Correction to: Liquid biopsy in oncology: a consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology.

The article Liquid biopsy in oncology.

Liquid biopsy in oncology: a consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology.

The proportion of cancer patients with tumours that harbour a potentially targetable genomic alteration is growing considerably. The diagnosis of these genomic alterations can lead to tailored treatment at the onset of disease or on progression and to obtaining additional predictive information on immunotherapy efficacy. However, in up to 25% of cases, the initial tissue biopsy is inadequate for precision oncology and, in many cases, tumour genomic profiling at progression is not possible due to technical limitations of obtaining new tumour tissue specimens. Efficient diagnostic alternatives are therefore required for molecular stratification, which includes liquid biopsy. This technique enables the evaluation of the tumour genomic profile dynamically and captures intra-patient genomic heterogeneity as well. To date, there are several diagnostic techniques available for use in liquid biopsy, each one of them with different precision and performance levels. The objective of this consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology is to evaluate the viability and effectiveness of the different methodological approaches in liquid biopsy in cancer patients and the potential application of this method to current clinical practice. The experts contributing to this consensus statement agree that, according to current evidence, liquid biopsy is an acceptable alternative to tumour tissue biopsy for the study of biomarkers in various clinical settings. It is therefore important to standardise pre-analytical and analytical procedures, to ensure reproducibility and generate structured and accessible clinical reports. It is essential to appoint multidisciplinary tumour molecular boards to oversee these processes and to enable the most suitable therapeutic decisions for each patient according to the genomic profile.

4Kscore Test, Prostate Cancer Prevention Trial-Risk Calculator y European Research Screening Prostate-Risk Calculator en la predicción del cáncer de próstata de alto grado; estudio preliminar / A Preliminary Study of the Ability of the 4Kscore test, the Prostate Cancer Prevention Trial-Risk Calculator and the European Research Screening Prostate-Risk Calculator for Predicting High-Grade Prostate Canc

Introducción: Frente al sobrediagnóstico y al sobretratamiento en cáncer de próstata (CaP) se establecen estrategias terapéuticas como la vigilancia activa o la terapia focal, o métodos para precisar el diagnóstico del CaP de alto grado (CaP-AG), Gleason ≥ 7, como la resonancia magnética multiparamétrica o nuevos marcadores como el 4Kscore Test (4KsT). Es nuestro propósito testar mediante un estudio piloto la capacidad del 4KsT como identificador de CaP-AG (suma de Gleason ≥ 7) en biopsia de próstata (Bx) y compararlo con otros modelos pronósticos multivariantes disponibles, como el Prostate Cancer Prevention Trial-Risk Calculator 2.0 (PCPTRC 2.0) y elEuropean Research Screening Prostate Cancer-Risk Calculator 4 (ERSPC-RC 4). Material y métodos: Cincuenta y un pacientes sometidos a BxP según práctica clínica habitual, con un mínimo de 10 cilindros. Diagnóstico de CaP-AG consensuado por 4 uropatólogos. Comparación de las predicciones ofrecidas por los diferentes modelos mediante prueba U Mann-Whitney, áreas bajo la curva ROC (AUC) (test de DeLong), funciones de densidad de probabilidad, diagramas de caja y curvas de utilidad clínica (CUC). Resultados: Un 43% presentaron CaP y un 23,5% CaP-AG. Las medianas de probabilidad de 4KsT, PCPTRC 2.0 y ERSPC-RC 4 fueron significativamente diferentes entre los pacientes con CaP-AG y no CaP-AG (p ≤ 0,022), siendo más diferenciadas en el caso de 4KsT (mediana en CaP-AG: 51,5% [percentil 25-75: 25-80,5%], frente a 16% [P 25-75: 8-26,5%] en no CaP-AG [p = 0,002]). Todos los modelos mostraron AUC por encima de 0,7 sin diferencias significativas entre ninguno de ellos y 4KsT (p ≥ 0,20). Las funciones de densidad de probabilidad y diagramas de caja muestran una buena capacidad discriminativa, especialmente en los modelos de ERSPC-RC 4 y 4KsT. Las CUC muestran como un punto de corte del 9% de 4KsT identifica a todos los CaP-AG y permite un ahorro del 22% de biopsias, similar a lo que ocurre con los modelos de ERSPC-RC 4 y un punto de corte del 3%. Conclusiones: Los modelos predictivos evaluados ofrecen una buena capacidad de discriminación del CaP-AG en Bx. 4KsT es un buen modelo clasificatorio en su conjunto, seguido de ERSPC-RC 4 y PCPTRC 2.0. Las CUC permiten sugerir puntos de corte de decisión clínica: 9% para 4KsT y 3% en ERSPC-RC 4. Este estudio preliminar debe ser interpretado con cautela por su limitado tamaño muestral

Introduction: To prevent the overdiagnosis and overtreatment of prostate cancer (PC), therapeutic strategies have been established such as active surveillance and focal therapy, as well as methods for clarifying the diagnosis of high-grade prostate cancer (HGPC) (defined as a Gleason score ≥7), such as multiparametric magnetic resonance imaging and new markers such as the 4Kscore test (4 KsT). By means of a pilot study, we aim to test the ability of the 4 KsT to identify HGPC in prostate biopsies (Bx) and compare the test with other multivariate prognostic models such as the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPTRC 2.0) and the European Research Screening Prostate Cancer Risk Calculator 4 (ERSPC-RC 4). Material and methods: Fifty-one patients underwent a prostate Bx according to standard clinical practice, with a minimum of 10 cores. The diagnosis of HGPC was agreed upon by 4 uropathologists. We compared the predictions from the various models by using the Mann-Whitney U test, area under the ROC curve (AUC) (DeLong test), probability density function (PDF), box plots and clinical utility curves. Results: Forty-three percent of the patients had PC, and 23.5% had HGPC. The medians of probability for the 4 KsT, PCPTRC 2.0 and ERSPC-RC 4 were significantly different between the patients with HGPC and those without HGPC (p≤.022) and were more differentiated in the case of 4 KsT (51.5% for HGPC [25-5 percentile: 25-80.5%] vs. 16% [P 25-75: 8-26.5%] for non-HGPC; p=.002). All models presented AUCs above 0.7, with no significant differences between any of them and 4 KsT (p≥.20). The PDF and box plots showed good discriminative ability, especially in the ERSPC-RC 4 and 4 KsT models. The utility curves showed how a cutoff of 9% for 4 KsT identified all cases of HGPC and provided a 22% savings in biopsies, which is similar to what occurs with the ERSPC-RC 4 models and a cutoff of 3%. Conclusions: The assessed predictive models offer good discriminative ability for HGPCs in Bx. The 4 KsT is a good classification model as a whole, followed by ERSPC-RC 4 and PCPTRC 2.0. The clinical utility curves help suggest cutoff points for clinical decisions: 9% for 4 KsT and 3% for ERSPC-RC 4. This preliminary study should be interpreted with caution due to its limited sample size

A Preliminary Study of the Ability of the 4Kscore test, the Prostate Cancer Prevention Trial-Risk Calculator and the European Research Screening Prostate-Risk Calculator for Predicting High-Grade Prostate Cancer.

INTRODUCTION: To prevent the overdiagnosis and overtreatment of prostate cancer (PC), therapeutic strategies have been established such as active surveillance and focal therapy, as well as methods for clarifying the diagnosis of high-grade prostate cancer (HGPC) (defined as a Gleason score ≥7), such as multiparametric magnetic resonance imaging and new markers such as the 4Kscore test (4KsT). By means of a pilot study, we aim to test the ability of the 4KsT to identify HGPC in prostate biopsies (Bx) and compare the test with other multivariate prognostic models such as the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPTRC 2.0) and the European Research Screening Prostate Cancer Risk Calculator 4 (ERSPC-RC 4). MATERIAL AND METHODS: Fifty-one patients underwent a prostate Bx according to standard clinical practice, with a minimum of 10 cores. The diagnosis of HGPC was agreed upon by 4 uropathologists. We compared the predictions from the various models by using the Mann-Whitney U test, area under the ROC curve (AUC) (DeLong test), probability density function (PDF), box plots and clinical utility curves. RESULTS: Forty-three percent of the patients had PC, and 23.5% had HGPC. The medians of probability for the 4KsT, PCPTRC 2.0 and ERSPC-RC 4 were significantly different between the patients with HGPC and those without HGPC (p≤.022) and were more differentiated in the case of 4KsT (51.5% for HGPC [25-75 percentile: 25-80.5%] vs. 16% [P 25-75: 8-26.5%] for non-HGPC; p=.002). All models presented AUCs above 0.7, with no significant differences between any of them and 4KsT (p≥.20). The PDF and box plots showed good discriminative ability, especially in the ERSPC-RC 4 and 4KsT models. The utility curves showed how a cutoff of 9% for 4KsT identified all cases of HGPC and provided a 22% savings in biopsies, which is similar to what occurs with the ERSPC-RC 4 models and a cutoff of 3%. CONCLUSIONS: The assessed predictive models offer good discriminative ability for HGPCs in Bx. The 4KsT is a good classification model as a whole, followed by ERSPC-RC 4 and PCPTRC 2.0. The clinical utility curves help suggest cutoff points for clinical decisions: 9% for 4KsT and 3% for ERSPC-RC 4. This preliminary study should be interpreted with caution due to its limited sample size.

Nerve compression syndromes of the hand and forearm associated with tumours of non-neural origin and tumour-like lesions.

Nerve compression syndromes caused by non-neural tumours or tumour-like lesions are rare. We retrospectively reviewed 541 consecutive patients operated on by the same surgeon to study nerve compression syndromes in the forearm and hand. There were 414 due to nerve compression and 127 caused by tumours. Twenty-two patients showed compression neuropathy associated with 17 tumours and six tumour-like lesions, with 13 different pathological types. The most common types were fatty and vascular tumours. Twenty-one tumours were extraneural and one was intraneural. The median nerve was affected in nine cases, the ulnar nerve or the dorsal sensory branch of the ulnar nerve in five cases, the posterior interosseous nerve or the superficial radial branch in four cases and the common digital nerves in two cases. There was a concomitant involvement of the median and ulnar nerves in two other patients. Clinically, there were eight different compression neuropathies, of which the most frequent was the carpal tunnel syndrome. The postoperative histology was consistent with preoperative magnetic resonance imaging findings in the vascular and fatty tumours. Pain disappeared completely in 15 out of 16 patients with preoperative pain. All patients had preoperative paraesthesia, which persisted after tumour excision in three patients: attenuated in two patients and unchanged in one. In three patients, we did not observe any change in paresis or amyotrophy. The mean postoperative follow-up was 31 months, without tumour recurrence. The quick Disabilities of the Arm, Shoulder and Hand (DASH) score went from 49.9 points preoperatively to 10.2 points after surgery.

Inter-alpha-trypsin inhibitor heavy chain 4 as a marker of acute rejection in pancreas allotransplantation in pigs.

BACKGROUND/AIMS: An early, simple, and reliable marker for acute pancreatic allograft rejection is not available. Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is an interleukin-6-dependent acute-phase positive protein that can act as an anti-inflammatory protein. We studied the response of the ITIH4 in pigs undergoing pancreas allotransplantation (PT) and evaluated this protein as a biomarker for acute graft rejection. METHODS: PT with enteric drainage of the exocrine secretion and systemic venous drainage was performed on 12 Landrace pigs. No immunosuppression was administered. Serum concentrations of glucose, amylase, lipase, insulin, C-peptide, and ITIH4 were determined daily. RESULTS: The response of ITIH4 to PT was early, intense, and prolonged, with 2 peaks in serum concentration. The first peak, which started on day 1 and reached maximum (around 6 mg/dL) on day 3, was attributed to the systemic acute phase response to surgical stress. The second peak, which exceeded the first peak and reached maximum (>8 mg/dL) on day 6, began when the recipients were still normoglycemic, and preceded onset of the diabetic state caused by acute graft rejection by an average of 4 days. CONCLUSION: Serum ITIH4 could help to predict subclinical acute graft rejection after PT in pigs.

Linfangioma quístico de localización inusual / Cystic lymphangioma in unusual location

Se describe el caso de una paciente con una masa tumoral benigna congénita, que fue detectada tras un cuadro febril agudo. La masa, de 7 cm de diámetro, estaba localizada en la región pectoral derecha y fue diagnosticada mediante resonancia magnética. Tras su extirpación, se observaba una masa quística de paredes gruesas y cubierta de tejido graso. El estudio anatomopatológico constató la existencia de quistes con contenido linfático, lo que confirmaba que se trataba de un linfangioma quístico (AU)

We report the case of a patient with a congenital benign tumor, which was incidentally discovered after acute fever. The tumor had a diameter of 7 centimetres, located in the right pectoral region and was diagnosed by MRI. The cyst was totally excised. The lesion consisted of a thick-wall cystic mass covered with fatty tissue. Histopathological examination revealed lymphatic cysts, which lead to the diagnosis of cystic lymphangioma (AU)

Analysis of ionic ratios in the interventricular wall and their relation with cardiac damage as seen in anatomo-pathological and cardiac biomarkers.

UNLABELLED: In the present work, we have compared the behaviour of some commonly used markers for the immunohistochemical diagnosis of cardiac suffering (myoglobin, myosin, troponin I), with the modifications of the ionic quotients (K(+)/Na(+), Ca(2+)/Mg(2+) and Ca(2+)/Zn(2+)) that are observed in the interventricular partition in different causes of death. MATERIALS AND METHOD: we have studied a total of 50 hearts coming from autopsies carried out in the Legal Medicine Institute of Murcia (Spain) deceased 21 by natural cardiac deaths, 9 by mechanical asphyxias, 5 by politraumatism, 5 cardiac ruptures and 10 by craneoencephalic trauma. For the biochemical analysis, samples were taken from weave of 0.5 g of the interventricular partition, the corresponding dilutions were made in bidistilled water for flame atomic absorption spectrophotometry with a hollow cathode multielement lamp. For the immunohistochemical study, samples were taken from the same locations, kept in tamponed formol, dyed with hematoxylin-eosin and later 3 microm-sections were practised, antigenic recovery by heat, in pressure cooker. Our results show the existence of a statistically significant relation between the modifications of the K(+)/Na(+) quotient and the found values of troponin, which confirms its utility for the precocious diagnosis of the cardiac ischemia.

Association between immunohistochemical markers of myocardial damage and apoptosis.

Cardiac disease is the most common cause of sudden unexpected death. In forensic practice there is a need for more sensitive diagnostic methods for the post-mortem diagnosis of myocardial damage. The aim of this study was to evaluate the association of the markers routinely used for the diagnosis of acute cardiac necrosis (myosin, troponin I and myoglobin with) and the presence of apoptosis, in order to evaluate the utility of apoptosis for use as a diagnostic marker during the early stage of acute myocardial damage. A positive correlation was observed between neovascularization and signs of recent and past necrosis. Not relationship was observed between age at death, post-mortem interval and apoptosis. No statistical association was found between the expression of acute cardiac necrosis markers and the presence of apoptosis.

Primary anaplastic large cell lymphoma of the testis.

Anaplastic large cell lymphoma (ALCL) was first described by Stein et al. in 1985, at that time neoplastic cells were labeled by the monoclonal antibody CD30. ALCL was included as a differentiate entity in the reviewed Kiel and REAL classification. ALCL carries the t (2; 5) (p23; q35) translocation; the absence of ALK kinase from normal lymphoid cells indicates that immunohistochemical expression of ALK is specific for the (2; 5) translocation. This disease is characterized by a diffuse proliferation of large anaplastic cells with kidney-shaped/horse-shoe nuclei. A distinguishing feature is a perinuclear eosinophilic region that represents a prominent Golgi apparatus. These cells are named hallmark-cells being almost pathognomonic. Immunohistochemically the most important features are that tumor cells consistently express CD30 and EMA on the cell membrane and in the Golgi region, while ALK immunostaining is usually both, cytoplasmic and nuclear. To our knowledge only two cases of primary ALCL of the testis have been reported. Hereby we present a case of a typical ALCL expressing ALK and CD30, which presented with subcutaneous nodules and bilateral testicular mass, without systemic involvement.

[Kikuchi-Fujimoto's disease and the association with systemic lupus erythematosus]. / Enfermedad de Kikuchi-Fujimoto y su asociación a lupus eritematoso sistémico.

Kikuchi-Fujimoto's disease (KFD), Histiocytic Necrotizing lymphadenitis, is a rare self-limiting condition characterized by lymphadenopathy, fever and neutropenia. The aetiology of KFD is controversial, and its diagnosis is confirmed histologically. Although KFD has rarely been reported associated to Systemic lupus erythemotosus (SLE) should be ruled out given its different prognosis and management. We present the clinical, histological and evolution the two cases of patients with Kikuchi's disease; one case had evolution classic and the other case were associated with SLE.

[Parotid metastases of a neuroendocrine cutaneous carcinoma]. / Metástasis parotídea de un carcinoma neuroendocrino cutáneo.

A case of metastatic Merkel-cell carcinoma to lymph nodes on the left side of the neck nad left parotid is described. Neuroendocrine cutaneous carcinoma, also called Merkel cell carcinoma (MCC), is an uncommon primary skin tumor most often seen in elderly. Literature is reviewed and comment about more important features of these lesions, like differential diagnosis, prognosis and treatment.

Enfermedad de Kikuchi-Fujimoto y su asociación a lupus eritematoso sistémico / Kikuchi-Fujimoto's disease and its association with systemic lupus erytematosus

La enfermedad de Kikuchi-Fujimoto (EKF) o linfadenitis necrotizante histiocítica es una patología autolimitada que se caracteriza por linfadenopatías, fiebre y neutropenia entre otros síntomas. La etiología de la EKF es controvertida y será el estudio histológico el que proporcione el diagnóstico de confirmación. Aunque la EKF no es muy frecuente, se han publicado varios casos en los cuales se asocia a Lupus Eritematoso Sistémico (LES) lo cual se ha de tener presente, puesto que modifica tanto el pronostico como el manejo terapéutico de estos pacientes.Se presentan dos casos de enfermedad de Kikuchi: el primero de los casos presente una evolución clásica de la enfermedad, mientras que el segundo caso asoció un LES (AU)

Metástasis parotídea de un carcinoma neuroendocrino cutáneo / Parotideal metastasis of a cutaneous neuroendocrine carcinoma

Presentamos un caso de carcinoma neuroendocrino cutáneo con metástasis cervicales y en glándula parótida izquierda. El carcinoma neuroendocrino cutáneo, también llamado carcinoma de células de Merkel (MCC), es un raro tumor de la piel que aparece en edades avanzadas de la vida. Una vez revisada la literatura, discutimos sobre las características más importantes de estas lesiones, como sonel diagnóstico diferencial, pronóstico y tratamiento (AU)

A case of metastatic Merkel-cell carcinoma to lymph nodes on the left side of the neck nad left parotid is described. Neuroendocrine cutaneous carcinoma, also called Merkel cell carcinoma (MCC), is an uncommon primary skin tumor most often seen in elderly. Literature is reviewed and comment about more important features of these lesions, like differential diagnosis, prognosis and treatment (AU)

[Chronic sclerosing mediastinitis: infrequent cause of unilateral diaphragmatic paralysis]. / Mediastinitis esclerosante crónica: una causa infrecuente de parálisis diafragmática unilateral.

Chronic sclerosing mediastinitis (CSM) is a rare disease whose etiology varies and which usually develops through mediastinal compression syndromes, generally due to occlusion of the superior vena cava. We report a case of CSM diagnosed after a chance finding of unilateral diaphragm paralysis, a circumstance not previously reported in the literature. We review the clinical, radiological and histological features of CSM.

"Variante proximal" de sarcoma epitelioide: informe de un caso con estudio inmunohistoquímico / "Proximal-type" epithelioid sarcoma: a case report with immunohistochemical study

Introducción: Se presenta un caso de tumor de partes blandas de patrón epitelioide, con rasgos clínicos, histológicos e inmunohistoquímicos acordes con la recientemente descrita "variante proximal" de sarcoma epitelioide. Material y métodos: Un varón de 28 años debuta con un tumor profundo localizado en la región perineal. Resultados: Microscópicamente, mostró hábito epitelioide, con marcada atipia citológica y frecuentes rasgos rabdoides, siendo el patrón de inmunoreactividad superponible al del sarcoma epitelioideclásico. Conclusiones: Ante un tumor con rasgos intermedios entre un sarcoma epitelioide clásico, un tumor rabdoide y un carcinoma indiferenciado, hay que pensar en la variante proximal del sarcoma epitelioide (AU)

Mediastinitis esclerosante crónica: una causa infrecuente de parálisis diafragmática unilateral / Chronic sclerosing mediastinitis: a rare cause of unilateral diaphragmatic paralysis

La mediastinitis esclerosante crónica es una enfermedad de escasa frecuencia y de etiología variada, que suele cursar con síndromes de compresión mediastínica, generalmente por oclusión de la vena cava superior. Presentamos un caso de mediastinitis esclerosante crónica diagnosticado a partir del hallazgo radiológico casual de una parálisis diafragmática unilateral, hecho no referenciado previamente en la bibliografía. Se actualizan sus rasgos clínicos, radiológicos e histológicos (AU)

[Interferon alpha and systemic mastocytosis. Analysis of therapeutic efficacy in 6 cases]. / Interferón-alpha y mastocitosis sistémica. Análisis de la eficacia terapéutica en seis casos.

OBJECTIVE: To report the results obtained with the application of alpha-IFN for the treatment of a small group of patients diagnosed of systemic mastocytosis (SM) in the setting of a general hospital. PATIENTS AND METHODS: Six patients out of a group of 14 with the diagnosis of MS were prospectively selected from January 1991 to December 1996. Two patients had aggressive variant with lymph node involvement and eosinophilia and the other four had severe and repeated crises through release of mediators not controlled under symptomatic therapy. All patients received alpha-2b-IFN with gradual doses until a mean dose of 9 MU/week was obtained, associated with anti-H1 and anti-H2 antithistaminic agents and ketotiphen. Monthly clinical and analytical studies were performed until stabilization of the clinical picture and histamine metabolite measurements in urine every 6 months and histologic evolution of bone marrow every 12 months. RESULTS: Mean age at diagnosis was 41 years (range: 26-28), M/F ratio 3/3, mean evolution time 50.5 months and mean time under therapy with alpha-IFN 15.6 months (range: 3-26). Six months after therapy was initiated a decrease in the frequency and severity of crises through release of mediators and a slight improvement in cutaneous lesions, resolution of liver enlargement and ascites were observed. Treatment tolerance was quite acceptable and dose reduction was required in only two cases. Bone marrow assessment at one year showed a similar involvement, with decrease in the number of paratrabecullar nodules. CONCLUSIONS: The efficacy of alpha-2b-IFN therapy in SM is not clearly established, although the results obtained in this study seem encouraging. To obtain valid conclusions, a larger number of patients with similar characteristics and a longer follow-up with uniform assessment criteria are required.

[Benign rheumatoid nodules. Report of 4 cases]. / Nódulos reumatoides benignos. Presentación de cuatro casos.

Benign rheumatoid nodules are subcutaneous nodules morphologically and histologically identical to the ones appearing in patients with rheumatoid arthritis. They usually happen in healthy people without neither clinical nor serologic manifestations of any rheumatic illness. These nodules are more usual in children and they are considered exceptional beyond the age of eighteen. In the literature, only two hundred cases in children and twenty five cases in adults have been properly documented, with histological confirmation. We report four new cases of benign rheumatoid nodules histologically proved, two children and two adults, and we confirm the optimistic prognosis of these patients.