Estudio inmunohistoquímico de los factores de trancripción de desarrollo neural (TTF1, ASCL1 y BRN2) en los tumores neuroendocrinos de próstata / Immunohistochemical study of the neural development transcription factors (TTF1, ASCL1 and BRN2) in neuroendocrine prostate tumours

Objetivo: El carcinoma neuroendocrino de célula pequeña de próstata es una neoplasia infrecuente que supone el 0,5-1% de todas las neoplasias prostáticas. La mediana de supervivencia cáncer-específica de los pacientes con carcinoma neuroendocrino de célula pequeña de próstata es de 19 meses, y el 60,5% de los pacientes presentan enfermedad metastásica. Los factores de transcripción de desarrollo neural son moléculas implicadas en la organogénesis del sistema nervioso central y de precursores neuroendocrinos de diversos tejidos, que incluyen la glándula suprarrenal, el tiroides, el pulmón y la próstata, entre otros órganos. Material y métodos: Presentamos 3 casos de esta infrecuente entidad, aplicando los nuevos criterios de la OMS. Realizamos estudios mediante tinción de H-E y analizamos la expresión de los factores de transcripción de desarrollo neurales Achaete-scute homolog like 1, Thyroid transcription factor 1 y los factores de transcripción clase iii/iv POU, como nueva línea de investigación en la carcinogénesis de los tumores neuroendocrinos de próstata. Resultados: En el caso 1 no se observó inmunoexpresión para TTF1. Los casos 2 y 3 presentaron inmunotinción positiva para ASCL1, e inmunotinción negativa en el caso 1. La inmunotinción para BRN2 fue negativa en el caso 1 y positiva en los casos 2 y 3. Conclusión: Actualmente, la OMS no reconoce ningún marcador molecular ni genético con valor pronóstico. ASCL-1 está relacionado con las vías de señalización NOTCH y WNT. ASCL-1, TTF1 y BRN2 podrían usarse para el diagnóstico precoz y como factor pronóstico y diana terapéutica

Objective: Prostatic small-cell neuroendocrine carcinoma is an uncommon malignancy that constitutes 0.5-1% of all prostate malignancies. The median cancer-specific survival of patients with prostatic small-cell neuroendocrine carcinoma is 19 months, and 60.5% of the patients have metastatic disease. Neural development transcription factors are molecules involved in the organogenesis of the central nervous system and of neuroendocrine precursors of various tissues, including the suprarenal gland, thyroid glands, lungs and prostate. Material and methods: We present 3 cases of this uncommon condition, applying the new World Health Organisation criteria. We conducted studies through haematoxylin and eosin staining and analysed the expression of the neural development transcription factors achaete-scute homolog like 1, thyroid transcription factor 1 and the class III/IV POU transcription factors, as a new research line in the carcinogenesis of prostatic neuroendocrine tumours. Results: In case 1, there was no TTF1 immunoexpression. Cases 2 and 3 had positive immunostaining for ASCL1, and Case 1 had negative immunostaining. BRN2 immunostaining was negative in case 1 and positive in cases 2 and 3. Conclusion: The World Health Organisation does not recognise any molecular or genetic marker with prognostic value. ASCL-1 is related to the NOTCH and WNT signalling pathways. ASCL-1, TTF1 and BRN2 could be used for early diagnosis and as prognostic factors and therapeutic targets

Gastrointestinal stromal tumors (GISTs): SEAP-SEOM consensus on pathologic and molecular diagnosis

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Society of Pathology and the Spanish Society of Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (< 10 mm-35 cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%), or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually exclusive activating mutations in genes coding for the type III receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method employed (AU)

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Clinicopathological and immunohistochemical analysis of oral melanocytic nevi and review of the literature.

INTRODUCTION: Oral melanocytic nevi (OMNs) are uncommon benign melanocytic tumors, histologically similar to their cutaneous counterparts. The aim of this study was twofold: to contribute to the epidemiology with a literature review with the first Spanish series of OMNs, and to report on clinicopathological, immunohistochemical and demographic findings. MATERIALS AND METHODS: A retrospective analysis of cases attended over the period 1999-2010 was carried out using data drawn from the pathology unit files at two public hospitals in the Spanish region of Andalusia, serving between them a population of 823.614 inhabitants (11%). RESULTS: Ten cases of OMNs were retrieved, accounting for 0.18% of the total 5499 oral biopsies performed over the period. The female-to-male ratio was 1.5:1; mean patient age was 30. The palate was the most common location (70%). Relative frequencies of histologic types were as follows: subepithelial (40%), common blue (30%), compound (20%) and junctional (10%). Immunohistochemical examination showed strong S-100 protein expression, variable reactivity to HMB-45 and high c-Kit expression by junctional melanocytes. Ki-67 was ≤3 in all cases. CONCLUSIONS: Although this first clinicopathologic analysis of OMNs reported in Spain was based on a small patient series, the results are in line with those reported in larger series and additionally provide new demographic data. Since OMNs and early melanomas are usually detected at routine dental examination, detailed oral exploration should always be performed, and in case of doubt a biopsy should be taken to ensure an accurate diagnosis.

Immunohistochemical study of the neural development transcription factors (TTF1, ASCL1 and BRN2) in neuroendocrine prostate tumours. / Estudio inmunohistoquímico de los factores de trancripción de desarrollo neural (TTF1, ASCL1 y BRN2) en los tumores neuroendocrinos de próstata.

OBJECTIVE: Prostatic small-cell neuroendocrine carcinoma is an uncommon malignancy that constitutes 0.5-1% of all prostate malignancies. The median cancer-specific survival of patients with prostatic small-cell neuroendocrine carcinoma is 19 months, and 60.5% of the patients have metastatic disease. Neural development transcription factors are molecules involved in the organogenesis of the central nervous system and of neuroendocrine precursors of various tissues, including the suprarenal gland, thyroid glands, lungs and prostate. MATERIAL AND METHODS: We present 3 cases of this uncommon condition, applying the new World Health Organisation criteria. We conducted studies through haematoxylin and eosin staining and analysed the expression of the neural development transcription factors achaete-scute homolog like 1, thyroid transcription factor 1 and the class III/IV POU transcription factors, as a new research line in the carcinogenesis of prostatic neuroendocrine tumours. RESULTS: In case 1, there was no TTF1 immunoexpression. Cases 2 and 3 had positive immunostaining for ASCL1, and Case 1 had negative immunostaining. BRN2 immunostaining was negative in case 1 and positive in cases 2 and 3. CONCLUSION: The World Health Organisation does not recognise any molecular or genetic marker with prognostic value. ASCL-1 is related to the NOTCH and WNT signalling pathways. ASCL-1, TTF1 and BRN2 could be used for early diagnosis and as prognostic factors and therapeutic targets.

Gastrointestinal stromal tumors (GISTs): SEAP-SEOM consensus on pathologic and molecular diagnosis.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Society of Pathology and the Spanish Society of Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (<10 mm-35 cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%), or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually exclusive activating mutations in genes coding for the type III receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method employed.

Recommendations of a gropu of experts for the pathological assessment of tumor regression of liver metastases of colorectal cancer and damage of non-tumour liver tissue after neoadjuvant theray

Colorectal cancer (CRC) incidence has increased during the past decades in Spain, being the first malignant tumour in incidence. Observed mortality for CRC is mainly due to liver and lung metastases. The only curative treatment is surgery; new surgical techniques and neoadjuvant treatments have increased the number of surgery candidate patients. Patients should be managed with a multidisciplinary approach that includes imaging techniques, chemotherapy, surgery and pathological assessment. As an answer to this approach, a group of pathology experts interested on CRC liver metastases aimed to review the diagnosis and prognosis of liver mestastases and developed practical recommendations for its assessment. The expert group revised the current literature and prepared questions to be discussed based on available evidence and on their clinical practise. As a result, recommendations for the assessment of tumour regression of liver metastases are proposed, which could be implemented in oncology centres allowing assessment standardisation for these patients. Prospective multi-center studies to evaluate these recommendations validity will further contribute to improve the standard care of CRC liver metastases patients (AU)

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Guidelines for biomarker testing in gastroenteropancreatic neuroendocrine neoplasmas: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

The annual incidence of neuroendocrine tumours in the Caucasian population ranges from 2.5 to 5 new cases per 100,000 inhabitants. Gastroenteropancreatic neuroendocrine tumours is a family of neoplasms widely variable in terms of anatomical location, hormone composition, clinical syndromes they cause and in their biological behaviour. This high complexity and clinical heterogeneity, together with the known difficulty of predicting their behaviour from their pathological features, are reflected in the many classifications that have been developed over the years in this field. This article reviews the main tissue and clinical biomarkers and makes recommendations for their use in medical practice. This document represents a consensus reached jointly by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) (AU)

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Guidelines for biomarker testing in gastroenteropancreatic neuroendocrine neoplasms: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology.

The annual incidence of neuroendocrine tumours in the Caucasian population ranges from 2.5 to 5 new cases per 100,000 inhabitants. Gastroenteropancreatic neuroendocrine tumours is a family of neoplasms widely variable in terms of anatomical location, hormone composition, clinical syndromes they cause and in their biological behaviour. This high complexity and clinical heterogeneity, together with the known difficulty of predicting their behaviour from their pathological features, are reflected in the many classifications that have been developed over the years in this field. This article reviews the main tissue and clinical biomarkers and makes recommendations for their use in medical practice. This document represents a consensus reached jointly by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP).

Recommendations of a group of experts for the pathological assessment of tumour regression of liver metastases of colorectal cancer and damage of non-tumour liver tissue after neoadjuvant therapy.

Colorectal cancer (CRC) incidence has increased during the past decades in Spain, being the first malignant tumour in incidence. Observed mortality for CRC is mainly due to liver and lung metastases. The only curative treatment is surgery; new surgical techniques and neoadjuvant treatments have increased the number of surgery candidate patients. Patients should be managed with a multidisciplinary approach that includes imaging techniques, chemotherapy, surgery and pathological assessment. As an answer to this approach, a group of pathology experts interested on CRC liver metastases aimed to review the diagnosis and prognosis of liver mestastases and developed practical recommendations for its assessment. The expert group revised the current literature and prepared questions to be discussed based on available evidence and on their clinical practise. As a result, recommendations for the assessment of tumour regression of liver metastases are proposed, which could be implemented in oncology centres allowing assessment standardisation for these patients. Prospective multi-center studies to evaluate these recommendations validity will further contribute to improve the standard care of CRC liver metastases patients.

Head and neck cancer. An aetiopathogenetic study of non-endemic lymphoepithelioma.

An aetiopathogenetic analysis of non-endemic nasopharyngeal carcinoma (NPC) in European and Southern American patient groups was performed. Specifically, the study sought to determine the proportion of Epstein-Barr Virus (EBV)-positive tumour cells in NPC patients in two very different populations (Europe and South America) in areas not associated with a high incidence of NPC. Clinical data (age, sex and onset of clinical disease) were also analyzed. A total of 50 NPC samples, 24 from a European hospital (EH) and 26 from two South American hospitals (SAH), were included. Nuclear staining for Epstein-Barr virus-encoded small RNA (EBER) was performed by in situ hybridization (ISH). Latent membrane protein 1 (LMP1) expression was measured by immunohistochemical (IHC) analysis. A higher incidence of NPC was observed in patients > 40 years of age in EH; in SAH, by contrast, the incidence was higher in patients aged ≤ 40 years. Cervical lymph node metastasis was detected in 31 patients (of whom 84.6% were from SAH). A total of 72% of samples were EBERpositive; the incidence of EBER positivity was greater in type 3 NPCs. EBV was detected in a large proportion of epithelial cells in samples from both EH and SAH (75% vs. 69.2%, respectively). An association was found between EBER detection in lymphocytes and patient origin (p = 0.0001). LMP1 expression was detected in 64% of patients. ISH for the detection of EBER is the most sensitive technique for demonstrating EBV in tumour tissue. The incidence of EBV was not significantly greater in either of the study populations, but was significantly higher in patients with type 3 NPC. Definitive histological diagnosis of NPC was reached earlier in EH than in SAH, where metastases were more frequently diagnosed, suggesting that the disease had reached a more advanced stage by the time treatment was started.

Application of fluorescence in situ hybridization as a diagnostic tool in melanocytic lesions, using paraffin wax-embedded tissues and imprint-cytology specimens.

BACKGROUND: Accurate histopathological diagnosis of certain melanocytic skin lesions as benign or malignant can be notoriously difficult. Recently, four-colour fluorescence in situ hybridization (FISH) has emerged as an important tool for classifying these lesions. AIM: To evaluate the sensitivity and specificity of a melanoma FISH probe kit for accurate diagnosis of melanocytic tumours, and to validate its use with imprint-cytology specimens from the cut surface of tumours. METHODS: In total, 50 melanocytic skin lesions (31 malignant melanomas, 10 benign melanocytic naevi, and 9 histologically challenging benign melanocytic skin lesions) were evaluated. The samples comprise 47 tissue specimens embedded in paraffin wax, and three imprint-cytology specimens from the cut surface of melanomas. FISH was performed using four locus-specific identifier probes [Ras responsive element binding protein (RREB)1, myeloblastosis viral oncogene homologue (MYB), cyclin (CCN)D1 and centromere of chromosome (CEP)6], and results were compared with the clinical long-term follow-up and histopathological diagnosis data. RESULTS: The melanoma FISH probe distinguished between naevi and melanomas with a sensitivity of 100% and a specificity of 94.1%. The most sensitive criterion was a gain in 6p25 (RREB1), seen in 100% of cases, followed by CEP6-related MYB loss (48.1%), CCND1 gain (37%) and MYB gain (22.2%). More than three-quarters (77.8%) of melanomas were positive for two or more criteria. Positive FISH results were also obtained for the imprint-cytology specimens. CONCLUSIONS: FISH is a valuable diagnostic tool for differentiating between benign and malignant melanocytic lesions, providing a high degree of sensitivity and specificity. The probes displayed exceptional discriminative capacity in difficult or ambiguous lesions. To our knowledge, his is the first reported use of imprint-cytology specimens for FISH diagnosis.

Gastrointestinal stromal tumors (GISTs): CD117, DOG-1 and PKCθ expression. Is there any advantage in using several markers?

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Expression of CD117, DOG1 and PKCθ was investigated immunohistochemically in a series of 99 paraffin-embedded GISTs in order to determine the sensitivity and diagnostic value of these markers. KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were amplified by PCR and sequenced. A total of 94/99 (94%) GISTs stained positive for CD117, 81/99 (82%) for PKCθ and 90/99 (91%) for DOG-1. A significant correlation was noted between CD117 and DOG-1 expression (p=0.0001). All three markers were expressed in 74% (73/99) of GISTs. Of the five CD117-negative cases, two were PKCθ-negative/DOG1-negative and had mutations in KIT exon 11. Two were PKCθ-positive/DOG1-positive and had mutations in PDGFRA (one each in exons 12 and 18), and one was DOG1-negative/PKCθ-positive, with a PDGFRA exon 18 mutation. The most sensitive marker was CD117, followed by DOG-1 and PKCθ. Although PKCθ was less sensitive, and its staining is more challenging and difficult to interpret, the use of this marker is highly recommended, particularly in CD117-negative/DOG-1-negative GISTs.

The cadherin-catenin complex in laryngeal squamous cell carcinoma.

Abnormal Wnt signaling and impaired cell-cell adhesion due to abnormal E-cadherin and ß-catenin function have been implicated in many cancers, but have not been fully explored in laryngeal squamous cell carcinoma. In this study, ß-catenin cellular location and E-cadherin expression levels were analyzed in 16 laryngeal squamous cell carcinomas (LSCCs) (9 glottic and 7 supraglottic) and 11 samples of non-tumoral inflammatory larynx tissue, using immunohistochemical methods. All non-tumoral tissues showed equally strong membranous expression of ß-catenin, while cytoplasmic expression was found in only 3 of the 11 samples. By contrast, whereas 8/9 glottic LSCCs exhibited only membranous expression of ß-catenin, 6/7 supraglottic LSCCs displayed both membranous and cytoplasmic expression (p = 0.003). Strong E-cadherin staining was observed in 9/11 non-tumoral tissues and 7/9 glottic LSCCs, whereas 4/7 supraglottic LSCCs exhibited weak expression. Reduced membrane expression of E-cadherin and cytoplasmic retention of ß-catenin in supraglottic LSCC seems to be related with more aggressive biological behavior which has been described in clinical studies. Further research is required to clarify the involvement of ß-catenin in the mechanism associated with malignant transformation in laryngeal tissues.

Melanocitosis dérmica adquirida extrafacial / Acquired Nonfacial Dermal Melanocytosis

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Differential activation of MAPK and PI3K/AKT/mTOR pathways and IGF1R expression in gastrointestinal stromal tumors.

AIM: To characterize the differentially-activated mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K/Akt/mTOR) pathways in mutant (m) and wild-type (wt) GISTs and to investigate the role of insulin-like growth factor 1 receptor (IGF1R) expression. MATERIALS AND METHODS: Ninety-nine paraffin-embedded gastrointestinal stromal tumors (GISTs) were selected. CD117, IGF1R, phospho-ERK1/2, phospho-Akt, p70S6, eukaryotic initiation factor 4E-binding protein-1 (4EBP1) and pS6 expression were investigated using immunohistochemical methods. KIT exons 9, 11, 13 and 17 and platelet derived growth factor receptor alpha (PDGFRA) exons 12 and 18 were amplified by PCR and sequenced. RESULTS: Significant differences were found in the expression of phospho-ERK1/2 between mGISTs and wtGISTs. Complex evaluation of all PI3K/Akt/mTOR pathway markers revealed greater activation in mGISTs, particularly in PDGFRA-mutated GISTs. No significant correlation was observed between IGF1R expression and either mutational status or pathway activation. CONCLUSION: There appears to be no MAPK pathway activation in wtGISTs. Tumors harboring PDGFRA mutations tended to use the PI3K/Akt/mTOR signaling pathway. Most adult GISTs, irrespective of mutational status, displayed no IGFR1 expression; tumors positive for IGFR1 showed no preferential activation of the MAPK or AKT pathways.

Infarto cerebral secundario a trombosis de la carótida interna por traumatismo cervical / Cerebral infarction secondary to internal carotid thrombosis following cervical trauma

Se presenta el caso de una trombosis postraumática de la arteria carótida interna en un varón de 33 años, tras recibir un golpe con un balón en el cuello. La muerte se produjo 10 días después del golpe como consecuencia de un cuadro de hipertensión intracraneal y herniación cerebral secundaria a infarto isquémico extenso que afectaba a todo el territorio de la arteria cerebral media derecha, tanto superficial como profundo (AU)

In this paper, a case of post-traumatic thrombosis in the internal carotid artery after a blow with a ball in the neck of a 33-year-old male is presented. The death came 10 days after the coup as a result of intracranial hypertension and cerebral herniation secondary to ischemic infarction affecting the entire territory of the middle right cerebral artery, both superficial and profound. Macroscopic and microscopic findings that largely explain the mechanism of vascular injury with intimal dissection in the proximity of an atheroma plaque located above the carotid bifurcation are discussed (AU)