Patterns of metastases progression- The linear parallel ratio

Abstract

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.

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

“…The concept of OD envisioned by Samuel Hellman in 1995 has attracted much attention in recent years [ 1 – 5 , 8 , 11 , 12 ]. It hypothesizes an interim condition in which a tumor has spread to only a few sites and cure by MDT may be possible.…”

“…The model presented here, with the suggestion of qualifying only patients with a single metastatic cluster (representing a single clone) in the definition of OD, is obviously oversimplified. Yet it could be useful for planning clinical research in OD and may potentially provide better results compared to the poor results obtained with the standard definition of five metastases or less [ 3 – 5 , 8 ].…”

“…When the OD concept was employed in renal cell carcinoma, local results were good with 1-year in-field progression free survival of 70%, but only 39% 1-year out of field progression free survival [ 4 ]. In CR cancer, OD treatment with SABR provided a 3-year local control of 64.9% but relapse-free survival was only 24.9% [ 8 ]. Taken together, these results suggest that many patients currently diagnosed with OD have far more advanced, micrometastatic diseases.…”

Dormancy of cutaneous melanoma

“…Metastatic progression is assumed to be either linear or parallel [ 43 , 50 ]. In 1989, Clark et al describes metastasis as a linear process in which tumors accumulate genetic and epigenetic alterations and progress from radial, to vertical, to invasive growth phases after which tumor cells disseminate [ 51 ].…”

Evaluation of premetastatic changes in lymph nodes(pN0) of oral tongue tumour: A prospective observational Study

“…45,46 Metastatic progression is now presumed to be of linear and parallel models. [47][48][49] The genetic and epigenetic alterations within the primary tumor waves metastases in the linear progression model whereas in the parallel model, the preclinical distribution of less advanced disseminated tumor cells with self-regulating selection expands at the ectopic sites. [47][48][49] The presence of CTC can characterize both tumor progression models or even indicate lymph node skip metastasis.…”