A detection rate of 0.12% was reported in the usual mass screening of stomach and uterine cancer using radiographs and cytologic results in Japan.³ Because stomach and uterine cancer constitute almost half of the cancer cases in Japan, the morphologic cancer detection rate for all investigated sites is estimated to be less than 0.2%. Therefore, our cancer detection rate for all investigated sites of 29.5% (28 of 95) with the tumor marker combination assay among tumor stage V groups was at least 100 times more sensitive than conventional morphologic examinations using, for example, radiographs and cytologic results. Thus, our tumor marker method for prescreening. remarkably improves the efficiency of the screening test for cancer and can be applied to cancer in general. We proposed a model of the natural history of cancer (Fig. 4).

Gullino²⁴ and others^25-27 have reported the theoretical existence of microcancers, citing the biologic growth curve characteristics of clinical cancers. Recently, Sugano²⁸ histopathologically proved the existence of microcancers in resected stomachs and other organs of patients with malignant or benign diseases.²⁸ We hereby propose a classification of microcancers and preneoplasia into the following four tumor stages (Stages I to IV) and Stage V, which is cancer weighing more than 1 g, based on the data in Figures 1 and 2 and Table 4. • Tumor stage I: Undetectable, no ALP isoenzyme or RNase abnormalities are observed. Tumor-free, normal (N).

• Tumor stage II: Microcancer in the narrow sense (suggestive of microgram to a few milligrams (Ml]); a slight abnormality in the level of growth-related tumor markers is observed.
• Tumor stage III: The stage before the shift to preclinical cancer (Ml to several hundred milligrams [M21); slight abnormalities in growth-related tumor markers and tumor-associated tumor markers levels are observed.

• Tumor stage IV: Conventional Stage 0 cancer (GO); preclinical cancer; moderate abnormalities in growth-related tumor markers and tumor-associated tumor markers levels are observed and sometimes a slight abnormality in tumor-specific tumor markers levels.
• Tumor stage V: Suggestive of cancer of more than 1 g, in clinical stages Tl to T4 (clinical cancers were classified according to TNM classification as four cancer stages, parallel to Gl-G4 in our model), marked abmormalities are observed in tumor-associated tumor markers levels as well as in growth-related tumor markers levels. Sometimes an abnormality in tumor-specific tumor markers is also seen.

Figure 4. Illustration of the natural history of cancer. We classified the following five tumor stages (TS) according to the tumor weights, which were estimated using our cutoff values: TS I, tumor-free; TS II, micrograms (µ) to a few milligrams (M₁); TS III, M₁ to several hundred milligrams (M₂); TS IV, preclinical cancer (G₀); TS V, gram level (G₁-G₄) suggestive of cancer of more than 1 g.