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Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant soft tissue tumor of unpredictable clinical behavior. The morphological spectrum of EMC based on histology alone can be difficult. There is no precise immunohistochemical (IHC) profile that together with the clinical parameters is able to predict the clinical outcome. We studied 31 cases confirmed as EMC. Clinical and follow-up data were recorded. Histopathological, molecular, and IHC studies were performed. Association among histopathological parameters was assessed using a chi-square test to determine homogeneity or linear trend for ordinal variables. The Kaplan-Meier proportional risk test (log rank) was used to study the impact of the histological, IHC, and molecular factors on progression-free survival (PFS) and disease-specific survival (DSS). Most EMCs showed a typical architectural pattern. Only a few cases presented an atypical histology (higher cellularity and solid pattern). IHC positivity (focal or diffuse) was present for CDK4 (100%), STAT-6 (90%), CD117 (84%), HNK-1 (81%), SATB2 (68%), and S-100 (58%). Synaptophysin and INSM1 were expressed in 22.6% and 38.7% of cases respectively. The EWSR1::NR4A3 rearrangement was found in 19 cases and 7 tumors presented the TAF15::NR4A3 fusion. Positive surgical margins together with atypical histology and expression of p53 and Ki67 correlated with worse clinical prognosis. EMCs express several IHC markers which are also seen in other soft tissue sarcomas. The molecular detection of NR4A3 rearrangement supports the differential diagnosis. Positive surgical margins together with atypical histology and positive expression of p53 and Ki-67 seem to predict a poor clinical outcome with worse prognosis, increased rate of recurrence, metastasis, and poor overall survival.

Ewing sarcoma (ES) is an aggressive neoplasm with variable morphology. It has no specific immunoprofile or molecular signature. Neither CD99, NKX2.2 nor PAX7 immunoreactivity alone is completely specific, although diagnostic specificity improves when combined. The purpose of the present study was to investigate the immunohistochemical (IHC) expression of PAX7 in a large series of genetically confirmed ES. Existing results for CD99 and NKX2.2 immunoexpression, morphological findings and molecular studies (fusion gene subtypes) were retrieved from a previous study. Survival analyses were performed in cases with available clinical follow-up. PAX7 was positive in 95.5% of ES with diffuse staining ( 50%) in all positive cases and moderate or strong intensity for most cases. Nineteen ES displayed both PAX7 and CD99 immunoreactivity but lacked NKX2.2 immunoexpression. No relationships could be found between PAX7 expression and the histological types or ES gene fusion subtypes. Univariant/multivariate analysis showed that lack of PAX7 and/or NKX2.2 immunoexpression constitute independent poor prognostic factors for progression free survival (PFS) and overall survival (OS). In conclusion, IHC for CD99, NKX2.2, and PAX7 may be useful in daily practice for ES diagnosis, particularly in hospitals lacking facilities for molecular studies. In addition, the combination of strong CD99 membranous positivity and nuclear PAX7 and NKX2.2 immunoreactivity seems to be very reliable for ES diagnosis when supported by a corroborating histomorphologic and clinical picture. Although PAX7 is not entirely specific for ES, it seems to have a more extensive and strong nuclear immunoreactivity than NKX2.2 expression, even in tumors with decalcification artifact. Considering the prognostically significant data herein reported, we strongly recommend validation in prospective ES series that include localized and disseminated tumors.

We report the histopathological, immunohistochemical (IHC), and molecular findings in 3 patients with adult pancreatoblastoma, including 2 with autopsy features. The tumors were located in the tail and body of the pancreas, and the 2 autopsy examinations revealed liver and lung metastases. Histopathologically the neoplasms were composed of solid epithelial elements with nested or trabecular growth patterns, fibrous stroma, and squamoid clusters. Keratin 19 was positive mainly in squamoid corpuscles, and trypsin or chymotrypsin was positive in the acinar component. Neuroendocrine differentiation was observed in all tumors, and nuclear β-catenin expression in 2 tumors. Despite nuclear β-catenin expression, CTNNB1 mutation was found only in tumor 2. APC mutation was detected in tumor 1, and SMAD4 as well as MEN1 mutations in tumor 3. This last tumor also revealed chromosomal instability with many chromosomal losses and gains. The follow-up showed regional or distant metastases in all patients. Two patients died of disease after 3 and 26 months of follow-up and 1 patient is alive with no evidence of disease 6 years and 2 months after surgery. Adult pancreatoblastoma can display genetic heterogeneity, diverse histological appearance, and overlapping IHC findings. As a result, the differential diagnosis with other adult pancreatic tumors, such as acinar cell carcinoma, neuroendocrine neoplasm, solid pseudopapillary neoplasm, and mixed tumors may be challenging, especially when dealing with limited tumor tissue. The identification of squamoid corpuscles is essential for diagnosis. Although molecular findings might provide useful information, the integration of clinical, radiological, and histopathological findings is essential in pancreatoblastoma diagnosis.

Resumen La histiocitosis de celulas de Langerhans (HCL) es una enfermedad heterogenea caracterizada por una proliferacion de celulas de Langerhans y la presencia de la mutacion BRAF en aproximadamente la mitad de los casos. La afectacion osea es comun pero la presencia de grandes masas en partes blandas no es habitual. Reportamos un caso de un paciente pediatrico que comenzo con una gran masa tumoral en hueso iliaco izquierdo con extension a partes blandas adyacentes. La tomografia axial computarizada mostraba una lesion osteolitica con gran extension a partes blandas. Se realizo una biopsia quirurgica por curetaje y el diagnostico histopatologico fue de HCL con positividad intensa para CD1a en las celulas neoplasicas. El estudio molecular detecto la presencia de mutacion BRAF V600E. Se discute el diagnostico diferencial histopatologico e inmunohistoquimico con otras histiocitosis.

The clinical evolution of solitary fibrous tumor (SFT) remains unclear. Although various clinical, morphological and molecular criteria may indicate increased risk of malignancy, some SFT can still progress despite having a clearly benign appearance. Various risk stratification systems have been proposed, but unfortunately they are not sufficient to precisely determine the malignant potential. In this review, we discuss current knowledge on SFT, focusing on the following controversial issues: (i) the diverse morphologic spectrum: 'the great simulator;' (ii) malignant transformation or dedifferentiation; (iii) current risk stratification systems; and (iv) molecular factors associated with clinical evolution. The morphological spectrum of SFT and the list of differential diagnoses continue to expand. Both have increased considerably since the first descriptions of specific molecular alterations. A classification of malignant SFT should not be based on histology alone. The correlation of all pathological and molecular factors is recommended; its inclusion in risk stratification systems may help to improve diagnosis and prognosis.

Solitary fibrous tumors (SFTs) are a rare type of mesenchymal lesion in which specific clinicopathologic factors have been related to patient outcome. We collected clinical, pathological, and molecular data of 28 patients with histologically confirmed SFT having at least one pathological factor associated with aggressive behavior. Molecular analysis to detect NAB2/STAT6 gene fusion, TP53, and/or TERT promoter mutation was performed. We analyzed the pathological factors predictive of recurrence/metastasis and compared with clinical outcome. The risk of metastasis was calculated using four previously described scoring systems. Histopathologically, all tumors revealed hypercellularity, 11 had ≥ 4 mitoses/10 HPF, and 12 showed necrosis. Dedifferentiation was observed in three tumors. STAT6 was positive in all cases. Desmin, p16, INSM1, and HTER immunoexpressions were detected in 14, 18, 21, and 46% of the SFT, respectively. The NAB2/STAT6 gene fusion was detected in 16 tumors. After a median follow-up of 34 months, 32.0% recurred, 32.1% metastasized, and 35.7% died of disease. TERT mutations were detected in almost half the tumors. Tumors with TP53 mutations or with TP53 and TERT promoter mutations were almost always classified as high risk, and the patients developed metastases and/or died of disease. Tumors with intermediate-risk and TERT mutation had a worse evolution. SFTs with adverse pathological parameters were not always related with a poor outcome, thus confirming the unpredictable clinical behavior of SFT. The inclusion of molecular factors (TP53 and TERT promoter status) may provide new prognostic indicators for future risk stratification systems, especially in the intermediate-risk group.

Based on the French Federation Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, this study assesses the accuracy of conventional and modified core biopsy (CB) systems in predicting the final grade (low vs high) assigned to the resected specimen. Substituting Ki-67 immunoexpression for mitotic count, and radiological for histological assessment of necrosis, we used two modified FNCLCC CB grading systems: (1) Ki-67 immunoexpression alone, and (2) Ki-67 plus radiological assessment of necrosis. We graded 199 soft tissue sarcomas (STS) from nine centers, and compared the results for the conventional (obtained from local histopathology reports) and modified CB systems with the final FNCLCC grading of the corresponding resected specimens. Due to insufficient sample quality or lack of available radiologic data, five cases were not evaluated for Ki67 or radiological assessment of necrosis. The conventional FNCLCC CB grading system accurately identified 109 of the 130 high-grade cases (83.8%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (87.9%) of the 199 resected tumors; overestimating the final grade in three cases and underestimating in 21 cases. Modified system 1 (Ki-67) accurately identified 117 of the 130 high-grade cases (90.0%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (89.7%) of the 195 evaluated cases; overestimating seven and underestimating 13 cases. Modified system 2 (Ki-67 plus radiological necrosis) accurately identified 120 of the 130 high-grade cases (92.3%). This last matched the final FNCLCC grading (low vs high) in 177 (91.2%) of the 194 evaluated cases; overestimating seven and underestimating 10 cases. Modified system 2 obtained highest area under ROC curves, although not statistically significant. Underestimated CB grades did not correlate with histological subtypes, although many of the discrepant cases were myxoid tumors (myxofibrosarcomas or myxoid liposarcomas), leiomyosarcomas or undifferentiated pleomorphic/spindle cell sarcomas. Using modified FNCLCC CB grading systems to replace conventional mitotic count and histologic assessment of necrosis may improve the distinction between low and high-grade STS on CB. Our study confirms that classifying grade 1 as low grade and grades 2 and 3 as high grade improves correlation between CB and final grade by up to 21%, irrespective of CB system used. A higher than expected Ki-67 score in a low-grade sarcoma diagnosed on CB should raise concern that a higher-grade component may not have been sampled. Furthermore, correlation of all clinicopathological and radiological findings at multidisciplinary meetings is essential to assess the histological grade on CB as accurately as possible.

Our main goal was to investigate the potential utility of MDM2/CDK4 immunohistochemistry to act as surrogate for FISH to identify a subset of lipoma-like ALT/WDL that might, otherwise, be underdiagnosed on initial screening. Lack of cytologic atypia in lipomatous tumors with negative expression for MDM2/CDK4 IHC does not fully exclude the possibility of underlying MDM2/CDK4 amplification. Present study identified that isolated CDK4/p16 positive expression, in the absence of MDM2 expression, may have potential utility during the initial screening of these tumors but the proportion of conventional lipomas, which may also exhibit low levels of CDK4/p16 expression remains uncertain.

Background Despite extensive immunohistochemical (IHC) and molecular studies combined with morphologic findings, a group of round/ovoid cell tumors histologically similar to Ewing sarcomas (ES) but lacking EWSR1-rearrangements may remain unclassifiable. Design We retrospectively analyzed 41 Ewing-like tumors (formalin-fixed, paraffin-embedded) previously determined as negative or non-informative for EWSR1-rearrangements by FISH and/or RT-PCR. A new histopathology revision and additional IHC and molecular analyses were carried out in order to investigate whether additional IHC and/or molecular testing in combination with the morphological findings may help in reaching a definitive diagnosis. Results Almost all the tumors (n = 40) involved soft tissue and/or bone and half the patients died of disease. In the archival cases all diagnoses were Ewing sarcoma (ES), Ewing-like sarcoma (ELS), myoepithelial tumor and undifferentiated sarcoma (US). In the new review all the tumors were re-classified as, ES (n = 16), Ewing-like tumor with EWSR1 rearrangement and amplification and possible EWSR1-NFATC2 gene fusion (n = 1), CIC-rearranged sarcomas or undifferentiated sarcoma, most consistent with CIC-rearranged sarcoma (n = 7), sarcoma with BCOR-alteration or undifferentiated sarcoma, consistent with BCOR-associated sarcoma (n = 3), neuroblastoma (n = 2), unclassifiable neoplasm with neuroblastic differentiation (n = 1), malignant rhabdoid tumor (n = 2), lymphoblastic lymphoma (n = 1), clear cell sarcoma of the gastrointestinal tract (n = 1), small cell carcinoma (n = 1), sclerosing rhabdomyosarcoma (n = 1), desmoplastic small round cell tumor (n = 1), malignant peripheral sheath nerve tumor (n = 1), poorly-differentiated synovial sarcoma (n = 1), Possible gastrointestinal stromal tumor/GIST with predominant round cells (n = 1) and possible SMARCA4-deficient-sarcoma (n = 1). NKX2.2, ETV4 and BCOR immunoreactivity was observed in all ES, CIC-rearranged sarcomas and sarcomas with BCOR alteration, respectively. CIC-rearrangement by FISH was observed in many of the CIC-rearranged sarcomas. Conclusion Our analysis of 41 Ewing-like tumors confirms that there may be a significant pathological and IHC overlap among Ewing-like tumors, with prognostic and therapeutic impacts. Additional IHC (NKX2.2, ETV4 and BCOR) and molecular studies including FUS, CIC or BCOR analysis may support the final diagnosis when FISH or RT-PCR fail to detect EWSR1-rearrangements. Any molecular findings should always be interpreted in relation to the specific clinical and pathological context.

Ewing's sarcoma family of tumors (ESFT) are aggressive neoplasms with scant tumor-infiltrating lymphocytes. We analyzed the immunohistochemical (IHC) expression of PD-L1 and PD-1 and their prognostic significance in clinically localized neoplasms in a cohort of 370 ESFT. Slides prepared from tissue microarrays were stained for PD-L1, PD-1, and CD8. Membranous/cytoplasmic staining over 5% of tumor cells was regarded as positive for PD-L1 and PD-1. Prognostic analysis was done considering only clinically localized tumors (n = 217). PD-L1 expression was present in 19% of ESFT, while PD-1 was expressed in 26%. Forty-eight percent of tumors were negative and 12% were positive for both PD-L1 and PD-1. Metastatic tumors displayed higher expression of PD-L1 (p

Ewing sarcoma is an aggressive neoplasm of pediatric and adolescent patients. Immunohistochemistry (IHC) can be used to support the morphologic diagnosis of Ewing sarcoma family of tumors (ESFT) in a convincing clinical/radiological context. Although neither NKX2.2 nor CD99 alone are entirely specific, when combined, the diagnostic specificity is high. The aim of the present study was to investigate the IHC expression of NKX2.2, ETV4 and BCOR in a large series of genetically confirmed ESFT. The results for CD99 and CAV-1 immunoreactivity, and the histological and fusion gene subtypes were retrieved from our previous study. NKX2.2 demonstrated moderate or strong nuclear positivity in 91.2% of the tumors. The staining intensity was heterogeneous. Many of the ESFT with negative NKX2.2 immunoreactivity were in bone. Strong/moderate ETV4 nuclear expression was detected in two small round cell tumors, both were negative for NKX2.2. No relationships could be found between expression of NKX2.2 and the histological subgroups or ESFT gene fusion subtypes. BCOR was negative in all ESFT. In conclusion, NKX2.2, ETV4 and BCOR IHC may be helpful in daily practice for distinguishing ESFT from CIC or BCOR-associated sarcomas, especially in hospitals without access to molecular assays. In addition, the combination of strong CD99 membranous positivity and nuclear NKX2.2 positivity seems to be very reliable for ESFT diagnosis in an appropriate clinicoradiological setting. So far no antibody is entirely specific for ESFT diagnosis, and the IHC or molecular results in round cell tumors of bone may be strongly influenced by decalcification processes.

Desmoplastic melanoma (DM) and cutaneous malignant peripheral nerve sheath tumors (MPNST) reveal histological and immunohistochemical similarities, including S100 positivity and negative staining for conventional melanocytic markers. We present 3 cases of cutaneous S100-positive spindle cell tumors in elderly patients, in which first findings led to initial misdiagnoses as cutaneous MPNST and benign peripheral sheath nerve tumor (neurofibroma). The identification of adjacent atypical melanocytic hyperplasia in the overlying skin along with tumor cell proliferation, also in the superficial dermis, the neurotropic component and the absence of any relationship between the tumor and a major nerve, pre-existing neural benign tumor or the existence of stigmata suggestive of neurofibromatosis raised consideration of a DM. Careful attention should be paid to the presence of a firm dermal nodule and atypical scar lesions especially in sun-exposed areas (mainly head and neck region) in elderly patients associated with S100-positive spindle cell proliferation, solar elastosis and adjacent atypical melanocytic proliferation. In such cases, the possibility of a DM should be excluded with caution, especially if the tumor reveals a paucicellular morphology resembling various non-melanocytic neoplasms including malignant or benign peripheral sheath nerve tumors.

Given the potential for neuroendocrine differentiation in Ewing's sarcoma family of tumors (ESFT), we aimed to determine neuroendocrine expression in a large series of genetically-confirmed ESFT and its prognostic significance in clinically-localised neoplasms (n = 176). Slides prepared from tissue microarrays were stained for Insulinoma-associated protein 1 (INSM1), CD56, chromogranin-A and synaptophysin. INSM1 expression was present in 59% of ESFT, while synaptophysin, chromogranin-A and CD56 were expressed in only 13%, 8% and 5% of ESFT, respectively. Histological subtypes were only significantly correlated with INSM1 (p = 0.032) or CD56 (p = 0.016) immunoexpression. Regarding prognosis, no significant association was found between INSM1, synaptophysin or chromogranin-A immunoexpression and progression-free survival (PFS) or overall survival (OS). Despite the low proportion of tumors with CD56 immunoreactivity, CD56 expression was shown to correlate with both poor PFS (p < 0.001) and poor OS (p < 0.001) in the present series. In conclusion, neuroendocrine differentiation is often present in ESFT, and in the present study INSM1 expression in particular was found to be higher than previously described in Ewing's tumors. Nevertheless, this finding does not distinguish these tumors from other round cell tumors that may show focal or diffuse neuroendocrine differentiation. CD56 expression could be used as a prognostic factor in ESFT, although given the results herein obtained, we recommend a prospective validation in independent series including localized and disseminated tumors in ESFT.

SATB2 is commonly expressed in osteosarcomas. Although apparently being a valuable diagnostic marker for differentiating between small cell osteosarcoma (SCO) and other small round cell tumors of bone, for instance Ewing sarcoma family of tumors (ESFT), it has not been tested in a large series of ESFT and chondrosarcomas so far. We studied the immunohistochemical expression of SATB2 in 42 osteosarcomas, 31 chondrosarcomas, and 371 genetically confirmed ESFT. SATB2 positivity was detected in 90.4% of osteosarcomas, 87.5% of SCO, 91.3% of osteoblastic osteosarcomas, and in all chondroblastic and parosteal osteosarcomas. The osteoblastic and SCO subtypes expressed SATB2 more intensely than other histological types. SATB2 was expressed in 46.6% of chondrosarcomas, and in 1.3% of ESFT. Sensitivity and specificity of SATB2 immunoexpression were 90.4% and 95.3%, respectively. The positive and negative predictive values in osteosarcoma diagnosis were 66.6% and 98.9%, respectively. In chondrosarcoma, SATB2 immunoexpression was more frequent and intense in high-grade chondrosarcoma (Grade III) and uncommon in chondrosarcoma grade I. SATB2 positivity was detected in 55.6% of chondrosarcomas grade II. SATB2 apparently cannot distinguish between chondroblastic osteosarcoma and high-grade chondrosarcoma. Nevertheless, SATB2 is frequently expressed in osteogenic tumors, but is rarely positive in ESFT, and with the support of CD99 expression and specific molecular studies, it is very useful for distinguishing between these two lesions. Although SATB2 immunoexpression helps to distinguish osteosarcoma from their mimickers, the identification of malignant osteoid matrix formation and the integration of clinical and radiological data remain the corner stone of osteosarcoma diagnosis and as yet no antibody has equalled the diagnostic value of this important morphologic hallmark.

Hyaline globules and papillary fragments in cytologic samples from two intra-abdominal tumors in young females are presented including the cytological features and the correlation with the histopathologic and immunohistochemical findings. In the first case a cytologic study from an ovarian mass showed papillary structures and isolated tumor cells with epithelioid morphology, irregular reniform-like nuclear contour, pale or vacuolated cytoplasm, abundant hyaline globules and occasional glomeruloid structures resembling Schiller-Duval bodies. Yolk sac tumor (YST) was the diagnosis on the histological slides. Tumor cells showed positivity for cytokeratin (AE1/AE3), epithelial membrane antigen (EMA), alpha-fetoprotein (AFP) and Sal-like protein 4 (SALL4). In case number two the cytologic study from a liver metastasis displayed papillary and rosette-like clusters composed of uniform and bland cells showing occasional long cytoplasmic tails, hyaline globules and nuclear grooves. A diagnosis of hepatic metastasis from solid pseudopapillary neoplasm of the pancreas (SPNP) was rendered from the histology. Tumor cells revealed immunoreactivity for cytokeratin (AE1/AE3), Vimentin, Galectin-1 (GAL-1), Neuron specific-enolase, CD10, progesterone and β-catenin (nuclear stain). Regarding differential diagnosis, in the patient with the ovarian mass an ovarian clear cell carcinoma was considered, as well as other germ cell tumors or metastatic carcinoma, while in the patient with a liver metastasis a neuroendocrine carcinoma was taken into account. YST and SPNP share some cytological findings, including hyaline globules, papillary structures, clear cells and intercellular eosinophilic basement membrane deposits. Thus, a detailed study and careful interpretation of the cytological, histological and immunohistochemical findings may be worthwhile to avoid a potential misdiagnosis, particularly in the cytologic specimens of the ovarian and/or intra-abdominal mass, when involving young females. Diagn. Cytopathol. 2016;44:935-943. © 2016 Wiley Periodicals, Inc.

Background Differentiation of Ewing sarcoma family of tumors (ESFT) and Ewing-like tumors remains problematic. Certain ESFT with morphological and immunohistochemical (IHC) profiles lack the EWSR1-ETS transcript. To improve diagnostic accuracy we investigated the presence of several specific transcripts in 200 small round cell tumors (SRCT) displaying ESFT morphology and immunophenotype in which EWSR1 FISH analysis was non-informative or negative. Design 200 tumors (formalin-fixed, paraffin-embedded) were analyzed by RT-PCR. All tumors were tested for EWSR1-ETS , EWSR1 / WT1 , PAX3 / 7-FOX01 or SYT / SSX transcripts, and the negative tumors were subsequently analyzed for CIC / DUX4 , BCOR / CCNB3 and CIC / FOX04 transcripts. Results 133 (66.5%) ESFT displayed one of the above EWSR1-ETS translocations. Three cases (1.5%) revealed the SYT-SSX transcript for Synovial sarcoma, and one (0.5%) a EWSR1-WT1 transcript for Desmoplastic Small Round Cell tumor. The CIC-DUX4 translocation was found in six Ewing-like tumors (3%) with CD99 positivity. The BCOR-CCNB3 gene fusion was observed in 5 tumors (2.5%) displaying round or spindle cells with strong CCNB3 IHC expression in 3 tumors. Moreover, RT-PCR failed to detect any gene fusion transcripts in 19 tumors (9.5%) and were considered "undifferentiated small round cell sarcoma" (SRCS). Molecular biology results were non-informative in 33 SRCTs (16.5%) due to RNA degradation through inadequate fixation and/or decalcification. Conclusion Our analysis of 200 SRCTs confirms the molecular heterogeneity of neoplasms with ESFT morphology and highlight that molecular studies with RT-PCR including new emerging gene fusion transcripts are mandatory for the diagnosis when EWSR1 FISH is negative or non-informative. The incidence of CIC-DUX4 , BCOR-CCNB3 and CIC-FOX04 transcripts was relatively low. A small group of Ewing-like sarcomas or undifferentiated SRCS remains unclassified. Adopting appropriate tissue fixation and processing protocols is important to avoid degradation of fixed/embedded tissue when no frozen tumor is available.

Background Ewing sarcoma (EWS) is the second most common bone cancer in pediatric patients. Angiogenesis is a major factor for tumor growth and metastasis. Our aim was to carry out a histological, immunohistochemical, and molecular characterization of the neovascularization established between xenotransplanted tumors and the host during the initial phases of growth in nude mice in three angiogenesis experiments (ES2, ES3, and ES4). Methods The original human EWS were implanted subcutaneously on the backs of three nude mice. Tumor pieces 3 mm–4 mm in size from early passages of Nu432, Nu495, and Nu471 were also implanted subcutaneously on the backs of three sets (ES2, ES3, and ES4) of athymic Balb-c nude mice (n = 14 each). The animals were sacrificed at 24, 48, and 96 hours and at 7, 14, 21, and 28 days after implantation to perform histological, immunohistochemical, and molecular studies (neovascularization experiments). Results We observed histological, ultrastructural, and immunohistochemical changes in the xenografted tumor at different times after implantation. Chemokine ligand expression peaked twice, once during the first 48 hours and again in the second week. We observed that tumor cells in contact with murine peritumoral stroma presented higher expression of chemokine ligands as well as more tumor cells around the capillary vessels. Mouse serum vascular endothelial growth factor levels peaked twice, once in the first hours and then in the second week after tumor implantation. Conclusion Chemokines and other angiogenic factors may be relevant in the angiogenic mechanism during tumor growth. This model provides information on the early stages of the angiogenic process and could be a useful tool in researching anti-angiogenic drugs for new therapeutic strategies in EWS.

Neuroendocrine differentiation or aberrant expression of neuroendocrine markers is very uncommon in angiosarcomas (AS) and creates a challenging differential diagnosis with other superficial or soft tissue tumors. Herein, we report a new case of superficial AS presenting as a tumor lesion on the little finger of the right hand of a 52-year-old man. The tumor displayed CD56, chromogranin-A, and synaptophysin immunoreactivity. Tumor cells were positive for vascular markers (CD31, FLI1, ERG, D2-40, VE-cadherin, VEGR1,2, and 3), CD99, and EMA, but were negative for S100, CK (AE1/AE3), CK20, polyomavirus, and myogenic (desmin and myogenin) and melanocyte markers (melan-A and HMB45). Ki67 immunostains indicated high proliferative activity (>50%). The whole-body computed tomography did not reveal distant disease. The initial assessment considered several tumor subtypes as possible histological diagnoses, including Ewing sarcoma, Ewing-like sarcoma, Merkel cell carcinoma, and undifferentiated "small round cell sarcoma". Fluorescence in situ hybridization analysis was negative for EWSR1 translocation and molecular analysis failed to detect any EWSR1, CIC, SYT or BCOR rearrangement. As a follow-up investigation, we tested 17 cutaneous/superficial AS for neuroendocrine markers; however, only one of these showed focal CD56 and synaptophysin expression. In conclusion, the present findings indicate that neuroendocrine differentiation is a very infrequent feature in AS. We report an AS of the finger with an uncommon histological appearance and immunohistochemical profile: predominant round cell tumor proliferation and neuroendocrine differentiation. Pathologists should be aware of these potential histological and immunohistochemical pitfalls in AS.

Epithelioid hemangioma (EH) is a rare benign vascular lesion, characterized by endothelial cells with epithelioid/histiocytoid appearance. Heart involvement is extremely rare. We present an unusual case of cardiac EH in a young woman with supraventricular arrhythmia, nephrotic syndrome (membranous glomerulopathy), and peripheral eosinophilia after a pregnancy and normal partum resembling Kimura disease. Echocardiogram showed a large tumor mass in the right cardiac ventricle. The cardiac tumor was removed and the histopathology revealed an endothelial proliferation associated with abundant eosinophils. The neoplastic endothelial cells were eosinophilic and polygonal with epithelioid/histiocytoid morphology. Lymphoid nodules were occasionally seen. The neoplastic cells were positive for CD34, CD31, ERG, and factor VIII and negative for CK. A diagnosis of EH was rendered. The patient was alive and well after surgical resection. EH and Kimura disease represent separate entities, but clinical and/or histological overlapping can be observed. Epithelioid/histiocytoid endothelial cells constitute the hallmark feature that favors a final diagnosis of EH.

Resumen Los angiosarcomas son neoplasias malignas agresivas con diferenciacion de celulas endoteliales. La hemorragia espontanea debida a una coagulacion intravascular diseminada con coagulopatia de consumo es una forma poco comun de presentacion de estos tumores denominada sindrome de Kasabach-Merritt. En el presente estudio describimos 2 casos con estudio necropsico de angiosarcomas complicado con sindrome de Kasabach-Merritt. El primer caso con diagnostico de angiosarcoma mediastinico asociado a un tumor de celulas germinales y el segundo caso con angiosarcoma primario hepatico y multiples metastasis.

A new case of soft tissue myoepithelial carcinoma (MEC) with rhabdoid-like differentiation is presented including cytologic, histopathologic, immunohistochemical, and molecular biologic features. A 45-year-old woman was admitted to the Hospital with nodular mass involving the lower part of the abdominal wall. Fine-needle aspiration cytology showed a round cell tumor with abundant cytoplasm in the myxoid background. The nuclei were uniform, round to ovoid, with finely distributed chromatin, nucleoli, and pale, vacuolated, or eosinophilic cytoplasm with rhabdoid-like appearance resembling a soft tissue malignant rhabdoid tumor. The surgically removed tumor was poorly demarcated, yellow, soft, and myxoid. The histopathology revealed sheets of poorly differentiated round malignant cells with focal myxoid stroma and rhabdoid-like morphology. Immunohistochemistry showed positivity for CK (AE1/AE3), EMA, S100, vimentin, CD99, and SMA; however desmin, CD34, and gliofibrilar acid protein (GFAP) were negative. Tumor cells revealed loss of INI1 expression. The EWSR1 gene rearrangement was detected by fluorescence in situ hybridization (FISH), but molecular biology failed to detect EWSR1/ETS, EWSR1/NR4A3, EWSR1/DDIT3, EWSR1/ATF1, EWSR1-POU5F1, EWSR1/ZNF444, EWSR1-PBX1 gene fusions. The final diagnosis was soft tissue malignant myoepithelioma with rhabdoid changes and EWSR1 gene rearrangement. The differential diagnosis included soft tissue malignant rhabdoid tumor, cellular extraskeletal myxoid chondrosarcoma, proximal epithelioid sarcoma, and other soft tissue tumor with EWSR1 rearrangement. To our knowledge, this is the first case of MEC with rhabdoid features and description of fine-needle aspiration cytology.

Sinonasal tract (SNT) alveolar rhabdomyosarcoma (ARMS) are frequently misdiagnosed, especially in adults. Fifty-two adult (≥18 years) patients with SNT ARMS were reviewed and characterized by immunohistochemistry and molecular studies. Twenty-six females and 26 males (18–72 years; mean 43.2 years), presented after a short duration (mean 2.6 months) with a large (mean 5.5 cm) destructive nasal cavity mass, involving multiple contiguous paranasal sites (n = 46) and with cervical adenopathy (n = 41). The tumors showed an alveolar, nested to solid growth pattern below an intact, but often involved (n = 9) epithelium with frequent necrosis (n = 37), destructive bone invasion (n = 30), and lymphovascular invasion (n = 25). The neoplastic cells were dyshesive and dilapidated, with crush artifacts. Rhabdoid features (n = 36) and tumor cell multinucleation (n = 28) were common. Mitotic counts were high (mean 17/10 HPFs). The neoplastic cells showed the following immunohistochemical positive findings: desmin (100%), myogenin (100%), MYOD1 (100%), MSA (96%), SMA (52%), CAM5.2 (50%), AE1/AE3 (36%); other positive markers included S100 protein (27%), CD56 (100%), synaptophysin (35%), and chromogranin (13%). Overall, 54% show epithelial marker reactivity. Molecular studies showed FOXO1 translocations (81%) with PCR demonstrating PAX3 in 72.7% tested. Patients presented with high stage (IV 24; III 26) and metastatic disease (lymph nodes n = 41; distant metastases n = 25) (IRSG grouping). Surgery (n = 16), radiation (n = 41) and chemotherapy (n = 45) yielded an overall survival of 36.1 months (mean; range 2.4–286); 18 alive without disease (mean 69.6 months); 7 alive with disease (mean 11.0 months); 1 dead without disease (63.7 months); and 26 dead with disease (mean 18.5 months). SNT ARMS frequently present in adults as a large, destructive midline mass of short symptom duration, with high stage disease. The alveolar to solid pattern of growth of cells with rhabdoid-plasmacytoid features suggests the diagnosis, but epithelial immunohistochemistry markers are present in 54% of cases, leading to misdiagnosis as carcinomas if muscle markers are not also performed. Overall survival of 36.1 months is achieved with multimodality therapy, but 64% have incurable disease (16.9 months). Mixed anatomic site (p = 0.02) was a significant adverse prognostic indicator, while stage (0.06) and tumor size >5 cm (0.06) approached marginal significance.

Perivascular epithelioid cell tumors (PEComas) are infrequent neoplasms with peculiar myomelanocytic differentiation. The aggressive abdominopelvic variant is rare, with only a small number of published cases. We present an additional case of this unusual variant, which showed an aggressive histologic and clinical behavior with multiple liver metastases and resistance to several therapies. We also discuss the histological and immunohistochemical profiles as well as the differential diagnosis.

The present study describes a new case of EWSR1-negative undifferentiated sarcoma with CIC/DUX4 gene fusion. This case is similar to tumors described as primitive undifferentiated round cell sarcomas that occur mainly in the trunk and display an aggressive behavior. To our knowledge, this is the first report of such a tumor presenting locoregional lymph node metastasis. In view of previous studies that prove the existence of a particular variant of undifferentiated sarcoma with Ewing-like morphology and CIC/DUX-4 gene fusion, a search for this gene fusion in all undifferentiated round cell sarcomas should be considered if a conclusive diagnosis cannot be reached following other conventional studies. Although additional cases with more extensive follow-up studies are needed, we believe that EWSR1-negative undifferentiated small round cell sarcoma with CIC/DUX4 gene fusion should be added to the list of new sarcoma variants with the possibility of lymph node metastasis.

Galectin-1 (GAL-1) is frequently expressed in osteosarcomas. Although a valuable diagnostic marker to differentiate between chondroblastic osteosarcomas and conventional chondrosarcomas, it has not been tested in the Ewing sarcoma family of tumors (ESFTs). We studied by immunohistochemistry GAL-1 expression in 43 osteosarcomas, 23 chondrosarcomas, and 217 genetically confirmed ESFTs using a tissue microarray. GAL-1 was expressed in 78 % of osteosarcomas, 33 % of chondrosarcomas, and 8 % of ESFTs. Osteoblastic and small cell osteosarcoma subtypes expressed GAL-1 in a high percentage of cells when compared with the other histological subtypes, whereas two chondroblastic osteosarcomas were negative. GAL-1 was mainly expressed in high-grade chondrosarcomas (grade III). ESFTs were rarely positive (8 %), and this was not related to the histological subtype nor to the clinical outcome. Although GAL-1 expression distinguishes chondroblastic osteosarcomas from conventional chondrosarcomas and is usually negative in conventional chondrosarcomas, the final diagnosis needs to incorporate histopathology since some chondroblastic osteosarcomas fail to express GAL-1, while high-grade chondrosarcomas are GAL-1 positive. Since GAL-1 is frequently expressed in osteogenic tumors, including small cell osteosarcoma, but rarely positive in ESFTs, its expression seems a valuable tool for distinguishing between these lesions. GAL-1 immunoexpression is not indicative of prognosis in ESFT.

The objectives of this work are to study angiogenesis in pancreatic ductal adenocarcinoma using computerized morphometric and image analysis and to compare the microvascular density in intratumoral and peritumoral areas and normal pancreatic tissue. Microvascular density was analyzed in 60 cases of pancreatic ductal adenocarcinoma and 30 samples of normal pancreatic tissue using an avidin-biotin immunoperoxidase technique with an anti-CD31 antibody. Microvascular density (MVD) was analyzed through digital microimaging and computerized analysis. The blood vessel density in the tumor was significantly higher than in peritumoral areas and in normal pancreatic tissue. Well differentiated pancreatic ductal adenocarcinomas contained higher MVD than poorly differentiated carcinomas. In pancreatic adenocarcinoma, MVD is higher than in peritumoral tissue or normal pancreatic tissue.

Superficial/cutaneous small round-cell tumors comprise a heterogeneous group of neoplasms including sarcoma, carcinoma, melanoma, and lymphomas. Among superficial sarcomas, the Ewing's sarcoma family of tumors (ESFT) represents a poorly understood rare variant, having a behavioral difference characterized by a relative favorable prognosis. Several problems are still to be resolved in superficial ESFT, including the differential diagnosis between ESFT of bone (intraosseous or periosteal) with superficial infiltration and superficial ESFT with bone infiltration, especially in the fingers. Our aim is to review the most common types of small round-cell tumors included in the differential diagnosis of superficial ESFT, analyzing the histopathology, phenotype, and molecular alterations of each entity.

Summary Lysine-specific demethylase 1 (GeneID 23028), a flavin-dependent monoamine oxidoreductase and a histone demethylase, serves as an epigenetic coregulator of transcription. Lysine-specific demethylase 1 is up-regulated in neuroblastoma and in bladder, breast, colorectal, gastric, lung, and neuroendocrine cancers, and its overexpression drives the cell cycle of otherwise nontransformed human cells, suggesting oncogenic properties. Lysine-specific demethylase 1 was recently reported to be also overexpressed in several different mesenchymal tumors. We investigated lysine-specific demethylase 1 expression in over 500 sarcomas by gene expression profiling and tissue microarray-coupled immunohistochemical analyses and confirmed lysine-specific demethylase 1 overexpression in rhabdomyosarcoma and synovial sarcoma. We also show for the first time that lysine-specific demethylase 1 is also overexpressed in chondrosarcoma, Ewing's sarcoma, and osteosarcoma wherein it localizes in cell nuclei. We further show that a US Food and Drug Administration–approved drug that inhibits lysine-specific demethylase 1 also inhibits chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma cell growth in vitro. These data suggest that lysine-specific demethylase 1 plays a role in sarcoma pathology and that lysine-specific demethylase 1 inhibition strategies might represent a novel means to inhibiting growth of lysine-specific demethylase 1–overexpressing sarcomas.

Resumen El objetivo del presente trabajo es realizar una revision y actualizacion donde se describe el espectro de hallazgos morfologicos inmunohistoquimicos (IHQ) y geneticos moleculares en los sarcomas de Ewing/PNET (Ewing/PNET) asi como su diagnostico diferencial con otros tumores de celulas redondas y pequenas (TCRP) de hueso y partes blandas. La expresion IHQ de CD99, Fli1, HNK-1 y CAV1, unido a las alteraciones geneticas que muestran estos tumores, apoyan el diagnostico definitivo de esta neoplasia. La expresion de marcadores epiteliales (CK, EMA y/o CEA) en un TCRP no excluye la posibilidad de un Ewing/PNET; sin embargo, la diferenciacion miogenica practicamente excluye la posibilidad de un Ewing/PNET. La variante atipica de Ewing/PNET frecuentemente muestra solapamiento morfologico e IHQ con otros TCRP, por lo que en estos casos es preciso realizar una confirmacion genetica para un diagnostico definitivo. El metodo mas eficiente para llegar a un diagnostico concluyente asi como a un diagnostico diferencial en este tipo de neoplasias consiste en la integracion de los hallazgos clinicos, morfologicos, IHQ y genetico-moleculares.

During the 25-year period subsequent to the Chernobyl accident, the morbidity of malignant renal tumors in Ukraine has increased from 4.7 to 10.7 per 100,000 of the total population. Recent studies of our group have shown that increases in morbidity, aggressiveness, and proliferative activity of renal cell carcinomas (RCCs), especially clear-cell renal cell carcinoma (CCRCC), in Ukrainian patients continuously inhabiting the radio-contaminated areas could be explained by specific molecular changes influenced by the so-called "chronic persistent low-dose ionizing radiation" (CPLDIR) exposure. This study aimed to examine the role of angiogenesis in CCRCC carcinogenesis associated with CPLDIR in patients living more than 20 years in cesium 137 ((137)Cs) contaminated areas after the Chernobyl accident in Ukraine. Paraffin-embedded specimens of 106 CCRCs were studied: Control cases were 18 tumors from Spanish patients (group 1), 25 tumors from Ukrainian patients from so-called clean areas without known radio-contamination (group 2), and 63 tumors from Ukrainian patients from radio-contaminated areas (group 3). For intratumoral microvessel density (MVD) determination, anti-CD31 antibody was used. A computerized image analysis program was used to quantitatively calculate the vascular density. Seventy-three percent of group 3 and 72 % of group 2 CCRCCs displayed the highest MVD. A striking increase in MVD was seen in group 3 CCRCCs, in comparison with groups 1 and 2 (p 0.001). The majority of the hot spot vessels in group 3 was poorly differentiated. Moreover, MVD values for total vessels as well as for capillaries and tumor grade were strongly correlated. When we compared only tumor-node-metastasis tumor stages I and II, the differences remained statistically significant (p 0.1). The ratio of the average total vessels and capillaries in the Ukrainian groups combined was 1.65:1 in comparison to the Spanish group. Our results provide evidence that CPLDIR exposure increases MVD (particularly capillary) in CCRCCs and is associated with a higher histological grade.

Resumen El nefroblastoma o tumor de Wilms (WT) es una neoplasia de origen embrionario de histologia trifasica que simula estadios diferentes de la nefrogenesis, y esta constituido tanto por celulas blastemales indiferenciadas como por celulas epiteliales y estromales bien diferenciadas. El predominio de uno de sus componentes en mas de dos terceras partes permite clasificar al WT en blastemal, epitelial, estromal o mixto cuando no hay predominio de uno de ellos. Los tumores con predominio de elementos estromales con un 30% o mas de diferenciacion muscular se reconocen como de variante rabdomioblastica o con diferenciacion muscular. El presente trabajo comunica los hallazgos histologicos, inmunohistoquimicos y moleculares de tres casos de nefroblastoma con diferenciacion muscular en ninos menores de 5 anos. La inmunotincion se realizo seleccionando bloques de tejido con representacion de todos los componentes tumorales. Dos de los tres tumores presentaron masas solidas y uno fue poliquistico. En todos se observo franco predominio estromal con expresion variable del componente blastemal y de rabdomiogenesis. El blastema demostro positividad para marcadores mesenquimales y epiteliales identificando el componente germinal a partir del cual se diferencian los otros dos. La expresion citoplasmica de la β-catenina se correlaciono con la ausencia de mutacion en el gen WT1 , que se manifiesta habitualmente por una positividad nuclear para este anticuerpo. Ademas, no se encontraron mutaciones de los genes E-cadherina, β-catenina y APC , lo cual sugiere la existencia de mecanismos alternativos de activacion de la via Wnt.

Chondrosarcomas are malignant cartilage-forming tumors that represent the third most common malignant solid tumor of bone. In patients with grades II and III, local recurrence, increasing tumor size and dedifferentiation have been associated with lower survival rates. These biologically poorly-understood neoplasms vary considerably in clinical presentation and biological behavior. Cytogenetic studies have shown that heterogeneity is related to karyotypic complexity; moreover, alterations in the 9p21 locus and TP53 gene are related to disease progression. Despite the relatively high frequency of chondrosarcoma only a limited number of cell lines exist in the scientific community, limiting the possibility to study hypothesis-derived research or primary drug interaction necessary for pre-clinical studies. We report a chondrosarcoma cell line, CH-3573, derived from a primary tumor that may serve as a useful tool for both in vitro and in vivo models to study the molecular pathogenesis. In addition, xenograft passages in nude mice were studied to characterize the genetic stability over the course of tumor progression. In contrary to other reported cell lines, an important feature of our established cell line was the retained matrix production, a characteristic feature of a conventional grade II chondrosarcoma. The cell line (CH-3573) was characterized by pathological, immunohistochemical and molecular genetic methods.

Pleomorphic hyalinizing angiectatic tumor (PHAT) is an uncommon soft tissue tumor usually located in extremities or trunk. We report 3 new cases with histopathologic diagnosis of PHAT, one with recurrence and sarcomatous myxofibrosarcoma component and another with unreported soft tissue palpebral location. Clinical data, histopathology, immunohistochemistry, fluorescence in situ hybridization, and follow-up data are described. The histopathology showed a tumor with angiectatic blood vessel proliferation and perivascular hyaline material associated with focal pleomorphic cells. The recurrent tumor revealed a histopathologic pattern corresponding to a myxofibrosarcoma. Vimentin and CD99 were positive in tumor cells and CD34 was strongly positive in the tumor cells from the recurrence. Ki-67 was poor positive but with increased positivity in the recurrence. The positivity of p53 and chromosome 22 polysomy were detected in the recurrence. At present, the 3 patients are free of disease and no metastases have been detected. Indeed, the possibility that PHAT may represent a histopathologic pattern and not a true neoplastic entity with specific genetic alterations cannot be excluded at present, and further studies are required.

Notch can act as an oncogene or as a tumour suppressor and thus can either promote or inhibit tumour cell growth. To establish Notch status in Ewing's sarcoma family of tumours (ESFT), we investigated the Notch pathway by gene expression profiling meta-analysis or immunohistochemistry in samples obtained from 96 and 24 ESFT patients, respectively. We found that although Notch receptors were highly expressed, Notch did not appear to be active, as evidenced by the absence of Notch receptors in cell nuclei. In contrast, we show that Notch receptors known to be active in colon adenocarcinoma, hepatocarcinoma, and pancreatic carcinoma stain cell nuclei in these tumours. High expression of the Notch effector HES1 transcription factor, usually used as a surrogate marker for active Notch, was also restricted to outside of the nucleus in the majority of ESFT, and analysis of HES1 gene targets indicated HES1 to be transcriptionally inactive. Neither forced activation nor pharmacological or genetic blocking of Notch affected HES1 expression in ESFT cells, indicating HES1 expression to be uncoupled from the Notch pathway. Additional functional studies in ESFT cell lines confirmed Notch to be switched off. Finally, unlike experiments in which HES1 expression was modulated, experimental activation of Notch in ESFT cell lines via several means blocked cell proliferation and reduced their clonogenic potential in soft agar. These indicate that HES1 is uncoupled from Notch in ESFT, that EWS-FLI1-mediated inhibition of Notch contributes to ESFT aggressive cell growth, and support a role for Notch in ESFT tumour suppression, at least partly through the Notch effector HEY1.

Background Until now, only a few mouse-transplanted human tumors or experimental Wilms tumor (WT) cell lines have been described. The aim of this study was to show the biological behavior, including histology, immunohistochemistry (IHC), and molecular biology, of a WT including the original tumor and metastasis transferred into nude mice and followed for successive generations in xenografts. Methods A WT metastasis was xenotransplanted into nude mice and the mice was monitored for 7 passages over a period of 29 months; the original neoplasm was comparatively studied. The morphology was evaluated by optical and electron microscopy. The protein expression was analyzed by immunohistochemistry in whole sections and in tissue microarray. The molecular studies were carried out by multiplex ligation-dependent probe amplification and polymerase chain reaction analysis. Results The histology changed markedly between the fourth and fifth transfer. The tumor exhibited an increased epithelial component (>40%) together with a slowing in the growth rate (8 mo). An epithelial-mesenchymal transition seemed to take place in the fourth passage and increased thereafter. The genetic studies also showed a WT5 deletion and a MYCN gain in all the tumor samples in passage 4 and beyond, but did not show E-cadherin, β-catenin, and APC mutations. Conclusions An epithelial pattern was associated with slow tumor growth, whereas the predominance of mesenchymal spindle cells with striated muscle cell differentiation was related with a high growth rate. The in vivo reorganization of the tumor components (blastemal, epithelial, and mesenchymal) does not seem to be related with the Wnt and EMT pathways.

Background: Superficial/cutaneous Ewing’s sarcoma family of tumors (ESFT) are rare and have a relatively favorable prognosis compared with deep-seated tumors. The aim of the present study is to describe the clinicopathological characteristics of six genetically confirmed ESFT presenting a superficial location. Methods: Clinical data, radiology, histopathology, immunohistochemistry, molecular study [reverse transcriptase-polymerase chain reaction (RT-PCR)/fluorescence in situ hybridization], treatment and follow-up data were retrieved. Results: Locations included fingers (2), back (1), neck (1), thigh (1) and subcutaneous breast (1). Two tumors showed conventional morphology, one consisted of primitive neuroectodermal tumor and three tumors showed atypical vascular morphology with hemosiderin deposition and pigmentation. All cases showed CD99, FLI-1, HNK-1 and CAV-1 positivity. RT-PCR revealed the EWS/Fli1 gene fusion in all cases. Treatment was by wide excision in all cases; one received chemotherapy (CT) and one CT and radiotherapy. Available follow-up revealed the following: two patients with metastasis and death at 5 months and 2 years and one local recurrence at 18 years. Conclusions: Superficial ESFT appears to have a relatively favorable prognosis but further studies with additional series, a larger number of cases and more extensive follow-up are necessary to confirm this statement.

Artículo publicado en: International Journal of Surgical Pathology published online 18 July 2010 The purpose of this study was to examine the immunoexpression of cell adhesion molecules (CAMs) E-cadherin, CD44s, and CD44v3 in cervical cancer and compare it with that in benign exo-endocervical tissue. In all, 81 cervical cancer biopsy specimens and 22 benign controls were included. Primary monoclonal antibodies NHC-38, F10-44-2, and 3G5 for E-cadherin, CD44s, and CD44v3 were used, respectively. Statistical significance was evaluated by the ?2 test. Antigen expression was significantly different in cervical cancer specimens compared with controls, showing marked decrease in membrane expression: E-cadherin, 6.5% and 77.3% (P < .000); CD44s, 3.9% and 81.8% (P < .000); and CD44v3, 0% and 81.8% (P < .000), respectively. The immunoexpression was significantly heterogeneous in carcinomas (P < .034) and adenocarcinomas (P < .000) for E-cadherin and CD44s. For CD44v3, no case of cancer showed immunostaining in membranes. These findings reaffirm that cell adhesion is markedly altered in cervical cancer. The authors suggest that these proteins could serve as markers for invasive cervical neoplasia. tmorelva@ula.ve antonio.llombart@uv.es

Resumen Los tumores del estroma gastrointestinal (GIST) hasta 1998 fueron catalogados bajo otras designaciones o entidades (leiomioma, leiomioblastoma, o leiomiosarcoma), atendiendo a su apariencia histologica, sin embargo, los avances en la biologia molecular y la inmunohistoquimica en la ultima decada del siglo xx han permitido diferenciarlos y definirlos como una entidad clinica e histopatologica propia. En el trabajo se presenta una serie retrospectiva, de 39 casos diagnosticados dentro del grupo de tumores del musculo liso (entre 1984 y 1998), previo al descubrimiento de CD117 y su posterior reubicacion con la ayuda del marcador anteriormente mencionado y el estudio mutacional de c-KIT y PDGFRα. Finalmente, 30 casos han sido redefinidos diagnosticamente como GIST y 9 se mantuvieron con el diagnostico inicial.

To compare the sensitivity and specificity of fluorescence in situ hybridization (FISH) with reverse transcription polymerase chain reaction (RT-PCR) in the diagnosis of Ewing sarcoma family of tumors (ESFTs) and other small round-cell tumors (SRCTs) in formalin-fixed paraffin-embedded tissue assembled in tissue microarrays (TMAs). The second objective is to confirm the value of molecular methods and immunohistochemical (IHC) assays, to perform a differential diagnosis between ESFTs and SRCTs with similar or overlapping morphology.A total of 560 cases were selected for the present study out the 806 cases collected from the PROgnosis and THerapeutic Targets in the Ewing's Family of TumorS project. Case selection bias included only the cases with enough material to enable the TMA construction, as FISH analysis and the majority of IHC studies were performed in TMAs. Histopathologic, IHC, and molecular assays were carried out.Of the 560 total cases, 411 (73.4%) were considered informative (with results by FISH and/or RT-PCR assays). From the informative cases, 382 (92.9%) were diagnosed as ESFT, 23 cases (5.6%) as non-ESFT but with specific diagnosis for another established entity, and 6 cases (1.5%) as small round cell tumors not otherwise specified. Sensitivity and specificity for the FISH assays was 96.3% and 95.2%, respectively, whereas RT-PCR presented a sensitivity of 97.5% and specificity of 92.9%. In concordant cases, both methods showed a sensitivity and specificity of 99.2% and 100%, respectively. Twenty-nine cases (7.1%) initially interpreted at morphologic level as atypical ESFTs were finally reclassified, with the support of molecular methods and IHC, as either non-ESFT with another specific histologic type or as small round cell tumors not otherwise specified.FISH and RT-PCR are ancillary techniques possessing high sensitivity in the diagnosis of ESFT; nevertheless, FISH is more specific than RT-PCR in the diagnosis of formalin-fixed paraffin-embedded tissue. Both methods in combination displayed the highest sensitivity and specificity. The combination of histopathologic, IHC, and molecular findings is the method of choice for the diagnosis of ESFT, as well as for the differential diagnosis with other SRCTs.

Ewing sarcoma is a highly aggressive malignant bone tumor occurring preferentially in children and young adults. At present, only clinical features, such as patient age, presence of clinically evident metastases at diagnosis, and poor response to neoadjuvant chemotherapy, are widely accepted as prognostic indicators in Ewing sarcoma. In this study, we assessed the prognostic value of CCN3 (Nov), a matricellular protein that play crucial roles in bone formation. Polyclonal antibodies directed against each of the different CCN3 modules were used to identify variant CCN3 proteins in tumors and to draw potential relationships between the expression of these variants and the outcome of patients with Ewing sarcoma. Our results confirmed that expression of the full-length CCN3 in Ewing sarcoma is associated to a worse prognostic. Furthermore, we report a possible relationship between the expression of a CCN3 protein lacking an internal module (von Willebrand factor type C) and sensitivity to radiotherapy. We hypothesize that the increased level of variant CCN3 in the tumor cells reduces their tumorigenic potential and results in better outcome.

Artículo publicado en: Virchows Arch (2009) 455:235–243. DOI 10.1007/s00428-009-0818-7 Ubiquitin and telomerase immunohistochemical expression patterns in cervical cancer were compared with normal cervical tissue samples. Eighty-one cervical cancer cases and 22 normal exo–endocervical tissue were examined with polyclonal antibody for ubiquitin and 44G12 clone for telomerase using tissue microarrays. The results were interpreted using a semiquantitative scale The average age of patients was 50.67 years. The most frequent histological types were moderately differentiated epidermoid carcinoma (43.5%), according to the degree of differentiation, and endocervical adenocarcinoma (42.1%). Immunohistochemical findings were as follows: 98.7% of cervical cancers showed immunoexpression for ubiquitin and 52.6% for telomerase. Statistically significant differences were found in tumor immunoreactivity when compared with control tissue (p

Inflammatory fibroid polyp (IFP) is a benign reactive uncommon submucosal lesion of the gastrointestinal tract, the small intestine being the most common site of origin. Histologically, IFPs are characterized by spindle cells, a heavy inflammatory infiltrate including eosinophils and onion-sheet-like formation of lesional cells around blood vessels. We present a case report of an IFP harboring an activation mutation in the PDGFR alpha gene. The lesion was positive for CD34, PDGFR alpha, and p-PDGFR alpha immunostaining but was negative for c-KIT and desmin. After a sequencing analysis of KIT and PDGFR alpha, a mutation consisting of an in-frame deletion of codons 567-571 and a missense mutation in codon 566 (S566R) of PDGFR alpha was observed. This mutation could activate key cellular pathways with involvement in the pathogenesis of this entity. We concluded that more studies are necessary in order to clarify if this finding is a biologically distinct behavior or, on the contrary, represents a specific feature of the IFP.

We report two cases of malignant peripheral nerve sheath tumor (MPNST) in an uncommon location (heart and retropharynx) both with divergent osseous heterologous differentiation. We present the pathological and immunohistochemical studies that confirmed the neurogenic origin. The histopathology of the tumor arising in the retropharynx showed a transition from a neurofibroma to MPNST, making this a new report of an MPNST arising from a plexiform neurofibroma without neurofibromatosis. Primary cardiac MPNST with osseous differentiation has never been reported before. In conclusion, the histology of MPNSTs is very heterogeneous, showing no specific diagnostic immunoprofile or genetic alteration. Thus, it is important to rule out other histologically similar tumors, particularly in cases arising in uncommon locations or tumors with divergent heterologous differentiation.