Expression of EGFR, HER-2/neu and KIT in germ cell tumours.

BACKGROUND: Germ cell tumours (GCTs) represent an extraordinarily chemosensitive malignancy. However, 20-30% of patients with advanced disease cannot be cured by currently available treatments. The role of tyrosine kinase receptors has been widely studied in other malignancies. Yet, limited information is available on GCTs. METHODS: One hundred and nine paraffin-embedded GCTs in 84 patients were assessed by immunohistochemistry for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2)/neu and KIT (CD117) expression. Univariate and multivariate analyses were performed to evaluate their role as predictive and/or prognostic factors. RESULTS: EGFR and HER-2/neu staining was detected in 28% and 13% of tumours, respectively, predominantly in nonseminomatous GCTs. KIT protein was almost universally expressed in seminomas (97%), being virtually absent in choriocarcinoma and teratocarcinoma subtypes. EGFR expression showed inverse association with tumour response of borderline significance. With a median follow-up of 10.6 years, no significant association was observed between the expression of any of these markers and relapse-free or overall survival. CONCLUSIONS: EGFR, HER-2/neu and KIT have differential patterns of expression in GCTs according to histological subtypes. The expression of these markers in our series had no prognostic or predictive significance.

Transgenic mice expressing constitutively active Akt in oral epithelium validate KLFA as a potential biomarker of head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common human neoplasia, of poor prognosis and survival, which frequently displays Akt overactivation. Previously, we reported that mice expressing high levels of constitutively Akt activity (myrAkt) in oral epithelia develop lesions and tumors in the oral cavity. MATERIALS AND METHODS: Functional genomics of primary keratinocytes from different transgenic mouse lines and immunostaining of mouse and human samples were performed in order to identify and validate putative biomarkers of oral cancer progression. RESULTS: The expression of KLF4 was found to be increased only in tumor prone samples from mice bearing overactivation of Akt. Such increased expression was confirmed in oral dysplasias and tumors arising in those mice. Tissue microarray analysis of human samples confirmed the association between active Akt and increased KLF4 expression. CONCLUSION: These data support the notion that KLF4 is potentially a reliable marker of HNSCC, and that myrAkt transgenic mice are valuable tools for preclinical research of HNSCC.

Pre-treatment serum lactate dehydrogenase level is an important prognostic factor in high-grade extremity osteosarcoma.

BACKGROUND: Treatment of high-grade osteosarcoma remains a challenge. The prognostic significance of the pre-treatment serum lactate dehydrogenase (LDH) level is currently controversial. PATIENTS AND METHODS: We reviewed records from all patients diagnosed with conventional high-grade osteosarcoma at our institution over a 25-year period and analysed the prognostic significance of LDH in high-grade localised extremity osteosarcomas treated with chemotherapy. RESULTS: Between June 1977 and March 2003, 66 patients for whom follow-up was available were diagnosed with localised high-grade extremity osteosarcoma and treated with chemotherapy. The median age was 15 years, with only 3% older than 40 years, and the median follow-up was 100 months. The median progression-free survival (PFS) was 67 months and the median overall survival (OS) was 113 months. The absence of a response to chemotherapy was correlated with a trend toward lower PFS and OS. High serum pre-treatment LDH level was associated in multivariate analyses with a poorer prognosis for both PFS (HR=8.623, 95%CI: 1.71-43.37; p=0.009) and for OS (HR=9.38; 95%CI: 1.73-50.74; p=0.009). CONCLUSION: In this series, the pre-treatment serum LDH level had an independent prognostic value for both PFS and OS in patients with high-grade localised extremity osteosarcoma. This measurement should be included in a large prospective prognostic series.

Akt activation synergizes with Trp53 loss in oral epithelium to produce a novel mouse model for head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a common human neoplasia with poor prognosis and survival that frequently displays Akt overactivation. Here we show that mice displaying constitutive Akt activity (myrAkt) in combination with Trp53 loss in stratified epithelia develop oral cavity tumors that phenocopy human HNSCC. The myrAkt mice develop oral lesions, making it a possible model of human oral dysplasia. The malignant conversion of these lesions, which is hampered due to the induction of premature senescence, is achieved by the subsequent ablation of Trp53 gene in the same cells in vivo. Importantly, mouse oral tumors can be followed by in vivo imaging, show metastatic spreading to regional lymph nodes, and display activation of nuclear factor-kappaB and signal transducer and activator of transcription-3 pathways and decreased transforming growth factor-beta type II receptor expression, thus resembling human counterparts. In addition, malignant conversion is associated with increased number of putative tumor stem cells. These data identify activation of Akt and p53 loss as a major mechanism of oral tumorigenesis in vivo and suggest that blocking these signaling pathways could have therapeutic implications for the management of HNSCC.

Metastatic benign pleomorphic adenoma. Report of a case and review of the literature

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Pleomorphic adenoma (PA), originally called mixed tumour, is the most common neoplasm of the salivary glands and is generally accepted as benign biologically. Occasionally PA may give rise to metastasis. The metastasis may develop in a PA in which a malignant transformation occurs, either arising a carcinoma in the PA (carcinoma ex-mixed tumour) or as a carcinosarcoma (so–called true malignant mixed tumour). However, very rare benign PA eventually metastasise, usually after having a previous recurrence, displaying benign histological features as well in the primary tumour as in the metastasis. These tumours have been termed metastatic PA or metastatic mixed tumours. The aim of this paper is to report one case of metastatic histological benign pleomorphic adenoma, and to consider the clinical, pathological and therapeutic consequences of these rare tumours as well as its possible causes and mechanisms for its behaviour (AU)

Metastatic benign pleomorphic adenoma. Report of a case and review of the literature.

Pleomorphic adenoma (PA), originally called mixed tumour, is the most common neoplasm of the salivary glands and is generally accepted as benign biologically. Occasionally PA may give rise to metastasis. The metastasis may develop in a PA in which a malignant transformation occurs, either arising a carcinoma in the PA (carcinoma ex-mixed tumour) or as a carcinosarcoma (so-called true malignant mixed tumour). However, very rare benign PA eventually metastasise, usually after having a previous recurrence, displaying benign histological features as well in the primary tumour as in the metastasis. These tumours have been termed metastatic PA or metastatic mixed tumours. The aim of this paper is to report one case of metastatic histological benign pleomorphic adenoma, and to consider the clinical, pathological and therapeutic consequences of these rare tumours as well as its possible causes and mechanisms for its behaviour.

Extraskeletal cutaneous chondroblastic osteosarcoma: a case report.

Extraskeletal osteosarcoma is an uncommon neoplasm that usually arises in the deep soft tissues, especially in the lower extremities, with rare cases involving the subcutis or dermis. We report a 60-year-old man with an enlarging cutaneous mass in the right lower thigh. An incisional skin biopsy showed a well-defined, but non-encapsulated neoplasm, characterized by extensive cartilage with marked cellularity, atypia and high mitotic activity, involving the dermis and subcutis. Although osteoid or bone was not observed, a diagnosis of cutaneous chondroblastic osteosarcoma was suggested after excluding an origin in bone or other primary tumor sites by imaging techniques. Histopathologic features of the surgical specimen were characteristic, with a predominant high-grade chondroid component together with focal fibrosarcomatous zones, areas of multinucleated giant cells and foci of bone and osteoid formation. The patient underwent postoperative chemotherapy and is currently alive with pulmonary metastases 15 months after surgery. In summary, we report a unique case of cutaneous osteosarcoma of the chondroblastic subtype, diagnosed on incisional skin biopsy despite the absence of osteoid or bone during tumor sampling. As a rule, when an obviously malignant 'chondrosarcoma' is identified, one should always consider this entity.

Cordoma. Sus variantes y diagnóstico diferencial / Chordoma: its «variants» and differential diagnosis

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Cordoma. Sus variantes y diagnóstico diferencial / Chordoma: its «variants» and differential diagnosis

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Myxoinflammatory fibroblastic sarcoma: report of a case with fine needle aspiration cytology.

BACKGROUND: Myxoinflammatory fibroblastic sarcoma (MFS) is a distinct neoplasm that usually arises in the acral zones of distalextremities. We report, for the first time, the preoperative fine needle a,spiration cytology (FNAC) findings of an MFS case that was confirmed after surgical excision. CASE: An 81-year-old woman presented with a multinodular tumor in the distal right extremity that had been present for 1 year. FNA C of the lesion was performed and followed by local excision. The fine needle aspiration smears contained 2 of the 3 types of neoplastic cells that have been observed in MFS: spindled and ganglionlike cells. The background was myxoid, with a prominent inflammatory infiltrate. Histopathologic examination of the surgical specimen confirmed the diagnosis of MFS. CONCLUSION: Although the cytologic diagnosis was "pleomorphic sarcoma," MFS was considered and local excision recommended, given the reported low grade nature of this entity. However, the need for extreme caution in the diagnosis of soft tissue lesions on cytologic grounds alone cannot be overemphasized.

Exploring allelic imbalance within paraffin-embedded tumor biopsies using pyrosequencing technology.

BACKGROUND: The comparison of molecular genetic changes in healthy and pathological tissues has historically led to the identification of oncogenes and tumor suppressor genes. It is very common that studies investigating loss of heterozygosity are carried out retrospectively on paraffin-embedded samples. METHODS: In this study, we evaluated the power of pyrosequencing for determining the loss of heterozygotic regions. The present method uses the fact that pyrosequencing is an accurate, sensitive and reproducible technique. The method is also simple to perform, with results available in 96-well format, making the assays amenable to automation. Thus, we analyzed nine single nucleotide polymorphisms along 1 Mb between the EMSY and PAK1 genes on 11q13, a region frequently rearranged in different tumors and cell lines. We assessed the study using samples from breast cancer and thyroid cancer biopsies. RESULTS AND CONCLUSIONS: We conclude that this technique is capable of detecting variations of >10% in allele loss. However, strong allele imbalances were detected, depending on the origin of the sample. Seven out of the nine markers used exhibited differential allele amplification, depending on the DNA quality (p<0.01).

Condrosarcoma. Variantes de condrosarcoma / Chondrosarcoma. Different variants of chondrosarcoma

El término condrosarcoma es usado para describir ungrupo heterogéneo de tumores con características morfológicasy comportamientos clínicos diversos. Se asume quelos condrosarcomas son tumores malignos constituidos porcélulas de fenotipo cartilaginoso que usualmente muestranun patrón histológico lobulado y tienden a mantener sunaturaleza esencialmente cartilaginosa a lo largo de su evolución,independientemente de la localización del tumor,tanto en los tumores esqueléticos como extraesqueléticos.Se reconocen una serie de variantes, de características morfológicas,radiológicas y clínicas diferentes. En esta revisiónse exponen las referidas características de las diferentesvariantes de condrosarcoma, y las dificultades diagnósticaspara el patólogo, haciendo énfasis en los criterios parasu diagnóstico diferencial, incluyendo los nuevos conocimientosde citogenética y patología molecular

The term chondrosarcoma is used for describing a heterogeneousgroup of tumors with diverse morphological featuresand clinical behaviour. It is assumed that chondrosarcomasare malignant tumors composed of cells with a cartilaginousphenotype that usually show a lobulatedhistological pattern and tend to maintain their essentiallycartilaginous nature along their evolution, independently ofthe site of the tumor, as well in osseous as in extra skeletaltumors. Several variants of chondrosarcomas are recognized.They have different morphological, radiological andclinical features. In this revision the above mentioned featuresof the different variants and the diagnostic difficultiesfor the pathologist are commented, and emphasis is given tothe criteria for its differential diagnosis, including recentknowledge about cytogenetics and molecular biology

Non-monomelic synchronous primary multicentric chondrosarcoma: a case report.

We report a patient with simultaneous presentation of two histologically grade 2 conventional chondrosarcomas non-derived from pre-existing cartilaginous lesions, in the absence of pulmonary or visceral involvement. One tumour was located at the right proximal femur and the other one at the right scapula. There was no evidence of local recurrence or pulmonary or visceral involvement three years and a half after total scapulectomy and resection of the proximal third of the femur. To the best of our knowledge, this is the first report of a patient with two non-monomelic synchronous chondrosarcomas arising in two previously normal bones of the skeleton. Such cases are often difficult to differentiate from metastatic disease.

Cherubism associated with neurofibromatosis type 1, and multiple osteolytic lesions of both femurs: a previously undescribed association of findings.

We present a patient with neurofibromatosis type 1, with the clinical, radiological and histological features of cherubism mandibular lesions, and multiple osteolytic, geographic lesions in both femurs, consistent with multiple non-ossifying fibromas. We have been unable to find a similar case in the world literature. We discuss our findings in relationship with a number of syndromes that present clinical, radiological or pathological similarities.

Progression in cutaneous malignant melanoma is associated with distinct expression profiles: a tissue microarray-based study.

Cutaneous malignant melanoma remains the leading cause of skin cancer death in industrialized countries. Clinical and histological variables that predict survival, such as Breslow's index, tumor size, ulceration, or vascular invasion have been identified in malignant melanoma. Nevertheless, the potential relevance of biological variables still awaits an in-depth exploration. Using tissue microarrays (TMAs), we retrospectively analyzed 165 malignant melanoma samples from 88 patients corresponding to distinct histological progression phases, radial, vertical, and metastases. A panel of 39 different antibodies for cell cycle, apoptosis, melanoma antigens, transcription factors, DNA mismatch repair, and other proteins was used. Integrating the information, the study has identified expression profiles distinguishing specific melanoma progression stages. Most of the detected alterations were linked to the control of cell cycle G1/S transition; cyclin D1 was expressed in radial cases 48% (12 of 25) with significant lost of expression in vertical cases 14% (9 of 65), P = 0.002; whereas p16(INK4a) (89% in vertical versus 71% in metastatic cases, P = 0.009) and p27(KIP1) (76% in radial versus 45% in vertical cases, P = 0.010) were diminished in advanced stages. The study also defines a combination of biological markers associated with shorter overall survival in patients with vertical growth phase melanoma, that provided a predictor model with four antibodies (Ki67, p16(INK4a), p21(CIP1), and Bcl-6). This predictor model was validated using an independent series of 72 vertical growth phase melanoma patients.

Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial V.

BACKGROUND: The objective of this study was to clarify the prognostic and predictive value of immunoreactivity for the cyclin-dependent kinase inhibitor p27(Kip1) in patients with early-stage breast carcinoma and to investigate its relation with clinicopathologic features and other markers. METHODS: Immunoreactivity for p27 protein was analyzed on tumor slides from 461 patients who were enrolled in the International Breast Cancer Study Group (IBCSG) Trial V (median follow-up, 13 years), including 198 patients with lymph node negative disease and 263 patients with lymph node positive disease. Tumors with < 50% immunoreactive neoplastic cells were considered low expressors. Immunoreactivity for p27 was correlated with several clinicopathologic characteristics. Disease free survival (DFS) and overall survival were analyzed according to p27 immunoreactivity and treatment group. RESULTS: In the lymph node negative population, decreased p27 immunoreactivity was associated with higher tumor grade (P = 0.001) and HER-2/neu overexpression (P = 0.04). In the lymph node positive population, low p27 expression was associated with higher tumor grade (P = 0.01), low expression of thymidylate synthase (P = 0.001), and higher Ki-67 expression (P = 0.007). DFS was not significantly different according to p27 status in either lymph node negative patients (10-year DFS: low p27 expression, 53% +/- 5%; high p27 expression, 55% +/- 5%) or in lymph node positive patients (10 year DFS: low p27 expression, 33% +/- 4%; high p27 expression, 32% +/- 4%). However, in the lymph node negative population, the benefit of one course of perioperative chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil was confined exclusively to patients with tumors that showed reduced p27 immunoreactivity (P = 0.03; test for interaction). CONCLUSIONS: This analysis indicates that p27 immunoreactivity has little if any prognostic value in patients with early-stage breast carcinoma. However, these findings suggest that, in patients with breast carcinoma who have negative lymph node status, reduced p27 immunoreactivity is associated with HER-2/neu overexpression and may be predictive of a benefit from the early administration of adjuvant chemotherapy.

El diagnóstico de proliferación-neoplasiafolicular en la punción aspiracióncon aguja finaRevisión de la experiencia en 200 casos y 10 añosde seguimiento / Diagnosis of follicular proliferation/neoplasm using fine needle aspiration. A 10-year case review

El diagnóstico en punción aspiración con aguja fina de "Proliferación-Neoplasia Folicular" en la patología tiroidea es poco preciso en determinar la condición neoplásica benigna o maligna de las lesiones foliculares. Este diagnóstico se basa en que haya celularidad folicular destacable o aumentada de carácter neoplásico y escaso o ausente coloide de fondo, tratando de establecer un diagnóstico concreto de benignidad o malignidad, con prioridad en este último de la exéresis quirúrgica. En este trabajo relatamos nuestra experiencia en 200 casos con el diagnóstico citopatológico de "Proliferación Folicular" y la exéresis quirúrgica, excluyendo los diagnósticos de benignidad (Bocios Coloides, Tiroiditis) o malignidad (Carcinoma Papilar, Medular u otros) con características propias. Tras el examen histológico, 83 casos (42 por ciento) fueron lesiones benignas (71, Hiperplasia Uni o Multinodular; 6, Hiperplasia Difusa y 6, Tiroiditis Linfocitaria Crónica). 65 (32,5 por ciento) correspondieron a Adenomas Foliculares.52 casos (26 por ciento) fueron Carcinomas: (27, Carcinoma Papilar; 20, Carcinoma Folicular; 3, Carcinoma Medular; 1, Carcinoma Epidermoide de Laringe poco diferenciado; 1, Carcinoma Metastásico de Colon). En 58 casos (29 por ciento) se enunció ademas el diagnóstico de Sospecha de malignida, confirmándose en 39 (68 por ciento) la presencia de carcinoma. Se postula que en el 70 por ciento de estos diagnósticos, deben ser prioritarios para la cirugía por su carácter neoplásico, tratando de delimitar las lesiones neoplásicas más agresivas. La media de la exéresis quirúrgica en los casos que fueron Carcinomas fue de 11298 días (AU)

La Escuela de Cajal. La creación del primer Servicio de Anatomía Patológica en España por D. Francisco Tello / No disponible

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