Ulcerative and inflammatory conditions

Clinical findings

• Idiopathic aphthous ulcers: Onset is generally in the second and third decades of life with a 2:1 female predilection, and lesions diminish in severity with age with complete resolution by age 50 in most cases. Ulcers are episodic but may be continuous in severe/complex cases, be single or multiple, and occur almost exclusively on the nonkeratinized mucosa. They are sharply demarcated and painful, and composed of a yellow fibrin membrane with surrounding erythema.

• Four clinical types are recognized ( Fig. 7.1 A–E):

  • Minor ulcers are the most common (>80%), are <1 cm in size, and last 1 to 2 weeks; the number of episodes each year varies depending on the individual.

  • Herpetiform ulcers are uncommon and number more than 10 small ulcers (usually 0.1–0.5 cm) at each episode and last t to 2 weeks.

  • Major ulcers are the least common, are larger than 1 cm in size, last for weeks or months, and may be associated with scarring.

  • Severe/complex aphthous ulcers present as continuous minor aphthous ulcerations with overlapping episodes and few or no ulcer-free days for months.

  

• Aphthous-like ulcers associated with systemic disease may occur on the keratinized mucosa ( Fig. 7.1 ). Ulcers in periodic fever, aphthae, pharyngitis, and adenitis (PFAPA) tend to occur in the first decade and are associated with high white cell counts and C-reactive protein. Those associated with chemotherapy last for 1 to 2 weeks and resolve when neutropenia resolves, while those associated with targeted therapies (such as mechanistic target of rapamycin [mTOR] inhibitors or checkpoint inhibitors) regress on discontinuation of therapy ( Fig. 7.1 F–G). Aphthous-like ulcers associated with medications tend to occur in older individuals.

• Behçet disease is most frequently encountered in countries on the “Silk Road” especially Turkey and countries around the Mediterranean and has a male predilection, unlike idiopathic aphthous ulcers. It is an autoinflammatory vasculitic condition and diagnostic criteria based on a point system have been established for Behçet disease with high sensitivity. Oral aphthous-like ulcers, genital ulcers, and eye lesions (especially uveitis) are the most important and consistent findings ( Table 7.2 ) ( Fig. 7.1 H–I). Skin findings take the form of erythema nodosum and pseudofolliculitis, and >70% of patients are positive for HLA-B51 and for HLA-B5.

  TABLE 7.2

  International Criteria for Diagnosis of Behçet Disease by Point Scoring System

  Sign/Symptom	Points a
  Ocular lesions	2
  Genital ulcers	2
  Oral ulcers	2
  Skin lesions	1
  Neurologic manifestations	1
  Vascular manifestations	1
  Positive pathergy test	1 b

  a ≥4 points is strongly suggestive of Behçet disease.

  b Pathergy testing is optional and primary scoring system does not require this.

Etiopathogenesis and histopathologic features

Most cases of recurrent aphthae have a strong family history of recurrent aphthae, and some human leukocyte antigen A haplotypes have been identified that segregate families with this condition. Tumor necrosis factor (TNF)-α plays an important role in etiopathogenesis. PFAPA syndrome, Behçet disease, and idiopathic aphthous ulcers may share risk loci on IL12A , IL10 , and other genes. Histopathologic features of aphthous ulcers, traumatic ulcers, and ulcers of Behçet disease are indistinguishable, and it is the clinical findings and history that assist in the diagnosis. Biopsies are often performed to rule out an autoimmune vesiculobullous disease.

• Ulcers consist of a fibrin membrane with enmeshed neutrophils and underlying granulation tissue with acute and chronic inflammatory cells confined to the lamina propria and sometimes involving superficial skeletal muscle fibers.

• The adjacent epithelium exhibits spongiotic pustules and reactive atypia such as basal cell hyperplasia, nuclear hyperchromasia, and slight pleomorphism. ( Fig. 7.2 A–B).

  

• Secondary vasculitis with fibrinoid necrosis of endothelium and leukocytoclasis may be seen in severe cases but should not be misdiagnosed as a true primary vasculitis (see Fig. 7.2 C–D).

• Spread of inflammation to underlying muscle results in myositis and, if chronic, develops into traumatic ulcerative granuloma with or without stromal eosinophilia.

Differential diagnosis

• Traumatic ulcers often but not invariably exhibit parakeratosis adjacent to the ulcer, there is generally a history or signs of trauma, and they are not episodic (Fig 7.3).

  

• The epithelium adjacent to the ulcer should be evaluated for herpes simplex virus cytopathic effect, and the connective tissue should be scrutinized for cytomegalovirus, Epstein-Barr virus, and fungi in immunocompromised patients, and immunostains performed as necessary.

• Traumatic ulcerative granuloma is characterized by inflammation within the muscle associated with many eosinophils and macrophages, and muscle fragmentation and degeneration. Eosinophils may be seen at the base of aphthous ulcers but myositis is required for this diagnosis.

• Neutropenic ulcers have scarce neutrophils ( Fig. 7.4 ).

  

• Erythema multiforme involving only the oral cavity may be very difficult to distinguish histopathologically from aphthous ulcers, since typical satellite cell necrosis is infrequently encountered and it is the clinical presentation especially a previous bout of herpes labialis, that is more helpful.

Management and prognosis

• Topical corticosteroid therapy and topical analgesia are effective for managing acute episodes of aphthous ulcers, though idiopathic aphthous ulcers are episodic and will recur ( Appendix A ). Pentoxifylline is sometimes effective. Aphthous major and severe and/or continuous aphthous ulcers usually require systemic therapy with prednisone, colchicine, mycophenolate mofetil, thalidomide, and TNF-α inhibitors. Apremilast and cimetidine are efficacious for ulcers in Behçet disease and PFAPA syndrome, respectively.

• For systemic conditions presenting with aphthous-like ulcers, careful history taking and work-up establishes the diagnosis.

• Adenotonsillectomy may be effective in some patients with PFAPA syndrome.

Clinical findings

• Adult form: This occurs as a sharply punched-out ulcer, often with a white, keratotic rim, commonly on the lateral tongue, present for weeks, with or without pain, and raising the suspicion for malignancy. Any site with underlying muscle may be involved ( Fig. 7.5 A–C). Synchronous bilateral lesions or metachronous lesions may occur.

  

• Infantile form (Riga-Fede disease): This occurs in the first year of life when newly erupted incisors traumatize the ventral tongue or lip mucosa (see Fig. 7.5 D).

Etiopathogenesis and histopathologic features

Traumatic ulcerative granuloma is secondary to deeply penetrating inflammation involving the underlying skeletal muscle and is most often associated with trauma although less than 50% of patients report such a history. It may be primary or secondary to trauma to another preexisting condition.

• There is an ulcer with acute and chronic inflammation that penetrates into the muscle with separation and degeneration of muscle fibers, sometimes with a “checkerboard” pattern, proliferation of macrophages, and many eosinophils ( Figs. 7.6 and 7.7 A–C). However, eosinophils may be sparse or even absent, depending on the stage of the ulcer.

  

• Mononuclear cells are CD68+ and CD163+, and scattered factor XIIIa+ cells may be seen (see Fig. 7.7 D).

  

• Scattered CD30+ cells are seen in up to 50% of cases.

Differential diagnosis

• The mere presence of eosinophils at the base of an ulcer in the lamina propria is not sufficient for the diagnosis as this may occur as a nonspecific finding and is commonly seen in aphthous and traumatic ulcers.

• Diffuse, large B-cell lymphoma consists of sheets of large atypical cells that show immunohistochemical markers for lymphoma. It is unclear if previously reported cases of atypical histiocytic granuloma may represent such lymphomas.

• Epstein-Barr virus–associated mucocutaneous ulcers contain many CD30+ and Epstein-Barr virus–encoded RNA-positive B cells; atypical Hodgkin-like cells; and Reed-Sternberg–like cells (see Chapter 4 ).

Management and prognosis

• Lesions often heal after biopsy; otherwise, topical corticosteroids, intralesional corticosteroid injections, or complete excision are indicated (see Appendix A ).

• Recurrence is common, especially if the patient has a flabby or enlarged tongue such as in older patients who wear lower full dentures or who have lost teeth in the posterior mandible.