Oral sarcoidosis aiding in diagnosis of underlying systemic disease

Abstract

Sarcoidosis is a chronic, multisystemic, granulomatous disease of unknown aetiology characterised by the formation of non-caseating granuloma. It shows slight female predominance and has a bimodal age distribution. Lungs, skin, eye and liver are commonly affected. The oral lesion, though uncommon, may present as submucosal nodule, papule or superficial ulceration. Occasionally, oral lesion may be the first manifestation of underlying systemic disease. This case is interesting because it emphasises that dental practitioners may play a key role in early recognition of the clinical presentation of this multifaceted disease, and thereby aid in the diagnosis of the systemic condition. The present report deals with a case of sarcoidosis affecting the buccal mucosa in a 48-year-old woman. The patient was treated with oral prednisolone and within 4 months of corticosteroid therapy, the oral lesion regressed with no recurrence or new lesion noted over a period of 1 year.

Background

Sarcoidosis is a chronic, multisystemic, granulomatous disease of unknown aetiology characterised by the formation of non-caseating granulomas.^1–9 Its occurrence varies globally depending on the geographic location and ethnic distribution. North America, Sweden and Japan are most affected. Increased incidence is also seen in Taiwan, Thailand, Malaysia and India.¹⁰ Females are slightly more affected than males. It shows bimodal age distribution, involving young adults and elderly.1–3 6–9 Lungs, skin, eye and liver are commonly involved. Fatigue, malaise, non-productive cough, breathlessness, arthralgia and erythema nodosum are the common presenting features.1 2 4 5 9 Though head and neck involvement is seen in 10%–15% of the patients,³ oral sarcoidosis is uncommon.^{1 2} Usually, oral manifestations are seen in cases of systemic sarcoidosis. However, very rarely, oral sarcoidosis may be the earliest manifestation of subsequent systemic disease. A total of 60% of the cases resolve spontaneously. Corticosteroids are the drug of choice in patients requiring treatment.^{8 9} Here, we present a case of oral sarcoidosis which when investigated revealed involvement of other systems.

Case presentation

A 48-year-old female patient from a semiurban area reported to the Department of Oral and Maxillofacial Pathology, Guru Nanak Institute of Dental Science and Research, Kolkata, India, with the chief complain of a swelling in the left cheek region and subsequent discomfort for last 1 year. The swelling was small initially but gradually increased to attain the present size. A detailed history from the patient revealed that she had a similar swelling in that region 2–3 years back, which was locally excised along with the extraction of the adjacent carious tooth, 36 Federation Dentaire Internationale (FDI).

She also has a history of multiple ulcerations on face and enlargement of regional cervical lymph nodes 6 years ago, which subsided on taking medications. Her medical history revealed joint pain and dry cough for last 2 years.

Extraoral examination was unremarkable, except for the left submandibular lymph nodes, which were enlarged and tender on palpation. Intraorally, there was presence of a round-to-oval, firm, diffuse swelling (measuring 1.5×1×1 cm) on the left buccal mucosa with respect to 34, 35 and extracted 36. The overlying mucosa was normal in colour and mobile but showed mild granularity at places (figure 1A).

Figure 1.

(A) Intraoral photograph showing round-to-oval, firm, diffuse swelling on the left buccal mucosa with respect to 34, 35 and extracted 36. (B) PA view of the chest X-ray showing left ventricular hypertrophy with unfolding of aorta and pneumonitic changes in both hilar and paracardiac regions.

Investigations

Orthopantomograph did not reveal any dental or osseous changes.

Postero-anterior (PA) view of the chest X-ray revealed left ventricular hypertrophy (LVH) with unfolding of aorta and pneumonitic changes in both hilar and paracardiac regions (figure 1B). Routine blood examination, serum calcium and liver function tests were within normal limits, except Erythrocyte Sedimentation Rate (ESR), which was raised (40 mm/hour). The patient tested negative for HIV and hepatitis.

Tuberculosis (TB) PCR qualitative analysis did not reveal the presence of Mycobacterium tuberculosis complex or any non-tuberculous mycobacteria. QuantiFERON-TB Gold and Gamma interferon test yielded negative results as well. However, serum ACE level was elevated (61 IU/L).

Incisional biopsy was performed from the most representative site of the lesion and sent for histopathological evaluation to establish a diagnosis. Sections stained with H&E showed the presence of discrete, round-to-oval granulomas with no sign of necrosis (figure 2A,B). The granulomas were composed of epithelioid and giant cells. Both Langhans giant cells with arcuate arrangement of nuclei and foreign-body giant cells with random arrangement of nuclei were noted (figure 2C). The granulomas were surrounded by dense fibrous connective tissue and a rim of lymphocytes forming a ‘collarette’. The overall light microscopic features were suggestive of a non-caseating granulomatous disease.

Figure 2.

(A and B) H&E stained section showing the presence of discrete granuloma without caseation. (C) H&E stained section showing non-caseating granuloma made-up of Langhans-type and foreign-body-type multinucleated giant cells (×40).

Differential diagnosis

The presence of a nodular granulomatous growth in oral mucosa narrowed our differential diagnosis to granulomatous conditions, such as TB, sarcoidosis, leprosy, fungal infections, Crohn’s disease, foreign body granulomas and granulomatosis with polyangiitis (Wegener’s granulomatosis).1–3 6 9

TB needs to be differentiated from sarcoidosis since TB is more prevalent in Asian countries, particularly India, and closely mimics sarcoidosis. Oral manifestations of TB include chronic painful ulcers on tongue and gingiva or nodular swelling involving palate, lip and buccal mucosa. Pneumonitic changes can be noted in chest radiographs. Histopathologically, these lesions reveal granulomas with caseation necrosis and organisms in some cases. The presence of non-caseating granulomas, high ACE levels and negative results of TB PCR qualitative analysis, QuantiFERON-TB Gold and Gamma interferon test along with the absence of organisms in histopathological sections, excluded the possibility of TB.⁴

Granulomas mimicking sarcoidosis are also found in leprosy. But in leprosy, concomitant cutaneous involvement is always noted with subsequent sensory loss. Oral manifestations include papular growth in palate, gingiva, tongue, lip and buccal mucosa.⁵ For a definitive diagnosis, demonstration of acid-fast organisms is required, which was negative in the present case.

Histoplasmosis is a deep fungal infection primarily affecting the lungs. Rarely, oral manifestations are found in the form of ulcerations, papular or nodular growth in tongue, palate, buccal mucosa, gingiva and lips. Presence of granulomas along with causative organisms in periodic acid—Schiff and Grocott methenamine silver stained sections are noted histopathologically. No fungal hyphae, endospore or yeast could be detected in tissue sections, suggesting the absence of histoplasmosis.^{4 5}

Ulcerated granulomatous nodules with causative organisms can also be seen in coccidioidomycosis but this disease is primarily localised in Southwest USA.^{4 5}

Crohn’s disease is an inflammatory and immunologically mediated condition, chiefly affecting the gastrointestinal tract causing abdominal cramping, nausea and diarrhoea. Oral presentations include ulcerations, diffuse or nodular swelling of oral and perioral tissues, and cobblestone appearance of oral mucosa. Non-necrotizing granulomas are seen in histopathological evaluation. Absence of gastrointestinal manifestations excluded Crohn’s disease.⁵

Foreign body granulomas usually present as reddish-brown papules, nodules or ulcers. Radiographic findings vary, depending upon the nature and composition of the foreign body. The patient neither had any history of foreign body impaction nor any corresponding radiographic evidence.¹¹

The possibility of granulomatosis with polyangiitis was excluded as ear, nose and throat manifestations (persistent-recurrent nasal discharges, epistaxis, nasal bridge collapse and hearing loss) and lung involvements (wheezing, pulmonary nodules, cavitating lung lesions, pleuritis, pleural effusions and pulmonary haemorrhage) were absent.¹²

The presence of nodular swelling in oral mucosa, raised ACE level and ESR, and pneumonitic changes in lungs with non-caseating granulomas comprising epithelioid and giant cells in histopathological sections ruled out other pathologies and the case was finally diagnosed as sarcoidosis. Thus, by amalgamation of clinical features, radiologic interpretation, haematological parameters and histopathological evaluation, a confirmatory diagnosis of sarcoidosis was established. The patient was referred to the department of respiratory medicine of a government medical college and hospital in Kolkata for further evaluation of the systemic condition and necessary treatment.

Treatment

Corticosteroid, being the standard treatment, was instituted as the patient showed pneumonitic changes which could have progressed to fibrosis if left untreated. A total of 40 mg of oral prednisolone per day with gradual reduction by 5 mg/day every 2 weeks up to a maintenance dose of 15 mg/day for 8 months, followed by 2.5 mg reduction per month was prescribed.

Outcome and follow-up

The patient responded well, and regression of the oral lesion was noted by 4 months of therapy. She was kept on regular periodic follow-up and no recurrence or new lesion was found over a period of 1 year (figure 3).

Figure 3.

Intraoral view of the patient after regression of the lesion.

Discussion

Sarcoidosis, also known as Besnier-Boeck disease or Besnier-Boeck-Schaumann disease,⁹ is an idiopathic, multisystemic, chronic, granulomatous disease. Though the first case of sarcoidosis was reported by Jonathan Hutchinson in 1869, however, the term sarcoidosis was introduced by Boeck in 1899 which means ‘flesh-like condition’ in Greek. The first description of oral sarcoidosis was reported by Schroff in 1942 and Poe published the first histologically confirmed case involving mandible in 1943.^{1 2}

Commonly a disease of the West, a recent increase in incidence is being found in Taiwan, Thailand, Malaysia and India, mainly because in these regions, the disease was probably overshadowed by TB in the past.¹⁰ Although sarcoidosis can occur at any age, it has two incidence peaks—25–35 and 45–65 years. Sarcoidosis has a worldwide incidence of 16.5/100 000 in men and 19/100 000 in women, thus showing a slight female predilection. The patient under discussion was a female in the fifth decade.1–3 6–9

Genes like Human Leukocyte Antigen (HLA)-A1, HLA-B8 and HLA-DR3 are associated with susceptibility to sarcoidosis. Induced by an unidentified antigen, an uncontrolled and upregulated cell-mediated immune reaction takes place which leads to infiltration of the affected tissues by activated Th1 lymphocytes, monocytes and macrophages. Activated cells secrete Interleukin (IL)-1, IL-12, Interferon Gamma (IFN-γ) and Tumour necrosis factor alpha (TNF-α) which induce the formation of non-caseating granuloma.^2–5

Sarcoidosis is not an autoimmune disease but it may co-exist with autoimmune diseases, such as discoid lupus erythematosus, Sjögren’s syndrome and rheumatoid arthritis.³

It involves multiple organs and tissues, lungs being most commonly affected (90% of the cases), followed by skin (24%), lymphatics (15%), liver (18%), eyes (12%), kidneys (5%), nerves (5%), heart (2%) and bone, joint or muscle (0.9%).⁶

The common lung manifestations include bilateral hilar lymphadenopathy with/without pulmonary infiltrates, pneumonitis and dry cough.1 2 6 8 Skin lesions are usually in the form of erythema nodosum, pigmentations, subcutaneous nodules, maculopapular lesions or ulcers.^{1–6 9} A typical interventricular thinning is found in cardiac sarcoidosis. Less commonly, an increase in myocardial wall thickness is noted which mimics LVH.⁷ Arthralgia is another common feature.⁶ The clinical features of the patient were corroborative with the features reported by other authors previously.

Oral involvement of sarcoidosis is very uncommon.^{1 2 5} The areas mostly involved are buccal mucosa and vestibule (23%), tongue (23%), lip (23%), hard and soft palate (17%) and gingiva (14%).⁸ So far, only 25 cases of oral sarcoidosis involving buccal mucosa have been reported.^{1 13 14}

Clinically, they present as asymptomatic, well-circumscribed, firm submucosal nodules, papular eruptions or superficial ulcerations.^{1–3 8} Our patient had a non-tender, firm, diffuse swelling on the left buccal mucosa, which was in accordance with the clinical features reported in the literature.

A total of 50%–80% of sarcoidosis cases show raised ACE value, which can be used as an adjunct in diagnosis along with other clinical symptoms. Anaemia, elevated ESR, increased liver enzymes and hypercalcaemia are other common findings.^{2 5 6} Biochemical and haematological reports of the patient also revealed raised ACE level (61 IU/L) and ESR (40 mm/hour).

Histopathologically, there is the presence of discrete, round-to-oval, multinodular non-caseating granulomas which are chiefly composed of epithelioid histiocytes and multinucleated giant cells. Giant cells can be of Langhans type, with arcuate arrangement of nuclei, or foreign-body type, with random arrangement of nuclei. Though not diagnostic, the giant cells occasionally contain inclusion bodies, such as Schumann bodies or stellate or asteroid bodies. Schumann (conchoidal) bodies are lysosome-derived, large, concentric, calcified, basophilic and laminated bodies made-up of calcium oxalate crystals. The stellate or asteroid bodies, found in 2%–9% of the cases, are spicule-like in shape and represent entrapped collagen. There is fibrosis surrounding the granuloma and a ‘collarette’ predominantly composed of lymphocytes. Our case showed similar histologic presentations, although Schumann or asteroid bodies were not found.^{2–5 9}

Sarcoidosis is a diagnosis of exclusion as there is no sensitive diagnostic test or marker for confirmation of this heterogeneous disease. Thus, the diagnosis was made based on an admixture of history, clinical features, radiologic interpretation, haematological and biochemical parameters, and histopathological evaluation after excluding the differential diagnoses.

Due to high prevalence of asymptomatic organ involvement, high rate of spontaneous resolution and the complications of long-term corticosteroid use, most experts recommend simple observation as 60% of these cases resolve spontaneously within 6 months of onset. Treatment is required in cases of symptomatic organ involvement that might result in permanent organ damage.^{3 8 9} Reported modalities include topical, intralesional or systemic medications, surgery and radiotherapy.^{1 2} Corticosteroids are the drug of choice. Usually, oral prednisolone at an initial dose of 0.5 mg per kg of body weight is prescribed.⁹ The regimen includes loading dose of 40 mg of oral prednisolone per day, which is gradually decreased by 5 mg/day every 2 weeks to the maintenance dose of 10–15 mg/day for the next 8 months, followed by reduction of daily dose by 2.5 mg/month.¹⁵ The patient, in this case, had pneumonitic changes in lungs, features of LVH, cough and arthralgia. So, oral prednisolone 40 mg/day was prescribed and gradually tapered as recommended.

A total of 13%–75% of sarcoidosis cases relapse within 1 month to 1 year once medications are withdrawn. Previous use of corticosteroids is an important risk factor for relapse.¹⁶ Depending on the severity of disease, site of involvement, age, ethnicity and gender, mortality rates in sarcoidosis range from 1% to 8%. It increases in Hispanic blacks, women and in ages over 55 years.¹⁷

In our case, after 4 months of therapy, the oral lesion regressed and even after a year of post-treatment follow-up, no recurrence was noted.

This case is unique and deserves special mention because oral manifestation of systemic sarcoidosis is unusual and in our case, it was the initial presentation which led to the diagnosis of systemic sarcoidosis. Moreover, the patient showed signs of LVH which is also uncommon.

Learning points.

• Sarcoidosis is a systemic disease with rare oral involvement.

• The oral lesions may present as submucosal nodule, papule or superficial ulceration.

• Sarcoidosis is a multisystemic disease. So, dental practitioners should be aware of the systemic symptoms as undiagnosed cases might result in permanent organ damage.

• It needs to be differentiated from other granulomatous diseases so that proper treatment can be instituted.