There is a widely held belief among pathologists, biologists and clinicians alike that metastatic tumors are histologically similar to the primary. Although this theory has never been scientifically tested, it has formed the conceptual foundation upon which research on cancer metastasis has been based for decades. This theory has led to the formulation of the second theory which posits that cells which exit the primary tumor must themselves travel to distant organs and colonize to form secondary tumors such that they resemble the primary. Yet, after decades of research the mechanistic basis of the metastatic cascade has not been satisfactorily elucidated1,2. An alternative line of research has suggested that nucleic acids derived from dying cancer cells that are carried via blood stream to distant organs are the instigators of metastasis by their ability to transform cells of the target organs to generate new tumors that masquerade as metastasis3-9. If this theory were to be true, secondary tumors should not be histologically similar to the primary. We undertook a study to blindly test the veracity of the two theories of metastasis. We retrieved 298 paraffin blocks of metastatic tumors from the archives of the Pathology Department of the Hospital. The blocks comprised of metastatic tumors arising at 9 different sites viz. brain, bone, lung, liver, cutaneous nodules, inguinal lymph node, mediastinal lymph node, mesenteric lymph node and supra-clavicular lymph node. These metastatic tumors had arisen from primary tumors at 22 different sites (Supplementary Table 1, https://links.lww.com/IJSOPEN/A45). The paraffin blocks were sectioned and fresh histological slides were prepared and stained with H&E. The slides were blindly coded. Three highly experienced professor grade cancer pathologists with at least 20 years of professional experience were asked to identify the primary sites of origin of the metastatic tumors. The three examiners are co-correspondents of this letter. Of the 298 slides, 110 were examined by all three examiners while 188 slides were examined by two examiners. The predictions made by the examiners were tabulated against the appropriate primary sites and the accuracy of prediction was recorded (Supplementary Table 2, https://links.lww.com/IJSOPEN/A46). Inter-examiner concordance was determined by Kappa statistics. The accuracy of prediction of the primary site of origin was 46%, 46% and 45% for the first, second and third examiner respectively. However, there was very little inter-observer agreement, and Kappa statistic generated the value of 0.27 which is much below the figure of 0.4 required to detect even a moderate level of concordance (highlighted in yellow, Supplementary Table 2, https://links.lww.com/IJSOPEN/A46). In only 56/298 (18.8%) cases did the examiners agree with each other’s diagnosis. Thus the possibility cannot be excluded that the correct diagnoses made by the examiners had happened by play of chance. Perhaps another way to conduct this study would have been to use paired samples of primary and metastatic tumors form the same patients and ask the examiner to opine whether they looked histologically similar. But, such a study would have been confounded by bias and would not have constituted a scientific experiment. To the best of our knowledge, this is the first study to blindly test the entrenched belief that a metastatic tumor is histologically similar to the primary. Metastasis is the leading cause of death from cancer, yet it is arguably the most poorly understood aspect of cancer research. In spite of decades of intensive investigation and millions of dollars spent on research, the mechanistic basis of the various steps involved in the metastatic cascade remains poorly understood1,2. We believe that the obstacle to progress in the field is the dogma that metastatic tumors are histologically similar to the primary, especially since the entire body of current metastasis research is founded upon such a premise. By raising an element of doubt, our study may help to energize new ideas and new avenues of research leading to better understanding of the metastatic process and development of new cancer therapies.
Singh et al. (Tue,) studied this question.