振在直肠癌术前T N分期、环周切缘有无累及淋巴结转移的评估价值

摘要 目的：研究3.0 T高分辨磁共振（MRI）在直肠癌术前T N分期、环周切缘有无累及淋巴结转移的评估价值。方法：将我院从2018年1月～2019年12月收治的直肠癌患者120例纳入研究。所有患者均接受3.0 T高分辨MRI检查,以术后病理结果为金标准,分析其对术前T N分期、环周切缘有无累及淋巴结转移的评估价值。结果：直肠癌术前3.0 T高分辨MRI T分期与病理结果一致性较高,检验结果显示Kappa值=0.543,P值=0.000。直肠癌术前3.0 T高分辨MRI N分期与病理结果一致性较高,检验结果显示Kappa值=0.519,P值=0.000。以术后病理结果为金标准,直肠癌术前3.0 T高分辨MRI诊断环周切缘累及的灵敏度、特异度、准确度、阴性预测值、阳性预测值分别为92.50%（37/40）、93.75%（75/80）、93.33%（112/120）、96.15%（75/78）、88.10%（37/42）。直肠癌淋巴结转移者MRI边缘模糊、肠周围脂肪信号不均匀占比较无淋巴结转移者更高,且短径较无淋巴结转移者更长（均P＜0.05）。结论：3.0 T高分辨MRI在直肠癌术前T N分期、环周切缘有无累及淋巴结转移的评估价值较高,具有一定的临床应用价值。     

Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.

Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms' tumor (nephroblastoma). To investigate its possible role, we have analyzed the coding exons of the Wilms' tumor suppressor gene (WT1) for germline mutations. In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found. Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II). These mutations directly affect DNA sequence recognition. In two families analyzed, the mutations were shown to arise de novo. Wilms' tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele. Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development.     

Evaluation of Chemotherapy Response with Serum Squamous Cell Carcinoma Antigen Level in Cervical Cancer Patients: A Prospective Cohort Study

MRI does not always reflect tumor response after chemotherapy. Therefore, it is necessary to explore additional parameters to more accurately evaluate tumor response for the subsequent clinical determination about radiotherapy or radical surgery. A training cohort and an external validation cohort were used to examine the predictive performance of SCC-ag to evaluate tumor response from teaching hospital of Harbin Medical University. The study included 397 women with SCC (age: 28–73 years). Patients consecutively enrolled between August 2008 and January 2010 (n = 205) were used as training cohort. Patients consecutively enrolled between February 2010 and May 2011 (n = 192) were used as validation cohort. A multivariate regression analysis of the data from the training cohort indicated that serum SCC-ag level is an independent factor for neo-adjuvant chemotherapy (NACT) response. Analysis of the data from the validation cohort suggested that chemotherapy response could be more accurately predicted by SCC-ag than by magnetic resonance imaging (MRI) (sensitivity (Se): 0.944 vs. 0.794; specificity (Sp): 0.727 vs. 0.636; positive predictive value (PPV): 0.869 vs. 0.806; negative predictive value (NPV): 0.873 vs. 0.618; the area under ROC curve (AUC): 0.898 vs. 0.734). Combining SCC-ag with MRI was more powerful than MRI alone (Se: 0.952 vs. 0.794; Sp: 0.833 vs. 0.636; PPV: 0.916 vs. 0.806; NPV: 0.902 vs. 0.618; AUC: 0.950 vs. 0.734). Our study indicates that serum SCC-ag level is a sensitive and reliable measure to evaluate cervical cancer response to chemotherapy. Using SCC-ag in combination with MRI findings further improves the predictive power.     

Importance of signaling via the IFN-α/β receptor on host cells for the realization of the therapeutic benefits of cyclophosphamide for mice bearing a large MOPC-315 tumor

Here we show that low-dose cyclophosphamide (CY), that depends for its therapeutic effectiveness on the immunopotentiating activity of the drug for T cell-mediated tumor-eradicating immunity, is curative for ~80% of wild-type (WT) mice bearing a large s.c. MOPC-315 tumor, but only for ~10% of IFN-α/βR^−/− mice bearing a large s.c. MOPC-315 tumor. Histopathological examination of the s.c. tumors of such mice on day 4 after the chemotherapy revealed that the low dose of CY led to accumulation of T lymphocytes in both the WT and the IFN-α/βR^−/− mice. However, in the CY treated tumor bearing WT mice the T lymphocytes were present throughout the tumor mass and in direct contact with tumor cells, but in the CY treated tumor bearing IFN-α/βR^−/− mice most of the T lymphocytes remained in blood vessels. In addition to being important for CY-induced transendothelial migration of T lymphocytes into the tumor mass, we show here that signaling via the IFN-α/βR is also important for CY-induced control of metastatic tumor progression in the spleen and liver of the tumor bearing mice. Finally, CY cured tumor bearing WT mice were resistant to a subsequent challenge with MOPC-315 tumor cells, but the few CY cured tumor bearing IFN-α/βR^−/− mice were not. Thus, signaling via the IFN-α/βR on host cells in MOPC-315 tumor bearers is important for CY-induced: (a) transendothelial migration of T lymphocytes into the tumor mass and the eradication of the primary tumor, (b) control of metastatic tumor progression, and (c) resistance to a subsequent tumor challenge. This work was supported by Research Grant 03-19 from the American Cancer Society-Illinois Division.     

Genetische Prädisposition für Wilms-Tumor

Wilms tumor (WT) is an embryonal tumor of the kidney and is due to aberrant proliferation of early precursor cells. WT1 mutations are found in 10–15% of WT. The WT1 gene has a function during normal kidney and genital development. Germline mutations in this gene are found in patients with urogenital abnormalities, isolated nephrotic syndrome, Denys Drash syndrome, Frasier syndrome, WAGR syndrome (Wilms tumor, aniridia, genital malformation, and mental retardation), and some rare cases of familial WT. These patients are at high risk of unilateral WT, and also of synchronous or metachronous bilateral WT, which may occur later in life. An elevated risk of WT is also observed in some overgrowth syndromes, various tumor predisposition syndromes, and specific constitutional aneuploidies. Embryonal tumors develop during early phases of development when cells still have a high doubling rate. Aberrations that delay or inhibit the switch from proliferation to differentiation lead to an expanded cell pool, in which further mutations can occur in various genes that regulate this process. This may explain the heterogeneous diseases/genetic aberrations that are associated with an elevated risk of WT.     

Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia

Aniridia is a severe eye disease characterized by iris hypoplasia; both sporadic cases and familial cases with an autosomal dominant inheritance exist. Mutations in the PAX6 gene have been shown to be the genetic cause of the disease. Some of the sporadic cases are caused by large chromosomal deletions, some of which also include the Wilms tumor gene (WAGR syndrome), resulting in an increased risk of developing Wilms tumor. Based on the unique registration of both cancer and aniridia cases in Denmark, we have made the most accurate risk estimate to date for Wilms tumor in sporadic aniridia. We have found that patients with sporadic aniridia have a relative risk of 67 (confidence interval: 8.1-241) of developing Wilms tumor. Among patients investigated for mutations, Wilms tumor developed in only two patients out of 5 with the Wilms tumor gene (WT1) deleted. None of the patients with smaller chromosomal deletions or intragenic mutations were found to develop Wilms tumor. Our observations suggest a smaller risk for Wilms tumor than previous estimates, and that tumor development requires deletion of WT1. We report a strategy for the mutational analysis of aniridia cases resulting in the detection of mutations in 68% of sporadic cases and 89% of familial cases. We also report four novel mutations in PAX6, and furthermore, we have discovered a new alternatively spliced form of PAX6.