Gingival Swelling as the Initial Manifestation of Granulomatosis with Polyangiitis

Abstract

We describe a case of granulomatosis with polyangiitis (GPA; formerly named Wegener granulomatosis) that presented initially as florid areas of gingival swelling. The patient also had upper respiratory symptoms that included sinus congestion and cough of recent onset. Clinical-pathologic correlation aided the interpretation of non-specific biopsy findings and immediate referral to an appropriate medical specialist. Treatment was rendered at an early stage of disease with a good response to date. Review of the literature indicates that gingival swelling, often with the characteristic appearance of “strawberry gingivitis” may represent the initial sign of disease in 2% of patients with GPA. Biopsy of gingival lesions often shows a non-specific histologic appearance that should be interpreted in the context of the clinical appearance and pertinent medical history. The clinical investigations that lead to definitive diagnosis and treatment are presented to facilitate the management of this uncommon but potentially fatal condition.

History

A 44 year-old man presented with a one-month history of slowly advancing, bilateral gingival swelling that started in the mandible and extended to the maxilla. He was being treated by his family physician for persistent sinus congestion and non-productive cough of recent onset. He was otherwise in good health and not on any medications. He had no known allergies. He was a former smoker.

Clinical Findings

On examination, he was afebrile and in no apparent distress. There was bilateral submandibular lymph node tenderness. Intra-oral examination showed areas of purplish–red gingival swelling with a boggy consistency and a friable surface that bled easily (Fig. 1a, b). The gingival swelling involved mostly the buccal gingiva and covered 2–3 mm of the adjacent tooth crown. The differential diagnosis included vesiculobullous diseases such as pemphigus vulgaris and mucous membrane pemphigoid, contact stomatitis, plaque-related hyperplastic gingivitis, foreign body gingivitis and scurvy. The possibility of leukemic gingival infiltrates was considered but thought to be unlikely because the patient did not have signs and symptoms of acute leukemia. Incisional biopsy was obtained from multiple sites of the abnormal gingiva from minimally affected to severely affected sites. There was brisk bleeding during the biopsy but hemostasis was achieved without difficulty.

Fig. 1.

Clinical appearance of gingival swelling. a, b Purplish-red swelling of the buccal gingiva in 3 quadrants at initial presentation; c reduction in gingival swelling 1 week after commencement of prednisone; the gingival swelling had the characteristic strawberry-like appearance; d No evidence of gingival lesions at 1-year follow-up

Diagnosis and Treatment

The incisional biopsy showed multiple nodular samples of oral mucosa with a similar histologic appearance throughout. The mucosal surface was covered by hyperplastic stratified squamous epithelium with foci of ulceration. The connective tissue contained many dilated small blood vessels that were associated with areas of extravasated blood and a dense inflammatory infiltrate consisting predominantly of neutrophils, with smaller numbers of macrophages, plasma cells and lymphocytes. There was no evidence of granulomas on multiple sections and careful search revealed only a few multinucleated giant cells within the dense, mixed inflammatory infiltrate in one area of the biopsy (Fig. 2a–d). PASD and GMS stains did not show fungal organisms. The histologic diagnosis was non-specific, severe acute and chronic gingival inflammation. In view of the clinical presentation, the possibility of granulomatosis with polyangiitis (GPA) was considered, despite the inability to demonstrate vasculitis or granulomas in the biopsy.

Fig. 2.

Histologic findings in the gingival biopsy. a Low power view showing a densely cellular infiltrate beneath hyperplastic stratified squamous epithelium; b–d High power view showing dilated small blood vessels, extravasated blood, dense inflammatory infiltrate with predominance of neutrophils and rare multinucleated giant cells

Subsequent to the biopsy, the patient developed more gingival lesions with involvement of the lingual mandibular gingiva and palatal gingiva. His sinus congestion and cough worsened and he further developed daily epistaxis and drenching night sweats with no associated fever or weight loss. He was initially referred to Otolaryngology and was also sent for laboratory tests including complete blood count, creatinine and ANCA (antineutrophil cytoplasmic antibody) levels (Table 1). Based on the biopsy results and lab results, the patient was referred to Rheumatology for investigations and management of possible GPA.

Table 1.

Results of laboratory tests

Test name	Result	Reference range
Hemoglobin	124 g/L	135–157 g/L
White blood cell count	11.3 × E9/L	4.0–11.0 × E9/L
Neutrophils	9.3 × E9/L	2.0–7.5 × E9/L
Eosinophils	0.1 × E9/L	0.0–0.5 × E9/L
Platelet count	525 × E9/L	150–400 × E9/L
Creatinine eGFR	93 μmol/L 86 mL/min	67–117 μmol/L
Urinalysis	Negative for blood or protein
C-reactive protein	27.3 mg/L	< 6.0 mg/L
Albumin	39 g/L	35–52 g/L
c-ANCA (anti-PR3)	> 8 AI units	Negative < 1.0 AI units Positive > 1.0 AI units
p-ANCA (anti-MPO)	< 1.0 AI units	Negative < 1.0 AI units Positive > 1.0 AI units

Further investigations, including a chest x-ray showed a large lobulated mass at the right lung apex and several nodular opacities (Fig. 3). CT chest showed a 5 cm × 4.4 cm × 7.1 cm right upper lobe ill-defined mass with a central cavity containing non-enhancing solid necrotic material as well as multiple bilateral solid pulmonary nodules (Fig. 4). Bronchoscopy revealed granulomatous lesions on the vocal cords bilaterally as well as subglottic tracheal inflammation (Fig. 5). Infectious cultures (including tuberculosis and fungal) as well as cytology were negative.

Fig. 3.

Chest X-ray showing a lobulated mass at the right lung apex measuring 7.7 × 4.5 cm and several nodular opacities

Fig. 4.

Computed tomography (CT) scan of the chest showing a cavitary mass in the right upper lobe

Fig. 5.

Bronchoscopy showing white nodular lesions on the vocal cords bilaterally

The clinical, laboratory, imaging and pathology findings indicated a diagnosis of c-ANCA-associated GPA. The patient was given induction therapy with prednisone 1 mg/kg/day. The gingival enlargement started to resolve 1 week after commencement of prednisone (Fig. 1c). However, his pulmonary symptoms worsened and he was given Rituximab (375 mg/m² weekly × 4 doses). He was then placed on maintenance therapy with Azathioprine 2 mg/kg/day. Over time, the patient had complete resolution of his upper and lower respiratory tract symptoms, had no further gingival lesions (Fig. 1d) and his repeat chest X-ray showed complete resolution of the cavitary lesion and pulmonary nodules. His repeat c-ANCA on indirect immunofluorescence and proteinase 3 (PR3) antibodies on enzyme-linked immunosorbent assay (ELISA) were negative.

Discussion

According to the 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides [1], GPA is defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract with necrotizing vasculitis affecting predominantly small to medium vessels. It may present over a wide age range but the mean age at diagnosis is between 40 and 55; males and females are equally affected. The cause is unknown but several etiological factors have been implicated. There is evidence of environmental factors such as dust inhalation or exposure to silica, infectious agents particularly through molecular mimicry and genetic factors demonstrated via a genome-wide association study [2]. The disease predominantly affects the upper and lower respiratory tract and kidneys but lesions may develop in many other tissues including eyes, ears, skin, musculoskeletal and nervous systems [3]. Patients may present with head and neck manifestations such as sinusitis, nasal obstruction, epistaxis, ocular inflammation, otitis media, or dyspnea [4]. It is not uncommon for patients to present initially with sinonasal complaints that are interpreted as infectious or allergic diseases, leading to delay in the diagnosis of GPA [4]. Other manifestations include constitutional symptoms such as fever, fatigue and weight loss. Pulmonary involvement is seen in 50–90% of patients and ranges from pulmonary nodules and infiltrates to acute alveolar haemorrhage [2]. The most common radiographic abnormalities at presentation are lung nodules and masses that are usually multiple and bilateral and, with progression of disease, tend to increase in size and number and sometimes coalesce and cavitate [5]. Diagnosis is challenging and is based on a number of factors including clinical findings, serology, imaging and biopsy, if feasible.

Although head and neck manifestations are common in patients with GPA, and are often the initial signs of disease, oral lesions are relatively rare [4, 6]. In the oral cavity, GPA may present as gingival swelling, deep mucosal ulcers or bone necrosis [3, 7]. Gingival swelling is an early sign of disease and often has a characteristic granular-nodular, purple-red appearance described as “strawberry gingivitis”. A literature review of the gingival manifestations of GPA revealed 46 case reports describing 50 cases (Table 2). The average patient age was 44 years (range 6 to 87) and there was a slight male predilection (M:F = 1.2:1). Both the maxillary and mandibular gingiva were involved in 66% of cases (33/50), while exclusive maxillary involvement was seen in 18% of cases (9/50), followed by 10% of cases showing exclusive mandibular involvement (5/50) and 3 cases in which the distribution of the gingival lesions was not specified. Among the GPA-associated gingival lesions described in the literature, 84% (42/50) were reported to be “strawberry gingivitis”, while the remaining 8 cases were variably described as gingival hyperplasia, hypertrophy, sores, ulcers, petechiae and erythema. Two cases represented recurrences of known GPA, while the remaining 48 patients did not have a previous diagnosis of GPA. Interestingly, of these cases without an existing GPA diagnosis, gingival lesions were the presenting complaint in 73% (35/48) of the patients. Constitutional signs and symptoms and/or involvement of the upper respiratory tract, lower respiratory tract, skin, kidneys, joints, salivary glands and/or lymph nodes were identified in 88% (42/48) of cases. Conversely, 13% (6/48) of the cases presented exclusively with gingival lesions and no additional signs and symptoms. The histologic features of gingival biopsies were described in 40 cases. Giant cells were noted in 48% (19/40) of cases, microabscesses or suppuration in 40% (16/40), pseudoepitheliomatous hyperplasia in 38% (15/40), eosinophils in 33% (13/40), hemorrhage or red blood cell extravasation in 30% (12/40), granulomas or granulomatous inflammation in 20% (8/40) and vasculitis in 20% (8/40).

Table 2.

Summary of literature review on gingival manifestations in GPA

Author (year)	Age	Sex	Distribution of lesions	Presenting oral complaint	Other signs & symptoms	Gingival biopsy histology	ANCA status
Allen et al. (1991) [11]	23	M	SG (L Mx, canine to second molar)	Yes	RU lobe infiltrate, cavitary mass	Severe chronic inflammation, vasculitis	Negative
Allen et al. (1991) [11]	62	F	SG (R Md canine gingiva), palatal ulcer	Yes	Sinus thickening, atelectasis, acute renal failure	Vasculitis, necrotizing granulomas	N/A
Amin et al. (2013) [12]	9	F	Gingival hypertrophy and bleeding	No	Epistaxis, fever, weight loss, hearing loss, sinusitis, saddle nose	N/A	c-ANCA+
Anthony et al. (1999) [13]	48	M	Gingival sores and hyperplasia	Yes	Fatigue, arthralgia, sinusitis, fever, digit gangrene, skin lesions	Epithelial hyperplasia, mixed infiltrate	c-ANCA+, PR3+
Aravena et al. (2014) [14]	54	F	SG (Md anterior gingiva, R canine to L canine, buccal & lingual)	Yes	Arthritis, skin lesions	Intense inflammation, giant cells, RBC extravasation	N/A
Beyer et al. (2012) [15]	26	M	SG (Mx & Md, generalized)	Yes	Chronic sinusitis	N/A	MPO-ANCA+
Bhatt and Hall (2009) [16]	87	M	SG (Mx & Md, generalized)	Yes	Neck mass, floor of mouth mass	Acute inflammation, microabscesses	c-ANCA+, PR3+
Chambers et al. (2013) [17]	67	M	SG (Mx & Md, generalized)	Yes	None	PEH, ulceration, PMN infiltration within vessels	c-ANCA+
Clark et al. (1998) [18]	74	F	SG (Mx & Md generalized, buccal & lingual)	Yes	None	Edema, perivascular & granulomatous inflammation	p-ANCA+
Cohen and Meltzer (1981) [19]	57	M	SG (Mx & Md, generalized)	No	Hemoptysis, fever, SOB, LU lobe infiltrate, skin lesion, polyarthralgia	Acute necrotizing vasculitis, PEH	N/A
De Rossi et al. (2012) [20]	21	M	SG (Mx & Md, generalized)	Yes	Malaise, nasal congestion, rhinorrhea, epistaxis, dyspnea, cervical lymphadenopathy	PEH, hemorrhage, PMNs, mixed inflammation, giant cells, vasculitis	c-ANCA+, PR3+
Eufinger et al. (1992) [21]	67	M	SG (Mx & Md generalized, all teeth)	Yes	Lung infiltrates, segmental glomerulonephritis, polyarthralgia	Epithelial hyperplasia, hemorrhage, PMNs, eosinophils, giant cells	ANCA+ (initially negative)
Fonseca et al. (2017) [22]	75	F	SG (Md gingiva, R second premolar to L second premolar)	Yes	Fever, dyspnea, lung opacification, submandibular lymphadenopathy	RBC extravasation, giant cells, microabscesses, eosinophils, PEH	c-ANCA+, PR3+
Genuis and Pewarchuk (2014) [23]	32	F	Mx gingival ulcers	Yes	Fever, fatigue, lung nodules, pleural effusions, hearing loss, hematuria	N/A	c-ANCA+, PR3+
Ghiasi (2017) [24]	42	F	SG (Mx & Md, generalized)	Yes	Skin ulcers, epistaxis, lung nodules	N/A	c-ANCA+, PR3+
Handlers et al. (1985) [25]	11	M	Hyperplastic gingivitis with petechiae and clefting	Yes	Epistaxis, lung infiltrates, otitis media, hematuria	PEH, edema, giant cells, eosinophils, hemorrhage	N/A
Hanisch et al. (2016) [26]	72	F	SG (Mx & Md gingiva, buccal & lingual)	Recurrence	Glomerulonephritis, sinusitis	Inflammation with PMN infiltration	c-ANCA+
Heera et al. (2012) [27]	54	M	SG (entire Mx gingiva, focally Md gingiva)	Yes	Malaise	PEH, intraepithelial abscess, PMNs, giant cells	Negative
Hernandez et al. (2008) [28]	64	F	SG (Mx central incisors)	Yes	Pulmonary nodules, otitis media, albuminuria	PEH, granulomatous inflammation, PMNs, microabscesses, eosinophils, hemorrhage	c-ANCA+
Horan et al. (1986) [29]	36	F	SG (Md > Mx gingiva)	Yes	Fever, skin lesions, myalgias, arthralgias, lung opacities, epistaxis, focal necrotizing glomerulonephritis	PEH, hemorrhage, necrosis, acute and chronic inflammation	N/A
Knight et al. (2000) [30]	21	M	SG (Mx, Md, predominantly labial)	No	Sinus congestion & mucosal thickening, weight loss, ear pain, skin ulcers	Papillary epithelial hyperplasia, granulation tissue, abscess, giant cells	c-ANCA+
Kumar et al. (2019) [31]	19	M	SG (Mx & Md, generalized)	No	Epistaxis, ethmoid sinusitis, lung nodules, glomerulonephritis	N/A	c-ANCA+, PR3+
Liam (1993) [32]	30	M	SG (Mx & Md, generalized)	Unknown	Epistaxis, ear pain, deafness	N/A	N/A
Lilly et al. (1998) [33]	51	F	SG (L posterior Md, Mx anterior labial gingiva)	Yes	Possible L lung mass, sinus opacification	PEH, giant cells, granulomatous inflammation	c-ANCA+, PR3+
Lourenco and Nico (2006) [34]	45	F	SG (Md gingiva)	Yes	None	PEH, micro-abscesses, eosinophils, giant cells, hemorrhage, focal necrosis	Negative
Lutcavage et al. (1991) [35]	47	M	SG (L Mx gingiva)	Yes	Sinusitis, sinus thickening, cavitary lung lesions, parotid mass	PEH, chronic inflammation	N/A
Manchanda et al. (2003) [36]	37	M	SG (Mx & Md, generalized)	Unknown	Eyelid lesion, nasal cavity mass + obstruction, ear discharge, joint pain	Mucosal hyperplasia, infiltrate of PCs + PMNs	ANCA+
Nand et al. (1991) [37]	64	M	SG (Mx & Md generalized)	Yes	Bloody nasal discharge, antral opacity, lethargy, microscopic hematuria	Papillary epithelial hyperplasia, edema, microabscesses	ANCA+
Napier et al. (1993) [38]	36	F	SG (Mx & Md premolars, buccal & lingual)	Yes	Malaise, epistaxis	PEH, edema, microabscesses, PMNs, eosinophils, giant cells	Negative
Ottoman (2015) [39]	11	M	SG (Mx & Md, buccal & palatal)	Yes	N/A	Edema, PMNs, fibrinoid necrosis, vasculitis	N/A
Pandiarajan et al. (2016) [40]	11	F	SG (Mx & Md, buccal & lingual)	Yes	Ear discharge, arthritis, microscopic hematuria, glomerulonephritis	Necrosis, PMNs	c-ANCA+, PR3+
Parsons et al. (1992) [41]	64	M	SG (Mx & Md generalized, buccal > lingual)	Yes	Bloody nasal discharge, lethargy, antral opacity	Papillary epithelial hyperplasia, edema, suppuration	ANCA+
Patrick and Altman (2019) [42]	56	F	SG (Mx & Md, generalized, all quadrants)	Yes	Cough, nasal congestion, epistaxis	Microabscesses, eosinophils, giant cells	c-ANCA+
Prasetyo and Johnson (2017) [43]	53	M	Petechial rash on gingiva (Mx anterior)	Unknown	Fatigue, polyarthralgia, epistaxis, sinus thickening	Inflammation, giant cells	c-ANCA+, PR3+
Rafiei et al. (2019) [44]	24	M	Gingival hypertrophy, palatal ulcers	No	Epistaxis, arthralgia, congestion, blepharitis, skin lesions, hematuria	N/A	c-ANCA+, PR3+
Ruokonen et al. (2009) [45]	51	F	SG (Mx premolars & Md R canine to L canine, buccal & lingual)	Yes	Fatigue, arthralgia, nasal crusting	Severe inflammation, PMNs, eosinophils, giant cells, RBC extravasation	c-ANCA+, PR3+
Scott and Finch (1972) [46]	23	F	SG (generalized, all teeth)	Yes	Ear discharge, skin ulcers, cavitating lung masses	PEH, granulomatous inflammation, giant cells, microabscesses, hemorrhage, eosinophils	N/A
Siar et al. (2011) [47]	50	M	SG (Mx labial gingiva R premolar to L central incisor)	Yes	None	PEH, giant cells, mixed inflammation, micro-abscess, eosinophils	N/A
Staines and Higgins (2009) [48]	25	F	SG (L Mx buccal gingiva)	Recurrence	Epistaxis, cough, sinus thickening	PMNs, extravasated RBCs, giant cells	c-ANCA+, PR3+
Stewart et al. (2007) [49]	62	M	SG (R Mx & Md buccal and lingual gingiva, Md anterior)	Yes	Fatigue, sinusitis, myalgia, nasal ulceration and crusting	Papillary surface, giant cells, fibrinoid deposits, eosinophils	N/A
Stewart et al. (2007) [49]	34	F	SG (Mx & Md, generalized)	Yes	Skin lesion, sinusitis	Edema, subacute inflammation, giant cells	N/A
Stewart et al. (2007) [49]	53	M	Generalized chronic periodontitis, erythematous lower anterior gingiva	No	Sinusitis, nasal congestion, bloody discharge, balanitis, collapsed bridge of nose	N/A	c-ANCA+
Sung et al. (2015) [50]	57	M	SG (Mx & Md, buccal & lingual)	No	Skin ulcers	Mixed inflammation, microabscesses, fibrinoid vasculitis, granulomas	c-ANCA+, PR3+
Thompson et al. (2018) [7]	43	M	SG (Mx & Md generalized)	Yes	Fever, lethargy, epistaxis, sinusitis	PEH, ulceration, microabscesses, eosinophils	Negative
Thompson et al. (2018) [7]	63	F	SG (Mx labial gingiva, R canine to L lateral incisor)	Yes	None	Microabscesses, giant cells, eosinophils, granulomas	c-ANCA+, PR3+
van der Leeuw et al. (2018) [51]	55	F	SG (Mx & Md, generalized)	Yes	Cervical lymphadenopathy, fatigue, back pain	Chronic inflammation, granulomas, vasculitis	c-ANCA+, PR3+
Vastbinder et al. (2012) [52]	24	F	SG (Mx gingiva)	No	Skin ulcers, malaise, fever, nasal obstruction, epistaxis	N/A	c-ANCA+, PR3+
Vineetha et al. (2011) [53]	54	F	SG (Md R second premolar to L second premolar gingiva, buccal only)	Yes	Submandibular gland enlargement, ear blockage, cutaneous vasculitis	Hemorrhage, intraepithelial abscesses	c-ANCA+
Wawrzycka et al. (2014) [54]	49	M	SG (Mx & Md anterior, Mx > Md)	No	Fatigue, epistaxis, hearing loss, tinnitus, proteinuria, lung nodules, sinus and ear masses	N/A	c-ANCA+, PR3+
Xing (2011) [55]	6	M	Diffuse gingival hyperplasia & erythema, tooth mobility & bone loss, oral ulcers	Yes	Lung infiltrates and nodules	Small vessel vasculitis, necrosis, perivascular inflammation	c-ANCA+, PR3+

c-ANCA cytoplasmic anti-neutrophil cytoplasmic antibody, Md mandibular, Mx maxillary, N/A not available, PC plasma cell, PEH pseudoepitheliomatous hyperplasia, PMN polymorphonuclear leukocyte, PR3 proteinase 3, RBC red blood cell, SOB shortness of breath, SG strawberry gingivitis

In the present case, the patient was referred to the oral and maxillofacial surgeon for biopsy of unusual, progressive, multiple areas of gingival swelling. Biopsy of representative areas of abnormal gingiva showed non-specific findings of severe inflammation with abundant extravasated blood. Correlation of the histologic findings with the clinical appearance of the gingival swelling and the history of persistent sinus congestion prompted laboratory testing for c-ANCA and referral to a rheumatologist for further investigation into the possibility of GPA. ANCA status was reported in 38 cases in our review of the literature (Table 2). Of these cases, 71% were c-ANCA-positive (27/38), 5% were p-ANCA-positive (2/38), 11% were ANCA-positive without a specified pattern (4/38) and 13% were ANCA-negative (5/38). Overall, ANCA was detected in 87% (33/38) of the cases in which ANCA results were available.

Treatment of severe GPA involves 2 phases: (1) induction therapy with glucocorticoids and another immunosuppressive agent (cyclophosphamide or Rituximab) and (2) maintenance therapy, once remission is achieved [8]. Maintenance therapy (most often azathioprine or methotrexate) is given for a minimum of 18 to 24 months but a longer course is recommended in PR3 ANCA-positive patients due to a higher relapse risk [9]. Before the introduction of cyclophosphamide, the 1-year mortality rate of GPA was approximately 90% but with current treatment protocols, the 1-year survival rate for ANCA-associated vasculitis is approximately 90%, with a 5-year survival rate of 75% [10]. The main causes of mortality include uncontrolled active disease, adverse events, infection and cardiovascular disease [10].

Conclusion

Gingival swelling is a rare manifestation of GPA in the early stage of disease and presents with a characteristic appearance. However, the histologic appearance of the gingival lesion is often non-specific. Clinicopathological correlation is important in interpretation of the biopsy. Immediate referral to the appropriate medical specialist should be made for further investigations, diagnosis and treatment.

Compliance with Ethical Standards

Conflict of interest

The authors have no conflict of interest to disclose.