Erythematous and Vascular Oral Mucosal Lesions: A Clinicopathologic Review of Red Entities

Abstract

Erythematous lesions of the oral mucosa are common and can reflect a variety of conditions, ranging from benign reactive or immunologically-mediated disorders to malignant disease. Together with vascular abnormalities, which can vary from reddish to bluish-purple in color, the differential diagnosis for erythematous oral mucosal change is quite diverse. This review focuses on salient clinical features and histopathologic findings of selected conditions which clinically present as red or vascular-like oral mucosal alterations, including oral vascular malformations and neoplasms, pyogenic granuloma, localized juvenile spongiotic gingival hyperplasia, denture stomatitis, benign migratory glossitis (geographic tongue), orofacial granulomatosis, granulomatosis with polyangiitis (Wegener granulomatosis), megaloblastic anemia, and erythroplakia. Recognition of the characteristic clinical features of these conditions, in conjunction with thorough patient history, will allow clinicians to narrow the differential diagnosis and guide appropriate clinical decision making, including the need for tissue biopsy, in order to complete the diagnostic process and initiate optimal patient care.

Introduction

Erythematous lesions of the oral mucosa are common and may result from a variety of tissue alterations, including inflammation, erythrocyte extravasation, and atrophy or reduced keratinization of the surface epithelium. Together with vascular processes, which can vary from reddish to bluish-purple in color, the differential diagnosis for erythematous mucosal change is quite diverse and includes both benign and malignant vascular anomalies, reactive processes, immune-mediated diseases, hematologic disorders as well as potentially malignant (precancerous) and malignant epithelial lesions.

This review focuses on salient clinical features and histopathologic findings of select conditions that clinically present as erythematous or vascular-appearing oral mucosal alterations (Table 1). Differential diagnosis and diagnostic pitfalls are discussed to aid both clinicians and pathologists as integral members of the multidisciplinary care team.

Table 1.

Differential diagnosis of erythematous and vascular oral mucosal lesions

Vascular anomalies

Vascular malformations

Vascular tumors

Reactive processes

Pyogenic granuloma

Peripheral giant cell granuloma

Localized spongiotic gingival hyperplasia

Denture stomatitis

Erythematous candidiasis

Infammatory papillary hyperplasia

Immune-mediated diseases

Benign migratory glossitis

Desquamative gingivits

Orofacial granulomatosis

Granulomatosis with polyangiitis

Hematologic disorders

Megaloblastic anemia

Lymphoproliferative disease

Epithelial neoplasia

Erythroplakia

Squamous cell carcinoma

Vascular Anomalies

Vascular anomalies consist of a diverse collection of congenital and acquired lesions composed of vascular structures. Significant progress has been made in our understanding and distinction between anomalies, aided by the work of Mulliken and Glowacki [1] and expanded by the International Society for the Study of Vascular Anomalies (ISSVA) [2]. According to their classification scheme, vascular anomalies can be categorized as vascular malformations or vascular tumors.

Vascular Malformations

Vascular malformations (VMs) are structural abnormalities of vascular channels that exhibit normal endothelial cell turnover and arise from formational errors during fetal development. The majority are sporadic, but they can be associated with a number of inherited genetic mutations [3]. VMs are usually congenital and tend to grow proportionately with the patient; however, they may not be recognized until adolescence or adult life. Spontaneous involution is rarely reported and some VMs may exhibit episodes of rapid enlargement secondary to traumatic injury, infection, attempted intervention or hormonal fluctuation [1, 4]. VMs can be subclassified by endothelial cell origin and rheostatic (high- vs. low-flow) characteristic. High-flow lesions contain an arterial component and include arterial malformations, arteriovenous malformations, capillary arteriovenous malformations and arteriovenous fistulae. Low-flow VMs are devoid of an arterial component and are classified by their predominant endothelial cell type, namely capillary, venous, lymphatic or combined lesions [3, 5].

Vascular Tumors

Vascular tumors (VTs) consist of benign and malignant neoplasms of endothelial cell origin. The majority are hemangiomas, a term restricted to benign neoplasms composed of vessels that exhibit disproportionate growth relative to the patient. The ISSVA classification recognizes more than a dozen subclassifications of hemangioma [2], details of which are beyond the scope of this manuscript. While pyogenic granuloma (lobular capillary hemangioma) is a subtype commonly seen intraorally, most oral pyogenic granulomas are considered reactive rather than neoplastic proliferations [6, 7]. Locally aggressive/borderline and malignant vascular neoplasms, including hemangioendothelioma, Kaposi sarcoma and angiosarcoma, rarely present intraorally [8–12].

Clinical Features

Vascular anomalies have a predilection for the head and neck and can involve any intraoral location. The majority of oral mucosal lesions are small and superficial, but they can present as large, bulky tumors involving deep submucosal structures. Deeply situated lesions may appear normal in color, while superficial presentations appear erythematous to blue or purplish depending upon the mix of arterial-capillary-venous vascular channels. In the absence of thrombosis, VAs are usually soft and compressible. Characteristically, the application of gentle pressure results in a loss of color or tissue blanching, indicating that the reddish color is due to blood contained within a lesional vessel (Fig. 1). This clinical procedure, termed diascopy, can provide evidence to support the clinical impression of a benign vascular proliferation. In contrast, an area of recent hemorrhage will not blanch. Since malignant vascularity is often poorly formed with extensive erythrocyte extravasation, the absence of blanching must be correlated with the complete clinical presentation.

Fig. 1.

a Reddish purple vascular anomaly of the gingiva. b Loss of color (blanching) is observed upon application of pressure (diascopy)

Lymphatic malformations (LMs), sometimes referred to as lymphangioma or cystic hygroma, can occur at any oral mucosal location and exhibit unique clinical features. They show a propensity for the anterior two-thirds of the tongue and are generally superficial with a distinct pebbly surface exhibiting erythematous, pink and translucent vesicles that have been described as resembling frog eggs or tapioca pudding (Fig. 2).

Fig. 2.

aLymphatic malformation presenting as pink to reddish pebbly appearance of dorsal tongue. b Histopathologic features show dilated lymphatic and vascular channels partially replacing connective tissue papillae

Histopathology

A detailed discussion of the histopathologic features of vascular anomalies is beyond the scope of this manuscript. In general, helpful immunohistochemical markers include CD31, a sensitive and relatively specific endothelial marker. Differentiation between endothelial cell types can be achieved with ETS-related gene (ERG) and D2-40 (podoplanin), which are selectively and strongly expressed in vascular and lymphatic endothelia respectively [13].

Differential Diagnosis

A varix (varicosities, varices) should be included in the differential diagnosis for a lesion exhibiting a vascular appearance. This lesion represents a dilated and tortuous vein, thought to result from age-related degeneration of elastic support for the vessel wall, and usually presents as a solitary, reddish to bluish-purple nodule. While they may appear on any oral mucosal surface, the lips, buccal mucosa and tongue are favored locations [14]. Numerous non-vascular entities may also appear bluish in color, clinically mimicking a vascular process. Differential considerations could include salivary gland lesions (mucocele, salivary duct cyst, benign and malignant salivary tumors), gingival cyst, amalgam tattoo and blue nevus. While histopathologic assessment is often required for diagnosis, diascopy (as described above) can also be helpful in discriminating vascular processes from non-vascular counterparts.

Reactive Processes

Pyogenic Granuloma (Lobular Capillary Hemangioma)

Pyogenic granuloma (PG) is a common, reactive soft tissue and vascular proliferation associated with chronic, low-grade irritation. While it may occur at any cutaneous or mucosal site, oral presentations show a striking predilection for the gingiva, particularly the anterior maxillary region, followed by extragingival locations such as the lips, tongue and buccal mucosa [15, 16]. PG occurs across a broad age range, with mean age in second to third decades of life [7, 16, 17]. A female predilection is thought to be secondary to hormonal influences.

Clinical Features

PG presents as an exophytic, smooth or lobulated nodule that frequently exhibits a pedunculated base and ranges in color from pinkish-red to purplish (Fig. 3a). While generally asymptomatic, the surface is often ulcerated and hemorrhagic. Lesions typically range in size from a few millimeters to 2 cm, although larger lesions have been reported together with rapid enlargement, features concerning for malignancy [15, 17].

Fig. 3.

a Ulcerated erythematous nodule of the mandibular gingiva diagnosed as pyogenic granuloma on biopsy. b Velvety erythematous lesion of the marginal attached gingiva of a 14-year-old female diagnosed as localized juvenile spongiotic gingival hyperplasia (LJSGH) on biopsy. c LGSGH histopathologically exhibits a nonkeratinized epithelial proliferation exhibiting prominent spongiosis and leukocytic exocytosis

Histopathology

PG may present as a cellular, highly vascular proliferation that resembles granulation tissue or as a lobular collection of blood vessels, also termed lobular capillary hemangioma [15]. The mucosal surface is frequently ulcerated with variable edema, vascular dilation and mixed inflammation (including neutrophils, plasma cells and lymphocytes) together with the endothelial cell and capillary proliferation. As lesions mature, sclerotic changes may develop with persistence of ectatic vascular channels, aggregates of inflammatory cells and intervening areas of fibrosis.

Differential Diagnosis

For presentations on the gingiva or alveolar ridge, the clinical differential diagnosis for PG will include other reactive gingival epulides, such as peripheral giant cell granuloma, peripheral ossifying fibroma and inflammatory fibrous hyperplasia (fibroma). Malignant processes, such as metastatic disease, sarcoma and lymphoma, may enter the clinical differential, particularly when lesions arise from an extraction socket, exhibit rapid enlargement and/or attain significant size. Biopsy and histopathologic diagnosis of suspected PG lesions is required. Brierley et al. provide a detailed review of gingival lesions [18].

Localized Juvenile Spongiotic Gingival Hyperplasia

Localized juvenile spongiotic gingival hyperplasia (LJSGH) is a unique gingival alteration that was initially described in 2007 as juvenile spongiotic gingivitis [19]. While the etiopathogenesis is unknown, some evidence suggests that LJSGH may result from exteriorized junctional or sulcular epithelium which is minimally keratinized and, therefore, susceptible to local irritants, such as mouth breathing or minor local trauma [19, 20]. This process does not appear to be bacterial plaque-related as conventional periodontal treatment fails to improve the problem [19, 21].

LJSGH shows a female predilection and primarily affects young patients, with up to 96% of cases diagnosed before the age of 15 [19, 21]. The juvenile designation, however, is not entirely appropriate, as this process has occasionally been observed in adults [19, 21].

Clinical Features

LJSGH consistently presents as an elevated, bright red gingival alteration that exhibits a papillary, granular or velvety surface architecture (Fig. 3b). It shows a strong predilection for the maxillary anterior facial attached gingiva and typically develops along the marginal gingiva. Lesions range in size between 2 and 10 mm in diameter and are generally solitary; however, multifocal gingival involvement has been reported [22, 23].

Histopathology

The histopathologic features of LJSGH include an exophytic, epithelial hyperplasia exhibiting variable papillomatosis, elongated and interconnecting rete ridges, and prominent intercellular edema with inflammatory cell exocytosis composed primarily of neutrophils [19, 21] (Fig. 3c). The epithelial proliferation is generally nonkeratinized, reminiscent of junctional epithelium of the gingival sulcus [20]. Dilation and congestion of the superficially capillary network is frequently seen within connective tissue papillae, in association with mixed inflammation.

Differential Diagnosis

The distinct clinical presentation of LJSGH significantly limits the clinical differential. Some clinicians may consider puberty gingivitis or foreign body gingivitis, although the localized presentation, exophytic nature, and lack of response to oral hygiene measures may be more suggestive of early pyogenic granuloma or, if a prominent papillary surface architecture is observed, squamous papilloma. Histopathologic findings of LGSGH are characteristic and should exclude other clinical considerations. While overlapping features of inflamed squamous papilloma may be observed, papillomas generally exhibit variable parakeratosis.

Denture Stomatitis

Denture stomatitis (DS) is an inflammatory condition limited to denture-bearing mucosa underlying a removable prosthesis. This is a common pathosis affecting up to 70% of denture wearers, particularly their palatal and maxillary alveolar mucosal surfaces, that clinically presents as smooth, atrophic mucosa exhibiting variable erythema and petechial hemorrhage [24]. The zone of erythema may be localized or diffuse with a well-delineated border following the contour of the denture base (Fig. 4a). The etiology of DS is poorly understood and likely multifactorial, with increased risk associated with suboptimal denture fit, poor denture hygiene, colonization by C. albicans, nocturnal denture wear and smoking [24, 25]. While DS is often categorized as a form of erythematous candidiasis, this association is controversial. Some authorities view DS as a mucosal inflammatory reaction to bacterial and fungal microorganisms colonizing the denture base as opposed to a true host tissue infection [25–27]. Increased suspicion for candidal infection may arise in clinical settings suggestive of chronic multifocal candidiasis. Such patients may exhibit, in addition to palatal erythema, redness and cracking at the oral commissures, termed angular cheilitis, as well as well-delineated erythema with atrophy of filiform papillae at the midline of the posterior dorsal tongue, termed central papillary atrophy or median rhomboid glossitis. Detailed discussion of oral candidiasis is provided by Hellstein [28].

Fig. 4.

a Diffuse erythema of alveolar and palatal mucosa that follows contour of denture base consistent with denture stomatitis (Courtesy of Dr. Vimi Mutalik). b Erythematous, cobblestone surface of inflammatory papillary hyperplasia involving the anterior hard palate associated with an ill-fitting removable prosthesis

A reactive tissue overgrowth, inflammatory papillary hyperplasia (IPH), may also develop on palatal denture-bearing mucosa in association with chronic denture irritation. Provided the overlapping risk factors and clinical setting, some investigators classify this process within the spectrum of denture stomatitis [29, 30]. The asymptomatic erythematous to pink palatal alterations associated with IPH, however, typically exhibit an exophytic, cobblestone-like surface architecture (Fig. 4b). This process may rarely be observed on palatal mucosa of dentate patients (non-denture wearers), particularly in the clinical setting of a high palatal vault and mouth-breathing habit [31, 32]. IPH is often diagnosed on clinical features, however histopathologic assessment shows epithelial hyperplasia with bulbous, papillary surface projections in association with chronically inflamed, well-vascularized, edematous to densely collagenous fibrous connective tissue cores.

Immune-Mediated Diseases

Benign Migratory Glossitis (Geographic Tongue; Erythema Migrans)

Benign migratory glossitis (BMG) is a chronic, inflammatory condition of the tongue estimated to occur in 1.0–2.5% of the population across a broad age range, but most commonly affecting children and young adults [33, 34]. While the etiopathogenesis is poorly understood, BMG is believed to be an immunologically-mediated process and frequently occurs in conjunction with fissured tongue [34]. Possible association with psoriasis of the skin has long been debated, most recently fueled by identification of a common genetic marker, the human leukocyte antigen (HLA) HLA-Cw6; however, the existence of disease-related oral lesions of psoriasis remains controversial [35–37].

Clinical Features

BMG most frequently presents as multiple, well-demarcated zones of erythema and atrophy of the filiform papillae of the anterior two-thirds of the dorsal and lateral surfaces of the tongue. These zones are at least partially surrounded by thin, circinate or serpentine yellowish-white borders (Fig. 5a). The size and shape of lesions tend to morph or “migrate” over days or weeks, hence the designation of wandering rash of the tongue or benign migratory glossitis. The atrophic or depapillated areas of the tongue have also been described as reminiscent of continents on a globe, leading to the popular term geographic tongue. Characteristic lesions occasionally involve the ventral tongue (Fig. 5b). Less commonly, lesions may develop at extraglossal sites, such as buccal mucosa, labial mucosa, soft palate and floor of mouth, where they have been termed ectopic geographic tongue or erythema migrans (Fig. 5c). Most cases of BMG are asymptomatic and identified on routine head and neck examination, however mild tenderness may be reported and prompt patients to seek medical evaluation.

Fig. 5.

aBenign migratory glossitis (BMG) of the dorsal tongue presenting as multiple zones of erythema and atrophy encircled by thin yellowish borders. b BMG involving the ventral tongue. cEctopic geographic tongue exhibiting characteristic yellowish circinate borders partially surrounding erythema. d The classic histopathologic features of BMG include psoriasiform mucositis with prominent neutrophilic microabscess formation

Histopathology

BMG is often diagnosed on clinical examination alone; however, incisional biopsy may be performed in some cases. Characteristic histopathologic features include parakeratosis, variable spongiosis with elongation of epithelial rete ridges and atrophy of suprapapillary plates (Fig. 5d). Collections of neutrophils (Munro microabscesses) are frequently noted within the parakeratin with occasional involvement of the superficial stratum spinosum [37]. These microabscesses are most apparent at the periphery of lesions and correspond clinically to the observed yellowish-white circinate borders. In samples obtained from the dorsal tongue, atrophy or absence of the normal papillary architecture is characteristic. The lamina propria typically supports a mild influx of lymphocytes and neutrophils. These histopathologic features are reminiscent of psoriasis, and thus referred to as psoriasiform mucositis.

Differential Diagnosis

From a clinical perspective, the yellowish-white borders that surround zones of erythema should prevent confusion with entities such as erythroplakia, atrophic glossitis of anemia, or erythematous candidiasis. However, prominence of the yellowish borders is variable and may only partially (or focally) encircle the erythema. Thus, careful clinical inspection may be necessary. Additional distinguishing features of erythematous candidiasis include location centered at the midline of the posterior dorsal tongue (termed central papillary atrophy or median rhomboid glossitis) and absence of migratory pattern (Fig. 6).

Fig. 6.

Well-defined erythema and atrophy of the posterior dorsal tongue consistent with central papillary atrophy (Erythematous candidiasis); note absence of the yellowish border seen in benign migratory glossitis

The histopathologic finding of superficial microabscess formation may suggest the possibility of candidiasis. Candidal organisms are rarely superimposed on BMG, thus the identification of candidal hyphae by Periodic acid-Schiff (PAS) or Gomori-methenamine silver (GMS) staining would most likely correlate with erythematous candidiasis. With appropriate antifungal treatment, the zones of erythema and atrophy would be expected to resolve.

Desquamative Gingivitis

Desquamative gingivitis (DG) is a clinical term used to describe gingival erythema resulting from peeling or desquamation of the epithelial surface. It is generally limited to the attached gingiva and can present in a localized or generalized distribution (Fig. 7). DG is not specific for any one condition; this clinical presentation can be seen with a number of vesiculobullous (vesiculoerosive) disease processes, such as erosive lichen planus, lichenoid reactions (lichenoid drug reaction, foreign body gingivitis or contact stomatitis), mucous membrane pemphigoid and pemphigus vulgaris. Less likely considerations could include chronic ulcerative stomatitis, systemic lupus erythematosus, linear IgA disease, epidermolysis bullosa acquisita and paraneoplastic pemphigus [38, 39]. Definitive diagnosis rests on incisional biopsy with a tissue portion submitted in 10% neutral-buffered formalin for standard light microscopic examination and a portion submitted in Michel’s solution for direct immunofluorescent studies. Fitzpatrick et al. review oral manifestations of select vesiculobullous diseases [40].

Fig. 7.

Desquamative gingivitis presenting as patchy erythema and erosions diffusely involving the maxillary and mandibular facial attached gingiva

Orofacial Granulomatosis

Orofacial granulomatosis (OFG) is a term used to describe a variety of clinical presentations resulting from granulomatous inflammation of the oral and perioral soft tissues. Medical evaluation to rule out known causes of granulomatous inflammation, such as Crohn disease, sarcoidosis, chronic granulomatous disease, and mycobacterial or deep fungal infection, should precede the designation of OFG.

While the precise etiopathogenesis remains unknown, OFG is speculated to be an abnormal immune reaction to various inciting agents, including a variety of foods and food additives (such as cinnamon and benzoate compounds), dental restorative materials and microbial infections [41–43]. Given the uncommon nature of this process, reliable epidemiologic data is lacking; however, it seems to occur across a broad age range, most often arising in young adults [41, 43].

Clinical Features

The clinical presentation of OFG is highly variable. Non-tender, persistent lip swelling, termed cheilitis granulomatosa (of Miescher), is the most frequent clinical finding and may be accompanied by vertical lip fissuring, exfoliation, and angular cheilitis. Intraorally, however, erythematous oral mucosal alterations predominate. The labial mucosa may develop a granular pink to reddish appearance, with formation of translucent mucosal “blebs” corresponding to ectatic superficial lymphovascular channels. Generalized erythema and swelling of the buccal mucosa may impart a “cobblestone” architecture, which may be seen in association with gingivitis, granular gingival overgrowth, and chronic oral ulceration with linear hyperplastic tissue folds of the mucobuccal sulcus (Fig. 8a).

Fig. 8.

a Granular gingival erythema and linear tissue folds of the buccal sulcus diagnosed as orofacial granulomatosis on biopsy. b Papillary gingival hyperplasia with petechial hemorrhage consistent with early “strawberry gingivitis”, suggestive of granulomatosis with polyangiitis (Wegener granulomatosis). c Gingival biopsy from lesion depicted in b shows epithelial hyperplasia and dense inflammation with microabscess formation and occasional giant cells. d In other areas, the inflammatory infiltrate supports lymphocytes, plasma cells and scattered eosinophils in association with prominent hemorrhage

Histopathology

Histopathologic features of OFG include edema of the superficial connective tissue with dilation of lymphatic channels, perivascular lymphocytic infiltration and variable noncaseating granulomatous inflammation. Granulomas are often sparse and poorly formed, consisting of vague collections of lymphocytes and epithelioid histiocytes with or without associated multinucleated giant cells. As a result, their absence may simply represent sampling error and does not preclude a diagnosis of OFG [43]. When granuloma formation is identified, special stains to exclude microorganisms should be performed. Polarized light microscopy and careful inspection for foreign material may also be indicated to rule out a foreign body reaction.

Differential Diagnosis

OFG is often a diagnosis of exclusion, as similar clinical features and histopathologic evidence of granulomatous inflammation can be seen with a number of local and systemic conditions. Patient work-up can include detailed medical history, serologic studies, radiologic imaging, and/or endoscopic investigation to rule out Crohn disease, sarcoidosis, chronic granulomatous disease, mycobacterial or deep fungal infection. If systemic granulomatous disease is identified, orofacial lesions would presumably be associated with that process. Even when the initial assessment is negative, however, it has been estimated that approximately 20% of OFG patients will subsequently develop manifestations of systemic granulomatous disease, and several investigators have reported that childhood onset of OFG carries significant risk for future development of Crohn disease [44, 45].

Granulomatosis with Polyangiitis (Wegener Granulomatosis)

Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, is an uncommon systemic vasculitis that is highly associated with anti-neutrophil cytoplasmic antibodies (ANCA). While the precise etiopathogenesis is unknown, this process seems to represent an abnormal immune reaction to environmental or infectious agents in genetically predisposed individuals. Mean age at diagnosis is between 45 and 60 years in a primarily Caucasian population [46].

This process is classically associated with a triad of (1) necrotizing granulomatous inflammation of the upper and lower respiratory tract, (2) glomerulonephritis and (3) systemic small vessel vasculitis. Almost any organ system can be involved and reported prevalence of oral lesions varies widely, affecting between 10–62% of patients [47]. Oral lesions may represent the initial sign of disease and can persist as a localized or limited form of GPA for long periods of time prior to multi-organ involvement. The diagnosis of GPA can be challenging and recognition of its unique oral mucosal alterations may be pivotal for timely diagnosis. In the absence of appropriate medical management, significant morbidity and mortality may be seen [48].

Clinical Features

The most characteristic oral manifestation of GPA is a hyperplastic gingivitis termed “strawberry gingivitis”, which can be an early and pathognomonic finding [47, 49]. Affected gingiva is enlarged and friable with numerous short projections exhibiting red to purple petechial hemorrhage, resulting in an appearance reminiscent of the surface of a strawberry (Fig. 8b). These alterations generally originate at the interdental papillae with gradual lateral progression to diffusely involve the entire attached gingiva. Additional oral manifestations of GPA may include persistent oral ulceration, destruction of bone, tooth mobility and oral-antral fistulae [47].

Histopathology

The characteristic leukocytoclastic vasculitis and necrotizing granulomatous inflammation seen in lung biopsies of GPA are rarely observed in oral specimens due to the paucity of large vessels in most oral mucosal biopsies. In contrast, the histopathologic features of oral lesions may include vague collections of histiocytes together with lymphocytes, neutrophils, eosinophils, and multinucleated giant cells[47]. Samples obtained from areas of strawberry gingivitis will typically demonstrate pseudoepitheliomatous hyperplasia with extensive subepithelial hemorrhage, intense mixed inflammation and microabscess formation (Fig. 8c, d).

Differential Diagnosis

Characteristic histopathologic findings, in conjunction with a classic clinical presentation of strawberry gingivitis, are highly suggestive of GPA. However, the clinical presentation of early or localized cases may not be considered pathognomonic and the differential could include conditions such as reactive gingival hyperplasia, granulomatous disease, foreign body reaction, specific infection, benign or malignant vascular proliferation, lymphoproliferative disease and papillary squamous cell carcinoma. A combination of clinical and histopathologic features, often in conjunction with laboratory finding of cytoplasmic-staining ANCA (PR3-ANCA), are employed to establish a diagnosis of GPA [48].

Hematologic Disorders

Megaloblastic Anemia

Megaloblastic anemia (MA) generally occurs in older adults and can result from any condition that interferes with nucleic acid synthesis. Vitamin B12 deficiency is the most common basis for MA and may arise in the clinical setting of insufficient dietary intake or malabsorption, often associated with autoimmune destruction of intrinsic factor (pernicious anemia) or gastric bypass surgery [50]. Clinical symptoms of MA, including fatigue, headache and dyspnea, are often insidious and oral mucosal alterations may represent the first sign of disease [51].

Clinical Features

Oral manifestations of MA include patchy areas of diffuse mucosal erythema and atrophy involving any oral mucosal surface, which may be accompanied by hyperesthesia or a burning sensation [51, 52]. Involvement of the dorsal tongue typically exhibits patchy erythema with atrophy of the filiform papillae.

Histopathology

Histopathologic evaluation of oral mucosal erythema associated with MA shows mild chronic mucositis with marked epithelial atrophy and abbreviated or absent rete ridges. Keratinocytes may exhibit increased nuclear-to-cytoplasmic ratio, however the nuclei are generally pale staining with clumped peripheral chromatin [51, 52]. The observed cytologic atypia may erroneously suggest the possibility of early preneoplastic change.

Differential Diagnosis

The clinical diagnosis of MA is often challenging due to non-specific clinical and histopathologic features. The differential for multifocal, diffuse oral erythema and atrophy could include erythematous candidiasis, immune-mediated processes such as contact mucositis or physical irritation. It is important for clinicians to consider the possibility of MA when nonspecific chronic mucositis, epithelial atrophy and/or epithelial atypia are histopathologically observed in an appropriate clinical setting. Once suspected, serologic studies are warranted to confirm the diagnosis of MA.

Lymphoproliferative Disease

Lymphoproliferative processes that affect the oral mucosa are diverse. The clinicopathologic spectrum includes reactive lymphoid hyperplasia, histiocytic disorders such as Langerhans cell histiocytosis, plasma cell dyscrasias such as plasmacytoma and multiple myeloma, and various forms of leukemia and extranodal lymphoma. Though not frequently encountered, lymphoid malignancies represent the third most common oral malignancy following squamous cell carcinoma and malignant salivary gland tumors [53].

Detailed discussion of lymphoproliferative disorders is beyond the scope of this manuscript; however, this category of disease should not be overlooked in the differential diagnosis of exophytic, erythematous to purplish lesions, particular those presenting as gingival or palatal swellings (Fig. 9a) or diffuse hemorrhagic gingival enlargement [54, 55].

Fig. 9.

aNon-hodgkin lymphoma presenting as an erythematous palatal swelling in a 73-year-old male (Courtesy of Dr. Christine Harrington). bErythroplakia presenting as a well-defined red patch diffusely involving the soft palate and diagnosed as squamous cell carcinoma on biopsy (Courtesy of Dr. Phillip Cary)

Epithelial Neoplasia

Oral squamous cell carcinoma (OSCC) is the most common malignancy affecting the oral cavity, with an estimated 33,950 new cases diagnosed in the United States in 2018, resulting in 6800 deaths [56]. Risk factors include male gender, increasing age, smoking, excessive alcohol use, immunosuppression and poor diet. Human papillomavirus (HPV) infection is a well-recognized risk factor for oropharyngeal cancer; however, this infection appears to have minimal role in the development of OSCC, with less than 5% of oral mucosal cases being HPV-related [57, 58].

OSCC generally arises from surface precursor lesions called potentially malignant disorders (PMDs), which harbor increased risk for malignant transformation. While the majority of oral PMDs present as leukoplakia (well-defined white plaques or patches), some lesions may have an erythematous presentation, termed erythroplakia (well-defined red plaques or patches) (Fig. 9b) or erythroleukoplakia (mixed red and white lesions). The erythematous alterations hold the greatest malignant potential; up to 90% of true erythroplakic lesions demonstrate histopathologic evidence of high-grade dysplasia or superficially invasive squamous cell carcinoma at the time of initial biopsy [59, 60]. Distinguishing clinical characteristics of erythroplakia include well-defined margins and a velvety, micropapillary or granular surface texture. Clinicians should also hold a heightened level of suspicion for lesions arising in high-risk sites, including the ventrolateral tongue, floor of mouth, retromolar area, soft palate, and anterior tonsillar pillars. These anatomic locations comprise roughly 20% of the total oral cavity surface area yet give rise to approximately 75% of OSCC [61]. In the absence of clinical features allowing for diagnosis of any other condition, histopathologic assessment is required to distinguish true erythroplakia from the vast number of conditions (such as those discussed in this manuscript) that may also present with a similar erythematous clinical appearance.

Summary

Despite vast differences in etiology and pathogenesis, many disease processes may present with erythematous or vascular-appearing alterations of the oral mucosa. Recognition of characteristic clinical features, in conjunction with thorough patient history, will allow clinicians to narrow the differential diagnosis and guide appropriate clinical decision making, including the need for tissue biopsy. Since proper management and, in some cases, patient prognosis are reliant upon a timely and accurate diagnosis, practitioners should be aware that both clinical and microscopic features may be needed to complete the diagnostic process and initiate optimal patient care.

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.