De Quervain's Tenosynovitis: This condition, which affects the tendons on the thumb side of the wrist, is a common cause of pain and tenderness in the area described, especially in middle-aged women. It often occurs without a history of trauma and can be related to repetitive activities or hormonal changes.

Osteoarthritis of the First Carpometacarpal Joint: This condition can cause pain and tenderness in the thumb, particularly in the thenar prominence area, and is common in middle-aged women. It may result from wear and tear over time.
Trigger Thumb: Although more common in the flexor tendon, trigger thumb can cause pain and a palpable nodule in the thenar area, leading to discomfort and tenderness.
Ganglion Cyst: A ganglion cyst near the wrist or on the thumb can cause localized pain and tenderness, although it might not directly cause thenar prominence.

Giant Cell Tumor of the Tendon Sheath: Although rare, this tumor can present as a painful mass in the thenar area and must be considered to avoid missing a potentially treatable condition.
Infection (e.g., Cellulitis or Abscess): Infections in the hand can quickly become serious, requiring prompt antibiotic treatment or drainage. While less likely without trauma, they are critical not to miss.
Neoplastic Processes (e.g., Sarcoma): Although extremely rare, any unexplained mass or persistent pain without a clear cause should prompt consideration of a neoplastic process.

Sesamoiditis: Inflammation of the sesamoid bones within the tendons of the thumb can cause pain but is less common.
Thenar Hypertrophy: A rare condition where the thenar muscles are overdeveloped, which could potentially cause prominence but is less likely to cause significant pain without other symptoms.
Neurological Conditions (e.g., Neuroma): A neuroma in the thumb area could cause pain and tenderness but would typically have additional neurological symptoms like numbness or tingling.