HER2 in Metastatic Colorectal Cancer: Pathology, Somatic Alterations, and Perspectives for Novel Therapeutic Schemes.

HER2 is an emerging biomarker in colorectal cancer (CRC). This oncogene plays an essential role in regulating cell proliferation, differentiation, migration, and, more in general, tumorigenesis and tumor progression. The most frequent types of HER2 alterations in CRC include gene amplification and missense mutations in 7-8% of CRC, often being mirrored by HER2 protein overexpression, representing founder events in solid tumors, including CRC. There are currently no approved HER2-targeted therapy guidelines for CRC; however, several studies have shown that HER2 can be effectively targeted in meta-static CRC settings. In this review, we discuss the current knowledge of HER2 testing in CRC and the immediate future perspectives for HER2 targeting in the metastatic setting.

A New Possible Cut-Off of Cytokeratin 19 mRNA Copy Number by OSNA in the Sentinel Node of Breast Cancer Patients to Avoid Unnecessary Axillary Dissection: A 10-Year Experience in a Tertiary Breast Unit.

(1) Background: The main discriminant in breast cancer prognosis is axillary lymph node status. In a select cohort of patients, axillary lymph node dissection (ALND) may be safely spared. This study aimed to determine a new possible cut-off of cytokeratin (CK) 19 mRNA copy number in the SLN to predict cases at high risk of positive ALND. (2) Methods: Clinical records of 1339 patients were retrospectively reviewed and were separated into two groups according to the axillary status (negative: ALNs- and positive ALNs+). Receiver operative characteristic (ROC) curves were used to identify a new optimal cut-off of CK19 mRNA copy number in SLN; (3) Results: Large tumor size and high grade were found mostly in ALNs+. Results from the ROC analyses, with an AUC of 82.1%, identified a new cut-off (9150 CK19 mRNA copies) showing 94% sensitivity, 67.3% specificity, 61.2% positive, and 95.3% negative predictive values; (4) OSNA remains the most-important intra-operative tool to identify patients who can benefit from ALND but with the traditional cut-off, many patients undergo needless ALND. The results of the present study suggest a new cut-off helpful to personalize surgical treatment and avoid unnecessary invasive procedures.

Osteoclast-like stromal giant cells in invasive ductal breast cancer: A case series.

INTRODUCTION: Breast Cancer with osteoclast-like stromal giant cells (OLGCs) is a rare pattern of invasive non-special type ductal carcinoma. The OLGCs are specific type of macrophage and are likely distinct from true osteoclasts. The aim of this case series was to describe the characteristics of this invasive ductal carcinoma rare histotype. PRESENTATION OF CASES: The authors present the cases of two young women that, during national screening, discovered with mammography X-ray a breast lump suspected for malignancy. The core needle biopsy confirmed the malignancy of both nodule and in one patient the histological analysis revealed pre-operative OLGCs. In both cases the sentinel lymph node biopsy was negative therefore a quadrantectomy without axillary lymphadenectomy was done. The definitive histopathological examination was positive for invasive ductal carcinoma with OLGCs and CD 68 marker positivity. After surgery, patients underwent adjuvant therapy and multidisciplinary follow-up. DISCUSSION: The origin and mechanism for developing osteoclast-like giant cells is unknown. The OLGCs directly descend from the precursors of the monocyte-macrophage. The rarity of this entity often promotes a misleading diagnosis, with >50 % of erroneous diagnosis of benign lesion. The prognostic significance of OLGCs in breast cancer is controversial, however it doesn't seem to influence the axillary lymph nodes spread. The presence of preoperative OLGCs didn't modify our surgical and oncological approach. CONCLUSION: Breast Cancer with OLGCs is a rare tumour that has a similar prognosis to other carcinomas of identical grade and stage in most cases. The rarity and characteristics of this neoplasm require personalized treatments, discussed by a multidisciplinary team.

Evaluation of computer-aided diagnosis in breast ultrasonography: Improvement in diagnostic performance of inexperienced radiologists.

PURPOSE: To evaluate if a computer-aided diagnosis (CAD) system on ultrasound (US) can improve the diagnostic performance of inexperienced radiologists. METHODS: We collected ultrasound images of 256 breast lesions taken between March and May 2020. We asked two experienced and two inexperienced radiologists to retrospectively review the US features of each breast lesion according to the Breast Imaging Reporting and Data System (BI-RADS) categories. A CAD examination with S-Detect™ software (Samsung Healthcare, Seoul, South Korea) was conducted retrospectively by another uninvolved radiologist blinded to the BIRADS values previously attributed to the lesions. Diagnostic performances of experienced and inexperienced radiologists and CAD were compared and the inter-observer agreement among radiologists was calculated. RESULTS: The diagnostic performance of the experienced group in terms of sensitivity was significantly higher than CAD (p < 0.001). Conversely, the diagnostic performance of inexperienced group in terms of both sensitivity and specificity was significantly lower than CAD (p < 0.001). We obtained an excellent agreement in the evaluation of the lesions among the two expert radiologists (Kappa coefficient: 88.7%), and among the two non-expert radiologists (Kappa coefficient: 84.9%). CONCLUSION: The US CAD system is a useful additional tool to improve the diagnostic performance of the inexperienced radiologists, eventually reducing the number of unnecessary biopsies. Moreover, it is a valid second opinion in case of experienced radiologists.

Role and evaluation of pathologic response in early breast cancer specimens after neoadjuvant therapy: consensus statement.

Pathologic evaluation of early breast cancer after neoadjuvant therapy is essential to provide prognostic information based on tumor response to treatment (pathologic complete response [pCR] or non-pCR) and to inform therapy decisions after surgery. To harmonize the pathologist's handling of surgical specimens after neoadjuvant therapy, a panel of experts in breast cancer convened to developed a consensus on six main topics: (1) definition of pCR, (2) required clinical information, (3) gross examination and sampling, (4) microscopic examination, (5) evaluation of lymph node status, and (6) staging of residual breast tumor. The resulting consensus statements reported in this document highlight the role of an accurate evaluation of tumor response and define the minimum requirements to standardize the assessment of breast cancer specimens after neoadjuvant therapy.

Atypical Ductal Hyperplasia after Vacuum-Assisted Breast Biopsy: Can We Reduce the Upgrade to Breast Cancer to an Acceptable Rate?

(1) Background: to evaluate which factors can reduce the upgrade rate of atypical ductal hyperplasia (ADH) to in situ or invasive carcinoma in patients who underwent vacuum-assisted breast biopsy (VABB) and subsequent surgical excision. (2) Methods: 2955 VABBs were reviewed; 141 patients with a diagnosis of ADH were selected for subsequent surgical excision. The association between patients' characteristics and the upgrade rate to breast cancer was evaluated in both univariate and multivariate analyses. (3) Results: the upgrade rates to ductal carcinoma in situ (DCIS) and invasive carcinoma (IC) were, respectively, 29.1% and 7.8%. The pooled upgrade rate to DCIS or IC was statistically lower at univariate analysis, considering the following parameters: complete removal of the lesion (p-value < 0.001); BIRADS ≤ 4a (p-value < 0.001); size of the lesion ≤15 mm (p-value: 0.002); age of the patients <50 years (p-value: 0.035). (4) Conclusions: the overall upgrade rate of ADH to DCIS or IC is high and, as already known, surgery should be recommended. However, ADH cases should always be discussed in multidisciplinary meetings: some parameters appear to be related to a lower upgrade rate. Patients presenting these parameters could be strictly followed up to avoid overtreatment.

Complete Removal of the Lesion as a Guidance in the Management of Patients with Breast Ductal Carcinoma In Situ.

Background: Considering highly selected patients with ductal carcinoma in situ (DCIS), active surveillance is a valid alternative to surgery. Our study aimed to show the reliability of post-biopsy complete lesion removal, documented by mammogram, as additional criterion to select these patients. Methods: A total of 2173 vacuum-assisted breast biopsies (VABBs) documented as DCIS were reviewed. Surgery was performed in all cases. We retrospectively collected the reports of post-VABB complete lesion removal and the histological results of the biopsy and surgery. We calculated the rate of upgrade of DCIS identified on VABB upon excision for patients with post-biopsy complete lesion removal and for those showing residual lesion. Results: We observed 2173 cases of DCIS: 408 classified as low-grade, 1262 as intermediate-grade, and 503 as high-grade. The overall upgrading rate to invasive carcinoma was 15.2% (330/2173). The upgrade rate was 8.2% in patients showing mammographically documented complete removal of the lesion and 19% in patients without complete removal. Conclusion: The absence of mammographically documented residual lesion following VABB was found to be associated with a lower upgrading rate of DCIS to invasive carcinoma on surgical excision and should be considered when deciding the proper management DCIS diagnosis.

Wireless ultrasound-guided vacuum-assisted breast biopsy: Experience in clinical practice at European Institute of Oncology.

In the last few years, ultrasound-guided vacuum-assisted breast biopsy (US-VABB) has replaced surgical biopsy due to higher diagnostic accuracy and lower patient discomfort, and, at present, an even greater possibility is represented by the new wireless ultrasound-guided VAB device (Wi-UVAB). The purpose of our study is to determine the diagnostic accuracy of this new device in a sizeable representative number of patients. From January 2014 to June 2018, 168 biopsies were performed in our institution using the new Wi-UVAB device. We analyzed sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of biopsies obtained with the new device using surgical results as reference point, following patients for at least one year. In our cohort, we obtained a complete sensitivity of 97.5%, an absolute sensitivity of 94.3%, a complete specificity of 98%, and an absolute specificity of 98%. The positive predictive value of the procedure was 97.5% while the negative predictive value was 98%. The diagnostic accuracy was 98%. The Wi-UVAB is a safe procedure with high diagnostic accuracy, comparable to that of the traditional vacuum-assisted breast biopsy and even higher than that of core needle biopsy (CNB). Moreover, the Wi-UVAB is easy to use and shows low costs as core needle biopsy (CNB).

COVID-19 and breast fine needle aspiration cytology method: What should we change?

INTRODUCTION: Air-dried slide preparation for fine needle aspiration cytology procedures is currently considered unsafe because of the risk of infectious aerosols of coronavirus 19. This study compares the safety and accuracy of two different protocols, one with and one without air-dried slides. METHODS: Starting from 3 March 2020, we discontinued the use of air-dried slides during breast fine needle aspiration procedures. We selected cases collected during two periods: 2 months before and 2 months after 3 March. In both groups, the number of procedures was recorded together with the distribution of the diagnostic categories and the concordance between cytological and histological results on surgical specimens for lesions suggestive of malignancy, using the chi-squared test. RESULTS: Of the 100 procedures performed during the pre-COVID-19 period, 55% were negative (C2), 3% were non-diagnostic (C1) and 40% were positive (C4 or C5). Of the 75 procedures obtained during the COVID-19 period, 44% were negative (C2), 2.7% were non-diagnostic (C1) and 52% were positive (C4 or C5). Despite the use of a new protocol during the COVID-19 period, we observed concordance between cytological and histological results for lesions suggestive of malignancy. There was no statistically significant difference concerning the distribution of the diagnostic categories in the two groups. CONCLUSIONS: Taking into account the slightly lower number of procedures being analysed during the COVID-19 period, the introduction of a new protocol that does not include air-dried slides is safe and reliable.

Primary Breast Extranodal Marginal Zone Lymphoma in Primary Sjögren Syndrome: Case Presentation and Relevant Literature.

The association between autoimmune diseases, mostly rheumatoid arthritis, systemic lupus erythematosus, celiac disease and Sjögren syndrome, and lymphoma, has been widely demonstrated by several epidemiologic studies. By a mechanism which has not yet been entirely elucidated, chronic activation/stimulation of the immune system, along with the administration of specific treatments, may lead to the onset of different types of lymphoma in such patients. Specifically, patients affected by Sjögren syndrome may develop lymphomas many years after the original diagnosis. Several epidemiologic, hematologic, and histological features may anticipate the progression from Sjögren syndrome into lymphoma but, to the best of our knowledge, a definite pathogenetic mechanism for such progression is still missing. In fact, while the association between Sjögren syndrome and non-Hodgkin lymphoma, mostly extranodal marginal zone lymphomas and, less often, diffuse large B-cell, is well established, many other variables, such as time of onset, gender predilection, sites of occurrence, subtype of lymphoma, and predictive factors, still remain unclear. We report on a rare case of primary breast lymphoma occurring three years after the diagnosis of Sjögren syndrome in a 57-year-old patient. The diagnostic work-up, including radiograms, core needle biopsy, and histological examination, is discussed, along with emerging data from the recent literature, thus highlighting the usefulness of breast surveillance in Sjögren syndrome patients.

Clinical performance of contrast-enhanced spectral mammography in pre-surgical evaluation of breast malignant lesions in dense breasts: a single center study.

PURPOSE: To compare the efficacy of contrast-enhanced spectral mammography, with ultrasound, full field digital mammography and magnetic resonance imaging in detection and size estimation of histologically proven breast tumors. METHODS: This open-label, single center, prospective study, included 160 dense breast women with at least one suspicious mammary lesion evaluated by ultrasound, full field digital mammography and magnetic resonance imaging in whom a mammary tumor was histologically proven after surgery performed at the European Institute of Oncology between January 2013 and December 2015. Following the complete diagnostic procedure, the patients were further investigated by contrast-enhanced spectral mammography prior to surgery. RESULTS: Overall, the detection rate of malignant breast lesions (in situ and invasive) was 93.8% (165/176) for contrast-enhanced spectral mammography, 94.4% (168/178) for ultrasound, 85.5 (147/172) for full field digital mammography and 97.7% (173/177) for magnetic resonance imaging. Radiological measurements were concordant with the post-surgical pathological measurements of the invasive tumor (i.e., within 5 mm) in: 64.6% for contrast-enhanced spectral mammography, 62.0% for ultrasound, 45.2% for full field digital mammography (p < 0.0001) and 69.9% for magnetic resonance imaging (p = 0.28); underestimated in: 17.4% for contrast-enhanced spectral mammography, 19.6% for ultrasound, 24.2% for full field digital mammography (p = 0.03) and 6.7% for magnetic resonance imaging (p = 0.0005); and overestimated in: 16.2% for contrast-enhanced spectral mammography, 16.6% for ultrasound, 16.6% for full field digital mammography and 22.7% for magnetic resonance imaging (p = 0.02). CONCLUSIONS: Our data suggest that contrast-enhanced spectral mammography improves on full field digital mammography and is comparable to ultrasound and magnetic resonance imaging in terms of detection sensitivity and size estimation of malignant lesions in dense breasts.

Metastatic Tumors of the Oro-Facial Tissues: Clear Cell Renal Cell Carcinoma. A Clinico-Pathological and Immunohistochemical Study of Seven Cases.

Metastases to orofacial tissues are infrequent, their incidence being 1-8% of malignant oral tumors, sometimes manifesting as the first clinical sign of an occult cancer. Renal cell carcinoma (RCC) is the second most common metastatic carcinoma to the oro-facial tissues, involving the jawbones, gingiva, oral mucosa, tongue or salivary glands. Also, RCC frequently displays a prominent clear cell component, which may predominate in the clear cell renal cell carcinoma subtype (CCRCC) and histologically mimic many other clear cell tumors, both benign and malignant, which can be epithelial (from keratinizing epithelia, cutaneous adnexa, salivary glands and odontogenic epithelium), melanocytic or mesenchymal in origin. In view of the necessity for prompt and accurate diagnosis of such unusual neoplasms, we report on the salient clinico-pathological features of 7 CCRCC metastatic to the oro-facial tissues, and highlight their immunohistochemical profile, to more accurately discriminate this neoplasm from other tumors of the oral cavity with a prominent clear cell component.

Intra-Cystic (In Situ) Mucoepidermoid Carcinoma: A Clinico-Pathological Study of 14 Cases.

AIMS: To report on the clinico-pathological features of a series of 14 intra-oral mucoepidermoid carcinomas showing exclusive intra-cystic growth. Materials and methods: All mucoepidermoid carcinomas diagnosed in the period 1990­2012 were retrieved; the original histological preparations were reviewed to confirm the diagnosis and from selected cases, showing exclusive intra-cystic neoplastic components, additional sections were cut at three subsequent 200 m intervals and stained with Hematoxylin­Eosin, PAS, Mucicarmine and Alcian Blue, to possibly identify tumor invasion of the adjacent tissues, which could have been overlooked in the original histological preparations. Additionally, pertinent findings collected from the clinical charts and follow-up data were analyzed. Results: We identified 14 intraoral mucoepidermoid carcinomas treated by conservative surgery and with a minimum follow up of five years. The neoplasms were located in the hard palate (nine cases), the soft palate (two), the cheek (two) and the retromolar trigone (one). In all instances, histological examination revealed the presence of a single cystic space, containing clusters of columnar, intermediate, epidermoid, clear and mucous-producing cells, the latter exhibiting distinct intra-cytoplasmic mucin production, as confirmed by PAS, Mucicarmine and Alcian Blue stains. The cysts were entirely circumscribed by fibrous connective tissue, and no solid areas or infiltrating tumor cell clusters were detected. Conservative surgical resection was performed in all cases, and no recurrences or nodal metastases were observed during follow up. Conclusions: Mucoepidermoid carcinomas showing prominent (>20%) intra-cystic proliferation currently are considered low-grade tumors. In addition, we also unveil the possibility that mucoepidermoid carcinomas, at least in their early growth phase, may display an exclusive intra-cystic component and might be considered as in situ carcinomas, unable to infiltrate adjacent tissues and metastasize.

Inflammatory cells infiltrate and angiogenesis in locally advanced and metastatic cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is the second most common subtype of primary hepatobiliary cancer and one of the most aggressive characterized by an extremely poor prognosis with limited treatment options. Inflammatory cells in tumour microenvironment support tumour growth in term of progression, angiogenesis and metastatic capacity. A link between inflammation and biliary carcinogenesis has been previously observed but the mechanisms involved remain to be determined. METHODS: We investigated the microvascular density (MVD) and inflammatory cells in tissue samples from 40 patients with CCA with locally advanced CCA and metastatic CCA by means of immunohistochemical analysis of macrophages, mast cells, B and T lymphocytes and we correlated inflammatory infiltrate with MVD. RESULTS: We observed significant decrease in the levels of CD31 positive vessels, and CD8, CD4, CD68 and tryptase-positive cells in metastatic lesions as compared to the localized ones. A negative correlation between CD31 and CD8 and CD31 and CD4 in localized CCA samples was found as assessed by Spearman correlation analysis. CONCLUSIONS: In locally advanced CCA patients, there is a significant increase of immune cell infiltrate constituted by CD8+ and CD4+ lymphocytes, macrophages and mast cells as compared to the metastatic ones. This alteration in the tumour microenvironment infiltrate is related to a significant increased MVD in localized CCA lesions compared with the metastatic ones. Moreover, we observed a negative correlation between MVD and CD8+ , CD4+ cells in localized CCA patients.

Comparison of Treatment Outcome Between Invasive Lobular and Ductal Carcinomas in Patients Receiving Partial Breast Irradiation With Intraoperative Electrons.

PURPOSE: To investigate the local outcome of patients after accelerated partial breast irradiation with intraoperative electrons (IORT) for invasive lobular carcinoma (ILC) compared with invasive ductal carcinoma (IDC). METHODS AND MATERIALS: From 1999 to 2007, 2173 patients were treated with breast-conserving surgery and IORT (21 Gy/1 fraction) as the sole local treatment: 252 patients with ILC (11.6%) were compared with 1921 patients with IDC in terms of local control. RESULTS: Compared with the IDC subgroup, patients with ILC had a low-risk profile and were more hormone responsive. The 5- and 10-year in-breast tumor reappearance (IBTR) rates were 5.5% and 14.4%, respectively, for the IDC group and 7.5% and 21.8%, respectively, for the ILC group (log-rank P=.03). The excess risk of IBTR associated with ILC was particularly high for small tumors (≤1 cm: hazard ratio [HR], 2.24; 95% confidence interval [CI], 1.03-4.85), elderly patients (60-69 years: HR, 2.27; 95% CI, 1.11-4.63; ≥70 years: HR, 3.28; 95% CI, 1.08-10.0), low-grade tumors (grade 1: HR, 3.50; 95% CI, 1.05-11.7), and luminal A molecular subtype (HR, 3.18; 95% CI, 1.49-6.77). Among the ILC histologic variants, no difference between classic and nonclassic subgroups was observed, although the signet ring cell and solid variants had the worst local control. CONCLUSIONS: Despite a favorable tumor profile, accelerated partial breast irradiation with IORT led to a higher incidence of IBTRs in patients with ILC compared with those with IDC. Our institutional experience emphasized the importance of the size of the irradiation field, pointing to the use of larger collimators, even when dealing with small tumors, to improve local control.

DCIS and LCIS are confusing and outdated terms. They should be abandoned in favor of ductal intraepithelial neoplasia (DIN) and lobular intraepithelial neoplasia (LIN).

The terms ductal and lobular intraepithelial neoplasia (DIN and LIN) were introduced by Tavossoli 15 years ago, who proposed they should replace, respectively, ductal and lobular carcinoma in situ (DCIS and LCIS). This proposal has been slowly gaining ground. We argue that DCIS and LCIS should now be definitively abandoned. Bringing together 'in situ' and other entities into the simpler and more logical DIN/LIN framework--as has been done with intraepithelial neoplasias of cervix, vagina, vulva, prostate, and pancreas--would eliminate the artificial and illogical distinctions between 'not cancers' (e.g. flat epithelial atypia, atypical ductal hyperplasia--now classified as low grade DIN) and 'cancers' (e.g. DCIS--now considered medium-high grade DIN). Elimination of the term 'carcinoma' from entities that cannot metastasize will reduce confusion among health professionals and patients, and contribute to reducing the risk of overtreatment, as well as reducing adverse psychological reactions in patients.

Accelerated partial breast irradiation with intraoperative electrons: using GEC-ESTRO recommendations as guidance for patient selection.

PURPOSE: To evaluate outcomes among early-stage breast cancer patients after conservative surgery and full-dose intraoperative radiotherapy electrons (ELIOT) by applying the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) recommendations for partial breast irradiation (APBI). MATERIALS AND METHODS: One-thousand eight-hundred and twenty-two patients were stratified into the three GEC-ESTRO categories of "good candidates", "possible candidates" and "contraindication" in order to assess outcomes. RESULTS: All the 1822 cases except 7 could be classified according to GEC-ESTRO groups: 573 patients met the criteria to be included in the "good candidates" group, 468 patients in the "possible candidates" group and 767 patients in the "contraindication" group. Median and mean follow-up length was 3.5 years (range 0-10.5 years) and 3.8 years (SD 2.2), respectively. The 5-year rate of in-breast tumor reappearances for "good candidates", "possible candidates" and "contraindication" groups were 1.9%, 7.4% and 7.7%, respectively (p 0.001). While the regional node relapse showed no difference, the rate of distant metastases was significantly different in the "contraindication" group compared to the other two categories, having a significant impact on survival. CONCLUSIONS: Among the ELIOT population, the GEC-ESTRO recommendations enabled the selection of the good candidates with a low rate of local recurrence, but failed to differentiate the "possible candidates" and the "contraindication" groups.

Risk of locoregional recurrence in patients with false-negative frozen section or close margins of retroareolar specimen in nipple-sparing mastectomy.

BACKGROUND: Our purpose was to evaluate the locoregional recurrence (LRR) of patients with false-negative, frozen-section or close margins of retroareolar specimen in nipple-sparing mastectomy (NSM) procedure. METHODS: From 2002-2008, we recruited patients who had atypia or presence of cancer cells in definitive histology of retroareolar tissue despite of absence of tumor cell in intraoperative retroareolar frozen section. We also included the close margin cases defined as the presence of tumor cells at the first frozen section, but after deeper core out of retroareolar tissue were revealed free of malignancy. The incidence of LRR and NAC recurrence were reported, and the factors associated were analyzed. RESULTS: Of 948 NSM procedures, there were 88 false-negative, frozen-sections and 10 close margin cases. The 5-year cumulative incidence of LRR and NAC recurrence was 11.2 % (10/98 patients) and 2.4 % (2/98 patients), respectively. Analyzing the definitive results of retroareolar tissue, the 5-year cumulative incidence of LRR was 42.9 % (n = 4) for atypia, 10 % (n = 2) for lobular carcinoma in situ (LCIS), 10 % (n = 1) for close margins, 8.7 % (n = 3) for ductal carcinoma in situ (DCIS), and 0 % for invasive carcinoma. In situ carcinoma as a primary tumor was a significant predictor of NAC recurrence (P < 0.01). CONCLUSIONS: Despite a high reliability of frozen section, there is still a minority of false-negative results. Nevertheless, the LRR is considerably low. This fact suggests the possibility of preservation of the NAC after discussion with the patient.

Paget's disease as a local recurrence after nipple-sparing mastectomy: clinical presentation, treatment, outcome, and risk factor analysis.

BACKGROUND: Paget's disease is a rare clinical and histological type of local recurrence (LR) after breast cancer treatment both in case of conservative surgery or nipple-sparing mastectomy (NSM) with or without intraoperative radiation. METHODS: We performed an analysis of 861 NSM with electron beam intraoperative radiotherapy (ELIOT) patients treated at the European Institute of Oncology from 2002 to 2008, focused on Paget's disease local recurrence. RESULTS: In 861 patients (713 invasive carcinoma and 148 intraepithelial neoplasia), there were 36 local recurrences (4.18%), and among these were 7 Paget's disease local recurrences (0.8%). Median follow-up was 50 months. Four cases presented with nipple areola complex (NAC) erosions, two crusted lesions, and one ulcerated NAC. The average latency period from the NSM to Paget's disease local recurrence is 32 months (range, 12-49). Complete NAC removal was performed in all seven recurrences. The average follow-up after NAC removal was 47.4 months (range, 20-78). We found neither locoregional relapse nor metastatic event in this group. All patients were alive without disease. CONCLUSIONS: Paget's disease local recurrence can be found in a significant proportion after NSM. Any suspicious lesion on NAC requires prompt pathological confirmation. Primary carcinoma with ductal intraepithelial neoplasia or invasive ductal carcinoma with extensive in situ component, negative hormonal receptor, high pathological grade, overexpression of HER2/neu, and "HER2 positive (nonluminal)" subtype tend to be significantly associated with more Paget's disease local recurrence and should be followed carefully.

How do the ASTRO consensus statement guidelines for the application of accelerated partial breast irradiation fit intraoperative radiotherapy? A retrospective analysis of patients treated at the European Institute of Oncology.

PURPOSE: To verify how the classification according to the American Society for Therapeutic Radiation Oncology (ASTRO) consensus statement (CS) for the application of accelerated partial breast irradiation (APBI) fits patients treated with intraoperative radiotherapy with electrons (ELIOT) at a single institution. METHODS AND MATERIALS: The study included 1,822 patients treated with ELIOT as the sole radiation modality outside of a clinical trial at the European Institute of Oncology after breast-conserving surgery for invasive breast cancer, who were classified into CS groups of suitable, cautionary, and unsuitable. The outcome in terms of ipsilateral breast recurrence, regional node relapse, distant metastases, progression free-survival, cause-specific survival, and overall survival were assessed. RESULTS: All the 1,822 cases except for 25 could be classified according to ASTRO CS: 294 patients met the criteria for inclusion into the suitable group, 691 patients into the cautionary group, and 812 patients into the unsuitable group. The 5-year rate of ipsilateral breast recurrence for suitable, cautionary, and unsuitable groups were 1.5%, 4.4%, and 8.8%, respectively (p = 0.0003). Whereas the regional node relapse showed no difference, the rate of distant metastases was significantly different in the unsuitable group compared with the suitable and cautionary groups, having a significant impact on survival. CONCLUSION: In the context of patients treated with ELIOT, the ASTRO guidelines identify well the groups for whom APBI might be considered as an effective alternative to whole breast radiotherapy and also identify groups for whom APBI is not indicated.