Sclerosing Paraganglioma of the Carotid Body: A Potential Pitfall of Malignancy

Paragangliomas (PGs) of the head and neck region are typically benign, slow-growing neuroendocrine tumours. At times, they may exhibit unusual histological features, such as prominent stromal sclerosis (sclerosing PG), which may raise concerns of malignancy. We describe a case of sclerosing PG of the carotid body, emphasizing the value of immunohistochemical stains for differential diagnosis. A 43-year-old woman presented with a painless lump on the neck. A magnetic resonance imaging scan demonstrated a hypervascular lesion of the carotid body, which was surgically excised. Grossly, the lesion measured 1.8 cm at maximum diameter. On microscopic examination, irregular nests and tiny bundles of neoplastic cells were found between thick bands of fibrous tissue. Focal nuclear cytomegaly and marked pleomorphism were noted. Neoplastic cells proved to be immunoreactive for chromogranin, synaptophysin and neuron specific enolase, but negative for cytokeratins, smooth muscle actin and CD34. Ultrastructurally, numerous mitochondria, rough endoplasmic reticulum structures and endocrine granules were seen in the cytoplasm of the tumour cells. On consideration of the above-mentioned clinico-pathological and ultrastructural findings a diagnosis of sclerosing PG was established. Sclerosing PG is a rare entity which may mimic a malignant neoplasm. The recognition of this unusual morphological variant of PG, together with appropriate immunostains, leads to the correct diagnosis.     

XLP1 inhibitory effect by 2B4 does not affect DNAM‐1 and NKG2D activating pathways in NK cells

X‐linked lymphoproliferative disease 1 (XLP1) is a rare congenital immunodeficiency caused by SH2D1A (Xq25) mutations resulting in lack or dysfunction of SLAM‐associated protein adaptor molecule. In XLP1 patients, upon ligand (CD48) engagement, 2B4 delivers inhibitory signals that impair the cytolytic activity of NK (and T) cells. This causes the selective inability to control EBV infections and the occurrence of B‐cell lymphomas. Here, we show that in the absence of SLAM‐associated protein, co‐engagement of 2B4 with different activating receptors, either by antibodies or specific ligands on target cells, inhibits different ITAM‐dependent signaling pathways including activating killer Ig‐like receptors. In XLP1 NK cells, 2B4 affected both the cytolytic and IFN‐γ production capabilities, functions that were restored upon disruption of the 2B4/CD48 interactions. Notably, we provide evidence that 2B4 dysfunction does not affect the activity of DNAM‐1 and NKG2D triggering receptors. Thus, while CD48⁺ B‐EBV and lymphoma B cells devoid of NKG2D and DNAM‐1 ligands were resistant to lysis, the preferential usage of these receptors allowed XLP1 NK cells to kill lymphomas that expressed sufficient amounts of the specific ligands. The study sheds new light on the XLP1 immunological defect and on the cross‐talk of inhibitory 2B4 with triggering NK (and T) receptors.     

Molecular events underlying interleukin‐6 independence in a subclone of the CMA‐03 multiple myeloma cell line

We explored the molecular mechanisms involved in the establishement of CMA‐03/06, an IL‐6‐independent variant of the multiple myeloma cell line CMA‐03 previously generated in our Institution. CMA‐03/06 cells grow in the absence of IL‐6 with a doubling time comparable with that of CMA‐03 cells; neither the addition of IL6 (IL‐6) to the culture medium nor co‐culture with multipotent mesenchymal stromal cells increases the proliferation rate, although they maintain the responsiveness to IL‐6 stimulation as demonstrated by STAT1, STAT3, and STAT5 induction. IL‐6 independence of CMA‐03/06 cells is not apparently due to the development of an autocrine IL‐6 loop, nor to the observed moderate constitutive activation of STAT5 and STAT3, since STAT3 silencing does not affect cell viability or proliferation. When compared to the parental cell line, CMA‐03/06 cells showed an activated pattern of the NF‐κB pathway. This finding is supported by gene expression profiling (GEP) analysis identifying an appreciable fraction of modulated genes (28/308) in the CMA‐03/06 subclone reported to be involved in this pathway. Furthermore, although more resistant to apoptotic stimuli compared to the parental cell line, CMA‐03/06 cells display a higher sensibility to NF‐κB inhibition induced by bortezomib. Finally, GEP analysis suggests an involvement of a number of cytokines, which might contribute to IL‐6 independence of CMA‐03/06 by stimulating growth and antiapoptotic processes. In conclusion, the parental cell‐line CMA‐03 and its variant CMA‐03/06 represent a suitable model to further investigate molecular mechanisms involved in the IL‐6‐independent growth of myeloma cells. © 2013 Wiley Periodicals, Inc.     

Interobserver reproducibility of the controlled attenuation parameter (CAP) for quantifying liver steatosis

Purpose

This study was conducted to prospectively investigate the interobserver reproducibility of controlled attenuation parameter (CAP) measurements and the relationship among the CAP and body mass index (BMI), gender and age.

Methods

Consecutive subjects were studied using the M+ probe of the FibroScan device (Echosens, Paris, France). Measurements were performed by two raters (rater1 and rater2). Interobserver agreement was assessed by using the concordance correlation coefficient (CCC). The Pearson r coefficient was used to test correlation between two study variables, and linear regression was used for the multivariate model.

Results

Three hundred fifty-one subjects (227 males and 124 females) were prospectively studied. The CCC was 0.82 (95 % CI 0.78–0.85) overall, 0.80 (95 % CI 0.75–0.85) for BMI <25 kg/m², 0.76 (95 % CI 0.69–0.84) for BMI 25–29 kg/m² and 0.65 (95 % CI 0.41–0.88) for BMI ≥30 kg/m². The CCC was 0.44 (95 % CI 0.31–0.56) for CAP values ≤240 dB/m and 0.72 (95 % CI 0.65–0.79) for CAP values >240 dB/m. In univariate analysis, age and BMI by gender were correlated with the CAP. Multiple regression analysis confirmed the relationship of the CAP with age and BMI, but not with gender.

Conclusions

The results of this study show that the interreader agreement in CAP measurement is good. In healthy volunteers, the CAP is strongly correlated with age and BMI.