Purpose: As an approach to evaluate the expression pattern and status of activation of signaling pathways in clinical specimens from head and neck squamous cell carcinoma (HNSCC) patients, we established the Head and Neck Cancer Tissue Array Initiative, an international consortium aimed at developing a high-density HNSCC tissue microarray, with a high representation of oral squamous cell carcinoma. Experimental Design: These tissue arrays were constructed by acquiring cylindrical biopsies from multiple individual tumor tissues and transferring them into tissue microarray blocks. From a total of 1,300 cases, 547 cores, including controls, were selected and used to build the array. Results: Emerging information by the use of phosphospecific antibodies detecting the activated state of signaling molecules indicates that the Akt-mammalian target of rapamycin (mTOR) pathway is frequently activated in HNSCC, but independently from the activation of epidermal growth factor receptor or the detection of mutant p53. Indeed, we identified a large group of tissue samples displaying active Akt and mTOR in the absence of epidermal growth factor receptor activation. Furthermore, we have also identified a small subgroup of patients in which the mTOR pathway is activated but not Akt, suggesting the existence of an Akt-independent signaling route stimulating mTOR. Conclusions:These findings provide important information about the nature of the dysregulated signaling networks in HNSCC and may also provide the rationale for the future development of novel mechanism-based therapies for HNSCC patients.

The fine structure of the lymphatic capillary and the surrounding tissue areas was investigated. Instead of a continuous basal lamina (basement membrane) surrounding the capillary wall, these observations revealed the occurrence of numerous fine filaments that insert on the outer leaflet of the trilaminar unit membrane of the lymphatic endothelium. These filaments appear as individual units, or they are aggregated into bundles that are disposed parallel to the long axis of the lymphatic capillary wall and extend for long distances into the adjoining connective tissue area among the collagen fibers and connective tissue cells. The filaments measure about 100 A in width and have a hollow profile. They exhibit an irregular beaded pattern along their long axis and are densely stained with uranyl and lead. These filaments are similar to the microfibrils of the extracellular space and the filaments observed in the peripheral mantle of the elastic fibers. Infrequently, connections between these various elements are observed, suggesting that the lymphatic anchoring filaments may also contribute to the filamentous units of the extracellular space. It is suggested that these lymphatic anchoring filaments connect the small lymphatics to the surrounding tissues and represent the binding mechansim that is responsible for maintaining the firm attachment of the lymphatic capillary wall to the adjoining collagen fibers and cells of the connective tissue area.

The lymphatic capillaries possess salient morphological features which differentiate them from the blood capillaries. Instead of a definitive basement lamina surrounding the lymphatic wall, there are numerous fine filaments (about 60 A in diameter) that are attached to the lymphatic endothelia at areas of increased electron density that are similar to half desmosomes. The filaments extend for varying distances into the adjoining connective tissue area and seem to anchor the lymphatic vessel to the surrounding connective tissue. Endothelial projections occur along both the luminal and abluminal surfaces of the cell. The intercellular junctions are varied in structure along the lymphatic wall.

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