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.

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.

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.

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.

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.

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.

Modified core wash cytology procedure for the immediate diagnosis of core needle biopsies of breast lesions.

BACKGROUND: Core wash or touch imprint cytology is often used to obtain a quick, preliminary diagnosis on a core needle biopsy (CNB) of breast lesions, essential for the management of the 1-day breast clinic. Contradictory results of both techniques in the literature led to this preclinical study investigating an alternative method of touch imprint and core wash cytology. METHODS: Thirty breast lesions were biopsied by a core needle in a laboratory setting. The CNBs were collected in RPMI fluid (Roswell Park Memorial Institute fluid). The touch imprint cytology was performed taking the biopsy out of the fluid and smearing it on a microscopic slide and May-Grunwald Giemsa stained. The core wash cytology was made by fixating the remaining cells in Fixcyt and prepared with a liquid-based preparation method and Papanicolaou stained. The cytologic findings were categorized into benign, atypical favoring benign, atypical, suspicious, and malignant and compared with the histologic CNB results. RESULTS: The CNBs showed 20 of 30 samples to be malignant, 2 to be phylloides tumors, 7 to be benign, and 1 to be unsatisfactory. Both techniques showed a sensitivity of 95% and specificity of 100%. Touch imprint yielded insufficient diagnoses (13.3%), compared with core wash (6.6%). Of the core wash cases, 86% showed a good quality versus 30% in touch imprint cytology. CONCLUSIONS: This preclinical study on modified touch imprint and core wash techniques led to results that were comparable to or better than those in the literature. The core wash cytology is preferred to touch imprint because of the better morphology.

The role of laboratory processing in determining diagnostic conclusiveness of breast fine needle aspirations: conventional smearing versus a monolayer preparation.

AIM: To compare breast fine needle aspiration (FNA) specimens prepared by conventional smearing (CS) versus monolayer preparation (MP), with respect to the conclusiveness of the cytopathological diagnosis. METHODS: From 1992 to 1996, aspirators prepared aspirates themselves by direct smearing onto 2-4 slides. From 1999 to 2003, aspirate preparation was performed in the laboratory, creating a MP, using a Hettich cytocentrifuge. FNA diagnoses were categorised into inadequate (C1), benign (C2), atypical (C3), suspicious for malignancy (C4) and malignant (C5). The reference standard constituted histological follow-up. A conclusive FNA diagnosis was defined as C2 in lesions benign on follow-up and C5 in lesions malignant on histology. RESULTS: From 1992 to 1996, 692 aspirates were processed by CS, whereas from 1999 to 2003, 1301 aspirates were processed by MP. More FNA were ultrasound-guided in the MP group (85.6% versus 21.5%, p<0.001). When compared with CS, MP-prepared FNA had conclusive diagnoses significantly more often (72.8% versus 58.5%, p<0.001). This effect remained significant when corrected for the difference in ultrasound guidance (adjusted odds ratio 1.7, 95% confidence interval 1.3 to 2.2, p<0.001), and was larger for malignant lesions than for benign lesions (51.7% versus 79.9%, p<0.001). CONCLUSION: Patients presenting with breast lesions can more often be offered a same-day, conclusive cytopathological diagnosis when FNA are prepared by a manual MP processing technique.

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.

Testicular granulocytic sarcoma without systemic leukemia.

This case report describes a unilateral testicular granulocytic sarcoma or chloroma. Because of the relatively immature nature of the tumor cells, the histological diagnosis can be difficult. Granulocytic sarcomas are well known in patients with systemic leukemia and can sometimes precede a systemic leukemic outcome. A solitary granulocytic sarcoma not followed by a hematological proliferation of the myelocytic stem cells is very rare. No prognostic factors that are able to predict a systemic outcome are known. Therefore, in this case with no signs of systemic disease, we adopted a wait-and-see policy after radical orchidectomy. Up to now, after a follow-up period of 7 years, the patient is still free of disease. Diagnosis and therapy of this urologic disease are discussed and the literature is reviewed.

Intraoperative scrape cytology of the sentinel lymph node in patients with breast cancer.

BACKGROUND: Intraoperative examination of the sentinel lymph node (SLN) may detect metastatic disease, allowing immediate axillary lymph node dissection and therefore avoiding the need for reoperation. The aim of this study was to evaluate the accuracy of scrape cytology of the SLN in patients with early breast cancer. METHODS: Sentinel node biopsy was performed in 148 patients with clinical T1-2 N0 breast cancer. After harvesting, the SLN was bisected and cells from both halves were scraped with a scalpel blade on to a slide and stained with a Papanicolaou and Giemsa stain. Scrape cytology results were compared with the results of paraffin sections stained with haematoxylin and eosin and with immunohistochemistry. RESULTS: The intraoperative diagnosis was correct in 126 patients (85 per cent). Sensitivity and specificity were 67 and 98 per cent respectively; positive and negative predictive values were 95 and 81 per cent. CONCLUSION: Scrape cytology is a useful method for intraoperative evaluation of the SLN in patients with breast cancer.