Annamaria Anniciello

Fine needle aspiration biopsy of hepatic focal fatty change. A report of two cases.

BACKGROUND In rare instances, hepatic steatosis produces a circumscribed, nodular lesion described as focal fatty liver change (FFLC). The ultrasonographic and computed tomographic patterns are those of an isointense or hyperechoic nodule, sometimes simultating metastasis. CASES Fine needle aspiration biopsy was performed under ultrasonographic control in two men aged 65 and 67 years who had previously undergone emicolectomy and gastrectomy for adenocarcinoma. Routine hepatic ultrasound showed solitary nodules, of 3 and 4 cm in diameter. The microscopic patterns were similar and highly cellular in both cases. Cells were isolated or organized in sheets and characterized by large, intracytoplasmic, clear vacuoles that displaced nuclei to the periphery of the cells, flattening them against the cytoplasmic membrane and giving these cells a signet-ring appearance. Nuclei were generally round and nucleolated or dense and hyperchromatic when flattened onto the cytoplasmic membrane. Normal hepatocytes were interspersed in the background, and in some areas of the slides hepatocytes with one or more small intracytoplasmic vacuoles with cytologic features intermediate between those of vacuolated cells and normal hepatocytes were present. Digested periodic acid-Schiff staining, performed on destained, fixed smears, gave negative results. The cytologic diagnosis was FFLC. Clinical and echographic follow-up confirmed the cytologic diagnosis. CONCLUSION The ultrasonographic and microscopic features of FFLC may mimic those of metastasis. A proper cytologic diagnosis may contribute to the diagnostic workup of these rare lesions.

Increased HOX C13 expression in metastatic melanoma progression

BackgroundThe process of malignant transformation, progression and metastasis of melanoma is not completely understood. Recently, the microarray technology has been used to survey transcriptional differences that might provide insight into the metastatic process, but the validation of changing gene expression during metastatic transition period is poorly investigated. A large body of literature has been produced on the role of the HOX genes network in tumour evolution, suggesting the involvement of HOX genes in several types of human cancers. Deregulated paralogous group 13 HOX genes expression has been detected in melanoma, cervical cancer and odonthogenic tumors. Among these, Hox C13 is also involved in the expression control of the human keratin genes hHa5 and hHa2, and recently it was identified as a member of human DNA replication complexes.MethodsIn this study, to investigate HOX C13 expression in melanoma progression, we have compared its expression pattern between naevi, primary melanoma and metastasis. In addition HOXC13 profile pattern of expression has been evaluated in melanoma cell lines.ResultsOur results show the strong and progressive HOX C13 overexpression in metastatic melanoma tissues and cytological samples compared to nevi and primary melanoma tissues and cells.ConclusionsThe data presentated in the paper suggest a possible role of HOX C13 in metastatic melanoma switch.

Variability in Immunohistochemical Detection of Programmed Death Ligand 1 (PD-L1) in Cancer Tissue Types

In normal cell physiology, programmed death 1 (PD-1) and its ligand, PD-L1, play an immunoregulatory role in T-cell activation, tolerance, and immune-mediated tissue damage. The PD-1/PD-L1 pathway also plays a critical role in immune escape of tumor cells and has been demonstrated to correlate with a poor prognosis of patients with several types of cancer. However, recent reports have revealed that the immunohistochemical (IHC) expression of the PD-L1 in tumor cells is not uniform for the use of different antibodies clones, with variable specificity, often doubtful topographical localization, and with a score not uniquely defined. The purpose of this study was to analyze the IHC expression of PD-L1 on a large series of several human tumors to correctly define its staining in different tumor tissues.

LncRNA HOTAIR As Prognostic Circulating Marker and Potential Therapeutic Target in Patients with Tumor Diseases

In the recent years the importance of the role played by non-coding RNA on the regulation of gene expression was increased by numerous studies. The research mainly focused on small ncRNAs, such as miRNAs, while the functions of long non-coding RNA (lncRNA) have been much less studied. lncRNAs can be transcribed from intergenic, intragenic or specific chromosomal regions. Compared to miRNAs, lncRNAs have a complex secondary and tertiary structure which allows to bind proteins, RNA, DNA and to carry out their regulatory functions. Several studies showed that extracellular ncRNAs can circulate in the blood of both healthy and diseased patients. Most of the circulating ncRNAs are included in lipid or lipoprotein vesicles, such as apoptotic bodies, macrovesicles or exosomes, in which they are highly stable. The presence of circulating ncRNAs in the blood of cancer patients versus normal subjects suggested the possibility that these molecules may represent new diagnostic markers. HOTAIR is a HOX transcript antisense RNA, located in the HOXC locus, able to repress transcription in the posterior region of the HOXD locus. HOTAIR has been involved in the evolution of several primary tumors, wherein increase of HOTAIR expression has endorsed invasion and metastasis. In this review, we describe the experimental evidences on the potential role as circulating marker of lncRNA HOTAIR.

SPARC/osteonectin is involved in metastatic process to the lung during melanoma progression

The existence of a “metastasis gene signature” that predisposes primary breast cancer cells to metastasize to the lungs has been recently highlighted by gene expression profiling studies. The combination of genes responsible for this process includes genes encoding several metalloproteinases as well as the gene encoding SPARC (secreted protein acidic and rich in cysteine)/osteonectin. SPARC is involved in normal tissue remodeling as it regulates the deposition of extracellular matrix, but also plays a role in neoplastic transformation. Aberrant SPARC expression has been detected both in stromal cells associated with cancer and in cancer cells. The main aim of this study was to investigate whether or not SPARC might be involved in directing metastasis of other types of cancer to the lung. We constructed a tissue microarray containing lung metastases from a variety of primary tumors in different organs and used immunohistochemistry to assess SPARC expression. We found SPARC overexpressed mainly in lung metastases from melanoma. We then assessed the expression of SPARC mRNA and protein in metastatic melanoma from different anatomic sites and in their corresponding primary tumors, and found that it is overexpressed in lung metastases. Our data strongly support the hypothesis that SPARC is involved in directing melanoma metastases specifically to the lung, which underpins its potential as prognostic marker and novel target for specific therapy.

Peripheral T-cell Lymphoma with Cyclin D1 overexpression: a case report.

Peripheral T-cell lymphomas not otherwise specified are generally considered aggressive non-Hodgkin lymphomas, because of poor natural outcome and response to therapy. They show a complex karyotype without any specific genetic hallmark. We report a case of peripheral T-cell lymphoma not otherwise specified with heterogeneous nuclear Cyclin D1 immunohistochemical overexpression, due to gene copy gain, a phenomenon similar to that observed in Mantle Cell Lymphoma characterized by t(11;14)(q13;q32). In this case report we underline the diagnostic pitfall rapresented by Cyclin D1 immunoistochemical overexpression in a T-cell lymphoma. Several pitfalls could lead to misinterpretation of diagnosis, therefore, we underlined the need to integrate the classical histology and immunohistochemistry with molecular tests as clonality or Fluorescence in situ hybridization.Virtual slideThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1117747619703769

Microenvironment and tumor progression of melanoma: New therapeutic prospectives

Malignant melanoma is a very representative disease in terms of tumor progression processes. During its evolution, a series of events takes place; among these, the cells’ ‘out-of-control’ growth and loss of homeostasis play crucial roles in the genesis of the tumor itself and its subsequent progression. These events involve several molecular mechanisms associated with both melanocyte transformation and changes to/in the surrounding microenvironment. In particular, interactions between transformed cells and between these cells and the local extracellular matrix (ECM) play key roles in melanoma progression. A description of main ECM molecules involved in melanoma tumor progression, of different cell types present in the tumor microenvironment, and the interactions between all these elements, will be discussed in this review. Taking a broad view of the activity of these cells, molecules, and systems and mechanisms that allow for interference with their expression/function could be useful for designing potential combinations of specific target therapies and immunotherapies that could be more efficient approaches against malignant melanoma.

Can High-Resolution Ultrasound Avoid the Sentinel Lymph-node Biopsy Procedure in the Staging Process of Patients with Stage I–II Cutaneous Melanoma?

PURPOSE The objective of our study was to define the diagnostic accuracy of high-resolution ultrasound (US) in detecting nodal involvement before sentinel lymph node biopsy (SLNB) in patients with cutaneous melanoma, to define the sonographic criteria used to assess nodal metastases, and to establish if high-resolution US can directly select patients to radical lymphadenectomy, sparing selective lymphadenectomy. MATERIALS AND METHODS 623 patients underwent high-resolution US of the regional lymph nodes, 24 hours prior being submitted to the sentinel lymph node biopsy procedure. The US findings were compared with histological findings. RESULTS In 14.7 % out of 122 excised lymph nodes, high-resolution US showed sonographic features consistent with malignant involvement before the surgical step. US scan sensitivity and specificity were 15 and 100 %, respectively, since positive and negative predictive values were 100 and 87 % respectively. CONCLUSION US is an effective modality in the presurgical detection of subclinical deposits within sentinel lymph nodes. However, preoperative staging work-up with high-resolution US cannot substitute the SLNB, mainly because of low sensitivity due to missing many micrometastases.

Ran signaling in melanoma: Implications for the development of alternative therapeutic strategies

We performed a comparative study between two human metastatic melanoma cell lines (A375 and 526), and melanocytes (FOM78) by gene expression profiling and pathway analysis, using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software. Genes involved in Ran signaling were significantly over-represented (p ≤ 0.001) and up-regulated in melanoma cells. A melanoma-associated molecular pathway was identified, where Ran, Aurora Kinase A (AurkA) and TERT were up-regulated, while c-myc and PTEN were down-regulated. A consistent high Ran and AurkA gene expression was detected in about 48% and 53%, respectively, of 113 tissue samples from metastatic melanoma patients. AurkA down-regulation was observed in melanoma cells, by Ran knockdown, suggesting AurkA protein is a Ran downstream target. Furthermore, AurkA inhibition, by exposure of melanoma cells to MLN8054, a specific AurKA inhibitor, induced apoptosis in both melanoma cell lines and molecular alterations in the IPA-identified molecular pathway. These alterations differed between cell lines, with an up-regulation of c-myc protein level observed in 526 cells and a slight reduction seen in A375 cells. Moreover, Ran silencing did not affect the A375 invasive capability, while it was enhanced in 526 cells, suggesting that Ran knockdown, by AurkA down-regulation, resulted in a Ran-independent enhanced melanoma cell invasion. Finally, AurK A inhibition induced a PTEN up-regulation and its action was independent of B-RAF mutational status. These findings provide insights relevant for the development of novel therapeutic strategies as well as for a better understanding of mechanisms underlying therapy resistance in melanoma.