Nodal status assessment in melanoma.

Melanoma is the fastest growing and deadliest skin cancer with 5-year survival rates below 20 percent for advanced stage disease. Melanoma metastasis spread via the lymphatic system making the nodal status the most important prognostic indicator for overall survival and treatment decisions. The current gold standard to assess the SLN status consists of sentinel lymph node (SLN) detection via scintigraphy, followed by SLN excision and histology, a highly invasive procedure with radioactive burden for the patient. 80% of excised SLNs are negative and patients could have been spared the procedure if there was a method for non-invasive nodal status assessment.

In a clinical pilot study conducted at the University Hospital Essen, MSOT has shown the potential for non-radioactive localization of SLNs by tracking the lymphatic drainage of the near-infrared dye indocyanine green (ICG) from the primary tumor site to the nodal basin. Besides ICG detection, MSOT was able to visualize melanin deposits in the SLNs. The absence of melanin signal indicates tumor-free SLNs. This could potentially spare 50% of patients an unnecessary surgical procedure in the future. Ex vivo MSOT scans have also been used to guide pathology to melanin hotspots in the SLNs and increase cancer detection rate.

SLN detection with MSOT

A: Schematic drawing of axillary, cervical and inguinal locations of lymph nodes. ICG is injected intradermally at the borders of the primary tumor site. LN basins are screened by MSOT for lymphatic vessels that lead to the primary draining lymph node, the SLN, depicted in green.
B
: Schematic of the optoacoustic effect: Pulsed laser light in the near infrared wavelength range (NIR) is absorbed by tissue resulting in an ultrasound signal that is acquired by the MSOT detector.
C
Spectral image decomposition and analysis for ICG presence enables the visualization of draining lymphatic vessels and SLNs in the inguinal, cervical and axillary regions. Optoacoustic signal is overlaid on B-mode ultrasound.

Non-invasive SLN status assessment in melanoma patients

Patients were first imaged by a gamma camera (99mTc lymphoscintigraphy) to localize the SLNs (left column). MSOT (ICG and melanin) and histology were applied, as indicated here for three different patients.
A: Patient with no detectable metastasis. r. ax., right axillary node
B: Patient with a melanin signal in MSOT that is confirmed by the presence of pigmented cells in the high-magnification histology (marked by red arrows), where no evidence for metastasis was found in histology. l. ax., left axillary node
C: Patient with an SLN that is both MSOT-positive and positive for staining by MelanA immunohistochemistry

MSOT guidance for SLN pathology

A: Maximum intensity projection (MIP) visualization of an excised sentinel lymph node (SLN) scanned by MSOT. Melanin signal is pseudo-colored in red and superimposed on the single-wavelength optoacoustic image of the SLN.
B: Analysis of melanin content shows a peak concentration at a specific position depicted by the dotted line. This information can be used for guidance of pathological sectioning.

Furthermore, in a recent preclinical study performed at the Memorial Sloan-Kettering Cancer Center, MSOT was shown to be highly specific for detection of melanoma metastasis, enabling visualization of lymph node micro-metastasis as well as in-transit melanoma metastasis that were not detectable via FDG PET/CT scans.

MSOT vs. FDG-PET/CT imaging of melanoma metastasis

A: MSOT and FDG-PET/CT imaging of popliteal lymph nodes of a melanoma mouse model. Lymph nodes on the right-hand side (green dashed circles) are infiltrated with micrometastasis, whereas the contralateral side (white dashed circles) is tumor-free.
B: Quantification of MSOT and FDG-PET/CT signal in SLNs with micrometastasis relative to the contralateral healthy control node: Only MSOT is sensitive enough to detect micrometastasis.
C: Quantification of MSOT vs. FDG-PET imaging of in-transit melanoma metastasis (images not shown). Again, only MSOT shows higher signal in the metastasis than in the control side.

Stoffels, I., Morscher, S., Helfrich, I., Hillen, U., Leyh, J., Burton, N. C., Sardella, T.C.P., Claussen, J., Poeppel, T., Bachmann, H.S., Roesch, A., Griewank, K., Schadendorf, D., Gunzer, M., Klode, J., Metastatic status of sentinel lymph nodes in melanoma determined noninvasively with multispectral optoacoustic imaging, Sci. Transl. Med. 09 Dec 2015. DOI: 10.1126/scitranslmed.aad1278.

Neuschmelting V, Lockau H, Ntziachristos V, Grimm J, Kircher MF, Lymph Node Micrometastases and In-Transit Metastases from Melanoma: In Vivo Detection with Multispectral Optoacoustic Imaging in a Mouse Model. Radiology. 2016 May 4:160191. DOI: 0.1148/radiol.2016160191.

  • Ingo Stoffels et al.,
    Metastatic status of sentinel lymph nodes in melanoma determined noninvasively with multispectral optoacoustic imaging,
    Sci. Transl. Med. 09 Dec 2015. DOI: 10.1126/scitranslmed.aad1278.
    Link
  • Neuschmelting V et al.,
    Lymph Node Micrometastases and In-Transit Metastases from Melanoma: In Vivo Detection with Multispectral Optoacoustic Imaging in a Mouse Model,
    Radiology. 2016 Jul;280(1):137-50. DOI: 10.1148/radiol.2016160191.
    Link
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