Reliability of preoperative breast biopsies showing ductal carcinoma in situ and implications for non-operative treatment: a cohort study.

PURPOSE: The future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen. METHODS: We studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000-2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded. RESULTS: Among 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3-18.1) were upstaged to IBC and a further 14.6% (11.3-18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, pdifference = 0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, pdifference < 0.001) and with use of 14G core-needle rather than 9G vacuum-assisted biopsy (22.8% vs 7.0%, pdifference < 0.001). Larger mammographic size increased the risk of both upgrading (pheterogeneity = 0.01) and upstaging (pheterogeneity = 0.004). CONCLUSIONS: The risk of upstaging of DCIS in preoperative biopsies is lower than previously estimated and justifies conducting randomized clinical trials testing the safety of active surveillance for lower grade DCIS. Selection of women with low grade DCIS for such trials, or for active surveillance, may be improved by consideration of the additional factors identified in this study.

Prostate tumor delineation using multiparametric magnetic resonance imaging: Inter-observer variability and pathology validation.

BACKGROUND AND PURPOSE: Boosting the dose to the largest (dominant) lesion in radiotherapy of prostate cancer may improve treatment outcome. The success of this approach relies on the detection and delineation of tumors. The agreement among teams of radiation oncologists and radiologists delineating lesions on multiparametric magnetic resonance imaging (mp-MRI) was assessed by measuring the distances between observer contours. The accuracy of detection and delineation was determined using whole-mount histopathology specimens as reference. MATERIAL AND METHODS: Six observer teams delineated tumors on mp-MRI of 20 prostate cancer patients who underwent a prostatectomy. To assess the inter-observer agreement, the inter-observer standard deviation (SD) of the contours was calculated for tumor sites which were identified by all teams. RESULTS: Eighteen of 89 lesions were identified by all teams, all were dominant lesions. The median histological volume of these was 2.4cm(3). The median inter-observer SD of the delineations was 0.23cm. Sixty-six of 69 satellites were missed by all teams. CONCLUSION: Since all teams identify most dominant lesions, dose escalation to the dominant lesion is feasible. Sufficient dose to the whole prostate may need to be maintained to prevent under treatment of smaller lesions and undetected parts of larger lesions.

(18)F-fluorodeoxyglucose positron emission tomography versus computed tomography in predicting histopathological response to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in resectable non-small cell lung cancer.

PURPOSE: To prospectively evaluate diagnostic computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for identification of histopathologic response to neoadjuvant erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with resectable non-small cell lung cancer (NSCLC). METHODS: This study was designed as an open-label phase 2 trial, performed in four hospitals in the Netherlands. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. CT and FDG-PET/CT were performed at baseline and after 3 weeks of treatment. CT was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. FDG-PET/CT, tumor FDG uptake, and changes were measured by standardized uptake values (SUV). Radiologic and metabolic responses were compared to the histopathological response. RESULTS: Sixty patients were enrolled onto this study. In 53 patients (22 men, 31 women), the combination of CT, FDG-PET/CT, and histopathological evaluation was available for analysis. Three patients (6 %) had radiologic response. According to European Organisation for Research and Treatment of Cancer (EORTC) criteria, 15 patients (28 %) showed metabolic response. In 11 patients, histopathologic response (≥50 % necrosis) was seen. In predicting histopathologic response, relative FDG change in SUVmax showed more SUVmax decrease in the histopathologic response group (-32 %) versus the group with no pathologic response (-4 %) (p = 0.0132). Relative change in tumor size on diagnostic CT was similar in these groups with means close to 0. CONCLUSIONS: FDG-PET/CT has an advantage over CT as a predictive tool to identify histopathologic response after 3 weeks of EGFR-TKI treatment in NSCLC patients.

Tumor response and toxicity of neoadjuvant erlotinib in patients with early-stage non-small-cell lung cancer.

PURPOSE: The development of targeted therapy has introduced new options to improve treatment outcome in selected patients. The objective of this prospective study was to investigate the safety of preoperative erlotinib treatment and the (in vivo) response in patients with early-stage resectable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This study was designed as an open-label phase II trial, performed in four hospitals in the Netherlands, according to a Simon's minimax two-stage procedure. Initially, operable patients with early-stage NSCLC (n = 15) were entered from an enriched population (never-smoker, female sex, nonsquamous histology, or Asian ethnicity); thereafter, unselected patients were included to a total of N = 60. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. Response to treatment was evaluated using [18F] fluorodeoxyglucose positron emission tomography (PET) and computed tomography (CT) scans during treatment and histologic examination of the resection specimen. Primary end points were toxicity and pathologic response. RESULTS: Sixty patients were included. Seven patients stopped treatment prematurely (12%). Skin toxicity was present in 37 patients (62%), and diarrhea was present in 21 patients (35%). PET evaluation revealed metabolic response (> 25% standardized uptake value decrease) in 16 patients (27%); CT evaluation using Response Evaluation Criteria in Solid Tumors (RECIST) showed response in three patients (5%). At surgery, no unexpected complications occurred. Pathologic examination showed more than 50% necrosis in 14 patients (23%), of whom three (5%) had more than 95% tumor necrosis. The response rate in the enriched population was 34% (10 of 29 patients). CONCLUSION: According to predefined criteria, neoadjuvant erlotinib has low toxicity and sufficient activity to deserve further testing in future studies in an enriched population.

MRI of the breast in patients with DCIS to exclude the presence of invasive disease.

OBJECTIVES: Core biopsy underestimates invasion in more than 20% of patients with preoperatively diagnosed ductal carcinoma in situ (DCIS) without evidence of invasion (pure DCIS). The aim of the current study was to evaluate the efficacy of preoperative magnetic resonance imaging (MRI) to discriminate between patients with DCIS who are at high risk of invasive breast cancer and patients at low risk. METHODS: One hundred and twenty-five patients, preoperatively diagnosed with pure DCIS (128 lesions; 3 bilateral) by core-needle biopsy, were prospectively included. Clinical, mammographic, histological (core biopsy) and MRI features were assessed. All patients underwent breast surgery. Analyses were performed to identify features associated with presence of invasion. RESULTS: Eighteen lesions (14.1%) showed invasion on final histology. Seventy-three lesions (57%) showed suspicious enhancement on MRI with a type 1 (n = 12, 16.4%), type 2 (n = 19, 26.0%) or type 3 curve, respectively (n = 42, 57.5%). At multivariate analysis, the most predictive features for excluding presence of invasive disease were absence of enhancement or a type 1 curve on MRI (negative predictive value 98.5%; A(Z) 0.80, P = 0.00006). CONCLUSION: Contrast medium uptake kinetics at MRI provide high negative predictive value to exclude presence of invasion and may be useful in primary surgical planning in patients with a preoperative diagnosis of pure DCIS. KEY POINTS: It is important to determine invasion in breast DCIS. • MRI contrast medium uptake kinetics can help exclude the presence of invasion. • However, the positive predictive value for the presence of invasion is limited. • MRI features were more accurate at predicting invasion than mammographic features alone.

Identification of high risk pathological node positive penile carcinoma: value of preoperative computerized tomography imaging.

PURPOSE: Patients with penile carcinoma, and 3 or more histopathologically proven unilateral metastatic inguinal nodes, and/or extranodal extension, and/or pelvic metastasis are considered a subgroup with prognostically unfavorable parameters for disease specific death and local recurrence after inguinal lymphadenectomy. We established radiographic criteria for the preoperative identification of such patients. MATERIALS AND METHODS: Preoperative diagnostic computerized tomography studies of 30 patients with penile carcinoma with proven unilateral or bilateral lymph node metastasis were reviewed independently by 2 radiologists blinded for patient data. All computerized tomography images were analyzed per side (60). Several radiographic criteria were assessed for regional lymph nodes with short-axis diameter 8 mm or greater and/or central nodal necrosis. Sides were characterized as high risk if histopathology revealed 3 or more metastatic inguinal nodes and/or extranodal extension and/or pelvic nodal involvement. RESULTS: Histopathological nodal involvement was found in 38 sides (63%) including 22 sides (37%) defined as high risk. The presence of central nodal necrosis and/or irregular nodal border of the regional lymph nodes on the preoperative computerized tomography identified the high risk subgroup with a sensitivity of 95% (21 of 22) and a specificity of 82% (31 of 38). All 7 sides falsely designated as high risk harbored inguinal metastases but they were classified as low risk. The interobserver agreement of each radiographic parameter was almost perfect. CONCLUSIONS: The presence of central nodal necrosis and/or an irregular nodal border of the regional lymph nodes on preoperative computerized tomography images are accurate and reproducible criteria to identify high risk pathological node positive penile cancer. These criteria can be used for risk stratification and patient counseling.

Tumour thickness in oral cancer using an intra-oral ultrasound probe.

OBJECTIVES: To investigate tumour-thickness measurement with an intra-operative ultrasound (US) probe. METHODS: A retrospective data analysis was undertaken for a total of 65 patients with a T1-2 oral cavity cancer, who were seen at a tertiary referral centre between 2004 and 2010. The correspondence between tumour thickness measured by ultrasonography and histopathology was assessed by Pearson's correlation coefficient, and also between tumour thickness and the development of neck metastasis. RESULTS: In 11 cases, intra-oral measurement was not optimal due to limited mouth opening (n=2) or impossibility to depict the lesion (n=9). Tumour thickness measured by US correlated well with histopathology (n=23, R=0.93). Tumour thickness of ≤7 mm carries a risk of lymph node metastasis of 12%, whereas in tumours exceeding 7 mm this risk is 57% (p=0.001). Twenty-five percent developed neck metastasis and 19% had local recurrence. CONCLUSION: Tumour thickness is an important predictive marker for lymph node metastases. As such, it can help in decision-making with regard to management of the primary tumour and neck. Based upon our findings, a wait-and-see policy is only warranted for superficial lesions with tumour thickness of less than 7 mm, but only if regular follow-up using US-guided aspiration of the neck is ensured.

18F-FDG PET/CT for monitoring induction chemotherapy in patients with primary inoperable penile carcinoma: first clinical results.

PURPOSE: The aim of this study was to explore the role of (18)F-FDG PET/CT for monitoring treatment response in patients with primary inoperable (i.e. advanced) penile carcinoma treated with induction chemotherapy and to compare the metabolic tumour response with the radiological evaluation provided by CT imaging. METHODS: Eight patients with advanced penile carcinoma were studied. All had undergone (18)F-FDG PET/CT imaging at baseline and after two cycles of induction chemotherapy. The metabolic tumour response was evaluated according to European Organisation for Research and Treatment of Cancer (EORTC) criteria for therapy response. The radiologic tumour response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Response evaluations were done separately and blinded for other patient data. For definition of the reference, all patients were rated as responders or non-responders by a multidisciplinary tumour board. RESULTS: PET/CT showed hypermetabolic uptake of FDG matching with malignancy in all eight patients. According to the reference, six patients were responders and two non-responders after two cycles of chemotherapy. The metabolic tumour response was considered accurate in all eight patients. In seven of the eight patients, the radiological tumour response was in agreement. In three patients correctly identified as responders, the radiological tumour response was deemed suboptimal compared with the metabolic assessment. Five of the six responders continued chemotherapy after response evaluation up to four cycles and were operated subsequently. Histopathological analysis confirmed the metabolic tumour response. CONCLUSION: (18)F-FDG PET/CT imaging is feasible for monitoring response in patients with advanced penile carcinoma treated with induction chemotherapy. Our preliminary results suggest that PET/CT is potentially more reliable than CT alone.

Breast tomosynthesis in clinical practice: initial results.

PURPOSE: The purpose of this study was to assess the potential value of tomosynthesis in women with an abnormal screening mammogram or with clinical symptoms. Mammography and tomosynthesis investigations of 513 woman with an abnormal screening mammogram or with clinical symptoms were prospectively classified according to the ACR BI-RADS criteria. Sensitivity and specificity of both techniques for the detection of cancer were calculated. In 112 newly detected cancers, tomosynthesis and mammography were each false-negative in 8 cases (7%). In the false-negative mammography cases, the tumor was detected with ultrasound (n = 4), MRI (n = 2), by recall after breast tomosynthesis interpretation (n = 1), and after prophylactic mastectomy (n = 1). Combining the results of mammography and tomosynthesis detected 109 cancers. Therefore in three patients, both mammography and tomosynthesis missed the carcinoma. The sensitivity of both techniques for the detection of breast cancer was 92.9%, and the specificity of mammography and tomosynthesis was 86.1 and 84.4%, respectively. Tomosynthesis can be used as an additional technique to mammography in patients referred with an abnormal screening mammogram or with clinical symptoms. Additional lesions detected by tomosynthesis, however, are also likely to be detected by other techniques used in the clinical work-up of these patients.

Evaluation of (18)F-FDG PET-CT for differentiation of pulmonary pathology in an approach of outpatient fast track assessment.

INTRODUCTION: The aim of our study was to evaluate the clinical performance/ implementation of integrated F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) for differentiation of pulmonary pathology in an approach of outpatient fast track assessment. METHODS: A prospective study was performed in 114 consecutive patients with pulmonary symptoms and/or abnormal chest x-ray were referred for fast track assessment to the Netherlands Cancer Institute from March 2005 to September 2007. The presence of malignancy was evaluated in a multidisciplinary setting, including F-fluorodeoxyglucose-PET, diagnostic CT, and bronchoscopy (including biopsy), with histopathological evaluation as the reference standard. RESULTS: In 105 patients (92%), a final diagnosis was achieved. A malignancy was diagnosed in 84% of the patients; non-small cell lung cancer in 67%, small cell lung cancer in 7%, and metastases or other malignancies in 10%. Nonmalignant lesions were found in 16% of the patients. Sensitivity, specificity, accuracy, positive predictive value and negative predictive value of positive PET/CT for the presence of malignancy were 97, 56, 90, 92, and 77%, respectively. PET/CT showed unexpected M1 disease (not detected on CT) in 10% of the patients. Almost half of the patients with a malignancy were scheduled for curative treatment, of whom 29 patients for surgery and 14 patients for chemoradiotherapy. CONCLUSION: In this outpatient fast track setting, PET/CT provides valuable information for diagnosing lung cancer, with a high positive predictive value, and is useful for clinical decision making.

Scanning with 18F-FDG-PET/CT for detection of pelvic nodal involvement in inguinal node-positive penile carcinoma.

BACKGROUND: Penile carcinoma patients with inguinal lymph node involvement (LNI) have an increased risk for pelvic nodal involvement with or without distant metastases. OBJECTIVE: To evaluate the diagnostic accuracy of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) with computed tomography (CT; 18F-FDG PET/CT) scanning in determining further metastatic spread in patients with tumour-positive inguinal nodes. DESIGN, SETTING, AND PARTICIPANTS: Eighteen patients with penile squamous cell carcinoma with unilateral or bilateral cytologically tumour-positive inguinal disease underwent whole-body 18F-FDG-PET/CT scanning for tumour staging. MEASUREMENTS: Images were blindly assessed by two nuclear medicine physicians. All scans were evaluated for pelvic nodal involvement per basin and for distant metastases. Histopathology (when available), radiologic imaging, and clinical follow-up (with a minimum of 1 yr) served as a reference standard. The diagnostic value of PET/CT scanning for predicting pelvic nodal involvement was evaluated using standard statistical methods. RESULTS AND LIMITATIONS: The reference was available in 28 of the 36 pelvic basins. Of the 11 tumour-positive pelvic basins, 10 were correctly predicted by PET/CT scan, as were all 17 tumour-negative pelvic basins. PET/CT scan showed a sensitivity of 91%, a specificity of 100%, a diagnostic accuracy of 96%, a positive predictive value of 100%, and a negative predictive value of 94% in detecting pelvic nodal involvement. Additionally, PET/CT scans showed distant metastases in five patients. In four patients, the presence of distant metastases could be confirmed, while in one patient, no radiologic confirmation was found for that particular lesion. A potential limitation is that the diagnostic accuracy of PET/CT scanning was calculated on 28 pelvic basins only. Furthermore, no comparison was made with conventional CT scans, as not all patients had undergone contrast-enhanced CT scans. CONCLUSIONS: PET/CT scanning appears promising for detecting pelvic lymph node metastases with great accuracy, and it identifies distant metastases in penile carcinoma patients with inguinal LNI. In our practice, PET/CT scanning has become part of routine staging in such patients.

Validation of semiautomatic measurement of the extent of breast tumors using contrast-enhanced magnetic resonance imaging.

OBJECTIVES: The aim of this study was to assess whether the semiautomatic measurement of breast-tumor extent using contrast-enhanced magnetic resonance imaging (CE-MRI) decreases measurement variation compared with manual evaluation and increases precision with respect to tumor extent measured at histopathology. MATERIALS AND METHODS: Forty-three patients who underwent breast-conserving therapy for 46 tumors were consecutively included. Extended histopathology analysis was performed on the excision specimens. Two experienced breast-MR radiologists independently manually assessed the largest diameter of the tumors at preoperative CE-MRI. Two observers used a semiautomatic segmentation technique to independently obtain the largest diameter and the volume of the tumors. RESULTS: Semiautomatic volumetric measurement of tumor volume was more accurately correlated with histopathology (adjusted R-square 0.84 and 0.81) compared with conventional measurement (adjusted R-square 0.56 and 0.70) and semiautomatic measurement (adjusted R-square 0.63 and 0.60) of the largest diameter of the tumor. The interobserver variability between the volumetric measurements was significantly smaller than the interobserver variability between the largest-diameter measurements of tumor extent obtained by the radiologists (P < 0.001). CONCLUSIONS: Semiautomatic volumetric measurement of breast-tumor extent at CE-MRI provides a more accurate assessment of tumor extent with respect to histopathology and reduces measurement variation compared with manual assessment of the largest diameter. Automated volumetric measurement thus provides potential for increased precision in establishing response to treatment.

Ultrasonography-guided fine-needle aspiration cytology before sentinel node biopsy in patients with penile carcinoma.

OBJECTIVE: To assess the accuracy of ultrasonography (US)-guided fine-needle aspiration cytology (FNAC) for detecting occult lymph node metastases in patients with squamous cell carcinoma of the penis. PATIENTS AND METHODS: Forty-three patients with 83 clinically node-negative inguinal regions were assessed with US and FNAC. The results were compared with histology from subsequent dynamic sentinel-node biopsy (DSNB) or inguinal lymph node dissection. RESULTS: Thirty-four groins in 27 patients were considered to be suspicious by US and the lymph nodes were aspirated. Nine nodes contained tumour cells and this was confirmed by subsequent lymph node dissection. The sensitivity and specificity of US-guided FNAC were 39% (nine of 23) and 100% (60 of 60), respectively. The number of groins requiring DSNB was reduced by 11% (nine of 83). CONCLUSION: US-guided FNAC can be used as the initial investigation in clinically node-negative groins. If tumour is confirmed then therapeutic inguinal lymph node dissection can be earlier and fewer DSNBs are required.