ZEB1 hypermethylation is associated with better prognosis in patients with colon cancer.

BACKGROUND: Colon cancer (CC) is a heterogeneous disease that is categorized into four Consensus Molecular Subtypes (CMS) according to gene expression. Patients with loco-regional CC (stages II/III) lack prognostic factors, making it essential to analyze new molecular markers that can delineate more aggressive tumors. Aberrant methylation of genes that are essential in crucial mechanisms such as epithelial mesenchymal transition (EMT) contributes to tumor progression in CC. We evaluate the presence of hyper- and hypomethylation in subrogate IHC markers used for CMS classification (CDX2, FRMD6, HTR2B, ZEB1) of 144 stage II/III patients and CC cell lines by pyrosequencing. ZEB1 expression was also studied in control and shRNA-silenced CC cell lines and in paired normal tissue/tumors by quantitative PCR. The pattern of ZEB1 staining was also analyzed in methylated/unmethylated tumors by immunohistochemistry. RESULTS: We describe for the first time the hypermethylation of ZEB1 gene and the hypomethylation of the FRMD6 gene in 32.6% and 50.9% of tumors, respectively. Additionally, we confirm the ZEB1 re-expression by epigenetic drugs in methylated cell lines. ZEB1 hypermethylation was more frequent in CMS1 patients and, more importantly, was a good prognostic factor related to disease-free survival (p = 0.015) and overall survival (p = 0.006) in our patient series, independently of other significant clinical parameters such as patient age, stage, lymph node involvement, and blood vessel and perineural invasion. CONCLUSIONS: Aberrant methylation is present in the subrogate genes used for CMS classification. Our results are the first evidence that ZEB1 is hypermethylated in CC and that this alteration is an independent factor of good prognosis.

Estudio del ganglio centinela en el cáncer de mama por el método OSNA (One-Step Nucleic Acid Amplification) tras neoadyuvancia en el Hospital Universitario de Navarra / Sentinel lymph node study in breast cancer using the OSNA (one-step nucleic acid amplification) method after neoadjuvant treatment at Hospital Universitario de Navarra

Introducción: la biopsia selectiva de ganglio centinela (GC) es la técnica estándar para la estadificación axilar en el cáncer de mama. No hay consenso en el empleo del método OSNA (One-Step Nucleic Acid Amplification) para el análisis del GC en las pacientes que recibieron el tratamiento neoadyuvante (TNA). En este trabajo analizamos los resultados obtenidos con OSNA en estas pacientes para justificar su implantación en nuestro centro. Material y métodos: se seleccionaron 42 casos del grupo de 163 pacientes con CM tratadas con TNA en nuestro centro, a las que se realizó OSNA del GC, obteniéndose una media de 2,1 ganglios por paciente. Se analizó además la expresión de citoqueratina 19 (CK19), grado tumoral, fenotipo molecular y el grado de respuesta al TNA de estas pacientes. Se estudiaron los GC mediante técnica OSNA y los no centinelas por el método tradicional. Resultados: el grado tumoral fue 2-3 en el 97,6% de los casos, el fenotipo luminal A (17%), luminal B (38%), triple-negativo (26,1%) y HER2 (19%). La respuesta al TNA fue completa en el 59,5% de las pacientes y la expresión de CK19 no se vio modificada. Los ganglios estudiados fueron positivos en 9 pacientes (21,4%) en las que posteriormente se realizó una linfadenectomía y un único caso presentó ganglio no centinela afecto (2,3%). Conclusiones: el método OSNA para el estudio del GC tras el TNA es muy superior al método tradicional, ya que permite la detección intraoperatoria de grupo celular aislado y micrometástasis no detectables con los métodos tradicionales, evitando segundas intervenciones y falsos negativos al analizarse completo el GC, y demuestra que no se altera la expresión de CK19 con el TNA. (AU)

Background: Selective sentinel node (SN) biopsy is the standard technique for axillary staging in breast cancer (BC). There is no consensus on the use of OSNA (One-Step Acid Nucleic Amplification) method for SN in patients undergoing neoadjuvant treatment (NAT). We have studied the results obtained in our centre to justify the advantages of its implementation. Material and methods: 42 cases were selected from the group of 163 patients with BC treated with NAT, who underwent OSNA of the SN, obtaining a mean of 2.1 nodes per patient. We also analyzed cytokeratin 19 (CK19) expression, tumour grade, molecular phenotype and the degree of response to NAT in these patients. The SN were studied using the OSNA technique and non-sentinel nodes using the traditional method. Results: Tumour grade was 2-3 in 97.6% of cases, phenotype luminal A (17%), luminal B (38%), triple-negative (26.1%) and HER2 (19%). The response to NAT was complete in 59.5% of patients and CK19 expression was unchanged. The nodes studied were positive in 9 patients (21.4%) in whom lymphadenectomy was performed and only one case had a non-sentinel node involvement (2.3%). Conclusions: The OSNA method for the study of SN after NAT is far superior to the traditional method as it: It allows intraoperative detection of isolated cell group and micrometastases not detectable with traditional methods, avoiding second interventions. It avoids false negatives when the whole SN is analyzed. It shows that CK19 expression is not altered by NAT. (AU)

Modification of Breast Cancer Milieu with Chemotherapy plus Dendritic Cell Vaccine: An Approach to Select Best Therapeutic Strategies.

BACKGROUND: The addition of dendritic cell vaccines (DCV) to NAC could induce immune responses in those patients with residual disease (RD) by transforming the tumor microenvironment. METHODS: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the vaccinated group plus NAC (VG) and 42 in the control group (CG, treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using immunohistochemistry and the automated cellular imaging system (ACIS III) in paired samples. RESULTS: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). This enrichment was seen in up to 67% of TNBC patients in the experimental arm as compared with the CG (20%). An association between CD8 TILs before NAC (4% cut-off point) and pathological complete response in the VG was found in the univariate and multivariate analysis (OR = 1.41, IC95% 1.05-1.90; p = 0.02, and OR = 2.0, IC95% 1.05-3.9; p = 0.03, respectively). CONCLUSION: Our findings suggest that patients with TNBC could benefit from the stimulation of the antitumor immune system by using DCV together with NAC.

Clinical, Histopathologic and Genetic Features of Rhabdoid Meningiomas.

Rhabdoid meningiomas (RM) shows heterogeneous histological findings, and a wide variety of chromosomal copy number alterations (CNA) are associated with an unpredictable course of the disease. In this study, we analyzed a series of 305 RM samples from patients previously reported in the literature and 33 samples from 23 patients studied in our laboratory. Monosomy 22-involving the minimal but most common recurrent region loss of the 22q11.23 chromosomal region was the most observed chromosomal alteration, followed by losses of chromosomes 14, 1, 6, and 19, polysomies of chromosomes 17, 1q, and 20, and gains of 13q14.2, 10p13, and 21q21.2 chromosomal regions. Based on their CNA profile, RM could be classified into two genetic subgroups with distinct clinicopathologic features characterized by the presence of (1) chromosomal losses only and (2) combined losses and gains of several chromosomes. The latter displays a higher frequency of WHO grade 3 tumors and poorer clinical outcomes.

Sentinel node tumor burden in cutaneous melanoma. Survival with competing risk analysis and influence in relapses and non-sentinel node status: retrospective cohort study with long follow-up in a Spanish population.

Several authors have studied the potential of sentinel lymph node (SLN) tumor burden as prognostic factor but the microscopic classifications used in different study groups were variable. We examined the prognostic role of tumor burden in SLN on melanoma specific-survival and competing causes of death. We also analysed clinical and histological factors as predictors of disease relapses and additional non sentinel lymph node (NSLN) metastases. We included all patients with cutaneous melanoma that underwent SLN biopsy between 2002 and 2012 at Complejo Hospitalario de Navarra (Spain). The study end-points were death due to melanoma, melanoma relapse and involvement of NSLN. We used Fine-Gray test for competing risk analysis. A logistic regression model was performed to predict the risk of involvement of NSLN. Between 2002 and 2012, there were 348 patients who underwent SLN biopsy in our centre (308 were eligible for the study). 26.9% patients positive SLN. 88 patients died during the follow-up period and 66 (75%) died from melanoma. The 5-year cumulative incidence of melanoma death was 15.33% (95 % CI 15.25-15.42). The cumulative probability of death from melanoma was associated with gender, histological subtype, Breslow thickness, mitotic rate, ulceration and SLN tumor burden. In multivariable analysis, Breslow thickness and SLN tumor burden remained as independent prognostic factors. SLN tumor burden appears to be an important prognostic factor. It is very important reporting these characteristics in pathological reports. More prospective studies would be necessary to analyze these variables and to be able to make recommendations in management of melanoma patients.

Prognostic Factor Utility of BAP1 Immunohistochemistry in Uveal Melanoma: A Single Center Study in Spain.

Even today, the mortality rate for uveal melanoma (UM) remains very high. In our research, we sought to determine which pathological and clinical features were correlated with the prognosis of UM. BAP1 (BRCA1-Associated Protein 1) gene mutation has been analyzed as one of the strongest predictors for metastasis in UM. The BAP1 gene codifies the BAP1 protein which has a tumor suppressor function. The presence of this protein can be determined by BAP1 immunohistochemical staining. Eighty-four uveal melanoma patients and forty enucleated eyeballs were examined. Metastasis was present in 24 patients. Nuclear BAP1 staining was low in 23 patients. The presence of a higher large basal diameter tumor (p < 0.001), tumor infiltrating lymphocytes (p = 0.020), and a lack of nuclear BAP1 immunostaining (p = 0.001) ocurred significantly more often in the metastatic group. Metastasis-free survival was lower in patients with low nuclear BAP1 staining (p = 0.003). In conclusion, to the best of our knowledge, this is the first time that BAP1 staining has been studied in uveal melanoma in a Spanish community. We believe that this technique should become routine in the pathological examination of uveal melanoma in order to allow adequate classification of patients and to establish an individual follow-up plan.

A DNA Methylation-Based Gene Signature Can Predict Triple-Negative Breast Cancer Diagnosis.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype and lacks targeted treatment. It is diagnosed by the absence of immunohistochemical expression of several biomarkers, but this method still displays some interlaboratory variability. DNA methylome aberrations are common in BC, thereby methylation profiling could provide the identification of accurate TNBC diagnosis biomarkers. Here, we generated a signature of differentially methylated probes with class prediction ability between 5 non-neoplastic breast and 7 TNBC tissues (error rate = 0.083). The robustness of this signature was corroborated in larger cohorts of additional 58 non-neoplastic breast, 93 TNBC, and 150 BC samples from the Gene Expression Omnibus repository, where it yielded an error rate of 0.006. Furthermore, we validated by pyrosequencing the hypomethylation of three out of 34 selected probes (FLJ43663, PBX Homeobox 1 (PBX1), and RAS P21 protein activator 3 (RASA3) in 51 TNBC, even at early stages of the disease. Finally, we found significantly lower methylation levels of FLJ43663 in cell free-DNA from the plasma of six TNBC patients than in 15 healthy donors. In conclusion, we report a novel DNA methylation signature with potential predictive value for TNBC diagnosis.

[Intraepidermal Merkel cell carcinoma with INSM1 expression. A case report]. / Carcinoma de Merkel intraepidérmico. Presentación de un caso con expresión de INSM1.

We report the case of a 90-year-old male who presented with an erythematous desquamative plaque on his left cheek. Histopathology demonstrated an epidermal lesion with multifocal epithelial growth. The cells were small, with scant cytoplasm and hyperchromatic nuclei with molding and a high mitotic and apopototic rate. Immunohistochemistry showed positivity for CK20, CK7, synaptophysin and INMS1. These findings are consistent with a Merkel cell carcinoma in situ. This tumor corresponds to a primary neuroendocrine neoplasm of the skin, which usually affects elderly people with sun-exposed skin. Usually, it presents as a dermal tumor but intraepidermal involvement alone is extremely rare. In this scenario, a broad differential diagnosis should be considered, excluding all neoplasms that may present intraepidermal forms. The evolution of this entity is unknown.

Carcinoma adenoide quístico de mama, 22 años de experiencia / Adenoid cystic carcinoma of the breast, 22 years of experience

INTRODUCCIÓN: El carcinoma adenoide quístico (CAQ) es una neoplasia infrecuente en la mama (menos del 0,1%). Típicamente es triple negativo con un pronóstico favorable. Su baja frecuencia y su curso indolente provocan dificultades en el convenio de la evaluación y el consenso terapéutico, así como en el uso de la técnica del ganglio centinela en estos carcinomas. OBJETIVO: Aportar una serie nueva de casos procedentes del Complejo Hospitalario de Navarra, mediante la revisión retrospectiva en un periodo de 22 años. MATERIAL Y MÉTODOS: Se revisan todos los casos de CAQ mamario diagnosticados entre 1998 y 2020. Analizamos los datos clínicos y anatomopatológicos y los comparamos con la literatura. RESULTADOS: Identificamos 12 CAQ, de un total de 18.241 pacientes con diagnóstico de carcinoma de mama, con un tamaño tumoral medio de 23,8mm y una edad media de 63,5 años. Todos ellos se encontraban en un estadio I-II al diagnóstico. Un caso presentó una micrometástasis ganglionar. Un caso presentó recidiva local y un caso presentó metástasis a distancia a los 5 meses del diagnóstico (93,5 meses de seguimiento medio). Según el grado histológico de Nottingham, 8 casos tuvieron un grado 1, 2 casos un grado 2 y 2 pacientes un grado 3. Según la clasificación de Ro et al., 3 casos fueron grado 1, 4 casos grado 2 y 5 casos grado 3. Un caso fue RE positivo (10%). Ningún caso presentó positividad para BRAF V600E con inmunohistoquímica. CONCLUSIÓN: El manejo y pronóstico del CAQ mamario, dentro de la benignidad, sigue siendo incierto, siendo necesarios más datos para comprender la evolución clínica y realizar un adecuado manejo terapéutico

INTRODUCTION: Adenoid cystic carcinoma (ACC) is an uncommon neoplasm in the breast (less than 0.1%). ACC is typically triple negative with a favourable prognosis. Its low frequency and indolent course cause difficulties in the agreement of the evaluation and therapeutic consensus, as well as the use of the sentinel node excision in these carcinomas. OBJECTIVE: Our goal is to provide a new series of cases from the Complejo Hospitalario de Navarra, through retrospective review over a period of 22 years. MATERIAL AND METHODS: Every case of breast ACC diagnosed between 1998-2020 is reviewed. We analyze the clinical and pathological characteristics, and compare them with the literature. RESULTS: We identified twelve cases of ACC, from a total of 18,241 patients diagnosed with breast carcinoma, with an average tumor size of 23.8mm and mean of 63.5 years. All of them were in a stage I-II at diagnosis. One case presented a lymph node micrometastases. One of them presented local recurrences and one case presented metastases 5 months after diagnosis (93.5 months of mean follow-up). According to Nottingham Histological Score, eight cases had a grade 1, two grade 2 and two grade 3. According to the classification of Ro et al., three were grade 1, four grade 2 and five grade 3. One case was ER positive (10%). No case presents positivity for BRAF-V600E in immunohistochemistry. CONCLUSION: The management and prognosis ACC of breast, within benignity, remains uncertain, with more studies being needed to understand the clinical evolution and perform adequate therapeutic management

[Adenoid cystic carcinoma of the breast, 22 years of experience]. / Carcinoma adenoide quístico de mama, 22 años de experiencia.

INTRODUCTION: Adenoid cystic carcinoma (ACC) is an uncommon neoplasm in the breast (less than 0.1%). ACC is typically triple negative with a favourable prognosis. Its low frequency and indolent course cause difficulties in the agreement of the evaluation and therapeutic consensus, as well as the use of the sentinel node excision in these carcinomas. OBJECTIVE: Our goal is to provide a new series of cases from the Complejo Hospitalario de Navarra, through retrospective review over a period of 22 years. MATERIAL AND METHODS: Every case of breast ACC diagnosed between 1998-2020 is reviewed. We analyze the clinical and pathological characteristics, and compare them with the literature. RESULTS: We identified twelve cases of ACC, from a total of 18,241 patients diagnosed with breast carcinoma, with an average tumor size of 23.8mm and mean of 63.5 years. All of them were in a stage I-II at diagnosis. One case presented a lymph node micrometastases. One of them presented local recurrences and one case presented metastases 5 months after diagnosis (93.5 months of mean follow-up). According to Nottingham Histological Score, eight cases had a grade 1, two grade 2 and two grade 3. According to the classification of Ro et al., three were grade 1, four grade 2 and five grade 3. One case was ER positive (10%). No case presents positivity for BRAF-V600E in immunohistochemistry. CONCLUSION: The management and prognosis ACC of breast, within benignity, remains uncertain, with more studies being needed to understand the clinical evolution and perform adequate therapeutic management.

Dual staining for p16/Ki67 is a more specific test than cytology for triage of HPV-positive women.

Globally, cervical cancer (CC) screening is moving from cytology-based to HPV screening or a combination of both (co-testing). Most HPV-positive women clear the virus and do not develop relevant disease. Additional triage approaches are needed to reduce unnecessary colposcopy referrals. The p16/Ki67 dual stain cytology test (DSCT) is one of the most promising, but it has not (yet) been included as a recommendation in European guidelines. Previous studies in Spain on this issue are lacking. We studied the performance of p16/Ki67 DSCT for the triage of HPV-positive women in Navarra to detect precursor lesions (PLs) and CC compared to cytology only. We selected 1865 HPV-positive women with p16/Ki67 DSCT results and 304 women with an available biopsy result. Sensitivity, specificity and predictive values of the p16/Ki67 DSCT to detect underlying PLs and CC compared to cytology were calculated, using the biopsy as the gold standard. Cytology and p16/Ki67 DSCT showed similar sensitivity (99.0% vs. 98.0%), but cytology had significantly lower specificity (6.9 vs. 39.1%). Of the CIN2+/HPV+ women, triage using cytology only would have resulted in 40.2% true PLs and CC, while using p16/Ki67 DSCT this was 98.0% qualifying the women for colposcopy referral. Our results show that p16/Ki67 DSCT detects more than twice as many true PLs and CC than cytology only in this population. Thus, this test can be considered as an important additional tool in HPV testing-based screening strategies, to avoid unnecessary colposcopy referrals and to reduce health care costs.

Porokeratotic eccrine and hair follicle nevus: a report of two cases and review of the literature.

Porokeratotic eccrine and hair follicle nevus is a very rare non-hereditary disorder of keratinization with eccrine and hair follicle involvement with only 9 cases described in the literature. In 2009 the term porokeratotic anexial ostial nevus was proposed to comprehend porokeratotic eccrine and hair follicle nevus and a related and more common process without follicular involvement: porokeratotic eccrine ostial and dermal duct nevus Recent findings suggest that both entities may be produced by a mutation in GJB2 gene, which is associated to KID syndrome. Herein we report 2 cases of porokeratotic eccrine and hair follicle nevus and review the existing cases in the Spanish and English literature.

Hidradenitis ecrina neutrofílica en un paciente en tratamiento con antirretrovirales de gran actividad / Neutrophilic eccrine hidradenitis in a patient treated with highly activity antiretroviral therapy

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Porokeratotic eccrine and hair follicle nevus: a report of two cases and review of the literature

Abstract: Porokeratotic eccrine and hair follicle nevus is a very rare non-hereditary disorder of keratinization with eccrine and hair follicle involvement with only 9 cases described in the literature. In 2009 the term porokeratotic anexial ostial nevus was proposed to comprehend porokeratotic eccrine and hair follicle nevus and a related and more common process without follicular involvement: porokeratotic eccrine ostial and dermal duct nevus Recent findings suggest that both entities may be produced by a mutation in GJB2 gene, which is associated to KID syndrome. Herein we report 2 cases of porokeratotic eccrine and hair follicle nevus and review the existing cases in the Spanish and English literature.

Calcifilaxia. Estudio de 9 casos / Calciphylaxis. A review of 9 cases

Fundamento y objetivo: La calcifilaxia es una vasculopatía cutánea isquémica de vasos de pequeño tamaño con una alta morbimortalidad. Hasta el momento actual han sido publicadas muy pocas series de pacientes con esta enfermedad, ninguna procedente de un hospital español. Los principales objetivos de este trabajo son analizar el perfil demográfico, clínico e histológico de los pacientes diagnosticados de calcifilaxia en nuestro servicio, para identificar posibles factores de riesgo y potenciales estrategias terapéuticas. Material y método: Estudio retrospectivo de los casos vistos en el Servicio de Dermatología con diagnóstico de calcifilaxia con una biopsia confirmatoria, en el periodo de enero de 2010 a agosto de 2015. Resultados: Se estudiaron 9 pacientes, con edades de 76-86 años. Todos tenían comorbilidades cardiovasculares y el 67% tenía insuficiencia renal. Se observó un 33% de mortalidad. Conclusiones: Ante el posible diagnóstico de calcifilaxia debe realizarse una analítica sanguínea completa para descartar otras causas de úlceras cutáneas. El tratamiento de estos pacientes debe llevarse a cabo por un equipo multidisciplinar. Resaltamos el papel del tiosulfato sódico en el tratamiento de esta entidad (AU)

Background and objective: Calciphylaxis is a cutaneous ischaemic vascular disease of small vessels with high morbidity and mortality. To date very few series of patients with this disease have been published, none from a Spanish hospital. The main objectives of this work are to analyze the demographic, clinical and histological profile of patients diagnosed in our department to identify risk factors and potential therapeutic strategies. Material and method: We made a retrospective study of the cases seen in the dermatology department with a diagnosis of calciphylaxis and who had a confirmatory biopsy in the period between January 2010 to August 2015. Results: Nine patients were studied, with an age range of 76-86 years. All had cardiovascular comorbidities and 67% had renal failure. A 33% mortality was observed. Conclusions: Faced with a possible diagnosis of calciphylaxis, a complete blood analysis is mandatory to rule out other causes of skin ulcers. The management of these patients should be undertaken by a multidisciplinary team. We emphasize the role of sodium thiosulfate in the treatment of this condition (AU)

[Calciphylaxis. A review of 9 cases]. / Calcifilaxia. Estudio de 9 casos.

BACKGROUND AND OBJECTIVE: Calciphylaxis is a cutaneous ischaemic vascular disease of small vessels with high morbidity and mortality. To date very few series of patients with this disease have been published, none from a Spanish hospital. The main objectives of this work are to analyze the demographic, clinical and histological profile of patients diagnosed in our department to identify risk factors and potential therapeutic strategies. MATERIAL AND METHOD: We made a retrospective study of the cases seen in the dermatology department with a diagnosis of calciphylaxis and who had a confirmatory biopsy in the period between January 2010 to August 2015. RESULTS: Nine patients were studied, with an age range of 76-86 years. All had cardiovascular comorbidities and 67% had renal failure. A 33% mortality was observed. CONCLUSIONS: Faced with a possible diagnosis of calciphylaxis, a complete blood analysis is mandatory to rule out other causes of skin ulcers. The management of these patients should be undertaken by a multidisciplinary team. We emphasize the role of sodium thiosulfate in the treatment of this condition.

Linfoma cutáneo CD8+ en paciente con infección por el VIH, con resolución tras la instauración de tratamiento antirretroviral de gran actividad / Cutaneous CD8+ T-cell lymphoma. Regression after HIV antiviral triple therapy

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En defensa de un informe anatomopatológico completo. No sin la descripción / In defense of the complete pathological report. Not without the description

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