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Review Article

Granulomatous conditions in the oral cavity – A review N. Vidulasri, M. P. Brundha*

ABSTRACT

Granulomatous diseases represent a unique form of the chronic inflammatory response with granulomatous diseases of the oral soft and hard tissues being an uncommon occurrence. When observed clinically, it presents a definite diagnostic dilemma due to the wide variety of possible etiologic diseases. Granulomatous diseases are also frequently observed due to a wide variety of infections. A is a distinct, compact microscopic structure composed of epithelioid-shaped macrophages typically surrounded by a rim of lymphocytes. Fibroblasts and collagen fibers are also seen immediately surrounding the lymphocytes. Granulomatous disorders comprise a large family of lesions that share a common histological feature: Granuloma formation. Therefore, an extensive clinical, microscopic, and laboratory evaluation is required to identify the source of the oral granulomatous disease. Therefore, the purpose of this article is to highlight the etiology, histopathological features, and differential diagnosis of various granulomatous diseases that affect the oral soft and hard tissues. KEY WORDS: Granuloma, Infectious disease, , Macrophages, Oral lesions

INTRODUCTION small, non-necrotizing or non-caseating with an aggregation of peripheral lymphocytes, A granuloma can be defined as a firm, tumor-like central epithelioid histiocytes, and presence of granulation with a compact collection of epithelioid multinucleated giant cells.[5,6] Granulomatous lesions cells and inflammatory cells formed as a reaction to present themselves as sessile, lobulated, moderately chronic inflammation due to foreign bodies, fungi, firm, and relatively non-tender nodules and papules [1] and bacteria. Oral granulomatous diseases are with normal coloration with little or no erythematous frequently observed due to a wide variety of infections. changes surrounding them.[7] The term granulomatous diseases include those conditions characterized by the histological presence Foreign substances such as endogenous and of granuloma resembling those of tuberculosis (TB) exogenous substances are the most common source of as well as condition without microscopic granuloma triggering localized granulomatous inflammation in formation but with the prominent proliferation of the oral cavity. These reactions present as non-descript granulation tissue.[2] Granulomas are normally the masses with the presence of erythema, localized or result of defensive mechanisms and form when generalized edema, pain, or even the presence of acute inflammatory processes are unable to destroy ulceration of the tissues.[8] On progression, some of invading agents and are believed to be the end the granulomas may ulcerate centrally and present result of a series of pathological events.[3] They as squamous cell carcinomas. The treatment of these possess a multifactorial etiology and may arise due conditions depends on the systemic cause. Localized to a reaction to environmental or genetic factors, lesions without systemic connection can be treated by infectious organisms, or may also be idiopathic, for conservative surgical removal.[9] The presence of signs which there is no trigger factor.[4] A wide variety of and symptoms may warrant additional clinical and granulomatous disorders can involve the orofacial laboratory testing to identify other possible sources of tissues. Such lesions of the oral cavity present as the inflammation, unless the foreign substance is not identified in microscopic sections, the granulomatous Access this article online inflammation generally presents a diagnostic dilemma for the clinicians. Often, the differential Website: jprsolutions.info ISSN: 0975-7619 diagnosis includes foreign body reactions, infection,

Department of General Pathology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India

*Corresponding author: Dr. M. P. Brundha, Department of General Pathology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, 162, Poonamallee High Road, Chennai - 600 077, Tamil Nadu, India. Phone: +91-9884421482. E-mail: [email protected]

Received on: 12-08-2019; Revised on: 08-09-2019; Accepted on: 17-10-2019

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Crohn’s disease (CD), sarcoidosis, and orofacial involve other organs as well which are, respectively, granulomatosis (OFG).[10] Knowledge of the clinical classified as pulmonary and extra-pulmonary TB.[16] and histologic patterns of granulomatous diseases will Primary pulmonary disease results from initial allow easier interpretation for practitioners to provide infection with M. tuberculosis. Most individuals are a useful differential diagnosis, thus facilitating asymptomatic with lesions that heal spontaneously appropriate clinical management.[11] Therefore, the but which later becomes evident with the presence of aim of this article is to provide information regarding small calcified nodules known as Ghon’s complex. the histology and oral manifestation of granulomatous Secondary pulmonary TB is a post-primary disease conditions that commonly affect the oral cavity. due to the endogenous reactivation of latent infection which may be primarily due to immunosuppression.[17] CLASSIFICATION OF GRANULOMATOUS Histopathology [12,13] Tuberculous granulomas are characterized by the CONDITIONS presence of central caseous necrosis. The site is As there is great variation among the possible encircled by epithelioid cells, lymphocytes, histiocytes, [18] etiological factors, the classification of granulomatous fibroblasts, and occasionally Langhans giant cells. disorders may include many conditions. These In some instances, caseating granulomas may not comprise infections, vascular irregularities, be present but may show non-caseating granulomas. immunological upsets, leucocyte oxidase defects, A biopsy exhibiting granulomatous inflammation and hypersensitivity reactions, and neoplasia. Broadly microscopic evidence of mycobacterial organisms are these causes may be categorized as: often suggestive of TB. 1. Bacterial • TB Oral manifestation • Leprosy Oral TB may occur at any location on the oral mucous • Syphilis membrane with the and gingiva being most • Cat-scratch disease commonly involved. Other sites include the , 2. Fungal , buccal mucosa, gingiva, palatine tonsil, and • Histoplasmosis floor of the mouth.[19] Other manifestations include • Blastomycosis it presents as a single or multiple painless ulcers and • Paracoccidioidomycosis usually appear as irregular, well-circumscribed with • Aspergillosis surrounding erythema, which usually extends from the 3. Reactive lesions (Trauma, and hypersensitivity) gingival margin to the depths of the adjacent vestibule • Pyogenic granuloma and is often associated with enlargement of cervical • Peripheral giant cell granuloma lymph nodes, localized masses, and swellings. In • Periapical granuloma rare cases, there is the involvement of the 4. Foreign bodies and which usually results in tuberculous • Oral foreign body reactions osteomyelitis as a result of the penetration of gingival 5. Other causes (Unknown, autoimmune, and/or lesions into jaw bones.[20] vascular origin) • Sarcoidosis Leprosy • CD Leprosy is a slowly progressive infectious disease caused • granulomatosa by Mycobacterium leprae. The disease is presented as • Eosinophilic granuloma either lepromatous leprosy – a low resistance form • Wegener’s granulomatosis or tuberculoid leprosy, the highly resistant form. The initial event is a chronic mycobacterial infection that TB elicits a range of cellular immune responses followed TB is a chronic granulomatous disease caused by by the second response is a peripheral neuropathy that various strains of mycobacteria, usually attributed is initiated by the infection, followed by immunologic to the bacteria Mycobacterium tuberculosis. Among events. The conditions affect the skin and peripheral all infectious diseases, TB remains to be among the nerves, resulting in disabling deformities.[21] Mild world’s most notorious, contributing to high morbidity to moderate effects on other organs which include and mortality rates.[14] Although, oral manifestations systems such as the liver, kidneys, eyes, , of TB have a rare occurrence, it has been considered lymph nodes, bones, and joints and gonads. to account for 0.1–5% of all TB infections.[15] These lesions are usually secondarily inoculated with infected Histology sputum or due to hematogenous spread. The most The typical granulomatous shows collections commonly affected organs are the lungs, but may also of epithelioid cells and lymphocytes in a fibrous

Drug Invention Today | Vol 13 • Issue 1 • 2020 173 N. Vidulasri and M. P. Brundha stroma. Langhans type giant cells are variably present An indurate ulceration of the dorsum of the tongue, with vacuolated macrophages called lepra cells these hyperplasic foliate papillae, is the only clinical signs are scattered throughout the lesions and often contain of the disease. Erythema, edema, and petechial the bacilli.[21] hemorrhage with or without the presence of a chancre may occur in the soft palate. The asymmetry of the Oral manifestation uvula or tonsillar pillar can be noticed in the initial The oral lesions in leprosy are slow to progress and are stages. Oral lesions in primary and secondary syphilis usually asymptomatic. The lesions are usually present are nonspecific and characterized by squamous on the hard and soft palate of the uvula, on the lips that extends deep into the submucosa.[26] and , and on the tongue.[22] They lesions appear The two principal oral features of secondary syphilis as papules, nodules, and ulcers, which may show are mucous patches and maculopapular lesions, bacillary positivity, these multiple nodules progress to although nodular lesions may rarely arise. These necrosis. The lips appear woolen and rigid. Commonly ulcers tend to be oval or serpiginous, with slightly observed lesions include multiple superficial ulcers, raised borders or shallow ulcers with an erythematous mild , loss of papillae, chronic atrophic halo. There is the presence of grey or silver-white candidiasis, and . Oral lesions of membranous exudates. In tertiary syphilis, there is leprosy occur in areas of the mouth where the surface gumma formation on the hard palate, tongue, or lower temperature is low and usually tends to occur in cases alveolus. The gumma is often seen on the hard palate of lepromatous leprosy. Interestingly, lepromatous as a chronic, progressive lesion that may perforate leprosy usually begins in the form of chronic rhinitis. through the palatal bone into the . The Nodular lesions in anterior tongue give a pavement tongue appears atrophic, fissured, lobulated, and stone appearance and ultimately lead to scarring. The leukoplakic plaque is present in the dorsal surface of muscles of the tongue are usually spared.[23] the tongue.[27]

Syphilis Histoplasmosis Syphilis is a sexually transmitted disease caused by the Histoplasmosis is a granulomatous systemic mycosis spirochete Treponema pallidum. The bacteria survive in which was first described by Samuel Darling in untreated patients for years and can be transmitted from 1905. It is caused by Histoplasma capsulatum syphilitic mothers to the fetus.[24] Syphilis can occur at which is a dimorphic fungus that grows at ambient three stages, namely, primary, secondary, and tertiary. temperatures.[28] Infection with H. capsulatum occurs Primary syphilitic lesions are referred to as chancre of while carrying day-to-day activities in areas where the oral mucosa which arises through venereal contact as H. capsulatum is highly endemic or in the course of a result of orogenital sexual practice. The lesions appear occupational and recreational activities that disrupt as painless ulcers. The secondary syphilis appears the soil or accumulated dirt. after 6 weeks–6 months if the primary syphilis is left untreated. The signs and symptoms of the primary and The fungus can spread through the hematogenous secondary forms of syphilis resolve spontaneously and route, with the involvement of the phagocytic system. patients then enter the latent stage of infection, where The severity rate is proportional to the amount of patients who are untreated are at risk of developing inhaled spores. In immunodeficient individuals, tertiary syphilis. Manifestations may take up to 10 years histoplasmosis may be fulminant and is not associated to re-appear and they appear as gummatous lesions, with the formation of epithelioid-cell granulomas.[29] cardiovascular syphilis, or neurosyphilis.[25] Histopathology Histopathology Characteristic features include the presence of foamy Primary syphilis demonstrates an acanthotic epidermis macrophages, Langhans cells, and epithelioid cells. which erodes with time to become ulcerated. Under the bed, there is a typically dense lymphocytic Oral manifestation response, numerous plasma cells, and endothelial Although oral manifestations occur rarely; when swelling. Secondary syphilis exhibits considerable present, they occur in association with the disseminated histopathologic variability and may be easily form or sometimes as a localized lesion, which could misinterpreted. The epidermis is often involved and be the initial or the only manifestation of the disease.[30] shows psoriasiform hyperplasia with superficial These may appear as papules, nodules, vegetations or neutrophils. Tertiary syphilis, on the other hand, as ulcers. Single lesions if left untreated progress from shows necrotizing granulomatous inflammation.[25,26] firm papules to nodules that ulcerate on progressive growth with the common presentation being a shallow Oral manifestations or deep infiltrated ulceration with a pseudomembrane. Primary syphilis of the mouth manifests as a solitary They tend to occur most often on the palate, buccal ulcer usually of the or, more rarely, the tongue. mucosa and may involve the tongue.[31]

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Blastomycosis in facial mobility and inhibit movement of the lower [37] Blastomycosis is a fungal disease caused by an jaw or the jaw bone. The oral lesions are single or fungus Blastomyces dermatitidis. Blastomycosis multiple with the lesion being either granulomatous or is usually transmitted by spore inhalation, and the ulcerative in appearance. These lesions typically show lungs are the most commonly affected organ. The an erythematous granular hyperplasia with detectable disease usually presents as two forms which may be hemorrhages. The lesions spread to the oral cavity [38] acute or chronic. In the chronic form, granulomatous extending to the hard and soft palate. lesions of the oropharyngeal mucosa and skin are Pyogenic Granuloma commonly observed. Skin and mucosal lesions appear as proliferative verrucous growth with ulceration and Pyogenic granuloma is one of the inflammatory scarring. Mucosal lesions usually appear to mimic hyperplasia of the oral cavity which is caused due carcinomas.[32] For the ideal diagnosis of blastomycosis, to irritants such as , plaque, overhanging cytological or histopathological examination of tissue margins, dental appliances, and trauma due to sharp [39] along with identification of the organism by the culture cusp impinging on the mucosa. It is most commonly of sputum or fresh biopsy material is recommended. observed in young females in the second decade of life because of the vascular effects caused by the increased Histology hormonal secretion. Blastomycosis appears as a mixed inflammatory Histology reaction with clusters of polymorphonuclear leukocytes and granulomas that are usually noncaseating, It represents exuberant granulation tissue, which is covered by atrophic/hyperplastic epithelium with epithelioid histiocytes and giant cells. There that may be ulcerated. Pathognomonic features of is a presence of prominent pseudoepitheliomatous pyogenic granulomas include numerous endothelium- hyperplasia that histologically may resemble lined vascular spaces.[40] In addition, these lesions . The classic appearance also demonstrate fibroblast proliferation budding of B. dermatitidis is the presence of a round to oval, endothelial cells. The presence of mixed inflammatory multinucleate yeast cell which is 8–15 μm in diameter, cell infiltration is also observed in these lesions. with a single broad-based bud.[33,34] Oral Manifestation Oral manifestation The lesions manifest as an exophytic growth which Oral manifestation of blastomycosis is not so common. is generally sessile commonly seen in gingiva If present, it appears as single or multiple lesions. followed by the tongue, buccal mucosa, and hard They may, however, appear as verrucous lesions or as [41] [35] plate. Other sites include the cheek, lips, tongue, draining lesions in the maxilla or mandible. palate, mucobuccal fold, and frenum. Intraorally, Paracoccidioidomycosis it can present with a range of clinical appearances from a sessile lesion to an elevated mass. Pyogenic Paracoccidioidomycosis is an acute to chronic granulomas usually appear as soft, painless, and deep systemic mycosis caused by fungi of the genus red to reddish-purple in color.[42] Paracoccidioides. The primary site of infection is the lung, with the fungus being able to disseminate Sarcoidosis to many organs. This results in the development of Sarcoidosis is a multisystem disorder of unknown secondary lesions that frequently occur in mucous etiology. Young- and middle-aged females between membranes, lymph nodes, and skin. the age group of 20–39 years are more predisposed to the disease with the involvement of the heart, Histology liver, spleen, bones, skin, eyes, lymph nodes, parotid Non-keratinized stratified squamous epithelium with glands, and less commonly the oral cavity.[43] The most acanthosis and focal areas of exocytosis is present. common complaints are the presence of a persistent The underlying connective tissue shows an intense dry cough, dyspnea, and chest pain. However, it is not lymphocytic and polymorphonuclear infiltrate in unusual to encounter entirely asymptomatic patients addition to multinuclear giant cells and coagulation even with objective evidence of disease in the form necrosis. The characteristic feature of this organism of characteristic findings, including bilateral hilar is the presence of multiple minute narrow-based buds lymphadenopathy which can be observed on a chest surrounding the large round fungal forms which are radiograph.[44] Cutaneous manifestations may be often referred to as “captain wheels.”[36] the initial signs of sarcoidosis which vary from the relatively common (papular eruptions, erythematous Oral manifestation scaling plaques, scar, and erythema nodosum) to On the invasion of the oral tissues, especially the lips the relatively uncommon (hypopigmentation or and cheeks, this infection may cause a severe reduction ulcerations) to rare features such as alopecia.[45]

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Histopathology diffuse or nodular swelling of the oral and perioral All affected tissues show classic non-caseating tissues with a characteristic cobblestone appearance granulomas composed of an aggregate of highly of the oral mucosa. Oral complications are more clustered epithelioid cells, often with Langhans or prevalent in children than in adults. The findings may foreign body type giant cells. In chronic cases, a include aphthous , painless swelling of the fibrous rim may be seen surrounding the cellular lips, with frequent vertical fissuring. Lesions may be aggregate.[46] Inclusion bodies such as Schaumann papular lesions with localized or diffuse erythema or bodies which are laminated concretions composed of edema, , and/or mucosal tags. Deep linear calcium and proteins as well as asteroid bodies that ulcerations may be embedded within the vestibular are stellate inclusions are seen in over 90% of cases folds which is the only pathognomonic findings of sarcoidosis.[47] associated with the disease.[54-56]

Oral manifestations OFG Lesions may be multifocal and include the lips, It is a non-infectious granulomatous condition of gingiva, and the hard palate. These lesions may be the lips, face, and oral cavity which is histologically seen as a reddish-purple nodular mass in the middle associated with non-caseating epithelioid granulomas of the palate or as erythematous hyperplastic gingiva with multinucleated Langhans type cells within the oral in the maxillary incisor area.[48] Other variations mucosa.[57] The term OFG refers to a set of conditions seen on the gingiva include brownish-red or violet restricted to the oral region without any identifiable papules or submucosal nodules.[49] Most oral lesions systemic granulomatous diseases. OFG may develop are asymptomatic or mildly symptomatic with at any age with no particular sex predilection, and minimal discomfort during eating or drinking if unknown etiology. It presents as an unusual allergic the lesions involve the tongue.[50] When the major reaction to a certain food, dental materials, or any glands are affected, the patients may present with other environmental agent.[58,59] either unilateral or bilateral enlargement. A clinical variant of sarcoidosis, known as Heerfordt disease or Histology uveoparotid fever, is characterized by parotid gland OFG is often identified by the presence of enlargement, fever, uveitis, and facial palsy.[51] In rare parakeratinized stratified squamous epithelium of cases, sarcoidosis affects the bone and, in the orofacial variable thickness and multinucleated giant cells that region, may present as progressive alveolar bone loss, are surrounded by modified macrophages.[60] thereby mimicking aggressive .[28] Oral manifestations CD The features of OFG include facial or lip swelling, CD is an inflammatory bowel disorder that mainly , oral ulcerations, vertical fissures affects the gastrointestinal tract, including the oral of the lips, , mucosal tags, cavity.[52] Extraintestinal manifestations and other taste alteration, decreased salivary production, immune disorders are also prevalent in CD patients. and cobblestone appearance of buccal mucosa and CD is a multifactorial disease with genetic and sometimes lymph node involvement. If left untreated, environmental factors, including diet, psychological Melkersson-Rosenthal syndrome is seen to occur stress, and smoking, which plays important roles which is characterized by orofacial swelling, facial in disease pathogenesis or exacerbation. Oral palsy, less commonly, and fissured tongue.[61] manifestations of the disease are often present in patients with an advanced intestinal disease with Wegener’s Granulomatosis granulomatous inflammatory lesions in the intestinal Wegener granulomatosis is a multisystemic tract. Transmural inflammation of the gut results in the granulomatous disorder with vasculitis that most development of fissures, abscesses, fistulae, thickening predominantly affects the upper and lower airway of the bowel wall, and limited distensibility.[53] tract and the kidneys, when it affects any organic represents as an inflammatory destructive disease Histopathology that has widespread systemic involvement which Examination of the biopsies from CD patients was first categorized as a syndrome by Friedreich reveals non-caseating granulomatous inflammation Wegener in 1936.[62] It presents itself as a classical in approximately 50% of cases and in the remaining triad of necrotizing granulomatous inflammation cases non-specific perivascular lymphocytic infiltrate. involving the upper respiratory tract, necrotizing glomerulonephritis and systemic vasculitis involving Oral manifestations small- and medium-sized blood vessels. The most These lesions may occur at any time during the course commonly affected sites involve the middle ear, of the disease. The oral manifestations include a gingiva, and nasal mucosa.

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