CASE REPORT

Rare Manifestation of Granulomatosis With PolyangiitisManoj Bhattarai,* Weijia Yuan,† Paul Fletcher,‡ Adam Gersten,x Anthony Chang,‖ Robert Spiera,† Anne Bass,†

Doruk Erkan,† and Dennis Tarnow{

Introduction: Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, is a multisystemdisorder that mainly involves airways and kidneys. Oral GPA may present as ulcerations or strawberry gingivitis. Early diag-nosis and intervention are crucial for overall prognosis.

Case Presentation: An unusual case of oral GPA manifested by chronic localized inflammation, leading to failure ofdental implants in an elderly woman, is presented. Diagnosis was based on antineutrophil cytoplasmic testing and histo-pathologic evidence of necrotizing vasculitis. Disease remission was achieved with cyclophosphamide and steroids.

Conclusion: Familiarity with oral manifestations of GPA will help dentists and oral surgeons diagnose and treat earlyor incipient GPA without delay. Clin Adv Periodontics 2013;3:45-50.

Key Words: Antineutrophil cytoplasmic antibodies; cocaine; cyclophosphamide; gingivitis; proteinase 3; Wegenergranulomatosis.

BackgroundGranulomatosis with polyangiitis (GPA)1 usually presentswith unexplained constitutional symptoms. Oral manifes-tation is relatively uncommon and often misdiagnosed oris diagnosed late. Disease progression could be fatalwithout appropriate intervention.

Clinical PresentationA76-year-oldwhitewomanwith pastmedical history of peri-odontal disease, osteoporosis treated with bisphosphonates,hypertension, and osteoarthritis presented to the New YorkPresbyterian Hospital in 2008 with a left-sided neck massthat had been enlarging over 1 month.

The patient’s periodontal disease started 9 years beforepresentation, manifesting as discomfort on the left side ofher mouth when biting. She had poorly fitting crowns ontwo implants in the left maxillary first and second molarpositions, which were subsequently replaced. During thisperiod she developed intermittent gingival inflammationaround the implants and increased periodontal pocketingon the palatal aspect of the implants indicating 6-mm boneloss (Fig. 1). The affected area was debrided multiple timeswithout remarkable improvement. These implants wereeventually removed and primary closure was obtained.Despite antibiotic therapy (amoxicillin for five days) thepatient developed a yellow mucus draining ulcer near theremoved implants. She returned with a non-healing surgi-cal site and firm swelling at the left angle of the mandiblethat did not respond to clindamycin. She was a retiredpharmacist with no history of tobacco, alcohol, or recreationaldrug use.

* Department of Internal Medicine, Memorial Hospital of Rhode Island,Pawtucket, RI.

† Department of Rheumatology, Hospital for Special Surgery, New York,NY.

‡ Division of Periodontics, Columbia University College of Dental Medicine,New York, NY.

x Department of Pathology, New York Presbyterian Hospital/Weill CornellMedical Center, New York, NY.

‖ Department of Radiology, Hospital for Special Surgery.

{ Department of Dental and Oral Surgery, Columbia University College ofDental Medicine.

Submitted November 29, 2011; accepted for publication March 4, 2012

doi: 10.1902/cap.2012.110107

Clinical Advances in Periodontics, Vol. 3, No. 1, February 2013 45

Onintraoral examination, anulcerative lesionof the left pos-terior hard palate was observed. The previously approximatedsurgical flaps had opened, leaving exposed bone and necrotictissue at the surgical site (Fig. 2b). Additionally, there was gen-eralized gingival inflammation along with discrete areas of in-tensely red patches appearing as granular strawberry gingivitis(Fig. 2a). The left submandibular area had a non-tender 6- to8-cm ulcerated mass, draining purulent material.

Cardiopulmonary, abdominal, neurologic, and muscu-loskeletal examinations were unremarkable.

Case ManagementThe patient was admitted for additional workup of mandib-ular swelling.Her basic laboratory tests, includingurinalysis,were unremarkable and urine for toxicology was negative.Signed consentwasobtainedprior to admissionof treatment.

Computed tomographic axial imaging of the head andneck exhibited bilateral maxillary sinusitis (Fig. 3a), a het-erogeneously enhancing left submandibular mass (Fig. 3b)measuring 3.9� 2.9� 4.1 cm, and fistula at the left maxillaconnecting to the failed implant site. Incidentally, a spicu-lated right apicalmass (Fig. 4a)measuring4.3� 2.5 cmwiththe central hypoattenuation abutting the superior mediasti-num was identified. Small foci of air were noted within themass reflecting cavitation or small airways passing throughthe lesion. Multiple spiculated masses were seen in bilaterallungs (Fig. 4b); the largest was located on the left upper lobeand measured 1.3 � 0.9 cm.

Biopsy of ulcerated squamous mucosa from palate andrightmaxillary gingiva under high-power view demonstrateddying neutrophils (leukocytoclastic response) (Fig. 5a) andlymphocytes infiltrating smaller and larger vessels (Fig. 5b),which suggested focal fibrinoid necrosis/vasculitis. Well-formed granulomas and giant cells were not seen.

Biopsy of the left submandibular and right apical lungmasswas consistentwith acute inflammation. The right lower lobewedgebiopsy, observedvia video-assisted thoracoscopy,dem-onstrated necrotizing granulomatous inflammation (Fig. 6a)and vasculitis (Fig. 6b). Stains for acid-fast bacilli and fungiwere negative. The routine cultures of right lower lobewedgetissue and right lung fine-needle aspirate were negative.

Rheumatologic workup demonstrated positive antineu-trophil cytoplasmic auto-antibodies and elevated proteinase3 (PR3), at 700 IU/mL (normal<19 IU/mL). The presence ofa non-healing surgicalwound around the dental implant site,lung nodules with necrotizing granuloma, cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA), and an elevatedPR3 level supported the diagnosis of oral GPA.

Clinical OutcomesCyclophosphamide (2 mg/kg daily) was started in combi-nationwith prednisone (60mgdaily), resulting in amarkeddecrease of the left neck mass and gingival inflammationafter 6 weeks (Fig. 7). Eventually both medications werestopped and the patient was asymptomatic during her fol-low-up three years after presentation.

DiscussionA 76-year-old woman presented with an oral ulcer afterdental implant removal, friable gingiva, neck and rightlung apical mass, multiple lung nodules, positive c-ANCA,elevated PR3 level, and necrotizing granulomatous vascu-litis of lung tissue.

GPA is a chronic, relapsing necrotizing granulomatousvasculitis primarily limited to upper and lower respiratory

FIGURE 1 X-ray of left upper dental implants with evidence of bone loss(arrow).

FIGURE 2 Before treatment. 2a Buccal surface of gingiva. 2b Palatalsurface.

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tracts as well as kidneys. However, GPA can affect any or-gan system, such as heart, nerves, and skin.2,3 Unusual oralpresentations of GPA include: 1) palatal osteonecrosis; 2)palatal and lingual ulcerations; 3) oroantral fistulae; 4)postextraction poor wound healing; 5) labial mucosal nod-ules; 6) salivary gland swelling; 7) cranial nerve palsies; and8) friable-granular gingivitis with tooth mobility.4-9 Ap-proximately 20% of patients with GPA develop oral ulcersand oral lesions can be a presenting feature in 2% ofcases.10,11 Hyperplastic gingivitis (dark red to purple incolor with a granular surface), also known as strawberrygingivitis, is a rare manifestation of GPA but is consideredpathognomonic.12 The patient had long-term peri-implantdisease, but because she was on bisphosphonates for >3years, it cannot be discounted that the rapid bone destruc-tion and subsequent loss of the implants was not ultimatelyattributable to bone necrosis secondary to long-term bis-phosphonate therapy. Leukemia may present with gingivalmanifestations but with much smoother gingival surfaces.13

Pyostomatitis vegetans commonly results in bumpiness onFIGURE 3 Coronal computerized tomography of head and neck. 3a Airfluid level (arrow). 3b Left submandibular mass (arrow).

FIGURE 4 Coronal computerized tomography of chest. 4a Spiculatedmass (arrow). 4b Satellite nodules (arrow).

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Bhattarai, Yuan, Fletcher, et al. Clinical Advances in Periodontics, Vol. 3, No. 1, February 2013 47

gingival surfaces but extends beyond gingiva to oralmucosa.14 Pemphigus exhibits superficial non-granulo-matous ulcerations with erythematous non-swollen gin-gival, starts from oropharynx or soft palate, and movesforward in the mouth (Nikolsky’s sign is present, inwhich horizontal pressure to mucosa results in peelingaway of blisters).15 Kaposi sarcoma, although rare, is pri-marily seen in human immunodeficiency virus (HIV) andinvolves the entire gingiva, palate, and maxilla.16 Behcetdisease–related ulcers are flat and resemble aphthous ul-cers, and sarcoidosis involves oral mucosa, includingperiodontium.17

The mortality rate in untreated generalized GPA is 82%in 1 year, with a mean survival of 5 months.18 Timely diag-nosis is crucial, which was challenging in this patient be-cause of the atypical presentation. The incidental findingof lung mass led to additional investigation, and she metthree of the four diagnostic criteria for GPA (Table 1) basedon the American College of Rheumatology.19 Noteworthy,the specificity and sensitivity of c-ANCA are 96% and92%, respectively, for patients with generalized disease,which is also helpful in measuring disease activity and

possible relapse, but it is often negative in the limited orearly disease.20,21 False-positive c-ANCA test results havebeen reported in patients with tuberculosis, Hodgkin lym-phoma,HIV infection, nasal septal perforation,monoclonalgammopathies, and drug-induced GPA-like disease.22-27

Rachapalli and Kiely28 have reported two cases of cocaine-induced midline destructive lesions (CIMDLs) mimickingear, nose, and throat-limited GPA that presented with ele-vated erythrocyte sedimentation rate andC-reactiveprotein,positive perinuclear antineutrophil cytoplasmic antibody,negative myeloperoxidase and PR3 antibodies, and incon-clusive histology. Human neutrophil elastase ANCA is fre-quently detected in these patient populations as opposedto other autoimmune disease patients; hence, it can helpto distinguish CIMDL from GPA.29

Approximately 90% of GPA cases receiving cyclophos-phamide achieve remission; rituximab is as effective as cy-clophosphamide for induction therapy.30,31 Methotrexateor azathioprine are used for maintenance therapy. Trimeth-oprim/sulfamethoxazole can also be used toprevent relapsesand has been used by clinicians as a remission-inducingagent in limited disease. n

FIGURE 5a Focus of neutrophilic micro-abscesses in squamous epithe-lium (arrow). 5b Fibrinoid necrosis of the underlying small vessels, gingival(arrow). Hematoxylin and eosin; original magnification, �40.

FIGURE 6 Focus of granulomatous inflammation (arrow) (6a) and vasculitis(arrow) (6b), right lung lower lobe. Hematoxylin and eosin; originalmagnification, �20.

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Summary

Why is this case new information? j This case is an atypical manifestation of GPA.

What are the keys to successfulmanagement of this case?

j The incidental finding of lung and neck mass led to additionalinvestigation and final diagnosis.

What are the primary limitations tosuccess in this case?

j Appropriate diagnosis was delayed as a result of unusualmanifestations.

AcknowledgmentDr. Spiera has received financial support for research andlecture fees from Genentech, South San Francisco, Califor-nia; all other authors report no conflicts of interest relatedto this case report.

CORRESPONDENCE:Dr. Manoj Bhattarai, 111 Brewster St., Pawtucket, RI 02860. E-mail:manoj_bhattarai@brown.edu.

FIGURE 7 After treatment. 7a Buccal surface ofgingiva. 7b Palatal surface.

TABLE 1 The American College of Rheumatology 1990 Criteria for the Diagnosis of GPA

Criteria Definition

Oral or nasal manifestations Oral ulcers or purulent/bloody nasal discharge

Abnormal findings on chest radiograph or hemoptysis during illness Nodules, cavities, or fixed infiltrates in chest x-ray

Abnormal urinary sediment Red cell casts or >5 red blood cells per high-power field

Granulomatosis Granulomatous inflammation on biopsy of small arteries, affecting the perivascularor extravascular wall

At least two of four criteria must be met for the diagnosis. The presence of ‡2 criteria is associated with a sensitivity of 88.2% and specificity of 92.0%.Adapted from Leavitt et al.19

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