Modeling Multiscale Necrotic and Calcified Tissue Biomechanics in Cancer Patients: Application to Ductal Carcinoma In Situ (DCIS) - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 364

Fig. 12 Early DCIS simulations [ 57 ] neglected fast necrotic cell swelling and implemented a gradual
volume loss over 15 days. The simulations could not reproduce the tear at the perinecrotic boundary.
Necrotic cell lysis was too slow to sustain linear growth. Adapted with permission from [ 57 ]
[ 28 , 39 ]. Moreover, casting-type calcifications can be absent from small,
high-grade DCIS, while present in larger, low-grade DCIS [ 28 ]. Additional
biophysics (e.g., secretions, heterogeneous adhesion mechanics, or degradation over
long time scales) are required to model the broader spectrum of observed calcifi-
cations in DCIS. Our H&E images (Fig. 11 ) support this idea. The central regions of
many calcifications—which we have shown are associated with the ''oldest''
necrotic material—demonstrate significant cracks that suggest extensive degrada-
tion and weak cohesion.
Phospholipids—such as those from subcellular structures that likely form a
''backbone'' for the formation of microcalcifications—degrade with half-lives on
the order of 80 [ 3 ]-300 h [ 45 ] in non-pathologic tissue. Given this time scale, we
would expect necrotic tissues and their associated microcalcifications to degrade
over the course of a few months. This may partly explain rare cases of spontaneous
resolution of calcifications in mammograms, where calcifications become smaller
or occult without alternative explanations [ 81 ]: in slow-growing DCIS (e.g., with
both high PI and AI, as observed in high-grade DCIS [ 11 ]), calcifications may be
degraded more quickly than they are replaced by new necrotic material.
5 Discussion and Looking Forward
As we have seen, tissue necrosis and calcification are truly multiscale processes.
Early tissue-scale modeling [ 51 , 58 - 62 ]( Sect. 3 ) provided key insights on the role of
tissue necrosis in steady tumor spheroid sizes, and its potentially destabilizing role
when volume loss is rapid. Notably, these models can sufficiently predict the impact
of the necrotic core on the long-time volume and morphology of a tumor, allowing
quantitative predictions of progression. However, continuum modeling has thus far
focused on the slower time scale processes of fluid loss and solid degradation;
reformulation would be required to incorporate fast time scale processes like
swelling and lysis. This is an interesting shortcoming, given that these are key fea-
tures used to differentiate necrosis (and oncosis) from apoptosis in pathology.