Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis.

BACKGROUND: The dioxin (AhR) receptor can have oncogenic or tumor suppressor activities depending on the phenotype of the target cell. We have shown that AhR knockdown promotes melanoma primary tumorigenesis and lung metastasis in the mouse and that human metastatic melanomas had reduced AhR levels with respect to benign nevi. METHODS: Mouse melanoma B16F10 cells were engineered by retroviral transduction to stably downregulate AhR expression, Aldh1a1 expression or both. They were characterized for Aldh1a1 activity, stem cell markers and migration and invasion in vitro. Their tumorigenicity in vivo was analyzed using xenografts and lung metastasis assays as well as in vivo imaging. RESULTS: Depletion of aldehyde dehydrogenase 1a1 (Aldh1a1) impairs the pro-tumorigenic and pro-metastatic advantage of melanoma cells lacking AhR expression (sh-AhR). Thus, Aldh1a1 knockdown in sh-AhR cells (sh-AhR + sh-Aldh1a1) diminished their migration and invasion potentials and blocked tumor growth and metastasis to the lungs in immunocompetent AhR+/+ recipient mice. However, Aldh1a1 downmodulation in AhR-expressing B16F10 cells did not significantly affect tumor growth in vivo. Aldh1a1 knockdown reduced the high levels of CD133(+)/CD29(+)/CD44(+) cells, melanosphere size and the expression of the pluripotency marker Sox2 in sh-AhR cells. Interestingly, Sox2 increased Aldh1a1 expression in sh-AhR but not in sh-AhR + sh-Aldh1a1 cells, suggesting that Aldh1a1 and Sox2 may be co-regulated in melanoma cells. In vivo imaging revealed that mice inoculated with AhR + Aldh1a1 knockdown cells had reduced tumor burden and enhanced survival than those receiving Aldh1a1-expressing sh-AhR cells. CONCLUSIONS: Aldh1a1 overactivation in an AhR-deficient background enhances melanoma progression. Since AhR may antagonize the protumoral effects of Aldh1a1, the AhR(low)-Aldh1a1(high) phenotype could be indicative of bad outcome in melanoma.

The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis.

Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR- /- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of ß1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.

Fine needle aspiration cytology in cutaneous and subcutaneous endometriosis.

OBJECTIVE: To study the role of fine needle aspiration cytology (FNAC) in the diagnosis of cutaneous and subcutaneous endometriosis. STUDY DESIGN: We present 7 cases of endometriosis in abdominal wall, inguinal region and perineum diagnosed by FNAC. All cases were confirmed with histologic follow-up. Cytologic and histologic material was prepared using standard methods. RESULTS: The smears were highly cellular, showing a hemorrhagic background with hemosiderin-laden macrophages and sheets of epithelial and stromal cells. Occasionally, these cellular components were closely associated. CONCLUSION: FNAC is useful in the diagnosis of cutaneous and subcutaneous endometriosis, providing a rapid and accurate preoperative diagnosis.

Intraoperative consultation on pediatric central nervous system tumors by squash cytology.

Squash cytology (SC) is a very useful procedure during neurosurgical intraoperative consultation (IOC), and it is especially recommended for the evaluation of soft tumors or tumors that are highly cellular (just the characteristics of pediatric central nervous system [CNS] tumors). The aim of this review is to familiarize pathologists with the range of cytomorphologic appearances that can occur during IOC for pediatric CNS tumors and with the diagnostic dilemmas and pitfalls encountered in this setting. This article is based on the medical literature and the authors' experience with a large series of cases accrued over a 12-year period at 3 institutions. SC is a specially recommended procedure in IOC for pediatric CNS tumors; it reveals the fine cellular details and background features in a manner not seen in corresponding frozen sections. Indeed, a differential diagnosis between histologically look-alike processes can be achieved with more confidence if SC is employed.

Polymorphous low grade adenocarcinoma of the salivary gland. Diagnosis by fine needle aspiration cytology.

OBJECTIVE: To describe the fine needle aspiration cytology findings of polymorphous low grade adenocarcinoma of the salivary gland. STUDY DESIGN: The authors reviewed the cytologic findings of 5 cases of polymorphous low grade adenocarcinoma. All cases were confirmed by histologic examination. RESULTS: All cases showed similar cytologic findings. The smears had high cellularity with a population of mixed epithelial and myoepithelial cells. These cells formed branching papillae, sheets and clusters. The epithelial cells were uniform, with round to ovoid nuclei; absent or inconspicuous nucleoli; and a moderate amount of dense cytoplasm. Occasionally the cells formed spherical structures containing hyaline globules. Myxoid matrix, either dispersed in the background or interspersed with the cellular elements, was also seen often. CONCLUSION: Polymorphous low grade adenocarcinoma should be cytologically differentiated from adenoid cystic carcinoma, monomorphic adenoma and pleomorphic adenoma. Recognition of subtle cytologic features. may be useful in the differential diagnosis.

Fine needle aspiration diagnosis of extramedullary hematopoiesis resembling mediastinal and paravesical tumors. A report of 2 cases.

BACKGROUND: Extramedullary hematopoiesis is a compensatory phenomenon that occurs when normal function of the bone marrow is disturbed. It is most often seen in patients with hematologic disorders. Although the sites most frequently involved are the spleen, liver and lymph nodes, other organs may be involved. We report on 2 cases of extra-medullary hematopoiesis mimicking posterior mediastinum and paravesical tumors and diagnosed by fine needle aspiration cytology. CASES: Two men, aged 72 and 82 years, with hemolytic anemia (thalassemia intermedia and idiopathic) presented with solid masses involving the posterior mediastinum and paravesical region. The patients underwent computed tomography-guided fine needle aspiration. The smears were composed of normal bone marrow elements. Both cases were diagnosed as extramedullary hematopoiesis. CONCLUSION: Fine needle aspiration cytology is an useful method of diagnosing extramedullary hematopoiesis and aids in planning treatment.

Sialadenitis with crystalloid formation. Fine needle aspiration cytodiagnosis of 15 cases.

OBJECTIVE: To assess the utility of fine needle aspiration cytology in the diagnosis of sialadenitis with crystalloid formation. STUDY DESIGN: In 15 cases, salivary gland masses were aspirated using a disposable, 20-mL syringe and 25-gauge needles, maintaining negative pressure. Smears routinely were air dried and stained by Diff-Quik (Dade Behring AG, Düdingen, Germany). Occasionally smears were fixed in alcohol and stained by the Papanicolaou method. RESULTS: The smears showed large numbers of non-birefringent crystalloids of varying sizes and shapes. The crystalloids stained deep blue with Diff-Quik and bright orange with Papanicolaou stain. Multinucleated histiocytes, neutrophilic leukocytes and benign salivary gland parenchyma were found, also. CONCLUSION: Fine needle aspiration cytology provides an accurate diagnosis of sialadenitis with crystalloids and is useful for avoiding unnecessary surgery.

Hydatid cyst in soft tissues mimicking malignant tumors. Diagnosis by fine needle aspiration cytology.

OBJECTIVE: To evaluate the role of fine needle aspiration cytology in the diagnosis of soft tissue hydatid cysts. STUDY DESIGN: Five cases of soft tissue hydatid cyst were diagnosed primarily by fine needle aspiration cytology. RESULTS: In all cases, large fragments of acellular material, finely lamellated, were found. There were no complications related to fine needle aspiration, and histologic studies confirmed the diagnosis of hydatid cyst. CONCLUSION: When acellular, laminated fragments suggestive of a laminated layer are identified on smears, hydatid cyst should be considered in the differential diagnosis, even in atypical locations and in the absence of hooklets, protoscolices or both.

Low grade mucoepidermoid carcinoma arising in cervical lymph nodes. A report of two cases with fine needle aspiration findings.

BACKGROUND: Heterotopic islands of salivary tissue are commonly found in the intraparotid lymph nodes and, less commonly, within extraparotid cervical nodes. Salivary gland tumors, both benign and malignant, can develop within this ectopic salivary tissue. CASES: Two patients presented with a solitary, painless mass in the cervical region. Fine needle aspiration cytology was performed, and the smears revealed a mixture of intermediate and mucus-secreting cells associated with extracellular mucin. The tumors were removed, and the diagnosis of mucoepidermoid carcinoma was confirmed by histologic study. CONCLUSION: The finding of a malignant cervical salivary gland tumor does not necessarily represent a metastasis from an occult site.

Cutaneous intralymphatic histiocytosis associated with rheumatoid arthritis: report of a case and review of the literature.

Various dermatoses have been described associated with rheumatoid arthritis. Recently, a specific cutaneous lesion termed "intravascular histiocytosis" has been proposed as a new entity among these dermatoses. We report the case of a 50-year-old woman with rheumatoid arthritis for about 10 years who developed erythematous patches on the extensor surface of lower extremities. Histopathologically, the lesions showed intraluminal proliferation of CD68-positive histiocytes in vessels lined with endothelial cells expressing D2-40, a selective marker for lymphatic endothelium.

Immortalized mouse mammary fibroblasts lacking dioxin receptor have impaired tumorigenicity in a subcutaneous mouse xenograft model.

Although the dioxin receptor, the aryl hydrocarbon receptor (AhR), is considered a major regulator of xenobiotic-induced carcinogenesis, its role in tumor formation in the absence of xenobiotics is still largely unknown. Trying to address this question, we have produced immortalized cell lines from wild-type (T-FGM-AhR+/+) and mutant (T-FGM-AhR-/-) mouse mammary fibroblasts by stable co-transfection with the simian virus 40 (SV-40) large T antigen and proto-oncogenic c-H-Ras. Both cell lines had a myofibroblast phenotype and similar proliferation, doubling time, SV-40 and c-H-Ras expression and activity, and cell cycle distribution. AhR+/+ and AhR-/- cells were also equally able to support growth factor- and anchorage-independent proliferation. However, the ability of T-FGM-AhR-/- to induce subcutaneous tumors (leimyosarcomas) in NOD/SCID-immunodeficient mice was close to 4-fold lower than T-FGM-AhR+/+. In culture, T-FGM-AhR-/- had diminished migration in collagen-I and decreased lamellipodia formation. VEGFR-1/Flt-1, a VEGF receptor that regulates cell migration and blood vessel formation, was also down-regulated in AhR-/- cells. Signaling through the ERK-FAK-PKB/AKT-Rac-1 pathway, which contributes to cell motility and invasion, was also significantly inhibited in T-FGM-AhR-/-. Thus, the lower tumorigenic potential of T-FGM-AhR-/- could result from a compromised adaptability of these cells to the in vivo microenvironment, possibly because of an impaired ability to migrate and to respond to angiogenesis.

Early morphologic changes following microwave endocardial ablation for treatment of chronic atrial fibrillation during mitral valve surgery.

INTRODUCTION: The aim of this study was to investigate the early qualitative and quantitative structural changes in the left atrial wall after endocardial microwave ablation in patients with chronic atrial fibrillation (AF) undergoing mitral surgery. METHODS AND RESULTS: Seven patients with chronic AF of for at least 6 months underwent surgical microwave energy ablation. Linear isolation of pulmonary veins was performed in all patients by microwave energy applications to the endocardial surface delivered by catheter at 65-W constant power for 45 seconds. Biopsies were obtained from a selected site (below the right lower pulmonary vein) of the left atrial posterior wall before and after the ablation procedure in all patients. Control tissues from the same sites were obtained at autopsy from patients with noncardiac causes of death. Light and electron microscopy was used to examine qualitative and quantitative changes in tissue morphology. Tissues after endocardial ablation procedure showed significantly increased loss of contractile material. Electron microscopy of atrial tissue demonstrated loss of profile of perinuclear and plasma membranes of myocytes, disruption of the endothelial cells of capillary vessels, and presence of macrophages. CONCLUSION: Lesions created by endocardial microwave energy ablation revealed a transmural effect on the left atrial wall without a significant reduction in thickness but a significant increase in the myolytic areas involving the entire cytosol and occlusion of the small intramyocardial vessels within the ablative lesion.