Koei Ikeda

Diffusion-weighted magnetic resonance imaging for diagnosing malignant pulmonary nodules/masses: Comparison with positron emission tomography

Introduction: Recent developments of diffusion-weighted magnetic resonance imaging (DWI) make it possible to image malignant tumors to provide tissue contrast based on difference in the diffusion of water molecules among tissues, which can be measured by apparent diffusion coefficient (ADC) value. The aim of this study is to examine the usefulness of DWI for benign/malignant discrimination of pulmonary nodules/masses compared with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Methods: PET and DWI were carried out prospectively in 104 patients with 140 pulmonary nodules/masses before surgery. FDG uptake of each lesion was quantitatively measured by a contrast ratio of standard uptake value (SUV-CR) between the lesions and contralateral lung. Diffusion of water molecule in each lesion was quantitatively measured by a minimum ADC (ADC-min). The diagnostic results were compared between the two modalities. Results: The receiver operating characteristics curve showed cutoff values of the ADC-min and the SUV-CR for benign/malignant discrimination to be 1.1 × 10−3 mm2/s and 0.37, respectively. DWI and PET showed sensitivities of 0.70 and 0.72 and specificities of 0.97 and 0.79, respectively. Although there was no significant difference in sensitivity between the two methods, DWI showed a significantly higher specificity than PET because of fewer false-positives for active inflammatory lesions (p = 0.03). The ADC-min and SUV-CR values showed a significant reverse correlation (r = −0.504, p < 0.001). Conclusions: DWI may be able to be used in place of FDG-PET to distinguish malignant from benign pulmonary nodules/masses with fewer false-positive results compared with FDG-PET.

Diffusion-weighted magnetic resonance imaging can be used in place of positron emission tomography for N staging of non–small cell lung cancer with fewer false-positive results

OBJECTIVE One of the deficiencies of positron emission tomography for N staging in lung cancer is a false-positive result caused by concurrent lymphadenitis. Recently, diffusion-weighted magnetic resonance imaging has been reported to be able to image tumors of body organs. The aim of this study is to examine the usefulness of diffusion-weighted magnetic resonance imaging for N staging of non-small cell lung cancer compared with positron emission tomography-computed tomography. METHODS Both positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging were prospectively used in 88 patients before surgical intervention for non-small cell lung cancer to examine 734 lymph node stations. The diagnostic results of positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging were compared. The diameters of the metastatic foci within lymph nodes were measured on hematoxylin and eosin-stained sections to compare the detectable size of metastatic foci between positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging. RESULTS The accuracy of N staging in the 88 patients was 0.89 with diffusion-weighted magnetic resonance imaging, which was significantly higher than the value of 0.78 obtained with positron emission tomography-computed tomography (P = .012), because of less overstaging in the former. Among the 734 lymph node stations examined pathologically, 36 had metastases, and the other 698 did not. Although there was no significant difference in the diagnosis of the 36 metastatic lymph node stations between the 2 methods, diffusion-weighted magnetic resonance imaging was more accurate for diagnosing the 698 nonmetastatic stations than positron emission tomography-computed tomography because of fewer false-positive results (P = .002). The detectable size of metastatic foci within lymph nodes was 4 mm in both positron emission tomography-computed tomography and diffusion-weighted magnetic resonance imaging. CONCLUSIONS Diffusion-weighted magnetic resonance imaging can be used in place of positron emission tomography-computed tomography for N staging of non-small cell lung cancer with fewer false-positive results compared with positron emission tomography-computed tomography.

Is diffusion-weighted magnetic resonance imaging superior to positron emission tomography with fludeoxyglucose F 18 in imaging non–small cell lung cancer?

OBJECTIVE This retrospective analysis examined whether diffusion-weighted magnetic resonance imaging might be as useful as positron emission tomography with fludeoxyglucose F 18 for (1) discriminating between non-small cell lung cancer and benign pulmonary nodules and (2) predicting aggressiveness of non-small cell lung cancer. METHODS Diffusion-weighted magnetic resonance imaging and positron emission tomography were performed before surgery in 110 patients with 124 pulmonary nodules smaller than 3 cm, including 96 non-small cell lung cancers and 28 benign nodules. Diffusion of water molecules in magnetic resonance imaging was measured by minimum value of apparent diffusion coefficient. The criterion standard was the result of histologic diagnosis or follow-up examination. Sensitivity and specificity for differentiating between cancers and benign nodules were compared between diffusion-weighted imaging and positron emission tomography. Apparent diffusion coefficient in diffusion-weighted imaging and fludeoxyglucose F 18 uptake in positron emission tomography were examined with respect to pathologic tumor stage; lymphatic, vascular and pleural involvements; and histologic differentiation. RESULTS There were no significant differences between diffusion-weighted magnetic resonance imaging and positron emission tomography in sensitivity or specificity for non-small cell lung cancer. Whereas positron emission tomography showed significant differences in fludeoxyglucose F 18 uptake between pathologic stages IA versus IB or more advanced stages; between tumors with and without lymphatic, vascular, or pleural involvement; and between well-differentiated and moderately or poorly differentiated adenocarcinomas (P <.01-0.001), no significant differences in apparent diffusion coefficient values in were observed. CONCLUSION Diffusion-weighted magnetic resonance imaging is equivalent to positron emission tomography in distinguishing non-small cell lung cancer from benign pulmonary nodules but is not as useful for predicting aggressiveness of non-small cell lung cancer.

Novel Germline Mutation: EGFR V843I in Patient With Multiple Lung Adenocarcinomas and Family Members With Lung Cancer

A novel germline transmission of the epidermal growth factor receptor (EGFR) mutation V843I in a family with multiple members with lung cancer is reported. The proband was a 70-year-old woman with multiple adenocarcinomas who exhibited secondary EGFR mutations, either L858R or L861Q, in the specimens of resected tumors, in addition to a germline EGFR V843I mutation. These observations suggest that the germline EGFR V843I mutation might have altered EGFR signaling in the multicentric development of adenocarcinoma, bronchoalveolar carcinoma, and atypical adenomatous hyperplasia and also might have had a role in the development of lung cancer in multiple members of her family.

Epidermal Growth Factor Receptor Mutations in Multicentric Lung Adenocarcinomas and Atypical Adenomatous Hyperplasias

Background: The mechanisms of generation and progression of multicentric lung adenocarcinoma (AD), bronchioloalveolar carcinoma (BAC), and atypical adenomatous hyperplasia (AAH) in the peripheral lung is not well known. In this study, we analyzed epidermal growth factor receptor (EGFR) mutations in the cases of multicentric AD, BAC, and AAH to reveal the role of EGFR mutation in their generations and progressions. Method: Ninety-seven AAH, BAC, or AD lesions less than 3 cm in size in 26 patients were surgically resected. Of these, EGFR mutations of the nodules with the highest and the second highest grade of histologic malignancy were examined in each patient by using the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp method. Results: EGFR mutations could be examined in 48 nodules in the 26 patients. The EGFR mutations were found more frequently in lesions with higher histologic malignancy, ie, 9 of 10 ADs (90%), 16 of 28 BACs (57%), and one of 10 AAHs (10%). In 22 patients who could be examined of EGFR mutations for the two lesions in each patient, only two patients (9%) had the same mutation patterns between the two lesions, whereas 15 patients (68%) had the different statuses and the remaining five (23%) had no mutations. Conclusion: Our data demonstrated that EGFR mutations seem to contribute to the acquisition of malignant potential in the AAH-AD sequence and occur independently in each lesion and in the cases of multicentric AD, BAC, and AAH.

Marking of small pulmonary nodules before thoracoscopic resection: injection of lipiodol under CT-fluoroscopic guidance.

RATIONALE AND OBJECTIVES The aim of the present study was to examine the usefulness and record the complications of preoperative lipiodol marking using computed tomographic (CT) fluoroscopy for the intraoperative localization of 107 pulmonary nodules. METHODS Lipiodol marking was performed under CT fluoroscopic guidance in 65 patients with 107 nodules. Of these, 65 (60.7%) were nodules with ground-glass opacity, and 42 were solid nodules on CT images. All nodules were marked with 0.3 to 0.5 mL lipiodol under CT fluoroscopic guidance 1 or 3 days before or on the day of surgery. At surgery, marked nodules were grasped with ring-shaped forceps under a C-arm fluoroscope and resected. Postoperatively, all 55 patients with malignant tumors (n = 78) were followed by computed tomography at 3-month intervals to detect needle tract or pleural recurrence. RESULTS All 107 nodules were marked with lipiodol; under the C-arm fluoroscope, they appeared as radiopaque spots. On postprocedural computed tomography, pneumothorax occurred in 20 patients (31%); its incidence was higher in patients with lung emphysema surrounding the nodules (P = .09), three of whom required tube drainage. Computed tomography detected pulmonary hemorrhage in 10 patients (15%); it was more frequent in patients with deep than shallow nodules (>or=6 cm from the pleural surface and <6 cm from the pleural surface, respectively; P = .04). No patients presented with recurrence in needle tracts or on the pleural surface during a median postoperative follow-up of 14 months. CONCLUSION Lipiodol marking under CT fluoroscopic guidance is a useful and safe procedure for the intraoperative localization of ground-glass opaque and/or small, deep, solid nodules.

Aberrant methylation of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer

Genome-wide DNA hypomethylation and gene hypermethylation play important roles in instability and carcinogenesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. Slit homolog 2 (SLIT2), myelin and lymphocyte protein gene (MAL) and insulin-like growth factor binding protein 7 (IGFBP7) are known to be hypermethylated in various malignancies. The aim of the present study was to assess the precise methylation levels of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer (NSCLC) using a pyrosequencing assay. Methylation of all regions was examined in 56 primary NSCLCs using a pyrosequencing assay. Changes in mRNA expression levels of SLIT2, MAL and IGFBP7 were measured before and after treatment with a demethylating agent. Methylation of these genes was also examined in 9 lung cancer cell lines using RT-PCR and a pyrosequencing assay. Frequencies of hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7, defined by predetermined cut off values, were 55, 64, 46 and 54% in NSCLCs, respectively and exhibited tumor-specific features. The hypermethylation of all genes was well correlated with changes in expression. The methylation level and frequency of MAL were significantly higher in smokers and in patients without EGFR mutations. Through accurate measurement of methylation levels using pyrosequencing, hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7 were frequently detected in NSCLCs and associated with various clinical features. Analysis of the methylation profiles of these genes may, therefore, provide novel opportunities for the therapy of NSCLCs.

Long interspersed nucleotide element 1 hypomethylation is associated with poor prognosis of lung adenocarcinoma.

BACKGROUND Genome-wide DNA hypomethylation is known to play important roles in genomic instability and carcinogenesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. The aim of this study was to evaluate prognostic significance of LINE-1 hypomethylation in lung adenocarcinoma. METHODS A consecutive series of 211 lung adenocarcinoma patients who underwent curative resections without any preoperative chemotherapy or radiotherapy at Kumamoto University Hospital between April 2010 and December 2012 were included. The LINE-1 methylation levels were quantified in tumor and noncancerous tissue by Pyrosequencing assay. RESULTS Higher histologic grade and positive findings for vascular invasion were significantly associated with lower methylation levels. The disease-free survival in the hypomethylation group was significantly shorter than that of the non-hypomethylation group. The prognostic difference was more obvious in advanced cases (stage II, III) than in stage I cases. CONCLUSIONS The LINE-1 methylation level is associated with histologic grade and vascular invasion of lung adenocarcinoma. Additionally, LINE-1 hypomethylation is a useful biomarker to predict early recurrence of lung adenocarcinoma.

The expression of type IV collagen α6 chain is related to the prognosis in patients with esophageal squamous cell carcinoma

BackgroundThe destruction of the basement membrane (BM) is the first step in cancer cell invasion and metastasis. Type IV collagen is a major component of the BM, and is composed of six genetically distinct α(IV) chains: α1(IV) to α6(IV). The loss of α5/α6(IV) chains from the epithelial BM at the early stage of cancer cell invasion has been reported in several cancers. However, the expression of α5/α6(IV) chains in esophageal squamous cell carcinoma (ESCC) remains unclear.MethodsThe expression of α(IV) chains in 116 resected ESCC specimens was immunohistochemically examined. The role of α6(IV) chain was assessed in ESCC cell lines by short interfering RNA (siRNA).ResultsIn intraepithelial carcinoma, the α5/α6(IV) chains were stained in a continuous linear pattern in the BM. In some cases of ESCC with the invasion beyond the lamina propria, the α5/α6(IV) chains were lost in the BM zone surrounding the cancer cell nests, but in other cases they remained. In the former, the disease-free survival and overall survival were significantly better than in those with the latter. The down-regulation of α6(IV) chain expression by siRNA revealed a slight increase of cancer cell invasiveness.ConclusionsThe evaluation of α5/α6(IV) chains may be a useful marker for determining tumor cell properties, as a prognostic factor, in patients with ESCC.

Differential expression of basement membrane type IV collagen α chains in gastric intramucosal neoplastic lesions

BackgroundThe histological diagnosis of gastric intramucosal neoplastic lesions (GINLs) is controversial among experienced pathologists. Although the destruction of the epithelial basement membrane (BM) and the invasion of neoplastic epithelial cells into the interstitium of the lamina propria is distinct proof of “intramucosal carcinoma,” histological evaluation of GINLs is difficult and ambiguous, especially intestinal-type adenocarcinoma. Type IV collagen is a major component of the BM, and comprises six genetically distinct α(IV) chains, α1(IV) to α6(IV). In several types of carcinomas, the loss of α5/α6(IV) chains of the epithelial BM at an early invasive stage has been reported. However, the expression of α5/α6(IV) chains in GINLs is still unclear. We examined the immunohistochemical expression of α(IV) chains in GINLs and investigated whether the expression pattern was a diagnostic marker of gastric intramucosal carcinoma.MethodsThe expression of α(IV) chains and Ki-67 in 60 resected GINL specimens was immunohistochemically examined.ResultsIn normal gastric epithelium, α1(IV), α2(IV), α5(IV), and α6(IV) chains were expressed continuously in the BM. In most tubular adenomas (Japanese classification), these four chains were stained continuously in the BM, whereas in tubular adenocarcinomas (Japanese classification), the α5/α6(IV) chains had disappeared, partially or completely. The expression of α5/α6(IV) chains was closely related to the grade of histological atypia. In addition, the loss of α5/α6(IV) chains was significantly correlated with tumor cell growth activity.ConclusionsThe loss of α5/α6(IV) chains might be a useful diagnostic finding for gastric intramucosal carcinoma in GINL cases.