THE PATHOANATOMY OF CANCER
To comprehend the pathoanatomy of cancer one has to know the anatomy of the normal tissue. Conventional academic teaching conveys primarily form and function of the anatomical structures. This is not optimal to trace the locoregional spread of cancer as neither form nor function are the major spatial determinants of tumor propagation. The ontogenetic cancer field model has been deduced from aspects of evolution, development, immunity and wound healing/regeneration in multicellular animals and has been verified, so far by the locoregional spread of female genital and alimentary tract carcinomas.
The model postulates:
- Cancer cells canonically respond to the disruption of tissue homeostasis caused by their uncontrolled proliferation with progressive de-differentiation, which paradoxically enlarges the cancer wound instead of healing it.
- The de-differentiating cancer cells adhere in reverse sequence to a principle of topological order laid down during embryonic development by the metazoan cell type differentiation trajectory.
- Regional carcinoma spread is facilitated by the export of the local cancer field's determinants to draining lymph nodes by innate and adaptive immune responses involving pro-regenerative macrophages and regulatory T cells.
According to the cancer field model, the pathoanatomy of malignant solid tumors is accurately delineated and predicted by ontogenetic anatomy, which indicates the topology and genealogy of the anatomical structures, i.e. the spatial and developmental relations of a tissue of interest to its neighboring tissues.
Ontogenetic anatomy enables to decipher complex opaque anatomical regions such as the subperitoneum or the upper abdominal retroperitoneum unbiased by dissection artifacts. It is the foundation of cancer field surgery and immune network-directed lymph node dissection.
The ontogenetic cancer field model of locoregional tumor spread
The development of organisms from the fertilized oocyte (ontogenesis) proceeds with trajectories of successive bifurcations making up the pathways for the different cell types (cell lineage specification, cell fate progression). Complex epigenetic processes generate temporarily stable global chromatin structures that determine form and function of the corresponding cell type at the intermediate and terminal stages.
Each step in fate progression increases the morphological and functional complexity of the cell type at the cost of its plasticity concomitant with reduced positional potential. The tissue domains permissive for a distinct cell type become more and more specified.
Before determination, cells comprise the expanding habitats of multiple cell types whose stem cells can transdifferentiate into each other. Populations of determined cell types are confined to topographically defined compartments further segregating into subcompartments and finally zones of the mature organism.
The cancer field model considers cancer progression as pathological fate regression of transformed stem cells in the mature organism with a competent adaptive immune system. The tissues for potential local tumor progression, the cancer fields, represent the mature derivatives of the founder tissue domains in reverse sequence. Thus, an order of cancer is established. The topologic relationship between the local tumor extent and the mature tissues of sequential developmental steps determines the ontogenetic tumor stage (oT).
The regional lymph nodes executing peripheral immune tolerance for their tributary tissues provide additional permissive sites for discontinuous tumor spread, especially for epithelial neoplasms.
The ontogenetic cancer field model for regional progression of carcinomas assumes that memory Treg cells and memory Breg cells against peripheral antigens of the normal tributary tissue in the draining lymph node provide a proliferation matrix for tumor cells with similar antigens. Since the lymph nodes are invariably connected to their tributary regions through afferent lymphatics and exhibit common tissue antigens, the potential regional propagation field can be identified for each local cancer field of the individual neoplasm.
Considering the ontogenesis of the lymphatic system and secondary lymphoid tissue / lymph nodes allows the topographic identification of first-, second- and third-line lymph nodes with corresponding potential for metastases formation for any local cancer field and thus to establish an ontogenetic nodal staging system as well.
