NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease.

Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In addition, we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism.

Soft tissue aneurysmal bone cyst: a rare case in a middle aged patient.

Soft tissue aneurysmal bone cyst is a rare entity, with about 20 cases reported in literature, only 3 of which are in patients over 40 years of age. We present a case of a 41 year old Latin American female who presented for evaluation of atraumatic chest pain with radiation to the left shoulder. Her initial workup was negative, including radiographic imaging of the chest and left shoulder. 4 months later, she presented to her orthopedic surgeon with a palpable mass and mild left shoulder pain. Radiographs acquired at that time demonstrated a 7.0 × 5.5 × 6.7 cm mass with rim calcification in the region of the upper triceps muscle. Subsequent CT imaging showed central areas of hypodensity and thin septations, a few of which were calcified. MR evaluation showed hemorrhagic cystic spaces with multiple fluid-fluid levels and enhancing septations. Surgical biopsy was performed and pathology was preliminarily interpreted as cystic myositis ossificans, however on final review the diagnosis of soft tissue aneurysmal bone cyst was made. The lesion was then surgically excised and no evidence of recurrence was seen on a 3 year post-op radiograph. Following description of our case, we conduct a literature review of the imaging characteristics, diagnosis, and treatment of soft tissue aneurysmal bone cyst.

Use of telecytology for the immediate assessment of CT guided and endoscopic FNA cytology: diagnostic accuracy, advantages, and pitfalls.

Telecytology (TC) can assist cytopathologists in efficiently providing immediate evaluation for fine needle aspirations (FNAs) performed at remote locations. Our aim was to evaluate the accuracy and feasibility of TC for immediate assessments of FNAs. Phase I: Diff-Quik and Pap stained smears from two retrospective sets of 20 pilot cases each (n = 40) were included for TC assessments. For the first set, diagnoses were rendered by four pathologists and for the second set, in addition, four cytotechnologists also participated. Diagnostic concordance with the final diagnosis was assessed. Phase IIA: These were followed by real time assessments (RTA) of 56 TC FNAs and diagnostic concordance was compared to that of 100 conventional in-person immediate assessments (Phase IIB). Phase I: 79/80 (98.8%) diagnoses (20 cases × 4 pathologists) from the first set were accurate. On the second set, 160 diagnoses were rendered on Pap stained slides and 160 on Diff-Quik stained slides. The accuracy rate was 95% (76/80) for malignant diagnoses and 96.2% (77/80) for benign diagnoses on Pap stain. Diff-Quik stains were more difficult to interpret than Pap stains and accuracy rates for them were lower. Endoscopic bronchial ultrasound guided (EBUS) FNAs of paratracheal nodes were more difficult to interpret. Phase IIA and B: 95% (53/56) RTAs by TC were concordant with the final diagnoses compared with 97% (97/100) for in-person assessments. TC is a useful aid and yields concordance rates comparable to in-person assessments. Individual practices should perform pilot studies to understand the pitfalls and limitations before employing telecytology.

Biomarkers of cervical dysplasia and carcinoma.

Although cervical cytology screening has decreased the incidence of cervical cancer in industrialized countries, HPV-related cervical disease, including premalignant and malignant lesions, continues to represent a major burden on the health care system. Some of the problems include the potential for either under- or overtreatment of women due to decreased specificity of screening tests as well as significant interobserver variability in the diagnosis of cervical dysplastic lesions. Although not completely elucidated, the HPV-driven molecular mechanisms underlying the development of cervical lesions have provided a number of potential biomarkers for both diagnostic and prognostic use in the clinical management of these women.

Interferon-γ influences the composition of leukocytic infiltrates in murine lyme carditis.

Interferon (IFN)-γ is present in lesions of patients with Lyme disease and positively correlates with the severity of manifestations. To investigate the role of IFNγ in the development of Lyme carditis, wild-type and IFNγ-deficient C57BL/6 mice were infected with the causative bacterium, Borrelia burgdorferi. Histological analysis revealed no change in the severity of carditis between wild-type and IFNγ-deficient mice at 14, 21, 25, and 28 days after infection. However, a distinct shift in the types of leukocytes within the hearts of IFNγ-deficient mice was observed at 25 days. In the absence of IFNγ, the number of neutrophils in the heart was increased, whereas the number of T lymphocytes was decreased. Bacterial loads within hearts were the same as in wild-type mice. Macrophages secrete chemokines that recruit immune cells, which could contribute to the accumulation of leukocytes in murine Lyme carditis. The ability of IFNγ and B. burgdorferi to activate murine macrophages was examined, and the two stimuli synergistically induced chemoattractants for mononuclear cells (ie, CXCL9, CXCL10, CXCL11, CXCL16, and CCL12) and decreased those for neutrophils (ie, CXCL1, CXCL2, and CXCL3). IFNγ and B. burgdorferi also synergistically enhanced secretion of CXCL9 and CXCL10 by murine cardiac endothelial cells. These results indicate that IFNγ influences the composition of inflammatory infiltrates in Lyme carditis by promoting the accumulation of leukocytes associated with chronic inflammation and suppressing that of cells that typify acute inflammation.

Blue nevus of the colorectal mucosa.

The blue nevus is a well-described benign melanocytic proliferation that generally occurs on the skin. Infrequently, blue nevi are found on mucosal surfaces. The most common location for mucosal blue nevi is the oral mucosa, with reported cases in the sinonasal mucosa and genital tract, as well as in other locations. To our knowledge, blue nevi of the rectal mucosa have not been described. Here, we describe a case of blue nevus arising in the rectal mucosa. Blue nevi are benign melanocytic proliferations with the potential for malignant transformation and should be included in the differential diagnosis of pigmented mucosal lesions of the rectum.

Primary extrauterine endometrial stromal cell sarcoma: a case and review.

BACKGROUND: Extrauterine endometrial stromal sarcoma (ESS) is a rare neoplasm. Little is known about its pathophysiology or best treatment approach. CASE: We are describing a case of extrauterine ESS in a 70-year-old woman on hormone replacement therapy and with a history of endometriosis. We also present a brief review of the literature on ESS and its relationship to endometriosis and hormonal therapy. CONCLUSIONS: Complete resection should remain the treatment of choice for ESS. Unresectable or metastatic low-grade ESS may respond well to progestin therapy, but outcomes of high-grade ESS tend to be poor.

Cytologic diagnosis of invasive lobular carcinoma: factors associated with negative and equivocal diagnoses.

Fine-needle aspiration biopsy (FNAB) of invasive lobular carcinoma (ILC) is associated with notoriously high rates of false negative and equivocal diagnoses. To identify causative factors, we reviewed the cytologic features of presurgical FNAB smears of ILC and correlated the cytologic findings with the number of passes, tumor size, mammographic findings, and the histologic characteristics of the tumor. Smear cellularity, presence of single intact epithelial cells, nuclear size, nuclear atypia, palpability of the tumor, and histologic type of ILC (classic versus nonclassic) were statistically significant in establishing an unequivocally positive diagnosis. We also found that the cytologic cellularity of the lesion does not reflect the actual cellularity of the tumor but instead is an indicator of the architectural arrangement of the neoplastic cells; tumors that form epithelial cell groups, such as in nonclassic ILC, tend to yield more cellular aspirates that are diagnostic for carcinoma. In contrast, classic ILC, in which single neoplastic cells are embedded in fibrous stroma, is more likely to yield a paucicellular smear with subtle atypia and rare single intact epithelial cells. As such, an inconclusive diagnosis in a certain percentage of classic ILC cases may be unavoidable.

Glandular cell atypia on Papanicolaou smears: interobserver variability in the diagnosis and prediction of cell of origin.

BACKGROUND: The 2001 Bethesda System recommended qualification of atypical glandular cells (AGC) to indicate the site of origin and separated endocervical adenocarcinoma in situ (AIS) from "AGC favor neoplastic" as a specific diagnostic category. To the authors' knowledge, the literature evaluating the reproducibility of Papanicolaou (Pap) smear diagnosis of glandular cell abnormalities with emphasis on the cell of origin is limited. The aim of the current study was to investigate whether a variety of benign to neoplastic glandular lesions can be reliably classified on Pap smear with regard to diagnosis and cell of origin. METHODS: Twenty-three conventional Pap smears (CPS) with glandular cellular changes varying from benign to adenocarcinoma (ACA) were reviewed by six observers. They were asked to categorize each smear according to cell of origin (endocervical vs. endometrial) and diagnosis (benign, AGC, or ACA). Kappa statistics were used to evaluate interobserver agreement and correlation of interobserver agreement with experience. RESULTS: There was no consensus among observers for both the origin of the cells and the diagnosis. Interobserver agreement for site was poor (kappa < 0.4) especially in the AGC category. Unanimous agreement for site was reached for 7 of 23 smears (30%). Two of five endocervical AIS were classified as endometrial and another two were classified as benign by four observers. Interobserver agreement was poor in all diagnostic categories (kappa < 0.4) and showed slight correlation with level of experience. Unanimous agreement for diagnosis was reached for only 2 smears (9%). Three of 11 (27%) smears demonstrating preneoplastic/neoplastic processes were diagnosed as benign by 3 observers. Three (25%) benign CPS were diagnosed as ACA by 2 observers. Accurate prediction of the final histologic diagnosis by observers varied from 30% to 87% and did not correlate closely with experience. CONCLUSIONS: Cytologic diagnosis of glandular lesions by CPS was problematic and suffered from significant interobserver subjectivity.

Fine-needle aspiration cytology of unusual germ cell tumors of the mediastinum: atypical seminoma and parietal yolk sac tumor.

A 30-yr-old man presented with a mediastinal germ cell tumor that combined the histologic pattern of seminoma with the immunohistochemical profile of embryonal carcinoma (beta-HCG+/PLAP-). In FNA smears, this atypical seminoma presented as fragile large cells with scanty cytoplasm, vesicular nuclei, irregular and indistinct nucleoli, scattered singly and in loosely cohesive fragments without the characteristic lymphocytic or tigroid background. The cytologic features were more suggestive of a poorly differentiated carcinoma than seminoma, potentially leading to misdiagnosis and mismanagement. The second case was a 51-yr-old female smoker who presented with mediastinal parietal yolk sac tumor with extension to the lung, a rare occurrence, and contrary to the clinical impression of lung cancer with hilar lymph node metastasis. This case illustrates the value of using the unique cytologic features of parietal yolk sac tumor, i.e., the abundant, viscous, stringy metachromatic extracellular hyaline material associated with the tumor cells in reaching the accurate diagnosis.