ABSTRACT
The aim of the study was to assess incidence rate, hormonal activity, and local invasiveness and evaluate outcomes of so-diagnosed atypical pituitary adenomas that underwent endoscopic endonasal surgery at the Division of Neurosurgery of Università degli Studi di Napoli Federico II. According to the 2004 WHO classification, atypical pituitary adenomas are defined by an invasive growth, Ki-67/MIB-1 proliferative index greater than 3 %, high p53 immunoreactivity, and increased mitotic activity. A retrospective analysis of a series of 434 pituitary adenomas that underwent endoscopic endonasal surgery at our department between March 2007 and February 2013 was performed. Fifty adenomas (11.5 %) met the criteria of diagnosis of atypical lesions; 10 (21.6 %) of the 50 patients were recurrent tumors with a previous transsphenoidal surgery. Forty-one (82 %) were macroadenomas, and 21/50 (42 %) showed a clear invasion of the cavernous sinus. Histotype of atypical adenomas figured out to be nonfunctioning in 23 cases (46 %), PRL secreting in 10 cases (20 %), ACTH secreting and GH secreting each apart in 8 patients (16 %), and in a single case a GH/PRL secreting adenoma (2 %). The Ki-67 labeling index ranged from 3.5 to 22.5 % (mean 5.6 %). Tumor recurrence was observed in six cases (12 %) after a mean time of 18 months (range 9-24 months). Mean follow-up was 36.5 months (range 2-80 months). Atypical pituitary adenomas account for ca. 10 % of all pituitary adenomas; these lesions have peculiar features. It should be considered that a strong immunopositivity of p53 and higher Ki-67 LI could predict an increased risk of tumor recurrence, but more studies and larger series are expected to confirm and enlarge the diagnostic and therapeutic management process of these lesions.
Subject(s)
Adenoma/surgery , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/surgery , Neurosurgical Procedures , Pituitary Neoplasms/diagnosis , Pituitary Neoplasms/surgery , Adenoma/pathology , Adolescent , Adult , Aged , Endoscopy/methods , Female , Humans , Ki-67 Antigen/metabolism , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Pituitary Neoplasms/pathology , Prognosis , Retrospective Studies , Tumor Suppressor Protein p53/metabolism , Young AdultABSTRACT
PURPOSE: To compare the use of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) with the use of a combination of ultrasonography (US) and chest radiography for systematic follow-up of patients with high-risk Hodgkin lymphoma. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. In a single center between January 2001 and December 2009, patients with advanced-stage Hodgkin lymphoma who had responded completely to first-line treatment were randomly assigned (1:1) to follow-up with either PET/CT or US/chest radiography. Follow-up included clinical and imaging procedures at 4, 8, 12, 16, 20, 24, 30, 36, 48, 60, 84, and 108 months after treatment discontinuation. When clinical and/or imaging results were positive, recurrence was confirmed histologically. The primary endpoint was to compare the sensitivity of the two follow-up imaging approaches. Secondary endpoints were their specificity, positive and negative predictive values, time to recurrence detection, radiation risks, and costs. RESULTS: A total of 300 patients were randomized into the two arms. The study was closed after a median follow-up time of 60 months, with a relapse rate of 27%. Sensitivity for detection of Hodgkin lymphoma was similar for the two follow-up approaches. All of the relapses (40 of 40) were identified with FDG PET/CT (100%) and 39 of 40 relapses were identified with US/chest radiography (97.5%; P = .0001 for the equivalence test). US/chest radiography showed significantly higher specificity and positive predictive value than did PET/CT (96% [106 of 110] vs 86% [95 of 110], respectively; P = .02; and 91% [39 of 43] vs 73% [40 of 55], respectively; P = .01). Exposure to ionizing radiation was estimated to be 14.5 mSv for one PET/CT examination versus 0.1 mSv for one chest radiographic examination. Estimated cost per relapse diagnosed with routine PET/CT was 10-fold higher compared with that diagnosed with routine US/chest radiography. CONCLUSION: US and chest radiography are diagnostic tools that enable effective, safe, and low-cost routine surveillance imaging for patients at high risk of Hodgkin lymphoma relapse.
Subject(s)
Hodgkin Disease/diagnostic imaging , Neoplasm Recurrence, Local/diagnostic imaging , Adolescent , Adult , Aged , Algorithms , Combined Modality Therapy , Female , Fluorodeoxyglucose F18 , Hodgkin Disease/pathology , Hodgkin Disease/therapy , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Positron-Emission Tomography , Radiation Dosage , Radiopharmaceuticals , Sensitivity and Specificity , Tomography, X-Ray Computed , Ultrasonography, DopplerABSTRACT
Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with increased risk of embryonal tumors, such as Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma. We report on a patient with BWS that developed a giant fibroadenoma of the breast that was surgically removed. The tumor relapsed 8 months after the surgery and the patient underwent partial mastectomy. Although the patient presented several clinical features of BWS, a molecular diagnosis was not achieved despite extensive molecular investigations on both blood and tumor tissue. A SNP array revealed a de novo 7p22.1 loss in both blood and breast tumor involving the mismatch repair gene PMS2 gene that may be potentially associated with the breast tumor. In conclusion, it remains unclear whether BWS patients have an increased risk of breast lesions or a yet unknown molecular defect is responsible for the rare occurrence of this tumor in BWS.
Subject(s)
Beckwith-Wiedemann Syndrome/complications , Breast Neoplasms/complications , Adolescent , Beckwith-Wiedemann Syndrome/diagnosis , Breast Neoplasms/diagnosis , Breast Neoplasms/surgery , Chromosome Aberrations , Comparative Genomic Hybridization , DNA Methylation , Female , Fibrosis , Humans , HyperplasiaABSTRACT
BACKGROUND: Polymorphous hemangioendothelioma is a rare vascular tumor of borderline malignant potential and only 10 cases have been described in the literature so far. METHODS AND RESULTS: We report a case of nodal and extranodal polymorphous hemangioendothelioma and review the literature. A 66-year-old man with an unremarkable past medical history was admitted for a left submandibular mass. The main nodule was composed of angiosarcoma-like areas mixed with angiomatous features; some vascular spaces with hobnail endothelium were seen. The tumor involved two adjacent lymph nodes. Immunohistochemically, the neoplastic cells were strongly positive for CD31 and vimentin. After a few months the tumor recurred and the patient was treated with radiation therapy. CONCLUSIONS: Polymorphous hemangioendothelioma is a distinct entity in the hemangioendothelioma group with its own clinical and histological features.
Subject(s)
Hemangioendothelioma/pathology , Lymph Nodes/pathology , Soft Tissue Neoplasms/pathology , Aged , Biopsy, Fine-Needle , Hemangioendothelioma/metabolism , Hemangioendothelioma/therapy , Humans , Immunohistochemistry , Male , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Oral Surgical Procedures , Radiotherapy , Soft Tissue Neoplasms/metabolism , Soft Tissue Neoplasms/therapyABSTRACT
BACKGROUND: Gastrointestinal stromal tumors (GIST) exhibit an unpredictable clinical course and can rapidly progress to lethality. Predictions about the biological behavior of GIST are based on a number of canonical clinical and pathologic parameters whose validity in distinguishing between a benign and a malignant tumour is still imperfect. The aim of our study was to investigate the role of morphologic parameters and expression of cells cycle regulators as prognosticators in GIST. METHODS: We performed an immunohistochemical analysis for Ki67, p27Kip1, Jab1, and Skp2, on a Tissue Microarray (TMA) containing 94 GIST. Expression of the above proteins was correlated to classically used prognosticators, as well as to risk groups. Clinical significance of histologic and immunohistochemical features were evaluated in 59 patients for whom follow-up information was available. RESULTS: Overexpression of Ki67 and Skp2, and p27Kip1 loss directly correlated with the high risk group (p = 0.03 for Ki67 and Skp2, p = 0.05 for p27Kip1). Jab1 expression did not exhibit correlation with risk. In 59 cases provided with clinical follow-up, high cellularity, presence of necrosis, and Ki67 overexpression were predictive of a reduced overall survival in a univariate model. The same parameters, as well as mitotic rate, tumour size, and p27Kip1 loss were indicative of a shortened relapse free survival interval. High cellularity, and high mitotic rate retained their prognostic significance by multivariate analysis. CONCLUSION: Our data suggest that a number of histologic parameters in combination with immunohistochemical expression of cell cycle regulators can facilitate risk categorization and predict biologic behavior in GIST. Importantly this study demonstrates, for the first time, that Skp2 expression correlates with Ki67 expression and high risk in GIST.
Subject(s)
Biomarkers, Tumor/biosynthesis , Gastrointestinal Stromal Tumors/metabolism , Ki-67 Antigen/biosynthesis , S-Phase Kinase-Associated Proteins/biosynthesis , Adult , Aged , Aged, 80 and over , COP9 Signalosome Complex , Cyclin-Dependent Kinase Inhibitor p27/biosynthesis , Female , Gastrointestinal Stromal Tumors/pathology , Humans , Immunohistochemistry , Intracellular Signaling Peptides and Proteins , Male , Middle Aged , Peptide Hydrolases/biosynthesis , Risk FactorsABSTRACT
Cylooxygenase-2 (Cox-2) inhibitors have increasingly become therapeutic alternatives in some Cox-2-overexpressing neoplasms. As the treatment eligibility for these drugs hinges on Cox-2 expression, Cox-2 immunostaining has recently been widely examined in several malignant neoplasms. However, data on the expression of Cox-2 in Wilms' tumor (WT) are limited. In this study, we examined Cox-2 expression in 40 examples of WT to identify the prognostic impact, to evaluate the effects on tumorigenesis, and to answer the question of whether neoplasms with Cox-2 expression could benefit from treatment with specific Cox-2 inhibitors. Sections from paraffin-embedded tumor samples were immunostained by a standard ABC technique using Cox-2 mouse monoclonal antibody. As in other rare examples reported in the literature, Cox-2 immunoreactivity was analyzed and correlated with histological features and the staging of neoplasms. However, in contrast to other studies, we also evaluated the relation of Cox-2 positivity to age, sex, and survival of patients. The results of this study demonstrated that Cox-2 was ubiquitously expressed in all cases of WT and their neovasculature, independently of the type of neoplasm (tumors with a favorable or unfavorable histology), tissues which constitute the neoplasm (blastemal, mesenchymal and epithelial, heterologous or non-heterologous elements), patient age, sex, or stage of development and survival rate. Thus, Cox-2 inhibitors could be used for treating all cases of WT. Further studies, including molecular investigations, would be useful to confirm our hypotheses.
Subject(s)
Cyclooxygenase 2/biosynthesis , Kidney Neoplasms/enzymology , Kidney Neoplasms/pathology , Wilms Tumor/enzymology , Wilms Tumor/pathology , Child , Child, Preschool , Female , Humans , Immunohistochemistry , Infant , MaleABSTRACT
The expansion of triplet repeat microsatellite sequences is the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders. This finding prompted us to study these sequences in primary breast cancer in which there is evidence of genetic anticipation. We used a PCR/silver stain method to determine whether triplet-repeat instability (TRI) was present in DNA from malignant breast tumors, and analyzed microsatellite instability (MSI) in triplets SCA1, SCA2, SCA3, SCA6, HD, DRPLA and X25-GAA. We studied 54 consecutive primary breast cancers previously analyzed for dinucleotide instability (DI) at 9 loci. Microsatellite instability (TRI and/or DI) was found in 28/54 (52%) cases, ranging from 0 to 56% in each patient. Dinucleotide instability occurred at > or =2 loci in 19/54 (35%) cases and TRI in 6/54 (11%). Considering single locus instability, we found DI in 26/54 (48%) tumors and TRI in 13/54 (24%). Triplets DRPLA and X25-GAA were most frequently unstable (14% of cases); SCA2 instability was not detected. Interestingly, most tumors with TRI had DI (11/13, 85%). There was a correlation between TRI and DI in the same tumor (42 vs 7% in DI+ and DI- tumors respectively, p=0.0028). Furthermore, TRI appears more frequently associated with lymph node metastases and more advanced clinical stages and more frequent in patients <50 years old, with positive steroidal hormone receptor status, positive p185 and negative p53. These findings are of interest because they demonstrate a relationship between TRI and the clinicopathological characteristics of cancer aggressiveness. Triplet repeat alterations can interfere with gene expression and proteomic functions, which suggests they can play a role in the neoplastic progression of mammary cells. Furthermore, the association of TRI and DI in the same tumor suggests that alterations in the DNA repair gene could culminate in selective phenotypes and breast cancer progression in a considerable number of patients.
Subject(s)
Breast Neoplasms/genetics , Microsatellite Instability , Trinucleotide Repeats , Adult , Aged , Alleles , Breast Neoplasms/blood , Breast Neoplasms/pathology , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , Female , Humans , Male , Middle AgedABSTRACT
Primary childhood germ cell tumors (GCTs) represent a rare and heterogeneous group of tumors that varies in histologic differentiation, age of presentation and clinical outcome. In malignant neoplasms, apoptosis is a prognostic marker and a predictive factor of response to therapy. Therefore, the study of the expression and mutation of molecules involved in the regulation of apoptosis could be useful in order to both predict the clinical outcome and design self-tailored therapeutic approaches. We retrospectively analysed tissue samples of 54 childhood GCTs. The expression of p53 and BAX protein was assessed by immunohistochemistry (IHC). Moreover, we investigated the presence of mutations in the BAX and p53 genes SSCP-PCR and direct sequencing. IHC analysis of BAX protein expression showed that 14 out of 54 tumors (26%) had no BAX protein expression, in the remaining 40 patients (74%) the intensity of BAX was low in 20 patients (37%) and high/intermediate in 20 (37%). BAX was mutated in 6 patients. p53 was expressed in 43 patients (79.6%), was not detectable in the remaining 11 (20.4%) and mutated in only 3 patients. p53 mutational status and expression were not correlated to the overall survival (OS). On the other hand, both IHC score and mutations for BAX were correlated to sacrococcygeal primary localization. BAX mutations were inversely correlated with OS (p=0.0419) while BAX IHC intensity was directly correlated with OS (p=0.0376). The stratification for histotype showed a direct correlation between BAX IHC and OS in both immature teratoma (p=0.045) and mixed malignant GCT (p=0.010) while the correlation was lost in mature teratoma (p=0.300). These results indicate that both mutations and BAX protein levels are useful molecular biological markers for prognosis and clinical management of pediatric GCT.
Subject(s)
Mutation , Neoplasms, Germ Cell and Embryonal/genetics , bcl-2-Associated X Protein/genetics , Adolescent , Child , Child, Preschool , Female , Genes, p53 , Humans , Immunochemistry , Infant , Infant, Newborn , Male , Neoplasms, Germ Cell and Embryonal/metabolism , Neoplasms, Germ Cell and Embryonal/pathology , Phenotype , Prognosis , Retrospective Studies , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Protein p53/genetics , bcl-2-Associated X Protein/biosynthesisABSTRACT
PTEN/MMAC1/TEP1: (hereafter PTEN) is a tumor suppressor gene (located at 10q23) that is frequently mutated or deleted in sporadic human tumors. PTEN encodes a multifunctional phosphatase, which negatively regulates cell growth, migration and survival via the phosphatidylinositol 3'-kinase/AKT signalling pathway. Accordingly, Pten+/- mice develop various types of tumors including teratocarcinomas and teratomas. We have investigated PTEN expression in 60 bioptic specimens of germ cell tumors (32 seminomas, 22 embryonal carcinomas and six teratomas) and 22 intratubular germ cell neoplasias (ITGCN) adjacent to the tumors for PTEN protein and mRNA expression. In total, 10 testicular biopsies were used as controls. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not an early event in testicular tumor development. The loss of PTEN expression occurs mainly at the RNA level as determined by in situ hybridization of cellular mRNA (17/22) but also it may involve some kind of post-transcriptional mechanisms in the remaining 25% of cases. Analysis of microsatellites D10S551, D10S541 and D10S1765 in GCTs (n=22) showed LOH at the PTEN locus at 10q23 in at least 36% of GCTs (three embryonal carcinoma, three seminoma, two teratoma); one seminoma and one embryonal (9%) carcinoma presented an inactivating mutation in the PTEN gene (2/22). Finally, we demonstrated that the phosphatidylinositol 3'-kinase/AKT pathway, which is regulated by the PTEN phosphatase, is crucial in regulating the proliferation of the NT2/D1 embryonal carcinoma cells, and that the cyclin-dependent kinase inhibitor p27(kip1) is a key downstream target of this pathway.
Subject(s)
Cell Transformation, Neoplastic , Genes, Tumor Suppressor , Germinoma/genetics , Phosphoric Monoester Hydrolases/genetics , Testicular Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Animals , Breast Neoplasms , Cell Line, Tumor , Chromosomes, Human, Pair 10 , Female , Flow Cytometry , Humans , In Situ Hybridization , Loss of Heterozygosity , Male , Mice , PTEN Phosphohydrolase , RNA, Messenger/genetics , Testis/cytology , Testis/embryology , Testis/pathologyABSTRACT
OBJECTIVE: The somatic point mutation in the BRAF gene, which results in a valine-to-glutamate substitution at residue 600 (BRAF(V600E)), is an ideal hallmark of papillary thyroid carcinoma (PTC). However, its prevalence is varyingly reported in different studies, and its expression in the follicular variant PTC is controversial, reducing its potential usefulness as diagnostic marker. DESIGN AND METHODS: We developed an assay based on mutant allele-specific PCR amplification (MASA) to detect BRAF mutation. We compared the sensitivity of MASA, single-strand conformation polymorphism (SSCP) and direct DNA sequencing of PCR products. Then, we used MASA 78 to analyze 78 archival thyroid tissues, including normal samples, follicular adenomas, follicular carcinomas and PTC. RESULTS: The MASA assay proved to be a more sensitive method than SSCP and DNA sequencing of PCR products. BRAF mutation was found by MASA in 19/43 (44.2%) of PTC, including 14/31 (45.2%) classic forms and 5/12 (41.7%) follicular variants. No mutations of BRAF were detected in the normal thyroid tissues, nor in follicular adenomas or follicular carcinomas. No correlation was found between BRAF mutation and clinicopathologic features nor with recurrence during a postoperative follow-up period of 4-11 years. BRAF(V600E) significantly correlated with absence of node metastasis. CONCLUSIONS: BRAF(V600E) is present in PTC, both in the classic form and in follicular variant with similar prevalence. No correlation was found between BRAF mutation and aggressive clinical behavior. MASA-PCR proved to be a specific, sensitive and reliable method to detect BRAF T1799A in DNA extracted from different sources, including cytologic samples obtained either fresh or from archival glass slides. We propose this method as a useful tool to improve accuracy of preoperative diagnosis identifying PTC from biopsies with indeterminate cytologic findings.
Subject(s)
Carcinoma, Papillary/genetics , Point Mutation , Proto-Oncogene Proteins B-raf/genetics , Thyroid Neoplasms/genetics , Adult , Alleles , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Exons , Female , Humans , Male , Polymerase Chain Reaction/methods , Polymorphism, Single-Stranded Conformational , Retrospective Studies , Sequence Analysis, DNAABSTRACT
OBJECT: The authors studied the expression of angiogenic and growth factors and various proliferative indices in cavernous angiomas of the brain. The goal was to define whether the often progressive clinical course of both sporadic and familial forms of the lesion is correlated with different expression of these factors. METHODS: Forty-three cavernomas of the brain were investigated with immunohistochemical studies and stained for four growth factors (vascular endothelial growth factor [VEGF], tenascin, transforming growth factor-b [TGFb], and platelet-derived growth factor [PDGF]), and for Ki-67 and bcl-2. The intensity of expression was tested in all cases in the walls of cavernoma vessels, in the perivascular tissue, and in the perilesional brain parenchyma. Among the 43 cavernomas, 32 were stable and sporadic single lesions less than 2 cm in size, whereas 11 were cavernomas larger than 2 cm (up to 6 cm). These larger cavernomas had more aggressive behavior (documented growth in five cases, mass effect in eight, significant hemorrhage in four), familial occurrence (six cases), and/or multiple lesions (five cases). The expression of VEGF, tenascin, and PDGF in cavernomas did not significantly differ in the two groups of patients, whereas TGFb expression was higher in the more aggressive forms of cavernomas. The expression of Ki-67 and bcl-2 was always absent in stable lesions, and it was positive in eight (72.7%) of 11 aggressive lesions. The perilesional brain parenchyma showed a significantly higher expression of TGFb, PDGF, and tenascin in more aggressive cavernomas. CONCLUSIONS: The familial occurrence and more aggressive clinical behavior of cavernous angiomas of the brain are associated with higher expression of Ki-67 and bcl-2 in the cavernoma tissue, as in other proliferative lesions. These features are also associated with higher expression of some growth factors (excluding VEGF) in the perilesional brain parenchyma, suggesting that the neighboring vasculature and glia may be predisposed to and recruited for further growth and progression.
Subject(s)
Angiogenic Proteins/metabolism , Brain Neoplasms/physiopathology , Cerebral Veins/physiopathology , Growth Substances/metabolism , Hemangioma, Cavernous, Central Nervous System/physiopathology , Neovascularization, Pathologic/physiopathology , Adolescent , Adult , Aged , Angiogenic Proteins/genetics , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Cerebral Veins/abnormalities , Cerebral Veins/pathology , Child , Child, Preschool , Disease Progression , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Growth Substances/genetics , Hemangioma, Cavernous, Central Nervous System/genetics , Hemangioma, Cavernous, Central Nervous System/metabolism , Humans , Inheritance Patterns/genetics , Ki-67 Antigen/metabolism , Male , Middle Aged , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Platelet-Derived Growth Factor/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Tenascin/metabolism , Transforming Growth Factor beta/metabolism , Up-Regulation/physiology , Vascular Endothelial Growth Factor A/metabolismABSTRACT
PURPOSE: The sensitivity of lymph node excisional biopsy requires validation. Power Doppler ultrasound (US) helps predict the malignant status of lymphadenopathies. We used power Doppler US to select for biopsy the lymph node most suspected of malignancy. PATIENTS AND METHODS: One hundred fifty-two patients having lymphadenopathies with clinical suspicion of lymphoma were divided into two well-matched groups and randomly assigned to undergo either standard or power Doppler US-directed lymph node excisional biopsy. RESULTS: Histology showed a malignancy in 64% of patients in the standard group (lymphoma, 49 patients; carcinoma, two patients) and in 87% of patients in the US-assisted group (lymphoma, 62 patients; carcinoma, one patient). There were significantly fewer biopsy-related complications in the assisted group than in the standard group. During the follow-up of the patients with lymph nodes reported as being reactive, 14 of 29 patients in the standard group were rebiopsied and were found to have lymphoma (13 patients) or carcinoma at the subsequent lymph node histology, whereas none of the patients in the assisted group (nine patients) required a second biopsy. Thus, biopsy provided false-negative results for malignancy in 21% of patients affected by lymphoma in the standard group and never in the assisted group (P <.01). CONCLUSION: Power Doppler US is an accurate tool for screening lymphadenopathies to be removed by excisional biopsy in patients with suspected lymphoma.
Subject(s)
Carcinoma/diagnosis , Lymphatic Diseases/etiology , Lymphatic Diseases/pathology , Lymphoma/diagnosis , Ultrasonography, Doppler/methods , Ultrasonography, Interventional/methods , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy/adverse effects , Biopsy/methods , Carcinoma/pathology , False Negative Reactions , Female , Humans , Lymphoma/pathology , Male , Middle Aged , Sensitivity and SpecificityABSTRACT
PURPOSE: Tamoxifen (TAM) is increasingly administered to new early breast cancer patients. Because it is not devoid of toxic effects, we studied factors potentially predictive of its efficacy. EXPERIMENTAL DESIGN: From 1978 to 1983, 433 patients were enrolled in the GUN randomized trial: 206 were assigned to TAM versus 227 controls (no-TAM). Premenopausal patients with axillary lymph node involvement (60 TAM versus 65 no-TAM) also received nine CMF cycles. Eight biological markers were retrospectively assayed for most patients: estrogen; progesterone; prolactin receptors (PrlRs); microvessel count (MVC); S-phase fraction; tumor ploidy; epidermal growth factor receptor (EGFR); and HER2. We performed a multivariate test of the TAM/covariate interactions to establish whether these variables predicted for TAM efficacy. Estimates of the TAM effect were expressed as hazard ratio (HR) of death of TAM over no-TAM patients with 95% confidence intervals (95% CIs). RESULTS: At a median follow-up of 15 years, PrlRs, MVC, S-phase fraction, ploidy, and EGFR did not influence TAM efficacy. Differently, HER2 had an overall significant predictive effect: HR = 0.59 (95% CI: 0.40-0.87) in HER2-negative subjects versus HR = 1.09 (95% CI: 0.63-1.87) in HER2-positive subjects (interaction test: P = 0.04). The predictive effect of HER2 was also evident in the subgroup of patients with steroid receptor-positive tumors (HER2 positive: HR = 1.33, 95% CI: 0.70-2.51; HER2 negative: HR = 0.73, 95% CI: 0.47-1.14). CONCLUSIONS: With the statistical power of the present randomized trial, S-phase, ploidy, EGFR, PrlR, and MVC do not seem to predict for TAM efficacy. Conversely, our data support the hypothesis that tumors overexpressing HER2 might not benefit from adjuvant TAM.
Subject(s)
Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant , Tamoxifen/therapeutic use , Adolescent , Adult , Age Factors , Aged , Biomarkers, Tumor , Clinical Trials as Topic , ErbB Receptors/biosynthesis , Female , Humans , Lymphatic Metastasis , Microcirculation , Middle Aged , Neovascularization, Pathologic , Ploidies , Proportional Hazards Models , Receptor, ErbB-2/biosynthesis , Receptors, Prolactin/biosynthesis , S Phase , Time FactorsABSTRACT
Myelolipomas are uncommon benign tumors composed of mature adipose tissue mixed with hematopoietic elements; these tumors can occur in both the adrenal glands and extra-adrenal locations, the presacral region being the most frequent extra-adrenal site. We present a case of presacral myelolipoma diagnosed by fine needle aspiration (FNA) and core needle biopsy (CNB) in a 55-year-old woman with concurrent invasive ductal breast cancer. TC and RM imaging were consistent with the diagnosis of presacral myelolipoma. The lesion was discovered incidentally during the staging procedure for breast malignancy. The purpose of our work is to describe the FNA and CNB finding in combination with the imaging features of this uncommon lesion.
Subject(s)
Breast Neoplasms/pathology , Myelolipoma/diagnosis , Sacrum/pathology , Spinal Neoplasms/diagnosis , Biopsy, Fine-Needle , Biopsy, Large-Core Needle , Breast Neoplasms/complications , Female , Humans , Magnetic Resonance Imaging , Middle Aged , Myelolipoma/complications , Myelolipoma/diagnostic imaging , Myelolipoma/pathology , Radiography , Sacrum/diagnostic imaging , Spinal Neoplasms/complications , Spinal Neoplasms/diagnostic imaging , Spinal Neoplasms/pathologyABSTRACT
Familial adenomatous polyposis (FAP), an autosomal dominantly inherited condition accounting for about 1% of all colorectal cancers, results from mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. The clinical spectrum and severity of FAP varies greatly with the mutation site, and both between and within families. Using the protein truncation test, single strand conformation polymorphism analysis and DNA sequencing, we identified 30 (75%) mutant alleles in 40 unrelated FAP families, for a total of 22 different APC mutations. Of these, 18 are known and 4 are novel: c.1797C>A (C599X), c.893_894delAC, (c.3225T>A; c.3226C>A) and c.4526_4527insT. Of the 30 APC gene mutations, 5 (approximately 17%) are nonsense mutations, 17 (approximately 57%) are small deletions, 5 (approximately 17%) are small insertions and 3 (approximately 10%) are complete deletions. All mutations occurred in single pedigrees, except those at codons 1061 and 1062, each found in two unrelated families, and the mutation at codon 1309 in exon 15, found in five unrelated families. About 40% of mutations, mostly small deletions and insertions, are located at repeated sequences; they promote misalignment-mediated errors in DNA replication and could represent a hot spot mutation region. This study enlarges the spectrum of APC gene mutations and sheds light on the correlation between the site of APC germline mutations and clinical manifestations of FAP.
Subject(s)
Adenomatous Polyposis Coli Protein/genetics , Adenomatous Polyposis Coli/genetics , Mutation , Adenomatous Polyposis Coli/pathology , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Germ-Line Mutation , Humans , Italy , Pedigree , Polymorphism, Single-Stranded ConformationalABSTRACT
Hepatoblastoma (HB) is the most common liver tumor in childhood and differs in its environmental risk factors and genetic background from hepatocellular carcinoma. HB is associated with inherited conditions such as familial adenomatous polyposis and Beckwith-Wiedemann syndrome, suggesting the importance of genetic abnormalities in the pathogenesis and progression of this disease. It has a very polymorphous morphology. A diverse range of cytogenetic alterations has been reported to date, the most frequent being trisomy 2 and trisomy 20. Thirty-five HB specimens from 31 patients (22 purely epithelial, 4 purely mesenchymal, 9 mixed) were examined by comparative genomic hybridization (CGH), a technique that enables us to screen the entire tumor genome for genetic losses and gains. Our aims were as follows: (1) to characterize chromosome abnormalities that appear in this tumor and (2) to identify possible differences between different histologic subtypes of HB. We found significant gains of genetic material, with very little difference in the number and type of alterations between the different histologic components of HB. The most frequent alterations were gains of Xp (15 cases, 43%) and Xq (21 cases, 60%). This finding was also confirmed by fluorescent in situ hybridization performed on nuclei extracted from 6 specimens. Other common alterations were 1p-, 2q+, 2q-, 4q-, and 4q+. We found no difference between different histologic subtypes, a finding that may be in agreement with the hypothesis of a common clonal origin for the different components. An hitherto-unreported high frequency of X chromosome gains may support the assumption that X-linked genes are involved in the development of this neoplasm.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, X , DNA, Neoplasm/genetics , Hepatoblastoma/genetics , Liver Neoplasms/genetics , Nucleic Acid Hybridization , Cell Nucleus/genetics , Cell Nucleus/pathology , Child , Child, Preschool , Chromosome Banding , Epithelial Cells/pathology , Female , Hepatoblastoma/pathology , Humans , In Situ Hybridization, Fluorescence , Infant , Infant, Newborn , Liver Neoplasms/pathology , Male , Stromal Cells/pathologyABSTRACT
We report 62 cases of invasive micropapillary carcinoma of the breast characterized by delicate pseudopapillary structures lacking a fibrovascular core and by tubuloalveolar structures freely floating in clear, empty spaces. All patients but 1 were women (median age, 57 years; range, 25-89 years). Tumor size ranged from 0.7 to 10 cm (median, 2.8 cm); 54 (87%) were grade 3. Psammoma bodies were identified in 29 (47%). Focal to massive lymphatic permeation was present in 39 (63%). Architectural features were retained in the node metastases, dermal lymphatics, and recurrences. Fifty-six patients (90%) had metastatic axillary nodes: 18 tumors were estrogen receptor-positive (32%); 11 were progesterone receptor-positive (20%); HER2/neu was overexpressed in 53 (95%) and p53 in 39 (70%). A peculiar immunoreactivity for MUC1 limited to the cytoplasmic membrane oriented toward the stroma and an absence of immunoreactivity for E-cadherin in the same side of the cytoplasmic membrane indicated inversion of cell polarization and a disturbance in the cell adhesion molecules. Of 41 patients with available follow-up, 29 (71%) had local recurrence (mean, 30 months) and 20 (49%) died of disease. These results underscore the aggressive behavior and poor prognosis of this breast carcinoma variant. Aggressive preoperative neoadjuvant chemotherapy should be considered.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/pathology , Carcinoma, Papillary/pathology , Adult , Aged , Aged, 80 and over , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms, Male/metabolism , Breast Neoplasms, Male/mortality , Breast Neoplasms, Male/pathology , Cadherins/metabolism , Carcinoma, Papillary/metabolism , Carcinoma, Papillary/mortality , Female , Genes, erbB-2 , Humans , Immunohistochemistry , Lymphatic Metastasis/pathology , Male , Middle Aged , Mucin-1/metabolism , Neoplasm Recurrence, Local/pathology , Ploidies , Prognosis , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
Inactivation of DNA mismatch repair genes (MRG) is a recently described pathway of cancer development and progression resulting in genetic instability. Germline mutations in MRG have been studied predominantly in patients with hereditary non-polyposis colorectal cancer (HNPCC) where it is associated with microsatellite instability (MSI). The expression of MRG in primary breast cancer is still largely unexplored. The hMSH2 MRG encodes a protein that recognizes and binds to mismatch sequences of DNA. We investigated the relation-ship between hMSH2 expression and clinicopathological and biological characteristics, including p53 and p185 expression, in 44 primary invasive breast cancers. hMSH2 was not expressed in 11 cases (25%). Interestingly, p53 (p=0.05), p185 and steroidal receptor expression (p=0.07) were more frequent in tumors without hMSH2 expression. Furthermore, in 30 of 44 cases we analyzed hMSH2 expression in relation to MSI at 9 dinucleotide loci, and found that MRG expression was not significantly related to MSI. The presence of hMSH2 and p53 alterations in the same tumor suggests that the two oncoproteins act through a common mutational pathway, whereas the absence of a correlation between hMSH2 and MSI suggests that oncogenetic mechanisms of progression in primary breast cancer differ from those in HNPCC.