Influencia de la creación de una Unidad de Mama en los parámetros quirúrgicos y criterios de calidad del tratamiento quirúrgico del cáncer de mama / Influence of the creation of a Breast Unit on the surgical parameters and quality criteria of the surgical treatment of breast cancer

Objetivos: La European Society of Mastology (EUSOMA) propone criterios de calidad en el diagnóstico y tratamiento del cáncer de mama y recomienda la evaluación de las Unidades de Mama aplicando dichos criterios. En nuestro centro, coincidiendo con la acreditación de la Unidad de Mama por la Sociedad Española de Senología y Patología Mamaria (SESPM) en el año 2000, se asignaron 2 cirujanos a dedicación preferente a la misma. El objetivo es evaluar la repercusión en parámetros quirúrgicos y los criterios de calidad relacionados con el tratamiento quirúrgico tras la adscripción de los cirujanos a la patología mamaria. Material y métodos: Estudio retrospectivo de pacientes tratadas de cáncer de mama entre 1990 y 2010, distribuidas en dos periodos, A; 1990-1999 y B; 2000-2010. Se evalúan datos demográficos, diagnósticos, el tratamiento aplicado, las complicaciones postoperatorias, el seguimiento, la recidiva y 10 criterios de calidad propuestos por EUSOMA. Resultados: La serie se compone de 1.881 mujeres intervenidas por cáncer de mama, 671 en el periodo A y 1.210 en el B. Se han encontrado diferencias significativas entre ambos periodos en la estancia (9,8 días vs. 2,7 días) y complicaciones postoperatorias (17,4% vs. 10%). Existe mejoría significativa en el periodo B en 6 de los 10 criterios evaluados. Conclusiones: La dedicación preferente de los cirujanos a la patología de la mama dentro de una Unidad de Mama ha conseguido reducir las complicaciones y la estancia hospitalaria postoperatoria, se ha obtenido mejoría en los criterios de calidad que evalúan el diagnóstico completo, la indicación y el tratamiento de los ganglios axilares y el seguimiento postoperatorio

Objectives: The European Society of Mastology (EUSOMA) has proposed quality criteria in the diagnosis and treatment of breast cancer and recommends the evaluation of breast units applying these criteria. In our centre, coinciding with the accreditation of the breast unit by the Spanish Society of Senology and Breast Pathology in 2000, two surgeons were assigned to work full-time in breast cancer. The objective of this study was to evaluate the effects of the surgeons' secondment to breast disease on the surgical parameters and the quality criteria related to surgical treatment. Material and methods: We performed a retrospective study that included patients treated for breast cancer between 1990 and 2010, divided into two periods, A; 1990-1999 and B; 2000-2010. We evaluated demographic data, diagnoses, treatment, postoperative complications, follow-up, recurrence, and the 10 quality criteria related to surgical treatment proposed by EUSOMA. Results: The series consisted of 1,881 women who underwent surgery for breast cancer: 671 in period A and 1210 in B. There were significant differences between the two periods in postoperative stay (9.8 vs. 2.7 days) and postoperative complications (17.4% vs. 10%). Significant improvement was found in period B in 6 of the 10 criteria evaluated. Conclusions: Assigning two surgeons to work full-time in a breast unit reduced complications and postoperative hospital stay, and improved the quality criteria that assess complete diagnosis, indication and treatment of axillary lymph nodes and postoperative follow-up

CDH22 hypermethylation is an independent prognostic biomarker in breast cancer.

BACKGROUND: Cadherin-like protein 22 (CDH22) is a transmembrane glycoprotein involved in cell-cell adhesion and metastasis. Its role in cancer is controversial because it has been described as being upregulated in colorectal cancer, whereas it is downregulated in metastatic melanoma. However, its status in breast cancer (BC) is unknown. The purpose of our study was to determine the molecular status and clinical value of CDH22 in BC. RESULTS: We observed by immunohistochemistry that the level of CDH22 expression was lower in BC tissues than in their matched adjacent-to-tumour and non-neoplastic tissues from reduction mammoplasties. Since epigenetic alteration is one of the main causes of gene silencing, we analysed the hypermethylation of 3 CpG sites in the CDH22 promoter by pyrosequencing in a series of 142 infiltrating duct BC cases. CDH22 was found to be hypermethylated in tumoral tissues relative to non-neoplastic mammary tissues. Importantly, this epigenetic alteration was already present in adjacent-to-tumour tissues, although to a lesser extent than in tumoral samples. Furthermore, CDH22 gene regulation was dynamically modulated in vitro by epigenetic drugs. Interestingly, CDH22 hypermethylation in all 3 CpG sites simultaneously, but not expression, was significantly associated with shorter progression-free survival (p = 0.015) and overall survival (p = 0.021) in our patient series. Importantly, CDH22 hypermethylation was an independent factor that predicts poor progression-free survival regardless of age and stage (p = 0.006). CONCLUSIONS: Our results are the first evidence that CDH22 is hypermethylated in BC and that this alteration is an independent prognostic factor in BC. Thus, CDH22 hypermethylation could be a potential biomarker of poor prognosis in BC.

CHL1 hypermethylation as a potential biomarker of poor prognosis in breast cancer.

The CHL1 gene encodes a cell-adhesion molecule proposed as being a putative tumour-suppressor gene in breast cancer (BC). However, neither the underlying molecular mechanisms nor the clinical value of CHL1 downregulation in BC has been explored. The methylation status of three CpG sites in the CHL1 promoter was analysed by pyrosequencing in neoplastic biopsies from 142 patients with invasive BC and compared with that of non-neoplastic tissues. We found higher CHL1 methylation levels in breast tumours than in non-neoplastic tissues, either from mammoplasties or adjacent-to-tumour, which correlated with lower levels of protein expression in tumours measured by immunohistochemistry. A panel of five BC cell lines was treated with two epigenetic drugs, and restoration of CHL1 expression was observed, indicating in vitro dynamic epigenetic regulation. CHL1 was silenced by shRNA in immortalized but non-neoplastic mammary cells, and enhanced cell proliferation and migration, but not invasion, were found by real-time cell analysis. The prognostic value of CHL1 hypermethylation was assessed by the log-rank test and fitted in a Cox regression model. Importantly, CHL1 hypermethylation was very significantly associated with shorter progression-free survival in our BC patient series, independent of age and stage (p = 0.001). In conclusion, our results indicate that CHL1 is downregulated by hypermethylation and that this epigenetic alteration is an independent prognostic factor in BC.

Differential involvement of RASSF2 hypermethylation in breast cancer subtypes and their prognosis.

Breast cancer is a heterogeneous disease that can be subdivided into clinical, histopathological and molecular subtypes (luminal A-like, luminal B-like/HER2-negative, luminal B-like/HER2-positive, HER2-positive, and triple-negative). The study of new molecular factors is essential to obtain further insights into the mechanisms involved in the tumorigenesis of each tumor subtype. RASSF2 is a gene that is hypermethylated in breast cancer and whose clinical value has not been previously studied. The hypermethylation of RASSF1 and RASSF2 genes was analyzed in 198 breast tumors of different subtypes. The effect of the demethylating agent 5-aza-2'-deoxycytidine in the re-expression of these genes was examined in triple-negative (BT-549), HER2 (SK-BR-3), and luminal cells (T-47D). Different patterns of RASSF2 expression for distinct tumor subtypes were detected by immunohistochemistry. RASSF2 hypermethylation was much more frequent in luminal subtypes than in non-luminal tumors (p = 0.001). The re-expression of this gene by lentiviral transduction contributed to the differential cell proliferation and response to antineoplastic drugs observed in luminal compared with triple-negative cell lines. RASSF2 hypermethylation is associated with better prognosis in multivariate statistical analysis (P = 0.039). In conclusion, RASSF2 gene is differently methylated in luminal and non-luminal tumors and is a promising suppressor gene with clinical involvement in breast cancer.

Consenso de seguimiento de pacientes con cáncer de mama de la Sociedad Española de Senología y Patología Mamaria / Consensus document of the Spanish Society of Senology and Breast Disease on the follow-up of patients with breast cancer

A pesar del aumento en la prevalencia del cáncer de mama, el seguimiento de estas pacientes no está totalmente estandarizado. La Sociedad Española de Senología y Patología Mamaria propuso la elaboración de un documento de consenso sobre el seguimiento que debería proponerse a las pacientes afectas de lesiones de mama in situ e infiltrantes en estadios i-iii, tratadas con intención curativa, una vez finalizados los tratamientos iniciales. En su realización han colaborado profesionales de toda España de distintas especialidades y ámbitos de actuación. Fue presentado en el Primer Congreso Español de la Mama, que se celebró en octubre de 2013 en Madrid, para su refrendo por parte de la Sociedad, y se recogieron las aportaciones de los asistentes a la sala. El objetivo principal del seguimiento es la detección precoz de recurrencias locorregionales y a distancia, de nuevos primarios, y valorar los efectos secundarios de los tratamientos aplicados. Debe también cubrir las necesidades de soporte psicológico, así como la rehabilitación y reinserción sociolaboral posterior y la educación para la salud, corrigiendo hábitos de vida no saludables. No se han descrito diferencias significativas entre el seguimiento minimalista y el intensivo, respecto al índice de recurrencia, la supervivencia global y la calidad de vida. El tipo y los años de seguimiento deberían ser distintos para cada paciente según su riesgo de recidiva y la clasificación molecular de su lesión. Este consenso ha tenido el apoyo de otras sociedades científicas relacionadas con la enfermedad mamaria, asistentes al Primer Congreso Español de la Mama (AU)

Despite the increasing prevalence of breast cancer, there is no standardized protocol for the follow-up of breast cancer survivors. The Spanish Society of Senology and Breast Disease has supported a consensus document on the follow-up of breast cancer survivors, aimed at patients diagnosed with stage i to iii disease and with invasive and intraepithelial (in situ) lesions, and treated with curative intent, after completion of the initial treatment. Practitioners from all over Spain, with different specialities and areas of activity, participated in the drafting in the document. It was presented at the First Spanish Breast Congress (Primer Congreso Español de la Mama), which took place in October 2013, for the Society's approval. Input from the audience was considered. The main aim of follow-up is the early detection of local and distant recurrences, of new primaries, and evaluation of the adverse effects of the therapies applied. Follow-up should also include psychological support, education on healthy habits, rehabilitation, and social and work reintegration. No significant differences between minimalistic and intensive follow-up have been reported regarding recurrence, overall survival, and quality of life. The length, intervals, and intensity of follow-up should be tailored according to each patient's individual risk of relapse and molecular subtype. This consensus document has the support and endorsement of other scientific societies related to breast disease and present at the congress (AU)

Biopsia selectiva del ganglio centinela tras quimioterapia neoadyuvante en el cáncer de mama: resultados del estudio GEICAM 2005-07 / Selective sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer: results of the GEICAM 2005-07 study

INTRODUCCIÓN: La utilidad de la biopsia selectiva del ganglio centinela (BSGC) en pacientes con cáncer de mama que precisan quimioterapia neoadyuvante (QTN) es controvertida. Nuestro objetivo es analizar la tasa de detección (TD) y de falsos negativos (FN) de la BSGC tras QTN así como la influencia de la afectación ganglionar inicial y de los protocolos aplicados. MÉTODOS: Estudio prospectivo observacional multicéntrico con mujeres con cáncer de mama tratadas con QTN y a las que se les realizó BSGC tras recibir la QTN y linfadenectomía posterior. Se calcularon las TD y las tasas de FN, tanto globales como dependientes de la afectación ganglionar inicial o del uso de protocolos de diagnóstico pre-BSGC. RESULTADOS: No se demostraron diferencias en la TD entre los casos sin afectación ganglionar inicial y los que sí la tuvieron (89,8 vs. 84,4%; p = 0,437). Sí se encontraron diferencias significativas (94,1 vs. 56,5%; p = 0,002) en el valor predictivo negativo, menor cuando existía afectación ganglionar inicial, y mayor tasa de FN, aunque no de forma significativa (18,2 vs. 43,5%; p = 0,252) en ese mismo supuesto. Un estudio de la axila antes de indicar la BSGC y tras la QTN disminuyó significativamente la tasa de FN en los casos en los que existía afectación inicial (55,6 vs. 12,5; p = 0,009). CONCLUSIONES: La QTN da lugar a una menor TD y a una mayor tasa de FN en la BSGC posterior, sobre todo si hay afectación ganglionar inicial. Los protocolos para la evaluación axilar después de administrar la QTN y antes de la BSGC disminuyen la tasa de FN en estas pacientes

INTRODUCTION: A controversial aspect of breast cancer management is the use of sentinellymph node biopsy (SLNB) in patients requiring neoadjuvant chemotherapy (NCT). This paper discusses the detection rate (DT) and false negatives (FN) of SLNB after NCT to investigate the influence of initial nodal disease and the protocols applied. METHODS: Prospective observational multicenter study in women with breast cancer, treated with NCT and SLNB post-NCT with subsequent lymphadenectomy. DT and FN rates were calculated, both overall and depending on the initial nodal status or the use of diagnostic protocols pre-SLNB. RESULTS: No differences in DT between initial node-negative cases and positive cases were found (89.8 vs. 84.4%, P=.437). Significant differences were found (94.1 vs. 56.5%, P= 0,002) inthe negative predictive value, which was lower when there was initial lymph node positivity, and a higher rate of FN, not significant (18.2 vs. 43.5%, P=.252) in the same cases. The axillary study before SLNB and after the NCT, significantly decreased the rate of FN in patients with initial involvement (55.6 vs 12.5, P=0,009). CONCLUSIONS: NCT means less DT and a higher rate of FN in subsequent SLNB, especially if there is initial nodal involvement. The use of protocols in axillary evaluation after administering the NCT and before BSGC, decreases the FN rate in these patients

Selective sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer: results of the GEICAM 2005-07 study.

INTRODUCTION: A controversial aspect of breast cancer management is the use of sentinel lymph node biopsy (SLNB) in patients requiring neoadjuvant chemotherapy (NCT). This paper discusses the detection rate (DT) and false negatives (FN) of SLNB after NCT to investigate the influence of initial nodal disease and the protocols applied. METHODS: Prospective observational multicenter study in women with breast cancer, treated with NCT and SLNB post-NCT with subsequent lymphadenectomy. DT and FN rates were calculated, both overall and depending on the initial nodal status or the use of diagnostic protocols pre-SLNB. RESULTS: No differences in DT between initial node-negative cases and positive cases were found (89.8 vs. 84.4%, P=.437). Significant differences were found (94.1 vs. 56.5%, P=0,002) in the negative predictive value, which was lower when there was initial lymph node positivity, and a higher rate of FN, not significant (18.2 vs. 43.5%, P=.252) in the same cases. The axillary study before SLNB and after the NCT, significantly decreased the rate of FN in patients with initial involvement (55.6 vs 12.5, P=0,009). CONCLUSIONS: NCT means less DT and a higher rate of FN in subsequent SLNB, especially if there is initial nodal involvement. The use of protocols in axillary evaluation after administering the NCT and before BSGC, decreases the FN rate in these patients.

Tumoral load quantification of positive sentinel lymph nodes in breast cancer to predict more than two involved nodes.

AIM: One-Step Nucleic Acid Amplification (OSNA) can detect isolated tumour loads in axillary lymph nodes of breast cancer patients. We investigated the predictability of the non-sentinel lymph node (SLN) metastatic involvement (MI) based on the OSNA SLN assessment in surgical invasive breast cancer. METHODS: We studied surgical breast invasive carcinoma patients, not taking neoadjuvant chemotherapy, having SLN positive by OSNA and having received axillary lymphadenectomy. Age, basic histopathological, immunohistochemical, SLN biopsy and lymphadenectomy data were compared between patients with or without MI of more than 2 non-SLN in both univariate and multivariate analyses. The discriminating capacity of the multivariate model was characterized by the ROC AUC. RESULTS: 726 patients from 23 centers in Spain aged 55.3 ± 12.2 years were analysed. The univariate analysis comparing patients with or without MI of more than 2 non-SLN detected statistically significant differences in primary tumour size, multifocality, presence of lymphovascular infiltration, positive proliferation index with ki67, immunophenotype and logTTL (Tumour Total Load). The multivariate logistic analyses (OR (95% CI)) confirmed multifocality (2.16 (1.13-4.13), p = 0.019), lymphovascular infiltration (4.36 (2.43-7.82), p < 0.001) and logTTL (1.22 (1.10-1.35), p < 0.001) as independent predictors, and exhibit an AUC (95% CI) of 0.78 (0.72-0.83) with an overall fit (Hosmer-Lemeshow test) of 0.359. A change in the slope of both sensitivity and specificity is observed at about 10,000 copies/µL, without relevant changes in the Negative Predictive Values. CONCLUSIONS: Using OSNA technique, the MI of more than 2 non-SLN can be reliably predicted.

Análisis de los factores relacionados con la sobreestadificación y la positividad del ganglio centinela en las pacientes con diagnóstico inicial de carcinoma ductal in situ / Analysis of factors related to upstaging and sentinel node positivity in the initial diagnosis of ductal carcinoma in situ

Objetivo. Determinar el porcentaje de pacientes con diagnóstico inicial de carcinoma ductal in situ (CDIS) que presentó infiltración tras la excisión quirúrgica e identificar los factores relacionados tanto con la sobreestadificación como con la positividad del ganglio centinela (GC) en el estudio definitivo. Material y métodos. Análisis retrospectivo de 135 pacientes diagnosticadas mediante biopsia core de CDIS a las que se les realizó biopsia selectiva del GC de forma consecutiva de 2003 a 2011. La técnica fue mixta en el período inicial y posteriormente mediante administración intraperilesional de radiocoloides. En 2009 se introdujo una gammacámara portátil y se inició el estudio intraoperatorio molecular mediante amplificación de ácido nucleico de un solo paso. Resultados. Se produjo sobreestadificación en 45 de las 135 pacientes (33,3%), de las que 30 (22,2%) presentaron CDIS con microinfiltración y 15 (11,1%) carcinoma infiltrante. Los CDIS con microinfiltración mostraron mayor tamaño, mayor porcentaje de alto grado, de HER2 positivo y de Ki-67 alto que los CDIS (p < 0,001, p < 0,001, p = 0,002 y p = 0,031, respectivamente). Los porcentajes de positividad del GC fueron del 3,6% en el CDIS, del 6,9% en el CDIS con microinfiltración y del 20% en los carcinomas infiltrantes, correspondiendo a 8 pacientes, de las cuales 6 presentaron HER2 positivo y Ki-67 alto. Conclusiones. El porcentaje global de infraestimación fue alto, principalmente debido a la presencia de microinfiltración. Tanto esta como la afectación metastásica del GC mostró relación con el HER2 positivo y el Ki-67 alto, por tanto, disponer de estos datos en la biopsia percutánea podría ser relevante para establecer la indicación de realización de biopsia selectiva del GC en el CDIS

Objective. To determine the percentage of patients with ductal carcinoma in situ (DCIS) with infiltration after surgical excision and to identify the factors related to both upstaging and sentinel node (SN) positivity in the final study. Material and methods. A retrospective analysis was performed in 135 patients diagnosed with DCIS by core biopsy who subsequently underwent sentinel lymph node biopsy from 2003 to 2011. In the first period of the study, the technique was mixed and subsequently consisted of intra-perilesional radiocolloid administration. In 2009, a portable gamma camera was introduced and we began to use intraoperative one-step nucleic acid amplification. Results. Upstaging occurred in 45 of the 135 patients (33.3%), of which 30 (22.2%) had DCIS with microinfiltration and 15 (11.1%) had invasive carcinoma. Compared with DCIS, DCIS with microinfiltration were larger and showed a higher percentage of high grade, HER2 positivity and high Ki-67 (P < .001, P < .001, P = .002 and P = .031, respectively). SN positivity rates were 3.6% in DCIS, 6.9% in DCIS with microinfiltration, and 20% in invasive carcinomas, corresponding to 8 patients, of whom 6 showed HER2-positivity and high Ki-67. Conclusions. Overall underestimation was high, mainly due to the presence of microinfiltration. Both microinfiltration and metastatic SN involvement were associated with HER2-positivity and high Ki-67. Therefore, the availability of this information in core needle biopsy could be relevant in establishing the indication for sentinel lymph node biopsy in DCIS

Linfoma de tejido linfoide asociado a mucosas primario de mama con infiltración de la piel / Primary mucosa-associated lymphoid tissue lymphoma of the breast with cutaneous involvement

El linfoma de células B extranodal de la zona marginal del tejido asociado a mucosas es de bajo grado de malignidad y representa el 0,04-0,53% de todos los tumores malignos de la mama y el 2,2% de los linfomas malignos extranodales. Se asocia a enfermedades autoinmunes. En la mama se presenta habitualmente como un tumor único, indoloro y de rápido crecimiento. En algunos casos existe compromiso de la piel y adenopatías axilares. Presentamos el caso de una mujer de 39 años con artritis reumatoide de 20 años de evolución, que presenta desde hace 5 meses una tumoración palpable en la mama izquierda de 4 cm y lesiones eritematosas cambiantes en la piel de ambas mamas. Los hallazgos radiológicos fueron similares a los del resto de las tumoraciones malignas, por lo que para su diagnóstico fue necesario un estudio anatomopatológico, inmunohistoquímico y molecular (AU)

Mucosa-associated lymphoid tissue lymphoma is a low-grade malignant tumor representing 0.04 to 0.53% of all malignant breast tumors and 2.2% of extranodal malignant lymphomas. This entity is associated with autoimmune diseases. In the breast, mucosa-associated lymphoid tissue lymphomas usually appear as a single, painless, and fast growing tumor. Some patients also have cutaneous involvement and axillary lymphadenopathy. We present a case of a 39-year-old woman with a 20-year history of rheumatoid arthritis and a 5-month history of a palpable 4 cm lump in the left breast and erythematous skin lesions on both breasts. Radiological findings were similar to those of other malignant tumors. Consequently, histopathological, immunohistochemical and molecular studies were required for diagnosis (AU)

[Training periods with experts improve results in colorectal laparoscopic surgery]. / Las estancias de formación con expertos mejoran los resultados en cirugía laparoscópica colorrectal.

OBJECTIVE: To analyse the effects of training in elective colorectal laparoscopic surgery with a minimum 6 months follow up to assess early and delayed complications, and comparing the first 40 cases in the 1st Period (P-1: 1996-2002) with the 100 cases in the 2nd Period (P-2: 2003-2008). One of the surgeons had two training courses between P-1 and P-2. MATERIAL AND METHODS: A total of 66 colorectal resections due to cancer were performed and 74 operations for benign disease. The cases of malignant diseases increased between P-1 and P-2 (P<0.001). (Odds-Ratio=0.16). RESULTS: There number of complex cases increased between P-1 and P-2 (Anterior resection-amputation, left hemicolectomy, total colectomy, rectopexy) vs. Others (Sigmoidectomy, right resections) (P<0.05), but the mean duration of the operations was reduced by 29 minutes P<0.01). There were 24% conversions, with no change in P-2 (P=0.85). Surgical mortality at 3 months (1.4%) showed no differences (P=0.49). The total complications rate (31%) was significantly lower in P-2 (P=0.001), because medical complications (P=0.05), the more serious surgical complications (with reintervention) (P=0.05) and wound infections (P=0.0001) were lower. There was no change in the other surgical complications (P=0.61). The overall mean stay was 7.8 days (3-36) (median=6 days), with no differences between P-1 and P-2 (P=0.165). Conversion significantly lengthened the mean hospital stay (P=0.015) (from 7.2+/-5 days to 10.1+/-7 days), but there was no increase in complications (P=0.31). CONCLUSION: Training in colorectal laparoscopy and training periods with experts improve results (duration, complications, more complex surgery). Conversions did not decrease with experience and the hospital stays lengthened, but they were not associated with more complications.