Epigenomic excision for proteus nevus lipomatosis, rare PTEN overgrowth, and robotic debulking

Dear Editor, Proteus syndrome is a very rare condition associated with asymmetric, mosaic and progressive overgrowth of various tissues (skin, adipose tissue, bone and vasculature) and is thus an early disorder onset, making the cutaneous and subcutaneous manifestations one of the earliest clinical indicators as they can be the first to show up1. Even though classic Proteus syndrome is most often associated with mosaic activating mutations in the AKT1 gene, PTEN-related overgrowth syndromes in the wider context of activating mutations in the PI3K/AKT/mTOR pathway have been described and are now thought to be within the spectrum of overgrowth disorders2. PTEN functions as a tumor suppressor gene and is central to regulating cellular proliferation and formation, a hallmark of such conditions3. A spectrum of PTEN-related overgrowth localized hyperplasia, lipomatous overgrowth, and cutaneous hamartoma are caused by a tumor suppressor, PI3K-AKT signaling receptor, which operates as a negative regulator (Post-zygotic loss of PTEN function)2. PTEN is a negative regulator in PI3K/AKT/ mTOR pathway which controls cell growth, proliferation and adipose differentiation. PTEN germline or somatic mutations lead to uninstigated downstream phenotypes of activation and overgrowth3. The loss of the PTEN mosaic offers the tissue regions with uneven rates of proliferation and structural heterogeneity that complicate clinical management and results in unequal distribution of lesions2. PI3K/AKT/mTORPI3K signaling, particularly mTOR inhibitors, sirolimus and everolimus have shown positive but incomplete somatic overgrowth using this pathway. The few cases and the initial trials suggest that no pharmacological modulatory cure, which can reverse the growth of proliferative activity of segmental overgrowth lesions, but not permanently reduce adult adipose and fibrotic foci can be found4. This is a partial effect or in some cases suppressive effect that is estimated to inhibit active growth by about 55% and underscores the fact that pharmacological suppressiveness alone may not be enough to reverse established hamartomatous tissues enough to warrant the need to depend on procedural strategies5. In addition to permanent genetic mutations, epigenomic control has a key role to play to describe the clinical heterogeneity of the Proteus syndrome and the associated overgrowth disorders. Such a heterogeneity of epigenomic regulation, such as DNA methylation and histone modification, can contribute to the observed patchy, segmental nature of overgrowth and the wide variability of disease severity even in individuals with similar genetic alterations2. This level of regulation is useful in explaining the mechanisms of disease progression and tissue specificity and provides a conceptual framework in future personalized therapeutic approaches. The surgical debulking has been long-standing in the treatment of symptomatic overgrowth and lipomatous lesions. Robotic-assisted surgery has the benefits such as high three-dimensional (3D) resolution imaging, tremor suppression, magnification, and articulated surgical instruments, capable of dissecting the body in millimeter increments. They make robotic-assisted debulking a potential development in the treatment of Proteus-related lesion since these features improve accuracy and manipulation of tissues. Proteus Nevus lipomatosis is extremely difficult to manage surgically due to the progressive nature, vascularity as well as the high rates of recurrence of the lesion. Traditionally, it was treated with staged surgical excision/debulking that was frequently conducted in a series of operations to minimize bleeding and maintain functionality. This method may reach temporary contour improvement however it frequently results in severe scarring, spotty growth and accrued morbidity. Most importantly, traditional excision is mostly anatomical but not biological6. Stage debulking never addresses the inherent mosaic overgrowth heterogeneity. There is both active and inactive tissue proliferation in that lesion. However, the surgical judgment was greatly motivated by the surface morphology and bulk as the basis. This incompatibility probably helps to cause partial clearance and reoccurrence. Recurrent surgeries can increase fibrosis and limit options in future reconstructive surgeries7. One of the largest but least well-known obstacles is the phenomenon of the vascular paradox as a result of PTEN-induced overgrowth lesions. These lesions frequently have ineffective and turbulent blood flow irrespective of their pronounced hypervascularity and atypical angiogenesis. Weak, dysplastic vessels are accompanied with areas of relative ischemia, whereby they leave an operative field that is likely to cause excessive bleeding but on the flip-side, poor wound healing is observed. This paradox makes traditional surgery more difficult, the stronger excision, the more at risk of hemorrhage, but the less radical excision, the risk of having residual biologically active tissue that might still proliferate8. When in this state, the laser-assisted selective ablation goes beyond saving tissue, but also more in line with the biological behavior of such lesions. Focused photothermolysis allows debulking fibrofatty tissue to occur in layers and even coagulates the abnormal vasculature curtailing blood loss and collateral tissue damage. This form of laser treatment enables the treatment to be directed to the metabolically active component only and leave the rest of the tissues intact thus reducing the amount of scarring. This technique is further improved by the use of robotic and image-guided debulking. Sonography or MRI-based 3D Photography incorporates AI-driven volumetric analytics in order to enforce close monitoring of the lesion load, to determine growth-dominant regions, and to plan the procedure, among others. The tools can assist the surgeons to calculate the adequate time and extent of intervention that may make surgery not a reactive but a data-driven and accurate approach7. The future of the surgical management of proteus-related nevus lipomatosis is in the transition of repetitive excision to biologically aware and precisely controlled debulking. Selective laser technology, sonography and modern imaging could decrease recurrence, morbidity of the procedure and functional losses in the long run. Developing organized surgical pathways to introduce these novelties would help enhance the outcomes of this rare and surgically complicated condition7. Although no direct studies have been performed regarding the role of robotic debulking in Proteus syndrome, given the infrequency of the disorder, there is evidence of its successful use in complicated tumors of soft-tissue. This implies that robotic assisted methods may work in selected patients especially in multidisciplinary centers with specialized skills. The best management of PTEN-related Proteus syndrome with nevus-associated lipomatosis should consider a multidisciplinary strategy that may include dermatologists, geneticists, and surgeons4. Long-term outcomes, standardized reporting of surgical procedures, and the further explanation of the role of epigenomic factors in the development of disease behavior should be considered as the directions of the future research2,3. The PTEN-associated Proteus syndrome in conclusion is a complicated combination of genetic dysregulation, the epigenomic regulation, and challenging clinical manifestations. The case of nevus-associated lipomatosis is an example of the challenges posed when dealing with such patients. The connection between the developments in the field of molecular biology and novel surgical procedures like robotic debulking is potentially a way forward in enhancing patient outcomes at the lowest possible functional cost1. This manuscripts adheres with the TITAN guidelines.9