218 A. Jögi et al. Differentiation as a prognostic parameter in surgical pathology In the realm of surgical pathology, the concept of cellular differentiation is made very concrete although used from a different angle and with a somewhat different content than its usage in developmental biology. Apart from performing the obvious task of ruling out/determining whether a tumor is malignant or benign, the pathologist also most often evaluates malignancies aiming to assess their degree of differ- entiation, implying that neoplastic cells have the potential to slide back along the line of differentiation. The result has prognostic implications where, as a rule, a high degree of differentiation purports a better prognosis than a low degree. Using morphological criteria, the degree of resemblance between the neo- plasia and its tissue of origin is gauged. A high degree of differentiation means that the neoplasia is morpho- logically similar to the native organ, forming neoplas- tic organoid structures, whereas the opposite is true for a low stage of differentiation, where cells gradually lose the capacity for structural organization and start to display reduced cohesiveness and where the term anaplasia denotes tumor morphology where all sim- ilarity with the origin has been lost. The results from evaluating the degree of differ- entiation are often presented using a two- or three- tiered scale as exempliﬁed by the common skin malignancy, squamous cell carcinoma (SCC). If a case of SCC grows in an outward (verrucous) fash- ion, still maintains keratin-forming capacity, has cells with ample cytoplasm, only slight nuclear aty- pia, and only few mitotic ﬁgures, it is regarded as highly differentiated. This means that no signs of invasion below the basal membrane are seen and metastatic disease is rare. On the other side of the scale is the SCC of low differentiation, where cells grow in sheets and with no signs of keratin formation. In these cases the mitotic index is often high, and occasionally immunohistochemistry has to be used to conclude that this cancer indeed is derived from the squamous epithelium. Biologically, these poorly differentiated cancers often invade deeply through the dermis and have a bad prognosis with a propen- sity for lymph node metastasis. In between these poles are the intermediately differentiated cases of SCC. Another pertinent example of how differentiation staging is used in modern surgical pathology is the Gleason scoring system developed for prostate can- cer. Neoplastic prostate glands are here judged for their capacity to form glandular structures. Grades 1 and 2 are similar to native glands, whereas grade 3 demonstrates glands of reduced diameter growing as separate units in the prostatic tissue, still respecting other glands, malignant as well as benign. Grade 4 heralds that the malignant glands start to coalesce and fuse, whereas grade 5 show malignant cells growing either in sheets or as single cell units, totally devoid of gland-forming capacity. To arrive at the Gleason score, the grade of the most commonly seen cancer (e.g. 3) is added to that of the minority pattern (e.g. 4), which gives a Gleason score of 7. In this case a composite score based on the degree of dedifferentiation is used, which has contributed sig- niﬁcantly to the prognostic power of the Gleason grading system. The morphological correlates of dedifferentiation have been known to pathologists for over a century, but an explanation of the mechanistic factors behind this process has been lacking and unexplored until recent times when the armamentarium of cellular and molecular tumor biology has been deployed to study this phenomenon. A process of interest in this context is the epithelial to mesenchymal transition (EMT). This term describes how epithelial cells phenotypically transdifferentiate towards a more mes- enchymal/ﬁbroblastoid/spindle-shaped cell, simulta- neously gaining increased capacity for invasiveness and motility. An important question in this context is to what degree EMT equates to dedifferentiation. Addressing this issue, it is important to remember that, by deﬁnition, carcinomas develop from epithelial cells. Epithelial cells, however, are not deﬁned at a cellular but at an architectural level, where epithelial cells form multidimensional cohesive cellular sheets of varying thickness resting upon the basal lamina, resulting functionally in immobile cells. The mesen- chymal cell, on the other hand, is deﬁned at a cellular level, being spindle-shaped, bipolar, and motile. These cellular categories are the two prototypic cells of chordates (1) from embryogenesis and onwards. Actually, the co-ordinated actions of these dual cell types form the very basis for development of higher life forms, above the level of amphioxi, under- scoring their fundamental developmental importance. With this deﬁnition in mind the terms dedifferentia- tion and EMT show a considerable degree of con- ceptual overlap. Although implicated during invasion, intravasation, and metastasis, clear-cut examples of clinically relevant EMT in cancers have been hard to demonstrate, even if attempts have been made (2). However, as pointed out, dedifferentiated tumors indeed have a considerably worse prognosis, and this category is more often found to invade vascular and neural structures and transgress histological boundaries such as organ capsules, which micro- scopically recapitulates the in vitro data on cells performing EMT.