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Malignant teratocarcinomas arise from developmentally totipotent normal stem cells. Whether the targets are embronal somatic cells or germinal cells has long been a matter of controversy. Past experiments on teratocarcinoma induction by ectopic grafting of early rodent embryos or fetal germinal ridges have remained ambiguous because embryos ordinarily soon form germ cells, and parthenogenetic germ cells form "embryos." In order to interrupt the developmental cycle at its most telling point, day 6 (egg-cylinder stage) mouse embryos of genetically sterile types were grafted; in such grafts, only a terminal residue of totipotent embryonal somatic ("ectoderm") cells is available, and subsequent germ cell development is severely impaired. One graft series, from Si J/+ matings, comprised 25% SIJ/SlJ presumptive sterile embryos; these grafts formed tumors containing embryonal carcinoma cells as often (47%) as did control +/+ grafts (41%)on the same genetic background. In another series, from WI+ matings, tumors of the sterile W/ Wgenotype were individually identified by means of a-closely linked marker, phosphoglucomutase (PGM, EC 2.7.5.1; Pgm-1 locus), coding for electrophoretic enzyme variants and incorporated into the stock Four tumors were obtained (out of 16) that had the PGM-1D phenotype diagnostic for WI W, and that also contained embryonal carcinoma cells. Therefore, the malignancy arises here in susceptible somatic embryonal stem cells at the terminal stage of their capacity for totipotency. Other teratocarcinomas-whether induced or spontaneous-of ostensible germ-cell origin by parthenogenesis ma also depend upon development of thesame somatic target cells before neoplastic conversion can occur. A general model based on these experiments is proposed for all malignancies: Malignant transformation of a particular kind of normal stem cell may be possible only when that stem cell has progressed to the threshold of further differentiation.

This pathologic study is based on 9 autopsies and many biopsies in cases of infectious mononucleosis. The gross changes were almost exclusively confined to enlargement of lymphoid tissues, especially the spleen. Nasopharyngeal lymphoid hyperplasia was constant, in one instance suggesting tumor. Other tissues presented no significant gross features related to the primary disease except for (1) rather consistent enlargement of the liver, (2) infrequent icterus, and (3) occasional cutaneous rash. Histologic observations revealed more or less generalized lesions resembling those of certain known virus diseases, notably perivascular aggregates of normal and abnormal lymphocytes. Reaction of this type inconstantly involved all tissues studied except the bone marrow; here lymphocytes were virtually absent in sections, but were present in aspirated marrow because of dilution with peripheral blood. More specific changes were invariably noted in lymphoid tissues. The abnormal lymphocyte characteristic of the disease could be identified in thin, lightly stained sections. Lymph node reactions varied from a predominantly follicular hyperplasia to a blurred pattern simulating a malignant lymphoma; the latter was due to a lymphocytic and reticulo-endothelial proliferation in the medullary cords. The spleen displayed a lymphocytic infiltration in the thinned capsule and trabeculae, frequently dissolving the latter and rendering the organ liable to rupture. The pattern was partially effaced in most instances and the follicles widely spaced. Blood sinuses contained considerable numbers of normal and abnormal lymphocytes, and accumulations of these cells constantly cuffed intratrabecular arteries and lay beneath the intima of veins. Tonsils displayed ulceration and necrosis in several cases, and the lymphocytic proliferation closely resembled malignant tumor in a tonsil that enlarged rapidly. A pneumonic exudate in 1 case was almost exclusively of round cell type, while in another the pneumonia was of the usual lobular type with a neutrophilic exudate. Small myocardial infiltrates which we noted probably explain the electrocardiographic changes described in infectious mononucleosis. Other findings of particular interest were the periportal lymphoid collars in the liver which sometimes attained the proportions seen in leukemia, and the presence of meningo-encephalitis in 4 of the 6 brains examined. We believe that the majority of cells in the lymphocytic "infiltrates" of connective tissues and the perivascular collars are metaplastic rather than inwandering, i.e., that they are formed in situ and stem from cells of the reticulo-endothelial system.

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