Cutaneous Lymphomas In China’s Mainland And Biomarker Study Of Mycosis Fungoides

1.Background(1) The relative frequency of cutaneous lymphomas (CLs) differs according to geography and race. In2005, a new classification for primary cutaneous lymphomas (PCLs), named as WHO-EORTC classification was reached. Since then, many reports on the subtype distribution of PCL have been reported. Researchers have shown a difference in the subtype distribution of lymphoma between Asian countries and the West. Data that investigate the features of CLs is much more limited in China’s mainland, compared with the America and Europe. The etiology of CLs is still unknown. The difference in distribution may give some clue to identify the etiological factors of CLs.(2) Mycosis fungoides(MF) is the most common subtype of cutaneous lymphoma. Howeve, diagnosis of early-stage MF (patch and early plaque stage) is a challenge in dermatology due to the lack of sensitive and specific histological markers. Previous study demonstrated TOX gene is highly expressed in early-stage MF. The TOX gene’s expression ratio between MF and normal skin (NS) was10.38, while the ratio between MF and benign inflammatory diseases (BID) was5.36. Furthermore, the study also showed that TOX protein is positive stained in MF skin lesions by IHC, but not in normal skin or benign inflammatory diseases. So TOX may act as a molecular marker for histological diagnosis of MF. But since the study included only8cases for IHC, it was not convincible to prove TOX protein role as a marker for MF.2. Objective(1) To investigate the relative frequency of subtype of PCL and clinicopathological features of CLs in China and compared it with other countries, based on the2005WHO-EORTC classification.(2) To identify the expression of TOX protein in MF and analyze its role as a potential biomarker in differential diagnosis of MF.3. Methods(1)100patients with CLs attending the dermatologic department in China were reviewed and classified according to the2005WHO-EORTC classification.(2) Immunohistochemistry:In order to analyze TOX expression, we performed the immunochemistry in35cases of previously confirmed MF, with10cases of normal skin and20cases of BID (10cases of psoriasis,5cases of eczema,5cases of lichen planus) as controls.(3) Western blot and real-time PCR:Using TOX and CD4antibody, we performed Western blot in3newly-diagnosed MF cases, with2cases of normal skin and2cases of psoriasis as controls. We also conducted real-time PCR to analyze the expression of TOX mRNA.4. Results(1) Of100CL cases,98had primary cutaneous lymphomas (PCLs) and2had secondary cutaneous lymphomas (SCLs). The group of PCLs consisted of T-and natural killer-cell lymphomas (CTCLs)(94%), and cutaneous B-cell lymphomas (CBCLs)(6%). Compared with the West, Chinese population presented with a higher rate of CTCLs (94%vs.77%or71.3%) and a lower rate of CBCLs. The1-year overall survival rate was90%for all PCL patients after the diagnosis. Estimated survival of patients with mycosis fungoides depended on the stage. The1-year DSS in the early stage of MF was100.0%, whereas in advanced stage60%. The difference was statistically significant by Fisher’s exact test(P=0.002).(2) Immunohistochemistry:The MF cells were stained positive by TOX and CD4in32(91%) cases out of35MF skin specimens. The epidermotropic cells in Pautrier’s microabscesses were also stained. In the control group,8cases (40%)of BID and0case of NS were stained positive by TOX and CD4.(3) Western blot and real-time PCR:TOX protein was expressed in MF as well as in normal skin and psoriasis. TOX mRNA was highly expressed in MF, but in NS and BID, it was little expressed.5. Conclusion(1) The etiology of CLs is still unknown. Since the relative frequency of lymphomas differs according to geography and race, it may give some clue to identify the etiological factors of CLs. But, further investigations in other Asian countries are needed. The estimated survival rate of patients with CLs depended largely on the stage. It is important to improve the pathological methods and establish an early diagnosis.(2) TOX was positively expressed in91%MF skin lesions vs.0%in normal skin and40%in BID. The difference was significant by χ test. Furthermore, the high expression of TOX protein in MF was proved by Western blot. This study demonstrated TOX protein may serve as a molecular marker in differential diagnosis of MF. Further study with large number of cases is needed to verify this.