103 Critical review on STAS In this study more tumor cell clusters or loose cells were found in specimen freshly cut, compared to formalin fixed ones. Pulmonary collapse on the other hand is a more general phenomenon in pulmonary resections. During pulmonary resection, the air, lymph and probably also a certain amount of blood will flow out of the lung and give rise to a smaller handling volume of lung tissue. The extent of the volume reduction depends on the size of resection and the extent of disease. In any case, collapse resulting from reduction in the amount of air is recognized as close approximation of the alveolar walls. In invasive adenocarcinomas, a specific growth pattern of tumor cells along alveolar walls is called the lepidic pattern. If this is the only pattern present within a tumor smaller than 3 cm, this tumor is classified as adenocarcinoma in situ (AIS)4. A 2-dimensional representation of an AIS may mimic a papillary pattern in collapsed lung90. In collapsed lung, the compressed alveoli do not have the original open air-space presentation, but show variable shapes due to the very flexible nature of lung tissue. Therefore, in collapsed lung tissue in which there is a proliferation of tumor cells along the alveolar walls, the so-called lepidic pattern, cutting of slides in a 2-dimensional (2-D) plane will result in seemingly loose tumor cells or fragments. Most pathologists would agree that this should certainly not be given a special designation, apart from recognizing it as a cutting artifact120. Threedimensional reconstruction studies of pulmonary adenocarcinomas also demonstrated that seemingly tumor cell clusters were frequently interconnected to each other and with the main tumor mass at multiple points, when examined in 2-D145 132. Other authors have demonstrated similar findings using multiple serial sections of tumors, showing that many seemingly separate micropapillary tumor clusters present in alveolar spaces were in fact connected to the main tumor 40 41. These reconstruction studies may explain part of the 7% of seemingly tumor cell clusters present in the blocks before tumor cutting, as reported in the previously mentioned prospective study162. How to explain the association of ‘tumor cell clusters or loose cells’ with poor prognosis? A plausible biological explanation for the association of tumor cell clusters or loose cells with poor prognosis is that disruption of tumor cells is simply seen in poorly differentiated, highly discohesive tumors. It has been postulated that such poorly differentiated discohesive tumors have fewer intercellular adhesions between tumor cells, such as in micropapillary adenocarcinomas and poorly differentiated squamous cell carcinomas124,125,165,166. Interestingly, in micropapillary carcinoma (frequently associated with STAS) one study suggests that the loose cells have most likely acquired resistance to apoptosis and facilitated anchorage-independent growth, which are advantageous for proliferation during lymphatic cancer metastasis164. Dissociation of tumor cells is not a rare phenomenon and is recognized in diagnostic breast cytology where dissociation of epithelial cells is a useful artifact in favor of malignancy167. Moreover, studies that show a correlation between STAS and poor prognosis also demonstrate correlations between STAS and other prognosticators. In all these 7
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