Optical spectroscopy as a novel tool in the diagnostics of skin neoplasms.

Skin cancer is the most common type of cancer in The Netherlands. Research by
the Integrated Cancer Center Netherlands showed that in 2011 over 11.000 new
cases of skin cancer were reported. This figure is excluding the most common
type of skin cancer, basocellular carcinoma. Although not centrally registered,
it is estimated that this type is newly diagnosed over 20.000 times each year.

The diagnosis of skin cancer consists of several steps. First, the physician
will make a list of differential diagnoses based on clinical findings.
Subsequently, a biopsy is performed, which is sent to the pathologist for
histological examination. The treatment is based on the outcome of this
histological examination. The process of pathologic examination takes time and
money. Furthermore, subtle changes in the nanostructure of the tissue, early
indicators of disease, are missed in conventional, routine histology.

To expand the diagnostic process, this research proposal will investigate the
value of multi-diameter single fiber reflectance (MDSFR) spectroscopy. MDSFR is
a new quantitative diagnostic tool based on the light scattering, absorption
and fluorescence properties of tissue. It consists of a multiple fibers
embedded in a single probe with a light emitting and collecting part. Light
that is directed at the skin will be scattered in other directions by
(sub)cellular structures. Additionally, part of the light will be absorbed by
melanin in melanocytes and hemoglobin in erythrocytes. Furthermore, some
absorbing molecules (e.g. NADH, FAD, collagen, keratin) re-emit light at a
higher wavelength (fluorescence). Differences in the light scattering,
absorption and autofluorescence properties between normal and suspicious skin
can be measured with this new method. These changes may be related to cancer.
In a similar way, in other fields of research, lung cancer, diabetes mellitus
type and monitoring during photodynamic therapy (PDT) and outcome of PDT were
investigated.

MDSFR has been studied extensively in skin-mimicking phantoms. With the use of
mathematical models, behavior of light in this skin-like environment was
examined. Absorption, scattering and fluorescence could be readily measured.
Changes in the ultrastructure of the skin occur early in the development of
cancer. It is hypothesized that these changes are due to disturbances in the
cytoskeleton. We hypothesize that MDSFR spectroscopy will be sensitive to these
early changes and thus pick up cancer earlier in its development.

Primary Objective: To quantify the tissue light scattering, absorbing and
fluorescence properties of different stages of skin (pre)cancer using
multi-diameter single fiber reflectance (MDSFR) spectroscopy.

Secondary Objective(s): To correlate the measured light scattering properties
to the underlying nanoscale structural changes within the tissue by performing
electron microscopy on biopsies taken at the same location as the optical
measurements.

The design of the experiment will be an observational non-randomized cohort
study of which the majority of subjects will only undergo non-invasive
(optical) measurements. A small subset will also undergo a biopsy.

If conventional pathology concludes a different diagnosis as the clinical
diagnosis, the subject will be placed in the appropriate study arm or excluded.
Lesions that do not fit in any arm after conventional pathology will be
discarded.

No serious adverse side effects are expected from MDSFR measurements. The
intensity of the light (from a halogen light source) used in the measurements
is less than 200 microwatts, which is far beneath the threshold for thermal
damage of tissue; the patients tissue as well as the eyes of the bystanders are
not at risk. Other damage mechanisms at these wavelengths (>400 nm) are not
known. The intensity of the light from an LED (365 nm) to induce fluorescence
is less than 100 microwatts, which is an order of magnitude below the exposure
limit.

After biopsy, there is a small chance of hemorrhage or infection. Both risks
are low.