Diagnosing syphilitic proctitis requires a multimodal approach: demonstration of T. pallidum—specific serology (e.g., VDRL, TPPA), imaging studies revealing the characteristic “target sign” of rectal wall enhancement on contrast-enhanced CT or MRI, endoscopic evaluation showing erythema, exudates, and ulcerations—and supportive histopathology, where immunohistochemical stains such as ERG and CD38 can help characterize the inflammatory infiltrate and aid in the differential diagnosis. Here, CD38 is linked to proctitis.