Performance characteristics of specimen radiography for margin assessment for ductal carcinoma in situ: a systematic review.

BACKGROUND: Reducing positive margin rate (PMR) and reoperation rate in breast-conserving operations remains a challenge, mainly regarding ductal carcinoma in situ (DCIS). Intra-operative margin assessment tools have emerged to reduce PMR over the last decades, including specimen radiography (SR). No consensus has been reached on the reliability and efficacy of SR in DCIS. OBJECTIVE: We performed a systematic literature review to assess the performance characteristics of SR for margin assessment of breast lesions with pure DCIS and invasive cancers with DCIS components. METHODS: A literature search was conducted for diagnostic studies up to April 2017 concerning SR for intra-operative margin assessment of breast lesions with pure DCIS or with DCIS components. Studies reporting sensitivity and specificity calculated using final pathology report as reference test were included. Due to improved imaging technology, studies published more than 15 years ago were excluded. Methodological quality was assessed using quality assessment of diagnostic accuracy studies-2 checklist. Due to clinical and methodological diversity, meta-analysis was considered not useful. RESULTS: Of 235 citations identified, 9 met predefined inclusion criteria and documented diagnostic efficacy data. Sensitivity ranged from 22 to 77% and specificity ranged from 51 to 100%. Positive predictive value and negative predictive value ranged from 53 to 100% and 32 to 95%, respectively. High or unclear risk of bias was found in reference standard in 5 of 9 studies. High concerns regarding applicability of index test were found in 6 of 9 studies. CONCLUSIONS: The present results do not support the routine use of intra-operative specimen radiography to reduce the rate of positive margins in patients undergoing breast-conserving surgery for pure DCIS or the DCIS component in invasive cancer. Future studies need to differentiate between initial and final specimen margin involvement. This could provide surgeons with a number needed to treat for a more applicable outcome.

High-risk human papillomavirus detection in self-sampling compared to physician-taken smear in a responder population of the Dutch cervical screening: Results of the VERA study.

In 2017 the cervical cancer screening program in The Netherlands will be revised. Cervical smears will primarily be tested for the presence of high-risk human papillomavirus (hrHPV) instead of cytology, and vaginal self-sampling will be offered to non-responders. This includes a potential risk that part of the women who would otherwise opt for a cervical smear will wait for self-sampling. However, self-sampling for hrHPV in a responder population has never been studied yet. The aim of this study was to investigate the applicability and accuracy of self-sampling in detecting hrHPV in a screening responder population. A total of 2049 women, aged 30-60years, participating in the screening program in The Netherlands were included from April 2013 to May 2015. After they had their cervical smear taken, women self-collected a cervicovaginal sample with a brush-based device, the Evalyn Brush. Both the cervical smear and self-sample specimen were tested with the COBAS 4800 HPV platform. The hrHPV prevalence was 8.0% (95% CI 6.9-9.2) among the physician-taken samples, and 10.0% (95% CI 8.7-11.3) among the self-samples. There was 96.8% (95% CI 96.0-97.5) concordance of hrHPV prevalence between self-samples and physician-taken samples. Women in our study evaluated self-sampling as convenient (97.1%), user-friendly (98.5%), and 62.8% preferred self-sampling over a physician-taken sampling for the next screening round. In conclusion, self-sampling showed high concordance with physician-taken sampling for hrHPV detection in a responder screening population and highly acceptable to women. Implementation of HPV-self-sampling for the responder population as a primary screening tool may be considered.

Sentinel lymph node biopsy can be omitted in DCIS patients treated with breast conserving therapy.

Breast cancer guidelines advise sentinel lymph node biopsy (SLNB) in patients with ductal carcinoma in situ (DCIS) on core biopsy at high risk of invasive cancer or in case of mastectomy. This study investigates the incidence of SLNB and SLN metastases and the relevance of indications in guidelines and literature to perform SLNB in order to validate whether SLNB is justified in patients with DCIS on core biopsy in current era. Clinically node negative patients diagnosed from 2004 to 2013 with only DCIS on core needle biopsy were selected from a national database. Incidence of SLN biopsy and metastases was calculated. With Fisher exact tests correlation between SLNB indications and actual presence of SLN metastases was studied. Further, underestimation rate for invasive cancer and correlation with SLN metastases was analysed. 910 patients were included. SLNB was performed in 471 patients (51.8 %): 94.5 % had pN0, 3.0 % pN1mi and 2.5 % pN1. Patients undergoing mastectomy had 7 % SLN metastases versus 3.5 % for breast conserving surgery (BCS) (p = 0.107). The only factors correlating to SLN metastases were smaller core needle size (p = 0.01) and invasive cancer (p < 0.001). Invasive cancer was detected in 16.7 % by histopathology with 15.6 % SLN metastases versus only 2 % in pure DCIS. SLNB showed metastases in 5.5 % of patients; 3.5 % in case of BCS (any histopathology) and 2 % when pure DCIS was found at definitive histopathology (BCS and mastectomy). Consequently, SLNB should no longer be performed in patients diagnosed with DCIS on core biopsy undergoing BCS. If definitive histopathology shows invasive cancer, SLNB can still be considered after initial surgery.

Ultrasound-guided fine-needle aspiration of suspicious nodes in breast cancer patients; selecting patients with extensive nodal involvement.

The aim of this study was to evaluate the value of Ultrasonography (US) guided fine-needle aspiration (FNA) of the axilla to identify breast cancer patients with extensive nodal involvement. A prospective database of breast cancer patients who underwent US-guided FNA of suspicious nodes, diagnosed between 2000 and 2007 was analyzed. Patients with a negative axillary US or C2 (benign) FNA result underwent SLNB. Patients with C5 (malignant) FNA result underwent axillary lymph node dissection (ALND). All SLNB positive patients underwent completion ALND. The number of positive nodes after ALND was documented and analyzed. A total of 1,448 patients were included. US sensitivity was 34.2 %, specificity was 96.2 % and the accuracy was 71.7 %. For US-guided FNA this was 89, 100 and 90.4 %, respectively. In 234/1,448 patients (16.2 %) US-guided FNA was performed. A total of 19/41 C2 patients (46.3 %) had a positive SLNB. A median of 1 (range 1-6) positive node was found. A median of 4 (range 1-30) positive nodes were found in 158 C5 patients. In 376/1,214 patients with a negative US, SLNB was positive. A median of 2 (range 1-38) positive nodes were found. There was a significant difference in nodal involvement between C5 and SLNB positive patients (p = 0.043 and p < 0.0001, respectively). Ultrasound-guided FNA is a highly specific technique for detecting axillary metastases in breast cancer patients. Patients with US-guided FNA-diagnosed axillary metastases have significantly more involved nodes compared to SLNB positive patients.

Contribution of CSF cytology in the diagnostic work-up of breast cancer patients with neurological symptoms: a retrospective analysis over two decades.

The aim of this study was to evaluate the contribution of cytological analysis of cerebrospinal fluid (CSF) in the diagnostic work-up of breast cancer patients who present with neurological symptoms suspected for central nervous system (CNS) metastases. In the period 1989-2009, a total of 81 patients with breast cancer underwent CSF cytological examination. Relevant tumour characteristics, clinical presentation and radiological findings were scored. The CSF cytological diagnosis was classified according to the 1996 NCI-sponsored conference approach as malignant, suspicious for malignancy, atypical, benign or inadequate. During the course of 20 years, 145 CSF cytological examinations were performed. Relatively common neurological symptoms resulting in cytological CSF examination were headache (n = 25), nausea and vomiting (n = 19), sensory disturbances (n = 16), and cranial nerve dysfunction (n = 16). Of these, headache and nausea/vomiting were most often associated with malignant cells in the CSF (CSF(+)) (in 48 and 53% of the cases, respectively). The 4 patients with both headache and confusion/altered mental status all had CSF(+). In 10 patients, CSF(+) was found despite the absence of radiological evidence for metastasis in/around the CNS. In our series, repeated CSF analysis appeared to have limited additional value, and CSF(+) was strongly correlated with shorter survival. A substantial number of patients with neurological symptoms but without radiological abnormalities can have CSF(+). In our series, the additional value of repeated cytological examination of CSF was limited. Our study underscores the value of CSF cytology as a tool for the unequivocal diagnosis of metastatic spread of breast cancer to the CNS, and confirms that CSF(+) is a strong predictor of poor survival.

False-negative sentinel lymph node biopsy.

BACKGROUND: The clinical significance of false-negative axillary sentinel lymph node (SLN) biopsy has yet to be established. The aim of this study was to assess the axillary recurrence rate and false-negative rate, to identify prognostic factors and to monitor survival. METHODS: A prospective registry of sentinel lymph node biopsy (SLNB) procedures performed between 1998 and 2004 was analysed. All nodes retrieved were examined by haematoxylin and eosin and immunohistochemical staining. Further surgical treatment was performed only for positive SLNs. Adjuvant treatment was given according to Dutch guidelines. RESULTS: Of 592 patients, 392 had a negative SLNB. After a median follow-up of 65 months, 11 patients developed axillary recurrence (2.8 per cent). Ten of these patients were primarily treated by simple mastectomy and therefore had no external-beam radiation therapy; no further prognostic factors could be identified. The false-negative rate was 6.9 per cent. The median time from SLNB to detection of the axillary recurrence was 27 months. The median follow-up after recurrence was 35 months, and one patient developed systemic disease. Pathology revision revealed two previously undetected micrometastases. CONCLUSION: Axillary recurrence and false-negative rates after SLNB increase with longer follow-up.

[Granulomatous lobular mastitis: a benign abnormality that mimics malignancy]. / Granulomateuze lobulaire mastitis: een benigne afwijking die imponeert als maligniteit.

A palpable abnormality of the breast was found in three women, one aged 57 and two aged 41. The first two patients predominantly showed the characteristics of a purulent inflammation, and on mammogram the third patient appeared to have mastitis carcinomatosa. Histopathological investigation revealed a lobular, non-caseating granulomatous inflammation. They were treated with prednisone and the first and third patients also received azathioprine. After some time, the condition recurred in the contralateral breast in the second and third patients. Once again, medicinal treatment was given. When a palpable tumour of the breast is found the primary goal is to exclude malignancy. Granulomatous lobular mastitis is a rare and benign tumour of the breast that clinically mimics carcinoma. Often, conventional imaging does not lead to the diagnosis. A histological needle biopsy is the best way to reach a diagnosis. Immunosuppressive therapy is effective and is preferred over surgery.

The effect of Chinese herbal medicines (CHM) on menopausal symptoms compared to hormone replacement therapy (HRT) and placebo.

OBJECTIVE: To evaluate within the Traditional Chinese Medicine (TCM) setting, the effect of CHM-formulae on menopausal symptoms. DESIGN: A double-blind and double-dummy randomised placebo-controlled trial. METHOD: Between February and June 2002 and June and October 2004, 31 peri- and postmenopausal Dutch women were recruited to complete 12 weeks of treatment with either CHM formulae (n=10), HRT (n=11) or placebo (n=10) medications plus 4 weeks of non-treatment follow-up observation. Hereby a double-dummy setting is applied, i.e. the medications and placebo's taken were both capsules and liquid extracts. Appropriate to the TCM setting, the CHM-prescriptions could be adjusted according to the symptoms and signs of the individuals for that moment. MAIN OUTCOME MEASURES: The primary end-point was the reduction in frequency of vasomotor symptoms (hot flushes and night sweats). Secondary end-point were the improvements measured in quality of life questionnaire SF-36 and other symptoms and signs related to the peri- and postmenopausal period. RESULTS: Placebo had a score of 30%. Compared to Placebo, on average CHM is 29% significantly (p<0.05) more effective in reducing the amount of hot flushes, while HRT is almost 50%. Although quantitatively there was a significant difference in the reduction of hot flushes between groups, qualitatively there was no overall improvement. CONCLUSIONS: This pilot study proved clearly that CHM could help women with their menopausal problems. The chosen trial methodology with its TCM differential diagnosis after orthodox medicine diagnosis is fully compatible with TCM practice and hence acceptable for western and Chinese medical practitioners. For a place in the western health care system, we need to conduct a larger trial with a more menopause specific questionnaire.

Modified Core Wash Cytology: A reliable same day biopsy result for breast clinics.

BACKGROUND: Fine Needle Aspiration Biopsy (FNAB), Core Needle biopsy (CNB) and hybrid techniques including Core Wash Cytology (CWC) are available for same-day diagnosis in breast lesions. In CWC a washing of the biopsy core is processed for a provisional cytological diagnosis, after which the core is processed like a regular CNB. This study focuses on the reliability of CWC in daily practice. METHODS: All consecutive CWC procedures performed in a referral breast centre between May 2009 and May 2012 were reviewed, correlating CWC results with the CNB result, definitive diagnosis after surgical resection and/or follow-up. Symptomatic as well as screen-detected lesions, undergoing CNB were included. RESULTS: 1253 CWC procedures were performed. Definitive histology showed 849 (68%) malignant and 404 (32%) benign lesions. 80% of CWC procedures yielded a conclusive diagnosis: this percentage was higher amongst malignant lesions and lower for benign lesions: 89% and 62% respectively. Sensitivity and specificity of a conclusive CWC result were respectively 98.3% and 90.4%. The eventual incidence of malignancy in the cytological 'atypical' group (5%) was similar to the cytological 'benign' group (6%). CONCLUSION: CWC can be used to make a reliable provisional diagnosis of breast lesions within the hour. The high probability of conclusive results in malignant lesions makes CWC well suited for high risk populations.

Keratins 7 and 20 as diagnostic markers of carcinomas metastatic to the ovary.

The most common carcinomas metastatic to the ovary that mimic ovarian primaries are colonic adenocarcinomas and endometrial carcinomas. Conventional histochemical staining procedures, even in combination with additional immunohistochemical assays, are of limited value in distinguishing between these metastases and primary ovarian carcinomas. In this study we investigated whether the application of monoclonal antibodies against keratins 7, 8, and 20 could help in differentiating between these categories. The reactivity patterns of 40 carcinomas metastatic to the ovary were compared with those of their primary carcinomas on the one hand and with various primary ovarian carcinomas and mesotheliomas on the other. Colon cancer metastatic to the ovary was keratin 7 negative and keratin 20 positive in 94% of the cases; in contrast, all primary ovarian carcinomas were keratin 7 positive and keratin 20 negative, with the exception of two cases of mucinous cystadenocarcinoma. Ovarian metastases of gastric cancer usually contained keratins 7 and 20. Metastases of endometrial cancer to the ovary and primary ovarian carcinomas usually showed similar keratin expression. We propose that keratin 7 and 20 antibodies may be of help to distinguish between primary ovarian carcinomas and carcinoma metastases in the ovary.

An unusual case of multiple endocrine neoplasia type 1 and the role of 111In-pentetreotide scintigraphy.

A 50-year-old woman is described with a very unusual combination of MEN-1 syndrome with a negative family history. At first she had been treated because of a clinically non-functioning pituitary adenoma in the maxillary sinus. Six years later a carcinoid tumour was discovered by means of 111In-pentreotide scintigraphy.

Unexpected borderline malignant and malignant smooth muscle cell tumors of the uterine corpus in women treated with LH-RH analogues.

In this report, two cases of uterine smooth muscle cell tumors, one of uncertain malignant potential and one clearly malignant, are described in women treated for prolonged periods with luteinizing hormone-releasing hormone (LH-RH) analogues. Due to lengthy monitoring of LH-RH therapy, surgical intervention and histologic classification of these tumors was late in the course of disease, resulting in a delay in definite treatment. The risk to these women is discussed. The effects of LH-RH analogue therapy on fibroids is reviewed. Suggestions are put forward for monitoring LH-RH analogue therapy.

[Intra-abdominal adhesions and foreign-body granulomas following earlier laparotomy]. / Intra-abdominale adhesies en vreemd-lichaamgranulomen na eerdere laparotomie.

OBJECTIVE: To determine the prevalence of foreign body granulomas in intra-abdominal adhesions in patients subjected to relaparotomy. DESIGN: Cross-sectional. SETTING: University Hospital Rotterdam-Dijkzigt, the Netherlands. METHOD: From July 1991 to September 1992, 119 patients were subjected to relaparotomy. Presence, distribution and quality of adhesions were scored during the relaparotomy and adhesion samples were taken for histological examination. RESULTS: Adhesions were present in 94% of the patients; they were most frequently attached to small bowel (83%) and omentum (78%). The number of adhesions was significantly smaller in patients with a history of only one minor operation than in those with one major or multiple laparotomies. Foreign body granulomas were found in 22% of the patients with adhesions. These were caused by suture material (19%) or starch glove powder (6%); a combination of both occurred in 3% of the patients. When granulomas were present, the median interval between present and most recent laparotomy was significantly shorter than when no granulomas were found. In patients with adhesions who had had the previous operation less than 6 months previously, granulomas were present in 71%. In contrast, 13% of the patients operated upon longer than 6 months previously had granulomas. CONCLUSIONS: In young adhesions foreign body granulomas occur in large percentages of the cases. This suggests that the intra-abdominal presence of foreign material is an important cause of adhesion formation. Therefore, intra-abdominal contamination with suture material and glove powder should be avoided.

Is the sentinel lymph node pathology protocol in breast cancer patients associated with the risk of regional recurrence?

BACKGROUND: Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN) in breast cancer patients. Previously, we reported that ultra-staging led to more axillary lymph node dissections (ALND). The question was, whether ultra-staging is effective in reducing the risk of regional relapse. METHODS: From January 2002 to July 2003, 541 patients from 4 hospitals were prospectively registered when they underwent a SN biopsy. In hospitals A, B, and C, 3 levels of the SN were examined pathologically, whereas in hospital D at least 7 additional levels were examined. Patients with a positive SN, including isolated tumor cells, underwent an ALND. This analysis focuses on the 341 patients with a negative SN. Primary endpoint was 5-year regional recurrence rate. RESULTS: In hospital D 34% of the patients had a negative SN as compared to 71% in hospitals A, B, and C combined (p < 0.001). At 5 years follow-up, 9 (2.6%) patients had developed a regional lymph node relapse. In hospital D none of the patients had a regional recurrence, as compared to 9 (2.9%) cases of recurrence in hospitals A, B, and C. CONCLUSION: The less intensified SN pathology protocol appeared to be associated with a slightly increased risk of regional recurrence. The absolute risk was still less than 3%, and does not seem to justify the intensified SN pathology protocol of hospital D.

"Axillary recurrences after sentinel lymph node biopsy: a multicentre analysis and follow-up of sentinel lymph node negative breast cancer patients".

INTRODUCTION: The objective of this study was to conduct a multicentre data analysis to identify prognostic factors for developing an axillary recurrence (AR) after negative sentinel lymph node biopsy (SLNB) in a large cohort of breast cancer patients with long follow-up. PATIENTS AND METHODS: The prospective databases from different hospitals of clinically node negative breast cancer patients operated on between, 2000 and 2002 were analyzed. SLNB was performed and pathological analysis done by local pathologists according to national guidelines. Adjuvant treatment was given according to contemporary guidelines. Multivariate analysis was performed using all available variables, a p-value of <0,05 was considered to be significant. RESULTS: A total of 929 patients who did not undergo axillary lymph node dissection were identified. After a median follow up of 77 (range 1-106) months, fifteen patients developed an isolated AR (AR rate 1,6%). Multivariate analysis showed that young age (p = 0.007) and the absence of radiotherapy (p = 0.010) significantly increased the risk of developing an AR. Distant metastasis free survival (DMFS) was significantly worse for patients with an AR compared to all other breast cancer patients (p < 0,0001). CONCLUSION: Even after long-term follow up, the risk of developing an AR after a negative SLN in breast cancer is low. Young age and absence of radiation therapy are highly significant factors for developing an axillary recurrence. DMFS is worse for AR patients compared to patients initially diagnosed with N0 or N1 disease.

Conclusiveness of fine needle aspiration in 2419 histologically confirmed benign and malignant breast lesions.

We aimed to retrospectively assess (1) the conclusiveness of breast fine needle aspiration (FNA) in a histologically confirmed population and (2) the clinical and radiologic determinants of a conclusive diagnosis. Aspirates were diagnosed as inadequate, benign, atypical, suspicious or malignant. We defined a conclusive FNA diagnosis as 'benign' in histologically benign lesions and as 'malignant' in histologically malignant lesions. In 2419 breast lesions, the proportion of conclusive diagnoses was 46.1% (95% confidence interval, 42.0-50.2%) in histologically benign lesions (n = 571) and 81.6% (95% confidence interval, 79.8%-83.4%) in histologically malignant lesions (n = 1848). On multivariate analysis, factors associated with a conclusive preoperative diagnosis included tumour diameter of 2-2.9 cm (P < 0.001), malignant histology (P < 0.001) and the pathologist examining the aspirate (P = 0.02). Breast FNA has to be utilised selectively in the routine work-up of breast lesions. In suspicious lesions of large size, FNA may still be used to obtain a quick confirmation of malignancy.

Preoperative cytological and histological diagnosis of breast lesions: A critical review.

BACKGROUND: Non-operative pathology diagnoses constitute an essential part of the work-up of breast lesions. With fine needle aspiration (FNA) and core needle biopsy (CNB) both having unique advantages, there is an increasing acceptance of CNB. This paper aims to outline the scientific basis of this trend. Additionally, we provide an update on novel techniques that derive cytological specimens from CNB (i.e., touch imprint (TI) and core wash (CW) cytology) in an attempt to get the best of both worlds. METHODS: In addition to using the authors' experience, we performed a search of the Medline database combining the search terms "breast cancer diagnosis", "core needle biopsy", "fine needle aspiration", "touch imprint cytology", "core wash cytology" and "complications". We defined a conclusive non-operative diagnosis as "malignant" in lesions that were malignant on follow-up and "benign" in lesions that were benign on follow-up. RESULTS: CNB was more often conclusive than FNA in benign and malignant lesions in 4 prospective studies. Although the more rapid diagnoses by FNA result in less patient anxiety during diagnostic work-up, CNB allows for fairly reliable estimation of invasion, histological type, grade, and receptor expression. CW and TI cytology seem promising techniques with conclusiveness rates that are roughly comparable to that of FNA. CONCLUSIONS: All new suspicious breast lesions require careful non-operative investigation by CNB. However, additional cytological assessment by FNA can still be useful as a same-day diagnosis decreases patient anxiety and facilitates surgical treatment planning. TI and CW cytology techniques are promising same-day diagnosis modalities.

Modified core wash cytology (CWC), an asset in the diagnostic work-up of breast lesions.

AIM: A quick and reliable preliminary diagnosis is essential in the management of a same-day breast clinic. In a preclinical study we developed an alternative method of core wash cytology (CWC). This study is an evaluation of this new CWC method introduced into the clinical setting. METHODS: From April 2008 to April 2009, biopsies were taken from lesions in the breast. CWC was obtained from core needle biopsy (CNB) with a modified technique and classified into the categories: malignant, suspicious for malignancy, atypical, benign and inadequate. CWC and CNB diagnoses were correlated with the histopathology of subsequently obtained resection specimens. The sensitivity and specificity were calculated. RESULTS: CWC was obtained from 226 breast lesions. In 167 of these cases subsequent resection of the lesion was performed revealing 149 carcinomas and 18 benign lesions. Of the 149 malignant cases, 136 were considered as either malignant or suspicious for malignancy by CWC, 7 as atypical, 4 as benign and 2 as inadequate. None of the 18 benign lesions were classified as suspicious or malignant on CWC. Eight out of 149 resected carcinomas were not recognized as malignant by histological analysis of the CNB, while 7 of these cases the CWC was considered malignant. The sensitivity and specificity were 97% and 100%, respectively. CONCLUSIONS: In the vast majority of patients the modified CWC technique can provide a quick and reliable diagnosis of malignant breast lesions. Furthermore, combining CWC with CNB histology can improve adequate, preoperative recognition of the malignant character of breast lesions.