**3. Histopathological and biological effects of LITT**

**1. Introduction**

284 Neurooncology - Newer Developments

chapter.

Laser interstitial thermal therapy (LITT) has established itself as a new treatment modality in neurosurgery due to its minimally invasiveness nature, safety and efficacy. Nowadays, LITT has become a reality in the world of neuro-oncology [1–4], epilepsy surgery [5–7], and is also emerging as an attractive option in the fields of spine surgery [8–10] and chronic pain syn‐ dromes[10–12]. In neuro-oncology, LITT has emerged as an option for malignant gliomas, refractory brain metastatic disease and radiation necrosis. LITT is best suited, but not limited, for patients with tumors located in deep-seated, difficult-to-access areas that could develop significant postoperative neurological deficits and poor performance status with traditional microsurgical resection. It is a FDA-approved treatment option for intracranial lesions includ‐ ing recurrent glioblastomas [4]. Concerning brain metastatic disease, although stereotactic radiosurgery (SRS) has become the standard of care for most patients, the failure rate associat‐ ed with SRS is up to 23% [13–15]. Additionally, the potential risk of developing radiation necrosis following SRS can vary from 1.4 to 24% [16–18], and this complication can be refractory to standard therapeutic options like steroids and Bevacizumab. LITT has been effective in managing both radiosurgery-resistant brain metastasis [2, 3, 19–22] and radiation necrosis [3, 21–24].

The surgical applications of lasers are represented by three distinct functionalities of this technology: photocoagulation, photovaporization and photosensitization [25]. LITT is referred to the first one, photocoagulation, which implies tissue damage by thermal energy provided by a source of constant and continuous laser delivery to a planned target volume. It was first introduced in 1983 by Bown and colleagues [26], who used a neodymium-doped yttrium aluminum garnet (Nd:YAG) laser and achieved focal tissue coagulation in an experimental brain tumor model without tissue vaporization. Research using experimental animal models demonstrated the brain tissue changes in response to hyperthermia and confirmed that coagulation necrosis could result from the application of thermal energy to brain tissue [27– 30]. However, the inability to monitor and control the laser-induced thermal effects limited the widespread application of this technology. Recent advances in magnetic resonance (MR) thermography [31] allowed real-time image feedback of laser thermal energy delivery, making

In the present chapter, the authors describe the current applications of LITT in neuro-oncolo‐ gy, including malignant gliomas, brain metastatic disease and radiation necrosis together with the basic principles and technical nuances related to the surgical procedure and the current LITT systems available in clinical practice. We also touched upon other applications of LITT such as cancer-related refractory pain and epilepsy. Future directions are also discussed in this

Treating cancers with heat energy dates back to 1960s when Rosomoff et al. [32] first report‐ ed the application of ruby pulsed laser beam in two patients with GBM and in experimental

it possible to predict the thermal damage of a planned target in the brain.

**2. Laser interstitial thermal therapy: principles and rationale**

Delivering thermal injury with LITT causes some major biological changes in the tissues [39]. Laser photons in the near-infrared range, when directed to the target tissue, get absorbed and converted to heat energy. Aided by abundant blood flow, conduction, convection and refraction all play a significant role in distributing the heat energy around the target tissue [39]. The inherent biology of the surrounding structures and the physical properties of the laser determine the uniformity in the distribution of the heat applied. Ablation of the entire target lesion is the primary aim of using LITT [40].

Cellular homeostasis is usually not disturbed with mild elevation in temperature to approxi‐ mately 40°C. However, when the temperature is increased in the range of 42 to 45°C (hyper‐ thermia), there is a substantial increase in susceptibility to cellular damage [40, 41]. When the temperature is increased from 46 to 60°C, marked cytotoxicity and cell death ensue with considerably decreased time needed to kill the cells [42, 43]. Above 60°C, there is substantial damage to the mitochondrial enzymes, cytosol and the nucleic acid proteins that culminate to coagulation necrosis [44]. Super boiling temperatures like 105°C results in charring, tissue boiling, vaporization, and carbonization which if not released immediately might culminate in increased intracranial pressure. Apart from the true values of the temperature used, the time of exposure to such temperatures is also important. For example, 43°C for 2 min causes reversibledamage to the tissue, while the same temperature for 10 min causes permanenttissue damage and for 60 min causes coagulative necrosis [22, 45]. Based upon the Arrhenius equation, only shorter intervals are needed when using high temperatures to get the same results [46].

The target lesion usually undergoes central coagulation necrosis following LITT therapy, surrounded by a zone of edema next to the undamaged tissue [36]. By the end of 1st week, granulation tissue gradually replaces the zone of necrosis. The targeted lesion then develops into a cystic lesion with remnant necrotic debris surrounded by reactive gliosis with mesen‐ chymal deposits [47, 48].

Three distinct zones can be identified on MRI following LITT. The first central zone repre‐ sents the zone of coagulation necrosis and ifthe temperature inadvertently exceeds 100°C, then there is a chance of charring and vaporization followed by a pseudo cavity formation. Just outside the core area lays a non-viable part with increased interstitial fluid called the inter‐ mediate zone. The outermost marginal zone is viable consisting of edematous viable sur‐ rounding brain parenchyma following thermal exposure and sharply delineates itself from the inner two zones. The ultra-structure of the inner two zones of thermal injury show disrupt‐ ed organelles and evidence of apoptosis, whereas the outer zone shows only axonal swelling, neuronal shrinkage and hypertrophied endothelial cells with no evidence of vessel thrombo‐ sis [4, 49–51]. Following LITT therapy, the target lesions might exhibit an increase in size due to necrosis and perilesional edema, but eventually will shrink and form a rim of granulation tissue.
