The different clonal origins of metachronous and synchronous metastases.

BACKGROUND: Metastases are the leading cause of mortality in cancer patients. Linear and parallel are the two prominent models of metastatic progression. Metastases can be detected synchronously along with the primary tumor or metachronously, following treatment of localized disease. The aim of the study was to determine whether synchronous metastases (SM) and metachronous metastases (MM) differ only in lead-time or stem from different biological processes. MATERIALS AND METHODS: We retrospectively studied the chest CTs of 791 patients inflicted by eleven malignancy types that were treated in our institution in the years 2010-2020. Patient's population included 396 with SM and 395 with MM. The diameter of 15,427 lung metastases was measured. Clonal origin was deduced from the linear/parallel ratio (LPR)-a computerized analysis of metastases diameters. LPR of 1 suggests pure linear dissemination and - 1 pure parallel. RESULTS: Patients with MM were significantly older (average of 62.9 vs 60.7 years, p = 0.02), and higher percentage of them were males (58.7% vs 51.1%, p = 0.03). Median overall survival of patients with MM and SM was remarkably similar (23 months and 26 months respectively, p = 0.774) when calculated from the time of metastases diagnosis. Parallel dissemination (LPR ≤ 0) was found in 35.4% of patients with MM compared to only 19.8% of the patients with SM (p < 0.00001). CONCLUSION: Patients with SM and MM differ in demography and in clonal origin. Different therapeutic approaches may be considered in these two conditions.

Is it time for redefining oligometastatic disease? Analysis of lung metastases CT in ten tumor types.

BACKGROUND: Oligometastatic disease (OD) is usually defined arbitrarily as a condition in which there are ≤ 5 metastases. Given limited disease, it is expected that patients with OD should have better prognosis compared to other metastatic patients and that they can potentially benefit from metastasis-directed therapy (MDT). In this study, we attempted to redefine OD based upon objective evidence that fulfill these assumptions. METHODS: Chest CTSs of 773 patients with 15,947 lung metastases originating from ten malignancy types were evaluated. The number and largest diameter of each metastasis was recorded. Metastatic cluster was defined as a cluster of two or more metastases with diameter difference ≤ 1 mm. The prognostic power of seven statistical models on overall survival (OS) was analyzed. FINDINGS: Both the number of metastases and metastatic clusters had a highly significant impact on OS (p < 0.0001, p = 0.003 respectively). Patients with a single metastasis or a single cluster of metastases (regardless of metastases number), equaling 16.2% of all patients, had significantly better prognosis compared to other patients (p = 0.0002). If metastases diameter variability is ignored, as in the standard definition of OD, then patients with 2-5 and 6-10 metastases would have a similar prognosis. INTERPRETATION: Patients with a single cluster of metastases, theoretically originating from a single clone, have significantly better prognosis compared to patients with more than one cluster. Using this definition can potentially improve the results of MDT. The upper limit of metastases number should be determined by the technical capabilities of the MDT used.

Patterns of metastases progression- The linear parallel ratio.

BACKGROUND: Linear and parallel are the two leading models of metastatic progression. In this study we propose a simple way to differentiate between them. While the linear model predicts accumulation of genetic and epigenetic alterations within the primary tumor by founder cells before spreading as waves of metastases, the parallel model suggests preclinical distribution of less advanced disseminated tumor cells with independent selection and expansion at the ectopic sites. Due to identical clonal origin and time of dispatching, linear metastases are expected to have comparable diameters in any specific organ while parallel metastases are expected to appear in variable sizes. METHODS AND FINDINGS: Retrospective revision of chest CT of oncological patients with lung metastases was performed. Metastasis number and largest diameters were recorded. The sum number of metastases with a similar diameter (c) and those without (i) was counted and the linear/parallel ratio (LPR) was calculated for each patient using the formula (∑c-∑i)/(∑c+∑i). A LPR ratio of 1 implies pure linear progression pattern and -1 pure parallel. 12,887 metastases were measured in 503 patients with nine malignancy types. The median LPR of the entire group was 0.71 (IQR 0.14-0.93). In carcinomas of the pancreas, prostate, and thyroid the median LPR was 1. Median LPRs were 0.91, 0.65, 0.60, 0.58, 0.50 and 0.43 in renal cell carcinomas, melanomas, colorectal, breast, bladder, and sarcomas, respectively. CONCLUSIONS: Metastatic spread of thyroid, pancreas, and prostate tumors is almost exclusively by a linear route. The spread of kidney, melanoma, colorectal, breast, bladder and sarcoma is both linear and parallel with increasing dominance of the parallel route in this order. These findings can explain and predict the clinical and genomic features of these tumors and can potentially be used for evaluation of metastatic origin in the individual patient.