NONINFECTIOUS ULCERS

Aphthous ulcer and complex aphthosis

Epidemiology and clinical manifestations

Aphthous ulcers (“canker sores”) of the mouth occur in a very large proportion of the normal population. Studies in western societies suggest a point prevalence rate of 1–2% and a lifetime incidence rate of 60%. Risk factors for the development of oral aphthous ulcers include a positive family history, white race, high socioeconomic class, and psychological stress factors. Vitamin and iron deficiency is found fairly frequently but this may be coincidental because replacement of the deficiency does not improve the course of the disease. Lesions first begin to appear in childhood or adolescence. Peak frequency occurs in early adult life and then starts to decrease with age. Most patients tend to have periodic recurrences.

Gynecologists and dermatologists generally believe that aphthous ulcers occur only rarely on the vulva. The medical literature seems to support this belief. Even though the first patients with noninfectious vulvar ulcers of this type were reported by Lipschutz as far back as 1913, there are only a handful of such patients described in published reports. Only a single manuscript describes incidence or prevalence rates ¹. However, our own experience, along with discussion among colleagues, suggests that aphthous ulceration of the vulva occurs with some frequency. The risk factors for development of vulvar ulcers of this type are the same as those described for oral disease and, similarly, recurrences are common.

Oral aphthous ulcers have been classified into three groups: (1) minor aphthous ulcers – small lesions (< 1.0 cm) that heal without scarring in 7–10 days; (2) major aphthous ulcers – large, deep lesions (> 1.0 cm) that heal, often with scarring, in 10–30 days; and (3) herpetiform aphthous ulcers – multiple, clustered, shallow, small (1–3 mm) ulcers that heal quickly, generally without scarring. Vulvar lesions can be classified similarly, though a larger proportion falls into the category of major aphthous ulcers than is true for the mouth. The term “complex aphthosis” is used when vulvar ulcers occur synchronously or metachronously with oral ulcers.

The best data regarding vulvar aphthous ulcers are found in the recent report by Huppert et al.¹ These authors described 20 females with idiopathic vulvar ulcers. The mean age of the patients was 14 years (range 10–19 years). Most ulcers were less than 1 cm in diameter but one patient had a 5-cm lesion. Multiple lesions were almost always present, occurring in 17 of 20 patients. The most common site was within the vestibule but ulcers were also occasionally found on the keratinizing epithelial surfaces of labia majora and perineum. (This is in marked distinction to oral aphthae, which are never found on the perioral skin of the face.) Half of their patients reported oral lesions and one-third developed recurrences of their vulvar ulcers. My experience is very similar, though a larger proportion of my patients have had oral lesions and multiple vulvar recurrences.

Individual lesions start out as round to oval ulcers but coalescence of neighboring lesions can result in larger ulcers with serpiginous borders (Figures 21.1–21.5). A red rim of erythema (2–3 mmwide) is present and, at the base of the ulcers, there is usually a white coagulum of necrotic tissue. The ulcers are quite painful and healing generally requires 2–3 weeks. Scarring can occur but it seems less severe than would be expected given the size and depth of the lesions.

Figure 21.1 This painful ulceration was preceded by fever, sore throat, and myalgias in the 12-year-old daughter of a clinic nurse, who recognized the very typical clinical picture.

Figure 21.2 Although aphthae are more often seen on mucosae or the modified mucosae, they can occur on hair-bearing skin as well.

Figure 21.3 Oval, punched-out ulceration on modified mucous membranes is typical for aphthae.

Figure 21.4 Irregular, sharply demarcated aphthous ulcer with a yellow fibrin base in a patient with concomitant oral aphthae.

(Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 18-1), New York: Churchill Livingstone;1994.)

Figure 21.5 Very large aphthae sometimes heal with considerable scarring.

(Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 18-2), New York: Churchill Livingstone; 1994.)

Systemic symptoms and signs such as fever, malaise, headache, gastrointestinal distress, pharyngitis, and myalgia occur in many of these young women with complex aphthosis but these are usually mild, time-limited, and nondebilitating ¹.

Diagnosis and differential diagnosis

The appearance of these aphthous ulcers is sufficiently distinctive that, in association with a history of recurrence, a clinical diagnosis is possible. Since there are no microscopic or laboratory features that positively identify the disease, the only way to confirm a clinical diagnosis is to rule out conditions that simulate it (Table 21.1). Genital herpes (herpes simplex virus: HSV) is almost always a consideration but, with the exception of chronic HSV infection in the immunosuppressed, the lesions of herpes are not as large or deep. However, in some instances, immunofluorescent smears, culture, and biopsy may be necessary to rule out herpetic infection. Primary syphilis (chancre) can be identified by serology and biopsy. Cultures and/or biopsy are appropriate to rule out the anogenital ulcers of Crohn’s disease as well as the lesions of chancroid, granuloma inguinale, and various cutaneous malignancies.

Table 21.1 Aphthous Ulcers and Complex Aphthosis

Diagnosis

Painful, deep ulcers

No undermining of edges

Thin red border

White coagulum at the ulcer base

History of recurrence

Differential Diagnosis

Herpes simplex virus in the immunosuppressed

Crohn’s disease

Primary syphilis

Therapy

Rule out associated disease, especially Behçet’s disease

Lidocaine or silver nitrate for pain

Topical or intralesional steroids

Oral antibiotics as anti-inflammatory agents

Consider short-term systemic steroids

Consider dapsone, colchicine, thalidomide

As indicated above, complex aphthosis is the term used when vulvar aphthous ulcers occur in association with either a synchronous or metachronous history of oral aphthous ulcers. Patients with complex aphthosis and no related underlying disease are said to have primary complex aphthosis. When patients do have an associated systemic disorder, the term “secondary complex aphthosis” should be used.

Several systemic conditions occur in association with secondary complex aphthosis. Oral and vulvar ulcers are a consistent and characteristic feature of Behçet’s disease and this latter disorder must be considered when patients with complex aphthosis are encountered. However, it should be emphasized that, in Europe and North America, young women with complex aphthosis almost never have, or evolve into, Behçet’s disease. Needless to say, a diagnosis of Behçet’s disease should not be made unless the International Study Group (ISG) and/or O’Duffy diagnostic criteria are strictly met.

Aphthous ulcers also occur quite regularly in the setting of inflammatory bowel disease. For that reason patients should be queried regarding the symptoms and signs of associated Crohn’s disease and ulcerative colitis. Other rarely associated conditions include gluten-sensitive enteropathy, lupus erythematosus, cyclic neutropenia, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) infection, the MAGIC syndrome (mucosal and genital ulcers with inflamed cartilage) and the PFAPA syndrome (periodic fever, aphthosis, pharyngitis and adenitis).

Histology and laboratory tests

Aphthous ulcers have a rather nonspecific histologic appearance. The earliest lesions demonstrate a predominantly lymphocytic inflammatory infiltrate but later lesions show both a lymphocytic reaction and a central area of intense neutrophilic inflammation with blood vessel destruction and necrosis of the involved tissue. A pathologist encountering this inflammatory pattern will not be able to make a definitive diagnosis of aphthous ulceration but generally can state that such a biopsy is consistent with that diagnosis.

Because there are several medical problems that can be associated with complex aphthosis (see above), a complete medical history must be taken. Laboratory tests are then chosen based on a history of specific problems. Letsinger et al. have recently suggested specific steps for laboratory evaluation ².

Pathogenesis

The cause of aphthous ulceration is not known. Based on the high frequency of a positive family history, genetic factors are probably important. It has been hypothesized that inheritance involves the predisposition to develop a more brisk than normal cell-mediated immune response to one or another unrecognized antigen. Although the nature of the antigen(s) has not been identified, there is some evidence to suggest that microbial proteins, by way of molecular mimicry, initiate an autoreactive (autoimmune) response. In any event, activation of the cell-mediated immune response results in the generation of many inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-2. Both the activated immune cells and the cytokines they release are presumably cytotoxic to epithelial cells and possibly also to fibroblasts. Risk factors for the development of aphthous ulceration are discussed above. Specific triggers to the development of individual attacks include local tissue trauma (pathergy), psychological stress, and possibly acidic and salty foods.

Therapy and prognosis

Letsinger et al. have developed a widely accepted therapeutic ladder that starts with topical agents (local anesthetics, local steroids, and tacrolimus) and progresses to systemic therapy with oral colchicine, dapsone, a combination of these two agents and, if necessary, thalidomide ². However, as indicated in their manuscript, only about 5% of patients respond satisfactorily to topical agents alone. On the other hand, with systemic therapy, 88% of their patients achieved 50% or greater improvement².

I have found that topical anesthetics such as 5% lidocaine ointment and EMLA are of limited use. For the reduction of pain in small lesions I prefer the application of silver nitrate using standard silver nitrate sticks ³. Clobetasol 0.05% ointment and gel are only modestly effective anti-inflammatory agents. Intralesional injection with triamcinolone in a concentration of 10 mg/mL works much better but such therapy is painful and requires an office visit for each recurrence.

My initial treatment of choice is a brief “burst” of oral prednisone in a dose of 40 mg q a.m. for 7 days. Oral antibiotics, used for their anti-inflammatory properties, such as doxycycline 100 mg bid or minocycline 100 mg bid, can be started at the same time and may be continued indefinitely in an attempt to prevent the recurrence of additional lesions. Colchicine, 0.06 mg bid to tid, dapsone 100–150 mg/day, and pentoxyphylline 400 mg tid are useful alternatives to antibiotics ^4,⁵. Thalidomide and other tumor necrosis factor-alpha inhibitors are remarkably effective^6,⁷ but adverse side-effects, high cost, and relatively short history of their use limit this approach to patients who have failed more conventional therapy.

The prognosis for women with idiopathic (primary) complex aphthosis involving the vulva is unclear. The medical literature on Behçet’s disease states that patients may have oral and genital lesions (complex aphthosis) for several years prior to the development of systemic symptoms and signs. In the series reported by Letsinger et al., 15% of patients with complex aphthosis referred to their group met established criteria for the diagnosis of Behçet’s disease ². However, no information was provided in that paper as to whether the complex aphthosis preceded the Behçet’s disease or, if so, by how long. Importantly, none of the 20 patients studied by Huppert et al. had or developed Behçet’s disease when followed over a rather short mean period of 14 months¹. Finally, based on my own experience and on discussion with other vulvologists, I believe that progression to Behçet’s disease is extremely unlikely in women of European or North American background. Thus, when the standard diagnostic criteria for Behçet’s disease are not met, I feel that it is inappropriate to suggest that patients have, or are likely to develop, Behçet’s disease (see also discussion in the section on Behçet’s disease, below).