The present disclosure provides advantageous systems and methods for significantly increasing the sensitivity and selectivity for diagnostic procedures, e.g., optical biopsy. The disclosed systems and methods use a highly non-linear effect, the so-called photon avalanche. In the regime close to the avalanche threshold, small differences in density of the probe-ion under investigation or the excitation power can result in very large changes in up-conversion emission intensity. Through this effect, it becomes possible to accurately measure the signal of an optical biopsy probe-ion only in the location(s) where its concentration is highest, while at the same time significantly reducing or eliminating measurement of background signal from probe-ions distributed with a somewhat lower concentration throughout the measurement volume. Also background auto-fluorescence of the surrounding healthy tissue is essentially absent with this technique.