J Oral Maxillofac
Surg
49:1x32-1338.1991
Gingival Mass With Massive Soft-Tissue Necrosis GREGORY J. LUTCAVAGE DDS,* SIEGFRIED J. SCHABERG, DOUGLAS A. ARENDT, DDS,$ AND JAY P. MALMQUIST, Case Presentation
left canine eminence, multiple carious teeth, multiple periapical radiolucencies, and moderate to severe generalized periodontal bone loss (Fig 3). On February 20, 1989, two incisional biopsies of the mass in the left canine area were performed under local anesthesia. These showed atypical squamous epithelium, chronic inflammation, ulceration, and pseudoepithelial hyperplasia. On March 6, 1989, a mass involving the tail of the left parotid gland associated with a left Bell’s palsy was noted (Fig 4). No lymphadenopathy was present. A symptomatic upper left second molar was extracted, an additional incisional biopsy of the mass was performed, and tissue scrapings were obtained for fungal stains. Microscopic examination of the biopsy specimen showed severe inflammation and ulceration. The fungal stains were negative. Antibiotic therapy consisting of cefadroxil monohydrate (1 g/d) was initiated to control the chronic sinusitis. Laboratory studies included a complete blood count, which revealed a hemoglobin of 12.2 g/dL, hematocrit of 36. I%, white blood cell count of 11,2OO/p.L, and platelet count of 598,OOO/~L. The differential count was 76.8% polymorphonuclear neutrophils, 6.2% monocytes, and lymphocytes 17%. The serum electrolytes, blood urea nitrogen, and creatinine levels were normal and the rapid plasma reagin was nonreactive. A tuberculin purified protein derivative was negative. The erythrocyte sedimentation rate was markedly elevated, at 83 mm in 1 hour. A posteroanterior chest radiograph showed well circumscribed multiple cavitary lesions in the right and left lung fields (Fig 5). A large mass involving the upper lobe of the left lung measured approximately 8 cm. A fluid level was also noted in the left lung. Multiple, well circumscribed masses were noted on the anterior aspect of the lateral chest radiograph (Fig 6). A computed tomography (CT) scan of the face and neck was remarkable for a mass of the left parotid extending posteriorly into the ptergygomandibular space (Fig 7). On the basis of the preliminary findings, the patient was admitted on March 20, 1989, for a full diagnostic workup and appropriate consultations. A CT scan of the abdomen showed a 4-cm, right renal cyst (Fig 8). Fungal serology was negative. A fine-needle aspiration biopsy of the left upper lobe lesion showed necrotic cells with acute inflammation, but no organisms. Medical oncology and ENT consultations were obtained. On March 23, 1989, the patient underwent bronchoscopy, esophagoscopy, direct laryngoscopy, needle aspiration of the left parotid mass, and incisional biopsies of the posterior tracheal wall, left maxillary mucosa, left buccal mucosa, and the gingival mass under general anesthesia.
On February 20, 1989, a 47-year-old white man was referred by his general dentist for evaluation of a localized soft-tissue mass in the left maxilla. The patient sought treatment from his dentist because he had had a left maxillary canine removed approximately 1 month before and desired prosthetic replacement as well as the removal of multiple carious teeth in the anterior maxilla. The medical history included a motor vehicle accident in 1987 during which the patient had traumatically avulsed multiple teeth. In 1983, he sustained a renal contusion and rib fracture in another motor vehicle accident. The review of systems was significant for a recent unexplained weight loss and chronic maxillary sinusitis. He had a 30 packlyr history of cigarette usage, denied use of alcohol, and used salicylates for occasional pain. Examination revealed an extremely apprehensive, thin, talkative man in no acute distress. The head and neck examination was unremarkable. However, the oral examination revealed multiple carious teeth, gross generalized periodontitis, and a nonhealing maxillary left canine extraction site. A purplish-red soft-tissue mass with a granular surface measuring 2.5 x 2.0 cm was noted in the area of the left maxillary extraction site (Fig 1). Extensive tissue necrosis was present in the left maxillary vestibule extending from the maxillary tuberosity to the anterior midline and superiorly into the canine fossa, the infraorbital region, and the left maxillary sinus. In the right anterior maxillary vestibule, an erythematous punctate l-cm mucosal lesion was noted in the area of the canine eminence. A Water’s view radiograph showed left maxillary sinus mucosal thickening (Fig 2). A panoramic radiograph showed extensive osseous destruction in the area of the * Chairman, Department of Surgery, Attending Surgeon, Wayne Memorial Hospital; in private practice, Goldsboro, NC. t Attending Surgeon, Wayne Memorial Hospital; in private practice, Goldsboro, NC. $ Oral Pathologist, Naval Hospital San Diego, CA. 5 Associate Professor, Departments of Pathology and Oral and Maxillofacial Surgery, Oregon Health Sciences Center, Portland. The opinions contained herein are those of the authors and are not to be construed as offkial or as reflecting the views of the United States Navy or Department of Defense. Address correspondence and reprint requests to Dr Lutcavage: 2400 Wayne Memorial Dr, Goldsboro, NC 27534. 0 1991 American geons
Association
of Oral and Maxillofacial
DDS, PHD,t DMD§
Sur-
0278-2391/91/4912-0012$3.00/O
1332
LUTCAVAGE
FIGURE 1. presentation.
1333
ET AL
Gingival mass at time of initial
Differential Jay P. Malmquist,
Diagnosis
DMD
The differential diagnosis of the lesion involving multiple systems of this 47-year-old white man should include those diseases that appear as midline maxillary granulomas. These may be infectious, neoplastic, or inflammatory in origin. Diagnosis is dependent on the patient’s pertinent history and clinical and laboratory findings. Although the presenting signs and symptoms focus on the soft-tissue mass in the anterior maxillary vestibule, further investigation substantiates multiple system involvement. Infectious involvement can be ruled out by the lack of positive bacterial, fungal, or parasitic stains and cultures from tissue samples. The biopsies suggest no neoplastic component, as the predominant findings are inflammatory. This is further substantiated by a hematology report. which indicates a
FIGURE 2. Water’s view radiograph sinus mucosal thickening.
showing left maxillary
normal blood picture except for an elevation of the white blood cell count with a shift to the left, an elevated sedimentation rate, and elevation of platelets. In view of these findings, the differential diagnosis should exclude an infectious or neoplastic etiology and concentrate on inflammatory disease of unknown etiology. Two considerations would be Wegener’s granulomatosis and idiopathic midline destructive disease. Wegener’s granuloma is described as a necrotic vasculitis and granulomatosis inflammation that affects primarily the upper and lower respiratory tracts and kidneys. Conversely, a midline granuloma, which has also been characterized as midline lethal granuloma, lethal midline reticulosis, malignant granuloma, or granuloma gangrenescens, is characterized by local inflammation, destruction, and often mutilation of tissues in the upper respiratory tract and face. Generally this lesion is limited to the upper respiratory tract and does not involve other systems. The etiology of both inflammatory diseases is unknown, although a possible connection with hypersensitivity has been suggested. Wegener’s granulomatosis and midline lethal reticulosis can also be distinguished by different responses to therapy. Wegener’s granulomatosis responds well to treatment with cyclophosphamides and alternate day steroid therapy, but midline lethal granuloma responds better to radiation. In this case report, the patient’s clinical, radiographic, and laboratory studies suggest an inflammatory granulomatous disease consistent with Wegener’s granulomatosis. The patient has significant, unexplained weight loss and a left premaxillary mass with a raised granular surface and marked tissue necrosis. The lesion extended from the tuberosity on the left side to the anterior midline, with some right maxillary nodularity. Radiographs
1334
GINGIVAL MASS WITH NECROSIS
FIGURE J 3. Panoramic radiograph showing osseous destruction in the left canine region.
showed marked destruction of the alveolar complex on the left side, with extensive bone involvement. There was also evidence of mucosal thickening in the left maxillary sinus. Microscopic findings showed pseudoepithelial hyperplasia and atypical squamous epithelium of a granulomatous character; however, no vasculitis was reported. Laboratory stains were negative for fungus. The patient had noticeable elevation of the white cell
FIGURE 4. View of patient showing development of left Bell’s palsy and parotid mass 16 days after initial presentation.
count, with a slight shift to the left, and increased platelets and sedimentation rate. The radiographic evaluation of the lung fields show marked cavitary involvement consistent with Wegener’s disease. There was also evidence of renal involvement shown on CT scan of the abdomen. It would appear, however, from the laboratory data, that involvement of the kidney parenchyma had not progressed significantly because the patient’s electrolytes, blood urea nitrogen, and creatinine levels were within normal limits. Generally, one would expect progressive destructive segmental glomerular nephritis with such a lesion. A needle biopsy of the kidney may identify the extent of renal involvement. Generally, with Wegener’s granulomatosis, a leukocytosis is present that is consistent with the findings of an elevated white cell count. Also, there was an elevated sedimentation rate found in this patient. Approximately one half of patients will have a positive rheumatoid factor; however, this test apparently was not done during the initial evaluation. The differential diagnosis that includes Wegener’s granulomatosis would be based on the microscopic and clinical findings from the patient. There should be evidence of vasculitis and granulomatous inflammation. Pure vasculytic disease, such as systemic lupus, would not have granulomatous inflammation. Conversely, granulomatous diseases such as tuberculosis, fungal disease, or sarcoidosis would not have vasculitis. The difference between Wegener’s granulomatosis and midline lethal granuloma is that midline granuloma is restricted to the head and neck region without an associated vasculitis. Another poorly differentiated localized lymphoproliferative lesion that can also disseminate is polymorphic reticulosis (or midline malignant reticulosis). This condition, although centering on blood vessels, fails to exhibit vasculitis, thus distinguish-
LUTCAVAGE
1335
ET AL
FIGURE 5. Posteroanterior cavitary lesions.
chest radiograph showing multiple
ing it from Wegener’s granulomatosis. It may also be microscopically distinguished from Wegener’s granulomatosis by the presence of atypical polymorphic lymphoid or histocytic cells, and no giant cells, or librinoid necrosis. At times, the presence of papular skin lesions will assist in making the diagnosis. According to Batsakis,’ pleomorphic reticulosis is closely related to true lymphoma and transitions between polymorphic reticulosis and lymphoma have been observed. Batsakis2 believes that polymorphic reticulosis is a precursor to lymphoma. This entity also responds to therapeutic radiation. The histogenesis of polymorphic reticulosis
FIGURE 6.
Lateral chest radiograph showing multiple masses.
FIGURE 7. mass.
Computed tomography
scan showing left parotid
is the subject of debate as histiocytes and lymphocytes have both been considered to be the origin of this lesion. Assuming that the patient’s diagnosis is Wegener’s granulomatosis, the treatment of choice would be the use of cyclophosphamide, azathioprine, or other types of alkalyting agents. If the disease is progressing rapidly, intravenous use of cyclophosphamide therapy can induce remission in approximately 95% of patients with the remission lasting upwards to 15 years. To summarize, it is my impression that the overall differential diagnosis should include diseases which appear clinically as midline granulomas. Based on the history and clinical findings the diagnosis should include inflammatory diseases of unknown etiology, specifically Wegener’s granulomatosis or idiopathic midline granuloma. In view of the fact that the patient has systemic involvement of the
FIGURE 8. cyst.
Computed tomography
scan showing right renal
1336
GINGIVAL MASS WITH NECROSIS
FIGURE 9. Section from the gingiva showing two thin-walled vessels that show loss of integrity of their lumens and a perivascular collection of polymorphonuclear leukocytes, plasma cells, lymphocytes, and an occasional eosinophil (hematoxylin-eosin stain, original magnification X 100).
FIGURE 10. Section from the maxillary mucobuccal fold area showing an ill-defined granuloma in immediate proximity to a small artery and collapsed vein in which there is also marked acute and chronic inflammation (hematoxylin-eosin stain, original magnification X 100).
kidney and lower respiratory tract, it would appear that the most likely diagnosis is Wegener’s granulomatosis. The one difficulty with this diagnosis is that there is no mention of vasculitis in the microscopic evaluation. I would suggest reevaluation of the patient and additional biopsies to look for histologic evidence of vasculitis to substantiate the di-
the entire thickness of the specimen. The infiltrate was composed of scattered clusters of polymorphonuclear neutrophils, lymphocytes, histiocytes, and occasional eosinophils. Small, thin-walled vessels showed interruption of their lumens and adjacent eosinophilic material suggestive of fibrin. Small collections of polymorphonuclear neutrophils were intimately associated with these vessels (Fig 9). Biopsy specimens obtained 1 month later from the left aspect of the maxilla and mucobuccal fold area showed ill-defined granulomas with multinucleated giant cells in close proximity to several small vessels. A mixed angiocentric inflammatory cell infiltrate of predominantly polymorphonuclear neutrophils, plasma cells, and nuclear debris was also noted (Fig 10). The granulomatous and destructive angiitis were suggestive of Wegener’s granulomatosis but had to be correlated with clinical evidence of lower respiratory tract or renal involvement.
agnosis. If the diagnosis is Wegener’s granulomatosis, treatment can be accomplished using chemotherapeutic alkalating agents with an expected positive response. SUBSEQUENT Microscopic
CLINICAL COURSE
Findings
Microscopic examination of hematoxylin and eosinstained sections obtained from the gingival mass in the left canine fossa region showed hyperplastic surface epithelium and ulceration. Marked transepithelial migration by polymorphonuclear leukocytes and a mixed inflammatory cell infiltrate with necrosis was evident throughout
Case Management The patient was treated with cyclophosphamide and prednisone therapy administered as an outpatient. Resolution of his constitutional symptoms and multiple organ
FIGURE 11. Gingival area 2 months after initiation of treatment showing regression of lesion.
LUTCAVAGEETAL
1337
system disease ensued including the pulmonary lesions, the gingival (Fig 11) and parotid masses, the facial nerve paralysis, and chronic sinusitis. The patient was tapered off the steroid regimen 1 month after initiation of therapy. After 1 year of treatment with cyclophosphamide, the drug was discontinued. Within 1 month, the patient began to complain of leg aches, malaise, and ultimately developed a mononeuritis simplex, and multiple necrotic skin ulcers with arterial insufficiency of his upper and lower extremities. The patient was again given cyclophosphamide and steroid therapy, resulting in rapid clinical improvement. However, the patient ultimately underwent amputation of the second, third, and fifth fingers of his right hand due to factors directly attributable to his relapse. Twenty months following his initial presentation, the patient remains asymptomatic and continues on cytotoxic therapy.
Discussion A disease process resembling Wegener’s granulomatosis was first described by Klinger in 193 1.3 It was recognized as a specific disease syndrome by Wegener in 1936, 1939.4.5 It is classically described as a triad involving the pulmonary, renal, and vascular systems6 and is characterized by a necrotizing granulomatous vasculitis of the upper and lower respiratory tracts with glomerulonephritis.7 As the disease progresses, other organ systems may become involved, including the skin, nervous system, oral cavity, joints, and eyes. Interestingly, in Fauci’s review of 85 patients over 21 years, one patient presented with a parotid granuloma and six patients with facial nerve involvement.7 In another review of 30 patients, Le Thi Huong Du described one patient having a parotid mass and two patients with facial nerve involvement .* There is a slight male predominance with an average age of 40 years at time of onset. The age range of onset is 15 to 75 years.’ The precise cause of the disease is unknown. Patients most commonly present with symptoms related to upper airway disease, specifically, the nasal and maxillary sinus regions. Chronic sinusitis, persistent rhinorrhea, epistaxis, and nasal mucosal crusting without healing are the usual complaints. lo With the persistence of symptoms, increasing nasal obstruction with septal destruction and collapse are noted.’ In two separate reviews, greater than 90% of patients reported upper airway symptoms as described above.7,8 Conventional sinus radiographs usually show mucosal thickening, fluid levels, sclerosis, and bone destruction. ’ ’ Initial pulmonary manifestations include chest discomfort, cough, dyspnea, hemoptysis, and pleuritis. Fauci reported that 94% of patients in his study presented with evidence of lung disease.7 Characteristic findings on chest radiographs in-
eluded bilateral, multiple nodular infiltrates that displayed a tendency towards cavitation.7,12*‘3 Relapse does not always occur at the site of the original lesion(s).‘3 Renal involvement usually occurs in the later stages of Wegener’s granulomatosis and, if unrecognized, rapidly progresses to a fatal outcome. Renal pathology consists of a glomerulonephritis that can vary in degree of severity from mild focal glomerulonephritis with little or no urinary findings to diffuse fulminant necrotizing glomerulonephritis rapidly progressing to end-stage renal failure. Laboratory urinary findings may include proteinuria, hematuria, and red blood cell casts.14 Cytotoxic and steroid medications are the treatment of choice in Wegener’s granulomatosis. Oral administration of cyclophosphamide at an initial dose of 2 mg/kg body weight/d and prednisone at an initial dose of 1 mg/kg body weight/d are used to address the acute symptomology until the desired therapeutic effect of cyclophosphamide is attained. The steroid regimen is then converted to an alternate day routine and later tapered off so that the patient is maintained solely on cyclophosphamide. Cytotoxic therapy is continued for 1 year following complete clinical remission.7 At this time, tapering with discontinuance of cyclophosphamide is usually done. Careful clinical monitoring during this period is necessary to detect early signs of relapse. Without cytotoxic therapy, Wegener’s granulomatosis is rapidly fatal, with a mean survival period of 5 months.7*15 With the exception of renal disease, lesions associated with Wegener’s granulomatosis rapidly resolve when the appropriate chemotherapeutic regimen is administered. Damage to the glomerular apparatus is irreversible even with cyclophosphamide therapy. Thus, early diagnosis and initiation of treatment assumes paramount importance in the overall survival rates. In Fauci’s 21year study, 79 of 85 (93%) patients achieved complete remission following chemotherapy.7 Seventyfive patients were still alive and in remission for a survival rate of 88% with a mean follow-up period of 51 months. Focal gingival masses or generalized gingival enlargement associated with Wegener’s granulomatosis are rare as evidenced by the paucity of case reports. 15-26Reportedly arising at an early stage in the disease process, focal inflammation originates in the interproximal papilla spreading to the gingiva. 18.2’Gingival tissues enlarge and assume a granular appearance. The color is characteristically prominent red with intermittent blue petechial speckles on the surface. The term “strawberry gums” has been used to describe these impressive changes. 16q20Destruction of underlying alveolar
1338 bone will progress to the point of noticeable increase in tooth mobility even to the point of exfoliation. The gingival lesions can be localized or generalized,23 but the clinical appearance is at least characteristic, if not pathognomonic, of Wegener’s granulomatosis. Early recognition of this clinical marker assumes the utmost importance when considering that the mean survival of patients without initiation of cytotoxic therapy is 5 months.7*‘4,27 A high degree of clinical suspicion is mandatory considering the nonspecific microscopic findings reported from biopsy. Therefore, it is strongly recommended that multiple biopsies be taken if initial reports do not exhibit classic microscopic findings consistent with Wegener’s granulomatosis. Indeed, it is rare that a definitive diagnosis of Wegener’s granulomatosis can be made solely on the basis of gingival biopsy. However, this lack of specificity should alert the clinician to initiate a comprehensive diagnostic workup. Hesitation to initiate cytotoxic therapy in the presence of suspected Wegener’s granulomatosis will result in a tragic outcome.24 The oral and maxillofacial surgeon is placed in a unique position to aid in the early diagnosis of Wegener’s granulomatosis and thus provide a lifesaving service for a patient afflicted by this devastating disease. References 1. Batsakis JG: Wegener’s granulomatosis and midline (nonhealing) “granuloma.” Head Neck Surg 1:213, 1982 2. Bat&is JG, Luna MA: Midfacial necrotizing lesions. Semin Diagn Path01 490, 1987 3. Klinger H: Grenzformen der periarteritis nodosa. Frankfurt Z Path01 42:455, 1931 4. Wegener F: Uber generalisierte, septische Gefasserkranukungen. Verh Dtsch Ges Path01 29:202, 1936 5. Wegener F: Uber eine eigenartige rhinogene Granulomatose mit besonderer Beteiligung des Arteriensystems und der Nieren. Beitr Path01 102:36, 1939 6. Greer RO Jr: Wegener’s granulomatosis: Current clinicopathologic concepts and oral differential diagnosis. Q Nat1 Dent Assoc 32:17, 1973 7. Fauci AS, Haynes BF, Katz P, et al: Wegener’s granulomatosis: Prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 98:76, 1983
GINGIVAL MASS WITH NECROSIS
8. Le Thi Huong DU, Wechsler B, Cabane J, et al: Granulomatose de Wegener. Aspects cliniques, problemes nosologiques. Revue de la litterature a propos de 30 observations. Ann Med Inteme (Paris) 139:169. 1988 9. Thawley SE, Panje WR, Batsakis JG, et al: Comprehensive Management of Head and Tumors. Philadelphia, PA, Saunders, 1987 10. Brocheriou C, de Roquancourt A, D’Agay MF: Processus granulomateux crania-faciaux. Ann Path01 6: 13, 1986 11. Drake-Lee AB, Milford CA: A review of the role of radiology in non-healing granulomas of the nose and nasal sinuses. Rhinology 27:231, 1989 12. Gonzalez L, Van Ordstrand HS: Wegener’s granulomatosis. Review of 11 cases. Radioloav 107:295. 1973 13. Farrelly CA: Wegener’s granugmatosis: A radiological review of the pulmonary manifestations at initial presentation and during relapse. Clin Radio1 33:545, 1982 14. Fauci AS, Wolff SM: Wegener’s granulomatosis: Studies in eighteen patients and a review of the literature. Medicine 52:535, 1973 15. Hansen LS, Silverman S Jr, Pons VG, et al: Limited Wegener’s granulomatosis. Report of a case with oral, renal, and skin involvement. Oral Surg Oral Med Oral Path01 60:524, 1985 16. Glass EG, Lawton LR, Truelove EL: Oral presentation of Wegener’s granulomatosis. J Am Dent Assoc 120:523, 1990 17. Brooke RI: Wegener’s granulomatosis involving the gingivae. Br Dent J 127:34, 1%9 18. Cohen PS, Meltzer JA: Strawberry gums. A sign of Wegener’s granulomatosis. JAMA 246:2610, 1981 19. Horan RF, Kerdel FA, Moschella SL, et al: Recent onset of gingival enlargement. Arch Dermatol 122: 1436, 1986 20. Raustia AM, Autio-Harmainen HI, Knuuttila ML, et al: Ultrastructural findings and clinical follow-up of “strawberry gums” in Wegener’s granulomatosis. J Oral Path01 14:581, 1985 21. Scott J, Finch LD: Wegener’s granulomatosis presenting as gingivitis. Review of the clinical and pathologic features and report of a case. Oral Surg Oral Med Oral Pathol 34:920, 1972 22. Eveson JW, Slaney AE: Non-healing midline granuloma. Br J Oral Surg 20: 102, 1982 23. Israelson H, Binnie WH, Hurt WC: The hyperplastic gingivitis of Wegener’s granulomatosis. J Periodontol 52:81, 1981 24. Edwards MB, Buckerfield JP: Wegener’s granulomatosis: A case with primary mucocutaneous lesions. Oral Surg Oral Med Oral Pathol46:53, 1978 25. Menninger H, Sultan N, Muller R: Zur Klinik der Wegnerschen Granulomatose. Munch Med Wochenschr 114: 1646, 1972 26. Galan E, Sosovec V: Beitrag zur Wegnerschen Granulomatose. Dtsch Zahnarztl Z 28:438, 1973 27. Komblutt AD, Wolff SM, deFries HO, et al: Wegener’s granulomatosis. Otolaryngol Clin North Am 15:533, 1982
Surg
49:1x32-1338.1991
Gingival Mass With Massive Soft-Tissue Necrosis GREGORY J. LUTCAVAGE DDS,* SIEGFRIED J. SCHABERG, DOUGLAS A. ARENDT, DDS,$ AND JAY P. MALMQUIST, Case Presentation
left canine eminence, multiple carious teeth, multiple periapical radiolucencies, and moderate to severe generalized periodontal bone loss (Fig 3). On February 20, 1989, two incisional biopsies of the mass in the left canine area were performed under local anesthesia. These showed atypical squamous epithelium, chronic inflammation, ulceration, and pseudoepithelial hyperplasia. On March 6, 1989, a mass involving the tail of the left parotid gland associated with a left Bell’s palsy was noted (Fig 4). No lymphadenopathy was present. A symptomatic upper left second molar was extracted, an additional incisional biopsy of the mass was performed, and tissue scrapings were obtained for fungal stains. Microscopic examination of the biopsy specimen showed severe inflammation and ulceration. The fungal stains were negative. Antibiotic therapy consisting of cefadroxil monohydrate (1 g/d) was initiated to control the chronic sinusitis. Laboratory studies included a complete blood count, which revealed a hemoglobin of 12.2 g/dL, hematocrit of 36. I%, white blood cell count of 11,2OO/p.L, and platelet count of 598,OOO/~L. The differential count was 76.8% polymorphonuclear neutrophils, 6.2% monocytes, and lymphocytes 17%. The serum electrolytes, blood urea nitrogen, and creatinine levels were normal and the rapid plasma reagin was nonreactive. A tuberculin purified protein derivative was negative. The erythrocyte sedimentation rate was markedly elevated, at 83 mm in 1 hour. A posteroanterior chest radiograph showed well circumscribed multiple cavitary lesions in the right and left lung fields (Fig 5). A large mass involving the upper lobe of the left lung measured approximately 8 cm. A fluid level was also noted in the left lung. Multiple, well circumscribed masses were noted on the anterior aspect of the lateral chest radiograph (Fig 6). A computed tomography (CT) scan of the face and neck was remarkable for a mass of the left parotid extending posteriorly into the ptergygomandibular space (Fig 7). On the basis of the preliminary findings, the patient was admitted on March 20, 1989, for a full diagnostic workup and appropriate consultations. A CT scan of the abdomen showed a 4-cm, right renal cyst (Fig 8). Fungal serology was negative. A fine-needle aspiration biopsy of the left upper lobe lesion showed necrotic cells with acute inflammation, but no organisms. Medical oncology and ENT consultations were obtained. On March 23, 1989, the patient underwent bronchoscopy, esophagoscopy, direct laryngoscopy, needle aspiration of the left parotid mass, and incisional biopsies of the posterior tracheal wall, left maxillary mucosa, left buccal mucosa, and the gingival mass under general anesthesia.
On February 20, 1989, a 47-year-old white man was referred by his general dentist for evaluation of a localized soft-tissue mass in the left maxilla. The patient sought treatment from his dentist because he had had a left maxillary canine removed approximately 1 month before and desired prosthetic replacement as well as the removal of multiple carious teeth in the anterior maxilla. The medical history included a motor vehicle accident in 1987 during which the patient had traumatically avulsed multiple teeth. In 1983, he sustained a renal contusion and rib fracture in another motor vehicle accident. The review of systems was significant for a recent unexplained weight loss and chronic maxillary sinusitis. He had a 30 packlyr history of cigarette usage, denied use of alcohol, and used salicylates for occasional pain. Examination revealed an extremely apprehensive, thin, talkative man in no acute distress. The head and neck examination was unremarkable. However, the oral examination revealed multiple carious teeth, gross generalized periodontitis, and a nonhealing maxillary left canine extraction site. A purplish-red soft-tissue mass with a granular surface measuring 2.5 x 2.0 cm was noted in the area of the left maxillary extraction site (Fig 1). Extensive tissue necrosis was present in the left maxillary vestibule extending from the maxillary tuberosity to the anterior midline and superiorly into the canine fossa, the infraorbital region, and the left maxillary sinus. In the right anterior maxillary vestibule, an erythematous punctate l-cm mucosal lesion was noted in the area of the canine eminence. A Water’s view radiograph showed left maxillary sinus mucosal thickening (Fig 2). A panoramic radiograph showed extensive osseous destruction in the area of the * Chairman, Department of Surgery, Attending Surgeon, Wayne Memorial Hospital; in private practice, Goldsboro, NC. t Attending Surgeon, Wayne Memorial Hospital; in private practice, Goldsboro, NC. $ Oral Pathologist, Naval Hospital San Diego, CA. 5 Associate Professor, Departments of Pathology and Oral and Maxillofacial Surgery, Oregon Health Sciences Center, Portland. The opinions contained herein are those of the authors and are not to be construed as offkial or as reflecting the views of the United States Navy or Department of Defense. Address correspondence and reprint requests to Dr Lutcavage: 2400 Wayne Memorial Dr, Goldsboro, NC 27534. 0 1991 American geons
Association
of Oral and Maxillofacial
DDS, PHD,t DMD§
Sur-
0278-2391/91/4912-0012$3.00/O
1332
LUTCAVAGE
FIGURE 1. presentation.
1333
ET AL
Gingival mass at time of initial
Differential Jay P. Malmquist,
Diagnosis
DMD
The differential diagnosis of the lesion involving multiple systems of this 47-year-old white man should include those diseases that appear as midline maxillary granulomas. These may be infectious, neoplastic, or inflammatory in origin. Diagnosis is dependent on the patient’s pertinent history and clinical and laboratory findings. Although the presenting signs and symptoms focus on the soft-tissue mass in the anterior maxillary vestibule, further investigation substantiates multiple system involvement. Infectious involvement can be ruled out by the lack of positive bacterial, fungal, or parasitic stains and cultures from tissue samples. The biopsies suggest no neoplastic component, as the predominant findings are inflammatory. This is further substantiated by a hematology report. which indicates a
FIGURE 2. Water’s view radiograph sinus mucosal thickening.
showing left maxillary
normal blood picture except for an elevation of the white blood cell count with a shift to the left, an elevated sedimentation rate, and elevation of platelets. In view of these findings, the differential diagnosis should exclude an infectious or neoplastic etiology and concentrate on inflammatory disease of unknown etiology. Two considerations would be Wegener’s granulomatosis and idiopathic midline destructive disease. Wegener’s granuloma is described as a necrotic vasculitis and granulomatosis inflammation that affects primarily the upper and lower respiratory tracts and kidneys. Conversely, a midline granuloma, which has also been characterized as midline lethal granuloma, lethal midline reticulosis, malignant granuloma, or granuloma gangrenescens, is characterized by local inflammation, destruction, and often mutilation of tissues in the upper respiratory tract and face. Generally this lesion is limited to the upper respiratory tract and does not involve other systems. The etiology of both inflammatory diseases is unknown, although a possible connection with hypersensitivity has been suggested. Wegener’s granulomatosis and midline lethal reticulosis can also be distinguished by different responses to therapy. Wegener’s granulomatosis responds well to treatment with cyclophosphamides and alternate day steroid therapy, but midline lethal granuloma responds better to radiation. In this case report, the patient’s clinical, radiographic, and laboratory studies suggest an inflammatory granulomatous disease consistent with Wegener’s granulomatosis. The patient has significant, unexplained weight loss and a left premaxillary mass with a raised granular surface and marked tissue necrosis. The lesion extended from the tuberosity on the left side to the anterior midline, with some right maxillary nodularity. Radiographs
1334
GINGIVAL MASS WITH NECROSIS
FIGURE J 3. Panoramic radiograph showing osseous destruction in the left canine region.
showed marked destruction of the alveolar complex on the left side, with extensive bone involvement. There was also evidence of mucosal thickening in the left maxillary sinus. Microscopic findings showed pseudoepithelial hyperplasia and atypical squamous epithelium of a granulomatous character; however, no vasculitis was reported. Laboratory stains were negative for fungus. The patient had noticeable elevation of the white cell
FIGURE 4. View of patient showing development of left Bell’s palsy and parotid mass 16 days after initial presentation.
count, with a slight shift to the left, and increased platelets and sedimentation rate. The radiographic evaluation of the lung fields show marked cavitary involvement consistent with Wegener’s disease. There was also evidence of renal involvement shown on CT scan of the abdomen. It would appear, however, from the laboratory data, that involvement of the kidney parenchyma had not progressed significantly because the patient’s electrolytes, blood urea nitrogen, and creatinine levels were within normal limits. Generally, one would expect progressive destructive segmental glomerular nephritis with such a lesion. A needle biopsy of the kidney may identify the extent of renal involvement. Generally, with Wegener’s granulomatosis, a leukocytosis is present that is consistent with the findings of an elevated white cell count. Also, there was an elevated sedimentation rate found in this patient. Approximately one half of patients will have a positive rheumatoid factor; however, this test apparently was not done during the initial evaluation. The differential diagnosis that includes Wegener’s granulomatosis would be based on the microscopic and clinical findings from the patient. There should be evidence of vasculitis and granulomatous inflammation. Pure vasculytic disease, such as systemic lupus, would not have granulomatous inflammation. Conversely, granulomatous diseases such as tuberculosis, fungal disease, or sarcoidosis would not have vasculitis. The difference between Wegener’s granulomatosis and midline lethal granuloma is that midline granuloma is restricted to the head and neck region without an associated vasculitis. Another poorly differentiated localized lymphoproliferative lesion that can also disseminate is polymorphic reticulosis (or midline malignant reticulosis). This condition, although centering on blood vessels, fails to exhibit vasculitis, thus distinguish-
LUTCAVAGE
1335
ET AL
FIGURE 5. Posteroanterior cavitary lesions.
chest radiograph showing multiple
ing it from Wegener’s granulomatosis. It may also be microscopically distinguished from Wegener’s granulomatosis by the presence of atypical polymorphic lymphoid or histocytic cells, and no giant cells, or librinoid necrosis. At times, the presence of papular skin lesions will assist in making the diagnosis. According to Batsakis,’ pleomorphic reticulosis is closely related to true lymphoma and transitions between polymorphic reticulosis and lymphoma have been observed. Batsakis2 believes that polymorphic reticulosis is a precursor to lymphoma. This entity also responds to therapeutic radiation. The histogenesis of polymorphic reticulosis
FIGURE 6.
Lateral chest radiograph showing multiple masses.
FIGURE 7. mass.
Computed tomography
scan showing left parotid
is the subject of debate as histiocytes and lymphocytes have both been considered to be the origin of this lesion. Assuming that the patient’s diagnosis is Wegener’s granulomatosis, the treatment of choice would be the use of cyclophosphamide, azathioprine, or other types of alkalyting agents. If the disease is progressing rapidly, intravenous use of cyclophosphamide therapy can induce remission in approximately 95% of patients with the remission lasting upwards to 15 years. To summarize, it is my impression that the overall differential diagnosis should include diseases which appear clinically as midline granulomas. Based on the history and clinical findings the diagnosis should include inflammatory diseases of unknown etiology, specifically Wegener’s granulomatosis or idiopathic midline granuloma. In view of the fact that the patient has systemic involvement of the
FIGURE 8. cyst.
Computed tomography
scan showing right renal
1336
GINGIVAL MASS WITH NECROSIS
FIGURE 9. Section from the gingiva showing two thin-walled vessels that show loss of integrity of their lumens and a perivascular collection of polymorphonuclear leukocytes, plasma cells, lymphocytes, and an occasional eosinophil (hematoxylin-eosin stain, original magnification X 100).
FIGURE 10. Section from the maxillary mucobuccal fold area showing an ill-defined granuloma in immediate proximity to a small artery and collapsed vein in which there is also marked acute and chronic inflammation (hematoxylin-eosin stain, original magnification X 100).
kidney and lower respiratory tract, it would appear that the most likely diagnosis is Wegener’s granulomatosis. The one difficulty with this diagnosis is that there is no mention of vasculitis in the microscopic evaluation. I would suggest reevaluation of the patient and additional biopsies to look for histologic evidence of vasculitis to substantiate the di-
the entire thickness of the specimen. The infiltrate was composed of scattered clusters of polymorphonuclear neutrophils, lymphocytes, histiocytes, and occasional eosinophils. Small, thin-walled vessels showed interruption of their lumens and adjacent eosinophilic material suggestive of fibrin. Small collections of polymorphonuclear neutrophils were intimately associated with these vessels (Fig 9). Biopsy specimens obtained 1 month later from the left aspect of the maxilla and mucobuccal fold area showed ill-defined granulomas with multinucleated giant cells in close proximity to several small vessels. A mixed angiocentric inflammatory cell infiltrate of predominantly polymorphonuclear neutrophils, plasma cells, and nuclear debris was also noted (Fig 10). The granulomatous and destructive angiitis were suggestive of Wegener’s granulomatosis but had to be correlated with clinical evidence of lower respiratory tract or renal involvement.
agnosis. If the diagnosis is Wegener’s granulomatosis, treatment can be accomplished using chemotherapeutic alkalating agents with an expected positive response. SUBSEQUENT Microscopic
CLINICAL COURSE
Findings
Microscopic examination of hematoxylin and eosinstained sections obtained from the gingival mass in the left canine fossa region showed hyperplastic surface epithelium and ulceration. Marked transepithelial migration by polymorphonuclear leukocytes and a mixed inflammatory cell infiltrate with necrosis was evident throughout
Case Management The patient was treated with cyclophosphamide and prednisone therapy administered as an outpatient. Resolution of his constitutional symptoms and multiple organ
FIGURE 11. Gingival area 2 months after initiation of treatment showing regression of lesion.
LUTCAVAGEETAL
1337
system disease ensued including the pulmonary lesions, the gingival (Fig 11) and parotid masses, the facial nerve paralysis, and chronic sinusitis. The patient was tapered off the steroid regimen 1 month after initiation of therapy. After 1 year of treatment with cyclophosphamide, the drug was discontinued. Within 1 month, the patient began to complain of leg aches, malaise, and ultimately developed a mononeuritis simplex, and multiple necrotic skin ulcers with arterial insufficiency of his upper and lower extremities. The patient was again given cyclophosphamide and steroid therapy, resulting in rapid clinical improvement. However, the patient ultimately underwent amputation of the second, third, and fifth fingers of his right hand due to factors directly attributable to his relapse. Twenty months following his initial presentation, the patient remains asymptomatic and continues on cytotoxic therapy.
Discussion A disease process resembling Wegener’s granulomatosis was first described by Klinger in 193 1.3 It was recognized as a specific disease syndrome by Wegener in 1936, 1939.4.5 It is classically described as a triad involving the pulmonary, renal, and vascular systems6 and is characterized by a necrotizing granulomatous vasculitis of the upper and lower respiratory tracts with glomerulonephritis.7 As the disease progresses, other organ systems may become involved, including the skin, nervous system, oral cavity, joints, and eyes. Interestingly, in Fauci’s review of 85 patients over 21 years, one patient presented with a parotid granuloma and six patients with facial nerve involvement.7 In another review of 30 patients, Le Thi Huong Du described one patient having a parotid mass and two patients with facial nerve involvement .* There is a slight male predominance with an average age of 40 years at time of onset. The age range of onset is 15 to 75 years.’ The precise cause of the disease is unknown. Patients most commonly present with symptoms related to upper airway disease, specifically, the nasal and maxillary sinus regions. Chronic sinusitis, persistent rhinorrhea, epistaxis, and nasal mucosal crusting without healing are the usual complaints. lo With the persistence of symptoms, increasing nasal obstruction with septal destruction and collapse are noted.’ In two separate reviews, greater than 90% of patients reported upper airway symptoms as described above.7,8 Conventional sinus radiographs usually show mucosal thickening, fluid levels, sclerosis, and bone destruction. ’ ’ Initial pulmonary manifestations include chest discomfort, cough, dyspnea, hemoptysis, and pleuritis. Fauci reported that 94% of patients in his study presented with evidence of lung disease.7 Characteristic findings on chest radiographs in-
eluded bilateral, multiple nodular infiltrates that displayed a tendency towards cavitation.7,12*‘3 Relapse does not always occur at the site of the original lesion(s).‘3 Renal involvement usually occurs in the later stages of Wegener’s granulomatosis and, if unrecognized, rapidly progresses to a fatal outcome. Renal pathology consists of a glomerulonephritis that can vary in degree of severity from mild focal glomerulonephritis with little or no urinary findings to diffuse fulminant necrotizing glomerulonephritis rapidly progressing to end-stage renal failure. Laboratory urinary findings may include proteinuria, hematuria, and red blood cell casts.14 Cytotoxic and steroid medications are the treatment of choice in Wegener’s granulomatosis. Oral administration of cyclophosphamide at an initial dose of 2 mg/kg body weight/d and prednisone at an initial dose of 1 mg/kg body weight/d are used to address the acute symptomology until the desired therapeutic effect of cyclophosphamide is attained. The steroid regimen is then converted to an alternate day routine and later tapered off so that the patient is maintained solely on cyclophosphamide. Cytotoxic therapy is continued for 1 year following complete clinical remission.7 At this time, tapering with discontinuance of cyclophosphamide is usually done. Careful clinical monitoring during this period is necessary to detect early signs of relapse. Without cytotoxic therapy, Wegener’s granulomatosis is rapidly fatal, with a mean survival period of 5 months.7*15 With the exception of renal disease, lesions associated with Wegener’s granulomatosis rapidly resolve when the appropriate chemotherapeutic regimen is administered. Damage to the glomerular apparatus is irreversible even with cyclophosphamide therapy. Thus, early diagnosis and initiation of treatment assumes paramount importance in the overall survival rates. In Fauci’s 21year study, 79 of 85 (93%) patients achieved complete remission following chemotherapy.7 Seventyfive patients were still alive and in remission for a survival rate of 88% with a mean follow-up period of 51 months. Focal gingival masses or generalized gingival enlargement associated with Wegener’s granulomatosis are rare as evidenced by the paucity of case reports. 15-26Reportedly arising at an early stage in the disease process, focal inflammation originates in the interproximal papilla spreading to the gingiva. 18.2’Gingival tissues enlarge and assume a granular appearance. The color is characteristically prominent red with intermittent blue petechial speckles on the surface. The term “strawberry gums” has been used to describe these impressive changes. 16q20Destruction of underlying alveolar
1338 bone will progress to the point of noticeable increase in tooth mobility even to the point of exfoliation. The gingival lesions can be localized or generalized,23 but the clinical appearance is at least characteristic, if not pathognomonic, of Wegener’s granulomatosis. Early recognition of this clinical marker assumes the utmost importance when considering that the mean survival of patients without initiation of cytotoxic therapy is 5 months.7*‘4,27 A high degree of clinical suspicion is mandatory considering the nonspecific microscopic findings reported from biopsy. Therefore, it is strongly recommended that multiple biopsies be taken if initial reports do not exhibit classic microscopic findings consistent with Wegener’s granulomatosis. Indeed, it is rare that a definitive diagnosis of Wegener’s granulomatosis can be made solely on the basis of gingival biopsy. However, this lack of specificity should alert the clinician to initiate a comprehensive diagnostic workup. Hesitation to initiate cytotoxic therapy in the presence of suspected Wegener’s granulomatosis will result in a tragic outcome.24 The oral and maxillofacial surgeon is placed in a unique position to aid in the early diagnosis of Wegener’s granulomatosis and thus provide a lifesaving service for a patient afflicted by this devastating disease. References 1. Batsakis JG: Wegener’s granulomatosis and midline (nonhealing) “granuloma.” Head Neck Surg 1:213, 1982 2. Bat&is JG, Luna MA: Midfacial necrotizing lesions. Semin Diagn Path01 490, 1987 3. Klinger H: Grenzformen der periarteritis nodosa. Frankfurt Z Path01 42:455, 1931 4. Wegener F: Uber generalisierte, septische Gefasserkranukungen. Verh Dtsch Ges Path01 29:202, 1936 5. Wegener F: Uber eine eigenartige rhinogene Granulomatose mit besonderer Beteiligung des Arteriensystems und der Nieren. Beitr Path01 102:36, 1939 6. Greer RO Jr: Wegener’s granulomatosis: Current clinicopathologic concepts and oral differential diagnosis. Q Nat1 Dent Assoc 32:17, 1973 7. Fauci AS, Haynes BF, Katz P, et al: Wegener’s granulomatosis: Prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 98:76, 1983
GINGIVAL MASS WITH NECROSIS
8. Le Thi Huong DU, Wechsler B, Cabane J, et al: Granulomatose de Wegener. Aspects cliniques, problemes nosologiques. Revue de la litterature a propos de 30 observations. Ann Med Inteme (Paris) 139:169. 1988 9. Thawley SE, Panje WR, Batsakis JG, et al: Comprehensive Management of Head and Tumors. Philadelphia, PA, Saunders, 1987 10. Brocheriou C, de Roquancourt A, D’Agay MF: Processus granulomateux crania-faciaux. Ann Path01 6: 13, 1986 11. Drake-Lee AB, Milford CA: A review of the role of radiology in non-healing granulomas of the nose and nasal sinuses. Rhinology 27:231, 1989 12. Gonzalez L, Van Ordstrand HS: Wegener’s granulomatosis. Review of 11 cases. Radioloav 107:295. 1973 13. Farrelly CA: Wegener’s granugmatosis: A radiological review of the pulmonary manifestations at initial presentation and during relapse. Clin Radio1 33:545, 1982 14. Fauci AS, Wolff SM: Wegener’s granulomatosis: Studies in eighteen patients and a review of the literature. Medicine 52:535, 1973 15. Hansen LS, Silverman S Jr, Pons VG, et al: Limited Wegener’s granulomatosis. Report of a case with oral, renal, and skin involvement. Oral Surg Oral Med Oral Path01 60:524, 1985 16. Glass EG, Lawton LR, Truelove EL: Oral presentation of Wegener’s granulomatosis. J Am Dent Assoc 120:523, 1990 17. Brooke RI: Wegener’s granulomatosis involving the gingivae. Br Dent J 127:34, 1%9 18. Cohen PS, Meltzer JA: Strawberry gums. A sign of Wegener’s granulomatosis. JAMA 246:2610, 1981 19. Horan RF, Kerdel FA, Moschella SL, et al: Recent onset of gingival enlargement. Arch Dermatol 122: 1436, 1986 20. Raustia AM, Autio-Harmainen HI, Knuuttila ML, et al: Ultrastructural findings and clinical follow-up of “strawberry gums” in Wegener’s granulomatosis. J Oral Path01 14:581, 1985 21. Scott J, Finch LD: Wegener’s granulomatosis presenting as gingivitis. Review of the clinical and pathologic features and report of a case. Oral Surg Oral Med Oral Pathol 34:920, 1972 22. Eveson JW, Slaney AE: Non-healing midline granuloma. Br J Oral Surg 20: 102, 1982 23. Israelson H, Binnie WH, Hurt WC: The hyperplastic gingivitis of Wegener’s granulomatosis. J Periodontol 52:81, 1981 24. Edwards MB, Buckerfield JP: Wegener’s granulomatosis: A case with primary mucocutaneous lesions. Oral Surg Oral Med Oral Pathol46:53, 1978 25. Menninger H, Sultan N, Muller R: Zur Klinik der Wegnerschen Granulomatose. Munch Med Wochenschr 114: 1646, 1972 26. Galan E, Sosovec V: Beitrag zur Wegnerschen Granulomatose. Dtsch Zahnarztl Z 28:438, 1973 27. Komblutt AD, Wolff SM, deFries HO, et al: Wegener’s granulomatosis. Otolaryngol Clin North Am 15:533, 1982
