Paola Collini

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Lombardy, Italy

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Publications (190)796.85 Total impact

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    ABSTRACT: Purpose: Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor that is frequently difficult to distinguish among other childhood renal tumors due to its histological heterogeneity. This work evaluates genetic abnormalities carried by a series of CCSK samples by whole transcriptome sequencing (WTS), to identify molecular biomarkers that could improve the diagnostic process. Methods: WTS was performed on tumor RNA from 8 patients with CCSK. Bioinformatic analysis, with implementation of a pipeline for detection of intragenic rearrangements, was executed. Sanger sequencing and gene expression were evaluated to validate BCOR internal tandem duplication (ITD). Results: WTS did not identify any shared SNVs, Ins/Del or fusion event. Conversely, analysis of intragenic rearrangements enabled the detection of a breakpoint within BCOR transcript recurrent in all samples. Three different in-frame ITD in exon15 of BCOR, were detected. The presence of the ITD was confirmed on tumor DNA and cDNA, and resulted in overexpression of BCOR. Conclusion: WTS coupled with specific bioinformatic analysis is able to detect rare genetic events, as intragenic rearrangements. ITD in the last exon of BCOR is recurrent in all CCSK samples analyzed, representing a valuable molecular marker to improve diagnosis of this rare childhood renal tumor.
    Oncotarget 10/2015; DOI:10.18632/oncotarget.5882 · 6.36 Impact Factor
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    ABSTRACT: Multiple primary malignant neoplasms are rare entities in the clinical setting, but represent an important issue in the clinical management of patients since they could be expression of a genetic predisposition to malignancy. A high resolution genome wide array CGH led us to identify the first case of a de novo constitutional deletion confined to the FBXW7 gene, a well known tumor suppressor, in a patient with a syndromic phenotype characterized by focal segmental glomerulosclerosis and multiple primary early/atypical onset tumors, including Hodgkin's lymphoma, Wilms tumor and breast cancer. Other genetic defects may be associated with patient's phenotype. In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay. Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases.
    Scientific Reports 10/2015; 5:15454. DOI:10.1038/srep15454 · 5.58 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):3268-3268. DOI:10.1158/1538-7445.AM2015-3268 · 9.33 Impact Factor
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    ABSTRACT: Conventional skeletal chondrosarcoma is a bone neoplasm, which is poorly sensitive to anthracyclines-based chemotherapy. We report on an 18-month-long tumour response to gemcitabine as single agent in a young patient with an advanced secondary peripheral conventional chondrosarcoma, previously treated unsuccessfully with anthracyclines, ifosfamide, platinum, etoposide.
    03/2015; 2015(5):9. DOI:10.1186/s13569-015-0025-z
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    ABSTRACT: The aim of the present work was to improve the understanding of the impact of malignancy grade and myogenic/rhabdomyoblastic differentiation on the natural course of retroperitoneal liposarcoma. All consecutive patients affected by primary well-differentiated (WD)/dedifferentiated (DD) retroperitoneal liposarcoma, surgically treated at our institution between January 2002 and December 2011, were retrospectively evaluated. Tumors were stained for mdm2 and 5 myogenic markers (smooth muscle actin-α, h-caldesmon, calponin, desmin, myogenin). The French National Federation of the Centers for the Fight Against Cancer (FNCLCC) grading system was applied. Overall survival, crude cumulative incidence of local recurrence, and distant metastases were calculated. Multivariable analyses were carried out. A total of 144 patients were identified. Median follow-up was 68 months (interquartile range: 46 to 104 mo). Fifty-two patients were affected by WD/G1 and 92 by DD liposarcoma. Among the latter, 60 were grade G2 and 32 G3. Myogenic differentiation was present in 54 cases (8/52 WD/G1, 27/60 DD/G2, 18/32 DD/G3). Seven cases had a rhabdomyoblastic DD component (1/60 DD/G2 and 6/32 DD/G3). Five-year overall survival rates were 93%, 57%, and 21% for WD/G1 liposarcoma, G2 DD, and G3 DD liposarcoma, respectively, and 75%, 42%, and 29% for liposarcoma without myogenic differentiation, with myogenic differentiation, with rhabdomyoblastic differentiation, respectively (P<0.001). Of note, 5/6 patients affected by G3 DD liposarcoma with a rhabdomyoblastic component died within 8 months. FNCLCC grade and myogenic differentiation significantly predicted the outcome of retroperitoneal liposarcoma. These should be factored into treatment decision-making and possibly used to stratify patients in clinical trials.
    American Journal of Surgical Pathology 01/2015; 39(3). DOI:10.1097/PAS.0000000000000366 · 5.15 Impact Factor
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    ABSTRACT: Background Salivary gland carcinomas are extremely rare in pediatric age. We report the clinical features of a series of children/adolescents with salivary gland carcinomas prospectively registered in the Italian TREP (Rare Tumors in Pediatric Age) project.ProceduresDiagnostic/therapeutic guidelines were developed and shared among Italian pediatric oncology/surgical centers.ResultsSeventeen patients were registered between 2000 and 2012, representing 19% of the cases expected to be seen based on epidemiological data. Tumors arose mainly in the parotid gland (14 cases). In most cases they were low-grade tumors (14 cases), often with a favorable clinical presentation, and low-stage disease. All patients underwent surgical resection, achieving histologically free margins in 9/17 cases. Thirteen of the 14 patients with parotid gland tumors had parotidectomy (10 total, 3 superficial), while one had a tumorectomy. Postoperative facial nerve lesions were reported in two cases. Adjuvant radiotherapy was given to 6 patients. The overall prognosis was good: only one patient with a huge high-grade tumor experienced disease progression and died of the disease. The other 16 patients were alive in first continuous remission 1–8 years after diagnosis. In 4/17 cases, the salivary gland carcinoma was a second tumor occurring 6–9 years after another primary cancer.Conclusions This is the first reported prospective national cooperative series of pediatric salivary gland carcinoma patients. Compliance with the TREP recommendations was high. These tumors are rarely managed by pediatric oncologists/surgeons. A broader international cooperation and better networking with otolaryngologists and head-neck surgeons expert on adult salivary gland carcinomas would be advisable. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 11/2014; 61(11). DOI:10.1002/pbc.25139 · 2.39 Impact Factor
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    ABSTRACT: Diagnosis and proper management of atypical Spitz tumors in pediatric age are still controversial. We sought to investigate the clinicopathological and molecular features of atypical Spitz tumors in patients aged 18 years or younger. We performed a retrospective clinicopathological and fluorescence in situ hybridization study on 50 pediatric atypical Spitz tumors. Parameters that were significantly correlated with a diagnosis of atypical Spitz tumors over Spitz nevus included asymmetry, level IV/V, lack of maturation, solid growth, nuclear pleomorphism, high nuclear-cytoplasmic ratio, atypical and deep mitoses, and more than 6 mitoses/mm(2). In the atypical Spitz tumors group, a significantly higher mitotic rate was observed in prepuberal age (P = .04). The 4-probe fluorescence in situ hybridization melanoma assay did not discriminate atypical Spitz tumors from Spitz nevi. Heterozygous 9p21 loss was found in 3 of 37 cases and homozygous 9p21 loss in 2 of 37 cases. Only 1 child experienced a fatal outcome, showing genetic abnormalities by melanoma fluorescence in situ hybridization probe and a heterozygous 9p21 deletion. The limited number of adverse outcomes did not allow the prognostic analysis of single morphologic features. Pediatric atypical Spitz tumors are associated with minimal lethal potential. Atypical Spitz tumors require complete excision and careful follow-up while our data do not support any clinical benefit for the sentinel lymph node biopsy procedure and completion lymphadenectomy. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
    Journal of the American Academy of Dermatology 10/2014; 72(1). DOI:10.1016/j.jaad.2014.09.049 · 4.45 Impact Factor
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    ABSTRACT: Aim of study was to assess the correlation between computed tomography scan (CT) findings and histopathology. Data were collected on consecutive patients with suspected retroperitoneal sarcoma (RPS) referred to a tertiary sarcoma center. Patients underwent contrast enhanced multi-detector CT scans. Radiological features of lesions were classified according to the presence of a fatty (Group A) mass, or non-fatty (Group B) mass, both subdivided according to homogeneity and intralesional high-contrasted appearance. Radiological classification was compared with histopathological diagnosis. Sensitivity, specificity, positive/negative predictive value (PPV, NPV) were analyzed. Of 291 patients, 103/291 (35.4%) masses were classified in Group A and 188/291 (64.6%) in Group B. Diagnosis of mesenchymal tumor was obtained in 231/291 cases (79%) and non-mesenchymal tumor in 60/291 (21%). Sensitivity and specificity of Group A for liposarcoma were 76.7% and 92.0%; PPV and NPV were 86.4% and 85.6%. Sensitivity of Group B for a mesenchymal tumor was 55.4% and specificity was 0%; PPV and NPV were 68.1% and 0%. None of radiological criteria were sufficient to anticipate a specific diagnosis, with the only exception of well differentiated liposarcoma and angiomyolipoma. In a series of suspected RPS, 21% of the lesions were finally non-mesenchymal tumors. Copyright © 2014 Elsevier Ltd. All rights reserved.
    European Journal of Surgical Oncology 10/2014; 40(12). DOI:10.1016/j.ejso.2014.10.005 · 3.01 Impact Factor
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    ABSTRACT: Papillary thyroid carcinoma (PTC), tall cell (TC) variant, is exceptional in children. In adults it represents about 20% of PTCs, featuring a high-risk neoplasm, with a 4-fold risk of relapse and a 20-fold relapse-related risk of death. Out of 42 cases of pediatric PTCs, we found 3 cases of PTC-TC (7%) with clinical data at onset and follow-up up to June 2014. They were 3 females aged 13, 15, and 15 years. Local extrathyroid extension was present in 2 cases. Neither nodal nor distant metastases were found. Two patients underwent hemithyroidectomy and 1 patient a total thyroidectomy, followed in all cases by life-long suppressive hormonal therapy. On follow-up, the patients were alive and well after 29, 24, and 29 years, respectively. The rarity of PTC-TC in children was confirmed. The behavior was indolent after a median follow-up of about 29 years, following treatment with hemithyroidectomy in 2 cases and controlled by suppressive hormonal therapy. The results of this series, albeit small, suggest that TC morphology in PTC does not carry the same negative prognostic significance in children as it does in adults. A conservative approach should therefore be considered for these 'pediatric type' cases of this tumor type.
    International Journal of Surgical Pathology 09/2014; 22(6):499-504. DOI:10.1177/1066896914545399 · 0.95 Impact Factor

  • Pediatric Blood & Cancer 09/2014; 61(9). DOI:10.1002/pbc.24876 · 2.39 Impact Factor
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    ABSTRACT: With improvements in the survival rates after childhood cancer, many clinicians have turned their attention to reporting on late effects, and how they might be prevented or treated. In childhood the thyroid gland is especially vulnerable to the carcinogenic action of ionizing radiation. This retrospective study focused on secondary thyroid cancers seen at our institution over more than 30 years (between 1980 and 2012) in patients treated for other malignancies in pediatric age. 36 patients were identified. In most cases, the primary cancer had been Hodgkin disease, and all the patients had been administered radiotherapy for their first malignancy. The secondary thyroid cancers were treated with total thyroidectomy in 27 cases (six with lymphadenectomy), and hemithyroidectomy in nine (one with lymphadenectomy). 12 Patients were also given radiometabolic therapy. All but two had TSH suppression therapy. The histological diagnoses were: 31 papillary and five follicular carcinomas. At 5 and 10 years, the OS was 100 and 95 %, respectively, and the PFS was 96 and 83 %. None of the patients died of their thyroid disease. Nodal involvement at onset was the only factor correlating with recurrence. Surgical sequelae only occurred in patients who underwent total thyroidectomy. Survival in these patients did not depend on the extent of surgery on the thyroid parenchyma. Our data confirm a good prognosis for secondary thyroid cancer, prompting us to encourage a minimalist approach to the treatment of these particular patients wherever possible.
    Medical Oncology 08/2014; 31(8):121. DOI:10.1007/s12032-014-0121-6 · 2.63 Impact Factor
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    Journal of Pediatric Surgery 08/2014; 49(8):1341. DOI:10.1016/j.jpedsurg.2014.06.006 · 1.39 Impact Factor
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    ABSTRACT: Background Association of melanoma, neural system tumors and germ line mutations at the 9p21 region in the CDKN2A, CDKN2B and CDKN2BAS genes has been reported in a small number of families worldwide and described as a discrete syndrome in melanoma families registered as a rare disease, the melanoma–astrocytoma syndrome. Case presentation We here studied two young patients developing melanoma after radiotherapy for astrocytoma, both reporting lack of family history for melanoma or neural system tumors at genetic counselling. Patient A is a girl treated for anaplastic astrocytoma at 10 years and for multiple melanomas on the scalp associated to dysplastic nevi two years later. Her monozygotic twin sister carried dysplastic nevi and a slow growing, untreated cerebral lesion. Direct sequencing analysis showed no alterations in melanoma susceptibility genes including CDKN2A, CDK4, MC1R and MITF or in TP53. By microsatellite analysis, multiplex ligation-dependent probe amplification, and array comparative genomic hybridization a deletion including the CDKN2A, CDKN2B and CDKN2BAS gene cluster was detected in both twin sisters, encompassing a large region at 9p21.3 and occurring de novo after the loss of one paternal allele. Patient B is a boy of 7 years when treated for astrocytoma then developing melanoma associated to congenital nevi on the head 10 years later: sequencing and multiplex ligation-dependent probe amplification revealed a normal profile of the CDKN2A/CDKN2B/CDKN2BAS region. Array comparative genomic hybridization confirmed the absence of deletions at 9p21.3 and failed to reveal known pathogenic copy number variations. Conclusions By comparison with the other germ line deletions at the CDKN2A, CDKN2B and CDKN2BAS gene cluster reported in melanoma susceptible families, the deletion detected in the two sisters is peculiar for its de novo origin and for its extension, as it represents the largest constitutive deletion at 9p21.3 region identified so far. In addition, the two studied cases add to other evidence indicating association of melanoma with exposure to ionizing radiation and with second neoplasm after childhood cancer. Melanoma should be considered in the monitoring of pigmented lesions in young cancer patients.
    BMC Medical Genetics 05/2014; 15(1):59. DOI:10.1186/1471-2350-15-59 · 2.08 Impact Factor
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    ABSTRACT: Rhabdomyosarcoma (RMS) is a pediatric myogenic-derived soft tissue sarcoma that includes two major histopathological subtypes: embryonal and alveolar. The majority of alveolar RMS expresses PAX3-FOXO1 fusion oncoprotein, associated with the worst prognosis. RMS cells show myogenic markers expression but are unable to terminally differentiate. The Notch signaling pathway is a master player during myogenesis, with Notch1 activation sustaining myoblast expansion and Notch3 activation inhibiting myoblast fusion and differentiation. Accordingly, Notch1 signaling is up-regulated and activated in embryonal RMS samples and supports the proliferation of tumor cells. However, it is unable to control their differentiation properties. We previously reported that Notch3 is activated in RMS cell lines, of both alveolar and embryonal subtype, and acts by inhibiting differentiation. Moreover, Notch3 depletion reduces PAX3-FOXO1 alveolar RMS tumor growth in vivo. However, whether Notch3 activation also sustains the proliferation of RMS cells remained unclear. To address this question, we forced the expression of the activated form of Notch3, Notch3IC, in the RH30 and RH41 PAX3-FOXO1-positive alveolar and in the RD embryonal RMS cell lines and studied the proliferation of these cells. We show that, in all three cell lines tested, Notch3IC over-expression stimulates in vitro cell proliferation and prevents the effects of pharmacological Notch inhibition. Furthermore, Notch3IC further increases RH30 cell growth in vivo. Interestingly, knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation. Finally, the expression of Notch3IC and its target gene HES1 correlates with that of the proliferative marker Ki67 in a small cohort of primary PAX-FOXO1 alveolar RMS samples. These results strongly suggest that high levels of Notch3 activation increase the proliferative potential of RMS cells.
    PLoS ONE 05/2014; 9(5):e96238. DOI:10.1371/journal.pone.0096238 · 3.23 Impact Factor
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    ABSTRACT: The survival of patients with axial skeletal or pelvic osteosarcoma (OS) remains poor, and the management of these patients is challenging. The object of this study is a cohort of unselected patients aged < 19 years with primary high-grade pelvic/axial OS. Patients were treated with high-dose methotrexate, doxorubicin, cisplatin, ifosfamide followed or preceded by local treatment (surgery and/or radiotherapy). Twenty patients aged 3-19 years were treated. Eight patients had pelvic OS, 8 axial OS and 4 mandible/maxilla OS. All patients received chemotherapy, after which necrosis was evaluable in 9 patients (≥90 % in 3). Sixteen patients underwent surgery. Radiotherapy was administered to 8 patients (total dose 34-60 Gy). The median follow-up was 35 months (8-276), and the 5-year disease-free survival and overall survival rates were 37 and 40 %, respectively. Six patients were alive at the time of this report: 2 with pelvic OS (both responded well to chemotherapy, one underwent hemipelvectomy and the other had non-radical surgery plus radiotherapy); 1 with axial and multicentric OS (with a good histological response and radical surgery); 3 with mandible/maxilla OS. Two patients died of secondary tumors (one bone and one breast cancer). It is worth noting that 4 patients had a p53 mutation: 1 is alive, 2 died of their OS, 1 of breast cancer. Adequacy of local treatment and pathological response influenced the prognosis for axial OS, which remained dismal. A high incidence of p53 mutation emerged in our series of patients.
    Medical Oncology 04/2014; 31(4):875. DOI:10.1007/s12032-014-0875-x · 2.63 Impact Factor
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    ABSTRACT: Large intrathoracic tumors may occasionally present with massive infiltration of the lung and chest wall that would require pneumonectomy and total removal of the rib cage to obtain radical surgical excision, but this operation carries a prohibitive risk of death for cardiopulmonary failure in the absence of adequate chest wall reconstruction. We report here four consecutive cases of thoracopleuropneumonectomy (TPP) with en-bloc resection of the entire lung, chest wall, and diaphragm and immediate riblike reconstruction for recurrent thoracic sarcomas. Patients had undergone the initial thoracic surgical resection with curative intent 2-14 years before TPP. There was no postoperative mortality, and all patients were alive and free of disease 8-21 months after TPP. To our knowledge, this is the first report in the medical literature of such an extensive operation, demonstrating technical feasibility, tolerability, and efficacy of one-stage resection and reconstruction by a semirigid three-dimensional riblike prosthesis modeled on a human-derived aluminum cast. Selected patients with advanced low-intermediate thoracic sarcomas are the ideal candidates for this extreme procedure, to maximize the chance of long-term tumor control and possibly cure.
    Annals of Surgical Oncology 01/2014; 21(5). DOI:10.1245/s10434-014-3485-0 · 3.93 Impact Factor

  • 11th Annual ENETS Conference for the Diagnosis and Treatment of; 01/2014
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    PLoS ONE 01/2014; · 3.23 Impact Factor
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    ABSTRACT: AimsEwing sarcoma primary to the ileum (IES) has rarely been documented. Little is known about the pathogenesis and clinical implications of IES, which may be critical to identify novel molecular markers. EWSR1-FEV translocation is exceedingly rare in ES, as FEV expression is restricted to prostate, brain, and serotonin neuroendocrine cells (NE) and related tumors. Methods and resultsParaffin sections or snap-frozen material was used in this investigation. Tumors were investigated by means of immunohistochemistry, RT-PCR (EWSR1-FLI1, EWSR1-ERG and EWSR1-FEV transcripts), FISH analysis (EWSR1 break-apart and specific EWSR1-FEV translocation) and spectral karyotyping (SKY). Ten ileum neuroendocrine tumors (INET) made up the control group for EWSR1-FEV translocation.Among 445 ES cases spanning a period of 20 years, seven (1.6%) were IES. All tumors were immunoreactive for synaptophysin, CD99, FLI 1 and vimentin. FISH identified EWSR1 rearrangement in all cases, with EWSR1-FLI1 transcripts being detected in all but one tumor showing the uncommon EWSR1-FEV rearrangement upon SKY, RT-PCR and FISH confirmation. The mean survival of EWSR1-FLI1 patients was 14 months, whereas the EWSR1-FEV patient was alive after 15 years despite several recurrences controlled by surgery alone. No INET showed EWSR1 translocation. Conclusions Most IES share the common EWSR1-FLI1 translocation, but EWSR1-FEV could be specific of tumors arising in the ileum and showing better prognosis.This article is protected by copyright. All rights reserved.
    Histopathology 12/2013; 64(7). DOI:10.1111/his.12350 · 3.45 Impact Factor
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    ABSTRACT: The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.Oncogene advance online publication, 11 November 2013; doi:10.1038/onc.2013.471.
    Oncogene 11/2013; 33(32). DOI:10.1038/onc.2013.471 · 8.46 Impact Factor

Publication Stats

5k Citations
796.85 Total Impact Points


  • 1998-2015
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      • • s.c. Medicina Nucleare
      • • s.c. Pediatria Oncologica
      Milano, Lombardy, Italy
  • 2007-2012
    • CRO Centro di Riferimento Oncologico di Aviano
      • Division of Pathology
      Aviano, Friuli Venezia Giulia, Italy
  • 1993-2012
    • Istituto Nazionale Tumori "Fondazione Pascale"
      Napoli, Campania, Italy
  • 1994-2011
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
      Meldola, Emilia-Romagna, Italy
  • 2009
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 2002
    • University of Ferrara
      • Sezione di Endocrinologia
      Ferrare, Emilia-Romagna, Italy