Clinical pathologic correlation Case 1: child with diffuse gingival hypertrophy

Abstract

Clinical Presentation

14-year-old African American male presents with a past medical history of asthma, multiple skin lesions (atopic dermatitis, pruritus, prurigo nodularis, and keloids), and possible acromegaly (concern for large hands and feet) (Figure 1). The skin lesions were being treated with dupilumab and triamcinolone injections. He has a history of skin rashes and itching. He is constantly picking at the skin lesions, and they heal with hyperpigmentation and scarring. He also has keloids that have resulted from minor injuries. His endocrinology workup for large hands and feet found that his lab work and bone age x-rays were unremarkable. For the past year and a half, he has had gingival hypertrophy. The lesions started at the maxillary facial gingiva interproximally and progressed to cover his maxillary and mandibular teeth facially, palatally, and lingually (Figures 2 and 3) He was referred to OMFS, who diagnosed it as puberty gingivitis and planned a gingivectomy.

Differential Diagnosis

Given the patient's history of skin lesions and gingival enlargement, the differential diagnosis includes drug-related gingival hyperplasia, Crohn disease, leukemia, diabetes mellitus, granulomatosis with polyangiitis, and sarcoidosis.

Drug-related gingival hyperplasia should be considered in a patient with a history of prurigo nodularis (PN). PN is a chronic inflammatory skin disease characterized by symmetrical, hyperkeratotic, intensely pruritic nodules.¹ Its exact pathogenesis is unknown, but neural and immune dysregulation are believed to play a role.¹ Because of this, treatment may include systemic immunomodulating agents such as cyclosporine, a known trigger of gingival hyperplasia.¹ Therefore, a thorough investigation of the patient's medication history is warranted.

The presentation of PN in this patient raised suspicion of a possible systemic condition. Prurigo nodularis is reported to be associated with numerous systemic conditions including Crohn disease, hematologic malignancies, diabetes mellitus, human immunodeficiency virus, hepatitis C, Celiac disease, thyroid disease, end-stage renal disease, chronic obstructive pulmonary disease, cardiovascular disease, and several psychiatric conditions.² Of these, Crohn disease, hematologic malignancies, and diabetes mellitus may also exhibit gingival hypertrophy and are considered in this patient's differential diagnosis.

Crohn disease (CD) is a chronic granulomatous disease which may affect any portion of the gastrointestinal tract from mouth to anus.³ Oral manifestations are frequently reported and include swelling of oral and perioral tissues, mucosal tags, linear ulcers, aphthous-like ulcers, mucosal cobblestoning, and pyostomatitis vegetans.^3,4 Gingival lesions are noted in the form of gingival edema, erythema, and hyperplasia.⁴ CD can develop at any age but often first becomes evident in teenagers and oral symptoms may precede abdominal ones.³ Digital clubbing can occur with CD³ and may be the cause of the appearance of the patient's large hands and feet. Additionally, the patient's age factored into CD being high on the differential.

Also on the long list of comorbidities associated with PN are hematologic malignancies such as myeloid leukemia.⁵ Myeloid leukemia, particularly the acute type (AML), can exhibit oral alterations in up to 90% of patients.⁶ Within the oral cavity, AML has a range of presentations including petechiae, spontaneous bleeding, ulcers, infections, and diffuse gingival swelling.⁶ However, it is low on the differential as it would be unlikely for a patient to have undiagnosed AML, a normally aggressive disease, for a year and a half.

Diabetes mellitus (DM) wraps up the discussion of systemic diseases associated with both PN and gingival enlargement. Diffuse, erythematous gingival enlargement may be noted in patients with DM.⁷ While it was considered in the differential diagnosis, gingival hypertrophy to this degree would be unusual in a patient with DM.

Another consideration, given the patient's symptoms and age is granulomatosis with polyangiitis (GPA). GPA could be the cause of the patient's gingival enlargement, cutaneous symptoms, and asthma. GPA is a multisystem necrotizing granulomatous disease with vasculitis of small and medium-sized vessels.⁸ GPA may present orally with “strawberry gingivitis,” nonspecific ulcers, or hyperplastic gingivitis.⁹ Skin manifestations of GPA take on a multitude of forms that may include nodules and pruritis,⁸ which could have clinical overlap with PN. Additionally, in rare instances, lung involvement by GPA may be mistaken for asthma.¹⁰

Lastly, sarcoidosis is multisystem granulomatous disease of unknown etiology that could also account for the patient's presentation.¹¹ While any organ can be involved, the skin and lungs are most frequently affected.¹¹ Cutaneous sarcoidosis classically presents as erythema nodosum, lupus pernio, and maculopapular lesions.¹² However, sarcoidosis is known as “the great imitator” and occasionally takes an ulcerative form that may be confused with prurigo nodularis.¹¹ Additionally, sarcoidal scars, lesions of cutaneous sarcoidosis that emerge in preexisting scars, may appear as keloids.¹¹ Cutaneous sarcoidosis may also present with digital clubbing creating the appearance of large hands and feet.¹² Oral involvement by sarcoidosis is rare, but diffuse gingival enlargement has been reported.¹³ And finally, asthma and sarcoidosis share many symptoms and may be indistinguishable.¹⁴ Considering that this patient presented with asthma, skin lesions, gingival hyperplasia, large hands and feet, and keloids, sarcoidosis is a fitting diagnosis.

Diagnosis and Management

A maxillary and mandibular gingivectomy was performed under general anesthesia. Histopathologic examination of the excised tissue showed reactive surface oral squamous epithelium with non-necrotizing granulomatous inflammation in the underlying fibrous connective tissue (Figure 4). The presence of acid-fast rods and fungal organisms was excluded by GMS and Auramine-rhodamine stains. The infiltrate consisted of chronic inflammatory cells, histocytes and Langhans type multinucleated giant cells, some of which contained Schaumann bodies (Figure 5) as well as asteroid bodies (Figure 6). Based on these histopathologic features, as well as history of skin lesions the patient was worked-up for Sarcoidosis. His skin biopsies failed to find non-necrotizing granulomas, but since sarcoidosis can present with very nonspecific cutaneous lesions, they could not be completely ruled out. A chest x-ray was normal and did not show any hilar lymphadenopathy, but his pulmonary function test showed mild pulmonary restriction based upon FEV1/FVC. Additional clinical symptoms included joint pain, rash and eye redness. His laboratory tests showed the following abnormal values in his CBC: Monocytes 10.3% (High) (0%-10%), Eosinophils 10.7 (High) (0.0%-5%), Neutrophils, relative percent 78.6 (High) (40%-60%), lymphocytes, relative percent 11.1 (Low) (20%-50%) and Neutrophil Absolute Count 1.90 K/mm³ (Low) (2.00-6.60). Other abnormal lab values included: ESR 29 (High) (0-15), ACE 54 nmol/mL/min. (High) (<40 in Adults) and Lysozyme 5.4 (2.6-6.0). Based on histopathologic and clinical findings a diagnosis of pediatric sarcoidosis was given.

Discussion

While sarcoidosis predominantly affects adults—typically between the ages of 20 and 40—recent studies indicate a rising incidence among children and adolescents.¹⁵ In the US, pediatric cases have a higher incidence among African Americans. Geographically, 80% of pediatric cases have been reported in Virginia, North Carolina, South Carolina, Arkansas, and Louisiana. The triad of rash, uveitis, and arthritis characterizes cases of early onset (under 5 years of age). However, most reported cases in childhood have occurred in patients aged 13-15 years. In these patients, the most affected organs include lymph nodes, lungs, skin, and eyes and may be accompanied by nonspecific constitutional symptoms, such as fever, fatigue, malaise, and weight loss. Clinically, peripheral lymph node enlargement is noted in 40% to 70% of cases, and hepatosplenomegaly may occur in up to 43% of patients.¹⁶ Visual symptoms such as eye pain, blurry vision, photophobia, and redness may be present in 29% of the patients. The most common cutaneous sign is an erythematous rash occurring in 77% of young children and 24%-40% of older children.¹⁶ Other skin lesions of sarcoidosis include nodules, hyperpigmented or hypopigmented lesions, ulcers, and subcutaneous tumors. Other symptoms, such as arthritis, have been reported in 15% to 58% of children with sarcoidosis. Another unique finding in children is parotid gland enlargement, especially in the early onset type.

Recent reports have shown sarcoidosis-like reactions developing in any organ system after initiating the treatment of IL-4-alpha receptor monoclonal antibody (Dupilumab).¹⁷ Interestingly, this patient had been receiving Dupilumab treatments for his prurigo nodularis. This association still requires additional research to determine if there is a correlation.

Sarcoidosis is rarely present in the oral cavity. In a review article published in 2005, Suresh and Radfar found 68 cases reported in the English literature.¹⁸ Of these, 57% were females, and the ages ranged from 5-72 years with a median of 37 years. The buccal mucosa was the most frequently affected oral soft tissue, followed by the gingiva. Sarcoidosis has also been reported as a central lesion in the jaws. In 2021, Bouazizi et al. reported 12 additional cases of oral sarcoidosis.¹³ Most of these cases occurred in the tongue and lips. However, one case had gingival involvement, including gingival hypertrophy, with gingivitis and periodontitis.

The treatment of pediatric sarcoidosis varies. The first line of treatment is corticosteroids to reduce inflammation, but longer-term management may involve immunosuppressive agents for more severe or resistant cases.¹⁹ Prognosis can vary widely; some children experience spontaneous resolution, while others may develop chronic sarcoidosis with persistent symptoms. Recommendations for management include regular follow-up and monitoring to avoid potential complications, which can include organ damage, particularly in cases with significant pulmonary involvement.²⁰