TREATMENT CHALLENGES AND RISK STRATIFICATION FOR MELANOMA AND SARCOMAS

Background Patients with primary soft tissue sarcomas (STS) with negative prognostic features or primary cutaneous melanoma (CM) spreading to the regional lymph node (LN) are at risk of disease progression. This work is aimed at improving risk stratification for patients with high-risk STS and CM. Material and Methods In STS, we retrospectively investigated patients with primary tumours enrolled in two randomised controlled trials (RCT), one showing non-inferiority of three versus five perioperative chemotherapy cycles and one failing to demonstrate a survival advantage for adjuvant chemotherapy, using the prognostic nomogram Sarculator. Finally, tumour dedifferentiation, a prognostic feature embedded in this nomogram, was analysed in 20 patients with dedifferentiated (DD) retroperitoneal liposarcoma using RNA-sequencing. In CM, we investigated the prognostic value of sentinel LN (SLN) and non-SLN in a retrospective study (N=1,538). We examined immunohistochemistry (IHC)-detected lymphangiogenesis in patients with scalp CM (N=156). Finally, we tested whether IHC-detected markers of lymphangiogenesis and endothelial cell proliferation were associated to SLN and non-SLN metastasis in a retrospective analysis of 122 primary CM and SLN specimens. Results In high-risk STS, the Sarculator stratified three distinct overall survival (OS) categories (P<0.001) in a RCT investigating two different perioperative chemotherapy schedules. Tumour response according to Choi criteria differed across these categories and was associated with survival (P<0.001). When we applied Sarculator and used the same prognostic categories to stratify prognosis of STS enrolled in a RCT that tested the prognostic value of adjuvant doxorubicin plus ifosfamide, we showed that patients with extremity and trunk wall STS that fell in high and intermediate predicted OS categories did not show a survival benefit when treated with the study adjuvant chemotherapy. Conversely, patients with low predicted OS who received adjuvant chemotherapy had longer disease-free survival and OS. We also investigated tumour dedifferentiation showing that increased cell proliferation and reduced differentiation marked the transition from well differentiated (WD) to DD components. We investigated rhabdoid DD (R-DD) and myogenic DD (M-DD) and found suppression of genes related to inflammation and vasculature development in R-DD versus WD. Also, we identified an increase of genes related to immune and inflammatory response in the M-DD, a result that was validated using IHC markers CD4, CD34, CD163, and CD209. In SLN-positive CM patients, presence of non-SLN metastasis was an adverse prognostic factor for survival (P<0.001). AJCC TNM N stages were further stratified by non-SLN metastasis showing similar risk between patients with 1 positive SLN and 2-3 positive SLN with negative non-SLN (P<0.001). In scalp melanoma the degree of peritumoral and intratumoral blood vessel density (BVD) was greater than lymphatic vessel density (LVD) and ulceration was the only factor independently associated with intratumoral and peritumoral BVD. We then investigated several features of lymphangiogenesis in primary melanoma and SLN and found that peritumoral LVD in primary melanoma was associated with SLN metastasis, while proliferation index of lymphatics in the SLN was associated with metastatic spread to non-SLN. Also, intra/peritumoral blood/lymphatic vessel density in SLN metastasis was associated with patient survival. Conclusions In primary STS we showed the value of perioperative chemotherapy for higher risk patients and investigated the role of tumour differentiation. In CM, we demonstrated that SLN may act as a barrier for metastasis spreading through lymphatics a process that may be at least partially explain by lymphangiogenesis. These information may have implications for adjuvant/neoadjuvant treatments.