Tumors composed of undifferentiated cells are said to be anaplastic, a feature that is a reliable indicator of malignancy. The term anaplasia literally means “backward formation”—implying dedifferentiation, or loss of the structural and functional differentiation of normal cells. It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors, failure of differentiation of transformed stem cells, rather than dedifferentiation of specialized cells, accounts for their anaplastic appearance. Recent studies also indicate that in some cases, dedifferentiation of apparently mature cells occurs during carcinogenesis. Anaplastic cells often display the following morphologic features:
Pleomorphism (i.e., variation in size and shape) (
Fig. 6.4
Nuclear abnormalities, consisting of extreme hyperchromatism (dark-staining), variation in nuclear size and shape, or unusually prominent single or multiple nucleoli. Enlargement of nuclei may result in an increased nuclear-to-cytoplasmic ratio that approaches 1:1 instead of the normal 1:4 or 1:6. Nucleoli may attain astounding sizes, sometimes approaching the diameter of normal lymphocytes.
Tumor giant cells may be formed. These are considerably larger than neighboring cells and may possess either one enormous nucleus or several nuclei.
Atypical mitoses, which may be numerous. Anarchic multiple spindles may produce tripolar or quadripolar mitotic figures (
Fig. 6.5
Loss of polarity, such that anaplastic cells lack recognizable patterns of orientation to one another. Such cells may grow in sheets, with total loss of communal
Fig. 6.4 Pleomorphicmalignanttumor(rhabdomyosarcoma).Notethemarkedvariationincellandnuclearsizes,thehyperchromaticnuclei,andthepresenceoftumorgiantcells.(Courtesy of Dr. Trace Worrell, Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.) structures, such as glands or stratified squamous architecture.
Well-differentiated tumor cells are likely to retain the functional capabilities of their normal counterparts, whereas anaplastic tumor cells are much less likely to have specialized functional activities. For example, benign neoplasms and even well-differentiated cancers of endocrine glands frequently elaborate the hormones characteristic of their cell of origin. Similarly, well-differentiated squamous cell carcinomas produce keratin (see
Fig. 6.3 ), just as well-differentiated hepatocellular carcinomas secrete bile. In other instances, unanticipated functions emerge. Some cancers may express fetal proteins not produced by comparable cells in the adult. Cancers of nonendocrine origin may produce so-called “ectopic hormones.” For example, certain lung carcinomas may produce adrenocorticotropic hormone (ACTH), parathyroid hormone– like hormone, insulin, glucagon, and others. More is said about these so-called “paraneoplastic” phenomena later.
Also of relevance in the discussion of differentiation and anaplasia is dysplasia, referring to disorderly proliferation.
Fig. 6.5 High-powerdetailedviewofanaplastictumorcellsshowscellularandnuclearvariationinsizeandshape.Theprominentcellinthecenterfieldhasanabnormaltripolarspindle.
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Fig. 6.6 Carcinomainsitu.(A)Low-powerviewshowsthattheentirethicknessoftheepitheliumisreplacedbyatypicaldysplasticcells.Thereisnoorderlydifferentiationofsquamouscells.Thebasementmembraneisintact,andthereisnotumorinthesubepithelialstroma.(B)High-powerviewofanotherregionshowsfailureofnormaldifferentiation,markednuclearandcellularpleomorphism,andnumerousmitoticfiguresextendingtowardthesurface.Theintactbasementmembrane(below)isnotseeninthissection.