Table 1 Differential Diagnosis of TUGSE

Location in the oral cavity

Tongue, buccal and vestibular mucosa, palatal mucosa, retromolar area, gingiva, floor of the mouth

Bottom of the oral cavity, lateral side and tip of the tongue, lower lip, retromolar area

Rarely in the oral cavity, often recurring lesions

Lips, tongue, pharynx

Oropharyngeal mucosa

Non-keratinizing epithelial surfaces in the mouth (labial and buccal mucosa, soft palate, lower side of the tongue); in patients with Severe aphthous stomatitis, the keratinized mucosa can also be affected

Etiopathogenesis

Unknown, causal connection with repeated trauma

Causal connection with chronic tobacco and alcohol consumption and poor oral hygiene

Typically in patients with an impaired immune system

Most commonly spread through unprotected (oral) sexual intercourse or congenital infection

Associated with immunosuppression

Stress, trauma, hormonal fluctuations, allergic reaction (certain foods, drinks, toothpastes and mouth rinses)

Peak age

Two peaks of life incidence: one during the first two years of life and another between the 5th and 7th decade

Most commonly after the 5th decade of life (men more frequently affected than women)

Elderly (> 75 years)

Most commonly between the 3rd and the 4th decade of life (men more frequently affected than women)

Primarily elderly (> 75 y), any age

Any age but the frequency increases later in life

Clinical features

Ulcer with elevated and indurated margins and yellowish fibrinous base

Endophytic growth, nodose and shallow ulcer with elevated margins, often covered by a non-strippable reddish, whitish or mixed focus growing infiltrative and destructive

Nodules or ulceration, indolent clinical behavior, primary cutaneous manifestation possible

Stage I (primary syphilis): after an incubation period of 2–3 weeks, the papule at the portal of entry converts into a indolent and superficial ulcers with indurated margins (also called primary chancre) multifocal, aphthous enanthema

Sharply circumscribed indolent ulceration

Nonspecific shallow round or oval painful ulcer, covered by a grayish-white fibrin pseudomembrane with a sharply defined erythematous border

Histopathology

Granulomatous tissue with a dense, diffuse, polymorphic, inflammatory infiltrate predominately of eosinophils and histiocytes, often extending into the submucosa, deeper muscle fibers and salivary glands

Epithelial differentiated structures with cornification (hyperkeratosis, parakeratosis, horn beads and multiple dyskeratotic keratinocytes) and peritumoral inflammatory reaction composed of a mixed cellular infiltrate, which is rich in plasma cells

Infiltrate of atypical lymphoid cells admixed with eosinophils involving the oral epithelium and the deep soft tissues

Significant plasmacytosis, plasmacell phlebitis, vague granulomas, detectable spirochetes (Warthin-Starry, immunohistochemistry)

Polymorphous infiltrate with inflammatory cells and atypical large B-cells blasts often with Hodgkin/Reed-Sternberg (HRS) cell-like morphology, sharply demarcated towards deeper structures (assessible only on excisional biopsies)

Nonspecific ulcer, inflammatory cells, predominately T-cells, with high local levels of TNF-α

Immunohistochemistry

Mixture of phenotypically regular T-lymphocytes, occasionally CD30+

CK5/6+, CK19+, p63+, p40+

MUM1p+, MYC+, CD30+ T-cells with antigenic loss of T-cell markers

Detection of Treponema pallidum by the following tests: TPPA test (Treponema pallidum particle agglutination assay test), FTA-ABS test (fluorescent treponemal antibody absorption test)

EBER+ (EBV encoded small nuclear RNA), CD30+

Nonspecific