Metastatic Tonsil Squamous Cell Carcinoma: An Important Consideration in the Differential Diagnosis of Malignant Basaloid Neoplasms in the Skin: Case Report and Review of the Literature.

ABSTRACT: Malignant basaloid neoplasms of the skin are frequent, and their accurate diagnosis holds paramount importance for treatment and prognosis. However, these neoplasms can present diagnostic challenges because of their extensive differential diagnosis, which encompasses cutaneous metastasis among many other possibilities. We present a case of a 74-year-old man with a history of p16-positive palatine tonsil squamous cell carcinoma (SCC) treated with surgery and adjuvant radiation with no prior evidence of recurrence who presented to the dermatologist with 2 chin papules. The initial histopathologic evaluation of these lesions showed poorly differentiated malignant basaloid neoplasms. Subsequently, these biopsies were compared with the previous biopsies from his tonsil and lymph node, which showed similar findings including positive p16 staining and positive molecular testing for human papillomavirus-16, confirming the diagnosis of cutaneous metastasis from his previously diagnosed human papillomavirus-related tonsil SCC. Additional imaging studies found metastases to internal organs including the brain, and he was started on chemotherapy, immunotherapy, and radiation therapy. Cutaneous metastases from tonsil SCC are exceedingly rare, and only 5 cases have been described. Furthermore, this is the first case confirming the presence of high-risk human papillomavirus by molecular studies within the cutaneous metastases. The presented case underscores the importance of recognizing this unusual manifestation of tonsil SCC metastatic to the skin along with a good clinical patient history, ensuring accurate and prompt diagnosis and treatment of this condition.

Eosinophilic cytoplasmic inclusion bodies in vesicular multinucleated melanocytes: a clue to the diagnosis of benign melanocytic lesions.

Different types of multinucleated melanocytes have been described in benign and malignant melanocytic lesions. Here we describe a relatively common, though underappreciated, type of multinucleated melanocyte characterized by abundant vesicular and fibrillary-appearing cytoplasm containing one or multiple eosinophilic inclusion bodies. In our experience, these vesicular multinucleated melanocytes with inclusion bodies are invariably seen in nevi of long duration. The presence of these cells can be a reassuring histological finding when evaluating a melanocytic lesion.

Cytologic diagnosis of blastocystis hominis in peritoneal fluid: a case report.

BACKGROUND: Blastocystis hominis is the most common parasite identified in s worldwide. Although it is commonly identified in stool preparations, unusual to encounter B hominis in abdominal fluid. CASE: A 46-year-old woman presented with the clinical impression of acute peritonitis. The initial radiologic evaluation showed free air in the abdominal cavity and an abdominal mass. Abdominal fluid submitted for cytologic examination was diagnostic of acute inflammation with mixed bacteria and abundant cystlike forms of B hominis. The patient underwent an exploratory laparotomy that revealed a poorly differentiated adenocarcinoma involving her bowel and peritoneum. CONCLUSION: The present case highlights the unusual identification ofextraintestinal forms of B hominis in a peritoneal fluid sample from a patient with invasive, poorly differentiated adenocarcinoma and associated bowel perforation.

Epigenetics of cutaneous melanoma.

Tumorigenesis is traditionally thought to be caused by the imbalance between oncogenes and tumor-suppressor genes. Epigenetics is a recently described phenomenon that uses an alternative mechanism to explain the transcriptional inactivation of tumor-suppressor genes predominantly by hypermethylation of the promoter regions. Hypermethylation of these regions has been described extensively in many neoplasms, including cutaneous melanoma. Histone modification, primarily by acetylation and deacetylation, is a current potential target for melanoma therapy, but more research is required to understand the mechanisms involved and the therapeutic effectiveness of regimens involving these agents. These mechanisms not only are important for understanding the origin and progression of neoplasms but also have important potential therapeutic implications. Understanding the epigenetic mechanisms involved in melanoma can provide valuable information with significant implications in diagnosis, treatment, and prevention.

Genomic analysis of circulating cells: a window into atherosclerosis.

Translational studies using genomic techniques in cardiovascular diseases are still in their infancy. Access to disease-associated cardiovascular tissues from patients has been a major impediment to progress in contrast to the diagnostic advances made by oncologists using gene expression on readily available tumor samples. Nonetheless, progress is being made for atherosclerosis by carefully designed experiments utilizing diseased tissue or surrogate specimens. This review details the rationale and findings of a study utilizing freshly isolated blood mononuclear cells from patients undergoing carotid endarterectomy due to atherosclerotic stenosis and from matched healthy subjects. By querying this cardiovascular tissue surrogate, the messenger RNA levels of the Finkel-Biskis-Jenkins osteosarcoma gene in circulating monocytes were found to correlate with atherosclerosis severity in patients and with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy in healthy subjects. The major finding of this investigation is discussed in relation to observations from other human atherosclerosis gene expression studies. These distinct studies converge to demonstrate the unequivocal importance of inflammation in atherosclerosis. Although the clinical utility of the specific findings remains open, the identification of similar genes by different investigations serves to validate our report. They also provide us with insights into pathogenesis that may impact future translational applications.

p53 regulates mitochondrial respiration.

The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.

Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes.

The mechanisms regulating activation of monocytes remain incompletely understood. Herein we provide evidence that Kruppel-like factor 2 (KLF2) inhibits proinflammatory activation of monocytes. In vitro, KLF2 expression in monocytes is reduced by cytokine activation or differentiation. Consistent with this observation, KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. Adenoviral overexpression of KLF2 inhibits the LPS-mediated induction of proinflammatory factors, cytokines, and chemokines and reduces phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-kappaB and activator protein 1, in part by means of recruitment of transcriptional coactivator p300/CBP-associated factor. These observations identify KLF2 as a novel negative regulator of monocytic activation.

Atherosclerotic plaque macrophage transcriptional regulators are expressed in blood and modulated by tristetraprolin.

Circulating monocytes and plaque macrophages mediate inflammation in the pathogenesis of atherosclerosis. We purified these cells from patients undergoing carotid endarterectomy for advanced atherosclerosis and examined their in vivo transcriptomes using the serial analysis of gene expression (SAGE) technique. We observed striking differences in transcriptional regulators as monocytes transformed into plaque macrophages in contrast to monocytes and lung macrophages from normal subjects. Consistent with its role in moderating inflammation, tristetraprolin (TTP, ZFP36) was among the most highly expressed macrophage transcriptional regulators. Interestingly, the mRNAs of a subset of the macrophage transcriptional regulators specifically interacted with TTP, revealing a network of genes that may be important in controlling macrophage inflammatory activity. Giving functional significance to this interaction, the knockdown of TTP increased both cognate macrophage gene mRNAs and inflammatory tumor necrosis factor protein release. In contrast, transient overexpression of TTP resulted in decreased levels of the same genes supporting its role in regulating macrophage gene expression. Together, our results indicate that the in vivo gene expression analyses of cells involved in pathogenesis can provide biological insights for functional studies with potential clinical implications.

Circulating transcriptome reveals markers of atherosclerosis.

Circulating monocytes mediate inflammation in atherosclerosis and may serve as easily accessible reporters of disease. To search for markers of atherosclerosis, we compared the in vivo transcriptomes of monocytes purified from patients undergoing carotid endarterectomy and normal subjects by using the serial analysis of gene expression technique. We selected a subset of differentially expressed monocyte-specific genes and confirmed their expression levels. The Finkel-Biskis-Jinkins osteosarcoma (FOS) gene was significantly increased in patients, and the highest levels of FOS associated with patients who had previously undergone coronary revascularization. The correlation between coronary revascularization and FOS was higher than that compared with the cardiac risk marker high sensitivity C-reactive protein. In vitro inhibition of FOS using small interfering RNA and 3-hydroxy-3-methyl-glutaryl CoA reductase inhibitor simvastatin (statin) affected monocyte activation and suggested an important role in pathogenesis. Given the prominent role of FOS in inflammation and calcification, its association with atherosclerosis severity has clear pathophysiologic bases as well as clinical implications as a marker. Our results suggest that analysis of gene expression in circulating cells may provide biological and clinical insights into human atherosclerosis, and that this type of approach may be applicable for studying other types of diseases.

Current and future applications of SAGE to cardiovascular medicine.

The recently sequenced mammalian genomes represent unprecedented resources for advancing our understanding of human diseases. Characterizing gene expression is an important step in translating genomic sequences into clinically useful information. Currently, gene expression studies are revolutionizing the approaches taken to address both basic science and clinical questions. Two major methods have emerged for the global examination of the transcriptome: microarrays and Serial Analysis of Gene Expression (SAGE). The SAGE technique comprehensively maps gene transcription by using the genomic database, yet it remains relatively underutilized for studying cardiovascular biology. This review describes current cardiovascular studies using the SAGE technique and outlines some potential strategies for employing this powerful tool to further our understanding of the cardiovascular system in health and in disease.

Serial analysis of gene expression: technical considerations and applications to cardiovascular biology.

It has been 7 years since serial analysis of gene expression (SAGE) and microarray hybridization techniques were simultaneously introduced to allow the screening of thousands of expressed genes. Both techniques have stood up to the test of time as evidenced by their widespread use, and both have been used for studying cardiovascular diseases. SAGE has been used more extensively to study cancer cells, but it has also been used to examine gene expression in systems as divergent as rice seedlings, yeast, and Caenorhabditis elegans. In this review, a summary of the advances in SAGE technology and its unique attributes and potential applications to the cardiovascular system will be presented.