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1.  Correlation between Radiologic and Pathologic Tumor Size in Localized Renal Cell Carcinoma 
Korean Journal of Urology  2010;51(3):161-164.
To evaluate the accuracy of radiologic tumor size for making decisions regarding nephron-sparing surgery of localized renal cell carcinomas (RCCs), we compared tumor size measured by a preoperative radiologic modality with that measured in the pathologic specimen.
Materials and Methods
Between January 2003 and December 2007, a total of 186 patients with pT1 or pT2 RCC underwent radical or partial nephrectomy at our institute. We excluded 11 patients who had preoperative arterial embolization (n=9) or positive surgical margins (n=2), and a total of 175 patients were included in this study. Radiologic size was defined as the largest diameter on computed tomography (CT), and pathologic size was defined as the largest diameter of the surgical specimen of the tumor. We retrospectively analyzed the difference between radiologic and pathologic tumor size.
The radiologic and pathologic tumor sizes did not significantly differ (4.98±2.82 cm vs. 4.55±2.70 cm, respectively, p=0.152). In the subgroup analysis, the size difference was statistically significant only for tumor sizes of less than 6 cm. The size difference was largest in tumors of 3 to 4 cm, for which mean the radiologic size was 0.63±1.19 cm larger than the mean pathologic size (p=0.002). Histologic type had no significant influence on the difference between radiologic and pathologic size.
The tumor size of RCCs in preoperative CT seems to correlate well with pathologic tumor size. However, CT imaging may overestimate the size of a tumor in the small mass group (less than 6 cm). These results should be considered when making decisions about nephron-sparing surgery.
PMCID: PMC2855455  PMID: 20414390
Renal cell carcinoma; Nephrectomy; Radiology
2.  Comparative Analysis of Radiologically Measured Size and True Size of Renal Tumors 
Korean Journal of Urology  2013;54(11):738-743.
We evaluated the differences between radiologically measured size and pathologic size of renal tumors.
Materials and Methods
The data from 171 patients who underwent radical or partial nephrectomy for a renal tumor at Ajou University Hospital were reviewed. Radiologic tumor size, which was defined as the largest diameter on a computed tomographic scan, was compared with pathologic tumor size, which was defined as the largest diameter on gross pathologic examination.
Mean radiologic size was significantly larger than mean pathologic size for all tumors (p=0.019). When stratified according to radiologic size range, mean radiologic size was significantly larger than mean pathologic size for tumors <4 cm (p=0.003), but there was no significant difference between the sizes for tumors 4-7 cm and >7 cm. When classified according to histologic subtype, mean radiologic size was significantly larger than mean pathologic size only in clear cell renal cell carcinomas (p=0.002). When classified according to tumor location, mean radiologic size was significantly larger than mean pathologic size in endophytic tumors (p=0.043) but not in exophytic tumors. When endophytic tumors were stratified according to radiologic size range, there was a significant difference between the mean radiologic and pathologic sizes for tumors <4 cm (p=0.001) but not for tumors 4-7 cm (p=0.073) and >7 cm (p=0.603).
Our results suggest that in planning a nephron-sparing surgery for renal tumors, especially for endophytic tumors of less than 4 cm, the tumor size measured on a computed tomography scan should be readjusted to get a more precise estimate of the tumor size.
PMCID: PMC3830965  PMID: 24255754
Kidney; Neoplasms; Pathology; Radiology
3.  Renal cell carcinoma: Impact of mode of detection on its pathological characteristics 
Data correlating mode of presentation of renal cell carcinoma (RCC) with pathological prognostic factors is sparse from India. We compared RCC presenting incidentally with those presenting symptomatically with respect to pathological prognostic factors and assessed whether this could serve as a decision making resource for diagnosing small and more favorable tumors.
Materials and Methods:
The data were reviewed for 328 patients operated for renal tumors between January 2000 and October 2008 at our institute. The pathological factors (tumor size, stage, grade, histopathological type) in relation to the mode of presentation were analyzed according to 1997 TNM criteria. Statistical analysis was performed via the chi-square (Fisher exact) and Mann - Whitney U test. The statistical significance level utilized was P < 0.05.
Among the patients assessed, 93 (28.4%) had incidental diagnosis and 235 (71.6%) had symptomatic presentation. Sex and side distribution was not significantly different in the two groups. Mean tumor size was 5.75 ± 2.73 cm in incidentally detected RCC (IRCC) and 9.32 ± 3.70 (P < 0.001) in symptomatic RCC (SRCC). Stage I and II tumors were significantly greater in IRCC than SRCC (p<0.001 and 0.005 respectively) whereas stage III and IV tumors were significantly less in IRCC than SRCC. There was a predominance of higher grade tumors in SRCC, 50% being higher grades (Fuhrman's grade III and IV) in SRCC than 28.1% in IRCC (P = 0.003). There were 4 tumors with collecting duct histology in SRCC and none in IRCC. Sarcomatoid differentiation was present in 14 and 1 patient in SRCC and IRCC respectively.
Incidental detection of renal carcinoma as compared to symptomatic tumors is lower in India as compared to western world. Incidental tumors have significantly favorable pathological prognostic factors. Our results might form a basis for further studies on how to pick RCC at an earlier stage.
PMCID: PMC2808651  PMID: 19955672
Incidental; pathology; symptomatic
4.  Contemporary Imaging of Renal Mass Patients 
BJU international  2008;103(1):24-27.
To evaluate the difference between radiographic size on computed tomography (CT) and the pathologic size of renal tumors using a contemporary cohort.
Materials and Methods
We retrospectively reviewed the records of 521 patients undergoing surgical resection of a renal mass between 2000 and 2007 who had tumor sizes recorded from both preoperative CT imaging and pathologic evaluation of the tumor specimen. Data regarding histologic tumor type were also extracted. The paired student’s t-test was utilized to compare the mean radiographic size as measured on CT with the mean pathologic size, and p values <0.05 were considered statistically significant.
For all patients, the mean radiographic size and mean pathologic size was 4.79 and 4.69 cm, respectively (p = 0.02). Therefore, on average, radiographic size overestimated pathologic size by 1 mm. In patients with a tumor size of 4 to 7 cm, radiographic size overestimated pathologic size by 0.21 cm (p = 0.007). However, no significant difference was noted in patients with a tumor size of <4 cm or >7 cm.
Using a contemporary cohort of patients, we observed a statistically significant overestimation of renal tumor sizes by CT imaging as compared to pathologic assessment. However, the overall difference between radiographic and pathologic tumor size was 1 mm, suggesting that CT provides an accurate modality with which to estimate renal tumor size.
PMCID: PMC2634853  PMID: 18710440
kidney neoplasms/pathology; kidney neoplasms/radiography; retrospective studies; tomography, x-ray computed; nephrectomy/methods
5.  A Multi-institutional Study on Histopathological Characteristics of Surgically Treated Renal Tumors: the Importance of Tumor Size 
Yonsei Medical Journal  2008;49(4):639-646.
The incidence of accidentally detected small renal tumors is increasing throughout the world. In this multi-institutional study performed in Korea, histopathological characteristics of contemporarily surgically removed renal tumors were reviewed with emphasis on tumor size.
Materials and Methods
Between January 1995 and May 2005, 1,702 patients with a mean age of 55 years underwent surgical treatment at 14 training hospitals in Korea for radiologically suspected malignant renal tumors. Clinicopathological factors and patient survival were analyzed.
Of the 1,702 tumors, 91.7% were malignant and 8.3% were benign. The percentage of benign tumors was significantly greater among those ≤ 4 cm (13.2%) than those > 4 cm (4.5%) (p < 0.001). Among renal cell carcinoma patients, the percentage of tumors ≤ classed as stage ≥ T3 was significantly less among tumors 4 cm (5.2%) than those > 4 cm (26.8%) (p < 0.001). The percentage of tumors classed as Fuhrman's nuclear grades ≥ 3 was also significantly less among tumors ≤ 4 cm (27.3%) than tumors > 4 cm (50.9%) (p < 0.001). The 5-year cancer-specific survival rate was 82.7%, and T stage (p < 0.001), N stage (p < 0.001), M stage (p = 0.025), and Fuhrman's nuclear (p < 0.001) grade were the only independent predictors of cancer-specific survival.
In renal tumors, small tumor size is prognostic for favorable postsurgical histopathologies such as benign tumors, low T stages, and low Fuhrman's nuclear grades. Our observations are expected to facilitate urologists to adopt function-preserving approach in the planning of surgery for small renal tumors with favorable predicted outcomes.
PMCID: PMC2615292  PMID: 18729308
Kidney neoplasms; renal cell carcinoma; nephrectomy; surgical pathology
6.  The Prognostic Factors for Patients with pT1a Renal Cell Carcinoma 
Korean Journal of Urology  2010;51(4):233-238.
Although the prognosis of patients with pT1a stage renal cell carcinoma (RCC) is generally good, some of these patients show distant metastasis. In this study, we intended to identify the perioperative and pathologic prognostic factors for patients with pT1a stage RCC.
Materials and Methods
A total of 93 patients who were diagnosed with pT1aN0M0 RCC between January 1995 and December 2004 were included. All the patients underwent radical (n=63, 67.7%) or partial (n=30, 32.3%) nephrectomy by a single surgeon. Preoperative data [age, sex, body mass index (BMI), and the presence of symptoms], follow-up duration, surgical methods, and pathological parameters (tumor size, tumor location, histologic type, Fuhrman's nuclear grade and the presence of microvascular invasion, hemorrhage, necrosis, calcification, and a cystic component in the tumor) were retrospectively analyzed to identify which of these were prognostic factors for pT1a RCC.
The patients' mean age was 55.0±11.4 years and the mean follow-up duration was 63.6±31.1 months. The 5-year cancer-specific survival rate and the 5-year recurrence- free survival rate were 100% and 88.1%, respectively. Nine patients (9.7%) showed distant metastasis, but local recurrence was not shown. Fuhrman's nuclear grade (p=0.040, OR=5.147), microvascular invasion (p=0.011, OR=13.500), and tumor necrosis (p<0.001, OR=26.000) had a significant impact on distant metastasis in the univariate analysis. The multivariate analysis subsequently showed that microvascular invasion (p=0.033, OR=17.947) and tumor necrosis (p=0.002, OR=15.922) were independent prognostic factors.
Microvascular invasion and tumor necrosis are the prognostic factors for patients with pT1a RCC.
PMCID: PMC2858860  PMID: 20428424
Prognosis; Renal cell carcinoma
7.  Intra-operative measurement of tumour size in breast cancer and its comparison with other methods: a prospective study 
Accurate measurement of breast tumour size determines staging and prognosis. Discrepancies amongst clinical examination (CE), ultrasonography (USG), mammography, pathological examination (PE) and magnetic resonance imaging have been reported. However, few studies have evaluated changes in breast tumour size from the operating table to the laboratory.
Objectives and methods:
A prospective study was designed to assess the intra-operative (IO) tumour size in 29 patients of breast cancer presenting to a tertiary care centre in Delhi and to compare it with CE, USG and PE.
Observations and results:
Twenty-nine patients (mean age: 47 years), presenting with invasive duct carcinoma (stage IIIA: 31%, stage IIB: 28%), were included in the study. Comparison with mean IO (4.2 cm) revealed that both USG and PE underestimated tumour size by a mean of 0.35 cm (8.4%) and 0.45 cm (10.7%), respectively, in most patients. CE tended to overestimate size by 0.82 cm (19.8%). All three modalities showed statistically significant correlation with IO (maximum Pearson’s correlation coefficient for PE=0.937, p<0.001; R2=0.877, maximum for PE). Two-way analysis of variance revealed mean difference in size to be statistically significant (p=0.000) only between CE and IO.
Formalin processing causes changes in tumour dimensions in the breast, causing reduction in tumour size. It may also have a bearing on the assessment of surgical margins in breast conservation surgery. Immediate post-operative measurement of the specimen is ideal. Protocols for specimen fixation should be standardized.
PMCID: PMC3234070  PMID: 22275977
8.  Radiological and pathological size estimations of pure ductal carcinoma in situ of the breast, specimen handling and the influence on the success of breast conservation surgery: a review of 2564 cases from the Sloane Project 
British Journal of Cancer  2010;102(2):285-293.
The Sloane Project, an audit of UK screen-detected non-invasive carcinomas and atypical hyperplasias of the breast, has accrued over 5000 cases in 5 years; with paired radiological and pathological data for 2564 ductal carcinoma in situ (DCIS) cases at the point of this analysis. We have compared the radiological estimate of DCIS size with the pathological estimate of DCIS size. We have correlated these sizes with histological grade, specimen-handling methods, particularly the use of specimen slice radiographs, and the success or failure of breast-conserving surgery (BCS).
The Sloane Project database was interrogated to extract information on all patients diagnosed with DCIS with complete radiological and pathological data on the size of DCIS, nuclear grade, specimen handling (with particular reference to specimen radiographs) and whether primary BCS was successful or whether the patient required further conservation surgery or a mastectomy.
Of 2564 patients in the study, 2013 (79%) had attempted BCS and 1430 (71%) had a successful single operation. Of the 583 BCS patients who required further surgery, 65% had successful conservation and 97% of them after a single further operation. In successful one-operation BCS patients, there was a close agreement between radiological and pathological DCIS size with radiology tending to marginally overestimate the disease extent. In multiple-operation BCS, radiology underestimated DCIS size in 59% of cases. The agreement between pathological and radiological size of DCIS was poor in mastectomies but was improved by specimen slice radiography, suggesting specimen-handling techniques as a cause.
In 30% of patients undergoing BCS for DCIS, preoperative imaging underestimates the extent of disease resulting in a requirement for further surgery. This has implications for the further improvement of preoperative imaging and non-operative diagnosis of DCIS so that second operations are reduced to a minimum.
PMCID: PMC2816666  PMID: 20051953
DCIS measurement; pathology; radiology; breast screening
9.  Decreased expression of dual-specificity phosphatase 9 is associated with poor prognosis in clear cell renal cell carcinoma 
BMC Cancer  2011;11:413.
The molecular mechanisms involved in the development and progression of clear cell renal cell carcinomas (ccRCCs) are poorly understood. The objective of this study was to analyze the expression of dual-specificity phosphatase 9 (DUSP-9) and determine its clinical significance in human ccRCCs.
The expression of DUSP-9 mRNA was determined in 46 paired samples of ccRCCs and adjacent normal tissues by using real-time qPCR. The expression of the DUSP-9 was determined in 211 samples of ccRCCs and 107 paired samples of adjacent normal tissues by immunohistochemical analysis. Statistical analysis was performed to define the relationship between the expression of DUSP-9 and the clinical features of ccRCC.
The mRNA level of DUSP-9, which was determined by real-time RT-PCR, was found to be significantly lower in tumorous tissues than in the adjacent non-tumorous tissues (p < 0.001). An immunohistochemical analysis of 107 paired tissue specimens showed that the DUSP-9 expression was lower in tumorous tissues than in the adjacent non-tumorous tissues (p < 0.001). Moreover, there was a significant correlation between the DUSP-9 expression in ccRCCs and gender (p = 0.031), tumor size (p = 0.001), pathologic stage (p = 0.001), Fuhrman grade (p = 0.002), T stage (p = 0.001), N classification (p = 0.012), metastasis (p = 0.005), and recurrence (p < 0.001). Patients with lower DUSP-9 expression had shorter overall survival time than those with higher DUSP-9 expression (p < 0.001). Multivariate analysis indicated that low expression of the DUSP-9 was an independent predictor for poor survival of ccRCC patients.
To our knowledge, this is the first study that determines the relationship between DUSP-9 expression and prognosis in ccRCC. We found that decreased expression of DUSP-9 is associated with poor prognosis in ccRCC. DUSP-9 may represent a novel and useful prognostic marker for ccRCC.
PMCID: PMC3198720  PMID: 21943117
10.  Survival Rates after Resection for Localized Kidney Cancer: 1989 – 2004 
Cancer  2008;113(1):84-96.
Mortality rates from kidney cancer have continued to rise despite increases in the detection of smaller renal tumors and rates of renal operations. To explore factors associated with this treatment-outcome discrepancy, we evaluated how changes in tumor size have affected disease progression in patients following nephrectomy for localized kidney cancer. Furthermore, we sought to identify factors that are associated with disease progression and overall patient survival following resection for localized kidney cancer.
We identified 1,618 patients with localized kidney cancer treated by nephrectomy at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1989 to 2004. Patients were categorized by year of operation: 1989–1992, 1993–1996, 1997–2000, and 2001–2004. Tumor size was classified according to the following strata: <2 cm, 2 to 4 cm, 4 to 7 cm, and >7 cm. Progression was defined as the development of local recurrence or distant metastases. Five-year progression-free survival (PFS) was calculated for patients in each tumor size strata, according to year of operation, using the Kaplan-Meier method. Patient, tumor, and surgery related characteristics associated with PFS and overall survival (OS) were explored using univariable analysis and all significant variables were retained in a multivariable Cox regression analysis.
Overall, the number of nephrectomies increased for all tumor size categories from 1989 to 2004. A tumor size migration was evident during this period, as the proportion of patients with tumors <2 cm and 2 to 4 cm increased while those with tumors >7 cm decreased. 179 patients (11%) developed disease progression after nephrectomy. Local recurrence occurred in 16 (1%) and distant metastases in 163 (10%). When 5-year PFS was calculated for each tumor size strata according to 4-year cohorts, trends in PFS did not improve nor differ significantly over time. Compared to historical cohorts, patients in more contemporary cohorts were more likely to undergo partial, as opposed to radical, nephrectomy and less likely to have a concomitant lymph node dissection and adrenalectomy. Multivariable analysis showed that pathologic stage and tumor grade were associated with disease progression while patient age and tumor stage were associated with overall patient survival.
Despite an increasing number of nephrectomies and a size migration towards smaller tumors, trends in 5-year PFS and OS did not improve nor differ significantly over time. These findings require further research to identify causative mechanisms and argue for a re-evaluation of the current treatment paradigm of surgically removing solid renal masses upon initial detection and consideration of active surveillance for patients with select renal tumors.
PMCID: PMC3985136  PMID: 18470927
11.  Histopathological analysis of T1 renal cell carcinoma: Does presentation matter? 
To study the differences in the clinico-pathological features of incidental and symptomatic T1 renal cell carcinoma (RCC) and to see, particularly in T1b RCC, if symptomatic presentation has adverse pathological features concerning the oncological safety of elective nephron-sparing surgery (NSS) in this subgroup.
Materials and Methods:
Of 278 patients who underwent radical nephrectomy for RCC from January 1995 to January 2005, 70 had tumor size up to 7 cm (T1). They were categorized as incidental or symptomatic and as T1a or T1b tumors. Clinico-pathological features were compared between incidental (IRCC) and symptomatic (SRCC) groups. Tumors were analyzed using the 1997 TNM staging and Fuhrman's grade.
Of the 70 with T1 tumors, 24 had T1a (IRCC, 12 and SRCC, 12) and 46 had T1b tumors (IRCC, 27 and SRCC, 19). Clear cell was the commonest histology. In T1a cancers, though no significant difference in histopathological pattern and grade was seen between the incidental and symptomatic groups, symptomatic tumors had more papillary, mixed histopathological pattern and higher nuclear grade. Among T1b tumors, 14 had papillary and mixed histology, 12 (86%) of which were symptomatic (P= <0.0001). In T1b, 15 (79%) symptomatic had higher nuclear grade (G2-3) while 22 (81%) incidental had lower Fuhrman′s grade (P= <0.0001).
Symptomatic T1b RCCs had higher nuclear grade and papillary histology. This difference was statistically significant. This may be relevant when considering elective NSS in symptomatic T1b disease.
PMCID: PMC2684406  PMID: 19468506
Incidental; nephron-sparing surgery; renal cell carcinoma
12.  CT-pathologic correlation in primary hepatocellular carcinoma: an implication for target delineation 
Journal of Radiation Research  2013;54(5):938-942.
The purpose of this investigation was to analyze the correlation between CT size and gross pathologic size for subjects with primary hepatocellular carcinoma (HCC). This analysis included 174 patients with HCC who underwent surgery. Enhanced computed tomography (CT) was performed up to 30 days before surgery. After resection, the size of the tumor on gross pathologic examination was recorded. The maximal measurement in one dimension on axial imaging and pathologic examination was extracted for statistical analysis. The clinical and pathologic sizes were compared using a percent size difference (%Δsize) as an end point. A regression analysis was applied to study the association between pathologic and radiographic size. The median radiographic and pathologic size were 70.58 ± 38.9 mm and 68.59 ± 40.56 mm, respectively. The radiographic size was larger than or equal to the pathologic size in 110/174 tumors (63.2%), and smaller in 64/174 (36.8%) tumors. Overall, the radiographic and pathologic sizes were positively correlated (r = 0.983, P = 0.000). CT seemed to overestimate the tumor size by 2.16 mm compared to final pathology (P = 0.024). The median %Δsize was 3.3%. Pathologic tumor size was significantly underestimated in patients with a tumor size 3–5 cm (P = 0.011), Grade I HCC (P = 0.023), with clear boundary (P = 0.013). We concluded that CT size and pathologic size were positively correlated, but differences did exist. Utilizing the radiographic tumor when planning radiation would have covered 63.2% of gross tumors. For a radiographic tumor size < 50 mm, utilizing a 3-mm margin around the radiographic tumor would have covered 90% of gross lesions, while a margin of 5 mm would have covered 95%, and a margin of 15 mm would have covered 100%.
PMCID: PMC3766302  PMID: 23616629
hepatocellular carcinoma; CT-pathologic relation; target delineation; radiation
13.  Clinical and Pathologic Impact of Select Chromatin Modulating Tumor Suppressors in Clear Cell Renal Cell Carcinoma 
European urology  2012;63(5):848-854.
Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Excitingly, recent sequencing efforts identified several novel, frequent mutations of histone modifying and chromatin remodeling genes in ccRCC, including PBRM1, SETD2, BAP1 and KDM5C. Intriguingly, PBRM1, SETD2 and BAP1 are located in close proximity to VHL within a commonly lost (~90%) 3p locus. To date the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown.
To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC.
Design, Setting, and Participants
Targeted sequencing was performed in 185 ccRCC and matched normal tissues from a single institute. Pathologic features, baseline patient characteristics and follow-up data were recorded.
Statistical Analysis
The linkage between mutations and clinical and pathologic outcomes was interrogated with Fisher’s exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer specific survival).
Results and Limitations
PBRM1, BAP1, SETD2 and KDM5C are mutated at 29%, 6%, 8% and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2 or KDM5C (19%) are more likely to present with stage 3+ diseases, p=0.01 and p=0.001, respectively. Small tumors (<4cm) with PBRM1 mutations are more likely to exhibit stage 3 pathologic features (OR 6.4, p=0.001). BAP1 mutations tend to occur in Fuhrman Grade 3–4 tumors (p=0.052) and associate with worse cancer specific survival (p=0.01). Clinical outcome data is limited by the number of events.
Most mutations of chromatin modulators discovered in ccRCC are loss-of-function, which associate with advanced stage, grade, and possibly worsened cancer specific survival. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.
PMCID: PMC3615105  PMID: 23036577
Chromatin; Histone; Mutation; Outcome; Renal Cell Carcinoma
14.  Comparison of conventional and 3-dimensional computed tomography against histopathologic examination in determining pancreatic adenocarcinoma tumor size: Implications for radiation therapy planning 
Background and purpose
This study seeks to: (a) quantify radiologic-pathologic discrepancy for pancreatic adenocarcinoma by comparing tumor size on conventional computed tomography (C-CT) and 3-dimensional CT (3D-CT) to corresponding pathologic specimens; and (b) to identify clinico-pathologic characteristics predictive of radiologic-pathologic discrepancy to assist radiotherapy planning.
Materials and methods
Sixty-three patients with pancreatic adenocarcinoma and preoperative C-CT and volume-rendered 3D-CT imaging within 6 weeks of resection were identified. Maximum tumor diameter (MTD) was measured on pathology, C-CT, and 3D-CT and compared for each patient as well as among different clinico-pathologic subgroups.
There was a trend toward C-CT underestimation of MTD compared to final pathology (p = 0.08), but no significant difference between 3D-CT MTD and pathology (p = 0.54). Pathologic tumor size was significantly underestimated by C-CT in patients with larger pathologic tumor size (>3.0 cm, p = 0.0001), smaller tumor size on C-CT (<3.0 cm, p = 0.003), higher CA19-9 (>90 U/mL, p = 0.008), and location in the pancreatic head (p = 0.015). A model for predicting pathologic MTD using C-CT MTD and CA19-9 level was generated.
3D-CT may allow for more accurate contouring of pancreatic tumors than C-CT. Patients with the above clinico-pathologic characteristics may require expanded margins relative to tumor size estimates on C-CT during radiotherapy planning.
PMCID: PMC4124599  PMID: 22883106
Pancreatic cancer; Resectable; Radiation treatment planning; 3D-CT; SBRT
15.  Preoperative Measurement of Breast Cancer Overestimates Tumor Size Compared to Pathological Measurement 
PLoS ONE  2014;9(1):e86676.
Tumor size is one of the most important factors in making clinical and pathological assessment of breast cancer. In the present study, we aimed to determine whether the preoperative measurement of tumor size, by imaging modalities, deviate from the postoperative pathological measurement in breast cancer.
Patients and Methods
1296 patients diagnosed with invasive ductal breast carcinoma (IDC) during 2007 and 2009 were involved. Pre- and postoperative measurements of tumor size were compared using paired t-test and Chi-square test.
The mean maximum diameters of tumors by imaging modalities and pathology were 27.9 mm and 22.4 mm, respectively. There was a statistically significant difference of 5.5 mm (95% CI: 4.7–6.2, p<0.001) between them. The discordance between pre- and post-surgical measurements of tumor size had significant effect on choosing surgery type, causing less application of breast conserving therapy (p<0.0001).
Compared to pathological size, preoperative measurement by imaging modalities tends to overestimate tumor size. These differences could have implications in the treatment of patients with breast cancer.
PMCID: PMC3906079  PMID: 24489766
16.  Extragastrointestinal stromal tumors: Computed tomography and magnetic resonance imaging findings 
Oncology Letters  2014;9(1):201-208.
Extragastrointestinal stromal tumors (EGISTs) are rare mesenchymal tumors that originate outside the gastrointestinal tract. The aim of the present study was to investigate the computed tomography (CT) and magnetic resonance imaging (MRI) features of EGISTs and analyze the correlations between radiological findings and pathological features. CT and MRI images of 24 patients with EGISTs were reviewed retrospectively. Patient demographics and tumor characteristics, including localization, size, contours, borders, cystic-necrotic components, calcification, hemorrhage, tumor vessels, attenuation and intensity, degree and pattern of enhancement, ascites, tumor invasion, lymphadenopathy and distant metastasis were recorded. Statistical analyses to compare the radiological characteristics of low- and high-grade EGISTs were performed with χ2 or Fisher’s exact tests. The mean patient age at the time of presentation was 53 years. A total of 24 EGISTs were detected, originating in the omentum (n=4), mesentery (n=19) and retroperitoneum (n=1), respectively. The EGISTs displayed a predominantly spindle cell subtype (87.5%; 21/24). The majority of the EGISTs appeared as large (>10 cm; 70.8%; 17/24), round or oval (66.7%; 16/24), cystic-solid (87.5%; 21/24) and ill-defined (66.7%; 16/24) soft-tissue masses. The EGISTs were hypodense (69.6%; 16/23) or isodense (30.4%; 7/23) on CT images, hypointense (50%; 3/6), isointense (33.3%; 2/6) or hyperintense (16.7%; 1/6) on T1-weighted imaging (T1WI), and hyperintense on T2WI (100%; 6/6) and diffusion-WI (DWI; 100%; 6/6). A total of 54.2% (13/24) of the EGISTs displayed tumor vessels. Overall, 95.8% (23/24) of the masses showed marked enhancement and 87.5% (21/24) demonstrated heterogeneous enhancement. Calcification, hemorrhage, ascites and lymphadenopathy were rare characteristics in the EGISTs. Distant metastases were present in 10 patients (41.7%). The size, borders, tumor vessels and distant metastasis correlated with high-grade EGISTs [>5 mitoses/50 high-power fields (HPFs)] (P<0.05). The results of the present study indicated that clinical and radiological features, including advanced age, a large tumor size, cystic-necrotic components, rare lymphadenopathy, a heterogeneous enhancement pattern and hepatic metastasis may aid in the diagnosis of EGISTs. Radiological characteristics, such as a large size (>10 cm), ill-defined borders, tumor vessels and distant metastasis, can provide useful information in identifying the malignant behavior of EGISTs.
PMCID: PMC4246649  PMID: 25435959
extragastrointestinal stromal tumors; computed tomography; magnetic resonance imaging; mitotic count
17.  The Impact of Renal Tumor Size on the Efficacy of Laparoscopic Renal Cryoablation 
Korean Journal of Urology  2010;51(3):171-177.
We evaluated the impact of renal tumor size on the oncologic and surgical efficacy of laparoscopic renal cryosurgery (LRC) according to our intermediate-term experience in Korea.
Materials and Methods
From June 2005 to October 2008, we enrolled 37 patients who underwent LRC for 40 renal tumors. Patients were stratified into four groups according to renal tumor size. Patients who presented with a maximum tumor diameter (MTD) of at least 1 cm but less than 2 cm were assigned to Group 1, those with an MTD equal to or greater than 2 but less than 3 cm were assigned to Group 2, those with an MTD equal to or greater than 3 but less than 4 cm were assigned to Group 3, and those with an MTD equal to or greater than 4 cm were assigned to Group 4. Oncologic and clinical outcomes in each group were compared.
The four groups showed no statistically significant differences in preoperative variables, including age, sex, body mass index, American Society of Anesthesiologists scores, baseline renal function and hemoglobin, and length of hospital stay. Regarding surgical aspects, however, operation time, estimated blood loss, and postoperative complications were significantly increased in patients with larger tumors. Three patients in Group 3 required postoperative transfusions, and 1 patient in Group 4 required conversion to open renal cryosurgery. During the mean follow-up period of 31.6 months, radiologic evidence of tumor recurrence was found in only 2 patients in Group 4.
In this series, LRC for renal tumors smaller than 3 cm was conducted safely without radiologic evidence of tumor recurrence during intermediate-term follow-up. For tumors larger than 3 cm, however, the transfusion rate increased, and for renal tumors larger than 4 cm, the tumor recurrence rate increased significantly.
PMCID: PMC2855452  PMID: 20414392
Cryosurgery; Laparoscopy; Renal cell carcinoma
18.  Stage T1N0M0 renal cell carcinoma: the prognosis in Asian patients 
Chinese Journal of Cancer  2011;30(11):772-778.
The prognostic features of T1N0M0 renal cell carcinoma (RCC) in Asian patients have not been well explored in large sample studies. In this study, we retrospectively analyzed the records of 713 patients undergoing nephrectomy for T1N0M0 RCC between 1991 and 2009 in three Asian hospitals. Univariate and multivariate analysis were performed to identify the independent predictive factors for T1N0M0 RCC prognosis among a series of Clinicopathological parameters, including age, gender, tumor size, Fuhrman grade, and histological classification. Our results showed that 388 of 713 patients had tumors 4.0 cm or smaller (stage T1a) and 325 of 713 patients had tumors 4.0–7.0 cm in size (stage T1b). Five-year cancer-specific survival (CSS) and recurrence-free survival (RFS) rates for this group of patients were 96.0% and 93.5%, respectively. The patients with T1b RCC had a significantly lower 5-year CSS and RFS rates than did those with T1a RCC (CSS, 93.1% vs. 98.6%, P = 0.026; RFS, 90.0% vs. 96.5%, P < 0.001). Patients with low grade (grades I–II) tumors had a higher 5-year CSS (97.8% vs. 91.2%, P = 0.001) and RFS (95.5% vs. 85.5%, P < 0.001) rate than did those with high grade (grades I–II) tumors. More interestingly, when stratifying patients to T1a and T1b groups, the role of grade in distinguishing prognosis could be only observed in patients with T1b disease. Cox regression showed tumor size and Fuhrman grade were significant in predicting CSS and RFS. Our study suggests that the prognosis of patients with T1N0M0 RCC is excellent, and these results are comparable to previously reported studies in Western patients. Furthermore, our data indicates that patients with T1b disease and high Fuhrman grade have high risk of tumor recurrence and death, thus requiring more frequent follow-up.
PMCID: PMC4013300  PMID: 22035858
Renal cell carcinoma; tumor size; Fuhrman grade; prognosis
19.  Clinical Outcomes of Bosniak Category IIF Complex Renal Cysts in Korean Patients 
Korean Journal of Urology  2012;53(6):386-390.
To assess the clinical reliability of the Bosniak IIF category and to determine the proper radiologic follow-up duration and intervals for category IIF complex renal cysts.
Materials and Methods
We studied 201 patients with category IIF renal cysts from January 1996 to January 2011. Renal cyst progression to category III was defined as an increase in complexity of the cyst in follow-up radiologic studies. We monitored radiologic changes and progression of renal cysts during the follow-up period and analyzed the pathologic results of those patients who were treated surgically.
At a mean follow-up of 20 months, only 14 cases (7%) showed evidence of progression to stage III, with a mean time to progression of 11 months (range, 3 to 65 months). There were no significant differences in age, gender, cyst size, or change in cyst size between the progressive and non-progressive groups. Of 12 cases treated surgically, 10 cases (83.3%) showed renal cell carcinoma with pT1 stage, and there was no recurrence during postoperative follow-up of 23 months. Of the 187 patients without radiologic progression, 23 cases were treated surgically, and all of them showed benign cysts.
The IIF category showed significant clinical reliability by a low rate of radiologic progression and a high rate of malignancy in the radiologic progressive group but a low rate of malignancy in the non-progressive group. Although it is hard to decide on a proper follow-up duration because of the variable time to progression, too frequent follow-up study seems to be unnecessary considering that most malignant cases were of a low stage.
PMCID: PMC3382686  PMID: 22741045
Carcinoma; Cysts; Disease progression; Kidney; Renal cell
Urology  2008;72(2):359-363.
While the classification of cancer has traditionally focused on gross and microscopic characteristics of the tumor, overall health of a patient can impact survival. Since patients with renal cell carcinoma (RCC) often have other medical conditions, we explored the impact of preexisting medical disease on survival following radical and partial nephrectomy.
Between January 1995 and August 2003, comorbidity status of 697 nonmetastatic RCC patients who underwent radical or partial nephrectomy was prospectively coded using the Adult Comorbidity Evaluation-27. Histopathologic review of all slides was performed according to the 2004 World Health Organization scheme. Other variables analyzed include age, gender, ethnicity, pathologic stage, Fuhrman grade, and tumor size. The effect of these factors on overall survival (OS) was analyzed using Cox Proportional Hazards Regression.
The median follow-up was 32.2 months for survivors and 36.5 months for all patients. OS rate at 1, 3, and 5 years was 92.0% (641 patients), 75.3% (525 patients) and 52.7% (367 patients). Univariate analyses demonstrated that age, comorbidity, tumor size, Fuhrman grade, and pathologic stage were significant predictors of OS. Multivariate analysis revealed that age (HR 1.42, 95% CI 1.10–1.82, p=0.0067), comorbidity (HR 1.37, 95% CI 1.16–1.63, p=0.0002), pathologic stage (HR 1.97, 95% CI 1.60–2.41, p<0.0001) and grade (HR 1.83, 95% CI 1.28–2.59, p=0.0008) predicted OS.
This study demonstrates that comorbidity is an independent prognostic factor for OS in RCC patients. Capturing comorbidity information using validated instruments can improve the preoperative evaluation of patients by providing more accurate prognostic information.
PMCID: PMC2570477  PMID: 18468663
21.  Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas 
PLoS Medicine  2015;12(2):e1001786.
Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality.
Methods and Findings
Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity’s associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed.
To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.
In this study, Rocco and colleagues examine data collected as part of a large, multi-institutional study, to validate a measure of tumor heterogeneity called MATH and determine whether intra-tumor heterogeneity is itself related to mortality.
Editors’ Summary
Normally, the cells in human tissues and organs only reproduce (a process called cell division) when new cells are needed for growth or to repair damaged tissues. But sometimes a cell somewhere in the body acquires a genetic change (mutation) that disrupts the control of cell division and allows the cell to grow continuously. As the mutated cell grows and divides, it accumulates additional mutations that allow it to grow even faster and eventually from a lump, or tumor (cancer). Other mutations subsequently allow the tumor to spread around the body (metastasize) and destroy healthy tissues. Tumors can arise anywhere in the body—there are more than 200 different types of cancer—and about one in three people will develop some form of cancer during their lifetime. Many cancers can now be successfully treated, however, and people often survive for years after a diagnosis of cancer before, eventually, dying from another disease.
Why Was This Study Done?
The gradual acquisition of mutations by tumor cells leads to the formation of subpopulations of cells, each carrying a different set of mutations. This “intra-tumor heterogeneity” can produce tumor subclones that grow particularly quickly, that metastasize aggressively, or that are resistant to cancer treatments. Consequently, researchers have hypothesized that high intra-tumor heterogeneity leads to worse clinical outcomes and have suggested that a simple measure of this heterogeneity would be a useful addition to the cancer staging system currently used by clinicians for predicting the likely outcome (prognosis) of patients with cancer. Here, the researchers investigate whether a measure of intra-tumor heterogeneity called “mutant-allele tumor heterogeneity” (MATH) is related to mortality (death) among patients with head and neck squamous cell carcinoma (HNSCC)—cancers that begin in the cells that line the moist surfaces inside the head and neck, such as cancers of the mouth and the larynx (voice box). MATH is based on whole-exome sequencing (WES) of tumor and matched normal DNA. WES uses powerful DNA-sequencing systems to determine the variations of all the coding regions (exons) of the known genes in the human genome (genetic blueprint).
What Did the Researchers Do and Find?
The researchers obtained clinical and WES data for 305 patients who were treated in 14 institutions, primarily in the US, after diagnosis of HNSCC from The Cancer Genome Atlas, a catalog established by the US National Institutes of Health to map the key genomic changes in major types and subtypes of cancer. They calculated tumor MATH values for the patients from their WES results and retrospectively analyzed whether there was an association between the MATH values and patient survival. Despite the patients having tumors at various subsites and being given different treatments, every 10% increase in MATH value corresponded to an 8.8% increased risk (hazard) of death. Using a previously defined MATH-value cutoff to distinguish high- from low-heterogeneity tumors, compared to patients with low-heterogeneity tumors, patients with high-heterogeneity tumors were more than twice as likely to die (a hazard ratio of 2.2). Other statistical analyses indicated that MATH provided improved prognostic information compared to that provided by established clinical and molecular characteristics and human papillomavirus (HPV) status (HPV-positive HNSCC at some subsites has a better prognosis than HPV-negative HNSCC). In particular, MATH provided prognostic information beyond that provided by standard disease staging among patients with mouth or laryngeal cancers.
What Do These Findings Mean?
By using data from more than 300 patients treated at multiple institutions, these findings validate the use of MATH as a measure of intra-tumor heterogeneity in HNSCC. Moreover, they provide one of the first large-scale demonstrations that intra-tumor heterogeneity is clinically important in the prognosis of any type of cancer. Before the MATH metric can be used in clinical trials or in clinical practice as a prognostic tool, its ability to predict outcomes needs to be tested in prospective studies that examine the relation between MATH and the outcomes of patients with identically treated HNSCC at specific head and neck subsites, that evaluate the use of MATH for prognostication in other tumor types, and that determine the influence of cancer treatments on MATH values. Nevertheless, these findings suggest that MATH should be considered as a biomarker for survival in HNSCC and other tumor types, and raise the possibility that clinicians could use MATH values to decide on the best treatment for individual patients and to choose patients for inclusion in clinical trials.
Additional Information
Please access these websites via the online version of this summary at
The US National Cancer Institute (NCI) provides information about cancer and how it develops and about head and neck cancer (in English and Spanish)
Cancer Research UK, a not-for-profit organization, provides general information about cancer and how it develops, and detailed information about head and neck cancer; the Merseyside Regional Head and Neck Cancer Centre provides patient stories about HNSCC
Wikipedia provides information about tumor heterogeneity, and about whole-exome sequencing (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information about The Cancer Genome Atlas is available
A PLOS Blog entry by Jessica Wapner explains more about MATH
PMCID: PMC4323109  PMID: 25668320
22.  Integrated FDG-PET/CT imaging is useful in the approach to carcinoid tumors of the lung 
Carcinoids enter the differential diagnosis of the solitary pulmonary nodule. Bronchial carcinoids have been traditionally considered as FDG-PET negative but recent studies have found an higher sensitivity of integrated FDG-PET/CT for the detection of these neoplasms. The purpose of this study was to investigate the value of integrated FDG-PET/CT for the evaluation of SPN suspected to be carcinoids.
All patients with pathologically proven bronchial carcinoids who had FDG-PET/CT scans between 2006 and 2012 have been retrospectively reviewed. PET/CT was performed with the same scanner and the same technique for all patients. The following data were retrieved: age, sex CT findings (side, location, size, shape, margins), SUVmax, type of operation, pathological findings (size and number of mitoses). Regarding PET findings, only SUVmax was considered, whereas the visual assessment was not undertaken. Carcinoids were defined as typical and atypical and as central and peripheral. The long-term follow-up was also recorded. The SUVmax was compared with the other clinical, radiological and pathological variables to find any significant difference or correlation.
Twenty-five patients were retrieved, 24 typical and one atypical carcinoid, 21 peripheral and 4 central lesions. The mean diameter on CT-scan was 25.3 mm and the clinical size correlated well with the pathological size. Sixty percent of the tumors were ovoid and 68% had smooth margins. The mean SUVmax was 3.6 (range 1.4-12.9). All the lesions were completely resected. The regression analysis showed a direct correlation between the SUVmax and the tumor size (p = 0.004). No further correlations were found between the SUVmax and the other variables. None of the patients had recurrent disease or died during the follow-up.
Our study showed that FDG-PET/CT might be a useful tool in the evaluation of SPNs suspected to be bronchial carcinoids. When a solitary pulmonary nodule shows an ovoid/round shape and smooth margins on the CT scan and demonstrates an FDG uptake higher than that of the normal lung and with a SUVmax value >1-1.5, a carcinoid should be suspected. If benign lesions can be presumably excluded, surgical resection or at least a biopsy of the lesion is recommended.
PMCID: PMC3879007  PMID: 24305515
Bronchial carcinoid; Positron emission tomography; Standardized uptake value
23.  Renal oncocytoma: experience of Clinical Urology A, Urology Department, CHU Ibn Sina, Rabat, Morocco and literature review 
Renal oncocytoma is a rare and benign renal tumor. Only few cases have been reported in Moroccan populations. In the present study, we report our experiences in the diagnosis, management and follow-up of this disease. We report on six cases of renal oncocytoma indentified between 1990 and 2008 in the urology department of “CHU Ibn Sina” in Rabat. These six cases are listed among 130 kidney tumors reported during the study period. We assess the clinical, radiological and therapeutic features of the patients and we review literature. Six cases of renal oncocytoma, representing 4.6% of all primitive kidney tumors treated in our institution during the study period. The mean age was 53 ±9.7 years (range 34 to 61 years). One patient was asymptomatic at presentation, five patients (83%) had flank pain and two (33%) had macroscopic hematuria. The tumor was right sided in 4 cases (66%) and left sided in 2 cases (33%). All patients underwent CT scan which showed, in three cases, a centrally located stellate area of low attenuation. The clinical suspicion of oncocytoma was made preoperatively in only 3 patients by imaging studies, but the suspicion of renal cell carcinoma persist and all patients were treated with radical nephrectomy. Definitive diagnosis was made in all cases postoperatively. All the tumors were well circumscribed but unencapsulated. The mean tumor size was 8,75±2,04 cm. Four patients were classified at stage pT2 and two at stage p T1. Most of the pathological features in our patients were typical of this entity. Predominant cell type was a typical oncocytoma with general low mitotic activity. No extension to peri-nephric fat tissue or lymphovascular invasion was observed. After a mean follow-up of 36 months (range 26-62 months), there was neither recurrence nor death from oncocytoma. Accordingly, the disease-specific survival was 100%. Renal oncocytoma has a benign clinical course with excellent long-term outcomes. In our series, it happened mostly in females and is more frequently symptomatic. Although radical nephrectomy is the usual treatment, a conservative approach should be considered whenever there are signs of clinical and radiological presumptions.
PMCID: PMC3473970  PMID: 23077705
Renal oncocytoma; tumor; diagnosis; treatment
24.  Association of Clinical and Radiographic Features with Perinephric “Sticky” Fat 
Journal of Endourology  2013;27(3):370-373.
Background and Purpose
The discovery of thick, adherent, perinephric sticky fat (PSF) is relatively common during open or laparoscopic retroperitoneal surgery. To our knowledge, however, there has been no previous analysis of clinical or radiographic features associated with the development of PSF or of perioperative outcomes for those patients in whom it is found. Our objective is to analyze potential predictive features and determine whether there is any effect on clinical or pathologic outcomes for patients with perinephric sticky fat.
Patients and Methods
Patients undergoing partial nephrectomy or laparoscopic cryoablation with available preoperative imaging were identified from 2005 to 2011. Operative records were reviewed to identify patients with and without PSF. Preoperative images and medical records were examined to obtain patient data regarding potential predictors as well as clinical and pathologic outcomes.
A total of 29 patients were identified—16 with PSF and 13 controls. Statistically significant factors associated with PSF included sex, tumor size, presence of perinephric stranding, tumor >50% exophytic, and thickness of perinephric fat (P<0.05). Median total operative time for patients with sticky fat was nearly 40 minutes longer than the control group (228 min vs 190 min, P<0.05). All four (17%) patients with Fuhrman grade 3 or 4 renal-cell carcinoma were from the sticky fat group (P=0.09).
Despite the small sample size, multiple possible factors associated with perinephric sticky fat were identified and may provide guidance for future investigation of this phenomenon.
PMCID: PMC4277038  PMID: 22966767
25.  Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value 
PLoS Medicine  2013;10(5):e1001453.
Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses.
Methods and Findings
Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype–like, normal-like, serrated CC phenotype–like), and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II–III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after adjusting for age, sex, stage, and the emerging prognostic classifier Oncotype DX Colon Cancer Assay recurrence score (hazard ratio 1.5, 95% CI 1.1–2.1, p = 0.0097). However, a limitation of this study is that information on tumor grade and number of nodes examined was not available.
We describe the first, to our knowledge, robust transcriptome-based classification of CC that improves the current disease stratification based on clinicopathological variables and common DNA markers. The biological relevance of these subtypes is illustrated by significant differences in prognosis. This analysis provides possibilities for improving prognostic models and therapeutic strategies. In conclusion, we report a new classification of CC into six molecular subtypes that arise through distinct biological pathways.
Please see later in the article for the Editors' Summary
Editors' Summary
Cancer of the large bowel (colorectal cancer) is the third most common cancer in men and the second most common cancer in women worldwide. Despite recent advances in the screening, diagnosis, and treatment of colorectal cancer, an estimated 608,000 people die every year from this form of cancer—8% of all cancer deaths. The prognosis and treatment options for colorectal cancer depend on five pathological stages (0–IV), each of which has a different treatment option and five year survival rate, so it is important that the stage is correctly identified. Unfortunately, pathological staging fails to accurately predict recurrence (relapse) in patients undergoing surgery for localized colorectal cancer, which is a concern, as 10%–20% of patients with stage II and 30%–40% of those with stage III colorectal cancer develop recurrence.
Why Was This Study Done?
Previous studies have investigated whether there are any possible gene expression profiles (identified through microarray techniques) that can help predict prognosis of colorectal cancer, but so far, there have been no firm conclusions that can aid clinical practice. In this study, the researchers used genetic information from a French multicenter study to identify a standard, reproducible molecular classification based on gene expression analysis of colorectal cancer. The authors also assessed whether there were any associations between the identified molecular subtypes and clinical and pathological factors, common DNA alterations, and prognosis.
What Did the Researchers Do and Find?
The researchers used genetic information from a cohort of 750 patients with stage I to IV colorectal cancer who underwent surgery between 1987 and 2007 in seven centers in France. The researchers identified relevant clinical and pathological staging information for each patient from the medical records and calculated recurrence-free survival (the time from surgery to the first recurrence) for patients with stage II or III disease. In the genetic analysis, 566 tumor samples were suitable—443 were used in a discovery set, to create the classification, and the remainder were used in a validation set, to test the classification. The researchers also used information from eight public datasets to validate their findings.
Using these methods, the researchers classified the colon cancer samples into six molecular subtypes (based on gene expression data) and, on further analysis and validation, were able to distinguish the main biological characteristics and deregulated pathways associated with each subtype. Importantly, the researchers found that that these six subtypes were associated with distinct clinical and pathological characteristics, molecular alterations, specific gene expression signatures, and deregulated signaling pathways. In the prognostic analysis based on recurrence-free survival, the researchers found that patients whose tumors were classified in one of two clusters (C4 and C6) had poorer recurrence-free survival than the other patients.
What Do These Findings Mean?
These findings suggest that it is possible to classify colorectal cancer into six robust molecular subtypes that might help identify new prognostic subgroups and could provide a basis for developing robust prognostic genetic signatures for stage II and III colorectal cancer and for identifying specific markers for the different subtypes that might be targets for future drug development. However, as this study was retrospective and did not include some known predictors of colorectal cancer prognosis, such as tumor grade and number of nodes examined, the significance and robustness of the prognostic classification requires further confirmation with large prospective patient cohorts.
Additional Information
Please access these websites via the online version of this summary at
The American Cancer Society provides information about colorectal cancer and also about how colorectal cancer is staged
The US National Cancer Institute also provides information on colon and rectal cancer and colon cancer stages
PMCID: PMC3660251  PMID: 23700391

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