International journal of dermatology · 2025
Upregulated NOTCH2 Expression Is Implicated in the Clinical Aggressiveness of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma.
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Lee Yi-Pei, Razegphpour Fahimeh, Sorescu Emilia, Stücker Markus, Gambichler Thilo
Аннотация
BACKGROUND: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) represent clinicopathological variants of a spectrum. It is known that AFX and PDS tumors harbor frequent NOTCH1/2 mutations. However, the expression of Notch signaling pathway-associated proteins in both tumor cells has not been studied before.
METHODS: We conducted an immunohistochemical study by performing NOTCH1, NOTCH2, NICD, and HES1 staining on the most representative formalin-fixed paraffin-embedded (FFPE) tumor tissues out of sixty-two patients with the first diagnosis of either AFX (n = 33) or PDS (n = 29) in a single tertiary medical center.
RESULTS: Ten patients (PDS, n = 9; AFX, n = 1) had disease progression in terms of locoregional relapse, including local recurrence and regional lymph node metastasis, with a median time-to-(first)-recurrence interval of 8 months after a wide local excision. Among all the Notch expression profiles, only the upregulated NOTCH2 expression has a positive correlation with disease progression [odds ratio (OR): 1.02, 95% confidence interval (CI): 1-1.04, p = 0.029]. Furthermore, HES1 is activated through the NOTCH2 signaling pathway (r (60) = 0.27, p = 0.032) rather than NOTCH1, and NOTCH1 does not appear to be functionally active.
CONCLUSIONS: Upregulated NOTCH2 expression plays a significant role in disease progression, in part through the canonical signaling pathway involving the downstream effector HES1. Targeting NOTCH2 signaling might hold therapeutic promise in patients with disease progression.
METHODS: We conducted an immunohistochemical study by performing NOTCH1, NOTCH2, NICD, and HES1 staining on the most representative formalin-fixed paraffin-embedded (FFPE) tumor tissues out of sixty-two patients with the first diagnosis of either AFX (n = 33) or PDS (n = 29) in a single tertiary medical center.
RESULTS: Ten patients (PDS, n = 9; AFX, n = 1) had disease progression in terms of locoregional relapse, including local recurrence and regional lymph node metastasis, with a median time-to-(first)-recurrence interval of 8 months after a wide local excision. Among all the Notch expression profiles, only the upregulated NOTCH2 expression has a positive correlation with disease progression [odds ratio (OR): 1.02, 95% confidence interval (CI): 1-1.04, p = 0.029]. Furthermore, HES1 is activated through the NOTCH2 signaling pathway (r (60) = 0.27, p = 0.032) rather than NOTCH1, and NOTCH1 does not appear to be functionally active.
CONCLUSIONS: Upregulated NOTCH2 expression plays a significant role in disease progression, in part through the canonical signaling pathway involving the downstream effector HES1. Targeting NOTCH2 signaling might hold therapeutic promise in patients with disease progression.